Embolic microspheres and methods

Abstract

To provide compositions and methods useful in therapeutic embolisation and particularly in methods for bariatric arterial embolisation (BAE).SOLUTION: A composition comprises a population of polymeric microspheres comprising a polymer and having a native size distribution in which not more than 10% of the microspheres have a diameter of less than 120 μm and not more than 10% of the microspheres have a diameter greater than 200 μm.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compositions and methods useful in methods for therapeutic embolization, particularly bariatric arterial embolization (BAE). [Background technology]

[0002] Therapeutic embolization is a minimally invasive procedure in which materials are introduced into blood vessels via a transcatheter route to occlude the vessels, slowing or stopping blood flow and causing tissue ischemia. This approach has previously been used to treat hypervascular tumors such as hepatocellular carcinoma and benign tumors such as uterine fibroids. Recent preclinical observations suggest that embolization of blood vessels supplying the gastric fundus (known as bariatric arterial embolization, or BAE) may be useful in controlling weight gain. Summary of the Invention

[0003] In some embodiments, the present invention provides a composition comprising a population of polymeric microspheres comprising a polymer, the population having a unique size distribution in which no more than 10% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 200 μm.

[0004] In some embodiments that can be used in combination with the above aspects, the microspheres may have an average compressive modulus of greater than 1000 kPa. In some embodiments that can be used in combination with the above aspects, the microspheres have an average compressive modulus that is at least 5 times that of Bead Block® 300-500.

[0005] In some embodiments that can be used in combination with the above aspects, the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 100 μm and no more than 5% of the microspheres have a diameter greater than 200 μm.

[0006] In some embodiments that can be used in combination with the above aspects, the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm.

[0007] In some embodiments that can be used in combination with the above aspects, no more than 10% of the microspheres have a penetration value of less than 80 μm in a pig kidney model. In some embodiments that can be used in combination with the above aspects, no more than 10% of the microspheres have a penetration value greater than 300 μm.

[0008] In some embodiments that can be used in combination with the above aspects, no more than 5% of the microspheres have a penetration value less than 80 μm and no more than 5% of the microspheres have a penetration value greater than 300 μm.

[0009] In some embodiments that can be used in combination with the above aspects, no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm.

[0010] Another aspect of the invention relates to a composition comprising a population of polymeric microspheres, the population of polymeric microspheres comprising a polymer, wherein no more than 10% of the microspheres have a permeation value of less than 80 μm in a porcine kidney model.

[0011] In some embodiments that can be used in combination with the above aspects, no more than 10% of the microspheres have a penetration value greater than 300 μm. In some embodiments that can be used in combination with the above aspects, no more than 5% of the microspheres have a penetration value less than 80 μm and no more than 5% of the microspheres have a penetration value greater than 300 μm.

[0012] In some embodiments that can be used in combination with the above aspects, no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm.

[0013] In some embodiments that can be used in combination with the above aspects, the microspheres have a unique size distribution in which no more than 10% of the microspheres have a diameter less than 120 μm and no more than 10 microspheres have a diameter greater than 200 μm.

[0014] In some embodiments that can be used in combination with the above aspects, the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm.

[0015] In some embodiments that can be used in combination with the above aspects, the microspheres have an average compressive modulus of greater than 1000 kPa. In some embodiments that can be used in combination with the above aspects, the microspheres have an average compressive modulus that is at least 10 times that of Beadblock® 300-500.

[0016] In some embodiments that can be used in combination with the above aspects, the polymer is a hydrogel. In some embodiments that can be used in combination with the above aspects, the polymer comprises polyvinyl alcohol.

[0017] In some embodiments that can be used in combination with the above aspects, the polymer is imageable. In some embodiments that can be used in combination with the above aspects, the polymer is radiopaque.

[0018] In some embodiments that can be used in combination with the above aspects, the polymer contains 70-150 mg of iodine per mL of precipitated microspheres covalently bound to the polymer, preferably 85-120 mg / mL of precipitated microspheres, and particularly 90-110 mg / mL of precipitated microspheres.

[0019] Another aspect of the present invention relates to a pharmaceutical composition comprising a population of polymeric microspheres according to the above aspects and embodiments, and a pharmaceutically acceptable diluent. Another aspect of the invention relates to a method for inducing weight loss or delaying weight gain in a patient in need thereof, the method comprising delivering an effective amount of a population of microspheres according to the above aspects and embodiments, or an effective amount of a pharmaceutical composition according to any one of the above aspects and embodiments, to the capillary bed of the gastric fundus of the patient.

[0020] Another aspect of the invention relates to a method for treating obesity in a patient in need thereof, the method comprising delivering an effective amount of a population of microspheres according to any one of the above aspects and embodiments, or an effective amount of a pharmaceutical composition according to any one of the above aspects and embodiments, to the capillary bed of the gastric fundus of the patient.

[0021] In some embodiments, the microspheres are delivered to the patient by a transcatheter route. Another aspect of the invention relates to a composition according to any one of the above aspects and embodiments for use in a method of inducing weight loss or delaying weight gain in a patient in need thereof. [Brief explanation of the drawings]

[0022] [Figure 1] Size distribution graph showing the inherent size distribution of a commercial microsphere preparation compared to test samples. [Figure 2] Size distribution histogram showing penetration values ​​of radiopaque 102 microspheres (129 mg iodine / mL) in porcine kidney. [Figure 3] Size distribution histogram showing penetration values ​​of radiopaque 304 microspheres (113 mg iodine / mL) in porcine kidney. [Figure 4] Size distribution histogram showing penetration values ​​of (non-radiopaque) Beadblock® 300-500 μm (nominal size range) microspheres (without iodine) in porcine kidney. [Figure 5] Graph showing weight gain in pigs treated with BAE using radiopaque 102 microspheres. [Figure 6] Scatter plot showing ulcer scores for radiopaque 102 microspheres compared to smaller microspheres (DC Bead LUMI® 40-90 μm nominal) and larger microspheres (DC Bead LUMI 100-300 μm nominal). The iodine content for the 40-90 μm size range is 131-169 mg / mL, and the iodine content for the 100-300 μm size range is 122-162 mg / mL. The scatter plot shows the mean and standard deviation of the ulcer scores for each microsphere population. Ulcer score: no ulcer = 0, small (<=2 cm) = 1, large (>2 cm) = 2, full-thickness ulcer = 3. [Figure 7] An alternative view of the data in Figure 6, where "BAE beads" are the 102 microspheres (100-200 um) in Figure 6, and the ulcer scores have been normalized. [Figure 8] Graph showing weight gain for individual pigs plotted against fundus coverage, where data was obtained from cone beam CT scans of individual animals in Example 4 (102 microspheres), and fundus coverage indicates the area of ​​radiopacity within the fundus as a percentage of the total fundus area. DETAILED DESCRIPTION OF THE INVENTION

[0023] As noted above, the present invention relates to compositions and methods useful in therapeutic embolization, particularly bariatric arterial embolization (BAE) procedures. Therapeutic embolization is a minimally invasive method in which materials are introduced into blood vessels via a transcatheter route to occlude the vessels, slowing or stopping blood flow and causing ischemia in the supplied tissue. This approach has previously been used to treat hypervascular tumors such as hepatocellular carcinoma and benign tumors such as uterine fibroids.

