Process for preparing a granular hydrogel

Abstract

The invention relates to a process for preparing a granular hydrogel by subjecting a hydrogel to high-pressure homogenization. A granular hydrogel obtained in this way has a highly increased adhesiveness as compared to granular hydrogels obtained by conventional methods. In addition, it also has an increased cohesiveness. These properties are advantageous when the fragmented hydrogel is used to prepare a medical patch that has to stick by itself to for example a wound. Moreover, the granular hydrogel has a viscosity that allows application of the medical patch via injection in the event that the wound is present in a body cavity. Another advantage of the process of the invention is that it allows to steer hydrogel properties in a particular direction by changing the pressure that is applied in the high-pressure homogenization. In this way, hydrogels can purposively be prepared with particular properties. Such control over the properties is highly advantageous for the development of hydrogels for specific (medical) applications.

Description

[0001] PROCESS FOR PREPARING A GRANULAR HYDROGEL

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for preparing a granular hydrogel, to a granular hydrogel obtainable by such process, to a composition comprising such granular hydrogel and to a granular hydrogel or granular hydrogel composition for medical use.

[0004] BACKGROUND

[0005] Hydrogels are attractive materials for use in the medical field. Most prominent is their application as substrates for cell culture, templates for tissue engineering and vehicles for the delivery of drugs and proteins. One way of preparing hydrogels is to crosslink suitable natural or synthetic polymers into continuous volumes (bulk hydrogels). Besides many advantageous applications, such bulk hydrogels have drawbacks in cases where they need to be injected or where smaller portions of hydrogel are required. Therefore, as an alternative, hydrogels may also be prepared as a population of hydrogel microparticles having sizes that range from ~1 to 1 ,000 pm. These granular hydrogels are distinct from bulk hydrogels in that their particulate nature gives the gel mechanical properties (e.g. viscosity, cohesiveness, elasticity) that are different from those of bulk hydrogels. This enables hydrogel injection through small needles and the dosing of small hydrogel quantities by e.g. particle inhalation. However, these granulated hydrogels have the drawback that they are low cohesive whilst maintaining their viscous and elastic properties.

[0006] One of the conventional methods for preparing a granular hydrogel comprises the fragmentation of a bulk hydrogel, for example by mechanically forcing the gel through a fine steel mesh or by crushing the gel with a homogenizer. In other conventional methods, the hydrogel is prepared directly as particles, making a post-synthesis fragmentation step unnecessary.

[0007] Hydrogels obtained by conventional methods are however still not always suited for their intended applications. For example, their adhesiveness and / or cohesiveness fall short for applications where, respectively, stickiness is desiredfor adherence to body tissue and / or firmness for gel integrity. Often also an intermediate degradation profile is desired. And when applied via a syringe, a viscosity is preferred that is suitable for convenient injection.

[0008] An example of an application where one or more of these properties for a hydrogel are desired is application in the sinus cavity after functional endoscopic sinus surgery (FESS). The hydrogel is applied to the inner wall of the sinus to form a coating, so as to protect the wound during the healing process of approximately 4-6 weeks. During this time, the gel needs to stick to the cavity wall so that it can be effective in the sinus during the entire period. Another desirable property is a slow but not too slow degradation of the hydrogel in the humid sinus environment. One or more of the abovementioned properties of a hydrogel are also desired when the hydrogel is applied in other body cavities such as the middle ear or the nasal cavity.

[0009] In addition to the protection of the wound, the hydrogel is preferably also suited to deliver a drug such as an analgesic, a corticosteroid or an antibiotic. This requires a fast water absorption by the hydrogel for the loading of the hydrogel with a solution of the drug just prior to administration of the hydrogel. During wound healing, the drug is then released out of the hydrogel to e.g. minimize an inflammatory response or relieve pain. So, there is a particular need for a hydrogel that has a suitable water absorption profile and at the same time also has the other desired properties.

[0010] A disadvantage of current preparation methods is that it is difficult to optimize the properties of granular hydrogels for a given application in a controlled manner and / or in a systematical way. Current state of the art focuses mainly on the optimization of the chemical structure of the (bio)polymer to obtain improved mechanical properties of the granular hydrogel (e.g. chemical modification of the polymer), rather than that they tune the particles’ specifications to arrive at an improvement of the mechanical properties.

[0011] Another drawback associated with conventional hydrogel preparation methods is that the production process, particularly the fragmentation of bulk hydrogel into microparticles, is typically performed in a batch-wise manner, which limits scalability and throughput. This renders commercial manufacturing labor-intensive, time-consuming, and difficult to standardize.In addition, many conventional methods rely on the use of auxiliary compounds or processing agents to achieve specific product characteristics.

[0012] However, the presence of such substances, or their degradation products, is generally not permitted in the final hydrogel formulation, especially not when intended for medical use. Consequently, additional purification steps are required to remove these agents or remnants thereof, further complicating the production process and reducing overall efficiency and cost-effectiveness in large-scale manufacturing.

[0013] SUMMARY OF THE INVENTION

[0014] It is therefore an object of the present invention to provide a process for preparing granular hydrogels that have improved properties as compared to known hydrogels, in particular improved adhesive and / or cohesive properties. It is more in particular an object that this is accomplished together with a viscosity that makes the hydrogel suitable for injection.

[0015] It is also an object that the process allows to modify one or more certain properties of a granular hydrogel in a more or less predictable and / or systematical way. And, moreover, that this technology can be translated to different types of hydrogels so that a platform technology is provided for the preparation of hydrogel particles of all different kinds of hydrogels.

[0016] It is also an object to provide a hydrogel with properties that are not known in the prior art for such hydrogel, in particular to provide a hydrogel that can be applied in the sinus cavity, for example after a sinus surgery, or in the middle ear or nasal cavity.

[0017] It is also an object that the hydrogel has a better capability of delivering a drug to a site of application of the hydrogel, for example an analgesic, a corticosteroid or an antibiotic.

[0018] It has now been found that a particular treatment of a bulk hydrogel may overcome these shortcomings. Accordingly, the present invention relates to a process for preparing a granular hydrogel, the process comprising

[0019] - providing an initial hydrogel; then

[0020] - subjecting the initial hydrogel to high-pressure homogenization to obtain the granular hydrogel.The invention further relates to a granular hydrogel obtainable by such process.

[0021] The invention further relates to a granular hydrogel composition comprising 1) the abovementioned obtained granular hydrogel as a first hydrogel; and 2) a second hydrogel, in particular a granular hydrogel.

[0022] The invention further relates to a granular hydrogel or granular hydrogel composition as described above, for use as a medicament.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 schematically displays a cross-section of a high-pressure homogenizer in a process of the present invention.

[0025] Figure 2 displays micrographs of hydrogels that are produced with a conventional process.

[0026] Figure 3 displays micrographs of hydrogels that are produced with a process of the invention under a range of different pressures.

[0027] Figure 4 displays in a graph the G’ behavior of not completely swollen granular HA hydrogels (comparative as well as according to the invention).

[0028] Figure 5 displays in a graph the G” behavior of not completely swollen granular HA hydrogels (comparative as well as according to the invention).

