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(12) Patent Application Publication (10) Pub. No.: US 2014/0296257 A1 Hersel Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0296257 A1 Hersel Et Al US 20140296257A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0296257 A1 Hersel et al. (43) Pub. Date: Oct. 2, 2014 (54) HIGH-LOADING WATER-SOLUABLE Publication Classification CARRIER-LINKED PRODRUGS (51) Int. Cl. A 6LX3/59 (2006.01) A613 L/428 (2006.01) (75) Inventors: Ulrich Hersel, Heidelberg (DE): A647/48 (2006.01) Guillaume Maitro, Mannheim (DE); (52) U.S. Cl. Harald Rau, Dossenheim (DE); Dirk CPC ......... A61 K3I/519 (2013.01); A61K47/48215 Vetter, Heidelberg (DE) (2013.01); A61 K3I/428 (2013.01) USPC ....... 514/259.41: 548/163; 544/282: 514/367 (73) Assignee: Ascendis Pharma A/S, Hellerup (DK) (57) ABSTRACT The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein B, A and Hyp form the (21) Appl. No.: 14/237,429 carrier, B is a branching core, each A is independently a poly(ethylene glycol)-based polymeric chain, each Hyp is (22) PCT Filed: Aug. 10, 2012 independently a branched moiety, each SP is independently a spacer moiety, each L is independently a reversible prodrug (86). PCT No.: PCT/EP2012/065731 linker moiety, each D is independently a biologically active S371 (c)(1), moiety, each X is independently 0 or 1, each m is indepen (2), (4) Date: May 13, 2014 dently an integer of from 2 to 64, n is an integer from 3 to 32: or the pharmaceutically acceptable salt thereof. It further (30) Foreign Application Priority Data relates to pharmaceutical compositions comprising said water-soluble carrier-linked prodrugs, their use as medica Aug. 12, 2011 (EP) .................................. 11177405.5 ment or diagnostic, and methods of treatment. US 2014/02962.57 A1 Oct. 2, 2014 HGH-LOADING WATER-SOLUABLE 0009. A major drawback of predominantly enzymatic CARRIER-LINKED PRODRUGS cleavage is interpatient variability. Enzyme levels may differ significantly between individuals resulting in biological 0001. The present application claims priority from PCT variation of prodrug activation by the enzymatic cleavage. Patent Application No. PCT/EP2012/065731 filed on Aug. The enzyme levels may also vary depending on the site of 10, 2012, which claims priority from German Patent Appli administration. For instance it is known that in the case of cation No. EP 11177405.5 filed on Aug. 12, 2011, the disclo Subcutaneous injection, certain areas of the body yield more sures of which are incorporated herein by reference in their predictable therapeutic effects than others. To reduce this entirety. unpredictable effect, non-enzymatic cleavage or intramo lecular catalysis is of particular interest. FIELD OF THE INVENTION 0010. Therefore, enzyme-independent autocatalytic 0002. It is noted that citation or identification of any docu cleavage of carrier and drug is preferred. In most cases this is ment in this application is not an admission that such docu achieved by an appropriately designed linker moiety between ment is available as prior art to the present invention. the carrier and the drug, which is directly attached to a func 0003 Drugs frequently exhibit short plasma half-life due tional group of a drug via covalent bond. to renal and receptor-mediated clearance, aggregation, pro 0011. A number of such enzyme-independent prodrugs teolytic degradation, poor bioavailability and physical prop suitable for different classes of biologically active moieties erties which preclude efficient formulations. This is highly are known in the art. Examples can be found in the interna undesirable as it leads to the need for frequent and repeated tional patent applications WO-A 2005/099768, WO-A 2006/ administration of the drug, resulting in increased costs and 13565869, WO-A 2009/095479, and WO-A 2011/012722. inconvenience for the patient. 0012 Typically, carrier-linked prodrugs have a stoichiom 0004 One mechanism for enhancing the availability of etry of one drug molecule conjugated to one carrier moiety. drugs is by conjugating them with derivatizing compounds, However, for many medical applications such stoichiometry which include, for example, poly(ethylene glycol) (PEG) and is disadvantageous as large Volumes of Such conjugates poly(propylene glycol). Some of the benefits recognized would have to be applied to a patient to ensure a high enough include lowered immunogenicity and antigenicity, increased dose of drug, causing undue pain and possibly requiring duration of action, and altered pharmacokinetic properties increased amounts of time for the administration process and (Veronese, F. M.. “Enzymes for Human Therapy: Surface thus increasing the costs of the treatment. In Such situations, Structure Modifications.” Chimica Oggi, 7:53-56, 1989). carrier-linked prodrugs in which more than one drug moiety 0005 To enhance physicochemical or pharmacokinetic is conjugated to a carrier molecule might be better Suited as properties of a drug in vivo, drugs can be bound to carriers in they provide a higher drug loading and thus require Smaller a non-covalent way, using physicochemical formulations of Volumes of the pharmaceutical composition to