US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015
(54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ...... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ...... 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015
DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds. This approach is DRUGS applied to various classes of molecules, from So-called Small molecules, through natural products up to larger proteins. 0001. The present application is a continuation of U.S. patent application Ser. No. 13/574,092 filed on Jul.19, 2012, 0008 Liraglutide is an example of a peptide drug that which claims priority from PCT Patent Application No. PCT/ achieves an extended half-life by permanent covalent modi EP2011/050821 filed on Jan. 21, 2011, which claims priority fication with a palmitoyl moiety. The fatty acid alkyl chain from European Patent Application No. EP 10 151564.1 filed serves to provide albumin binding in Vivo and the palmitoy on Jan. 22, 2010, the disclosures of which are incorporated lated peptide forms an albumin complex that acts as a drug herein by reference in their entirety. reservoir in the blood stream. 0009 Albuferon is an example of a protein drug that FIELD OF THE INVENTION achieves an extended half-life by permanent covalent modi fication with another protein that in itself has a long half-life. 0002 The present invention is directed to carrier-linked The corresponding fusion protein of albumin and interferon prodrugs having temporary amide linkages between Substi alpha, Albuferon, exhibits a significantly extended half-life as tuted dipeptide moieties and aliphatic amine groups of bio compared to interferon alpha. logically active entities such as peptides, proteins, natural 0010 Many small molecule medicinal agents, like alka products or synthetic chemical compounds. Such carrier loids and anti-tumor agents, show low solubility in aqueous linked prodrugs are characterized by slow release of unmodi fluids. One way to solubilize these small molecule com fied biologically active entity. pounds is to conjugate the Small molecule compounds to 0003. It is noted that citation or identification of any docu hydrophilic (water-soluble) polymers. A variety of water ment in this application is not an admission that such docu soluble polymers, such as human serum albumin, dextran, ment is available as prior art to the present invention. lectins, poly(ethylene glycol) (PEG), poly(styrene-co-maleic 0004 Typically, carriers employed for extended time-ac anhydride), poly(N-hydroxypropylmethacrylamide), poly tion engineering in drug delivery are either used in a non (divinyl ether-co-maleic anhydride), hyaluronic acid have covalent fashion, with the drug physicochemically formu been described for this purpose (R. Duncan, Nature Rev. Drug lated into a solvent-carrier mixture, or by permanent covalent Disc., 2003, 2, 347-360). attachment of a carrier reagent to one of the drug's functional 0011 Covalent modification of biological molecules with groups. poly(ethylene glycol) has been extensively studied since the 0005. Non-covalent drug encapsulation into polymeric late 1970s. So-called PEGylated proteins have shown carriers has been applied to depot formulations for long improved therapeutic efficacy by increasing solubility, reduc acting release profiles. Typically, the drug is mixed with car ing immunogenicity, and increasing circulation half-live in rier material and processed in Such fashion, that the drug Vivo due to reduced renal clearance and proteolysis by becomes distributed inside the bulk carrier. For instance poly mer-drug aggregates may be shaped as microparticles which enzymes (see, for example, Caliceti P., Veronese F. M., Adv. are administered as an injectable Suspension or the polymer Drug Deliv. Rev. 2003, 55, 1261-1277). drug aggregates are formulated as gels which are adminis 0012 However, many biological molecules such as IFN tered in a single bolus injection. Known in the art are also alfa 2, saquinavir or Somatostatin are inactive or show liposomal formulations, where the carrier may be a polymeric decreased biological activity when a carrier is covalently or non-polymeric entity capable of Solubilizing the drug. conjugated to the drug (T. Peleg-Shulman et al., J. Med. Drug release occurs when the carrier Swells or physically Chem., 2004, 47, 4897-4904). deteriorates or chemical degradation allows diffusion of the 0013. In order to avoid shortcomings imposed by either drug to the exterior and Subsequently into the biological envi the non-covalent polymer mixtures or the permanent covalent ronment. Such chemical degradation processes may be auto attachment, it may be preferable to employ a prodrug hydrolytic or enzyme-catalyzed. An example for a marketed approach for chemical conjugation of the drug to the polymer drug based on bolus administration of a drug-polymer gel is carrier. In Such polymeric prodrugs, the biologically active Lupron Depot. An example for a marketed drug based on moieties (drugs, therapeutic, biological molecule, etc.) are Suspended microparticles is Nutropin Depot. An example for typically linked to the polymeric carrier moiety by a tempo a marketed drug based on a liposomal formulation is DOXil. rary bond formed between the carrier moiety and a hydroxy, 0006. A disadvantage of the non-covalent approach is that amino or carboxy group of the drug molecule. in order to prevent uncontrolled, burst-type release of the 0014 Prodrugs are therapeutic agents that are almost inac drug, encapsulation of the drug has to be highly efficient by tive perse but are predictably transformed into active molecu creating a sterically highly crowded environment. Restrain lar entities (see B. Testa, J. M: Mayer in Hydrolysis in Drug ing the diffusion of an unbound, water Soluble drug molecule and Prodrug Metabolism, Wiley-VCH, 2003, page 4). The requires strong van der Waals contacts, frequently mediated carrier prodrug approach may be applied in Such a fashion through hydrophobic moieties. Many conformationally sen that the drug is released in vivo from the polymer in order to sitive drugs, such as proteins or peptides, are rendered dys regain its biological activity. The reduced biological activity functional during the encapsulation process and/or during of the prodrug as compared to the released drug is of advan Subsequent storage of the encapsulated drug. In addition, tage if a slow or controlled release of the drug is desired. In Such amino-containing drugs readily undergo side reactions this case, a relatively large amount of prodrug may be admin with carrier degradation products (see, for example, D. H. Lee istered without concomitant side effects and the risk of over et al., J. Contr. Rel., 2003, 92,291-299). Furthermore, depen dosing. Release of the drug occurs over time, thereby reduc dence of the release mechanism of the drug upon biodegra ing the necessity of repeated and frequent administration of dation may cause interpatient variability. the drug. US 2015/0202317 A1 Jul. 23, 2015
00.15 Prodrug activation may occur by enzymatic or non nucleophilicity as compared to hydroxylic or phenolic enzymatic cleavage of the temporary bond between the car groups. This is particularly true for proteins and peptides rier and the drug molecule, or a sequential combination of which may contain a great variety of different reactive func both, i.e. an enzymatic step followed by a non-enzymatic tionalities, where non-selective conjugation reactions lead to rearrangement. In an enzyme-free in-vitro environment Such undesired product mixtures which require extensive charac as an aqueous buffer Solution, a temporary bond such as an terization or purification and may decrease reaction yield and ester oramide may undergo hydrolysis, but the corresponding therapeutic efficiency of the product. rate of hydrolysis may be much too slow and thus outside the 0022 Amide bonds are usually much more stable against therapeutically useful range. In an in vivo environment, hydrolysis than ester bonds, and the rate of clevage of the esterases or amidases are typically present and the esterases amide bond would be too slow for therapeutic utility in a and amidases may cause significant catalytic acceleration of carrier-linked prodrug. Therefore it is advantageous to add the kinetics of hydrolysis from twofold up to several orders of structural chemical components such as neighbouring groups magnitude (see, for example, R. B. Greenwald et al. J. Med. in order to exert control over the cleavability of the prodrug Chem. 1999, 42 (18), 3857-3867). amide bond. Such additional cleavage-controlling chemical 0016 Prodrugs fall in two classes, bioprecursors and car structures that are provided neither by the carrier entity nor by rier-linked prodrugs. the drug are termed “linkers’. Prodrug linkers can have a 0017 Bioprecursors do not contain a carrier group and are strong effect on the rate of hydrolysis of a given temporary activated by the metabolic creation of a functional group. In bond. Variation of the chemical nature of these linkers allows carrier-linked prodrugs the active Substance is linked to a the engineering of the properties of the linker to a great extent. carrier moiety by a temporary linkage. The carrier may be 0023 Several examples have been published of the pro biologically inert (for instance PEG) or may have targeting drug activation of amine-containing biologically active moi properties (for instance antibodies). This invention is con eties by specific enzymes for targeted release. A prerequisite cerned with polymeric carrier-linked or macromolecular pro for enzymatic dependence is that the structure of the linker drugs, where the carrier itself is a macromolecule Such as a displays a structural motif that is recognized as a Substrate by carrier protein or polysaccharide or poly(ethylene glycol). a corresponding endogenous enzyme. In these cases, the 0018 Cleavage of a carrier prodrug generates a molecular cleavage of the temporary bond occurs in a one-step process entity (drug) of increased bioactivity and at least one side which is catalyzed by the enzyme. G. Cavallaro et al. (Bio product, the carrier. After cleavage, the bioactive entity will conjugate Chem. 2001, 12, 143-151) describe the enzymatic reveal at least one previously conjugated and thereby pro release of an antitumoral agent by the protease plasmin. Cyt tected functional group, and the presence of this group typi arabin is coupled via the tripeptide sequence D-Val-Leu-Lys cally contributes to the drug's bioactivity. to the polymer alpha, beta-poly(N-hydroxyethyl)-DL-aspar 0019. In order to implementaprodrug strategy, at least one tamide (PHEA). Enzymatic release of cytarabin is effected by selected functional group in the drug molecule is employed the protease plasmin which concentration is relatively high in for attachment of the carrier polymer. Preferred functional various kinds of tumor mass. groups are hydroxyl oramino groups. Consequently, both the 0024 Enzyme-catalyzed acceleration of prodrug cleavage attachment chemistry and hydrolysis conditions depend on is a desirable feature for organ or cellular targeting applica the type of functional group employed. tions. Targeted release of the bioactive entity is effected, only 0020 Numerous macromolecular prodrugs are described if an enzyme, that selectively cleaves the linkage, is specifi in the literature where the temporary linkage is a labile ester cally present in the organ or cell-type chosen for treatment. bond. In theses cases, the functional group provided by the 0025. A major drawback of predominantly enzymatic bioactive entity is eithera hydroxyl group or a carboxylic acid cleavage is interpatient variability. Enzyme levels may differ (e.g. Y Luo, M R Ziebell, G D Prestwich, “A Hyaluronic significantly between individuals resulting in biological Acid Taxol Antitumor Bioconjugate Targeted to Cancer variation of prodrug activation by the enzymatic cleavage. Cells’, Biomacromolecules 2000, 1, 208-218, J Cheng et al. The enzyme levels may also vary depending on the site of Synthesis of Linear, beta-Cyclodextrin Based Polymers and administration. For instance it is known that in the case of Their Camptothecin Conjugates, Bioconjugate Chem. 2003, Subcutaneous injection, certain areas of the body yield more 14, 1007-1017, R. Bhatt et al. Synthesis and in Vivo Antitu predictable therapeutic effects than others. To reduce this mor Activity of Poly(L-glutamic acid) Conjugates of 20OS)- unpredictable effect, non-enzymatic cleavage or intramo Campthothecin, J. Med. Chem. 2003, 46, 190-193; R. B. lecular catalysis is of particular interest (see, for example, B. Greenwald, A. Pendri, C. D. Conover, H. Zhao, Y. H. Choe, A. Testa, J. M: Mayer in Hydrolysis in Drug and Prodrug Martinez, K. Shum, S. Guan, J.Med. Chem., 1999, 42,3657 Metabolism, Wiley-VCH, 2003, page 5). 3667; B. Testa, J. M: Mayer in Hydrolysis in Drug and Pro 0026. Furthermore, it is difficult to establish an in vivo-in drug Metabolism, Wiley-VCH, 2003, Chapter 8). vitro correlation of the pharmacokinetic properties for 0021. Especially for therapeutic biomacromolecules but enzyme-dependent carrier-linked prodrugs. In the absence of also for certain Small molecule drugs, it may be desirable to a reliable in vivo-invitro correlation optimization of a release link the carrier to amino groups of the bioactive entity (i.e. profile becomes a cumbersome task. N-terminus or lysine amino groups of proteins). This will be 0027. Other carrier prodrugs employing temporary link the case if masking the drug's bioactivity requires conjuga ages to amino groups present in the drug molecule are based tion of a certain amino group of the bioactive entity, for on a cascade mechanism. Cascade cleavage is enabled by instance anamino group located in an active center or a region linker compounds that are composed of a structural combi or epitope involved in receptor binding. Also, during prepa nation of a masking group and an activating group. The mask ration of the prodrug, the amino groups may be more ing group is attached to the activating group by means of a chemoselectively addressed and serve as a better handle for first temporary linkage Such as an ester or a carbamate. The conjugating the carrier and the drug because of their greater activating group is attached to an amino-group of the drug US 2015/0202317 A1 Jul. 23, 2015 molecule through a second temporary linkage, for instance a enzymatic removal of the ester-linked masking group, a sec carbamate. The stability or susceptibility to hydrolysis of the ond temporary bond cleaves and releases the drug compound. second temporary linkage (e.g. carbamate) is dependent on 0034. D. Shabatetal. (Chem. Eur. J. 2004, 10,2626-2634) the presence or absence of the masking group. In the presence describe a polymeric prodrug system based on a mandelic of the masking group, the second temporary linkage is highly acid activating group. In this system the masking group is stable and unlikely to release the drug with therapeutically linked to the activating group by a carbamate bond. The useful kinetics. In the absence of the masking group, this activating group is conjugated permanently to a polyacryla linkage becomes highly labile, causing rapid cleavage and mide polymer via an amide bond. After enzymatic activation drug release. of the masking group by a catalytic antibody, the masking 0028. The cleavage of the first temporary linkage is the group is cleaved by cyclization and the drug is released. The rate-limiting step in the cascade mechanism. This first step activating group is still connected to the polyacrylamide poly may induce a molecular rearrangement of the activating mer after drug release. group Such as a 16-elimination. The rearrangement renders 0035) M.-R. Lee et al. describe (Angew. Chem. 2004, 116, the second temporary linkage so much more labile that its 1707-1710) a similar prodrug system based on a mandelic cleavage is induced. Ideally, the cleavage rate of the first acid activating group and an enzymatically cleavable ester temporary linkage is identical to the desired release rate for linked masking group. the drug molecule in a given therapeutic scenario. Further 0036. Nevertheless, in these linkers the 1,6-elimination more, it is desirable that the cleavage of the second temporary step still generates a highly reactive aromatic intermediate. linkage is Substantially instantaneous after its lability has Even if the aromatic moiety remains permanently attached to been induced by cleavage of the first temporary bond. the polymeric carrier, side reactions with potentially toxic 0029. Examples of polymeric prodrugs based on 1.6- products or immunogenic effects may be caused. elimination have been described by R. B. Greenwald et al. J. 0037 For these reasons, there is a need to provide novel Med. Chem., 1999, 42,3657-3667& PCT Patent Application linker technologies for forming polymeric prodrugs of amine WO-A-99/30727, F. M. H. DeGroot et al. (WO-A 02/83 180 containing active agents using aliphatic prodrug linkers that and WO-A 04/43493A1), and D. Shabat et al. (WO-A are not enzyme-dependent and do not generate reactive aro 04/19993). matic intermediates during cleavage. 0030 Examples of polymeric amino-containing prodrugs 0038 A. J. Garman et al. (A. J. Garman, S. B. Kalindjan, based on trimethyllocklactonization were described by R. B. FEBS Lett. 1987, 223 (2), 361-365, 1987) use PEG5000 Greenwald et al. J. Med. Chem. 2000, 43(3), 457-487; PCT maleic anhydride for the reversible modification of amino Patent Application No. WO-A-02/089789). In this prodrug groups in tissue-type plasminogen activator and urokinase. system, Substituted o-hydroxyphenyl-dimethylpropionic Regeneration of functional enzyme from PEG-uPA conjugate acid is linked to PEG by an ester, carbonate, or carbamate upon incubation at pH 7.4 buffer by cleavage of the maleamic group as a first temporary linkage and to amino groups of drug acid linkeage follows first order kinetics with a half-life of 6.1 molecules by means of an amide bond as second temporary h. A disadvantage of the maleamic acid linkage is the lack of linkage. The rate-determining step in drug release is the enzy stability of the conjugate at lower pH values. This limits the matic cleavage of the first linkage. This step is followed by applicability of the maleamic acid linkage to active agents which are stable at basic (high) pH values, as purification of fast amide cleavage by lactonization, liberating an aromatic the active agent polymer conjugate has to be performed under lactone side product. basic (high pH) conditions to prevent premature prodrug 0031. The disadvantage in the abovementioned prodrug cleavage. systems described by Greenwald, DeGroot and Shabat is the 0039 More recently, R. B. Greenwaldet al. (Greenwaldet release of highly reactive and potentially toxic aromatic Small al. J. Med. Chem. 2004, 47, 726-734 and WO-A 2004/ molecule side products like quinone methides or aromatic 108070) described a PEG cascade prodrug system based on lactones after cleavage of the temporary linkage. The poten N,N-bis-(2-hydroxyethyl)glycine amide (bicine) linker. In tially toxic entities are released in a 1:1 stoichiometry with the this system two PEG carrier molecules are linked via tempo drug and can assume high in Vivo concentrations. rary bonds to a bicine molecule coupled to an amino group of 0032. A different group of cascade produgs with aromatic the drug molecule. The first two steps in prodrug activation is activating groups based on 1.6-elimination structurally sepa the enzymatic cleavage of the first temporary linkages con rates the masking group and the carrier. This may beachieved necting both PEG carrier molecules with the hydroxy groups by employing a permanent bond between the polymer carrier of the bicine activating group. Different linkages between and the activating group. This stable bond does not participate PEG and bicine are described resulting in different prodrug in the cascade cleavage mechanism. If the carrier is not serv activation kinetics. The second step in prodrug activation is ing as a masking group and the activating group is coupled to the cleavage of the second temporary linkage connecting the the carrier by means of a stable bond, release of potentially bicine activating group to the amino group of the drug mol toxic side products Such as the activating group is avoided. ecule. The main disadvantage of this system is the connection The stable attachment of the activating group and the polymer of the polymer to the bicine linker via temporary bonds and also suppresses the release of drug-linker intermediates with the slow hydrolysis rate of this second temporary bicine undefined pharmacology. amide linkage (t/2>3 h in phosphate buffer) which results in 0033 Antczak et al. (Bioorg Med Chem 9 (2001) 2843 the release of a bicine-modified prodrug intermediate that 48) describe a reagent which forms the basis for a macromo may show different pharmacokinetic, immunogenic, toxicity lecular cascade prodrug system for amine-containing drug and pharmacodynamic properties as compared to the parent molecules. In this approach an antibody serves as the carrier, native drug molecule. a stable bond connects the antibody to an activating group, 0040 Dipeptides are frequently utilized for prodrug carrying an enzymatically cleavable masking group. Upon development for targeting or targeted transport as they are US 2015/0202317 A1 Jul. 23, 2015