[0024] Recent preclinical observations suggest that embolization of blood vessels supplying the gastric fundus (known as bariatric arterial embolization or BAE) may be useful in controlling weight gain, particularly in the treatment of obesity and associated squamous obesity (Arepally et al., 2007; Bawudun et al., 2012; Paxton et al., 2013; Kipshidze et al., 2013; Weiss et al., 2014). These studies suggest that BAE leads to reduced weight gain, reduced circulating ghrelin levels, and a reduced number of ghrelin-secreting cells in the gastric fundus. For example, U.S. Patent No. 9,572,700 discloses the use of microspheres in the 300-500 μm size range (Beadblock® 300-500, Biocompatibles UK Ltd) for BAE treatment, suggesting that smaller size ranges may cause mucosal necrosis of the gastric fundus, gastric ulcers, and off-target embolization, such as in the esophagus, liver, and / or spleen. However, Fu et al. (2018) failed to demonstrate suppression of weight gain or a reduction in ghrelin-expressing cells in pigs using microspheres with a nominal diameter of 300-500 μm.

[0025] Although this method is promising, adverse events such as ulceration of the mucosal surface, including gastric corpus and gastritis, continue to be reported in animal models (Paxton et al., 2014, and Weiss et al., 2014). Thus, while BAE is a potentially useful approach for modulating weight gain, obesity, and related sequelae, it would be desirable to provide compositions and methods that achieve effective embolization of the gastric fundus while maintaining improved safety.

[0026] The inventors have determined that important factors in controlling mucosal damage are the depth within the vascular bed at which embolization occurs and the presence of off-target emboli in the mucosal region outside the gastric fundus. The inventors have further determined that one cause of mucosal damage is the presence of microspheres within the submucosa, and that embolization occurring only slightly proximal to the catheter (i.e., away from the mucosa) is effective in causing ischemia but generally does not cause long-term or significant mucosal damage. On the other hand, embolization occurring too proximally, i.e., too far from the mucosa, is thought to be less effective because the presence of collateral channels within the stomach wall reduces the effectiveness of the embolization.

[0027] Microspheres are generally formed as a population of spheres with a range of sizes depending on the method and sizing techniques used to prepare the microspheres, but the permeability of the microspheres themselves is governed by a variety of factors, including not only the size distribution but also the compressibility (compression modulus) of the spheres.

[0028] The ability to visualize the microspheres in situ is particularly useful because it allows the surgeon to determine in real time where the microspheres are deposited and identify off-target embolization. However, the addition of radiopaque components to the polymer can alter the compressibility of the microspheres, potentially affecting their permeability.

[0029] In a first aspect, the present invention therefore provides a composition comprising a population of polymeric microspheres having a unique size distribution such that no more than 10% of the microspheres have a diameter less than 100 μm and no more than 10% of the microspheres have a diameter greater than 200 μm.

[0030] The intrinsic size is the size of the microsphere before injection. For water-swellable polymers such as hydrogels, this is the size of the microsphere fully hydrated in normal saline (10 mM phosphate; 500 mM NaCl; pH 7.4).

[0031] Preferably, the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter less than 100 μm, more preferably, and alternatively, no more than 5% of the microspheres have a diameter less than 120 μm.

[0032] Preferably, the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter greater than 200 μm, more preferably, and alternatively, no more than 10% of the microspheres have a diameter greater than 185 μm.

[0033] In particularly preferred combinations, the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter less than 100 μm and no more than 5% of the microspheres have a diameter greater than 200 μm, and more preferably, the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm.

[0034] The above preferred characteristic size distributions should be construed as alternatives rather than additional. The compressibility (compression modulus) of the microspheres affects the depth of penetration into the vascular bed. The more compressible the microsphere, the deeper it will penetrate into the vascular bed for a given size. Measurement of the compressive modulus of microspheres is described in Caine et al. (2017) and Duran et al. (2016). To the extent that the measurement methods described herein deviate from the above methods, the methods described herein shall be construed as such. See Example 2 herein.

[0035] As described herein, the average compressive modulus is the average of at least 5 measurements taken from an individual microsphere; preferably, the modulus is the average of at least 25 measurements, although one skilled in the art will appreciate that the more readings taken, the more accurate the average. If the microspheres are hydrogels, the modulus should be measured when fully hydrated with normal saline.

[0036] The preferred elastic modulus of the microspheres is at least 500 kPa to 1000 kPa, preferably at least 2000 kPa, more preferably at least 4000 kPa, and even more preferably at least 5000 kPa. Preferably, the elastic modulus does not exceed 50,000 kPa, because such microspheres are more difficult to deliver, and the stiffness of the microspheres increases their tendency to cause catheter blockage, although this depends somewhat on the size of the catheter. The elastic modulus preferably does not exceed 30,000 kPa, more preferably does not exceed 25,000 kPa.

[0037] The preferred range of the elastic modulus is 2,000 kPa to 30,000 kPa, and more preferably 5,000 kPa to 25,000 kPa. Thus, in a preferred embodiment, the composition contains a population of polymeric microspheres having a unique size distribution such that no more than 10% of the microspheres have a diameter less than 100 μm and no more than 10% of the microspheres have a diameter greater than 200 μm, and the microspheres have an average compressive modulus of at least 1000 kPa.

[0038] Compression modulus can also be expressed in relative terms. Thus, the microspheres preferably have a compressive modulus at least five times that of BeadBlock® 300-500 microspheres. BeadBlock® microspheres may be prepared according to Example 1 of WO 2004 / 071495 for low AMPS and sieved to a size range of 300-500.

[0039] Preferably, the microspheres have an elastic modulus at least 10 times, more preferably at least 15 times, even more preferably at least 20 times, more preferably at least 25 times that of Beadblock® 300-500.

[0040] Preferably, the microspheres have a compressive modulus that is not more than 200 times that of Beadblock® 300-500, preferably less than 150 times, more preferably less than 125 times, more preferably less than 110 times, and even more preferably less than 100 times that of Beadblock® 300-500.