[0029] Figure 6 displays in a graph the G’ behavior of maximally swollen granular HA hydrogels (comparative as well as according to the invention).

[0030] Figure 7 displays in a graph the G” behavior of maximally swollen granular HA hydrogels (comparative as well as according to the invention).

[0031] Figure 8 displays a syringe (1) that is filled with a granular hydrogel composition according to the invention.

[0032] DETAILED DESCRIPTION OF THE INVENTION

[0033] Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in a figure may be exaggerated relative to other elements to help improve understanding of various exemplary embodiments of the present invention. For example, the relative dimensions of the different components of ahigh-pressure homogenizer and the chink that is defined for the passage of hydrogel cannot be derived from the figures.

[0034] Further, the terms “first”, “second”, and the like in the present description and claims, if any, are generally used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order.

[0035] In the context of the invention, by the term ‘hydrogel’ is meant a material that is a mixture of a porous solid and an interstitial aqueous liquid that makes up at least 10 wt.% of the hydrogel. In many cases, a hydrogel contains much higher amounts of the interstitial aqueous liquid, which may even reach 99.5 wt.%. The interstitial aqueous liquid is typically for the most part water, or even essentially completely water. It may comprise one or more salts that act as a buffer in the hydrogel, which may be the case in medical applications of the hydrogel.

[0036] The porous permeable solid of a hydrogel is a three-dimensional network of natural or synthetic polymers, typically obtained by cross-linking a precursor polymer. In the context of the present invention, such precursor polymer is termed a ‘hydrogel-forming polymer’, as it converts into a hydrogel upon crosslinking it (and upon allowing the presence of water which in the end is absorbed in the cross-linked polymer). Depending on the degree of cross-linking, a hydrogel may behave as a fluid.

[0037] When, in the present patent document, a hydrogel is identified by the term ‘granular hydrogel’, then this means that the hydrogel is present as an assembly of hydrogel particles. This does not necessarily mean that such particles are obtained by a fragmentation step (such as granulation or grinding) as is the case in the method of the invention. For example, a conventional granular hydrogel may, as an alternative to fragmentation, also be obtained by preparing the hydrogel directly in the form of particles without a fragmentation step.

[0038] The process of the invention is directed at reducing the particle size of a hydrogel. For the purpose of this description and the claims, such hydrogel is indicated by the term ‘initial hydrogel’. The reduction of the particle size of an initial hydrogel is realized by subjecting the initial hydrogel to high-pressure homogenization.

[0039] The initial hydrogel that is subjected to the high-pressure homogenization is usually present as a plurality of particles of a size that allows an easy feeding tothe high-pressure homogenizer, for example particles having at least one dimension, such as their largest dimension or their smallest dimension, in a range of 1-100 mm, in particular in a range of 5-50 mm. If present, these particles are usually obtained by fragmenting a hydrogel to smaller chunks prior to feeding the initial hydrogel to the high-pressure homogenizer. In principle, however, it is also possible that the initial hydrogel is fed to the high-pressure homogenizer as one single piece.

[0040] By high-pressure homogenization is meant a mechanical process which involves forcing a substance through a narrow nozzle at a high pressure, which may be as high as 4,000 bar. This causes that the substance is subjected to very high shear stress, thereby altering one or more mechanical or physical properties of the substance, such as the size and morphology of its particles. For example, it is known in the art that when an oil-water emulsion is subjected to high-pressure homogenization, then droplet size is decreased to yield a stable submicron emulsion. For convenience, high-pressure homogenization may hereinafter also be abbreviated as HPH.

[0041] When, according to a process of the present invention, a hydrogel is subjected to high-pressure homogenization, then the porous solid that holds the water is fragmented upon passage through the nozzle. This then yields a plurality of hydrogel fragments. The smaller the nozzle aperture and / or the higher the pressure, the smaller is the mass of the particles that are produced.

[0042] In a process of the present invention, the nozzle is preferably a slit nozzle, more preferably a ring-shaped slit nozzle. Such nozzle may be formed when a blocking unit (impact head (5)) is moved closely to a corresponding opening (impact ring (6)) of a container. This is then performed without completely blocking the opening, so that a small annular gap (7) is formed. The width of the gap in a process of the invention, i.e. the smallest distance between the impact ring and the passage head, is usually in a range of 1 to 500 pm.

[0043] Figure 1 schematically displays a cross-section of a high-pressure homogenizer (4) in a process of the present invention. During the process, particles of the initial hydrogel are guided through a passage head (8), after which they pass through an annular gap (7) that is defined by an impact head (5) and animpact ring (6). In this area, fragmentation to smaller hydrogel particles occurs. The resulting granular hydrogel then travels away from the annular gap (7).

[0044] The pressure that is applied in a high-pressure homogenization refers to the pressure that is exerted on the substance to force it through the nozzle of the high-pressure homogenizer. In a process of the invention, the applied pressure is usually in a range of 20-4,000 bar. It may be 3,500 bar or less, 3,000 bar or less, 2,500 bar or less, 2,000 bar or less, 1 ,500 bar or less, 1 ,250 bar or less, 1 ,000 bar or less, 750 bar or less or 500 bar or less. It may be 25 bar or more, 40 bar or more, 60 bar or more, 75 bar or more, 150 bar or more, 250 bar or more, 500 bar or more, 750 bar or more or 1 ,000 bar or more. It is for example in a range of 50-2,500 bar, in a range of 100-1 ,500 bar, in a range of 150-1 ,000 bar or in a range of 300-800 bar.

[0045] A person skilled in the art knows how to operate a high-pressure homogenizer and how to perform a high-pressure homogenization on a hydrogel in accordance with the present invention, by routine experimentation and without exerting an inventive effort.

[0046] It was surprisingly found that subjecting a hydrogel to high-pressure homogenization provides the obtained resulting granular hydrogel with one or more beneficial properties that cannot be obtained by conventional methods, such as conventional grinding methods or conventional manufacturing methods wherein a hydrogel is prepared directly in the form of particles without a fragmentation step. A quite characteristic observation is that a granular hydrogel obtained with a process of the invention has a highly increased adhesiveness as compared to granular hydrogels obtained by conventional methods. In addition, it typically also has an increased cohesiveness. These properties are advantageous when, for example, the fragmented hydrogel is used to prepare a medical patch that has to stick by itself to a body part. For example, it may be used to cover a wound as a result of a surgical intervention. Due to the high adhesiveness and high cohesiveness of the granular hydrogel, the patch stays in place and keeps the intended shape during the period that is needed for the healing of the wound. Moreover, when a wound is present in a body cavity and thus difficult to access, it is easy to apply the patch because it typically also has the viscosity that is needed for being injectable. It is particularly advantageous when a hydrogel of theinvention has this beneficial viscosity in combination with a high adhesiveness and high cohesiveness. Yet another advantage of a hydrogel of the invention is that it is capable of withstanding high mechanical forces / pressures. This allows application of the hydrogel in and around joints.

