US 20200163877A1 IN (19 ) United States (12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0163877 A1 SANTOS et al. (43 ) Pub . Date : May 28 , 2020 (54 ) LIPOSOME FORMULATIONS A61K 39/395 (2006.01 ) A61K 31/58 (2006.01 ) (71 ) Applicant: OPKO Pharmaceuticals , LLC , Miami, A61K 9/00 (2006.01 ) FL (US ) CO7K 16/22 (2006.01 ) (52 ) U.S. Ci. ( 72 ) Inventors : Arturo SANTOS, Zapopan (MX ) ; CPC A61K 9/1271 ( 2013.01 ) ; A61K 45/06 Phillip FROST , Miami Beach , FL (US ) ( 2013.01 ) ; A61K 39/3955 ( 2013.01) ; AIK 2039/55555 (2013.01 ) ; A61K 9/0048 ( 21 ) Appl. No .: 16 /712,261 ( 2013.01 ) ; CO7K 16/22 ( 2013.01) ; A61K 31/58 ( 22 ) Filed : Dec. 12 , 2019 ( 2013.01 ) Related U.S. Application Data ( 57 ) ABSTRACT (62 ) Division of application No. 14 /422,587 , filed on Feb. 19 , 2015 , now Pat. No. 10,548,841, filed as applica tion No. PCT/ US2013 /055084 on Aug. 15, 2013 . The present invention relates to pharmaceutical formula tions comprising an anti angiogenic compound such as a (60 ) Provisional application No. 61/ 862,300 , filed on Aug. monoclonal antibody or fragment thereof selected from , for 5 , 2013 , provisional application No. 61 / 791,693, filed example , ranibizumab , which is a vascular endothelial on Mar. 15, 2013 , provisional application No.61/691 , growth factor binder which inhibits the action of VEGF , and 455 , filed on Aug. 21, 2012 . a delivery agent selected from a pharmaceutically acceptable liposome. The formulations are useful in the treatment of a Publication Classification variety of angiogenic disorders and diseases in animals and (51 ) Int. Ci. people , and , preferably , in ophthalmic disorders selected A61K 9/127 ( 2006.01 ) from age- related macular degeneration diabetic macular A61K 45/06 ( 2006.01) edema and corneal neovascularization . Patent Application Publication May 28 , 2020 Sheet 1 of 7 US 2020/0163877 A1 * S Patent Application Publication May 28 , 2020 Sheet 2 of 7 US 2020/0163877 A1 2. 228 3 12 3 E Patent Application Publication May 28 , 2020 Sheet 3 of 7 US 2020/0163877 A1 Microscopy Pictures of QuSomes ********** Patent Application Publication May 28 , 2020 Sheet 4 of 7 US 2020/0163877 A1 ??????? UV Patent Application Publication May 28 , 2020 Sheet 5 of 7 US 2020/0163877 A1 - Patent Application Publication May 28 , 2020 Sheet 6 of 7 US 2020/0163877 A1 Patent Application Publication May 28 , 2020 Sheet 7 of 7 US 2020/0163877 A1 US 2020/0163877 A1 May 28 , 2020 LIPOSOME FORMULATIONS TIS® is approved for neovascular (wet ) age - related macular degeneration (AMD ) at a dosage strength of 0.5 mg (0.05 CROSS - REFERENCE TO RELATED mL ) by intravitreal injection one a month and , though less APPLICATIONS effective , the approved treatment may be administered to an injection every three months after an initial regimen of once [0001 ] The present application a divisional of U.S. Appli a month for at least four months . LUCENTIS® is also cation No. 14 /422,587 filed Feb. 19 , 2015 , which is a approved in the United States for macular edema following national phase application of PCT /US2013 / 055084 filed on retinal vein occlusion (RVO ) using 0.5 mg (0.05 mL ) on a Aug. 15 , 2013 , which claims priority of U.S. Provisional once - a -month intravitreal regimen . In addition , LUCEN Patent Application Nos. 61/ 862,300 filed on Aug. 5 , 2013 , TIS® is approved in Europe and in the. United States for 61/ 791,693 filed Mar. 15 , 2013 , and 61/ 691,455 filed Aug. diabetic macular edema in the injectable formulation . 21., 2012, which are all incorporated herein by reference in [0004 ] Sunitinib (SU - 11248 , Sutent) , was approved Janu their entirety. ary 2006 by FDA as a monotherapy for the treatment of metastatic renal cell cancer and gastrointestinal stromal FIELD OF THE INVENTION tumors . Sunitinib inhibits at least eight receptor protein [0002 ] The present invention relates to pharmaceutical tyrosine kinases including vascular endothelial growth fac formulations comprising an ophthalmic medication typically tor receptors 1-3 (VEGFR1 - VEGFR3) , platelet - derived applied by intravitreal injection to die eye and a liposomal growth factor receptors (PDGFRa and PDGFRB ). This delivery agent that permits topical application to the eye of compound inhibits angiogenesis by diminishing signaling said intravitreal medication . The present invention also through VEGFRI, VEGFR2 , and PDGFRB . PDGFRB is relates to an anti- angiogenic compound such as a monoclo found in pericytes that surround capillary endothelial cells nal antibody or fragment thereof selected from , for example , (Roskoski , 2007, PDF document attached ). There is evi ranibizumab , which is a vascular endothelial growth factor dence that the combined use of an anti -PDGF is superior to binder which