[0041] Preferably, the microspheres have a compressive modulus that is 10 to 200 times that of Beadblock® 300-500, more preferably 15 to 150 times, even more preferably 20 to 110 times, and even more preferably 25 to 110 times or 25 to 100 times that of Beadblock® 300-500.

[0042] Thus, in a further preferred embodiment, the composition contains a population of polymeric microspheres having a unique size distribution such that no more than 10% of the microspheres have a diameter less than 100 μm and no more than 10% of the microspheres have a diameter greater than 200 μm, and the microspheres have an average compressive modulus at least 5 times that of Beadblock® 300-500.

[0043] The depth into a vascular bed to which a microsphere penetrates is governed by many factors, including the microsphere's inherent size and compressibility (compression modulus). As used herein, the "penetration value" of a microsphere is the smallest diameter of a blood vessel at which a single microsphere remains when blocking the vessel. This was determined in a porcine kidney model in which a group of microspheres was delivered to the renal artery, causing embolization of the renal vasculature (see, e.g., Caine et al., 2017). Penetration value is determined microscopically after necropsy. The embolized kidney is sectioned and stained, and the smallest diameter of the blood vessel embolized by a single microsphere is measured (many blood vessels are cut at an angle that forms an ellipse, and the smallest diameter of the blood vessel is the smallest diameter of the ellipse). This is the penetration value of the microsphere (see also Example 3).

[0044] The microsphere population may, according to a second embodiment, have the permeation properties described below. In a second aspect, the present invention also provides a composition containing a population of polymeric microspheres, wherein no more than 10% of the microspheres have a permeability value of less than 80 μm in a porcine kidney model.

[0045] Preferably, no more than 5% of the microspheres have a permeation value of less than 80 μm, alternatively, and more preferably, no more than 5% of the microspheres have a permeation value of less than 90 μm. Preferably, no more than 10% of the microspheres have a permeation value of greater than 300 μm, more preferably no more than 5% of the microspheres have a permeation value of greater than 300 μm. Alternatively, even more preferably, no more than 5% of the microspheres have a permeation value of greater than 250 μm. Preferably, in a pig kidney model, no more than 10% of the microspheres in the population of microspheres have a permeation value of less than 80 μm and no more than 10% of the microspheres have a permeation value of greater than 300 μm. More preferably, no more than 5% of the microspheres have a permeation value of less than 80 μm and no more than 5% of the microspheres have a permeation value of greater than 300 μm. Alternatively, even more preferably, no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm.

[0046] The above upper and lower permeation distribution preferred values ​​should be construed as alternatives rather than additive. Such a population has a specific size distribution and compressibility properties as described above with respect to the first embodiment.

[0047] Preferably, the polymer is a hydrophilic polymer, as such polymers are generally more biocompatible. The hydrophilic polymer may be selected from the group consisting of acrylic polymers, acrylamides, acetals, allyls, polyamides, polycarbonates, polyesters, polyethers, polyimides, polyolefins, polyphosphates, polyurethanes, styrenics, vinyls, polysaccharides, or combinations and / or copolymers thereof. Preferably, the polymer contains monomers selected from vinyl alcohol, ethylene or propylene glycol, acrylates, methacrylates, acrylamides, or methacrylamides.

[0048] Preferred hydrophilic polymers include vinyl alcohol polymers such as polyvinyl alcohol (PVA); acrylic polymers such as polyacrylic acid and salts, poly(alkyl acrylates) such as poly(methyl acrylate), poly(alkyl acrylates) such as polymethyl methacrylate and polyethyl methacrylate; polyhydroxyalkyl(alkyl acrylates) such as polyhydroxyethyl methacrylate; acrylamide polymers such as polyacrylamide, poly(alkyl acrylamides), polymethacrylamides (hydroxyalkyl) acrylamides such as tris-(hydroxymethyl)methyl acrylamide; polyvinylpyrrolidone, polyethylene glycol (PEG) polymers such as PEG, PEG-acrylamide and diacrylamide, PEG-acrylate and diacrylate, PEG-methylate and dimethacrylate, and PEG-methacrylamide and dimethacrylamide; celluloses such as carboxymethyl cellulose and hydroxyethyl cellulose; chitosan, alginate, gelatin, starch, or a combination or copolymer comprising at least one of the above. The polymer may be crosslinked.

[0049] In certain embodiments, the polymer contains or is a polyhydroxylated polymer, i.e., a polymer containing repeating units having one or more pendant hydroxyls. Preferred polyhydroxylated polymers include polyol esters of acrylates and alkyl acrylates (e.g., methsylates), such as poly(hydroxyalkylacrylates) and poly(hydroxyalkyl(alkylacrylates), particularly polyhydroxyethyl(methacrylate); poly(hydroxyalkylacrylamides) and poly(hydroxyalkylmethacrylamides), e.g., tris(hydroxymethyl)methacrylamide; polymers containing vinyl alcohol, such as poly(vinyl alcohol) or (ethylene-vinyl alcohol) copolymers; and polymers containing polysaccharides, such as starch, chitosan, glycogen, celluloses, such as methylcellulose, alginates, and polysaccharide gums, such as carrageenan, guar, xanthan, gellan, locust bean gum, and gum arabic.

[0050] In a further embodiment, the hydrophilic polymer may be a polycarboxylated polymer, i.e., a polymer containing repeating units with one or more pendant carboxyl groups. These polymers include, for example, polyacrylic acid, polyalkylacrylic acid, polymethacrylic acid, etc., and copolymers thereof, particularly those containing PVA. Such polymers may be in the form of their salts, such as sodium or potassium salts.

[0051] Particularly preferred are polymers containing polyvinyl alcohol (PVA), such as homopolymers and copolymers of PVA, PEG polymers, PEG-acrylamides and diacrylamides, PEG-acrylates and diacrylates, PEG-methsylates and dimethacrylates, and PEG-methacrylamides and dimethacrylamides, and polyalkylacrylic acids, such as polymethacrylic acid. Most preferred are polymers containing PVA, such as homopolymers and copolymers of polyvinyl alcohol.

[0052] The polymer is preferably a cross-linked polymer. Cross-links can be covalent or non-covalent. Non-covalent bonds include, for example, physical cross-links due to the entanglement of polymer chains or the presence of crystalline regions. Ionic cross-links occur when charged groups on a polymer are cross-linked by oppositely charged multivalent groups. In some cases, this can be via divalent or higher metal ions such as calcium, magnesium, or barium, as in the case of alginate polymers. Covalent cross-linking can be achieved by any of the established methods for covalently linking functional groups on different chains. If achieved during the polymerization stage, this can be achieved by incorporating bifunctional monomers. If post-polymerization, this can be achieved by bifunctional species that can react with functional groups on the polymer, such as amine, hydroxyl, or carboxyl groups, or ethylenically unsaturated groups. The polymer may also contain pendant groups that themselves carry such cross-linkable groups. For example, it may contain ethylenically unsaturated groups.