Substrates for enzymes or biotransport systems. Less studied PEG chain has to be linked to the peptide without compro is the non-enzymatic route for dipeptide prodrug formation, mising its bioactivity, and it is well known that this is difficult namely the ability to undergo intramolecular cyclization to to achieve for many peptide-based bioactives. Furthermore, form the corresponding diketopiperazine (DKP) and release as the PEGylated peptide is bioactive, it may be expected that the active drug. the dipeptidic promoiety has an effect on the peptide's bio 0041. Such dipeptides may be attached to a drug via ester activity and may negatively affect its receptor binding prop bonds as was described for dipeptide esters of the drug parac erties. As it is well known, that many peptides may interact etamol (Santos, Gomes et al Bioorganic & Medicinal Chem with more than one receptor and that sequence extensions istry Letters, 2005). In this case, the cyclization reaction may affect the balance of Such multiple receptor binding, consists of a nucleophilic attack of the N-terminal amine of unpredictable in vivo performance and even side effects may the peptide on the ester carbon atom to form a tetrahedral OCCU. intermediate. This is followed by a proton transfer from the 0046. It is noted that in this disclosure and particularly in amine to the leaving group oxyanion with simultaneous for the claims and/or paragraphs, terms such as "comprises'. mation of a peptide bond to give the cyclic DKP product and “comprised', 'comprising and the like can have the meaning free drug. The reaction has been described for ester prodrugs attributed to it in U.S. Patent law; e.g., they can mean for example for cyclosporin A (Hamel, AR; Hubler, F: Car “includes”, “included”, “including, and the like; and that rupt, A: Wenger, RM; Mutter, M. J. Pept. Res., vol. 63, num. terms such as "consisting essentially of and "consists essen 2 (2004), p. 147-154). This method is applicable to hydroxyl tially of have the meaning ascribed to them in U.S. Patent containing drugs in vitro but has been found to compete with law, e.g., they allow for elements not explicitly recited, but enzymatic hydrolysis of the ester bond in vivo, as correspond exclude elements that are found in the prior art or that affect ing dipeptide esters released paracetamolata much faster rate a basic or novel characteristic of the invention. than in buffer (Gomes etal, Molecules 12 (2007)2484-2506). 0047. It is further noted that the invention does not intend 0042. The problem of susceptibility of dipeptide-based to encompass within the scope of the invention any previously prodrugs to peptidases may be addressed by incorporating at disclosed product, process of making the product or method least one non-natural amino acid in the dipeptide motif. Cor ofusing the product, which meets the written description and responding prodrugs of cytarabine (Wipfet al. Bioorg. Med. enablement requirements of the USPTO (35 U.S.C. 112, first Chem. 4 (1996) 1585-1596) and cyclosporine A (Hameletal, paragraph) or the EPO (Article 83 of the EPC), such that J. Peptide Res. 63 (2004) 147-154) were synthesized and applicant(s) reserve the right to disclaim, and hereby disclose tested. Still, endogenous enzymes capable of cleaving ester a disclaimer of any previously described product, method of bonds are not limited to peptidases, and the enzyme-depen making the product, or process of using the product. dence of Such prodrug cleavage still gives rise to unpredict able in vivo performance. SUMMARY OF THE INVENTION 0043. Enzyme-dependence by design was engineered into 0048. Therefore, an object of the present invention is to DKP prodrugs as described in U.S. Pat. No. 7,163,923, where dipeptide ester prodrugs were formylated at the amino termi provide carrier-linked prodrug linkers suitable for drugs con nus of the dipeptide, and enzymatic deformylation was used taining aliphatic amine groups from which free drug is as a trigger to set off diketopiperazine formation and Subse released with therapeutically useful half-lives. quent cleavage of the ester-dipeptide bond followed by drug 0049. This object is achieved by a polymeric prodrug or release. Similarly, vinblastine conjugates bearing an oli pharmaceutically acceptable salt thereof comprising a drug gopeptide were described (Brady et al., J. Med. Chem. 45 linker conjugate D-L, wherein (2002) 4706-4715). Here, an octapeptide was attached by an 0050 D is an aliphatic amine containing biologically ester linkage to the 4-hydroxyl group of vinblastine and found active moiety; and to undergo ester bond cleavage by DKP formation after spe 0051 L is a non-biologically active linker containing cific enzymatic removal of the N-terminal hexapeptide. I0052 i) a moiety L' represented by formula (I), 0044 Recently the scope of the DKP formation reaction was extended to amide prodrugs. U.S. Pat. No. 5,952.294 details prodrug activation using diketopiperazine formation (I) for dipeptidyl amide prodrugs of cytarabine. In this case, the temporary linkage was formed between the carbonyl of a dipeptide and the aromatic amino group of cytarabine. In another study, the utility of diketopiperazine activation was demonstrated for even more stable aliphatic amide prodrugs (G. A. R. Y Suaifan et al., Tetrahedron 62 (2006) 11245 11266). Neither of these studies teaches how a slow-release effect can be achieved for Such conjugates as there is no carrier or other half-life extending moiety or functionality present in the compounds disclosed. 0045 WO-A 2009/99763 describes dipeptide prodrugs of bioactive peptides such as GLP-1 capable of releasing the 0053 wherein the dashed line indicates the attachment peptide through diketopiperazine formation of the dipeptidic of L' to an aliphatic amino group of D by forming an extension. In this case, the bioactive peptide moiety may amide bond; carry an additional PEG chain on one of its amino acid side 0054 X is selected from 0, S or CH-R'". chain residues to achieve extended circulation of the bioactive 0055) R' and R'' are independently selected from H, peptide. A significant disadvantage of this approach is that the OH, CH, US 2015/0202317 A1 Jul. 23, 2015
0056 R. R. R. and R“ are independently selected 0068. The present invention addresses the disadvantages from Hand C alkyl, described above. The invention provides for carrier-linked 0057 R. Rare independently selected from H. C. prodrugs characterized by connecting a carrier via a dipeptide alkyl, and R linker to a primary or secondary amino group of an aliphatic 0058 R is selected from amine-containing drug molecule. The carrier is linked to the dipeptide linker via a permanent linkage and the bond between the dipeptide promoiety and the amine-containing drug molecule is a temporary amide linkage that exhibits extended autohydrolysis at a therapeutically useful rate at pH 7.4 and 37°C., i.e. under physiological conditions. 0069. Due to the presence of a permanent bond between co the carrier and the DKP linker, the prodrugs according to the present invention ensure release of unmodified native drug molecules from a stable conjugate comprising carrier and linker moiety. -(o- 0070. It was now surprisingly found, that aliphatic amide bonds can undergo autohydrolysis at a rate that is useful for carrier-linked prodrug applications if cyclization-activation is used as a prodrug principle. In particular detail, it was Surprisingly found that diketopiperazine formation can be NH used for carrier-linked amide prodrugs. Specifically, the link ers used in these carrier-linked amide prodrugs are designed Such that they consist of a carrier permanently attached to a dipeptide motif in Such a fashion that diketopiperazine-for mation can still be employed as a self-activation principle. Suprisingly, in these linker structures, the presence of the carrier entity still allows for therapeutically useful autohy drolysis rates, an essential prerequisite for prodrug applica tions. 0071. In the present application the following terms are used as described below. 0072 “Prodrug: A prodrug is any compound that under goes biotransformation before exhibiting its pharmacological -(NH effects. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient \-s- manner to alter or to eliminate undesirable properties in the parent molecule. 0059 Preferably, one of the pair R/R" is Hand the other (0073 “Promoiety” refers to the part of the prodrug which one is selected from R. is not the biologically active moiety. Promoiety thus refers to 0060 Preferably, one of R/R" is H. the linker and the carrier, if a carrier is present. 0061 Optionally, one or more of the pairs R/R, R/R“, 0074 “Carrier-linked prodrug or “carrier prodrug: A R/R may independently form one or more cyclic fragments carrier-linked prodrug is a prodrug that contains a temporary selected from C, cycloalkyl, 4 to 7 membered heterocyclyl, linkage of a given active Substance with a transient carrier or 9 to 11 membered heterobicyclyl. group that produces improved physicochemical or pharma 0062 Optionally, R. R. R. and R“ are further substi cokinetic properties and that can be easily removed in vivo, tuted; Suitable Substituents are alkyl (such as C. alkyl). usually by a hydrolytic cleavage. alkenyl (Such as Coalkenyl), alkynyl (such as C2-alkynyl), 0075 "Cascade prodrug: A cascade prodrug is a carrier aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky prodrug for which the cleavage of the carrier group becomes nyl, heteroaryl (such as aromatic 4 to 7 membered hetero effective only after unmasking an activating group. cycle) or halogen moieties. 0076 “Polymeric cascade prodrug': A polymeric cascade I0063) ii) a moiety L, which is a chemical bond or a prodrug is a carrier prodrug that contains a temporary linkage spacer, and L is bound to a carrier group Z, of a given active Substance with a transient polymeric carrier I0064 wherein L' is substituted with one to four (pref group for which the cleavage of the carrier becomes effective erably one) Limoieties, only after unmasking an activating group. 0065 Z is PEG or a hydrogel, more preferably Z is a 0077 "Bioprecursor prodrug': A bioprecursor prodrug is hydrogel, even more preferably Z is a PEG-based hydro a prodrug that does not imply the linkage to a carrier group, gel: but results from a molecular modification of the active prin 0.066 optionally, L is further substituted. ciple itself. This modification generates a new compound, 0067 Suitable substituents are alkyl (such as C. alkyl). able to be transformed metabolically or chemically, the alkenyl (Such as Coalkenyl), alkynyl (such as C2-alkynyl), resulting compound being the active principle. aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalky 0078 “Biotransformation: Biotransformation is the nyl, heteroaryl (such as aromatic 4 to 7 membered hetero chemical conversion of Substances by living organisms or cycle) or halogen moieties. enzyme preparations. US 2015/0202317 A1 Jul. 23, 2015
0079. The previous definitions are based on IUPAC, as methacrylates), poly(hydroxypropyloxazolines), poly(imi given under http://www.chem.qmul.ac.uk/iupac/medchem/ nocarbonates), poly(lactic acids), poly(lactic-co-glycolic (accessed on 8 Mar. 2004) acids), poly(methacrylamides), poly(methacrylates), poly 0080) “Linker: Cleavage-controlling chemical structures (methyloxazolines), poly(organophosphaZenes), poly(ortho or groups present in carrier prodrugs that are not provided by esters), poly(oxazolines), poly(propylene glycols), poly(si either the carrier entity or by the drug. loxanes), poly(urethanes), poly(Vinyl alcohols), poly(vinyl 0081. “Sustained release' or “substained release rate' amines), poly(vinylmethylethers), poly(Vinylpyrrolidones), means that the administration intervals of the respective pro silicones, celluloses, carbomethyl celluloses, hydroxypropyl drug are expanded. Drugs with a daily dosage may for methylcelluloses, chitins, chitosans, dextrans, dextrins, gela example be turned into a Sustained release form with a week tins, hyaluronic acids and derivatives, mannans, pectins, long or even longer interval between two administrations. rhamnogalacturonans, starches, hydroxyalkyl starches, 0082. A strong in vivo/in vitro correlation is observed, if hydroxyethyl starches and other carbohydrate-based poly the release kinetics exhibited by a hydrogel prodrug conju mers, Xylans, and copolymers thereof. gate according to the present invention has a half-life in vivo 0090 Suitable carriers can either be directly conjugated to that is not smaller than half the value exhibited by the same the linker or via a non-cleavable spacer. The term “polymer hydrogel prodrug conjugate in aqueous buffer of pH 7.4 at 37° prodrug” refers to carrier-linked prodrugs of a biologically C. active agent, wherein the carrier is a polymer. 0.083 “Cis-amide conformation inducer refers to a moi 0091. The term polymer describes a molecule comprised ety that stabilizes the preceeding cis-amide bond. Suitable of repeating structural units connected by chemical bonds in cis-amide conformation inducers are, for example, a linear, circular, branched, crosslinked or dendrimeric way pseudoprolines. or a combination thereof, which can be of synthetic or bio 0084 Aliphatic amine containing biologically active logical origin or a combination of both. Typically, a polymer moiety D' means the part, e.g. the moiety or fragment, of the has a molecular weight of at least 1 kDa. drug linker conjugate D-L, which results after cleavage in the drug D-H, the active agent, of known biological activity. In 0092. More preferably, Z is a biodegradable polyethylene addition, the Subterm “aliphatic amine containing' means glycol based water-insoluble hydrogel. that the respective moiety D and analogously the correspond 0093. The term “water-insoluble” refers to a swellable ing drug D-H contains at least one aliphatic fragment, and three-dimensionally crosslinked molecular network forming which at least one aliphatic fragment is substituted with at the hydrogel. The hydrogel if suspended in a large Surplus of least one amino group. water or aqueous buffer of physiological osmolality may take 0085 “Non-biologically active linker” means a linker up a substantial amount of water, e.g. up to 10-fold on a which does not show pharmacological effects. weight per weight basis, and is therefore swellable but after I0086) “Biologically active moiety D' means the part of the removing excess water still retains the physical stability of a drug linker conjugate, which results after cleavage in a drug gel and a shape. Such shape may be of any geometry and it is D-H of known biological activity. understood that such an individual hydrogel object is to be 0087 Suitable carriers are polymers and can either be considered as a single molecule consisting of components directly conjugated to the linker or via a non-cleavable spacer. wherein each component is connected to each other compo The term “prodrug according to the invention” refers to car nent through chemical bonds. rier-linked prodrugs of biologically active agents, wherein the (0094. The term “PEG or “pegylation residue” is used carrier is PEG or a hydrogel, preferably a PEG-based hydro herein exemplary for suitable water-soluble polymers char gel. The terms “PEG prodrug”, “PEG-linked prodrug’. acterized by repeating units. Suitable polymers may be “hydrogel prodrug and “hydrogel-linked prodrug” refer to selected from the group consisting of polyalkyloxy polymers, prodrugs of biologically active agents transiently linked to a hyaluronic acid and derivatives thereof, polyvinyl alcohols, PEG or to a hydrogel, respectively, and are used synony polyoxazolines, polyanhydrides, poly(ortho esters), polycar mously. bonates, polyurethanes, polyacrylic acids, polyacrylamides, I0088. The term “polyethylene glycol based” or “PEG polyacry-lates, polymethacrylates, polyorganophosp based as understood herein means that the mass proportion haZenes, polysiloxanes, polyvinylpyrrolidone, polycy of PEG chains or in the hydrogel is at least 10% by weight, anoacrylates, and polyesters. Preferred are polyalkyloxy preferably at least 25%, based on the total weight of the polymers, especially polyethylene glycol polymers contain hydrogel. The remainder can be made up of other polymers. ing at least 10% by weight ethylene oxide units, more pref 0089. Such other polymers are preferably selected from erably at least 25% by weight, even more preferably at least the group consisting of for example, 2-methacryloyl-oxy 50% by weight ethyl phosphoyl cholins, hydrogels, PEG-based hydrogels, 0.095 A “hydrogel' may be defined as a three-dimen poly(acrylic acids), poly(acrylates), poly(acrylamides), poly sional, hydrophilic or amphiphilic polymeric network (alkyloxy) polymers, poly(amides), poly(amidoamines), capable of taking up large quantities of water. The networks poly(amino acids), poly(anhydrides), poly(aspartamides), are composed of homopolymers or copolymers, are insoluble poly(butyric acids), poly(glycolic acids), polybutylene due to the presence of covalent chemical or physical (ionic, terephthalates, poly(caprolactones), poly(carbonates), poly hydrophobic interactions, entanglements) crosslinks. The (cyanoacrylates), poly(dimethylacrylamides), poly(esters), crosslinks provide the network structure and physical integ poly(ethylenes), poly(ethyleneglycols), poly(ethylene rity. Hydrogels exhibit a thermodynamic compatibility with oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly water which allows them to swell in aqueous media. The (glycolic acids), poly(hydroxyethyl acrylates), poly(hy chains of the network are connected in Such a fashion that droxyethyloxazolines), poly(hydroxymethacrylates), poly pores exist and that a Substantial fraction of these pores are of (hydroxypropylmethacrylamides), poly(hydroxypropyl dimensions between 1 nm and 1000 nm. US 2015/0202317 A1 Jul. 23, 2015