[0047] It is contemplated that the high shears to which the initial hydrogel is subjected during high-pressure homogenization cause that the initial hydrogel is torn apart into fragments that have several lobes, so that the fragments have a high surface-to-volume ratio. These lobes may then interlock with one another and so become responsible for the high adhesiveness and the high cohesiveness. Microscope pictures of an obtained granular hydrogel also point into this direction (see Examples and Figure 3), although it is difficult to discriminate the different particles from one another, likely because of the high cohesiveness as this results in agglomeration of the particles. The pictures of Figure 3 also demonstrate that particle morphology varies with the applied pressure, as the hydrogel particles contain more and larger lobes with an increasing HPH pressure.

[0048] In a process of the invention, the HPH may in principle be performed at any temperature that can be withstood by the hydrogel. It is for example performed at a temperature in a range of 0-80°C, in particular in a range of 20-50°C.

[0049] When the initial hydrogel is subjected to the high-pressure homogenization in a process of the invention, it usually comprises a buffered aqueous solution, such as a phosphate buffer. For a medical application, it is for example buffered at a pH in a range of 5.5-8.5, in a range of 6.5-7.5 or in a range of 6.8-7.2. Typically, it is buffered at a physiological pH.

[0050] For performing the HPH process as such, the pH of the initial hydrogel does not appear to be of a particular importance, except when the porous solid in the hydrogel relies on bonds (cross-links) which fall apart in a particular pH-range, for example when there are ionic cross-links in the hydrogel.

[0051] The process of the invention may comprise (and may in particular be preceded by) preparing the initial hydrogel. For example, it comprises cross-linking a hydrogel-forming polymer to form the initial hydrogel, such as a synthetic hydrogel-forming polymer and / or a natural hydrogel-forming polymer (a biopolymer), for example a polypeptide or a polysaccharide. In an embodiment, the hydrogel-forming polymer is selected from the group of alginate, gelatin,hyaluronic acid, gellan gum, chondroitin sulfate, polyethylene glycol, poly(vinyl alcohol), polyacrylate, polymethacrylate, chitosan, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

[0052] When a polysaccharide such as hyaluronic acid is used, the mass average molecular mass (Mw) of the polysaccharide, in particular of hyaluronic acid, is usually at least 10 kDa, in particular at least 50 kDa. Typically, it is in a range of 100-25,000 kDa, in particular it is in a range of 200-10,000 kDa and more in particular it is in a range of 400-4,000 kDa. Preferably it is in a range of 500-2,200 kDa or in a range of 1 ,000-2,000 kDa.

[0053] Accordingly, the initial hydrogel in a process of the invention may be a hydrogel comprising a cross-linked synthetic polymer or a cross-linked biopolymer such as a polypeptide or a polysaccharide. It may in particular comprise a crosslinked polymer selected from the group of agarose, alginate, gelatin, hyaluronic acid, polyethylene glycol), poly(vinyl alcohol), polyacrylate, polymethacrylate, chitosan, chondroitin, silk, fibroin, gellan, arabic gom, cellulose and carboxymethyl cellulose. Cross-links may also be of an ionic nature; citric acid can for example cross-link amino groups of chitosan or divalent cations can cross-link gellan.

[0054] For the preparation of a hydrogel, the cross-linking is usually performed by treating the hydrogel-forming polymer with a cross-linking agent selected from the group of dialdehydes, diglycidyl ethers, di-epoxyalkanes and divinyl sulfone, in particular from the group of 1 ,4-butanediol diglycidyl ether and divinyl sulfone.

[0055] The granular hydrogel obtained with a process of the invention may comprise one or more active pharmaceutical ingredients, for example one or more active pharmaceutical ingredients selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs. This may be realized by allowing a not-completely water-saturated initial or granular hydrogel to absorb an aqueous composition comprising the one or more active pharmaceutical ingredients. Therefore, the process of the invention may comprise a step of allowing the obtained granular hydrogel to absorb an active pharmaceutical ingredient, in particular by absorbing an aqueous phase that contains the pharmaceutical ingredient.

[0056] For an actual medical application of the granular hydrogel, the granular hydrogel is usually a part of composition wherein one or more other componentsare present. Therefore, the process of the invention may be followed by mixing the granular hydrogel with a second hydrogel. Such second hydrogel may in particular be a granular hydrogel. It for example comprises a (granular) cross-linked polymer, in particular a (granular) cross-linked polymer that is selected from the group of alginate, gelatin, hyaluronic acid, polyethylene glycol, poly(vinyl alcohol), polyacrylate, polymethacrylate, chondroitin, chitosan, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

[0057] A method of the invention may include a sterilization step, yielding the granular hydrogel as a sterile hydrogel. In case the method comprises the preparation of a composition that comprises the obtained granular hydrogel, the sterilization may also be performed on such composition.

[0058] For example, an obtained hydrogel may be exposed to an elevated temperature, e.g. to a temperature in a range of 80-140 °C, in particular in a range of 100-135 °C. The temperature and the period of exposure are then chosen such that any micro organisms are destroyed to a desired extent, whilst not degrading the hydrogel to an undesired extent. For example, the hydrogel is exposed during 15-20 minutes at a temperature in a range of e.g. 115-125 °C, or it is exposed during 2-10 minutes at a temperature in a range of e.g. 130-140 °C.

[0059] Sterilization may also be achieved by exposing the hydrogel to high energy radiation, in particular ionizing radiation such as gamma rays, electron rays, X-rays, and the higher ultraviolet part of the electromagnetic spectrum. The dosage to which a hydrogel may be exposed is e.g. 15, 25 or 50 kGy.

[0060] Besides just modifying the properties of a hydrogel, it appeared also possible to steer the hydrogel properties in a particular direction, so that it is possible to purposively prepare hydrogels with particular properties. Such control over the properties is possible by changing the pressure at which the high-pressure homogenization is carried out. It was for example found that when the high-pressure homogenization was performed on a hydrogel of hyaluronic acid, a higher pressure yielded hydrogels with a higher cohesiveness, a lower elasticity (G’ elastic modulus) and a lower viscosity (G” viscous modulus). This is demonstrated in the Examples and visualized in Figures 4-7. Further, microscope pictures appear to demonstrate that particle size (particle mass) decreases with an increasing pressure, and that more air was entrained in the hydrogel with anincreasing pressure. Particle morphology was also influenced, as the hydrogel particles appear to contain more and larger lobes with an increasing pressure. This is demonstrated in the Examples and visualized in Figure 3. It was also found that the adhesiveness increases upon increasing the pressure in the HPH process. The lowest adhesivenesses were obtained when a conventional fragmentation step was applied, using a non-HPH technique such as granulation, grinding or pressing the hydrogel through a sieve.

[0061] A person skilled in the art, having taken into account the present description of the invention, will be able to steer hydrogel properties in a desired direction, in particular one or more properties of the adhesiveness, the cohesiveness, the G’ elastic modulus and the G” viscous modulus. He will be able to arrive at a desired result by routine experimentation and without exerting an inventive effort.

[0062] Such control over the properties is highly advantageous for the development of hydrogels for specific (medical) applications. In the present description, this is elaborated for the preparation of a medical hydrogel composition that is suited for application to the inner wall of a body cavity such as the sinus cavity and the nasal cavity. This typically concerns the application on a wound resulting from surgery, so that the wound is protected during the healing process.