inhibits the action of VEGF, and / or as multi ranibizumab monotherapy in the treatment of some VEGF kinase VEGFR and PDGFR inhibitor, for example , suni related diseases . tinib , and a delivery agent selected from a pharmaceutically [ 0005 ] There are multiple side effects or potential side acceptable liposome. The formulations are useful in the effects including patient discomfort associated with the treatment of a variety of angiogenic disorders and diseases intravitreal injection of anti - VEGF antibodies and other in animals and people , and , preferably , in ophthalmic dis ophthalmic drugs . The intravitreal injection procedure orders selected from age - related macular degeneration , dia requires a dedicated clean room with ordinary aseptic rules ; betic macular edema and corneal neovascularization . resuscitation facilities must be immediately available . Com plications of this procedure include infectious endophthal BACKGROUND OF THE INVENTION mitis ; retinal detachment and traumatic cataract. Other pos [0003 ] Ophthalmic disease treatment typically requires sible complications of intravitreal injection include either topical administration or intravitreal injection of the intraocular pressure changes , especially intraocular pressure particular drug to the eye depending upon the particular elevations injection related intraocular pressure elevations disease or condition and the effectiveness of the route of which can occur immediately after injection of any kind of administration with respect to the particular drug and dis medication and drug specific -related intraocular pressure ease . In certain diseases or conditions of the eye effective changes which may be detected days or even months after treatment can only be achieved if the drug is administered by the injection . See Semin , Ophrhamol . 2009 March - April ;24 intravitreal injection . There are a litany of diseases and ( 2 ) : 100-5 . conditions of the eye that are effectively treated by intrav [0006 ] There is an urgent unmet medical need for new itreal injection . At the same time, these injections can cause topical treatment regimens of such anti - VEGF antibodies and /or are associated with serious side effects including eye and other effective ophthalmic drugs such as antimicrobials , infections ( endophthalmitis ), eye inflammation , retinal antivirals , corticosteroids and anti - vascular endothelial detachments and increases in eye pressure . Because of these growth factor agents which are the main classes of drugs that side effects or risks topical treatment of the eye has been are administered through intravitreal injections. The present both the preferred route of administration of drugs to treat invention comprises a combination of said Liposomes and eye conditions and the Holy Grail because in almost all any of said drugs within said drug classes in a topical cases, topical administration of the drug does not effectively formulation . While U.S. Pat . No. 6,884,879 generally dis treat certain eye conditions, especially those conditions that closes various possible delivery methods or reagents includ occur in the back of the eye . Thus there is a need to develop ing liposomes and various routes of administration including formulations that effectively treat said conditions and that topical administration of such VEGF monoclonal antibod eliminate the need to have intravitreal injections. The pres ies , the only approved form of ranibizumab is the intravitreal ent inventors believe they have found such a vehicle , U.S. form in a liquid formulation . There is a need for topical Pat . No. 6,884,879 discloses various anti - VGF antibodies . ranibizumab formulations that are effective in treating This patent specifically describes and claims the monoclonal people having VEGF related disorders including ophthalmic antibody ranibizumab which is approved and marketed disorders . under the brand name LUCENTIS® . The antibodies dis [ 0007 ] The inventors have met this unmet need and have closed therein are described as being capable of preventing , surprisingly found that certain liposomal formulations com reversing and / or alleviating the symptoms of various dis prising such VEGF monoclonal antibodies and certain lipo eases and are described as having the ability to inhibit somes provide effective relief in patients having diabetic VEGF - induced proliferation of endothelial cells and the macular edema. The formulations can be effectively admin ability to inhibit. VEGF - induced angiogenesis . LUCEN istered topically to the affected eye and are more effective US 2020/0163877 A1 May 28 , 2020 2 than topical application of the intravitreal formulation , U.S. [ 0009] Diabetic retinopathy (DR ) is the most common Pat . No. 6,958,160 discloses