0096) “Free form” of a drug refers to the drug in its 0106 “Clso alkenyl' means a branched or unbranched unmodified, pharmacologically active form, such as after alkenyl chain having 2 to 50 carbon atoms (unsubstituted being released from a polymer conjugate. Clso alkenyl), e.g. if present at the end of a molecule: 0097. The terms “drug”, “biologically active molecule', -CH=CH, -CH=CH-CH, -CH-CH=CH, “biologically active moiety”, “biologically active agent'. -CH=CH-CH CH-CH=CH-CH=CH, or e.g. “active agent’, and the like mean any Substance which can —CH=CH , when two moieties of a molecule are linked affect any physical or biochemical properties of a biological by the alkenyl group. Optionally, each hydrogen of a C-so organism, including but not limited to viruses, bacteria, fungi, alkenyl carbon may be replaced by a substituent as further plants, animals, and humans. In particular, as used herein, specified. Accordingly, the term “alkenyl relates to a carbon biologically active molecules include any substance intended chain with at least one carbon double bond. Optionally, one or for diagnosis, cure, mitigation, treatment, or prevention of more triple bonds may occur. The term Calkenyl is defined disease in humans or other animals, or to otherwise enhance accordingly. physical or mental well-being of humans or animals. 0107 “Clso alkynyl means a branched or unbranched 0098. The terms “spacer” or “spacer moieties” refer to any alkynyl chain having 2 to 50 carbon atoms (unsubstituted moiety Suitable for connecting two moieties, such as Clso Clso alkynyl), e.g. if present at the end of a molecule: alkyl, Clso alkenyl or Clso alkinyl, which fragment is -C=CH, -CH C=CH, CH-CH C=CH, CH optionally interrupted by one or more groups selected from C=C CH, or e.g. —C=C when two moieties of a mol —NH-, -N (C. alkyl)-, —O— —S , —C(O)—, ecule are linked by the alkynyl group. Optionally, each hydro —C(O)NH , —C(O)N(C. alkyl)-, —O—C(O)—, gen of a C-so alkynyl carbon may be replaced by a Substituent —S(O)— —S(O). , 4 to 7 membered heterocyclyl phenyl as further specified. Accordingly, the term “alkynyl relates to or naphthyl. a carbon chain with at lest one carbon carbon triple bond. 0099. “Functional groups' mean groups of atoms within Optionally, one or more double bonds may occur. The term molecules that exhibit a specific chemical activity. Examples C- alkynyl is defined accordingly. are amides, amines, alcohols, carbonyls, carboxylic acids, 0.108 “C., cycloalkyl or “C., cycloalkyl ring” means a thiols. cyclic alkyl chain having 3 to 7 carbon atoms, which may 0100 “Protective groups' refers to a moiety which tem have carbon-carbon double bonds being at least partially satu porarily protects a functional group of a molecule during rated (unsubstituted C-cycloalkyl), e.g. cyclopropyl. synthesis to obtain chemoselectivity in Subsequent chemical cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohep reactions. Protective groups for alcohols are, for example, tyl. Optionally, each hydrogen of a cycloalkyl carbon may be benzyl and trityl, protective groups for amines are, for replaced by a substituent. The term “C., cycloalkyl or “C., example, tert-butyloxycarbonyl, 9-fluorenylmethyloxycar cycloalkyl ring also includes bridged bicycles like norbo bonyl and benzyl and for thiols examples of protective groups nane (norbonanyl) or norbonene (norbonenyl). Accordingly, are 2,4,6-trimethoxybenzyl, phenylthiomethyl, acetamidom “Cs cycloalkyl means a cycloalkyl having 3 to 5 carbon ethyl, p-methoxybenzyloxycarbonyl, tert-butylthio, triph atOmS. enylmethyl, 3-nitro-2-pyridylthio. 4-methyltrity1. 0109) “Halogen' means fluoro, chloro, bromo or iodo. It is 0101) “Protected functional groups' means a functional generally preferred that halogen is fluoro or chloro. group protected by a protective group. 0110. “4 to 7 membered heterocyclyl or “4 to 7 mem 0102) Acylating agent’ means a moiety of the structure bered heterocycle” means a ring with 4, 5, 6 or 7 ring atoms R—(C=O)—, providing the acyl group in an acylation reac that may contain up to the maximum number of double bonds tion, optionally connected to a leaving group, such as acid (aromatic or non-aromatic ring which is fully, partially or chloride, N-hydroxy succinimide, pentafluorphenol and un-saturated) wherein at least one ring atom up to 4 ring para-nitrophenol. atoms are replaced by a heteroatom selected from the group 0103 “Alkyl means a straight-chain or branched carbon consisting of sulfur (including —S(O)— —S(O) ), oxy chain (unsubstituted alkyl). Optionally, each hydrogen of an gen and nitrogen (including=N(O)—) and wherein the ring alkyl carbon may be replaced by a substituent. is linked to the rest of the molecule via a carbon or nitrogen 0104. “Heteroalkyl refers to analogs of alkyls in which atom (unsubstituted 4 to 7 membered heterocyclyl). one or more than one methylene group is replaced by a het 0111 Examples for a 4 to 7 membered heterocycles are eroatom, such as nitrogen, oxygen, Sulfur, phosphorus, or aZetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrro boron. If the methylene group is replaced by nitrogen, phos line, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, phorous or boron, these heteroatoms may be further substi oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, tuted. Suitable substituents are alkyl, alkenyl, alkynyl, aryl, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahy heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl or halo drofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, gen moieties (such as those described above). The terms pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, heteroalkenyl and heteroalkynyl are defined accordingly. isothiazolidine, thiadiazolidine, Sulfolane, pyran, dihydropy 0105 “C. alkyl means an alkyl chain having 1 to 4 ran, tetrahydropyran, imidazolidine, pyridine, pyridazine, carbon atoms (unsubstituted C. alkyl), e.g. if present at the pyrazine, pyrimidine, piperazine, piperidine, morpholine, tet end of a molecule: methyl, ethyl, n-propyl, isopropyl. n-butyl, razole, triazole, triazolidine, tetrazolidine, diazepane, isobutyl, sec-butyl tert-butyl, or e.g. —CH2—, —CH2— azepine or homopiperazine. Optionally, each hydrogen of a 4 CH2—, —CH(CH)—, CH2—CH2—CH2—, CH to 7 membered heterocyclyl may be replaced by a substituent. (CHs)— —C(CH) , when two moieties of a molecule (O112 “9 to 11 membered heterobicyclyl” or “9 to 11 mem are linked by the alkyl group. Optionally, each hydrogen of a bered heterobicycle” means a heterocyclic system of two C. alkyl carbon may be replaced by a Substituent. Accord rings with 9 to 11 ring atoms, where at least one ring atom is ingly, "Clso alkyl means an alkyl chain having 1 to 50 shared by both rings and that may contain up to the maximum carbon atoms. The term C is defined accordingly. number of double bonds (aromatic or non-aromatic ring US 2015/0202317 A1 Jul. 23, 2015
which is fully, partially or un-saturated) wherein at least one ents, for example a drug or a prodrug, and one or more inert ring atom up to 6 ring atoms are replaced by a heteroatom ingredients, as well as any product which results, directly or selected from the group consisting of Sulfur (including indirectly, from combination, complexation or aggregation of —S(O)— —S(O) ), oxygen and nitrogen (including any two or more of the ingredients, or from dissociation of —N(O)—) and wherein the ring is linked to the rest of the one or more of the ingredients, or from other types of reac molecule via a carbon or nitrogenatom (unsubstituted 9 to 11 tions or interactions of one or more of the ingredients. membered heterobicyclyl). Accordingly, the pharmaceutical compositions of the present 0113. Examples for a 9 to 11 membered heterobicycle are invention encompass any composition made by admixing a indole, indoline, benzofuran, benzothiophene, benzoxazole, prodrug of the present invention and a pharmaceutically benzisoxazole, benzothiazole, benzisothiazole, benzimida acceptable excipient. Zole, benzimidazoline, quinoline, quinazoline, dihydro 0117 “Stable” and “stability” means that within the indi quinazoline, quinoline, dihydroquinoline, tetrahydroquino cated storage time the polymer conjugates remain conjugated line, decahydroquinoline, isoquinoline, and do not hydrolyze to a substantial extent and exhibit an decahydroisoquinoline, tetrahydroisoquinoline, dihydroiso acceptable impurity profile relating to the biologically active quinoline, benzazepine, purine or pteridine. The term 9 to 11 agent. To be considered stable, the composition contains less membered heterobicycle also includes spiro structures of two than 10 A, preferably less than 5% of the drug in its free rings like 1,4-dioxa-8-azaspiro4.5 decane orbridged hetero form. cycles like 8-aza-bicyclo[3.2.1]octane. Optionally, each 0118 “Therapeutically effective amount’ means an hydrogen of a 9 to 11 membered heterobicyclyl may be amount sufficient to cure, alleviate or partially arrest the replaced by a substituent. clinical manifestations of a given disease and its complica 0114. In case the prodrugs according to the present inven tions. An amount adequate to accomplish this is defined as tion contain one or more acidic or basic groups, the invention “therapeutically effective amount’. Effective amounts for also comprises their corresponding pharmaceutically or toxi each purpose will depend on the severity of the disease or cologically acceptable salts, in particular their pharmaceuti injury as well as the weight and general state of the Subject. It cally utilizable salts. Thus, the prodrugs which contain acidic will be understood that determining an appropriate dosage groups can be used according to the invention, for example, as may beachieved using routine experimentation, by construct alkali metal salts, alkaline earth metal salts or as ammonium ing a matrix of values and testing different points in the salts. More precise examples of Such salts include sodium matrix, which is all within the ordinary skills of a trained salts, potassium salts, calcium salts, magnesium salts or salts physician. Within the scope of this invention, therapeutically with ammonia or organic amines such as, for example, ethy effective amount relates to dosages that aim to achieve thera lamine, ethanolamine, triethanolamine or amino acids. Pro peutic effect for an extended period of time, i.e. for 12 hours, drugs which contain one or more basic groups, i.e. groups or 24 hours, or three days or longer, for instance one week or which can be protonated, can be present and can be used two weeks. according to the invention in the form of their addition salts 0119) “Excipients’ refers to compounds administered with inorganic or organic acids. Examples for Suitable acids together with the therapeutic agent, for example, buffering include hydrogen chloride, hydrogen bromide, phosphoric agents, isotonicity modifiers, preservatives, stabilizers, anti acid, Sulfuric acid, nitric acid, methanesulfonic acid, p-tolu adsorption agents, oxidation protection agents, or other aux enesulfonic acid, naphthalenedisulfonic acids, oxalic acid, iliary agents. However, in some cases, one excipient may have acetic acid, tartaric acid, lactic acid, Salicylic acid, benzoic dual or triple functions. acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid. Succinic acid, pimelic acid, fumaric acid, I0120 "Dry composition” means that the prodrug compo maleic acid, malic acid, Sulfaminic acid, phenylpropionic sition is provided in a dry form in a container. Suitable meth acid, gluconic acid, ascorbic acid, isonicotinic acid, citric ods for drying are spray-drying and lyophilization (freeze acid, adipic acid, and other acids known to the person skilled drying). Such dry composition of prodrug has a residual water in the art. If the prodrugs simultaneously contain acidic and content of a maximum of 10%, preferably less than 5% and basic groups in the molecule, the invention also includes, in more preferably less than 2% (determined according to Karl addition to the salt forms mentioned, inner salts or betaines Fischer). The preferred method of drying is lyophilization. (Zwitterions). The respective salts of the prodrugs of the I0121 “Lyophilized composition” means that the prodrug present invention can be obtained by customary methods composition was first frozen and Subsequently subjected to which are known to the person skilled in the art like, for water reduction by means of reduced pressure. This terminol example by contacting these with an organic or inorganic acid ogy does not exclude additional drying steps which occur in or base in a solvent or dispersant, or by anion exchange or the manufacturing process prior to filling the composition cation exchange with other salts. The present invention also into the final container. includes all salts of the prodrugs which, owing to low physi 0.122 “Lyophilization' (freeze-drying) is a dehydration ological compatibility, are not directly Suitable for use in process, characterized by freezing a composition and then pharmaceuticals but which can be used, for example, as inter reducing the Surrounding pressure and, optionally, adding mediates for chemical reactions or for the preparation of heat to allow the frozen water in the composition to sublime pharmaceutically acceptable salts. directly from the solid phase to gas. Typically, the sublimed 0115 The term “pharmaceutically acceptable” means water is collected by desublimation. approved by a regulatory agency, Such as the EMEA (Europe) I0123 “Reconstitution” means the addition of a liquid to and/or the FDA (US) and/or any other national regulatory bring back the original form of a composition. agency for use in animals, preferably in humans. 0.124 “Reconstitution solution” refers to the liquid used to 0116 “Pharmaceutical composition” or “composition s reconstitute the dry composition of a prodrug prior to admin means a composition containing one or more active ingredi istration to a patient in need thereof. US 2015/0202317 A1 Jul. 23, 2015
0.125 “Container” means any container in which the pro bamates, combinations thereof, and the like. Preferred biode drug composition is comprised and can be stored until recon gradable linkages are esters, carbonates, phosphoesters and stitution. Sulfonic acid esters and most preferred are esters or carbon 0126) “Buffer” or “buffering agent” refers to chemical ates. It is understood that for in vitro studies accelerated compounds that maintain the pH in a desired range. Physi conditions like, for example, pH 9, 37° C., aqueous buffer, ologically tolerated buffers are, for example, Sodium phos may be used for practical purposes. phate. Succinate, histidine, bicarbonate, citrate and acetate, Sulphate, nitrate, chloride, pyruvate. Antacids such as DETAILED DESCRIPTION OF EMBODIMENTS Mg(OH), or ZnCO may be also used. Buffering capacity may be adjusted to match the conditions most sensitive to pH 0.136. It is to be understood that the descriptions of the stability. present invention have been simplified to illustrate elements 0127. A “lyoprotectant” is a molecule which, when com that are relevant for a clear understanding of the present bined with a protein of interest, significantly prevents or invention, while eliminating, for purposes of clarity, many reduces chemical and/or physical instability of the protein other elements which are conventional in this art. Those of upon drying in general and especially during lyophilization ordinary skill in the art will recognize that other elements are and Subsequent storage. Exemplary lyoprotectants include desirable for implementing the present invention. However, Sugars, such as Sucrose or trehalose; amino acids such as because Such elements are well known in the art, and because monosodium glutamate or histidine; methylamines such as they do not facilitate a better understanding of the present betaine; lyotropic salts such as magnesium sulfate; polyols invention, a discussion of Such elements is not provided Such as trihydric or higher Sugar alcohols, e.g. glycerin, eryth herein. ritol, glycerol, arabitol. Xylitol, Sorbitol, and mannitol; ethyl 0.137 The present invention will now be described in ene glycol, propylene glycol; polyethylene glycol; pluronics; detail on the basis of exemplary embodiments. hydroxyalkyl starches, e.g. hydroxyethyl starch (HES), and 0.138. In the present invention, the hydrolytic lability combinations thereof. required for a temporary linkage may be introduced into the 012.8 “Surfactant refers to wetting agents that lower the prodrug amide bond by selecting the structural properties of Surface tension of a liquid. the linker for cyclization activation. In cyclization-activated 0129. “Isotonicity modifiers’ refer to compounds which amide bond cleavage, the cleavage products are a free amine minimize pain that can result from cell damage due to osmotic as part of the biologically active moiety and a cyclized resi pressure differences at the injection depot. due. The linker structures of the present invention are 0130. The term “stabilizers’ refers to compounds used to designed Such that highly stable rings are formed as cleavage stabilize the polymer prodrug. Stabilisation is achieved by products and the hydrolysis of the prodrug amide bond facili strengthening of the protein-stabilising forces, by destabili tates hydrolysis in a time range useful for drug delivery under sation of the denatured state, or by direct binding of excipi physiological conditions. Preferred cyclic cleavage products ents to the protein. are diketopiperazine rings. Prerequisite for Such cyclization 0131 “Anti-adsorption agents’ refers to mainly ionic or activation is the presence of an amine-containing nucleophile non-ionic Surfactants or other proteins or Soluble polymers in the linker structure and anotheramide bond which is not the used to coat or adsorb competitively to the inner surface of the temporary amide prodrug bond but a permanent amide bond. composition’s container. Chosen concentration and type of Preferably, such linker structures contain a cis-amide confor excipient depends on the effect to be avoided but typically a mation inducer. Alternatively, the cleavage might occur monolayer of surfactant is formed at the interface just above through intramolecular catalysis caused by neighbouring the CMC value. group effects. 0132 “Oxidation protection agents' refers to antioxidants 0.139. In case of diketopiperazine-activated prodrug cleav Such as ascorbic acid, ectoine, glutathione, methionine, age, the amine-containing nucleophile serves to attack the monothioglycerol, morin, polyethylenimine (PEI), propyl prodrug amide carbonyl group and consequently induces gallate, Vitamin E, chelating agents such aus citric acid, transamidation, and the permanentamide bond serves to form EDTA, hexaphosphate, thioglycolic acid. a stabilized six-membered ring structure. 