[0063] The high-pressure homogenization obviously modifies mechanical and physical properties of the hydrogel as a whole, but it is not clear what the underlying effects of the high-pressure homogenization are on the physical and / or chemical properties of an individual hydrogel particle. Particle characterization (particle size, particle shape) was for example difficult because of the high cohesion of the obtained particles, as this results in agglomeration of the particles.

[0064] The obtained hydrogel itself can therefore well be described in terms of the process that leads to its formation. Accordingly, the present invention further relates to a granular hydrogel that is obtainable by a process as described hereabove.

[0065] Just as with the initial hydrogel in the process as described above, the obtained granular hydrogel may be a hydrogel comprising a cross-linked synthetic polymer or a cross-linked biopolymer such as a polypeptide or a polysaccharide. Ahydrogel of the invention may therefore in particular be selected from the group of alginate hydrogel, gelatin hydrogel, hyaluronic acid hydrogel, polyethylene glycol) hydrogel, poly(vinyl alcohol) hydrogel, polyacrylate hydrogel, polymethacrylate hydrogel, chitosan hydrogel, chondroitin hydrogel, silk hydrogel, fibroin hydrogel, agarose hydrogel, gellan hydrogel, arabic gom hydrogel, cellulose hydrogel and carboxymethyl cellulose hydrogel.

[0066] In a particular embodiment, the granular hydrogel of the invention is part of a granular hydrogel composition, wherein the granular hydrogel composition comprises at least a first granular hydrogel and a second granular hydrogel.

[0067] In an embodiment, the second granular hydrogel in such granular hydrogel composition comprises a granular hydrogel selected from the group of granular alginate hydrogel, granular gelatin hydrogel, granular hyaluronic acid hydrogel, granular polyethylene glycol hydrogel, granular poly(vinyl alcohol) hydrogel, granular polyacrylate hydrogel, granular polymethacrylate hydrogel, granular chitosan hydrogel, granular chondroitin hydrogel, granular silk hydrogel, granular fibroin hydrogel, granular agarose hydrogel, granular gellan hydrogel, granular arabic gom hydrogel, granular cellulose hydrogel and granular carboxymethyl cellulose hydrogel.

[0068] The content of interstitial aqueous fluid in a granular hydrogel composition of the invention is usually at least 90 wt.%, based on the total weight of the product as such. The content may also be at least 92 wt.%, at least 94 wt.%, at least 95 wt.%, at least 96 wt.%, at least 97 wt.%, at least 98 wt.%, at least 98.5 wt.%, or at least 99 wt.%. The content may also be 99 wt.% or less, 98 wt.% or less, 96 wt.% or less or 94 wt.% or less. Preferably, the content is in the range of 93-98 wt.%.

[0069] A granular hydrogel composition according to the invention has a high adhesiveness to mucosal surfaces, ensuring that it firmly attaches to the moist tissue without being easily dislodged by gravity, mucus flow, or normal movements such as breathing or speaking. A granular hydrogel product according to the invention may therefore have a surface energy of at least 3 J / m2, at least 4 J / m2, at least 5 J / m2, at least 6 J / m2, at least 7 J / m2, at least 8 J / m2, at least 9 J / m2, at least 10 J / m2, at least 11 J / m2or at least 12 J / m2.

[0070] In a particular embodiment, a granular hydrogel composition of the invention comprises- a granular hyaluronic acid hydrogel as a first hydrogel; and

[0071] - a granular gelatin hydrogel as a second granular hydrogel;

[0072] wherein the granular hydrogel composition has an adhesion surface energy in a range of 5-20 J / m2, in particular in a range of 8-18 J / m2and more in particular in a range of 10-15 J / m2.

[0073] Herein, the adhesion surface energy is determined for adhesion to aluminum at 20 °C and measured with a rheometer configured in the following way: 40 mm parallel plate, Peltier plate aluminium, gap of 500 pm, trim gap offset of 50 pm, constant linear rate of 100 pm / s (see Example 3 for a more elaborate description).

[0074] These values for the adhesiveness are surprisingly high and they are unprecedented for this type of hydrogels. An advantage of the high adhesiveness is that the hydrogel sticks very well to the application site by itself, so that it is not necessary to fill the middle ear, the nasal cavity or the sinus completely with gel. In this way, normal physiological functions like drainage, mucociliary clearance, hearing, and breathing remain largely unaffected. This localized approach also reduces patient discomfort and the need for complex removal procedures.

[0075] In an embodiment, the viscosity of the hydrogel composition is in a range of 400-1 ,000 Pa*s, in particular in a range of 500-800 Pa*s.

[0076] Herein, the (dynamic) viscosity is determined at 20 °C with a rotational rheometer configured in the following way: 40 mm parallel plate, Peltier plate aluminium, gap of 500 pm, trim gap offset of 50 pm. The shear rate is increased from 0.002 s-1to 50 s-1during 180 s, after which the viscosity is calculated at a shear rate of 0.3775 s-1by taking the average of the viscosity at 0.356 s-1and 0.399 s-1(see Example 3 for a more elaborate description).

[0077] In an embodiment, the adhesion surface energy is in a range of 8-18 J / m2and the viscosity is in a range of 400-1 ,000 Pa*s; in particular the adhesion surface energy is in a range of 10-15 J / m2and the viscosity is in a range of 500-800 Pa*s.

[0078] A granular hydrogel composition of the invention preferably has a favorable cohesiveness. This allows it to effectively coat the wall of the middle ear, nasal cavity or sinus without sagging and / or withdrawal of the hydrogel (no disintegration of the coating), so that the hydrogel coating stays intact throughoutthe treatment period of typically 1-6 weeks. Cohesiveness of a substance is herein expressed as the ‘drop size’ or ‘drop mass’ of the substance, which is the mass of a drop of the substance that forms when the substance is released from an outlet of a reservoir. When the drop size increases during the release, there comes a moment when it falls off under its own weight. The weight of the fallen drop is then measured (the drop mass), which value represents the cohesiveness. A granular hydrogel composition of the invention preferably has a drop mass in a range of 40-400 mg, in particular in a range of 100-200 mg. The drop mass may also be in a range of 50-250 mg or in a range of 80-160 mg. It may be at least 35 mg, at least 45 mg, at least 65 mg, at least 95 mg, at least 125 mg, at least 150 mg, at least 180 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, or at least 325 mg. It may also be 420 mg or less, 375 mg or less, 350 mg or less, 325 mg or less, 300 mg or less, 275 mg or less, 250 mg or less, 225 mg or less, 200 mg or less, 175 mg or less, 150 mg or less or 125 mg or less.

[0079] Herein, the drop mass of a hydrogel is preferably determined by the following measuring method, performed at a temperature of 20 °C:

[0080] allowing a drop of the hydrogel to form at an outlet of a syringe by pressing a piston into the syringe that contains the hydrogel, wherein the syringe is positioned vertically with the outlet facing the ground; and then

[0081] increasing the drop size by continuing the pressing of the piston into the syringe until the drop releases from the syringe under its own weight; and then catching the released drop of hydrogel and measuring its mass.

