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WO 2017/025588 Al 16 February 2017 (16.02.2017) P O P C T

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WO 2017/025588 Al 16 February 2017 (16.02.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/025588 Al 16 February 2017 (16.02.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/127 (2006.01) A61K 47/48 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP20 16/069 107 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 11 August 2016 ( 11.08.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 2015291 11 August 2015 ( 11.08.2015) NL kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: EYESIU MEDICINES B.V. [NL/NL]; J.H. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Oortweg 19, 2333 CH Leiden (NL). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: GAILLARD, Pieter Jaap; Plantsoen 7, 2311 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, KE Leiden (NL). RIP, Jacob; Hartmanstraat 21, 23 13 NA SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Leiden (NL). GW, KM, ML, MR, NE, SN, TD, TG). (74) Agent: NEDERLANDSCH OCTROOIBUREAU; P.O. Published: Box 29720, 2502 LS The Hague (NL). — with international search report (Art. 21(3)) 00 00 o (54) Title: PEGYLATED LIPID NANOPARTICLE WITH BIOACTIVE LIPOPHILIC COMPOUND o (57) Abstract: The invention relates to nanoparticles for the systemic or topical delivery of lipophilic diagnostic or therapeutic agents to a subject in need thereof. The nanoparticles of the invention comprise a water soluble polymer and at least one of a biocompatible lipid and a lipophilic agent. The invention further relates to ophthalmic treatment using the nanoparticles of the in o vention. In addition, the invention pertains to compositions and formulations comprising the nanoparticle of the invention. Such for mulation may be an eye drop formulation. PEGylated lipid nanoparticle with bioactive lipophilic compound Field of the invention The present invention relates to the fields of medicine and pharmacy. In particular the invention relates to the field of drug formulation. The invention relates to nanoparticles with or without a diagnostic or therapeutic agent and comprise a biocompatible lipid and a water soluble polymer. The nanoparticles of the invention can be used for the administration of (highly) lipophilic agents, such as acylethanolamides and/or immunomodulatory macrolides (macrocyclic lactones) like cyclosporines, tacrolimus and/or sirolimus. Preferably, the stable, inert, clear and solvent-free nanoparticles of the invention can be used for ophthalmological, topical or systemic treatments. Background of the invention A major hurdle for the development of drug formulations is the hydrophobic nature of many therapeutic compounds, which hampers the solubility and bioavailability of a drug. To overcome this limitation, numerous new drug formulations are explored, such as liposomes, micelles and emulsions. Examples of such lipophilic therapeutic compounds are macrolides, such as cyclosporine (e.g. cyclosporine A (CsA)), rapamycin/sirolimus (RAP or SIR) and FK506/tacrolimus (TAC), or the like, such as everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, ascomycin, FK1012 or pimecrolimus, or structurally related compounds, or palmitoylethanolamide (PEA). CsA is an immunosuppressant agent widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T-cells. In particular, CsA binds to the cytosolic protein cyclophilin (immunophilin) present in lymphocytes, especially T-cells. This complex of cyclosporin and cyclophilin subsequently inhibits calcineurin, which is responsible for activating the transcription of interleukin 2 and related cytokines. Cyclosporine also inhibits lymphokine production and interleukin release and, therefore, reduces the function of effector T-cells. The first oral CsA formulation introduced into clinical use (Sandimmune) comprised a solution of CsA dissolved in a solvent system of olive oil and ethanol (Patentschrift (Switz.) CH 641 356, Feb. 29, 1984, Appl. 79/1949. Feb. 27, 1979). The oil was emulsified in water using a polyethoxylated oleic glyceride surfactant to give a coarse O/W emulsion. This system was found to be inherently thermodynamically unstable. As a result, the drug tended to precipitate out of solution, and thus not be absorbed. As described for CsA above, similar thermodynamically unstable solutions, leading to drug precipitation are known to occur for other macrolides, such as rapamycin/sirolimus and FK506/tacrolimus, or the like, such as everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, ascomycin, FK1012 or pimecrolimus, or structurally related compounds. Solvent-free formulations with relatively high concentrations of rapamycin and ridaforolimus using micelles with PEG-phospholipid conjugates (such as DSPE- PEG2000) have been described in the art (Remsberg et al, Pharmaceutics 2013, 5, 81-93; Vakil et al, Pharm. Res. 2008, 25, 2056-2064), as well as for a large range of other lipophilic drugs such as palmitoylethanolamide (PEA), miconazole, paclitaxel, docetaxel, nelfmavir mesylate, propofol, diazepam and ixabepilone. However, all these formulations were found to be thermodynamically unstable, both at storage conditions and (once diluted below the critical micelle concentration) in biological fluids. In fact, Remsberg et al. {supra) described that: "For unclear reasons, solubilization of ridaforolimus in DSPE-PEG2000 micelles did not dramatically increase the residence time or the overall systemic exposure of ridaforolimus. This may be indicative of a lack of in vivo stability or an inability to evade the mononuclear phagocyte system." In addition, Vakil et al. {supra) demonstrated that the micellar rapamycin formulation: "however, had no significant effect of the pharmacokinetic disposition of rapamycin with only a longer ti/2 being significant." These results are in accordance with the results found in the Remsberg at al. {supra) study. There clearly is a need in the art for a stable formulation for immunomodulatory macrolides, e.g. in biological fluids, as well as under storage conditions. The lipophilic agent PEA is a fatty acid amide that occurs naturally in humans, and belongs to the class of nuclear factor agonists. PEA has been demonstrated to bind to a nuclear receptor and exerts a great variety of biological functions related to chronic pain and inflammation. Currently, the only available form of this lipophilic drug is micronized, ultramicronized or a cyclodextrin-entrapped form. For example, the ultra- micronized form of palmitoylethanolamide, gives rise to high plasma levels of a metabolite of palmitoylethanolamide, 2-arachidonoylglycerol (2-AG), which is known to be less effective than PEA for the treatment of chronic pain and inflammation. Delivery of lipophilic drugs such as macrolides (e.g. CsA and/or SIR and/or TAC) and/or PEA to the eye is especially challenging, due to the unique protective mechanisms of the eye. In particular, there are three barriers to ocular penetration: The corneal epithelium, the blood-aqueous barrier and the blood-retinal barriers. The common routes of drug administration for the treatment of eye disorders are topical, systemic, periocular and intravitreal. Topical administration is the most preferred route because of the highest patient compliance and the least invasive nature. Upon topical administration, absorption of a drug takes place either through the corneal route (cornea, aqueous humor, intraocular tissues) or noncorneal route (conjunctiva, sclera, choroid/retinal pigment epithelium (RPE)). Only a small fraction of the topically applied drugs, generally less than 5%, reaches the intraocular tissues (Mishra GP et al. J. of Drug Delivery (201 1) 201 1:863734). Factors responsible for poor ocular bioavailability following topical instillation are precorneal drainage and the lipoidal nature of the corneal epithelium. In addition, a major fraction of the drug reaches the systemic circulation through conjunctival vessels and the nasolacrimal duct, which can lead to severe adverse effects. Hence, the topical route has only been successful to a limited extent so far. Systemic administration requires the administration of high doses due to the blood- aqueous barrier and blood-retinal barrier. Such high doses can lead to severe side effects. Furthermore, intravitreal administration requires frequent administration, which may cause susceptibility for vitreous haemorrhage, retinal detachment and endophthalmitis. Thus there is a clear need to improve the delivery of drugs to the eye. The lipophilic drug cyclosporine A (CsA) has been explored for dry
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