0133) “Antimicrobial refers to a chemical substance that 0140. The formation of the stabilized six-membered ring kills or inhibits the growth of microorganisms, such as bac structure is facilitated through a cis-amide conformation teria, fungi, yeasts, protozoans and/or destroys viruses. inducing pseudoproline. Pseudoprolines are artificially cre 0134) “PEG based' as understood herein means that the ated dipeptides, which contain an oxazolidine orthiazolidine mass proportion of PEG chains in the hydrogel is at least 10% ring. In peptide synthesis, pseudoprolines are used to increase by weight, preferably at least 25%, based on the total weight solvation and solubility. Due to the preference for a cis-amide of the hydrogel. The remainder can be made up of other bond with the preceding residue of C2-substituted spacers and/or oligomers or polymers, such as oligo- or polyl pseudoprolines, their incorporation results in a kink confor ysines. mation of the peptide backbone which decreases aggregation, 0135. The term “hydrolytically degradable' or “biode self-association and p-structure formation. gradable' refers within the context of the present invention to 0141 Preferred linker structures are composed of a dipep linkages which are non-enzymatically hydrolytically degrad tide promoiety conjugated through a permanent linkage to a able under physiological conditions (aqueous buffer at pH polymer carrier. Corresponding prodrugs are composed of a 7.4, 37° C.) with half-lives ranging from one hour to three dipeptide containing a permanent linkage to a polymer carrier months, include, but are not limited to, aconityls, acetals, and a temporary amide bond to an aliphatic amino-group carboxylic anhydrides, esters, imines, hydrazones, maleamic containing drug. acid amides, ortho esters, phosphamides, phosphoesters, 0.142 Preferably, linkers of the present invention have a phosphosilyl esters, silyl esters, Sulfonic esters, aromatic car hydrolysis rate between 1 h and 2 years at pH 7.4 and 37° C. US 2015/0202317 A1 Jul. 23, 2015 and hydrolysis rates in buffer and plasma are essentially iden terlipressin, tetanus toxin fragment, tilactase, thrombins, thy tical, i.e. the hydrolysis rates exhibit a strong in vivo/in vitro mosin, thyroid stimulating hormone, thyrotropin, tumor correlation. necrosis factor (TNF). TNF receptor-IgGFc, tissue plasmi 0143 Preferably, D-H is a small molecule bioactive agent nogen activator (tPA), TSH, urodilatin, urate oxidase, uroki or a biopolymer. nase, vaccines, vascular endothelial growth factor (VEGF), 0144 Preferably, D-H is a biopolymer selected from the vasoactive intestinal peptide, vasopressin, Ziconotide, lectin group of biopolymers consisting of proteins, polypeptides, and ricin. oligonucleotides, and peptide nucleic acids. 0147 Preferably, D-H is a protein prepared by recombi (0145 “Oligonucleotides' means either DNA, RNA, nant DNA technologies. single-stranded or double-stranded, siRNA, miRNA, aptam 0148 Preferably, D-H is a protein selected from the group ers, and any chemical modifications thereof with preferably 2 of proteins consisting of antibodies, antibody fragments, to 1000 nucleotides. Modifications include, but are not lim single chain antigen binding proteins, catalytic antibodies ited to, those which provide other chemical groups that incor and fusion proteins. porate additional charge, polarizability, hydrogen bonding, 0149 More preferably, D-H is a protein selected from the electrostatic interaction, and fluxionality to the nucleic acid group of proteins consisting of antibody fragments, single ligand bases or to the nucleic acid ligand as a whole. Such chain antigen binding proteins, catalytic antibodies and modifications include, but are not limited to. 2'-position Sugar fusion proteins. modifications, 5-position pyrimidine modifications, 8-posi 0150 Preferably, D-H is a small molecule bioactive agent tion purine modifications, modifications at exocyclic amines, selected from the group of agents consisting of central ner substitution of 4-thiouridine, substitution of 5-bromo or Vous system-active agents, anti-infective, anti-allergic, 5-iodo-uracil; backbone modifications, methylations, immunomodulating, anti-obesity, anticoagulants, antidia unusual base-pairing combinations such as the isobases iso betic, anti-neoplastic, antibacterial, anti-fungal, analgesic, cytidine and isoguanidine and the like. Modifications can also contraceptive, anti-inflammatory, steroidal, vasodilating, include 3' and 5' modifications such as capping and change of vasoconstricting, and cardiovascular agents with at least one Stereochemistry. primary or secondary amino group. 0146 Preferably, D-H is a polypeptide selected from the 0151. Preferably, D-H is a small molecule bioactive agent group of polypeptides consisting of ACTH, adenosine deami selected from the group of agents containing at least one nase, agallsidase, alfa-1 antitrypsin (AAT), alfa-1 proteinase aliphatic primary amine group: (-)-Draflazine, (-)-Indocar inhibitor (API), alteplase, amylins (amylin, symlin), anistre bazostatin B, (+)-23.24-Dihydrodiscodermolide, (+)-Disco plase, ancrod serine protease, antibodies (monoclonal or dermolide, (+)-R-Pramipexole, (R)-(+)-Amlodipine, (R)- polyclonal, and fragments or fusions), antithrombin III, antit (+)-Terazosin, (R)-Ganciclovir cyclic phosphonate, (R)- rypsins, aprotinin, asparaginases, atosiban, biphalin, bivaliru Sulfinosine, (R)-Zacopride, (S)-(+)-Ketoprofen trometamol, din, bone-morphogenic proteins, bovine pancreatic trypsin (S)-Norfluoxetine, (S)-Oxiracetam, (S)-Sulfinosine, (S)-Za inhibitor (BPTI), cadherin fragments, calcitonin (salmon), copride hydrochloride, 111 In-DTPA-Pro1, Tyrabombesin, collagenase, complement C1 esterase inhibitor, conotoxins, 90Y-DOTAGA-substance P, 99TcDemobesin 3, 99Tc cytokine receptor fragments, DNase, dynorphine A, endor Demobesin 4, Ala11, D-Leu15IOrexin B, Arg(Me)9] phins, enfuVirtide, enkephalins, erythropoietins, exendins, MS-10, D11G.K26R,Y40YR-Plecta sin, D11G.M13K, factor VII, factor VIIa, factor VIII, factor VIIIa, factor IX, K26R,Y40YR-Plecta sin, D9N.M13L.Q14R-Plectasin, fibrinolysin, fibroblast growth factor (FGF), growth hormone D9SQ14K.V36L-Plectasin, D-Tyr1Arg(Me)9] MS-10, releasing peptide 2 (GHRP2), fusion proteins, follicle-stimu D-Tyr1AzaGly7Arg(Me)9 MS-10, D-Tyr1 MS-10, lating hormones, gramicidin, ghrelin, desacyl-ghrelin, granu G1n30-Pancreatic polypeptide (2-36), Glu10.Nle17, locyte colony stimulating factor (G-CSF), galactosidase, glu Nle30-Pancreatic polypeptide (2-36), Glut O-Pancreatic cagon, glucagon-like peptides, glucocerebrosidase, polypeptide(2-36), L17K.K30R GLP-2 (1-33), Leu13 granulocyte macrophage colony stimulating factor (GM Motilin, N5R,M13Y,N17R-Plectasin, Niel 7.Nle30-Pan CSF), human heat shock proteins (HSP), phospholipase-ac creatic polypeptide(2-36), psiCH2NHITpg4Vancomycin tivating protein (PLAP), gonadotropin chorionic (hCG), aglycon, Ser12-Humanin, Trp 19 MS-10, Tyr24-Huma hemoglobins, hepatitis B vaccines, hirudin, human serine nin, 111 In-Pentetreotide, 13-Deoxyadriamycin hydrochlo protease inhibitor, hyaluronidases, idurnonidase, immune ride, 13-Deoxydoxorubicin hydrochloride, 17-Amino-17 globulins, influenza vaccines, interleukins (1 alfa, 1beta,2,3, demethoxygeldanamycin, 17-Aminogeldanamycin, 19-O- 4, 6, 10, 11, 12, 13, 21), IL-1 receptor antagonist (rhIL-1 ra), Methylgeldanamycin, 1-Methyl-D-tryptophan, insulins, insulin like growth factors, insulin-like growth fac 21-Aminoepothilone B, 2-Aminoaristeromycin, 2-Aminon tor binding protein (rhIGFBP), interferons (alfa 2a, alfa 2b, eplanocin A, 3-Chloroprocainamide, 3-Deazaadenosine, alfa 2c, beta1a, beta1b, gamma 1a, gamma lb), intracellular 3-MATIDA, 447-480 Human alpha-fetoprotein, 4-Aminopy adhesion molecule, keratinocyte growth factor (KGF), P-se ridine, 4-Aminosalicylic acid, 4-Chlorophenylthio-DADMe lectinglycoprotein ligand (PSGL), transforming growth fac immucillin-A, 4-epi-Adriamycin, 4'-epi-Doxorubicin, 5,4'- tors, lactase, leptin, leuprolide, levothyroxine, luteinizing Diepiarbekacin, 5-Aminosalicylic acid, 5-Aza-2'- hormone, lyme vaccine, natriuretic peptides (ANP, BNP. deoxycytidine, 5-azacitidine, 5'-Homoneplanocin A, CNP and fragments), neuropeptide Y, pancrelipase, pancre 6'-Homoneplanocin A, 8(R)-Fluoroidarubicin hydrochlo atic polypeptide, papain, parathyroid hormone, PDGF, pep ride, 99mTc-c(RGDfK*)2HYNIC, 9-Aminocamptothecin, sin, peptide YY. platelet activating factor acetylhydrolase A-42867 pseudoaglycone, Abacavir Succinate, Abacavir Sul (PAF-AH), prolactin, protein C, thymalfasin, octreotide, fate, Abanoquil mesilate, Abarelix, Acadesine, Acetyldina secretin, sermorelin, Soluble tumor necrosis factor receptor line, Acetylsalicylic acid lysine salt, Aciclovir, Acriflavine, (TNFR), superoxide dismutase (SOD), somatropins (growth Actinomycin D, Acycloguanosine, Acyclovir, Acyclovir elai hormone), Somatoprim. Somatostatin, Streptokinase, Sucrase, date, Acyclovir oleate, Acyline, AD Peptide, Adamantamine US 2015/0202317 A1 Jul. 23, 2015 11 hydrochloride, Adamplatin-IV, Adefovir, Adefovir dipivoxil, CapraZamycin F. Capromorelin, Cap Savanil, Carafiban Ademetionine tosylate Sulfate, Adenallene, Adenophostin A, maleate, Carbachol, Carbamazepine, Carbetocin, Carbovir, Adenophostin B, Adenosine, Aerothricin 1, Aerothricin 16, Carboxyamidotriazole, Cariporide mesilate, Carisbamate, Aerothricin 41, Aerothricin 45, Aerothricin 5, Aerothricin 50, Carnosine Zinc complex (1:1), Carperitide, Carpipramine, Aerothricin 55, Afamelanotide, Afloqualone, Ageliferin diac Carumonam sodium, Caspofungin acetate, Cavtratin, etate, Ageliferin dihydrochloride, Aica-riboside, ALA hexyl CecropinA(1-11) D(12-37), Cecropin D, Cefaclor, Cefalexin ester, ALA Me ester, Aladapcin, Alamifovir, Alatrofloxacin monohydrate, Cefcamate pivoxil hydrochloride, Cefcanel mesilate, Albolabrin, Alendronate Sodium, Alendronic acid daloxate hydrochloride, Cefcapene pivoxil hydrochloride, Sodium salt, Alestramustine, AlfuZosin hydrochloride, Cefdaloxime, Cefdaloxime Pentexil Tosilate, Cefdinir, Aliskiren fumarate, Alloferon-1. Alogliptin benzoate, alpha Cefditoren pivoxil, Cefepime, Cefetamet pivoxil, Cefetecol, Difluoromethylornithine hydrochloride, alpha-Human atrial Cefixime, Cefluprenam, Cefnmatilen hydrochloride hydrate, natriuretic polypeptide, alpha-Methylnorepinephrine, alpha Cefnmenoxime hydrochloride, Cefninox sodium, Cefodiz Methyltryptophan, Altemicidin, Alvespimycin hydrochlo ime, Cefodizime sodium, Cefoselis sulfate, Cefotaxime ride, Amantadine hydrochloride, Ambasilide, Ambazone, sodium, Cefotetan disodium, Cefotiam cilexetil, Cefotiam AmbroXol nitrate, Amdoxovir, Ameltolide, Amelubant, cilexetil hydrochloride, Cefotiam hexetil, Cefotiam hexetil Amezinium methylsulfate, Amfenac sodium, Amidox, Ami hydrochloride, Cefotiam hydrochloride, Cefoxitin, Cefozop fostine hydrate, Amikacin, Amiloride hydrochloride, Ami ran, CefoZopran hydrochloride, Ce?pirome, Cefpodoxime nocandin, Aminocaproic acid, Aminoglutethimide, Ami proxetil, Ce?prenam, Cefprozil, Cefprozil monohydrate, noguanidine, Aminolevulinic acid hexyl ester, Cefauinome, Cefsulodin sodium, Ceftaroline, Ceftazidime, Aminolevulinic acid hydrochloride, Aminolevulinic acid Cefiteram pivoxil, Ceftibuten, Ceftizoxime alapivoxil, Cefto methyl ester, Aminoquinuride, Aminosidine, Amisulpride, biprole, Ceftobiprole mediocaril, CeftraZonal bopentil, Amlexanox, Amlodipine, Amlodipine besylate. Amoxanox, CeftraZonal sodium, Ceftriaxone sodium, Cefuroxime, Amoxicillin, Amoxicillin trihydrate. Amoxycillin trihydrate, Cefuroxime axetil, Cefuroxime pivoxetil, Centanamycin, Amphotericin, Amphotericin B, Ampicillin Sodium, Cephalexin monohydrate, Ceranapril, Ceronapril, Cerulein, Amprenavir, Ampydin, Amrinone, Amrubicin hydrochloride, Ceruletide diethylamine, Cetefloxacin, Cetrorelix acetate, Amselamine hydrobromide, Amthamine, Anakinra, Anamo Chlorofusin, Chloroorienticin A, Chloroorienticin B, Chlo relin hydrochloride, Anatibant mesilate, Anginex, Angiopep rotetain, Cibrostatin 1, Ciclopiroxolamine, Cidofovir, Cilas tin acetate, Angiotensin II (human), Anisperimus, Antago tatin Sodium, Cilastatino, Cilengitide, Cimaterol, Cinitapride nist-G, Antide, Antide-1, Antide-2, Antide-3, Antiflammin-1, hygrogen tartrate, Cinnamycin, Cipamfylline, Circinamide, Antiflammin-10, Antiflammin-2, Antiflammin-3, Antiflam Cisapride hydrate, Cispentacin, Citicoline, Citrullimycine A, min-4, Antiflammin-5, Antiflammin-6, Antiflammin-7. Anti Cladribine, Clavanin A(K), Clavanin E(3-23), Clitocine, Clo flammin-8, Antiflammin-9, Antileukinate, Antocin II. Apad farabine, Clopidogrel sulfate, Colivelin, Conantokin-R, Con enoson, Apcitide technetium (99mTc), Aphidicolin tulakin G, Cortagine, Coumamidine gammal, Coumamidine glycinate, Apixaban, Aplonidine hydrochloride, Apoptozole gamma2, Cromoglycate lisetil hydrochloride, cyclic-Cido 1, Apoptozole 1, Apoptozole 2, Apoptozole 3, Apraclonidine fovir, Cycloplatam, Cycloserine, Cyclotheonamide A, hydrochloride, Apricitabine, Arbekacin, Arbekacin sulfate, Cyclothialidine, Cycloviolin A, Cycloviolin B, Cycloviolin Arborcandin A, Arborcandin B, Arborcandin C, Arborcandin C, Cycloviolin D, Cygalovir, Cypemycin, CySmethynil, Cys D, Arborcandin E, Arborcandin F. Arenicin, Arenicin-1, tamidin A, Cystamine, CystaZosin, Cystocin, Cytallene, Cyt Arenicin-2, Argatroban monohydrate, Argimesna, Arginine arabine, Cytarabine ocfosfate, Cytaramycin, Cytochlor, butyrate, Argiopine, Argiotoxin-636, Argipidine, Arotinolol Cytomodulin, Dabigatran, Dabigatran etexilate, DACH-Pt hydrochloride, Arterolane maleate, Asp(B14)-relaxin, (II)-bis-ascorbate, Dacopafant, Dactimicin, Dactinomycin, Aspoxicillin, Astromicin Sulfate, Atenolol, Atosiban, Dactylocycline A, Dactylocycline B, DADMe-Immucillin Atreleuton, Atrial natriuretic factor (99-126), Avizafone, G. Dalargin, D-allo-Ileu3 PYY(3-36), Danegaptide hydro AVorelin, AZacitidine, AZacytidine, AZalanstat, AZaromycin chloride, Daniquidone, Dapropterin dihydrochloride, Dap SC, AZelnidipine, AZetirelin, AZodicarbonamide, Azoxyba sone, Darbufelone mesilate, Darifenacin hydrobromide, cilin, Aztreonam, Aztreonam L-lysine, Aztreonam lysinate, Darinaparsin, Darunavir, Daunomycin, Daunorubicin, Dava AZumamide A, Baclofen, Bactobolin, Balapiravir hydrochlo saicin, Davunetide, D-Cycloserine, Debrisoquin sulfate, ride, Balhimycin, Baogongteng A, Barusiban, Batracylin, Debrisoquine Sulfate, Decahydromoenomycin A, Decapla Batroxostatin, Belactin A, Belactosin A, Belactosin C, Bena nin, Decitabine, Declopramide, Deferoxamine, Degarelix nomicin B, Benexate cyclodextrin, Benzocaine, Besifloxacin acetate, Dekafin 1, Dekafin 10, Delafloxacin, delta-Aminole hydrochloride, Binodenoson, Bivalirudin, Bleomycin A2 sul Vulinic acid hydrochloride, Deltibant, Deltorphin E. Dena fate, Boceprevir, Body protection compound-15, Bogorol A, gliptin hydrochloride, Denibulin hydrochloride, Denufosol Boholmycin, Brain natriuretic peptide, Brasilicardin A, tetrasodium, Deoxymethylspergualin, Deoxynegamycin, Bremelanotide, Brivanib alaninate, Brivaracetam, Brodi Deoxyspergualin hydrochloride, Deoxyvariolin B, moprim, Bromfenac sodium, Bromhexine hydrochloride, Desacetylvinblastinehydrazide/folate conjugate. Desferriox Brostallicin hydrochloride. B-Type natriuretic peptide, amine, des-F-sitagliptin, Desglugastrin tromethamine, Bunazosin hydrochloride, Buserelin acetate. Butabindide, Deslorelin, Desmopressin acetate. Desulfated hirudin (54 Butamidine, Buteranol, Cabin 1, Caerulein diethylamine, 65), Desulfated hirugen, Detiviciclovir diacetate, Dexamfe Calcium folinate, Calcium-like peptide 1, Calcium-like pep tamine sulfate, Dexamphetamine sulfate, DexelVucitabine, tide 2, Cambrescidin 800, Cambrescidin 816, Cambrescidin Dexibuprofen lysine, Dexketoprofen D.L-lysine, Dexketo 830, Cambrescidin 844, Camostat mesilate, Camostat mesy profen imidazole salt, Dexketoprofen lysine, Dexketoprofen late, Canfosfamide hydrochloride, Capadenoson, Capeserod trometamol, Dexormaplatin, Dextroamphetamine Sulfate, hydrochloride, Capimorelin, Capravirine, CapraZamycin A, Dextronatrin, Dezinamide, Dezocitidine, Diadenosine tetra CapraZamycin B, CapraZamycin C, CapraZamycin E, phosphate, Diaveridine, Dichlorobenzoprim, Dicloguamine US 2015/0202317 A1 Jul. 23, 2015
maleate, Didemnin X, DidemninY. Dideoxycytidine. Difura lin acetate, Human adrenomedullin, Human adrenomedulin Zone, Dilevalol, Dilevalol hydrochloride, Dirucotide, Dis (22-52), Human angiotensin II, Human corticotropin-releas agregin, Discodermolide, Disermolide, Disitertide, Diso ing hormone, Human lactoferrin (1-11), Human proislet pep dium pamidronate, Disopyramide phosphate, di-Val-L-dC. tide, Human Secretin, Hydrostatin A, Hydroxyakalone, Docosylcidofovir, Dolastatin 14, Dolastatin C, Donitriptan Hydroxycarbamide, Hydroxyurea, Hypeptin, Ibutamoren hydrochloride, Donitriptan mesilate, Doripenem, Dovitinib mesilate, Icatibant acetate, Iclaprim, Icofungipen, Idarubicin Lactate, Doxazosin mesylate, Doxorubicin hydrochloride, hydrochloride, Ilatreotide, Ilonidap, Imetit, Imidafenacin, Doxycycline hyclate, Doxycycline hydrochloride ethanol Imidazenil, Imiquimod, Immunosine, Impentamine, Incyc hydrate, D-Penicillamine, Draflazine, Droxidopa, DTPA-ad linide, Indanocine, Indantadol hydrochloride, Indium In 111 enosylcobalamin, d-trans-Tetraplatin, Dumorelin, Duramy pentetreotide, Indolicidin-11, Indolicidin-4, Indolicidin-8, cin, Dyofin-1, Dyofin-2, Dyofin-9, Ebrotidine, Ecenofloxacin Indomethacin trometamol, Indomethacin tromethamine, hydrochloride, Echistatin, Edotreotide yttrium, Efegatran Indoxam, Inogatran, Insulin chain B (9-23) peptide, Intri sulfate hydrate, Eflornithine hydrochloride, Eglumegad fiban, Iobenguane 131I. Iodorubidazone (p), Iotriside, hydrate. Eglumetad hydrate, Eicosyl cidofovir, Elacytara IrSogladine maleate, Isatoribine, Iseganan hydrochloride, bine, Elaidic acid-Cytarabine, Elastatinal B, Elastatinal C. Isepamicin sulfate, Isobatzelline A, Isobatzelline B, Isobat Elpetrigine, Eltrombopag olamine, Elvucitabine, Emoxyl, Zelline C, Isobatzelline D, Isobutyramide, Isodoxorubicin, Emtricitabine, Enalkiren, Endothelin, Endothelin 1, Enfu Isopropamide iodide