[0082] The invention further relates to a method for preparing a granular hydrogel composition as described above, comprising the mixing of a first granular hydrogel and a second granular hydrogel. In an embodiment, the first granular hydrogel that is applied in this method is a granular hyaluronic acid hydrogel with a viscosity in a range of 900-1300 Pa*s, to yield a granular hydrogel composition with a viscosity in a range of 500-800 Pa*s.

[0083] A granular hydrogel of the invention or a granular hydrogel composition of the invention may have undergone a sterilization process to provide the hydrogel as a sterile hydrogel. For example, the granular hydrogel (composition) is sterilized by exposure to high temperature (e.g. by steam sterilization) or to high energy radiation (e.g. gamma radiation). It was surprisingly found that sterilization of agranular hydrogel of the invention did not negatively affect its rheological properties such as adhesion and cohesion. This is in contrast to conventional hydrogels, which are known to suffer from sterilization with respect to their rheological properties.

[0084] A granular hydrogel of the invention or a granular hydrogel composition of the invention typically has a pH in a range of 5.5-8.5 or in a range of 6.5-7.5. The pH is in particular a physiological pH.

[0085] An important use of a granular hydrogel of the invention is in the medical field. The invention therefore further relates to a granular hydrogel as described hereabove for use in medical therapy, for use as a medicament and / or for use in medicine, typically for treatment of a subject during or after ear, nose and throat surgery, in particular for treatment of a subject during or after sinus surgery, more in particular for treatment of a person suffering from epistaxis.

[0086] The invention further relates to a granular hydrogel as described hereabove, for use in the treatment of a bleeding site, in particular a bleeding site in the nasal cavity or sinus cavity. In a preferred embodiment, a granular hydrogel according to the invention is provided for use in the treatment of epistaxis. This may be a granular hydrogel wherein 3-15 grams of the granular hydrogel are applied to the bleeding site, in particular 5-10 g.

[0087] The invention further relates to a method for treating a medical condition of a human or an animal, comprising administering to the human or animal, in particular at a bleeding site of the human or animal, an effective amount of a granular hydrogel as described hereabove.

[0088] The invention further relates to a method of treating a bleeding site of a human or an animal, the method comprising administering to the bleeding site an amount of a granular hydrogel as described hereabove effective to stop bleeding at the bleeding site, in particular to stop an epistaxis. The bleeding site is preferably the nasal cavity or sinus cavity in a human or an animal.

[0089] By the phrase “administering the granular hydrogel to the bleeding site” is meant that the hydrogel is applied to the bleeding site so that the hydrogel is in touch with the bleeding site. The effect of such treatment is that the bleeding stops and the wound heals. An effective amount of the granular hydrogel to stop bleeding at the bleeding site of a human or an animal is usually in a range of 3-15mL. In particular it is in a range of 3-9 mL, in a range of 6-12 mL or in a range of 9-15 mL, depending on the size of the cavity.

[0090] As used herein, the term "effective amount" means that amount of granular hydrogel obtainable by a process of the invention that will elicit the biological or medical response of an animal or human that is being sought, for instance, by a researcher or clinician.

[0091] The term medical condition as used herein is a broad term that includes all diseases, lesions, disorders, and nonpathological conditions that normally receive medical treatment, such as pregnancy or childbirth.

[0092] The granular hydrogel may be provided in any suitable form, for example in a syringe for ease of application to e.g. the nasal cavity. Accordingly, the invention further relates to a syringe comprising an effective amount of the granular hydrogel in order to stop bleeding at a bleeding site of a human or animal subject.

[0093] Figure 8 displays a syringe (1) that is filled with a granular hydrogel composition (2) of the invention. This syringe is suitable for applying a granular hydrogel of the invention to a human or animal. It contains an applicator (3) for access in body cavities such as the sinus cavity and the nasal cavity. In a preferred embodiment, the hydrogel is sterilized after or before filling the syringe (or other packaging means) with the hydrogel, in particular with the aim of increasing a shelf-life of the hydrogel.

[0094] The invention further relates to the use of a hydrogel as described hereabove for treating a bleeding site of a human or an animal, in particular a bleeding of the sinus or nasal cavity, such as an epistaxis. The hydrogel may also be used for the promotion of hemostasis in an individual in need thereof.

[0095] The invention further relates to the use of a granular hydrogel as described hereabove for the manufacture of a medicament for treating a bleeding site of a human or an animal, in particular a bleeding of the sinus or nasal cavity, such as an epistaxis. The granular hydrogel may also be used for the promotion of hemostasis in an individual in need thereof.EXAMPLES

[0096] Three different experiments were performed that demonstrate the operation and the effects of the present invention.

[0097] In the first experiment (Example 1), the elastic (G’) and viscous (G”) behavior of a 2.0 wt.% hyaluronic acid hydrogel was investigated by granulating the gel at different pressures using the high-pressure homogenizer (HPH).

[0098] In the second experiment (Example 2), the settings for high-pressure homogenization were optimized to prepare a granular hyaluronic acid hydrogel with a high elastic behavior (G’) of 1 ,100 ± 200 Pa and high adhesiveness. These make the hydrogel suitable for use as an ingredient in a medical hydrogel product (a hydrogel composition).

[0099] In the third experiment (Example 3), a medical hydrogel product that comprises the granular hyaluronic acid hydrogel as described in example 2 is compared with a conventional medical hydrogel product. This then allows a comparison of the suitability of both hydrogels for a particular medical application (e.g. as a wound dressing in the sinus cavity).

[0100] Example 1 : Effect of HPH on mechanical properties of a hydrogel

[0101] For the development of a hydrogel product, both the elastic (G’) and viscous (G”) behavior are critical product variables. In this Example, the G’ and G” behavior of a granular hyaluronic acid (HA) hydrogel was investigated as a function of HPH pressure settings. Further, the obtained values for G’ and G” were compared with values for G’ and G” obtained with a manual granulation procedure. This was performed for non-maximally swollen HA hydrogels (paragraphs 3 and 4 of Example 1) and for maximally swollen HA hydrogels (paragraph 5 of Example 1).

[0102] 1.1. General considerations

[0103] The chemicals and solvents were purchased from commercial sources and used without further purification. If necessary, residual water was removedfrom them prior to their use. When water itself was used in a procedure, it was demineralized prior to its use.

[0104] All prepared hydrogels contained a phosphate buffer to give the hydrogel a pH in the range 6.8-7.2.

[0105] The high-pressure homogenizer that was used in the preparation of the hydrogel particles was a laboratory homogenizer with a maximum operating pressure 2,000 bar and a rated flow of 5 L / h. The hydrogel is to be introduced into the apparatus via a feeding hopper and a jacketed feed tank with pneumatic pusher.

[0106] The elastic modulus G’ and viscous modulus G” of each granular hydrogel sample were measured using a Discovery hybrid rheometer AR G2. For each measurement, an SS geometry with a 40 mm diameter was used wherein the gap was set at 500 pm and the trim gap offset at 50 pm. The temperature was set at 25°C and the frequency at 0.7 Hz.

