(19) TZZ__T (11) EP 1 879 554 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/16 (2006.01) A61P 35/00 (2006.01) 04.03.2015 Bulletin 2015/10 A61K 49/04 (2006.01) A61K 49/18 (2006.01) (21) Application number: 06724766.8 (86) International application number: PCT/EP2006/004334 (22) Date of filing: 09.05.2006 (87) International publication number: WO 2006/119968 (16.11.2006 Gazette 2006/46) (54) COMPOSITIONS AND METHODS USING MICROSPHERES AND NON-IONIC CONTRAST AGENTS ZUSAMMENSETZUNGEN UND VERFAHREN UNTER VERWENDUNG VON MIKROKÜGELCHEN UND NICHTIONISCHEN KONTRASTMITTELN COMPOSITIONS ET PROCEDES D’UTILISATION DE MICROSPHERES ET AGENTS DE CONTRASTE NON IONIQUES (84) Designated Contracting States: (72) Inventor: REB, Philippe AT BE BG CH CY CZ DE DK EE ES FI FR GB GR F-77390 Chaumes-en-Brie (FR) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR (74) Representative: Bradley, Adrian et al Cleveland LLP (30) Priority: 09.05.2005 US 679348 P 10 Fetter Lane London EC4A 1BR (GB) (43) Date of publication of application: 23.01.2008 Bulletin 2008/04 (56) References cited: WO-A-99/12577 WO-A-2004/071495 (60) Divisional application: WO-A2-2005/087193 FR-A1- 2 784 580 11009832.4 / 2 484 344 Remarks: (73) Proprietor: Biosphere Medical, S.A. Thefile contains technical information submitted after 95958 Roissy-Charles-de-Gaulle Cedex (FR) the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 879 554 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 879 554 B1 2 Description cise positioning some visual control is required. There- fore it is desired to use an embolic material that is suitably Field of Invention labeled by the addition of a contrast agent. For reducing the interference with the catheters, solid embolic mate- [0001] The present invention relates to compositions 5 rials are preferred over liquid embolic materials, which and methods for treating diseases and disorders includ- can stick to the catheter. Microspheres have been used ing cancer and various other angiogenic-dependent dis- as a suitable solid material in passive embolization, i.e., eases, vascular malfunctions, arteriovenous malforma- mechanicalocclusion of particularvessels or sites invivo. tions (AVM), hemorrhagic processes and treatment of [0007] A further advantage of microspheres is their po- pain, in particular tumor-related pain by drug delivery 10 tential as agents for drug delivery or for active emboliza- and/or therapeutic embolization using microspheres. tion therapy. In drug delivery, the microspheres are used More particularly the invention relates to microspheres as a carrier for a drug/therapeutic or active agent, which containing non-ionic contrast agents, to compositions is then released from the microspheres at the desired comprising these microspheres, as well as methods for site in vivo, irrespective of whether mechanical blockage preparing and using such compositions for drug delivery 15 is desired or not. In active embolization therapy, the mi- and/or embolization therapy. Furthermore, the invention crospheres have a dual function: mechanical blockage relates to compositions and methods using detectable (embolization) and highly localized, in situ delivery of a microspheres for targeted drug delivery, irrespective of therapeutic agent. This agent can be used, for example, whether embolization is also needed. in the treatment of tumors with a chemotherapeutic or 20 radiotherapeutic agent. This type of regional therapy can Background of Invention localize treatment at the site of the tumor. Potential site effects and damage to healthy tissue can thus be re- [0002] Therapeutic vascular occlusions (emboliza- duced, in particular when using cytotoxic chemothera- tions) are techniques used to treat certain pathological peutic or radiotherapeutic agents. Regional administra- conditions in situ and involve the injection of an embolic 25 tion of the drug/agent (by active embolization or drug material into the vessel of concern. For example, blood delivery) has the further advantage of increasing peak vessels which nourish a tumor are deliberately blocked drug concentrations to the target tissue. This is not only byinjection ofan embolic material intothe vessel.Notably advantageous for the administration of chemotherapeu- in the case of tumors, vascular occlusion can suppress tic or radiotherapeutic agents but also for the administra- pain, limit blood loss on the surgical intervention to follow 30 tion of, for example, chemotherapeutic or pain relieving embolization, or even bring on a tumoral necrosis