[0053] In a preferred embodiment, the polymer may be substituted with functional groups that are charged at pH 7.4. Such functional groups may be positively or negatively charged and may reversibly bind to oppositely charged compounds at physiological pH (pH 7.4). A variety of charged groups may be used, including sulfonate, phosphate, ammonium, phosphonium, and carboxylate groups, with carboxylate and sulfonate groups being preferred. In one embodiment of the crosslinked polymer, the charged groups may be located on the crosslinking moiety.

[0054] Particularly preferably, the polymer is a hydrogel, i.e., the polymer is water-swellable but water-insoluble. It contains more than 50% by weight of water, preferably up to 98% by weight of water, preferably 65-85%, more preferably 75-85%. Polyhydroxylated or polycarboxylated polymers, and preferably crosslinked polyhydroxypolymers, are preferred in this regard due to their tendency to form such hydrogels.

[0055] In a particularly preferred embodiment, the polymer is a cross-linked polyvinyl alcohol polymer or copolymer in the form of a hydrogel. In one embodiment, such a polymer may be physically or covalently cross-linked. The polymer may contain pendant groups (other than -OH groups) with cross-linkable functionality, such as ethylenically unsaturated groups, through which the polymer may be cross-linked, or the polymer may be cross-linked via a cross-linking agent with multiple functional groups, such as an aldehyde or acid, that reacts with the hydroxyl groups of the PVA backbone.

[0056] Particularly preferred are polymers having charged groups as described above, especially when the polymer contains sulfonate or carboxylate groups (see, for example, WO 2004 / 071495 and WO 2017 / 037276).

[0057] A preferred type of polymer is a polyvinyl alcohol macromer, which has two or more ethylenically unsaturated pendant groups per PVA molecule and is formed by reacting PVA with an ethylenically unsaturated monomer. PVA macromers may be formed, for example, by providing a PVA polymer with pendant vinyl or acrylic groups. Pendant acrylic groups may be provided, for example, by reacting acrylic acid or methacrylic acid with PVA to form ester bonds through some of the hydroxyl groups. Compounds containing vinyl groups capable of bonding to polyvinyl alcohol are described, for example, in U.S. Pat. No. 4,978,713, preferably U.S. Pat. No. 5,508,317, and U.S. Pat. No. 5,583,163. Thus, a preferred macromer comprises a polyvinyl alcohol backbone bonded to an (alk)acrylaminoalkyl moiety. An example of such a polymer contains a PVA-N-acryloylaminoacetaldehyde (NAAADA) macromer, also known as Nelfilcon-B or acrylamide-PVA.

[0058] In a preferred embodiment, the macromer may be reacted with an ethylenically unsaturated monomer, optionally bearing a positive or negative charge, such as 2-acrylamido-2-methylpropanesulfonic acid (AMPS). Such polymers and methods for making them are described in WO 2004 / 071495, WO 2012 / 101455, and WO 2017 / 037276. DC Bead® is one such polymeric microsphere.

[0059] Particularly preferably, the microspheres are imageable. This aids in visualization during or after treatment. Imagability includes ultrasound, X-ray, magnetic resonance imaging, superparamagnetic resonance imaging, positron emission imaging (PET, etc.), or photon emission imaging (SPECT, etc.). Imagability is achieved by incorporating an imageable component, preferably incorporated throughout the microsphere. Particularly preferably, such an agent is covalently bound to the polymer of the microsphere.

[0060] In a preferred embodiment, the microspheres are imageable by X-ray. This can be achieved by incorporating radiopaque components into the polymer microspheres, either covalently or noncovalently. Examples of noncovalently incorporated radiopaque components include particulate materials such as barium salts (e.g., barium sulfate) (see, e.g., Thanoo et al. 1991), metals such as gold, iron, or tantalum, or iodized oils such as Lipiodol®. However, in a more preferred approach, the polymer may contain covalently bound radiopaque components such as iodine (e.g., WO 2015 / 033092) or bismuth (e.g., WO 2018 / 093566), preferably bound throughout the microsphere.

[0061] In one approach, polymer microspheres contain covalently attached groups, such as pendant groups containing radiopaque moieties. Preferably, the covalently attached pendant groups are iodinated groups, such as iodinated aromatic groups, particularly phenyl groups. Those skilled in the art will understand that the amount of iodine in a polymer can be adjusted by controlling the degree of coupling of iodinated groups to the polymer, e.g., in the case of PVA, by controlling the number of pendant groups in the polymer or, for example, the number of iodines on the pendant groups. The iodine level can be conveniently expressed as mg of iodine per ml of microspheres. If the microspheres are water-swellable, e.g., a hydrogel such as cross-linked PVA, this refers to the amount of iodine per ml of fully hydrated beads in normal saline as a fill volume (e.g., quantified with a graduated cylinder). In the present invention, the microspheres have a level of iodine selected to provide adequate radiopacity (or radiodensity), while the compressibility of the microspheres allows for the required level of handling and penetration, and ensures that ease of catheter delivery and suspension properties are not unduly compromised.

[0062] The microsphere populations described herein may have iodine levels in the polymer ranging from 70 to 150 mg / ml, preferably 80 to 140 mg / ml, more preferably 85 to 120 mg / ml, and especially 90 to 110 mg / ml of precipitated microspheres. These levels have been found to impart good properties, particularly for microspheres in which the polymer is a PVA polymer or copolymer crosslinked as described herein.

[0063] Such functional groups may be attached to the polymer backbone via a variety of chemistries, depending on the availability of functional groups on the polymer. For example, in the case of polyhydroxylated polymers, the pendant groups may be attached via ether, ester, or cyclic acetal linkages. The iodinated aromatic group may be attached to the polymer directly via a linker or via a coupling group. Suitable linkers include those having a chain of 1 to 6 atoms selected from C, N, S, and O between the aromatic group and the coupling group, where the chain is formed to contain only one atom selected from N, S, and O, where C is optionally substituted with a group selected from =0, -CH3, and (-CH3)2, particularly =0, and N is selected from R 1 is replaced by R 1 is H and C 1-4 It is selected from alkyl, especially H and methyl, and S is a -SO2- group. S is less preferred in this linker. Suitable linkers include those of the formula -(CH2) p -O-(CH2) q -, where p and q are 0, 1, or 2, with the proviso that p and q cannot both be 0, and have the formula -(CH2) n NHC(O)—, where n is 1 or 2, of formula C 1-6 Preferred linkers include methylene, ethylene, and propylene groups, methoxyl, ethoxyl, oxymethylene, and oxyethylene groups, -(CH2) n NHC(O)—, where n is 1 or 2 and is selected from methylene, ethylene, and propylene groups.