[0107] 1.2. Preparation of a 2.5 wt.% cross-linked HA (initial) hydrogel

[0108] An amount of 348 ± 1 g of sodium hyaluronate powder (Mw = 1 ,500-1 ,700 kDa) was weighed into a plastic bottle. A 0.25 M NaOH solution was prepared by dissolving 22 g of NaOH pellets in 2,200 g of demineralized water, using a 5 L glass beaker and under mechanical stirring. An amount of 2,103 ± 5 g of this solution was transferred to a planetary mixer with a mixing bowl of 5L. The sodium hyaluronate powder was added thereto in 10 portions at intervals of 2.5 minutes, under continuous stirring. When all of the powder had dissolved under the formation of a gel, 38 ± 0.5 g of BDDE was slowly added to the gel. The mixture was then stirred for 20 minutes. Thereafter, 240 ± 5 g of the gel mixture was transferred to a 1 ,000 mL plastic container. The container was closed and placed in an oven at 45 °C during 4 hours. The container was taken out of the oven and the cross-linked gel was cut into pieces of approximately 2.5 x 2.5 cm. The gel pieces were then poured into a mixture of 0.75 M acetic acid and PBS buffer solution for 16 hours to neutralize the pH. Thereafter, the resulting swollen gel fractions were transferred to a fresh solution of PBS-buffer and left to swell further until the HA content had fallen to 2.0 wt.%, which was monitored by intermediateweighing of the swollen pieces. The swollen gel fraction was then ground into mm-sized particles using a blender (fractionation), to produce the hyaluronic acid (HA) hydrogel for subjection to HPH.

[0109] 1.3. Effect of HPH pressure on G’ and G” behavior of granular HA hydrogel

[0110] Six identical samples of the prepared fractioned cross-linked HA hydrogel (see paragraph 1.2.) were subjected to HPH at different pressures (each sample being subjected once to HPH by performing a run at a particular pressure), yielding samples #1-6. The HA content in these samples was 2.0 wt.% (the samples were not saturated with water, i.e. not completely swollen). In each run, the feed tank of the HPH was filled with the mm-sized particle gel and the pneumatic hopper was positioned. The pressure was set at the applicable value for the pressure and then the HPH apparatus was started. First, a frontrunning waste fraction was collected for 2 minutes. Then, product was collected until the tank became empty. The different pressures applied in the different runs were 30, 60, 100, 200, 300 and 400 bar. For each of the six runs, a separate sample was obtained. The values for G’ and G” were measured for each sample. The results are displayed in Table 1 and in Figures 4-5.

[0111] 1.4. Comparative: G’ and G” behavior of sieve-granulated HA hydrogel

[0112] Two additional samples of the prepared fractioned cross-linked HA hydrogel (not completely swollen) were subjected to a conventional granulation process. This concerns the manual pressing of a sample of fractioned HA through a sieve of a particular mesh to yield a sieve-granulated HA hydrogel (each sample being treated once by pressing the sample once through the sieve of a particular mesh). The different sieves applied were a 150 pm sieve and a 45 pm sieve. One run was performed for each sieve, yielding samples #7 and 8. The values for G’ and G” were measured for each sample. The results are displayed in Table 1 and in Figures 4-5.Table 1. G' and G” behavior of granular HA hydrogels (not completely swollen) Sample # HPH pressure HA content G’ at 0.7 Hz G” at 0.7 Hz (bar) (wt.%) (Pa) (Pa)

[0113] 1 30 2.0 672 66

[0114] 2 60 2.0 605 69

[0115] 3 100 2.0 494 53

[0116] 4 200 2.0 310 39

[0117] 5 300 2.0 217 35

[0118] 6 400 2.0 165 31

[0119] 7 manually ground 2.0 750 60 (comparative) (150 pm sieve)

[0120] 8 manually ground 2.0 799 85 (comparative) (45 pm sieve)

[0121]

[0122] 1.5. G’ and G” behavior at maximum swelling of granular HA hydrogel

[0123] The G’ and G” measurements as described in paragraphs 1.3 and 1.4 of Example 1 (see above) were now performed on a maximally swollen HA granular hydrogel. To this end, the same eight samples were used as those that were obtained from the HPH procedure (samples #1-6) and from the conventional sieving procedure (samples #7 and 8) as described in the above paragraphs 1.3 and 1.4, respectively.

[0124] Maximal swelling of a HA hydrogel sample was achieved in the following way. An amount of 1 gram of the granular hydrogel was weighed in a glass tube after which 8 gram of PBS buffer solution was added. The obtained gel mixture was then vortexed and left to stand for 6 hours, after which it was centrifuged for 10 minutes at 4,000 rpm (Eppendorf 5804). Excess water was discarded. The resulting gel was weighed to determine the HA content in wt.% by gravimetric ratio. Then, the values for G’ and G” were measured for each sample. The results are displayed in Table 2 and in Figures 6-7.Table 2. G' and G” behavior of granular HA hydrogels (completely swollen) Sample # HPH pressure HA content G’ at 0.7 Hz G” at 0.7 Hz (bar) (wt.%) (Pa) (Pa)

[0125] 1 30 1.05 265 75

[0126] 2 60 1.09 255 65

[0127] 3 100 1.14 200 55

[0128] 4 200 1.05 125 27

[0129] 5 300 1.25 102 20

[0130] 6 400 1.25 75 15

[0131] 7 manually ground 1.04 170 40 (comparative) (150 pm sieve)

[0132] 8 manually ground 1.05 180 66 (comparative) (45 pm sieve)

[0133]

[0134] 1.6. Particle characterization using confocal microscopy

[0135] The obtained hydrogels were further studied by characterizing the size and morphology of their HA particles using confocal microscopy. Microscope pictures of the hydrogels obtained at the different pressures are shown in Figure 3. This Figure also demonstrates how particle morphology varies with the applied pressure; the hydrogel particles contain more and larger lobes when the HPH is performed at a higher pressure.

[0136] For comparison, microscope pictures of hydrogels that are produced with the conventional sieving process are shown in Figure 2; the shape of these hydrogels most closely resembles that of a hydrogel obtained with a HPH pressure of 30 bar. So, the higher the HPH pressure, the more remote is the particle shape from the shape of conventional hydrogel particles.

[0137] 1.7. Conclusions

[0138] The measurements performed on granular hydrogels obtained by performing HPH at different pressures show that the elastic modulus G’ and theviscous modulus G” of the fractioned hydrogel both decrease with an increasing HPH pressure. This allows an estimation of the outcome of the HPH. When the fractioned hydrogel is swollen to its maximum capacity, the trend remains similar.

[0139] This is in contrast to the manually ground gels, where there is a limitation of the pressure that can be applied manually (no more than a few Newton).

[0140] Therefore, one cannot change the G’ or G” by manual granulation with a sieve. The same is true for sieve-granulation in a sieving machine, where applied pressures are also severely limited.

[0141] Visual inspection of the different images of Figure 3 reveals that the particles have a more complex morphology when their preparation involves a higher pressure in the HPH. They appear to have less regular contours and are possibly even composed of several lobes. From these pictures, it seems that the surface to volume ratio increases upon increasing the pressure of the HPH. This may be due to the high shear forces that are exerted onto the gel during the HPH, causing rupture to occur along long stretches of gel matter.