hydrochloride, Monamidocin, Monodansyl cadaverine, Pradimicin C, Pradimicin E, Pradimicin FA-2, Pralatrexate, Monoethanolamine oleate, Montirelin tetrahydrate, Pralmorelin, Pramipexole hydrochloride, Pramlintide Mosapride citrate, Moxilubant, Moxilubant maleate, acetate, Pranedipine tartrate, Prazosin hydrochloride, Pre Mozenavir mesilate, m-Phenylene ethynylene, mu-Cono folic A. Pregabalin, Preladenant, Prezatide copper acetate, toxin IIIA, Multiple sclerosis vaccine, muC-Conotoxin Primaquine phosphate, Prinomide tromethamine, Probestin, MrVIB, Muraminomicin A, Muraminomicin B, Muramino Procainamide hydrochloride, Procaine hydrochloride, micin C, Muraminomicin D, Muraminomicin E1, Murami Procaine Penicillin, Pro-diazepam, Propeptin, Propeptin T. nomicin E2, Muraminomicin F. Muraminomicin G, Murami Prostatin, Protegrin IB-367, Prucalopride, Prucalopride nomicin H. Muraminomicin I, Muraminomicin Z1. hydrochloride, Prucalopride succinate, Pseudomycin A", Muraminomicin Z2, Muraminomicin Z3, Muraminomicin Pseudomycin B", Pyloricidin B, Pymadin, Pyrazinamide, Z4, Muramyl dipeptide C. Mureidomycin A, Mureidomycin Pyrazinoylguanidine, Pyridazomycin, Pyriferone, B. Mureidomycin C, Mureidomycin D. Muroctasin, Myces Pyrimethamine, Pyrodach-2, Quinelorane hydrochloride, tericin E. Myriocin, Nafamostat mesilate, Nafamostat mesy R-(+)-Aminoindane, R9K-Retrocyclin, Ragaglitazar L-argi late, Nafarelin acetate, Naglivan, NagreStipen, Namitecan, nine salt, Ralfinamide, Ramoplanin A1, Ramoplanin A2, Naproxen piperazine (2:1), Napsagatran, Neboglamine, Ramoplanin A3. Ramorelix, Rat adrenomedulin, Ravido Nebostinel, Nebracetam fumarate, Nelarabine, Neldazosin, mycin N-Oxide, Razaxaban hydrochloride, Reblastatin, Nelzarabine, Nemifitide ditriflutate, Nemonoxacin, Neo Receptor mediated permeabilizer, Recombinant human par acridine, Neomycin B-arginine conjugate, Neomycin athyroid hormone (1-84). Recombinant Jerdostatin, Regad B-hexaarginine conjugate, Neomycin-acridine, Nepafenac, enoson, Relaxin-3/INSL5 chimeric peptide, Relcovaptan, Nepicastat hydrochloride, Neramexane hydrochloride, Remacemide hydrochloride, Remofovir mesylate, Residui Neridronate, Neridronic acid, Nesiritide, Netamiftide trifluo mod, Restricticin, Retaspimycin hydrochloride, Retigabine roacetate, Netilmicin sulfate, Neuromedin U-25, Neuropep hydrochloride, Rhodopeptin C1, Rhodopeptin C2, tide S. Neutrophil-activating factor, Niacinamide, Nicotina Rhodopeptin C3, Rhodopeptin C4, Rhodostreptomycin A, mide, Niduline, Nisin, Nitrovin, Nocathiacin I, Nocathiacin Rhodostreptomycin B. Ribamidine hydrochloride, Ribavirin, II, Nocathiacin III, Nocathiacin IV, NO-Gabapentin, Nolatr Ribavirin eicosenate cis, Ribavirin eicosenate trans, Ribavi exed dihydrochloride, NO-Mesalamine, Noraristeromycin, rin elaidate, Ribavirin oleate, Rilmazafone hydrochloride Nuvanil, O6-Benzylguanine, Ocimumoside A, Octacosami dihydrate, Riluzole, Rimacalib hydrochloride, Rimeporide cin A, Octacosamicin B, Octreother, Octreotide acetate, Oct hydrochloride, Riociguat, Ritipenem acoxil, r-Jerdostatin, reotide LAR, Oglufanide disodium, Olamufloxacin, Olamu Robalzotan hydrochloride, RobalZotan tartrate hydrate, floxacin mesilate, Olcegepant, Olradipine hydrochloride, Rociclovir, Romurtide, Rotigaptide, Roxifiban acetate, Omaciclovir, Ombrabulin, Ombrabulin hydrochloride, Ruboxyl, Rufinamide, Rumycin 1, Rumycin 2, S(-)-Norket omega-Conotoxin CVID, omega-ConotoxinMVIIA, Omiga amine, Sabarubicin hydrochloride, Sabiporide mesilate, Safi nan pentahydrochloride, Onnamide A, Opiorphin, Orbofiban namide mesilate, Safingol, Sagamacin, Sampatrilat, Sampir acetate, Orienticin A, Orienticin B, Orienticin C, Orienticin tine, Saprisartan, Sapropterin dihydrochloride, Saquinavir, D. Oritavancin, Oseltamivir carboxylate, Oseltamivir phos Saquinavir mesilate, Sardomozide, Sardomozide hydrochlo phate, Otamixaban, Otenabant hydrochloride, Ovothiol A, ride, Satoribine, Satraplatin, Saussureamine C, Saxagliptin, Oxaliplatin, Oxalysine-L, Oxazofurin, Oxcarbazepine, Oxi Secobatzelline A, Secobatzelline B, Seglitide, Selanc, glutatione sodium, Oxiracetam, OXolide, Oxynor, Oxyphe Selank, Seletracetam, Semapimod hydrochloride, Sempar narsine, Oystrisin, Ozarelix, Pachastrissamine, Pachymedusa atide, Senicapoc, Sepimostat mesilate, Seproxetine, dacnicolor Tryptophyllin-1, Paecilaminol, Pafuramidine Seraspenide, Sermorelin, Sevelamer carbonate. Sevelamer maleate, Palau'amine, Paldimycin B, Pamidronate sodium, hydrochloride. Shepherdin, Shiga vaccine, Siamycin I, Sia p-Aminoclonidine hydrochloride, Pancopride, Papuamide A, mycin II, Sibrafiban, Sifuvirtide, Silodosin, Silver sulfadiaz Papuamide B, Papuamide C. Papuamide D, Parasin I, Par ine, Silpatrigine, Sitafloxacin hydrate, Sitagliptin phosphate athyroid hormone (human recombinant), Paromomycin, monohydrate, S-Nitrosoglutathione, Sofigatran, Sonedeno Pasireotide, Paulomycin, Paulomycin A, Paulomycin A2, son, Sotirimod, Sparfloxacin, Sperabillin A, Sperabillin B, Paulomycin B, Paulomycin C, Paulomycin D. Paulomycin E, Sperabillin C, Sperabillin D, Sphingofungin F, Spifloxacin Paulomycin F. PaZufloxacin, PaZufloxacin mesilate, PEG hydrate, Spinorphin, Spisulosine, Spisulosine 285, Vancomycin, Pelagiomicin C, Peldesine, Pelitrexol, Pemetr Squalamine lactate, Stearyl-norleucine-VIP Streptomycin, exed disodium, Penciclovir, Penicillamine, Penicillin G Stressin1-A, Styloguanidine, Substance P(8-11), Sulcepha procaine, Pentafuside, Pentamidine gluconate, Pentamidine losporin, Sulfinosine, Sulfircin, Sulfostin, Sulphazocine, Sul isethionate, Pentamidine lactate, Peplomycin, Peptide Leu phostin, Sultamicillintosylate, Sunflower trypsin inhibitor-1, cine Arginine, Peramivir, Perphenazine 4-aminobutyrate, Surfen, Synadenol, Synguanol, Synthetic human secretin, Pexiganan acetate, Phakellistatin 5, Phe-Arg-beta-naphthyla Synthetic neutrophil inhibitor peptide, Synthetic porcine mide, Phentermine, Phortress, Phospholine, Pibutidine secretin, Tabilautide, Tabimorelin, Tacedinaline, Tacrine hydrochloride, Piceasin, Picumeterol fumarate, Pidorubicin, hydrochloride, Tafenoquine Succinate, Tageflar, Talabostat, Pimagedine, Pimeloylanilide o-aminoanilide, Piproxen, Talaglumetad hydrochloride, Talampanel, Talipexole dihy Piracetam, Pirarubicin, Piscidin 1, Piscidin 2, Piscidin 3, drochloride, Tallimustine hydrochloride, Talopterin, Talotr Pivampicillin, Pixantrone maleate, Pluraflavin A, Pluraflavin exin, Taltirelin, Tanespimycin, Tanogitran, Targinine, Targi B, Plusbacin A1, Plusbacin A2, Plusbacin A3, Plusbacin A4, nine hydrochloride, Taribavirin hydrochloride, Technetium Plusbacin B1, Plusbacin B2, Plusbacin B3, Plusbacin B4, (99mTc) apcitide, Technetium (99mTc) depreotide, Techne PMEO-5-Me-DAPy, Pneumocandin A0, Pneumocandin B0, tium Tc 99m depreotide, Teicoplanin-A2-1, Teicoplanin-A2 Pneumocandin B0 2-phosphate, Pneumocandin D0, Pola 2. Teicoplanin-A2-3, Teicoplanin-A2-3, Teicoplanin-A2-5, prezinc, Polydiscamide A, Polymer bound human leukocyte Telavancin hydrochloride, Telinavir, Temozolomide, elastase inhibitor, Poststatin, PPI17-24, Pradefovir mesylate, Temurtide, Tenidap, Tenidap sodium, Tenofovir, Tenofovir US 2015/0202317 A1 Jul. 23, 2015
DF, Tenofovir disoproxil fumarate, Terazosin hydrochloride, sin, D9N.M13L.Q14R-Plectasin, D9SQ14K.V36L Teriparatide, Terlipressin, Tertomotide, Tetracosylcidofovir, Plectasin, D-Tyr1Arg(Me)9] MS-10, D-Tyr1AzaGly7, Tetracycline hydrochloride, Tetrafibricin, Tetrahydrobiop Arg(Me)9 MS-10, D-Tyr1 MS-10, G1n30-Pancreatic terin, Texenomycin A, Textilinin-1, Tezacitabine, TGP. Tha polypeptide (2-36), Glu10.Nle17.Nle30-Pancreatic natin, Theprubicin, Thermozymocidin, Thioacet, Thiothio. polypeptide (2-36), Glut O-Pancreatic polypeptide(2-36), Thr10-Contulakin G, Thrazarine, Thymalfasin, Thymic L17K.K30R GLP-2 (1-33), Leu13-Motilin, N5R.M13Y. humoral factor gamma-2, Thymoctonan, Thymopentin, Thy N17R-Plectasin, Nle17.Nle30-Pancreatic polypeptide mosin alpha 1, Tiamdipine, TifuVirtide, Tigecycline, Tigilcy (2-36), IN-Melle4-cyclosporin, psiCH2NHITpg4Vanco cline, Tilarginine hydrochloride, Timirdine diethane mycin aglycon, Ser12-Humanin, Trp19 MS-10, Tyr24 Sulfonate, Timodepressin, Timogen, Tipifarnib, Tiplimotide, Humanin, 111 In-Pentetreotide, 12-Methylthiovinblastine TNF-alpha protease enzyme inhibitor, Tobramycin, Tocain dihydrochloride, 14beta-Hydroxydocetaxel, 14beta-Hy ide hydrochloride, Tokaramide A, Tomopenem, Topostatin, droxydocetaxel-1,14-acetonide, 14beta-Hydroxytaxotere, Torcitabine, Tosufloxacin, Tosufloxacintosilate, Tranexamic 15bbeta-Methoxyardeemin, 16-Aza-epothilone B, 16-Me acid, Trantinterol hydrochloride, Tranylcypromine sulfate, thyloxazolomycin, 17-Amino-17-demethoxygeldanamycin, Trelanserin, Tresperimus triflutate, Tribavirin, Trichomycin 17-Aminogeldanamycin, 18-Hydroxycoronaridine, A, Triciribine, Triciribine phosphate, Triciribine-5'-mono 18-Methoxycoronaridine, 19-O-Methylgeldanamycin, phosphate, Trientine hydrochloride, Trimazosin hydrochlo 1-Deoxynoirimycin, 2,7-Dibromocryptolepine, 2-Bromo-7- ride, Trimetrexate glucuronate, Trimexautide, Trimidox, Tri nitrocryptolepine, 2'-Palmitoylpaclitaxel, 3-Bromometh platin tetranitrate, Triproamylin acetate, Trovafloxacin, cathinone, 3-Chloroprocainamide, 3-Fluorothalidomide, Trovafloxacin hydrate, Trovafloxacin hydrochloride mesy 3-Indole, 4.5-Dianilinophthalimide, 4,6-diene-Cer, 447-480 late, Trovafloxacin mesilate, Trovafloxacin mesylate, Trox Human alpha-fetoprotein, 4-Chlorophenylthio-DADMe-im acitabine, Trybizine hydrochloride, Tubastrine ((+)-enanti mucillin-A, 4-Ethynylstavudine, 4-Hydroxyatomoxetine, omer), Tuftsin, Tumor necrosis factor-alpha protease 5,4'-Diepiarbekacin, 5-Fluorodeoxyuridine, 5-Iodofrederica inhibitor, Tyroservaltide, Tyroservatide, Tyrphostin 47, Tyr mycin A, 5-Methylurapidil, 5-Phenylthioacyclouridine, 6,7- phostin AG-213, Ubenimex, Ubenimex methyl ester, Ubesta tin, Ubidine, Uroguanylin, Valaciclovir, Valacyclovir, Val Dichloroisatin 3-oxime, 6alpha-7-Epipaclitaxel, 6-Mercap boroPro, Valganciclovir hydrochloride, Valnemulin, topurine, 7-Bromo-2-chlorocryptolepine, 7-Deoxytaxol. Valomaciclovir Stearate, Valonomycin A, Valonomycin B, 7-Oxostaurosporine, 9.9-Dihydrotaxol. 99mTc-c(RGDfK*) Valopicitabine, Valpromide, Valrocemide, Vamicamide, Van 2HYNIC, 9-Nitropaullone, A-42867 pseudoaglycone, Aba comycin hydrochloride, Vancoresmycin, Vapitadine hydro cavir succinate, Abacavir sulfate, Abafungin, Abarelix, Abe carnil, Abitesartan, Acamprosate calcium, Acarbose, chloride, Varespladib, Varespladib methyl, Varespladib Acebutolol hydrochloride, Aceclofenac, Acemannan, Ace mofetil, Vasonatrin peptide, Velnacrine maleate, Venorphin, neuramic acid sodium salt, Acetamidoxolutamide, Acetami Vesiculin, Vigabatrin, Vilazodone hydrochloride, Vindesine, nophen, Acetazolamide, Acetohexamide, Acetorphan, Ace Viramidine hydrochloride, Viranamycin-B, Virgisin-1, Virgi tylcysteine, Acetyldinaline, Aciclovir, AcitaZanolast, sin-2, Vitamin B3, W Peptide, Xemilofiban, Xenoxin-1, Acomustine, Acotiamide hydrochloride hydrate, AcreoZast, Xenoxin-2, Xenoxin-3, Xylocydine. Yttrium-90 edotreotide, Actarit, Actinomycin D, Actinoplanone B. Aculeacin Zalcitabine, Zanamivir, Ziconotide, Zileuton, Zofenoprilat Agamma, Acycloguanosine, Acyclovir, Acyclovir elaidate, arginine, Zoniporide hydrochloride, Zorubicin hydrochlo Acyclovir oleate, Acyline, AD Peptide, Adamantyl globotri ride, aosylceramide, Adaphostin, Adaprolol maleate, Adaprolol 0152 Preferably, D-H is a small molecule bioactive agent oxalate, Adatanserin hydrochloride, Adecypenol, Adelm selected from the group of agents containing at least one idrol, Adenopeptin, Aderbasib, Adjudin, Adosopine, Adoze aliphatic secondary amine group: (-)-2-(2-Bromohexade lesin, Adrafinil, Adrogolide hydrochloride, Aerothricin 1, canoyl)paclitaxel, ()-3-O-Acetylspectaline hydrochloride, ( Aerothricin 16, Aerothricin 41, Aerothricin 45, Aerothricin 5, )-3-O-tert-Boc-spectaline hydrochloride, (-)-Bemoradan, Aerothricin 50, Aerothricin 55, Aeruginosamide, Afamelan (-)-Bupivacaine hydrochloride, (-)-Calicheamicinone, (-)- otide, Afeletecan hydrochloride, Afobazol, Afobazole, Age Cicloprolol, (-)-Conophylline, (-)-Draflazine, (-)-Efaroxan, lasphin 517, Agelasphin 564, Ageliferin diacetate, Ageliferin (-)-Halofenate, (-)-Indocarbazostatin B, (-)-Nebivolol, (-)- dihydrochloride, Aglaiastatin C, Agomelatine, Alacepril, Norchloro-18F fluoro-homoepibatidine, (-)-Salbutamol Aladapcin, Aladotril, Alatriopril, Alatrofloxacin mesilate, hydrochloride, (-)-Salmeterol, (-)-Ternatin, (+)-(S)-Hy Albendazole, Albifylline, Albolabrin, Albuterol nitrate, droxychloroquine, (+)-AZacalanolide A, (+)-Efaroxan, (+)- Albuterol sulfate, Alchemix, Alfuzosin hydrochloride, Alini Indocarbazostatin, (+)-Isamoltan, (+)-Pemedolac, (+)-R- dine, Alisamycin, Aliskiren fumarate, Alizapride, Alkasar Pramipexole, (+)-Scyphostatin, (+)-SNAP-7180, (+)-Sotalol, 18, Allantoxamic acid, Alloferon-1, Allopurinol, Alminopro (+)-threo-Methylphenidate hydrochloride, (R)-(+)-Amlo fen, Almitrine bismesylate, Almitrine dimeSylate, dipine, (R)-Albuterol hydrochloride, (R)-Bicalutamide, (R)- Almorexant, Almotriptan, Alniditan, Aloracetam, Alosetron Clevidipine, (R)-Ganciclovir cyclic phosphonate, (R)-Nigul hydrochloride, Alosetron maleate, Aloxistatin, alpha-C-Ga dipine hydrochloride, (R)-NSP-307, (R)-Teludipine, (R)- lactosylceramide, alpha-Galactosylceramide, alpha-Galacto Thionisoxetine, (R)-Tulobuterol, (R)-Zacopride, (R,R)- sylceramide-BODIPY, alpha-Human atrial natriuretic Formoterol tartrate, (S)-Acetorphan, (S)-Clevidipine, (S)- polypeptide, alpha-Lactosylceramide, alpha-Methylepi N-Desmethyltrimebutine, (S)-Noremopamil, (S)- nephrine, alpha-Methyltryptophan, alpha-Nornicotine, Rivoglitazone, (S)-Sotalol, (S)-Zacopride hydrochloride, alpha-Sialosylcholesterol sodium salt, Alprafenone hydro 111 In-DTPA-Pro1,Tyr4 bombesin, 90Y-DOTAGA-sub chloride, Alprenolol hydrochloride, Alprenoxime hydrochlo stance P, 99TcDemobesin 3, 99TcDemobesin 4, Alal 1, ride. Alsterpaullone. Altemicidin, Altromycin A, Altromycin D-Leu15IOrexin B, Arg(Me)9 MS-10, D11G.K26R, C, Alvespimycin hydrochloride, Alvimopan hydrate, Amac Y40YR-Plecta sin, D11G.M13K.K26R,Y40YR-Plecta etam hydrochloride, Amamistatin A, Amamistatin B, Amba US 2015/0202317 A1 Jul. 23, 2015
Zone, AmbroXol nitrate, Ameltolide, Amesergide, Ame Belactosin A, Belactosin C, Belaperidone, Belinostat, Belo thocaine hydrochloride, Amfebutamone hydrochloride, tecan hydrochloride, Bemoradan, Benadrostin, Benafentrine Ami begron hydrochloride, Amifostine hydrate, Amiglumide, dimaleate, Benanomicin A, Benanomicin B, Benatoprazole, Amikacin, Amiloride hydrochloride, Amineptine, Ami Benazepril hydrochloride, Bendrofluazide, Bendroflumethi nocandin, Aminochinol, Aminoglutethimide, Aminoguani azide, Benexate cyclodextrin, Benidipine hydrochloride, dine, Aminoquinol, Aminoquinuride, Amisulpride, Amitivir, Benperidol, Benzimidavir, Benzylpenicillin sodium, Ber Amlodipine, Amlodipine besylate, Amobarbital, lafenone hydrochloride, Besonprodil, beta-CCM, beta-Me Amocarzine, Amodiaquine, Amosulalol hydrochloride, thyl-6-chloromelatonin, Betamipron, beta-Sialosylcholes Amoxapine, Amoxicillin, Amoxicillin trihydrate. Amoxycil terol sodium salt, beta-Tethymustine, Betaxolol lin trihydrate, Ampicillin Sodium, Ampiroxicam, hydrochloride, Bevantol hydrochloride, Bevantolol hydro Amprenavir, Amrinone, Amsacrine, Amsilarotene, Amsu chloride, Bezafibrate, Bicalutamide, Biemnidin, Bifemelane losin hydrochloride, Amtolimetin guacil, Amylobarbitone, hydrochloride, Bifeprunox mesilate, Bimatoprost, Binode Anabasine hydrochloride, Anagrelide hydrochloride, Anak noson, BinoSpirone mesylate, Biotinylated idraparinux, inra, Anamorelin hydrochloride, Anandamide, Anatibant Bioxalomycin alpha 1, Bipranol hydrochloride, Bis(7)-cog mesilate, Andolast, Androxolutamide, Anginex, Angiopeptin nitin, Bis(7)-tacrine, Bisantrene hydrochloride, Bisnafide acetate, Angiotensin II (human), Anidulafungin, Anisperi mesilate, Bisnafide mesylate, Bisoprolol fumarate, Bitolterol mus, Ansamycin, Antagonist-G, Antide, Antide-1, Antide-2, mesylate, Bivalirudin, Bizelesin, Bleomycin A2 sulfate, Boc Antide-3, Antiflammin-1, Antiflammin-10, Antiflammin-2, Belactosin A, Boceprevir, Boc-Lysinated betulonic acid, Antiflammin-3, Antiflammin-4, Antiflammin-5, Antiflam Body protection compound-15, Bogorol A, Bohemine, min-6, Antiflammin-7, Antiflammin-8, Antiflammin-9, Anti Boholmycin, Bopindolol, Bortezomib, Bosentan, Bosutinib, leukinate, Antimycin A11, Antimycin A12, Antimycin A13, Bradyzide, Brain natriuretic peptide, Brasilicardin A, Antimycin A14, Antimycin A15, Antimycin A16, Antocin II, Brecanavir, Bremelanotide, Brimonidine tartrate, Brinaz Apadenoson, Apadoline, Apalcillin Sodium, Apaxifylline, arone, Brinzolamide, Brivanib, Brivanib alaninate, Brivu Apcitide technetium (99mTc). Apicularen A, Apicularen B. dine, Bromantan, Bromantane, Bromazepam, Bromocriptine Apilimod, Apilimod mesylate, Apiodionene, AplaViroc mesilate, Bromotopsentin, Bromovinyldeoxyuridine, Bros hydrochloride, Aplidine, Aplindore fumarate, Aplonidine tallicin hydrochloride, Brovavir, B-Type natriuretic peptide, hydrochloride, Apoptozole 1, Apoptozole 2, Apraclonidine Bucillamine, Bucladesine sodium, Buflomedil pyridoxal hydrochloride, Apremilast, Aprepitant, Aprikalim, Aprosu phosphate, Bulaquine, Bumetanide, Bupivacaine hydrochlo late Sodium, Aptiganel, Aranidipine, Aranorosin, Aranorosi ride, Bupropion hydrochloride, Buserelin acetate. Butabin nol A, Aranorosinol B, Aranose, Aranoza, Araprofen, Arba dide, Buteranol, Butobarbitone, Butoctamide hemisuccinate, clofen placarbil sodium, Arbekacin, Arbekacin sulfate, Butofilolol, Butyl flufenamate. ButyZamide, Cabazitaxel, Arborcandin A, Arborcandin B, Arborcandin C, Arborcandin Cabergoline, Cabin 1, Cadralazine, Cadrofloxacin hydro D. Arborcandin E, Arborcandin F. Arbutamine hydrochlo chloride, Caerulein diethylamine, Calcium folinate, Cal ride, Archazolid A, Archazolid B, Archazolide A, Arcyriacya cium-like peptide 1, Calcium-like peptide 2, Caldaret nin A, Ardeemin, Arenicin, Arenicin-1, Arenicin-2, Arfor hydrate, Caldiamide Sodium, Calicheamicin gammal agly moterol tartrate, Argatroban monohydrate, ArgimeSna, cone, Calindol Dihydrochloride, Calothrixin A, Cambresci Arginine butyrate, Argiopine, Argiotoxin-636, Argipidine, din 800, Cambrescidin 816, Cambrescidin 830, Cambresci Argyrin A, Argyrin B, Arhalofenate, Aripiprazole, Arisostatin din 844, Camostat mesilate, Camostat mesylate, Camprofen, A. Arofylline, Arotinolol hydrochloride, Arterolane maleate, Canadensol, Candesartan, Candesartan cilexetil, Cande Artilide fumarate, Ascosalipyrrolidinone A, Ascosalipyrroli sartan hexetil, Candoxatril, Candoxatrilat, Canertinib dihy dinone B, Asobamast, Asp(B14)-relaxin, Asperlicin B, drochloride, Canfosfamide hydrochloride, Cangrelor tetraso Asperlicin C, Asperlicin D, Asperlicin E, Aspoxicillin, dium, Capecitabine, Capimorelin, CapraZamycin A, Astemizole, Ataciguat, Atalaphillidine, Atalaphillinine, CapraZamycin B, CapraZamycin C, CapraZamycin E, Ataquimast, Ataquimast hydrochloride, Atazanavir Sulfate, CapraZamycin F. Capridine beta, Caprolactin A, Caprolactin Atenolol, Atevirdine mesylate, Atipamezole, Atizoram, Ato B, Capromorelin, Capsavanil, Cap Sazepine, Carabersat, moxetine hydrochloride, Atorvastatin, Atorvastatin calcium, Caracasanamide, Caracasandiamide, Carafiban maleate, Car Atosiban, Atrial natriuretic factor (99-126), Aureobasidin A, bazomadurin A, Carbazomadurin B, Carbazomycin G. Car Auristatin E, Auristatin PE, Avasimibe, Avicin D, Avicin G, bazomycin H. Carbetocin, Carbidopa, Carbovir, Carfilzomib, Avitriptan, Avizafone, AVorelin, Avosentan, AVrainvillamide, Cariprazine hydrochloride, Carmethizole, Carmofur, Car Axitinib, Axitirome, AZ-36041, Azaromycin SC, AZasetron, moterol hydrochloride, Carmoxirole hydrochloride, Carmus AZasetron hydrochloride, AZathioprine, Anatoxin, AZelnid tine, Carnosine Zinc complex (1:1), Carperitide, Carprofen, ipine, AZepinostatin, AZetirelin, AZidothymidine, AZidothy Carquinostatin A, Carsatirin, Carteolol hydrochloride, Cart midine phosphonate, AZilsartan, AZilsartan medoxomil. eramine A, Carumonam sodium, Carvedilol, Carvotroline Aztreonam, Aztreonam L-lysine, Aztreonam lysinate, hydrochloride, Carzelesin, Caspofungin acetate, Catramilast, AZumamide A, AZumamide E. Bactobolin, Bafetinib, Bala Cavtratin, Cebaracetam, Cecropin A(1-11) D(12-37), glitaZone, Balamapimod, Balanol, Balaperidone, Balhimy Cecropin D, Cediranib, Cefaclor, Cefalexin monohydrate, cin, Balicatib, Balofloxacin, Balofloxacin dihydrate, Bal Cefazolin Sodium, CefbuperaZone sodium, Cefcamate piv Salazide disodium, Bamaquimast, Bambuterol, Bamirastine oxil hydrochloride, Cefcanel, Cefcanel daloxate hydrochlo hydrate, Banoxantrone, Baogongteng A, Barixibat, Barnid ride, Cefcapene pivoxilhydrochloride, Cefdaloxime, Cefdal ipine hydrochloride, Barusiban, Basifungin, Batimastat, oxime Pentexil Tosilate, Cefdinir, Cefditoren pivoxil, Batoprazine, Batroxostatin, Batzelline A, Batzelline B. Bat Cefepime, Cefetamet pivoxil, Cefetecol, Cefixime, Ceflupre Zelline C, Beauveriolide I, Beauveriolide III, Becampanel, nam, Cefnmatilen hydrochloride hydrate, Cefnmenoxime Becatecarin, Bederocin, Bedoradrine sulfate. Befol, hydrochloride, Cefninox sodium, Cefodizime, Cefodizime Befunolol hydrochloride, Begacestat, Belactin A, Belactin B, Sodium, Cefonicid sodium, CefoperaZone sodium, Cefoselis US 2015/0202317 A1 Jul. 23, 2015