be adminis drug-solvent-carrier mixtures. However, the non-covalent tered to a patient. approach requires a highly efficient drug encapsulation to 0013 Patent U.S. Pat. No. 7,744,861 B2 discloses multi prevent uncontrolled, burst-type release of the drug. Restrain arm prodrugs in which at least three arms extend from a ing the diffusion of an unbound, water Soluble drug molecule branching core and each of these arms carries one drug moi requires strong van der Waals contacts, frequently mediated ety. Similarly, WO-A 2010/019233 discloses multi-arm pro through hydrophobic moieties. Many conformationally sen drugs of which each arm of a carrier moiety is conjugated to sitive drugs, such as proteins or peptides, are rendered dys one drug moiety. Despite the multi-arm backbone structure, functional during the encapsulation process and/or during Such carrier-linked prodrugs still have a relatively low drug Subsequent storage of the encapsulated drug. In addition, load. Such amino-containing drugs readily undergo side reactions 0014 More carrier-linked prodrugs with two polymer with carrier degradation products. Furthermore, dependence based arms are disclosed in WO-A 2008/034119, wherein of the release mechanism of the drug upon biodegradation each arm is attached to a drug moiety, diagnostic agent or may cause interpatient variability. targeting moiety. 0006 Alternatively, the drugs may be conjugated to a car 00.15 Prodrugs of the anti-malaria drug artelinic acid are rier via a transient linker molecule, resulting in carrier-linked disclosed in U.S. Pat. No. 6,461,603 B2. The polymeric pro prodrugs. This approach is applied to various classes of mol drugs are also based on a backbone moiety from which arms ecules, from So-called Small molecules, through natural prod extend which each carry one drug moiety at their terminus. ucts up to larger peptides and proteins. 0016. Another approach to high-loading carrier-linked 0007 Prodrug activation may occur by enzymatic or non prodrugs involves the use of dendrimers. Dendrimers are enzymatic cleavage of the bond between the carrier and the repeatedly branched, roughly spherical, large molecules. drug molecule, or a sequential combination of both, i.e. an Dendrimers have been used to non-covalently embed drug enzymatic step followed by a non-enzymatic rearrangement. moieties and for covalent attachment of drug moieties to the 0008 Enzymatically induced prodrug activation is char termini of the dendrimer. acterized in that the cleavage in enzyme-free in vitro environ (0017 Taite & West (J. Biomater. Sci. Polymer Edn, 2006, ment such as an aqueous buffer Solution, of e.g., an ester or 17, 1159–1172) describe lysine-based dendrimer moieties in amide may occur, but the corresponding rate of hydrolysis which free amines have been converted to diazeniumdiolate may be much too slow and not therapeutically useful. In an NO-donors through the reaction with NO gas. The dendrim in-vivo environment, esterases or amidases are typically ers released NO over a period of 60 days. However, this present and the esterases and amidases may cause significant approach does not allow for the adjustment of release speed as catalytic acceleration of the kinetics of hydrolysis from two no reversible prodrug linkers have been used to attach the NO fold up to several orders of magnitude. Therefore, the cleav to the termini of the dendrimer and this approach is also not age is predominantly controlled by the enzymatic reaction. transferable to other drug moieties. US 2014/02962.57 A1 Oct. 2, 2014 0018 US 2010/0160299 A1 discloses dendrimers to eties. In addition, the poly(ethylene glycol)-based (PEG which therapeutic agents for the reduction and/or elimination based) polymeric chain allows for increased water-solubility. of pain are connected in a reversible manner. Similarly, WO-A 2010/075423 discloses modular dendrimer platforms DETAILED DESCRIPTION OF EMBODIMENTS suitable for the delivery of therapeutic agents, for example. 0036. It is to be understood that the figures and descrip 0019. However, dendrimers typically exhibit a low degree tions of the present invention have been simplified to illustrate of water-solubility. When poorly water-soluble drug moieties elements that are relevant for a clear understanding of the are coupled to the functional groups of Such dendrimers the present invention, while eliminating, for purposes of clarity, resulting conjugates are even less water-soluble. Therefore, many other elements which are conventional in this art. Those although dendrimers provide a high drug loading, their appli of ordinary skill in the art will recognize that other elements cability for prodrug approaches is limited. are desirable for implementing the present invention. How 0020. It is noted that in this disclosure and particularly in ever, because Such elements are well known in the art, and the claims and/or paragraphs, terms such as "comprises'. because they do not facilitate a better understanding of the “comprised', 'comprising and the like can have the meaning present invention, a discussion of Such elements is not pro attributed to it in U.S.
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