[0142] Example 2: Influence of HPH on a hyaluronic acid hydrogel

[0143] For the development of a hydrogel product, it is convenient if the specifications of a hydrogel can be tuned for a specific desired application. This Example shows the tuning of the G’ of a granular hyaluronic acid (HA) hydrogel to 1,100 ± 100 Pa.

[0144] 2.1. General considerations

[0145] The chemicals and solvents were purchased from commercial sources and used without further purification. If necessary, residual water was removed from them prior to their use. When water itself was used in a procedure, it was demineralized prior to its use.

[0146] All prepared hydrogels contained a phosphate buffer to give the hydrogel a pH in the range 6.8-7.2.The high-pressure homogenizer that was used in the preparation of the hydrogel particles was a laboratory homogenizer with a maximum operating pressure of 2,000 bar and a rated flow of 5 L / h. The hydrogel is to be introduced into the apparatus via a feeding hopper and a jacketed feed tank with pneumatic pusher.

[0147] The elastic modulus G’ and viscous modulus G” of each granular hydrogel sample were measured using a Discovery hybrid rheometer AR G2. For each measurement, an SS geometry with a 40 mm diameter was used wherein the gap was set at 500 pm and the trim gap offset at 50 pm. The temperature was set at 25°C and the frequency at 0.7 Hz.

[0148] 2.2. Preparation of a 2.0 wt.% cross-linked HA (initial) hydrogel

[0149] An amount of 348 ± 1 g of sodium hyaluronate powder (Mw = 1 ,500-1 ,700 kDa) was weighed into a plastic bottle. A 0.25 M NaOH solution was prepared by dissolving 22 g of NaOH pellets in 2,200 g of demineralized water, using a 5 L glass beaker and under mechanical stirring. An amount of 2,103 ± 5 g of this solution was transferred to a planetary mixer with a mixing bowl of 5L. The sodium hyaluronate powder was added thereto in 10 portions at intervals of 2.5 minutes, under continuous stirring. When all of the powder had dissolved under the formation of a gel, 38 ± 0.5 g of BDDE was slowly added to the gel. The mixture was then stirred for 20 minutes. Thereafter, 240 ± 5 g of the gel mixture was transferred to a 1 ,000 mL plastic container. The container was closed and placed in an oven at 45 °C during 4 hours. The container was taken out of the oven and the cross-linked gel was cut into pieces of approximately 2.5 x 2.5 cm. The gel pieces were then poured into a mixture of 0.75 M acetic acid and PBS buffer solution for 16 hours to neutralize the pH. Thereafter, the resulting swollen gel fractions were transferred to a fresh solution of PBS-buffer and left to swell further until the HA content had fallen to 2.5 wt.%, which was monitored by intermediate weighing of the swollen pieces. The swollen gel fraction was then ground into mm-sized particles using a blender (fractionation), to produce the hyaluronic acid (HA) hydrogel for subjection to HPH.2.3. Granulation of cross-linked hyaluronic acid with HPH

[0150] Two sets of three HA hydrogel samples were prepared for subjection to HPH. The samples differed in the wt.% of HA in the hydrogel. One set had three samples of 2.0 wt.% (prepared according to paragraph 1.2) and the other had three samples of 2.5 wt.% (prepared according to paragraph 2.2). The six HA hydrogel samples were subjected to HPH at different pressures (each sample being subjected once to HPH by performing a run at a particular pressure). In each run, the feed tank of the HPH was filled with the mm-sized particle gel and the pneumatic hopper was positioned. The pressure was set at the applicable value for the pressure and then the HPH apparatus was started. First, a frontrunning waste fraction was collected for 2 minutes. Then, product was collected until the tank became empty. The different pressures applied in the different runs were 60, 100, 150 and 200 bar. For each of the six runs, a separate sample was obtained. The values for G’ and G” were measured for each sample. The results are displayed in Table 3.

[0151] Table 3. Tuning of G’ and G” for different granular HA hydrogels

[0152] Sample # HPH pressure HA content G’ at 0.7 Hz G” at 0.7 Hz (bar) (wt.%) (Pa) (Pa)

[0153] 1 60 2.0 605 69

[0154] 2 100 2.0 494 53

[0155] 3 200 2.0 310 39

[0156] 4 100 2.5 1,138 98

[0157] 5 150 2.5 876 87

[0158] 6 200 2.5 610 72

[0159]

[0160] 2.4. Conclusions

[0161] This Example demonstrates that it is possible to prepare a granular hyaluronic acid hydrogel with a particular pre-set value for the storage modulus G’ (1 ,100 ± 100 Pa) by systematic variation of process conditions, rather than byrelying on trail and error. By applying a pressure of 100 bar in the high-pressure homogenization of a 2 wt.% hyaluronic acid hydrogel, a storage modulus G’ of 1 ,138 Pa could be obtained (sample #4 in the table).

[0162] Example 3: comparison of the viscosity with a conventional gel

[0163] 3.1. General considerations

[0164] The chemicals and solvents were purchased from commercial sources and used without further purification. If necessary, residual water was removed from them prior to their use. When water itself was used in a procedure, it was demineralized prior to its use.

[0165] The cohesiveness of the hydrogels was measured using a Hartech Multitest-i by slowly pressing the hydrogel out of a syringe that was positioned vertically with the outlet facing the ground. The drop shape was determined just before the moment that a drop fell off the syringe outlet. The fallen drop was caught and its drop mass was determined.

[0166] The adhesion surface energy of the hydrogels was measured using a Discovery hybrid rheometer AR G2, wherein the adhesion surface energy was determined for adhesion to aluminum at 20 °C. The rheometer was configured with the following geometry: 40 mm parallel plate, Peltier plate aluminium. The following procedure was applied. An amount of 1 mL of the hydrogel is placed on the bottom plate and then squeezed by the top plate (circular plate, 40 mm diameter). Excess hydrogel that is squeezed outside the plate perimeter is removed with a tissue. The gap is set at 500 pm and the trim gap offset at 50 pm. Next, the plates are pulled apart from one another at a constant linear rate of 100 pm / s. The adhesion surface energy is then determined taking into account the force required for this pulling apart.

[0167] The viscosity (= dynamic viscosity) of the hydrogels was measured using a Discovery hybrid (rotational) rheometer AR G2. The rheometer was configured with the following geometry: 40 mm parallel plate, Peltier plate aluminium. For each measurement, an SS geometry with a 40 mm diameter was used whereinthe gap was set at 500 pm and the trim gap offset at 50 pm. The temperature was set at 20°C and the shear rate was increased from 0.002 s-1to 50 s-1during 180 seconds with 20 points per decade. The viscosity at the shear rate of 0.3775 s-1was calculated by taking the average of the viscosity at 0.356 s-1and 0.399 s-1(acceptance criteria range: 301-901 Pa*s).

[0168] The extrusion force of the hydrogels was measured using a Hartech Multitest-i by measuring the pressure that was needed to eject the hydrogel from a 10 mL syringe that had applicator mounted to its tip via a Luer-lock.