[0064] When the polymer is or comprises PVA (PVA polymers and copolymers), the pendant groups (preferably iodinated phenyl groups) comprising the radiopaque moiety can be covalently attached to the polymer via cyclic acetal groups, as described in WO 2015 / 033092 and WO 2015 / 03309. Thus, in a particularly preferred embodiment, the microspheres comprise crosslinked polyvinyl alcohol polymers or copolymers in the form of hydrogels as described above, wherein the PVA backbone further comprises iodinated phenyl groups attached to the PVA backbone, for example via cyclic acetal bonds, preferably direct bonds via cyclic acetals.

[0065] Suitable iodinated phenyl groups are shown below.

[0066] [ka] The pendant group of choice is a functional group of formula A:

[0067] Processes for preparing PVA polymers and copolymers with such pendant groups are described in WO 2015 / 033092 and WO 2015 / 03309.

[0068] In a particularly preferred approach, the polymer is a hydrogel in the form of a crosslinked PVA polymer or copolymer, as described herein, that contains iodinated groups covalently attached throughout the polymer, such that the polymer contains 70-150 mg / ml iodine.

[0069] In one approach, an effective amount of one or more pharmaceutically active agents can be included in the composition. Since it may be desirable to deliver the active agent from the microsphere, the microsphere may contain such an active agent, which can be bound to or incorporated into the polymer, for example, by ionic interactions.

[0070] In an advantageous embodiment, the microspheres of the present invention have a net charge that allows charged pharmaceutically active agents to be loaded onto the microspheres, for example, by an ion-exchange mechanism. As a result, the therapeutic agent is electrostatically retained within the hydrogel and elutes from the hydrogel in an electrolytic medium, such as saline or in vivo, resulting in sustained release of the drug in blood or tissue over hours, days, or even weeks. In this embodiment, the microspheres of the present invention are particularly useful when they have a net negative charge over a range of pH, including physiological conditions (pH 7.4), so that positively charged drugs can be controllably and reproducibly loaded onto and electrostatically retained within the microspheres for sustained elution from the hydrogel in vivo. Such charges can come from ion-exchange groups, such as carboxyl or sulfonate groups, attached to the polymer matrix. Even drugs that are uncharged at physiological pH can be loaded into the microspheres of the present invention, which is particularly advantageous when rapid elution, or a "burst effect," is desired, e.g., immediately after embolization, or when the low elution properties of the drug under physiological conditions, rather than ionic interactions, determine the release profile of the drug.

[0071] Examples of such compounds include those that suppress plasma ghrelin levels, such as somatostatin and somatostatin analogues, for example octreotide (usually as the acetate salt), amino acids such as L-cysteine ​​(McGavin et al., 2015), or hormones such as insulin (Saad et al., 2002) and GLP-1.

[0072] The population of microspheres described herein typically comprises at least 1000 microspheres, more typically provided in microsphere units with a sedimentation volume of at least 25 or 50 μL, preferably at least 100 μL, more preferably at least 250 μL.

[0073] A third aspect of the present invention provides pharmaceutical compositions comprising a population of microspheres as described herein and a pharmaceutically active agent, such that the therapeutic agent can be absorbed into the microsphere matrix. Such active agents may be present in the population in a pharmacologically effective amount, i.e., the amount of active agent or microspheres necessary to achieve the desired effect from the population of microspheres. Such compositions generally contain the microspheres as described herein and a pharmaceutically acceptable diluent or carrier, typically an aqueous diluent or carrier. The aqueous diluent or carrier is preferably sterile, such as sterile water for injection or saline, and is preferably buffered to an appropriate pH, e.g., between pH 7 and 8, e.g., pH 7.4±0.2. Water for injection or normal saline is common. The diluent or carrier is typically suitable for injection or infusion and, therefore, is typically pyrogen-free, e.g., typically.

[0074] The pharmaceutical composition may also contain additional components such as a contrast agent (either ionic or non-ionic and / or iodized poppy seed oil (an oil-based contrast agent such as Lipiodol®)). Suitable non-ionic contrast agents include iopamidol, iodixanol, iohexol, iopromide, iobtilidol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol, and ioversol. Ionic contrast agents may be used, but are not preferred for use in combination with drug-loaded microspheres, especially if the polymer carries an ionic charge, because high ionic concentrations favor dissociation of the ionic drug from the matrix. Ionic contrast agents include diatrizoate, metrizoate, and ioxaglate.

[0075] Alternatively, the radiopaque hydrogel microspheres of the present invention may be provided in a dry form. If the microspheres or other radiopaque polymeric products are provided dry, it is advantageous to incorporate a pharmaceutically acceptable water-soluble polyol into the polymer prior to drying. This is particularly advantageous for hydrogels, as it protects the hydrogel matrix in the absence of water. Useful polyols are freely water-soluble sugars (mono- or disaccharides), such as glucose, sucrose, trehalose, mannitol, sorbitol, and the like.

[0076] Microspheres can be dried by any process recognized in the art, but drying under vacuum, such as freeze-drying (lyophilization), is advantageous because it allows microspheres to be dried and stored under reduced pressure.This approach provides improved rehydration, as disclosed in International Publication No. 2007 / 147902 (hereby incorporated by reference).Dried microspheres are usually stored at a pressure of less than 1 mBar (gauge).

[0077] Delivery of the microsphere compositions of the present invention to the gastric fundus induces weight loss or reduces the rate of weight gain in a patient. Delivery is typically via a catheter route. Suitable patients include mammalian patients, particularly human patients, although this approach can also be used in other mammalian species, including companion mammals, such as cats, dogs, and horses, to induce weight loss or reduce the rate of weight gain.

[0078] Thus, in a fourth aspect, the present invention provides a method of inducing weight loss or retarding weight gain in a patient, comprising delivering to the capillary bed of the patient's gastric fundus an effective amount of a population of microspheres as described herein. Such compositions may be delivered in the form of pharmaceutical compositions as described herein.

[0079] An effective amount of microspheres is the amount necessary to produce a measurable improvement in the indication being treated. This volume will depend on the patient being treated, but for larger mammals such as humans, it will typically range from 50 to 1000 μL to 1600 μL, preferably 100 to 800 μL, and more preferably 150 to 750 μL, measured as the packed microsphere volume.