sulfate, Cefotaxime sodium, Cefotetan disodium, Cefotiam erine, Debromoshermilamine, Decahydromoenomycin A, cilexetil, Cefotiam cilexetil hydrochloride, Cefotiam hexetil, Decaplanin, Decatromicin A, Decatromicin B, Declopra Cefotiam hexetil hydrochloride, Cefotiam hydrochloride, mide, Deferobiotin, Deferoxamine, Degarelix acetate, Cefoxitin, CefoZopran, CefoZopran hydrochloride, Ce?pimi Degrasyn, Dehydrodidemnin B, Dehydrodolastatin-13, Zole sodium, Ce?piramide sodium, Ce?pirome, Cefpodoxime Dekafin 1, Dekafin 10, Delaminomycin A, Delaminomycin proxetil, Cefprenam, Cefprozil, Cefprozil monohydrate, B. Delaminomycin C, Delapril hydrochloride, Delavirdine Cefauinome, Cefsulodin sodium, Ceftaroline, Ceftaroline mesilate, Delfaprazine hydrochloride, Delimotecan sodium, fosamil acetate, Ceftazidime, Cefteram pivoxil, Ceftibuten, Deltibant, Deltorphin E, Delucemine hydrochloride, Dem Ceftizoxime alapivoxil, Ceftizoxime sodium, Ceftobiprole, ethylallosamidin, Demethylasterriquinone B-1, Demetomi Ceftobiprole mediocaril, CeftraZonal bopentil, CeftraZonal dine, Demexiptiline hydrochloride, Denibulin hydrochloride, sodium, Ceftriaxone sodium, Cefuroxime, Cefuroxime Denopamine, Denufosol tetrasodium, Deoxycoformycin, axetil, Cefuroxime pivoxetil, Celiprolol hydrochloride, Deoxymethylspergualin, Deoxymulundocandin, Deoxyne Cemadotin hydrochloride, Centanamycin, Cephalexin gamycin, Deoxynoirimycin, Deoxyspergualin hydrochlo monohydrate, Cephazolin Sodium, Ceratamine A, Cerata ride, Depsipeptide, Deriglidole, Desacetylvinblastinehy mine B, Cerebrocrast, Cerebroside A, Cerebroside B, Cere drazide, Desacetylvinblastinehydrazide/folate conjugate, broside C. Cerebroside D, Cerulein, Ceruletide diethylamine, Desbutylbenflumetol, Desbutylhalofantrine hydrochloride, Cethromycin, Cetrorelix acetate, Cevipabulin, Chackol, Cha Desferri-danoxamine, Desferri-nordanoxamine, Desferriox etocin, Chetocin, Chinoin-169, Chloptosin, Chlorazicomy amine, Desferri-salmycin A, Desferri-salmycin B. Desferri cin, Chlordiazepoxide hydrochloride, Chlorofusin, Chloro salmycin C, Desferri-salmycin D. Desglugastrin orienticin A, Chloroorienticin B, Chloropeptin II, tromethamine, Desipramine hydrochloride, Desloratadine, Chlorotetain, Chlorothiazide, Chlorpropamide, Chlor Deslorelin, Desmin-370. Desmopressin acetate. Desulfated propham, Chlortalidone, Chlortenoxicam, Chlorthalidone, hirudin (54-65), Desulfated hirugen, Detomidine hydrochlo Chondramide A, Chondramide B, Chondramide C, Chondra ride, Devazepide, Dexecadotril, Dexefaroxan, Dexfenflu mide D, Cibenzoline succinate, Ciclosporin, Cifenline succi ramine hydrochloride, Dexketoprofen imidazole salt, Dexke nate, Cilastatin Sodium, Cilastatino, CilaZapril, Cilengitide, toprofen meglumine, Dexlansoprazole, Dexloxiglumide, Cilnidipine, Cilostazol, Ciluprevir, Cimadronate sodium, Dexmedetomidine hydrochloride, Dexmethylphenidate Cimaterol, Cimetidine, Cimetidine bismuth citrate, Cimeti hydrochloride, Dexniguldipine hydrochloride, Dexpemed dine bismuth L-tartrate, Cimetidine nitrate, Cinacalcet hydro olac, Dexrazoxane hydrochloride, Dexsotalol, Dextronatrin, chloride, Cinaldipine, Cinalukast, Cinitapride hygrogen tar Dexylosylbenanomycin A, d-Fenfluramine hydrochloride, trate, Cinnabaramide A, Cinnamycin, Cinnoxicam, D-Fluviabactin, DHA-paclitaxel, Diaplasinin, Diazepinomi Cipamfylline, Cipemastat, Cipralisant, Ciprofloxacin hydro cin, DiaZOxide, Dichlorobenzoprim, Diclofenac potassium, chloride, Ciprofloxacin silver salt, Ciprokiren, Ciproxifan, Diclofenac sodium, Diclofenac Zinc salt, Didanosine, Circinamide, Cisapride hydrate, Citropeptin, Citrullimycine Didemnin X, Didemnin Y. Dideoxyinosine, Diethyl-lactam, A, Clamikalant, Clausenamine A, Clavanin A(K), Clavanin Diethylnorspermine. Difurazone, Diheteropeptin, Dihy E(3-23), Clazosentan, Clazosentan sodium, Clevidipine drexidine, Dihydro-alpha-ergokryptine mesylate, Dihy butyrate, Clevudine, Clindamycin hydrochloride, Clitocine, droavenanthramide D. Dihydroeponemycin, Dihydroergota Clobenpropit, Clonazepam, Clonidine, Clonidine hydrochlo mine mesylate, Dilevalol, Dilevalol hydrochloride, ride (hydrochloride), Clopamide, Clopenphendioxan, Clopi Dimelamol, Dimethynur, Dimiracetam, di-mPEG5-Ataza dogrel sulfate, Cloranolol hydrochloride, Clorazepate dipo navir, Dinapsoline, Dinoxyline, Dioxolane T. Dioxolane tassium, Clospipramine hydrochloride, Cloturin, Clozapine, thymine nucleoside, Diperamycin, Dipivefrine hydrochlo Coenzyme PQQ, Collabomycin A, Coleneuramide, Colivelin, ride, Dipranol hydrochloride, Dicquafosol tetrasodium, Coluracetam, Complestatin, Conagenin, Conantokin-R, Dirithromycin, Dirlotapide, Dirucotide, Disagregin, Disala Coniosetin, Conivaptain hydrochloride, Conophylline, Con Zine, Discodermide, Discodermide acetate, Discorhabdin D, tulakin G, Cortagine, Coumamidine gammal, Coumamidine Discorhabdin P. Discorhabdin S, Discorhabdin T. Discorhab gamma2, Covidarabine, Creatine phosphate, Crilvastatin, din U, Disitertide, Dithiosteine, d-Methamphetamine hydro Crisinatol mesilate, Cronidipine, Cryptophycin 52, Cyclame chloride, Dobutamine hydrochloride, Dobutamine phos nol, Cyclo[His-Pro, Cyclocreatine, Cyclolinopeptide A, phate, Docarpamine, Docetaxel, Docetaxol. Dofetilide, Cyclolinopeptide B, Cyclomarin A, Cyclopenthiazide, Dolasetron, Dolasetron mesilate, Dolastatin 10, Dolastatin Cyclophosphamide, Cycloserine, Cyclosporin, Cyclosporin 13, Dolastatin 14, Dolastatin 15, Dolastatin C, Dolastatin D, A, Cyclosporin J. Cyclosporine, Cyclosporine A, Cyclothe Domitroban calcium hydrate, Domperidone, Donitriptan onamide A, Cyclothialidine, Cycloviolin A, Cycloviolin B, hydrochloride, Donitriptan mesilate, Dopexamine, Dopex Cycloviolin C, Cycloviolin D, Cygalovir, Cymserine, Cype amine hydrochloride, Doramapimod, Doripenem, Dor mycin, Cystamidin A, Cystemustine, Cystocin, Cytoblastin, mitroban, Dorrigocin A, Dorrigocin B, Dorzolamide hydro Cytochalasin B, Cytomodulin, Cytotrienin A, Cytotrienin I, chloride, Dovitinib Lactate, Doxifluridine, DoxoTam 12, Cytotrienin II, Cytotrienin III, Cytotrienin IV, Cytoxazone, d-Pseudoephedrine hydrochloride, Draflazine, Dronedarone Dabelotine mesilate, Dabigatran, Dabigatran etexilate, hydrochloride, Droperidol, Droximavir, d-threo-Meth Dabuzalgron hydrochloride, Dacinostat, Dactimicin, Dacti ylphenidate hydrochloride, DTPA-adenosylcobalamin, nomycin, Dactylocycline A, DADMe-Immucillin-G, Duloxetine hydrochloride, Dumorelin, Duocarmycin A, DADMe-Immucillin-H, Daglutril, Dalargin, Dalbavancin, Duocarmycin B1, Duocarmycin B2, Duocarmycin C1, Duo Dalcetrapib, Dalcotidine, Dalfopristin mesilate, D-allo-Ileu3 carmycin C2, Duocarmycin SA, Duramycin, Dutasteride, PYY(3-36), DANA, Danegaptide hydrochloride, Danusertib, Dynemicin A, Dynemicin C, Dyofin-1, Dyofin-2, Dyofin-9, Dapivirine, Daporinad, Dapropterin dihydrochloride, Dar EbalZotan, Ebanicline, Ebrotidine, Ecadotril, Echistatin, bufelone, DarglitaZone, Darinaparsin, Darunavir, Dasantafil. Ecomustine, Ecteinascidin 1560, Ecteinascidin 722, Ectein Dasatinib, Davasaicin, Davunetide, Daxalipram, D-Cyclos ascidin 729, Ecteinascidin 736, Ecteinascidin 743, Ecteinas US 2015/0202317 A1 Jul. 23, 2015
cidin 745, Ecteinascidin 770, Ecteinascidin 875, Edaglita linium DTPA, Gadolinium DTPA-BMA, Gadomelitol, Zone, Edonentan hydrate, Edotecarin, Edotreotide yttrium, Gadopentetate dimeglumine, Gadoterate meglumine, Edoxaban tosilate, Efaproxiral sodium, Efaroxan, Efavirenz, Gadoversetamide, Galactomycin I, Galactomycin II, Efegatran sulfate hydrate, Efepristin, Eflucimibe, Eflumast, Galdansetron, Gallinacin 1, Gallinacin 1alpha, Gallinacin 2, Efonidipine hydrochloride ethanol, Eformoterol fumarate, Galmic, Galnon, Galocitabine, Galparan, Gammaphos, Gan Elacridar, Elagolix sodium, Elarofiban, Elastatinal B, Elasta ciclovir, Ganciclovir elaidic acid, Ganciclovir monophos tinal C, Elbanizine, Eldacimibe, Elesclomol, Eletriptan, phate, Ganefromycin alpha, Ganefromycin beta, Ganglioside Elgodipine hydrochloride, Elinafide mesilate, Elinogrel GM1, Ganirelix, Ganirelix acetate, Ganstigmine hydrochlo potassium, Elliptinium acetate, Elliptoside A, Elliptoside E. ride, Gantofiban, Garenoxacin mesilate, Garomefrine hydro Elnadipine, Elopiprazole, Eltrombopag olamine, Embusar chloride, Gastrazole, Gastrophenzine, Gatifloxacin, Gavesti tan, Emicerfont, Emivirine, Emonapride, Emricasan, Enala nel sodium, Gedocarnil, Gefitinib, Gefitinib hydrochloride, pril maleate, Enalapril nitrate, Enalaprilat, Enalkiren, Enaza Gemopatrilat, Gibbosin, Gidazepam, Gilatide, Gilvusmycin, drem, Endothelin, Endothelin 1, Enfluvirtide, Eniluracil, Giracodazole, Giripladib, Girodazole, Girolline, Givinostat, Enkastin (D), Enkastin AD, Enkastin AE, Enkastin ID, Glaspimod, Glibenclamide, Gliclazide, Glidobactin PF-1, Enkastin IE, Enkastin VD, Enkastin VE, Enocitabine, Enoxa Glimepiride, Glipizide, Gliquidone, Glucagon-like peptide I cin, Enoximone, Entecavir, Enteric neural peptide, Enti (7-37), Glucarolactam potassium, Glucolanomycin, Glu nostat, Enzastaurin hydrochloride, Eperezolid, Eperezolid dopa, Glufanide, Glufosfamide, Glutapyrone, Glutathione N-oxide, Epervudine, Epibatidine, Epidepride-(125I), monoethyl ester, Glutathione monoisopropyl ester, Glute Epiderstatin, Epipachysamine E. Epithalon, Epocarbazolin thimide, Glyburide, Glycine-proline-Melphalan, Glycopin, A, Epocarbazolin B, Epofolate, Epolactaene, Eponemycin, Glycopril, Glycothiohexide alpha, Gold talaporfin sodium, Epostatin, Epoxomicin, Epristeride, Eprobemide, Epro Golotimod, Gomisin A glycinosuccinate Sodium salt, Gora tirome, Eptastigmine tartrate, Eptifibatide, Erbulozole, latide, Goserelin, Gosogliptin hydrochloride, Granisetron Erdosteine, Eremomycin, Ergotamine tartrate, Eribaxaban, hydrochloride, Grepafloxacin hydrochloride, Growth factor Eritoran tetrasodium, Erlosamide, Erlotinib hydrochloride, antagonist-116, Growth hormone releasing peptide 2. Ersentilide, Ersentilide hydrochloride, Ertapenem sodium, Growth Inhibitory Peptide, Guanabenz acetate, Guanadrel Erythromycin Salnacedin, Erythromycin stinoprate, Esculeo sulfate, Guanethidine monosulfate, Guanfacine hydrochlo genin A, Esculeoside A, Eserine Salicylate, Esmolol hydro ride, Gusperimus hydrochloride, Gusperimus trihydrochlo chloride, Esperamicin A1. Esperatrucin, Etacizin, Etamsy ride, Gyp setin, Habekacin, Habekacin sulfate, Halimide, late, Etaquine, Ethacizin, Ethamsylate, Ethimizol, Ethiofos, Halofuginone hydrobromide, Halovir A. Halovir B, Halovir Ethosuximide, Ethoxy-idazoxan, Ethyl loflazepate, Eth C, Halovir D, Halovir E. Harkoseride, Helvecardin A, Helve ylthio-DADMe-immucillin-A, Etidocaine hydrochloride, cardin B, Heptaminol AMP amidate, Heptylstigmine tartrate, Etodolac, Etodolic acid, Etravirine, Eugenodilol, Eurocin, Herquline B, Hesperadin, Hexa-D-Arginine, Himastatin, Eurystatin A, Eurystatin B. Examorelin, Exenatide, Hirudin desulfated, Hirulog-1. Hispidospermidin, Histamine Exenatide LAR, Exendin-4, Ezatiostat hydrochloride, Ezlo dihydrochloride. Histaprodifen, Histrelin, Histrelin acetate, pitant, Fabesetron, Fabesetron hydrochloride, Fadolmidine Homoepibatidine, Homoindanomycin, Hormaomycin, hydrochloride, Falnidamol, Famotidine bismuth citrate, Human adrenomedulin, Human adrenomedullin (22-52), Fanapanel, Farglitazar, Fasidotril, Fasobegron hydrochlo Human angiotensin II, Human corticotropin-releasing hor ride, Fasoracetam, Fasudil hydrochloride, Feglymycin, Feg mone, Human lactoferrin (1-11), Human proislet peptide, lymycine, Felodipine, Fenoldopam mesilate, Fenoterol Human Secretin, Hyaluronan, Hyaluronate sodium, Hydrala hydrobromide, Fenoximone, Fepradinol, Ferrochloroquine, zine hydrochloride, Hydrochlorothiazide, Hydroflumethiaz Ferroquine, Ferulinolol, Fidarestat, Fiduxosin hydrochloride, ide, Hydrostatin A, Hydroxyakalone, Hydroxycarbamide, Filarizone, Fimasartan, Fimbrigal P. Finafloxacin hydrochlo Hydroxychloroquine Sulfate, Hydroxymycotrienin A, ride, Finasteride, Fipamezole hydrochloride, Fish amunine, Hydroxymycotrienin B, Hydroxyurea, Hymenistatin 1, Flecainide acetate, Flibanserin, Flindokalner, Flomoxef Hypeptin, Ibipinabant, Ibodutant, Ibopamine, Ibrolipim, sodium, Flopristin, Flopristine, Florbetaben, Flovagatran Ibutamoren mesilate, Ibutilide fumarate, Icatibant acetate, sodium, Floxuridine, Flucytosine, Flufenoxine, FlumeZap Icopezil maleate, IdaZOxan hydrochloride, Idrabiotaparinux ine, Fluodipine, Fluorocytosine, Fluorofur, Fluoroindolocar Sodium, Idrapril, Ifetroban, Ifosfamide, Iganidipine hydro bazole A, Fluoroindolocarbazole B, Fluoroindolocarbazole chloride, Iguratimod, Ilaprazole, Ilatreotide, Ilepatril, Ilom C. Fluorouracil, Fluoxetine hydrochloride, Fluparoxan, Flu astat, Imatinib mesylate, Imetit, Imexon, Imidacrine, Imi pirtine maleate, Fluspirilene, Flutamide, Fluvirucin B2, Foe dapril, Imidapril hydrochloride, Imidazoacridinone, tidine 1, Foetidine 2, Folinic acid, Folinic acid calcium salt, Imidazole 24b, Imipemide. Imipenem, Imirestat, Imiso Fomepizole, Fondaparin Sodium, Fondaparinux sodium, pasem manganese, Immepip, Immepyr, Immethridine, Fonsartan potassium, Forasartan, Foretinib. Formobactin, Immucillin-H. Immunosine, Imoproxifan, Impentamine, Formoterol fumarate, Forodesine hydrochloride, Fosalvu Implitapide, Improgan, Incadronate, Incadronic acid sodium dine tidoxil, Fosamprenavir calcium, Fosamprenavir Sodium, salt, Indacaterol, Indanomycin, Indantadol hydrochloride, Fosaprepitant, Fosaprepitant dimeglumine, Fosopamine, Indapamide, Indeloxazine hydrochloride, Indibulin, Indi Fosphenytoin Sodium, Fostamatinib, Fostamatinib disodium, navir sulfate, Indisetron hydrochloride, Indisulam, Indium In Fotemustine, Fozivudine tidoxil, Fradafiban, Franidipine 111 pentetreotide, Indole-3-propionic acid, Indolicidin-11, hydrochloride, Freselestat, Frog neuromedin U. Frovatriptan, Indolicidin-4, Indolicidin-8, Indolmycin, Indomethacin Frusemide, Ftorafur, Furaldipine. Furavir. Furnidipine, Furo phenethylamide, Indomethacin-Simvastatin, Indoramin semide, G1 peptide, Gabadur, Gabapentin enacarbil, Gabex hydrochloride, Inogatran, Inosine pranobex, InoSiplex, Insu ate mesilate, Gaboxadol, Gadobenate dimeglumine, Gadobe lin chain B (9-23) peptide, Intaxel (from Himalayan Yew), nic acid dimeglumine salt, Gadocoletic acid trisodium salt, Integramycin, Intoplicine, Intrifiban, Iobenguane 131I. Gadodenterate, Gadodiamide, Gadodiamide injection, Gado Iobitridol, Iodixanol, Iodoproxyfan, Iodorubidazone (p), US 2015/0202317 A1 Jul. 23, 2015
Iofetamine hydrochloride 1-123, Iofratol, Iohexol, Iolopride glinat dialanetil, Manidipine hydrochloride, Manifaxine (123I), Iomeprol, Iopamidol, Iopentol, Iopromide, Iotriside, hydrochloride, Manitimus, Mannopeptimycin alpha, Man Iotrol, Iotrolan, Ioversol, Ioxilan, Ioxipride, Ipazilide fuma nopeptimycin beta, Mannopeptimycin delta, Mannopeptimy rate. Iptakalim hydrochloride, Irbesartan, Irciniastatin A, cin epsilon, Mannopeptimycin gamma, Manumycin A, Irciniastatin B. IroXanadine, Irtemazole, Isaglidole, Isaglita Manumycin B. Manumycin C. Manumycin E. Manumycin F, Zone, Isalsteine, Isatoribine, Isavuconazonium chloride Manumycin G. Manzamine A. Manzamine B. Manzamine C, hydrochloride, Iseganan hydrochloride, Isepamicin Sulfate, Manzamine D. Manzamine E. Manzamine F. Maprotiline Isocarboxazid, Isofagomine tartrate, Isoniazid, Isoquine, Iso hydrochloride, Maraviroc, Maribavir, Marimastat, Maropi segoline A, Isovanihuperzine A, Ispronicline, Isradipine, tant, Masilukast, Masitinib mesylate, Masnidipine hydro Itasetron, Itopride, Itopride hydrochloride, Itriglumide, chloride, MASTPROM, Matlystatin A, Matlystatin B, Iturelix, Ixabepilone, Janthinomycin A, Janthinomycin B, Matlystatin D. Matlystatin E. Matly statin F. Matristatin A1, Janthinomycin C, Jaspamide, Jasplakinolide, K9-Retrocy Matristatin A2, Matristatin B1, Matristatin D1, Matristatin clin-1, Kahalalide F, Kaitocephalin, Kanglemycin A, kappa E1, Matristatin F1, Maxadilan, Mazokalim, Mebrofenin, Conotoxin PVIIA, Kassinatuerin-1, Katanosin A, Katanosin Mecamylamine hydrochloride, Meclinertant, Meclofe B. Ketamine hydrochloride, Ketanserin, Kifunensine, Kine namate sodium, Medetomidine, Mefenamic acid, Mefloquine tin, Kistamicin A, Kopsinine, Korupensamine A, Korupen hydrochloride, Megovalicin A, Megovalicin B. Megovalicin samine B, Korupensamine C. Kosinostatin, Kurasoin B, C, Megovalicin D. Megovalicin G. Megovalicin H, Melagat Kynostatin-227, Kynostatin-272, Labedipinedilol A, Labe ran, Melanotan, Melanotan I, Melanotan II, Meldonium, dipinedilol B, Labetalol hydrochloride, Labradimil, Lacid Melogliptin, Meloxicam, Meluadrine, Meluadrine tartrate, ipine, Lacosamide, Lactosylphenyl trolox, Ladasten, Lados Memno-peptide A, Memoquin, Mephenytoin, Mephobar tigil tartrate, Laflunimus, Lafutidine, Lagatide, Lamectacin, bital, Mepindolol sulfate, Mepindolol transdermal patch, Lamifiban, Landiolol, Lanepitant, Lanreotide acetate, Lanso Mepirodipine hydrochloride, Mepivacaine hydrochloride, prazole, Lanthiopeptin, Lapatinib ditosylate, LaraZotide Mercaptopurine, Merimepodlib, Meriolin-3, Meropenem, acetate, Laromustine, Larotaxel dihydrate, Lasinavir, Lata Mersacidin, Mesopram, Metaglidasen, Me-Talnetant, Meta moxef sodium, Latrunculin S. Lavanduquinocin, LaZabe nicotine, Metaproterenol sulfate, Meterelin, Metergoline, mide hydrochloride, Lecimibide, Lecirelin, Leconotide, Metesind glucuronate, Metformin hydrochloride, Metham LedaZerol, Leflunomide, Lefradafiban, Leinamycin, Lemi phetamine hydrochloride, Methanobactin, Methicillin noprazole, Lemuteporfin, Lemuteporphin, Lenalidomide, sodium, Methimepip, Methoctramine, Methoin, Methotrex Lenampicillin hydrochloride, Lenapenem hydrochloride, ate, Methoxatin, Methyclothiazide, Methyl bestatin, Methyl Lenapenem hydrochloride hydrate, Lercanidipine hydro histaprodifen, Methylhomoindanomycin, Methylphenidate chloride, Lerisetron, Lestaurtinib, Leteprinim potassium, hydrochloride, Methylphenobarbital, Methylphenobarbi LetraZuril, Leualacin, Leucovorin calcium, Leuprolide tone, Methylthio-DADMe-immucillin-A, Methypranolol, acetate, Leuprorelin acetate, Leurubicin, Levalbuterol hydro Methysergide maleate, Meticillin sodium, Metipranolol, chloride, Levobetaxolol hydrochloride, Levobunolol hydro Metoclopramide hydrochloride, Metolazone, Metoprolol chloride, Levobupivacaine hydrochloride, Levofolinate cal fumarate, Metoprolol succinate, Metoprolol tartrate, Meza cium, Levoleucovorin calcium, Levonadifloxacin arginine copride, Mibefradil, Mibefradil hydrochloride, Micafungin salt, Levonebivolol, Levosalbutamol hydrochloride, Levosi sodium, Michellamine B, Microcin 25, Microcin J25, Micro mendan, Levosulpiride, L-Fluviabactin, L-Fluvibactin, colin A, Microcolin B, Micronomicin sulfate, Midafotel, L-Fluvibactine, L-Histidinol, L-Homothiocitrulline, Liaro Midaxifylline, Mideplanin, Midesteine, Midostaurin, Mila Zole, LiaroZole hydrochloride, Lilblomycin, Licostinel, Lida cemide2H. Milataxel, Milbemycin alpha-9, Milfasartan, midine hydrochloride, Lidanserin, Lidocaine hydrochloride, Milrinone, Milrinone lactate, Mimopezil, Minalrestat, Lifarizine, Lifarizine hydrochloride, Lignocaine, Limazocic, Minaprine hydrochloride, Minopafant, Mipragoside, Mira Linaprazan, Linarotene, LinaZolast, Linetastine, Linezolid, begron, Mirisetron, Mirodenafil hydrochloride, Mitiromycin, Linezolid oxide, Lingual antimicrobial peptide, Linifanib, Mitomycin, Mitomycin C. Mitoxantrone hydrochloride, Linopristin, Linopristine, Linotroban, Lintitript, Lintopride, Mitoxantrone hydrochloride, MivaZerol, Mivobulinisethion Lipohexin, Lipoxazolidinone A, Lipoxazolidinone B. ate, Mivotilate, Mixanpril, Mizolastine, Mobazol, Mocetin Lipoxazolidinone C. Liraglutide, Lirexapride, Lirimilast, ostat dihydrobromide, Moclobemide, Modecainide, Modi Lisdexamfetamine mesilate, Lisinopril, Lisuride maleate, pafant, Moenomycin A chloride bismuth salt, Moexipril Lisuride TTS, Litoxetine, Lixivaptan, L-Lysine-d-amphet hydrochloride, Moexiprilat, Monamidocin, Monodansyl amine dimesylate, 1-Nebivolol, Lobatamide C. Lobatamide cadaverine, Mono-L-aspartyl chlorin e6, Monophosphoryl F. LobeglitaZone Sulfate, Lobenzarit sodium, Lobophorin A, lipid A. Montirelin tetrahydrate, Moracizine hydrochloride, Lobophorin B, Lobradimil, Lobucavir, Lodamin, Lodenafil. Moranolin, Moricizine hydrochloride, Morniflumate, Lofexidine hydrochloride, Loloatin B, Lomefloxacin hydro Mosapramine hydrochloride, Mosapride citrate, Motesanib chloride, Lomeguatrib, Lometrexol, Lopinavir, Loprinone diphosphate, Motretinide, Moxalactam disodium, Moxifetin hydrochloride, Loracarbef hydrate, Lorazepam, Lorcaserin, hydrogen maleate, Moxifloxacin hydrochloride, Moxonidine Lorglumide, Lornoxicam, Losartan, Lotrafiban, Loviride, hydrochloride hydrate, Mozavaptan hydrochloride, Loxiglumide, LOXistatin, Loxoribine, L-Simexonyl mu-Conotoxin IIIA, Multiple sclerosis vaccine, muC-Cono homocysteine, L-Thiocitrulline, L-threitol ceramide, toxin MrVIB, Muraminomicin A, Muraminomicin B, L-threo-C6-pyridinium-ceramide-bromide, Lubazodone Muraminomicin C, Muraminomicin D, Muraminomicin E1, hydrochloride, Lufironil, Lumiracoxib, Lurosetron, Luzin Muraminomicin E2, Muraminomicin F. Muraminomicin G, dole, Lycopersicin, Lymphostin, Lysinated-betulonic acid, Muraminomicin H, Muraminomicin I, Muraminomicin Z1, Lysobactin, Lysuride maleate, Mabuterol hydrochloride, Muraminomicin Z2, Muraminomicin Z3, Muraminomicin Macitentan, Magainin II, Makaluvamine C, Makaluvamine Z4, Muramyl dipeptide C. Mureidomycin A, Mureidomycin D, Makaluvamine E. Makaluvamine F, Makaluvone, Mana B. Mureidomycin C, Mureidomycin D. Mureidomycin E, US 2015/0202317 A1 Jul. 23, 2015