and drugs. avoid the operation. [0008] However, the type of contrast agent loaded onto [0003] In the case of vascular malformations, such as the microspheres has been found to alter the properties AVM or arteriovenous fistulas, vascular occlusion ena- of the microspheres, such as reducing swellability of bles the blood flow to the tissues to be normalized, aids 35 swellable materials, capacity to load additional compo- in surgery, and limits the risk of hemorrhage. In hemor- nents, such as a drug, or suitability to be injected by a rhagic processes, vascular occlusion produces a reduc- catheter. Therefore, it is advantageous to provide micro- tion of flow, which promotes cicatrization of the arterial spheres suitable for embolization that are not only la- opening(s). beled but that are furthermore still capable of adsorbing [0004] Embolization can be used in the treatment of 40 or otherwise carrying a drug. Similarly, microspheres of uterine fibroids, postpartum and/post-caesarian bleed- the invention are useful for delivery of drugs or other ther- ing, post-surgical vaginal bleeding, the prevention and/or apeutics to particular cells, tissues or organs. treatment of hemorrhage from ectopic pregnancy, [0009] Thus, there is a demonstrated need for the fur- prophilatically prior to myomectomy and in obstetrical pa- ther development of microspheres comprising a contrast tients at high risk for bleeding, such as those patients 45 agent, a drug, and/or another therapeutic agent which with placenta previa, placenta accreta, and twin fetal optionally can swell to sizes greater than their initial size. death. Embolization can also be used to stop uncon- Therefore, it is an object of the present invention to pro- trolled bleeding, or to slow bleeding prior or during sur- vide contrast agent-containing microspheres with supe- gery, and for sealing endoleaks into aneurysm sacs. rior capacities for drug loading and/or delivery. It is an- Each of the above diseases or disorders is within the50 other object of the invention to provide contrast agent- scope of the invention. containing microspheres that have superior swelling [0005] Furthermore, depending on the pathological properties. It is a further object of the invention to provide conditions treated, drug delivery and/or therapeutic em- contrast agent-containing microspheres that have a hy- bolization can be carried out for temporary as well as drogel-like behavior. The contrast agent-containing mi- permanent objectives. 55 crospherescan be suitablein active embolizationtherapy [0006] Embolization is carried out generally by means and/or in drug-delivery, and, in particular, for the treat- of catheters making it possible to position particulate oc- ment of angiogenesis-dependent diseases and/or relief clusion agents (emboli) in the circulatory system. For pre- of tumor-related pain. 2 3 EP 1 879 554 B1 4 Summary of Invention trast agent may have one or more or all of the properties described in the detailed description of the invention. [0010] In therapy, it is generally desirable to use mi- [0017] In one embodiment, the invention provides crospheres that are visible to the practitioner during ad- compositions and methods for delivery of drugs, vac- ministration, and that the microspheres contain a drug 5 cines, polynucleotides, polypeptides, antibodies, which is slowly released at a low concentration so as to polysaccharides, and/or diagnostic or imaging agents to minimize the side-effects associated with the drug. Slow a mammal, using microspheres as a carrier. In a most release is sufficient for the desired treatment since the preferred embodiment, the invention provides micro- microsphere is already at a location or target at which spheres comprising a non-ionic contrast agent for the the drug is to be delivered. Additionally, the microsphere 10 delivery of at least one drug, a contrast agent, or a com- should have superior loading capacities, i.e., the micro- bination thereof. spheres are able to load a maximum amount of the drug [0018] In one embodiment, the invention provides a in the presence of the contrast agent. substantially spherical microsphere suitable for emboli- [0011] The most suitable microspheres for use in ac- zation and/or drug delivery, said microsphere compris- tive embolization and/or drug delivery are based on hy- 15 ing: (a) a biocompatible polymeric material comprising drophilic polymers, such as hydrophilic polymers com- PVA, and (b) a non-ionic contrast agent; wherein the mi- prising hyodroxy and/or amine