[0080] Treatment of a condition in a patient requiring weight loss or reduced rate of weight gain, such as obesity, is also expected to result in a reduction in comorbidities of the condition or a reduced risk of such conditions. Such conditions include chronic conditions such as insulin resistance, type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, sleep apnea, gallbladder disease, hyperuricemia, gout, and osteoarthritis, as well as acute conditions such as stroke. Therefore, in another aspect, the present invention also provides methods for treating these comorbid conditions. Because BAE is known to reduce ghrelin levels, reduce the number of ghrelin-secreting cells in the gastric fundus, and reduce hunger, the present invention also provides methods for reducing blood ghrelin levels, reducing the number of ghrelin-secreting cells in the gastric fundus, and reducing hunger in a patient.

[0081] In a fifth aspect, there is provided use of a composition containing a population of microspheres according to any one of the aspects herein in the manufacture of a medicament for the treatment or prevention of any of the conditions described herein. In a further aspect, there is provided a composition containing a population of microspheres according to any one of the aspects herein for use in any of the methods of treatment described herein. In each case, the method comprises delivering a composition described herein to the capillary bed of the gastric fundus of a subject.

[0082] The present invention will now be further described by the following non-limiting examples, with reference to the drawings, which are provided for illustrative purposes only, and in light of which those skilled in the art will recognize alternatives falling within the scope of the claims. All references cited herein are incorporated by reference.

[0083] Experimental example Example 1: Preparation of microspheres Crosslinked hydrogel microspheres were prepared according to Example 1 (high AMPS) of WO 2004 / 071495. The process was completed by vacuum drying the product to remove residual solvent and then sieving the microspheres to form the appropriate size range. Sieves of 500 μm, 425 μm, 355 μm, 323 μm, 250 μm, 212 μm, and 160 μm were used in sequence, and the microspheres were recovered from the sieves to form the samples used: 355-425 μm ("304"), 250-323 μm ("203"), and 160-212 μm ("102"). The beads were stored dry and, if necessary, acetalized with 2,3,5-triiodobenzaldehyde to form radiopaque iodinated microspheres according to the method described in WO 2015 / 033093.

[0084] Briefly, 1 g of dried microspheres and the appropriate amount of aldehyde (see Table 1 below) were placed in a nitrogen-purged container. 30 mL of anhydrous DMSO was added under a nitrogen blanket and stirred to keep the beads in suspension. The suspension was warmed to 50°C, and 2.2 mL of methanesulfonic acid was slowly added. The reaction slurry was stirred at 50°C for 22 hours while monitoring aldehyde consumption by HPLC. The reaction slurry was then settled, the reaction mixture was removed by suction, and the microspheres were washed five times with 30 mL of DMSO / 0.5% NaCl, followed by five washes with 50 mL of 0.9% NaCl. The washes were performed at 50°C. A 1.5 mL sample of the resulting microspheres was then stored in 5 mL of phosphate-buffered saline.

[0085] [Table 1] The size range of the actual microspheres was determined by measuring the diameter of approximately 200 random microspheres under a microscope, and the results are shown in Figure 1 in comparison with other commercially available cross-linked PVA hydrogel-based microspheres.

[0086] Example 2: Measurement of Elastic Compressibility (ECM) of Microspheres The elastic compressive modulus (ECM) of microspheres may be measured according to the protocols outlined in Cain et al. (2018) and Duran et al. (2016). Cain et al. (2018) also discloses a table of compressive modulus values ​​for various commercially available microspheres. Briefly, ECM was determined using a UNHT Bioindentor system (Anton Paar, Switzerland) operated by proprietary indentation software over a force range of 0.01–20 mN and a displacement range of 1 nm–100 μm. Microsphere samples were dispersed in a dish and submerged in normal saline. Individual microspheres were selected using the instrument's optical microscope, and their diameters were measured to the nearest 1 μm (at 5x magnification). Individual microspheres were compressed at 50 μm / min, followed by a 5-second pause, at which point the sample was unloaded at 50 μm / min. Acquisition was set at 20 Hz. The elastic modulus of each bead was calculated from the load curve by applying linear elastic Hertzian contact mechanics for a sphere compressed between two flat surfaces and was taken as the arithmetic mean of n = 5 replicates over an individual bead diameter compression range of 10–15%.

[0087] The results obtained for the experimental and commercial microsphere samples are shown in Table 2.

[0088] [Table 2] Both Beadblock® and DCBeads® are crosslinked PVA microspheres prepared by crosslinking PVA-N-acryloyl-aminoacetaldehyde dimethyl acetal (NAADA) macromers with 2-acrylamido-2-methylpropanesulfonic acid, as described in WO 2004 / 071495. DCBeadsLumi® is prepared according to DCBeads® and substituted with iodinated phenyl groups, as described in WO 2015 / 033092.

[0089] Example 3: In vivo renal embolization The renal arteries of female Yorkshire pigs weighing approximately 30 kg were embolized according to the following procedure.

[0090] The femoral artery was cannulated using the Seldinger technique under ultrasound guidance. A wire was advanced through the needle of the micropuncture set into the abdominal aorta. The needle was then removed, and a 5-6 French (1.7-2.3 mm) vascular sheath was placed in the femoral artery. IV heparin was administered at 5,000 IU and repeated several hours later if necessary. Under fluoroscopic guidance, a guide catheter was advanced over the wire into the aorta. Angiographic evaluation with iodinated contrast of the renal arteries was performed, and the artery was selected for embolization under fluoroscopic guidance. Nitroprusside (100 mg) was injected intraarterially to prevent vasospasm during selective arterial catheter insertion.

[0091] Embolic microspheres were then injected into the selected vessel using a 2.8 French Renegade® Hi-Flo microcatheter (Boston Scientific), with small droplets delivered intermittently to allow blood flow to deliver the beads to the kidney before administering the next droplet. Animals were then humanely euthanized by saturating overdose of barbiturate-based euthanasia, and the kidneys were removed.

[0092] Serial sections of the kidney were taken at ideal sectioning planes from the upper, lower, and lateral poles, including the collecting duct, medulla, and cortex, and stained with hematoxylin and eosin. The sections were then digitally scanned to assess the furthest penetration of the microspheres.

[0093] When a single microsphere was shown to occlude a vessel, the diameter of the occluded vessel was measured as the inner diameter of the vessel lumen at that site (in the case of transverse vessel sections) or as the smallest axis of the ellipse in oblique sections. In the case of longitudinal sections, the vessel diameter was measured at the level of the largest microsphere. At least 140 vessel diameters per kidney were analyzed.