Mureidomycin F. Mureidomycins, Muroctasin, Mycalamide Pachymedusa dacnicolor Tryptophyllin-1, Pachysamine E. A, Mycalamide B, Myxovirescin A1, Myxovirescin B, Paclitaxel, Paclitaxel ceribate, Pactimibe, Padeliporfin potas N1,N8-Bisnorcymserine, N1-Phenethylnorcymserine, sium, Pafenolol, Palau'amine, Paldimycin B, Palinavir, Pal N4-Hexadecyl-dC-AZT, Naamidine A. N-Acetylcolchinol, indore fumarate, Palmidrol, Palmitoylethanolamide, Palosu N-Acetylcysteine, N-Acetylesperamycin A1, N-Acetyles ran Sulfate, Pamapimod, p-Aminoclonidine hydrochloride, peramycin Alb, N-Acetylesperamycin A2, N-Acetyl-L-cys Pancopride, Pancratistatin disodium phosphate, Pancratista teine, Nadolol, Nafadotride, Nafamo.stat mesilate, Nafamo tin-3,4-cyclic phosphate Sodium salt, Panobinostat, Pan stat mesylate, Nafarelin acetate, Naglivan, Nagrestipen, tethine, Pantoprazole, Papuamide A, Papuamide B, Papua Nagstatin, Naltrindole, Naluzotan hydrochloride, Naminidil, mide C. Papuamide D, Paracetamol, Paraherquamide E. Naproxen piperazine (2:1), Napsagatran, Napsamycin A, Paraherquamide F, Paraherquamide G. Parasin I, Parathyroid Napsamycin B, Napsamycin C, Napsamycin D. Naratriptan hormone (human recombinant), Parcetasal, PardoprunoX hydrochloride, Nardeterol, Nateglinide, Navelbine, Navuri hydrochloride, Parodilol hemifumarate, Parogrelil hydro dine, Naxifylline, Nazasetron, Nazasetron hydrochloride, chloride, Paroxetine, Paroxetine ascorbate, Paroxetine cam N-demethylated sildenafil. N-Desmethylmilameline, Nebiv silate, Paroxetine hydrochloride, Paroxetine mesilate, Pasi olol, Neboglamine, Nebostinel, Necrostatin-1, Nefiracetam, reotide, Pazelliptine trihydrochloride, Pazelliptine Neihumicin, Nelfinavir mesilate, Nemifitide ditriflutate, trihydrochloride monohydrate, Pazopanib hydrochloride, Nemonapride, Neo-acridine, Neomycin B-arginine conju PEG40000-Paclitaxel, PEG5000-Paclitaxel, PEG-vancomy gate, Neomycin B-hexaarginine conjugate, Neomycin-acri cin, Peldesine, Pelitinib, Pelitrexol, Pemetrexed disodium, dine, Nepadutant, Nepaprazole, Nepicastat hydrochloride, Pemirolast, Pemirolast potassium, Pemoline, Penbutolol sul Neratinib, Nerfilin I, Nesbuvir, Nesiritide, Netamiftide trif. fate, Penciclovir, Penicillin G procaine, Penicillin G sodium, luoroacetate, Netilmicin sulfate, Netivudine, Netoglitazone, Pentafuside, Pentobarbital sodium, Pentobarbitone sodium, Neu5Ac2en, Neuromedin U-25, Neuropeptide S. Neutrophil Pentostatin, Peplomycin, Pepticinnamin E. Peptide Leucine activating factor, Nevirapine, Ngercheumicin A, Arginine, Peramivir, Perfosfamide, Pergolide mesylate, Per Ngercheumicin B. Ngercheumicin C, Ngercheumicin D, indopril, Perzinfotel, Pexiganan acetate. PG-camptothecin, Ngercheumicin E, Nibentan, Nicardipine hydrochloride, Phakellistatin 5, Phakellistatin 7, Phakellistatin 8, Phakel Nicavir, Nicorandil, Nicotredole, Niduline, Nifedipine, listatin9, Phe-Arg-beta-naphthylamide, Phendioxan, Phenel Nifekalant hydrochloride, Nifurzide, Niguldipine hydrochlo famycin F. Phenelzine sulfate, Phenobarbital, Phenobarbi ride, Nilotinib hydrochloride monohydrate, Nilutamide, Nil tone, Phenochalasin A, Phenochalasin B, Phenoxazole, vadipine, Nimesulide, Nimodipine, Nipradolol, Nisin, Nisol Phenserinetartrate, Phentolaminemesilate, Phenylisohydan dipine, Nitazoxanide, Nitracrine dihydrochloride hydrate, toin, Phenylpseudohydantoin, Phenytoin sodium, Phevalin, Nitrazepam, Nitrendipine, Nitrofenac, Nitroparacetamol, Phomopsichalasin, Phortress, Phosphazid, Phosphenytoin Nitroso-nifedipine, Nitrosopine, Nitrovin, Nivadipine, Niza sodium, Photofrin II, Physostigmine salicylate, Piboserod tidine, Noberastine, Noberastine citrate, Nocathiacin I, hydrochloride, Pibrozelesin hydrochloride, Pibutidine No.cathiacin II, No.cathiacin III, Nocathiacin IV, NO-ciprof hydrochloride, Piceasin, Piclamilast, Picotamide, Picume loxacin, N-Octyl-beta-valienamine, NO-ibuprofen, Nolatr terol fumarate, Pidobenzone, Pidolacetamol, Pidolate mag exed dihydrochloride, Nolomirole hydrochloride, NO-Nife nesium, Pidotimod, Pifatidine, Pikamilone, Piketoprofen, dipine, Nooglutil, Nooglutyl, NO-Paracetamol, Pilsicainide hydrochloride, Pimagedine, Pimavanserin tar Norastemizole, Nordazepam, Norfloxacin, Nornicotine, trate, Pimeloylanilide o-aminoanilide, Pimobendan, Norsegoline, Nortopixantrone hydrochloride, Nortopsentin Pimozide, Pinacidil, Pindolol, Pioglitazone, Pioglitazone A, Nortopsentin B, Nortopsentin C, Nortopsentin D, Nortrip hydrochloride, Pipalamycin, Piperacillin sodium, Piper tyline hydrochloride, Nostocyclopeptide M1, N-Retinoyl-D- afizine A, Piperafizine B, Piproxen, Piragliatin, Pirbuterol glucosamine, N-tert butyl isoquine, Nubiotic 2, Nutlin-3, hydrochloride, Pirenzepine hydrochloride, Piroxicam, Nutlin-3A, Nutlin-3-enantiomer A, Nuvanil, O6-Benzylgua Piroxicam cinnamate, Piroxicam pivalate, Piscidin 1, Pisci nine, Obatoclax mesylate, Oberadillol, Oberadilol monoethyl din 2, Piscidin 3, Pittsburgh Compound B, Pivagabine, Piv maleate, Octacosamicin A, Octacosamicin B, Octreother, ampicillin, Pixantrone maleate, Platencin, Platensimycin, Octreotide acetate, Octreotide LAR, Odanacatib, O-Demeth Plerixafor hydrochloride, Plevitrexed, Plinabulin, Plitidep ylmurrayafoline A, Oglufanide disodium, Olanexidine sin, Plusbacin A1, Plusbacin A2, PlusbacinA3, Plusbacin A4, hydrochloride, Olanzapine, Olanzapine pamoate, Olaparib, Plusbacin B1, Plusbacin B2, Plusbacin B3, Plusbacin B4, Olcegepant, Olmesartan, Olmesartan medoxomil, Olprinone Pneumocandin A0, Pneumocandin B0, Pneumocandin B0 hydrochloride, Olradipine hydrochloride, Omaciclovir, 2-phosphate, Pneumocandin D0, Polaprezinc, Polydiscam Omapatrilat, Ombrabulin, Ombrabulin hydrochloride, ide A, Polyglutamate camptothecin, Polymer bound human omega-Conotoxin CVID, omega-Conotoxin MVIIA, Ome leukocyte elastase inhibitor, Polythiazide, Porfimer sodium, prazole, Omiganan pentahydrochloride, Onnamide A, Onta Poststatin, Pozanicline hydrochloride, PPI 17-24, Pradimicin Zolast, Opaviraline, OPC-17083, Opiorphin, Orbifloxacin, A, Pradimicin B, Pradimicin C, Pradimicin D, Pradimicin E, Orbofiban acetate, Orciprenaline sulphate, Orienticin A. Ori Pradimicin FA-1, Pradimicin FA-2, Pradimicin FL, Pradimi enticin B, Orienticin C, Orienticin D. Oritavancin, Orlipastat, cin FS ((+)-enantiomer), Pradimicin L. Pradimicin S. Orlistat, Ortataxel, Oseltamivir carboxylate, Oseltamivir Pradimicin T1, Pradimicin T2, Pradofloxacin, Pralatrexate, phosphate, Osemozotan hydrochloride, Osutidine, Otamixa Pralmorelin, Pralnacasan, Pramipexole hydrochloride, ban, Otastat potassium, Otenabant hydrochloride, Oteracil Pramipide, Pramiracetam hydrochloride, Pramlintide potassium, Ovalicin A, Ovothiol B, Oxamflatin, Oxatomide, acetate, Pranazepide, Pranedipine tartrate, Pranidipine, Pran Oxazepam, Oxeclosporin, Oxiglutatione sodium, Oximidine lukast hydrate, Pratosartan, Prefolic A. Premafloxacin, Pre III, Oxonic acid, Oxprenolol hydrochloride, Oxymetazoline mafloxacin hydrochloride, Premafloxacin magnesium, hydrochloride, Oxymethacyl, Oxymorphazole dihydrochlo Prezatide copper acetate, Primaquine phosphate, Primidone, ride, Oxynor, Oxypertine, Oystrisin, Ozarelix, Ozenoxacin, Prinomastat, Prinomide tromethamine, Prisotinol, Pristina US 2015/0202317 A1 Jul. 23, 2015 20 mycin IA, Pristinamycin IB, Pristinamycin IIA, Pristinamy tin, Salbutamol nitrate, Salbutamol sulfate, Salcaprozic acid cin IIB, Proamipide, Probestin, Procainamide hydrochloride, sodium salt, Salicylihalamide A, Salicylihalamide B, Salina Procaine Penicillin, Procaterol hydrochloride hemihydrate, mide A, Salinosporamide A, Saliphenylhalamide, Sal Procysteine, Pro-diazepam, Proglumide, Propacetamol materol, Salmeterol, Salmeterolxinafoate, Salmisteine, Salu hydrochloride, Propafenone hydrochloride, Propeptin, brinal, Samixogrel, Sampatrilat, Sampidine, Sanglifehrin A, Propeptin T. Propranolol hydrochloride, Prostatin, Protaxel, Sanglifehrin B, Sanglifehrin C, Sanglifehrin D. Sanilvudine, Protegrin IB-367, Proterguride, Protriptyline hydrochloride, Sapacitabine, Saprisartan, Sapropterin dihydrochloride, Proxodolol, Prucalopride, Prucalopride hydrochloride, Pru Saquinavir, Saquinavir mesilate, Sardomozide, Sardomozide calopride succinate, Pruvanserin hydrochloride, Pseu hydrochloride, Saredutant, Sarizotan hydrochloride, Satorib doephedrine hydrochloride, Pseudomycin A", Pseudomycin ine, Saussureamine C, Saviprazole, SaZetidine-A, Schizan B', Psymberin, Ptidepsin, Pumaprazole, Pumosetrag hydro drin glycinosuccinate Sodium salt, Scyphostatin, SecinH-3, chloride, Purvalanol A, Pyloricidin B, Pymeprazole, Pyrazi Secobarbital sodium, Secobatzelline A, Secobatzelline B, noylguanidine, Pyrazoloacridine, Pyridinostatin, Pyridone-6, Seglitide, Segoline A, Segoline B, Selanc, Selank, Selodeno Pyriferone, Pyrindamycin A. Pyrindamycin B, Pyroxamide, son, Semagacestat, Semapimod hydrochloride, Semaxanib, Pyrrocidine A, Pyrrocidine B, Pyrroloquinoline quinone, Semaxinib, SemoXind, Semparatide, Sepimostat mesilate, Pyrrolosporin A. Pyrrophenone, Quarfloxin, Quinagolide Seraspenide, Sermorelin, Sertindole, Sertraline, Sertraline hydrochloride, Quinalbarbitone sodium, Quinapril hydro hydrochloride, Setamycin, Setastine hydrochloride, Setazin chloride, QuinethaZone, Quinotolast sodium, Quinoxapeptin dol, Setipafant, Sezolamide hydrochloride. Shepherdin, C, Quinupristin mesilate, R9K-Retrocyclin, Rabeximod, Shermilamine D, Shiga vaccine, Shishijimicin A, Shishijimi rac-Debromoflustramine E. rac-Deoxypseudophrynaminol, cin B, Shishijimicin C, Sialosylcholesterol-alpha sodium salt, Racecadotril, rac-Ptilocaulin nitrate, rac-threo-Methylpheni Sialosylcholesterol-beta sodium salt, Siamycin I, Siamycin date hydrochloride, Radequinil, Radezolid, Radolmidine II, Sibanomicin, Sibenadet hydrochloride, Sibrafiban, Sifu hydrochloride, Rafabegron, Ragaglitazar L-arginine salt, Virtide, Sildenafil citrate, Sildenafil mesilate, Sildenafil Ralfinamide, Raltegravir potassium, Raltitrexed, Raluridine, nitrate, Sildenafil N-oxide, Silodosin, Siltenzepine, Simen Ramatroban, Ramelteon, Ramipril, Ramoplanin A1, dan, Simotaxel, Sinorphan, Sitamaquine hydrochloride, Ramoplanin A2, Ramoplanin A3. Ramorelix, Ramosetron Sivelestat sodium hydrate, Sivifene, SNAP-7292, SNAP hydrochloride, Ranbezolid hydrochloride, Ranimustine, 7493, S-Nitrosoglutathione, Soblidotin, Socorromycin, Sofi Ranirestat, Ranitidine bismuth citrate, Ranitidine Bismutrex, gatran, Sofinicline, Solabegron hydrochloride, Solimastat, Ranitidine hydrochloride, Ranitidine nitrate, Ranitidine Zinc Solpecainol hydrochloride, Somocystinamide A, Sorafenib, chloride complex, Ranitidine Zinc citrate, Ranolazine, Rasa Sorafenib tosylate, Soraprazan, Sorbicillactone A, Sore giline mesilate, Rat adrenomedullin, Razaxaban hydrochlo tolide, Sorivudine, Sotalol hydrochloride, Sotrastaurin, Spar ride, Razupenem, Rebamipide, Rebamipide bismuth citrate floxacin, Sparoxomycin A1, Sparoxomycin A2, Sperabillin tetramethyledamine, Rebamipide bismuth L-tartrate tetram A, Sperabillin B. Sperabillin C, Sperabillin D. Spermidine/ ethyledamine, Rebimastat, Reblastatin, Reboxetine mesilate, lysine3/CTS6, Spermine dialdehyde, Spermine/lysine4/ Receptor mediated permeabilizer, Recombinant human par CTS8, Spinorphin, Spiralizone B, Spirapril, Spiriprostil, athyroid hormone (1-84). Recombinant Jerdostatin, Regad Spiroglumide, Spiroquinazoline, Spiruchostatin A, Spiru enoson, Reglitazar, Relacatib, Relaxin-3/INSL5 chimeric chostatin B, Sprodiamide, Squalamine lactate, Stampidine, peptide, Remacemide hydrochloride, Remikiren mesilate, Stavudine, Stearyl-norleucine-VIP, Sterenin C, Streptomy Reminertant, Remoxipride, Remoxipride hydrochloride cin, Stressin1-A, Styloguanidine, Suberanilohydroxamic monohydrate, Repaglinide, Reparixin, Repertaxin, Repino acid, Suberoylanilide hydroxamic acid, Substance P(8-11), tan, Repinotan hydrochloride, Repirinast, Reproterol hydro Sufotidine bismuth citrate, Sufugolix, SulaZuril, Sulcepha chloride, Resatorvid, Resequinil, Reserpine, Retaspimycin losporin, Sulfasalazine, Sulfostin, Sulofenur, Sulphasalazine, hydrochloride, Retigabine hydrochloride, Retosiban, Sulphostin, Sulpiride, Sulpiride L-(-), Sulprostone, Sulta Revaprazan hydrochloride, Reversine, Revizinone, micillin tosylate, Sultopride, Sulukast, Sumanirole maleate, Rhodopeptin C1, Rhodopeptin C2, Rhodopeptin C3, Sumatriptan succinate, Sunflower trypsin inhibitor-1, Suni Rhodopeptin C4, Rhodostreptomycin A, Rhodostreptomycin tinib malate, Super-Leu-Dox, Suplatast tosilate, Suprofenac B. Ricasetron, Rifabutin, Rifalazil, Rifamexil, Rifampicin, 1. Suprofenac 2, Suprofenac 3, Suradista, Suramin Sodium, Rifampin, Rifapentine, Rifaximin, Rilmazafone hydrochlo Surfen, Surinabant, Suronacrine maleate, Susalimod, Sym ride dihydrate, Rilmenidine dihydrogen phosphate, Rilpivir plostatin 1, Synguanol, Synthadotin, Synthetic human secre ine, Rimonabant, Rimoterol hydrobromide, Ripisartan, Riso tin, Synthetic neutrophil inhibitor peptide, Synthetic porcine tilide, Rispenzepine hydrochloride, Ritonavir, Ritonavir secretin, Tabilautide, Tabimorelin, Tacapenem pivoxil, Tace oxymethylphosphate, Rivanicline, RivaroXaban, dinaline, Tadalafil. Tafenoquine Succinate, Tageflar, Talaglu RivoglitaZone, Rizatriptan benzoate, Rizatriptan Sulfate, metad hydrochloride, Talaporfin gold sodium, Talaporfin r-Jerdostatin, Robenacoxib, Robotnikinin, Rocepafant, Rof sodium, Talarozole, Talibegron, Talibegron hydrochloride, lumilast, Rolapitant hydrochloride, Rolipram, Rolofylline, Tallimustine hydrochloride, Talnetant, Talniflumate, Talop Romergoline, Romidepsin, Romurtide, Ropinirole hydro terin, Talotrexin, Taltirelin, Taltobulin, Taludipine hydrochlo chloride, Ropivacaine hydrochloride, Rosabulin, Rosco ride, Talviraline, Tamandarin A, Tamandarin B, Tamatinib vitine, RosiglitaZone maleate, Rosonabant, Rotigaptide, fosdium, Tamibarotene, Tamsulosin hydrochloride, Tanapro Roxatidine acetate hydrochloride, Roxatidine bismuth cit get, Tandutinib, Tanespimycin, Tanogitran, TAP-doxorubi rate, Roxifiban acetate, Roxindole mesilate, Ruboxistaurin cin, Taranabant, Tarazepide, Targinine, Targinine hydrochlo hydrochloride, Ruboxistaurin mesilate hydrate, Rumycin 1, ride, Tariquidar, Tasidotin hydrochloride, Tasimelteon, Rumycin 2, Rupintrivir, Ruprintrivir, Sabiporide mesilate, Tasosartan, Taurohyodeoxycholic acid, Tauroiodeoxycholic Safinamide mesilate, Safironil, Sagamacin, Sagandipine, acid, Taurolidine, Tauropyrone, Taurosteine, Taxuyunnanine, Salazodine, Salazopyridazin, Salazosulfapyridine, Salbosta Tazanolast, Tazofelone, Tazopsine, Tebanicline, Tecadeno US 2015/0202317 A1 Jul. 23, 2015
son, Tecalcet hydrochloride, Tecastemizole, Technetium Ulvenzepine hydrochloride, Uncialamycin, Uniroyal JR, (99mTc) apcitide, Technetium (99mTc) bicisate, Technetium Unnarmicin A, Unnarmicin C, Upidosin, Upidosin hydro (99mTc) depreotide, Technetium Tc 99m depreotide, Tech chloride hydrate, Urapidil, Uroguanylin, Urukthapelstatin A, netium Tc99m bicisate, Tecovirimat, Tegafur, Tegaserod Utibapril, Utibaprilat, V. Vabicaserin hydrochloride, Valaci maleate, Teglicar, Teicoplanin-A2-1, Teicoplanin-A2-2, clovir, Valacyclovir, Valganciclovir hydrochloride, Valnemu Teicoplanin-A2-3, Teicoplanin-A2-5, Telaprevir, Telatinib, lin, Valomaciclovir Stearate, Valrocemide, Valrubicin, Valsar Telavancin hydrochloride, Telbivudine, Telcagepant, tan, Valsartan axetil, Valsartan cilexetil, Valsartan pivoxil, Telinavir, Teludipine hydrochloride, Temacrazine mesilate, Valspodar, Vancomycin hydrochloride, Vandetanib, Vanid Temafloxacin hydrochloride, Temocapril hydrochloride, ipinedilol, Vaninolol, Vapitadine hydrochloride, Vardenafil. Temocillin sodium, Temoporfin, Temurtide, Tenatoprazole, Vardenafil dihydrochloride, Vardenafil hydrochloride Tenovin 6, Tenoxicam, Terbequinil, Terbogrel, Terbutaline hydrate, Varenicline tartrate, Variapeptin, Varlitinib, sulfate, Terestigmine tartrate, Terguride, Teriflunomide, Teri Vasonatrin peptide, Vatalanib Succinate, Vatanidipine, paratide, Terlakiren, Terlipressin, Ternatin, Terodiline hydro Vatanidipine hydrochloride, V-Echinocandin, Velneperit, chloride, Tertatolol hydrochloride, Tertomotide, Terutroban Venorphin, Veralipride, Verongamine, Verticillatine, Vesicu Sodium, Tesetaxel, Tetrabromostyloguanidine, Tetracaine lin, Vesnarinone, Vestipitant mesylate. V-Glycopeptide, Vice hydrochloride, Tetrahydrobiopterin, Tetrahydrodercitin 1, nistatin, Vilazodone hydrochloride, Vildagliptin, Viloxazine Tetrahydroechinocandin B, Tetrahydrolipstatin, Tetrazolast hydrochloride, Vincristine sulfate, Vindesine, Vinflunine, meglumine, Tetrindol, Tetrindole, Texenomycin A, Textili Vinfosiltine sulfate, Vinleucinol, Vinorelbine, Vinxaltine sul nin-1, Tezampanel, Tezosentan, TGP. Thalidomide, Thana fate, Vinylamycin, Virginamycin M2, Virginiamycin M1, Vir tin, Theopederin D. Theoperidin E. Theophylline. Thiacym gisin-1, Virgisin-2, Viscosin, Vistonuridine, Vitilevuamide, serine. Thiamet-G, Thiamphenicol. Thiamylal. Thiatolserine, Voclosporin, Vofopiitant hydrochloride, Voglibose, Volpristin, Thiazinotrienomycin B. Thiazinotrienomycin F. Thiazinot Voreloxin, Vorinostat, Voxergolide hydrochloride, W Pep rienomycin G. Thiazohalostatin, Thiocoraline. Thiocoraline tide, Watanidipine, Watanidipine hydrochloride, Xamoterol A, Thiocoraline NF. Thiofedrine. Thiomarinol, Thiomarinol fumarate, Xemilofiban, Xenomin 1, Xenomin 2, Xenoxin-1, B. Thiomarinol C, Thiomarinol D, Thiomarinol E. Thiomar Xenoxin-2, Xenoxin-3, Ximelagatran, Xipamide, Yatakemy inol F. Thionisoxetine-(R). Thiopental sodium, Thiopentone cin, Yohimbine. Yttrium-90 edotreotide, Zabicipril hydro sodium, Thioviridamide. Thioxamycin, Thr10-Contulakin G, chloride, Zabiciprilat hydrochloride, Zabofloxacin hydro Threitol ceramide, Thymalfasin, Thymallene, Thymectacin, chloride, Zafirlukast, Zampanolide, Zanamivir, Zanapezil Thymic humoral factor gamma-2, Thymoctonan, Thymo fumarate, Zankiren, Zardaverine, Zatosetron, Zatosetron