[0169] 3.2. Preparation of mixed HA and gelatin hydrogel

[0170] The HA gel obtained in Example 2 having a storage modulus G’ of 1 ,138 Pa can be used as an intermediate for the production of a hydrogel for medical application, in particular for application in the sinus or nasal cavity. To this end, the HA gel obtained by HPH at 100 ± 5 bar (and still buffered at a pH in the range 6.8-7.2) was mixed with a cross-linked gelatin powder that was also buffered at a pH in the range 6.8-7.2 (the gelatine cross-linking was performed by treatment with 1.1 wt.% formaldehyde). A syringe was filled with a homogeneous mixture of both gels. After sterilization and packaging, the syringe was ready for use. The HA gel prepared in this way is optimized to maximize its cohesion and adhesion characteristics.

[0171] 3.3. Comparison of a hydrogel of the invention with a conventional hydrogel

[0172] The measured properties of the hydrogel product of the invention were compared with those of the commercially available Chitogel™ endoscopic sinus surgery kit. This product comprises a hydrogel based on a combination of chitosan, dextran and glycerol that is chemically crosslinked to a network (once the individual components are mixed, the crosslinking starts). The results of this comparison are displayed in Table 4.Table 4. Comparison of the mechanical properties of the two hydrogels

[0173] Entry Test Invention Chitogel™ 1 Cohesiveness by drop shape Yes Yes (elongated Y / N)

[0174] Cohesiveness by drop mass 149 13

[0175] (mg)

[0176] 2 Adhesion surface energy to 13 0.21

[0177] aluminum (J / m2)

[0178] 3 Absorption by weight (wt.%) 226 62

[0179] 4 Viscosity (Pa*s) 841 475

[0180] 5 Extrusion force (N) 44 51

[0181]

[0182] 3.4. Conclusions

[0183] The results show that by subjecting the HA hydrogel to HPH, a high viscosity in the final medical product is obtained, whilst maintaining high cohesive and adhesive properties that are significantly higher than those of the product known in the art.

Claims

CLAIMS1. Process for preparing a granular hydrogel, the process comprising- providing an initial hydrogel; then- subjecting the initial hydrogel to high-pressure homogenization to obtain the granular hydrogel.

2. Process according to claim 1 , wherein the high-pressure homogenization is performed by applying a pressure in a range of 10-2,000 bar, in particular in a range of 30-600 bar.

3. Process according to claim 1 or 2, wherein the process is followed by mixing the obtained granular hydrogel with a second hydrogel, in particular with a second granular hydrogel, more in particular with a second granular hydrogel comprising a cross-linked polymer selected from the group of alginate, gelatin, hyaluronic acid, polyethylene glycol), poly(vinyl alcohol), polyacrylate, polymethacrylate, chitosan, chondroitin, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

4. Process according to any one of claims 1-3, wherein the initial hydrogel has a pH value in a range of 5.5-8.5 or in a range of 6.5-7.5 when subjected to the high-pressure homogenization.

5. Process according to any one of claims 1-4, wherein the initial hydrogel comprises a cross-linked polymer selected from the group of alginate, gelatin, hyaluronic acid, polyethylene glycol, poly(vinyl alcohol), polyacrylate, polymethacrylate, chitosan, chondroitin, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

6. Process according to any one of claims 1-5, wherein providing the initial hydrogel comprises cross-linking a hydrogel-forming polymer to form the initial hydrogel, in particular a hydrogel-forming polymer selected from the group of alginate, gelatin, hyaluronic acid, gellan gum, chitosan, chondroitin,polyethylene glycol), poly(vinyl alcohol), polyacrylate, polymethacrylate, chitosan, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

7. Process according to claim 6, wherein the cross-linking is performed by treating the hydrogel-forming polymer with a cross-linking agent selected from the group of diglycidyl ethers, di-epoxyalkanes and divinyl sulfone, in particular from the group of 1 ,4-butanediol diglycidyl ether and divinyl sulfone.

8. Process according to any one of claims 1-7, wherein the process comprises allowing the obtained granular hydrogel to absorb an active pharmaceutical ingredient.

9. Process according to claim 8, wherein the active pharmaceutical ingredient is selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs.

10. Granular hydrogel obtainable by a process according to any one of claims 1- 9.

11. Granular hydrogel according to claim 10, wherein the granular hydrogel is selected from the group of alginate hydrogel, gelatin hydrogel, hyaluronic acid hydrogel, polyethylene glycol) hydrogel, poly(vinyl alcohol) hydrogel, polyacrylate hydrogel, polymethacrylate hydrogel, chondroitin hydrogel, chitosan hydrogel, silk hydrogel, fibroin hydrogel, agarose hydrogel, gellan hydrogel, arabic gom hydrogel, cellulose hydrogel and carboxymethyl cellulose hydrogel.

12. Granular hydrogel according to claim 10 or 11, wherein the granular hydrogel comprises a pharmaceutical ingredient such as a pharmaceutical ingredient selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs.

13. Granular hydrogel composition comprising- a first granular hydrogel according to any one of claims 10-12; and - a second granular hydrogel, in particular a second granular hydrogel which comprises a cross-linked hydrogel-forming polymer selected from the group of alginate, gelatin, hyaluronic acid, polyethylene glycol), poly(vinyl alcohol), polyacrylate, polymethacrylate, chondroitin, chitosan, silk, fibroin, agarose, gellan, arabic gom, cellulose and carboxymethyl cellulose.

14. Granular hydrogel composition comprising- a first granular hydrogel according to any one of claims 10-12, wherein the granular hydrogel is a granular hyaluronic acid hydrogel; and- a second granular hydrogel wherein the granular hydrogel is a granular gelatin hydrogel;wherein the granular hydrogel composition has an adhesion surface energy in a range of 5-20 J / m2, in particular in a range of 8-18 J / m2and more in particular in a range of 10-15 J / m2, wherein the adhesion surface energy is measured for adhesion to aluminum at 20 °C by means of a rheometer.

15. Granular hydrogel composition according any one of claims 10-14, wherein the granular hydrogel composition has a viscosity in a range of 400-1 ,000 Pa*s, in particular in a range of 500-800 Pa*s, wherein the viscosity is measured at 20 °C by means of a rotational rheometer.

16. Granular hydrogel composition according to any one of claims 10-15, wherein the granular hydrogel composition has a drop mass in a range of 40-400 mg, in particular in a range of 100-200 mg, wherein the drop mass is obtained by the following measuring method, performed at a temperature of 20 °C:- allowing a drop to form at an outlet of a syringe by pressing a piston into the syringe, wherein the syringe is positioned vertically with the outlet facing the ground; and then- increasing the drop size by continuing the pressing of the piston into the syringe until the drop releases from the syringe under its own weight; and then- catching the released drop and measuring its mass.

17. Granular hydrogel according to any one of claims 10-12, or granular hydrogel composition according to any one of claims 13-16, for use as a medicament, in particular for treatment of a subject after sinus surgery, more in particular for treatment of a person suffering from epistaxis.

18. Syringe comprising an effective amount of a granular hydrogel composition according to any one of claims 13-17, in order to stop bleeding at a bleeding site of a human or animal subject.

19. Method for treating a medical condition of a human or an animal, comprising administering to the human or animal, in particular at a bleeding site of the human or animal, a granular hydrogel according to any one of claims 10-12 or a granular hydrogel composition according to any one of claims 13-17.

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