[0094] Figures 2-4 show permeability data for sample microsphere preparations 102 (129 mg / mL iodine), 304 (113 mg / mL iodine), and a commercially available preparation, Beadblock® 300-500 μm (Biocompatibles UK Ltd).

[0095] (Example 4) Porcine gastric fundus embolization Radiopaque 102 microspheres (95 mg / mL iodine) were injected into the left gastroepiploic artery and the right gastric artery of healthy, growing pigs (~32 kg). These two arteries supply the gastric fundus. The microspheres were delivered at a 1:10 dilution with a non-ionic contrast agent. Three control pigs were sham-treated with saline injections.

[0096] All pigs received 40 mg of oral omeprazole daily from 3 days before BAE until 28 days after BAE as a gastroprotectant to prevent ulcers, as administered in previous studies, or were sham-treated.

[0097] Fasted pigs were sedated with ketamine (100 mg / mL), xylazine, and telazol intramuscularly at 1 mL per 25 kg and induced with propofol (~4 mg / kg) intravenously. General anesthesia was maintained with 1-2% isoflurane (Baxter Healthcare Corp., Deerfield, IL). The pigs were intubated and mechanically ventilated.

[0098] Access to the femoral artery was achieved percutaneously under ultrasound guidance (Zonare Medical Systems, Inc., Mountain View, CA), followed by placement of a 5-French introducer sheath. Under fluoroscopic guidance (Axiom Artis Zee, Forchheim, Germany), a 5-French angiographic guide catheter (Flexion Axis, Surefire Medical, Westminster, CO) was advanced over a 0.035-inch Bentson guidewire (Cook Medical, Bloomington, IN) into the abdominal aorta to select the celiac axis. A pre-embolization digital subtraction angiogram (DSA) of the abdominal cavity was then obtained with a 5-second iohexol injection at 4 mL / sec to map the vessels supplying the gastric fundus. Next, a microcatheter (Renegade®) was advanced over a 0.016-inch (approximately 0.04 cm) Fathom® guidewire (Boston Scientific, Marlborough, MA) into the fundic branch of the gastric artery. DSA of the selected vessel was obtained with gentle hand puffs of 50% iohexol to confirm subselection of the target artery. 100 micrograms of nitroprusside was then delivered to the vessel as a muscle relaxant to prevent spasm during microcatheter deployment. The artery was then embolized with microspheres. After achieving 5 beats of stasis, a second artery was selected and embolized to 5 beats using hand puff DSA. An intermediate single shot was obtained to record the location of the embolic beads. Next, hand puff DSA was obtained to confirm embolization of the target artery. If residual flow beyond 5 beats of stasis was observed, additional emboli were administered. A post-embolization CBCT was obtained to confirm the success of the embolization. Prior to embolization of the next arterial branch, the microcatheter was removed, flushed with saline, and repositioned.

[0099] Body weight was measured at baseline and 1 to 8 weeks after embolization. Digital subtraction angiography (DSA) of the abdominal cavity was obtained before and immediately after embolization and 8 weeks after embolization. Cone-beam CT (CBCT) images of the stomach were obtained immediately after embolization and 8 weeks before disposal. Gastric endoscopy was performed approximately 1 week after embolization to evaluate the effect of the microspheres on the gastric mucosa using a standard adult gastroscope (Pentax, Denver, Colorado).

[0100] Radiopaque microspheres were visualized by CBCT imaging up to 8 weeks after embolization. Endoscopic evaluation at week 1 revealed that all obese embolized animals developed small superficial mucosal ulcers in the fundus or corpus, which healed by week 8, whereas no ulcers developed in control animals. Obese embolized animals showed a significant decrease in the percentage of body weight gain compared with control animals (42.3% ± 5.7 vs. 51.6% ± 2.9, p < 0.001). Figure 5 shows the weight gain progression. This demonstrates that 100-200 μm microspheres are effective in suppressing weight gain in a porcine model. Figure 8 shows the relationship between fundus coverage and weight gain. Data were obtained from cone-beam CT scans of individual animals. Fundus coverage indicates the area of ​​radiopacity within the fundus as a percentage of the total fundus area. Fundus coverage represents the extent of embolization within the fundus region.

[0101] Table 3 shows the incidence of ulcers in the animals over one week.

[0102] [Table 3] *Study animal 3 died within 24 hours of surgery for reasons unrelated to the embolization. Study animal 5 had a large ulcer; it was unclear whether this was related to the treatment. Study animal 5 was euthanized 2 weeks after embolization for issues unrelated to the treatment.

[0103] Example 5: BAE with alternative sized microspheres Example 4 was carried out using commercially available radiopaque microspheres (DC Beads Lumi® nominal size 40-90 μm and nominal size 100-300 μm - Biocompatibles UK Ltd.) Each of these products had 10% or more of the microspheres smaller than 100 μm.

[0104] Table 4 below shows the incidence of ulcers in the animals.

[0105] [Table 4] Ulcer score: no ulcer = 0, small (<=2 cm) = 1, large (>2 cm) = 2, full thickness ulcer = 3.

[0106] S1 animals were treated with DC-beads Lumi® 40-90 μm microspheres delivered to one gastric artery. S2 animals were treated with DC-beads Lumi® 40-90 μm microspheres delivered to two gastric arteries. L2 animals were treated with DC-beads Lumi® 100-300 μm microspheres delivered to two gastric arteries. Figures 6 and 7 show the level of ulceration seen after BAE using the three types of microspheres. (References) Arepally et al (2007) Radiology, 244:138 -143 Bawudun et al (2012) Cardiovasc. Intervent. Radiol. 35:1460-1466.

[0107] Caine et al (2017) Journal of the Mechanical Behavior of Biomedical Materials 78:46-55. Duran et al (2016) Theranostics 6(1): 28-39 Fu et al (2018) Radiology 289(1):83-89.

[0108] Kipshidze et al(2013) Presented at the 62nd Annual Scientific Meeting of the American College of Cardiology; San Francisco, CA. 3 / 10 / 2013. McGavin et al(2015)International Journal of Obesity volume 39、pages 447-455。

[0109] Paxton et al(2013)Radiology 266:471-479. Paxton et al(2014). Vasc. Interv. Radiol. 25: 455-461. Saad et al(2002)JJ. Clin. Endocrinol. Metab.87: 3997–4000.

[0110] Thanoo et al(1991)J. App. Biomaterials, 2: 67-72. Weiss et al(2014)Presented at the 30th Annual Scientific Meeting of the European Society of Interventional Radiology; Glasgow, UK. 9 / 13-17 / 0 (Appendix 1) A composition comprising a population of polymer microspheres comprising a polymer, the population having a unique size distribution in which no more than 10% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 200 μm. (Appendix 2) 2. The composition of claim 1, wherein the microspheres have an average compressive modulus greater than 1000 kPa. (Appendix 3) 2. The composition of claim 1, wherein the microspheres have an average compressive modulus at least 5 times that of Beadblock® 300-500. (Appendix 4) 4. The composition of any one of claims 1 to 3, wherein the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 100 μm and no more than 5% of the microspheres have a diameter greater than 200 μm. (Appendix 5) 4. The composition of any one of claims 1 to 3, wherein the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm. (Appendix 6) 6. The composition of any one of claims 1 to 5, wherein in a pig kidney model, 10% or less of the microspheres have a permeability value of less than 80 μm. (Appendix 7) 6. The composition of any one of claims 1 to 5, wherein no more than 10% of the microspheres have a penetration value greater than 300 μm. (Appendix 8) 6. The composition of any one of claims 1 to 5, wherein no more than 5% of the microspheres have a penetration value less than 80 μm and no more than 5% of the microspheres have a penetration value greater than 300 μm. (Appendix 9) 6. The composition of any one of claims 1 to 5, wherein no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm. (Appendix 10) A composition comprising a population of polymeric microspheres comprising a polymer, wherein in a pig kidney model, no more than 10% of said microspheres have a permeability value of less than 80 μm. (Appendix 11) 11. The composition of claim 10, wherein 10% or less of the microspheres have a penetration value greater than 300 μm. (Appendix 12) 11. The composition of claim 10, wherein no more than 5% of the microspheres have a penetration value less than 80 μm and no more than 5% of the microspheres have a penetration value greater than 300 μm. (Appendix 13) 11. The composition of claim 10, wherein no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm. (Appendix 14) 14. The composition of any one of claims 10 to 13, wherein the microspheres have a unique size distribution in which no more than 10% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 200 μm. (Appendix 15) 13. The composition of any one of claims 9 to 12, wherein the microspheres have a unique size distribution such that no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm. (Appendix 16) 16. The composition of any one of claims 9 to 15, wherein the microspheres have an average compressive modulus greater than 1000 kPa. (Appendix 17) 16. The composition of any one of claims 9 to 15, wherein the microspheres have an average compressive modulus at least 10 times that of Beadblock® 300-500. (Appendix 18) 18. The composition of any one of claims 1 to 17, wherein the polymer is a hydrogel. (Appendix 19) 19. The composition according to any one of claims 1 to 18, wherein the polymer comprises polyvinyl alcohol. (Appendix 20) 20. The composition of any one of claims 1 to 19, wherein the polymer is imageable. (Appendix 21) 21. The composition of any one of claims 1 to 20, wherein the polymer is radiopaque. (Appendix 22) 22. The composition of any one of claims 1 to 21, wherein the polymer comprises 70 to 150 mg of iodine per mL of precipitated microspheres covalently bound to the polymer, preferably 85 to 120 mg / mL, particularly preferably 90 to 110 mg / mL of iodine per mL of precipitated microspheres. (Appendix 23) 23. A pharmaceutical composition comprising a population of polymer microspheres according to any one of claims 1 to 22, and a pharmaceutically acceptable diluent. (Appendix 24) 22. A method of inducing weight loss or delaying weight gain in a patient in need thereof, the method comprising delivering to the capillary bed of the gastric fundus of the patient an effective amount of a population of microspheres according to any one of claims 1 to 22, or a composition comprising an effective amount of the pharmaceutical composition according to claim 23. (Appendix 25) 22. A method of inducing weight loss or delaying weight gain in a patient in need thereof, the method comprising delivering to the capillary bed of the gastric fundus of the patient an effective amount of a population of microspheres according to any one of claims 1 to 22, or a composition comprising an effective amount of the pharmaceutical composition according to claim 23. (Appendix 26) 26. The method of claim 24 or 25, wherein the microspheres are delivered by a transcatheter route. (Appendix 27) 24. The composition of any one of claims 1 to 23, for use in a method for inducing weight loss or delaying weight gain in a patient in need thereof.

Claims

1. 1. A composition for use in therapeutic embolization in the gastric fundus, comprising a population of polymeric microspheres comprised of a polymer, said population of polymeric microspheres having a unique size distribution in which no more than 10% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 200 μm, said polymer comprising polyvinyl alcohol having pendant iodinated aromatic groups.

2. The composition of claim 1 , wherein the microspheres have an average compressive modulus greater than 1000 kPa.

3. 10. The composition of claim 1, wherein the microspheres have an average compressive modulus at least 5 times that of Bead Block® 300-500.

4. 4. The composition of claim 1, wherein the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 100 μm and no more than 5% of the microspheres have a diameter greater than 200 μm.

5. 4. The composition of claim 1, wherein the microspheres have a unique size distribution in which no more than 5% of the microspheres have a diameter less than 120 μm and no more than 10% of the microspheres have a diameter greater than 185 μm.

6. 6. The composition of any one of claims 1 to 5, wherein no more than 10% of the microspheres have a permeation value of less than 80 μm in a pig kidney model.

7. The composition of any one of claims 1 to 5, wherein no more than 10% of the microspheres have a penetration value greater than 300 μm.

8. 6. The composition of any one of claims 1 to 5, wherein no more than 5% of the microspheres have a penetration value less than 80 μm and no more than 5% of the microspheres have a penetration value greater than 300 μm.

9. 6. The composition of any one of claims 1 to 5, wherein no more than 5% of the microspheres have a penetration value less than 90 μm and no more than 5% of the microspheres have a penetration value greater than 250 μm.

10. The composition of any one of claims 1 to 9, wherein the polymer is a crosslinked polymer and the microspheres are hydrogel microspheres.

11. The composition according to any one of claims 1 to 10, wherein the polymer comprises polyvinyl alcohol.

12. The composition of any one of claims 1 to 11, wherein the polymer is imageable.

13. The composition of any one of claims 1 to 12, wherein the polymer is radiopaque.

14. 14. The composition of any one of claims 1 to 13, wherein the polymer comprises 70 to 150 mg of iodine per mL of precipitated microspheres covalently bound to the polymer.

15. A pharmaceutical composition for use in therapeutic embolization in the gastric fundus, comprising a population of polymeric microspheres according to any one of claims 1 to 14 and a pharmaceutically acceptable diluent.

16. 16. The composition of any one of claims 1 to 15 for use in a method for inducing weight loss or delaying weight gain in a subject in need thereof.

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