dolic acid, Thymopentin, Thymosin alpha 1, Tiamdipine, Tia maleate, Zelandopam hydrochloride, Zibotentan, Ziconotide, menidine, Tianeptine Sodium, Tiapafant, Tiapride hydrochlo Zidampidine, Zidovudine, Zilpaterol, Zinc aceXamate, ride, Tidembersat, Tienartan, Tienoxolol hydrochloride, Ziprasidone hydrochloride, Ziprasidone mesilate, Zofenop Tifenazoxide, Tifluvirtide, Tigecycline, Tigilcycline, Tilargi rilat arginine, Zolasartan, Zolmitriptan, Zonampanel, Zoru nine hydrochloride, Tilisolol hydrochloride, Timodepressin, bicin hydrochloride, Timodolic acid, Timogen, Timolol hemihydrate, Timolol 0153 D may contain further functional groups besides at maleate, Tinazoline hydrohloride, Tiobutarit, Tiocol 33, Tio least one aliphatic amino group to which the promoiety is col 54, Tiplimotide, Tipranavir, Tiracizine hydrochloride, bound, Such further functional group may be aliphatic or Tirofiban hydrochloride, Tiropramide, Tisartan, Tivirapine, aromatic amines, amides, alcohols, carbonyls, carboxylic Tizanidine hydrochloride, TNF-alpha protease enzyme acids, thiols. The term “aliphatic' (aliphatic fragment) means inhibitor, Toborinone, Tocainide hydrochloride, Tokaramide A, Tolafentrine, Tolbutamide, Tolfenamic acid, Tolvaptan, any aliphatic fragment known to a person skilled in the art. Tomatine, Tomeglovir, Tomopenem, Tomoxetine hydrochlo 0154 Preferably, the carrier group Z (PEG or hydrogel) is ride, Tonabersat, Topixantrone hydrochloride, Topostatin, a polymer with a molecular weights 500 g/mol. Topsentin, Topsentine B1, Torasemide, Torsemide, Tose dostat, Tozasertib, Trabectedin, Tramazoline, Trandolapril, (O155 In one embodiment, the carrier Z may be a PEG Trandolaprilat, Tranilast, trans,trans-Ceratospongamide, moiety. Such PEG moiety may be attached to the biologically Transdihydrolisuride, Trantinterol hydrochloride, Trapoxin active agent through one or more linkages. In case of one A, Trapoxin B, Trecetilide fumarate, Treprostinil diethanola linkage, the corresponding PEG in the PEG prodrug mono mine, Tresperimus triflutate, Trewiasine, Triacetylidynemicin conjugate may be linear or branched. In case of more than one C, Trichostatin D, Triciferol, Trientine hydrochloride, Triflu linkage. Such as in a bisconjugate, the corresponding PEG in proxim, Trifluridine, Trimetazidine, Trimetrexate glucur onate, Trimexautide, Triproamylin acetate, TroglitaZone, the PEG prodrug may be linear or branched. Bisconjugates Trombodipine, Tropisetron, Troquidazole,Trovirdine hydro may contain one or two transient linkages, and PEG may be chloride, Troxipide, Trunkamide A, Tryptamide, Tubastrine linear or branched or may contain a mixture of one linear and ((+)-enantiomer), Tubingensin B, Tubulysin A, Tubulysin B, one branched chain. In case the bisconjugate contains one Tubulysin C, Tuftsin, Tulathromycin A, Tulathromycin B, transient linkage and one linear and one branched chain the Tulobuterol hydrochloride, Tulobuterol-(R), Tulopafant, transient linkage may be on either chain. In case a branched Tumor necrosis factor-alpha protease inhibitor, Turbostatin 1, PEG chain is used, there may be one or more branching units. Turbostatin 2, Turbostatin 3, Turbostatin 4, Turofexorate iso propyl, Turosteride ((-)-enantiomer), Tyropeptin A10. 0156. A branched PEG is a PEG molecule consisting of a Tyropeptin A2, Tyropeptin A6, Tyropeptin A7, Tyropeptin branching point connecting two or more PEG chains, to form A9, Tyroservaltide, Tyroservatide, Ubenimex, Ubenimex a molecule with one anchoring point for attachment to the methyl ester, Ubestatin, Ubidine, Udenafil. Ufenamate, biologically active agent. This could be two 20 kDa PEG Ukrain, Ulicyclamide, Ulifloxacin, Ulithiacyclamide A, chains joined together to form one branched 40 kDa PEG US 2015/0202317 A1 Jul. 23, 2015 22 molecule. In the case where the molecule contains two or ited to carboxylic acid and derivatives, carbonate and deriva three branching points, the molecule is referred to 3- and tives, hydroxyl, hydrazine, hydroxylamine, maleamic acid 4-armed PEG, respectively. and derivatives, ketone, amino, aldehyde, thiol and disulfide. 0157. In summary and within the restrictions mentioned 0.167 Such biodegradable hydrogel may be composed of above, the PEG polymer is not limited to a particular structure backbone moieties interconnected by hydrolytically degrad and can be linear, branched, or multi-branched. able bonds. The backbone moiety is characterized by a num 0158 Preferably, Z is a hydrogel and more preferably a ber of functional groups, comprising interconnected biode PEG-based hydrogel. Preferably, the covalent attachment gradable functional groups and hydrogel-connected drug formed between the linker and the hydrogel Z is a permanent linker conjugates, and optionally capping groups. This means bond. The term "PEG based as understood herein means that that a backbone moiety is characterized by a number of the mass proportion of PEG chains in the hydrogel is at least hydrogel-connected drug-linker conjugates; functional 10% by weight, preferably at least 25%, based on the total groups, comprising biodegradable interconnected functional weight of the hydrogel. The remainder can be made up of groups; and optionally capping groups. Preferably, the Sum of spacers and/or oligomers or polymers, such as oligo- or polyl interconnected biodegradable functional groups and drug ysines. linker conjugates and capping groups is 16-128, preferred 0159 Moreover, the term “water-insoluble' refers to a 20-100, more preferred 24-80 and most preferred 30-60. swellable three-dimensionally crosslinked molecular net 0168 Preferably, the sum of interconnected functional work forming the hydrogel. If suspended in a large Surplus of groups and hydrogel-connected drug-linker conjugates and water or aqueous buffer of physiological osmolality the capping groups of a backbone moiety is equally divided by hydrogel may take up a substantial amount of water, e.g. up to the number of PEG-based polymeric chains extending from 10-fold on a weight per weight basis, and is therefore the branching core. For instance, if there are 32 intercon swellable but after removing excess water still retains the nected functional groups and hydrogel-connected drug physical stability of a gel and a shape. Such shape may be of linker conjugates and capping groups, eight groups may be any geometry and it is understood that such an individual provided by each of the four PEG-based polymeric chains hydrogel object is to be considered as a single molecule extending from the core, preferably by means of dendritic consisting of components wherein each component is con moieties attached to the terminus of each PEG-based poly nected to each other component through chemical bonds. meric chain. Alternatively, four groups may be provided by 0160 According to this invention, the hydrogel may be each of eight PEG-based polymeric chains extending from composed of backbone moieties interconnected by hydrolyti the core or two groups by each of sixteen PEG-based poly cally degradable bonds. meric chains. If the number of PEG-based polymeric chains 0161 Preferably, the backbone moiety has a molecular extending from the branching core does not allow for an equal weight in the range of from 1 kDa to 20 kDa, more preferably distribution, it is preferred that the deviation from the mean from 1 kDa to 15 kDa and even more preferably from 1 kDa number of the sum of interconnected functional groups and to 10 kDa. The backbone moieties are preferably also PEG hydrogel-connected drug-linker conjugates and capping based, comprising one or more PEG chains. groups per PEG-based polymeric chain is kept to a minimum. 0162 A preferred aspect of the present invention is a car 0169 Preferably, a backbone moiety is further character rier-linked prodrug comprising a biodegradable hydrogel as ized by having a branching core, from which at least three carrier, wherein a number of permanent linkages of the back PEG-based polymeric chains extend. Accordingly, in a pre bone moieties exist with the linker L to which the biologically ferred aspect the backbone reagent comprises a branching active moiety is covalently attached. core, from which at least three PEG-based polymeric chains 0163 Ideally, the hydrogel-connected drug-linker conju extend. Such branching cores may be comprised of poly- or gates are dispersed homogeneously throughout the hydrogel oligoalcohols in bound form, preferably suitably substituted according to the invention, and may or may not be present on derivatives of pentaerythritol, tripentaerythritol, hexaglycer the Surface of the hydrogel according to the invention. ine, Sucrose, Sorbitol, fructose, mannitol, glucose, cellulose, 0164. The functional groups may be attached to a linear amylases, starches, hydroxyalkyl starches, polyvinylalco chain. In this case, the functional groups may be spaced hols, dextranes, hyaluronans, or branching cores may becom regularly or irregularly across the chain, or alternatively, the prised of poly- or oligoamines such as ornithine, diaminobu chain may be terminated by two dendritic moieties, providing tyric acid, trilysine, tetralysine, pentalysine, hexalysine, for the total of functional groups. heptalysine or oligolysine, nonalysine, decalysine, undecal 0.165 Remaining reactive functional groups which are not ysine, dodecalysine, tridecalysine, tetradecalysine, pentade connected to a transient prodrug linker or to a spacer con calysine or oligolysines, low-molecular weight PEI, polyvi nected to a transient prodrug linker may be capped with nylamines, hexaglycerine, tripentaerythritol, in bound form. Suitable blocking reagents. 0170 Preferably, the branching core extends three to six 0166 Preferably, the covalent attachment formed between teen PEG-based polymeric chains, more preferably four to the reactive functional groups provided by the backbone moi eight. Preferred branching cores may be comprised of pen eties and the prodrug linker are permanent bonds. Suitable taerythritol, ornithine, diaminobutyric acid, trilysine, tetral functional groups for attachment of the prodrug linker to the ysine, pentalysine, hexalysine, heptalysine or oligolysine, hydrogel according to the invention include but are not lim low-molecular weight PEI, hexaglycerine, tripentaerythritol US 2015/0202317 A1 Jul. 23, 2015
in bound form. Preferably, the branching core extends three to 0.175 More preferably, the sum of interconnected and sixteen PEG-based polymeric chains, more preferably four to reactive functional groups of a backbone moiety is equally eight. Preferably, a PEG-based polymeric chain is a linear divided by the number of PEG-based polymeric chains poly(ethylene glycol) chain, of which one end is connected to extending from the branching core. For instance, if there are the branching core and the other to a hyperbranched dendritic 32 interconnected functional groups and reactive functional moiety. It is understood that a polymeric PEG-based chain groups, eight groups may be provided by each of the four may be terminated or interrupted by alkyl or aryl groups PEG-based polymeric chains extending from the core, pref optionally substituted with heteroatoms and chemical func erably by means of dendritic moieties attached to the termi tional groups. nus of each PEG-based polymeric chain. Alternatively, four 0171 Preferentially, a backbone moiety is characterized groups may be provided by each of eight PEG-based poly by having a branching core, from which at least three chains meric chains extending from the core or two groups by each extend. Such branching cores may be provided by suitably of sixteen PEG-based polymeric chains. substituted derivatives of poly- or oligoalcohols, preferably 0176 Such multi-arm PEG derivatives may be connected pentaerythritol, tripentaerythritol, hexaglycerine, Sucrose, to dendritic moieties to obtain additional functional groups. Sorbitol, fructose, mannitol, glucose, cellulose, amyloses, Preferably, each dendritic moiety has a molecular weight in starches, hydroxyalkyl starches, polyvinylalcohols, dex the range of from 0.4 kDa to 4 kDa, more preferably 0.4kDa tranes, hyualuronans, or branching cores may be provided by to 2 kDa. Preferably, each dendritic moiety has at least 3 Suitably Substituted derivatives of poly- or oligoamines Such branchings and at least 4 reactive functional groups, and at as trilysine, tetralysine, pentalysine, hexalysine, heptalysine, most 63 branchings and 64 reactive functional groups, pre octalysine, nonalysine, decalysine, undecalysine, dedecal ferred at least 7 branchings and at least 8 reactive functional ysine, tridecalysine, tetradecalysine, pentadecalysine or oli groups and at most 31 branchings and 32 reactive functional golysines, polyethyleneimines, polyvinylamines. Preferably, groups. the branching core extends three to sixteen chains, more 0177 Examples for such dendritic moieties are comprised preferably four to eight. Preferably, such chain is a linear of trilysine, tetralysine, pentalysine, hexalysine, heptalysine, polyethylene glycol chain, of which one end is connected to octadecalysine, nonadecalysine in bound form. Examples for the branching core and the other to a hyperbranched dendritic such preferred dendritic moieties are comprised of trilysine, moiety. tetralysine, pentalysine, hexalysine, heptalysine in bound 0172 Preferably, a PEG-based polymeric chain is a suit form, most preferred trilysine, pentalysine or heptalysine, ably substituted polyethylene glycol derivative (PEG based). ornithine, diaminobutyric acid in bound form. (0173 Preferred structures for corresponding PEG-based 0.178 Preferably, such dendritic moieties are comprised of polymeric chains extending from a branching core contained lysine, dilysine, trilysine, tetralysine, pentalysine, hexal in a backbone moiety are multi-arm PEG derivatives as, for ysine, heptalysine, most preferred trilysine, pentalysine or instance, detailed in the products list of Jenkem Technology, heptalyine, in bound form. USA (accessed by download from www.jenkemusa.com on 0179 Most preferably, the hydrogel of the prodrugs of the Jul. 28, 2009), 4ARM-PEG Derivatives (pentaerythritol present invention is characterized in that the backbone moiety core), 8ARM-PEG Derivatives (hexaglycerin core) and has a quarternary carbon of formula C(A-Hyp), wherein 8ARM-PEG Derivatives (tripentaerythritol core). Most pre each A is independently a poly(ethylene glycol) based poly ferred are 4arm PEG Amine (pentaerythritol core) and 4arm meric chain terminally attached to the quarternary carbon by PEG Carboxyl (pentaerythritol core), 8arm PEG Amine a permanent covalent bond and the distal end of the PEG (hexaglycerin core), 8arm PEG Carboxyl (hexaglycerin based polymeric chain is covalently bound to a dendritic core), 8arm PEG Amine (tripentaerythritol core) and 8arm moiety Hyp, each dendritic moiety Hyp having at least four PEG Carboxyl (tripentaerythritol core). Preferred molecular groups representing the interconnected functional groups and weights for such multi-arm PEG-derivatives in a backbone biodegradable and permanent linkages. moiety are 1 kDa to 20 kDa, more preferably 2.5 kDa to 15 0180 Preferably, each A is independently selected from kDa and even more preferably 5 kDa to 10 kDa. It is under the formula—(CH2)(OCH2CH)X , wherein n1 is 1 or stood that the terminal amine groups of the above mentioned 2; n is an integer in the range of from 5 to 50; and X is a multi-arm molecules are present in bound form in the back functional group covalently linking A and Hyp. bone moiety to provide further interconnected functional 0181 Preferably, A and Hyp are covalently linked by an groups and reactive functional groups of a backbone moiety. amide functional group. 0.174. It is preferred that the sum of interconnected func 0182 Preferably, the dendritic moiety Hyp is a hyper branched polypeptide. Preferably, the hyperbranched tional groups and reactive functional groups of a backbone polypeptide comprises lysine in bound form, most preferably moiety is equally divided by the number of PEG-based poly Hyp is heptalysinyl in bound form. Preferably, each dendritic meric chains extending from the branching core. If the num moiety Hyp has a molecular weight in the range of from 0.4 ber of PEG-based polymeric chains extending from the kDa to 4 kDa, more preferably in the range of from 0.4kDa to branching core does not allow for an equal distribution, it is 2 kDa. It is understood that a backbone moiety C(A-Hyp) preferred that the deviation from the mean number of the sum can consist of the same or different dendritic moieties Hyp of interconnected and reactive functional groups per PEG and that each Hyp can be chosen independently. Each moiety based polymeric chain is kept to a minimum. Hyp consists of between 5 and 32 lysines, preferably of at US 2015/0202317 A1 Jul. 23, 2015 24 least 7 lysines, i.e. each moiety Hyp is comprised of between gradable linkages are esters, carbonates, phosphoesters and 5 and 32 lysines in bound form, preferably of at least 7 lysines Sulfonic acid esters and most preferred are esters or carbon in bound form. Most preferably Hyp is comprised of heptal ates. It is understood that for in vitro studies accelerated ysinyl. conditions like, for example, pH 9, 37° C., aqueous buffer, 0183 The reaction of polymerizable functional groups a may be used for practical purposes. backbone reagent, more specifically of Hyp with the poly 0.190 Permanent linkages are non-enzymatically hydro merizable functional groups of PEG based crosslinker lytically degradable under physiological conditions (aqueous reagents results in a permanent amide bond. buffer at pH 7.4, 37° C.) with half-lives of six months or 0184 One preferred backbone moiety is shown below, longer, Such as, for example, amides. dashed lines indicate interconnecting biodegradable linkages 0191 The degradation of the hydrogel is a multi-step reac to crosslinker moieties and n is an integer of from 5 to 50: tion where a multitude of degradable bonds is cleaved result
0185. Preferably, C(A-Hyp) has a molecular weight in ing in degradation products which may be water-soluble or the range of from 1 kDa to 20 kDa, more preferably from 1 water-insoluble. However each water-insoluble degradation kDa to 15 kDa, more preferably from 2.5 kDa to 15 kDa and product further comprises degradable bonds so that it can be even more preferably 5 kDa to 10 kDa. cleaved in that water-soluble degradation products are 0186 Preferably, L is attached to Z through a thiosuccin obtained. These water-soluble degradation products may imide group which in turn is attached to the hydrogel's back comprise one or more backbone moieties. It is understood bone moiety through a spacer, Such as an oligoethylene glycol that released backbone moieties may, for instance, be perma chain. Preferably, the linkage of this spacer chain to the back nently linked to spacer or blocking groups and/or prodrug bone moiety is a permanent bond, preferably an amide bond. linker degradation products. 0187 Preferably, L is a chemical bond. 0.192 In such hydrogel-linked prodrugs according to the 0188 Biodegradability of the hydrogels according to the invention, it is desirable that almost all release of biologically present invention is achieved by introduction of hydrolyti active agent (>90%) has occurred before a significant amount cally degradable bonds. of release of the backbone degradation products (<10%) has 0189 The terms “hydrolytically degradable”, “biodegrad taken place. This can be achieved by adjusting the hydrogel able' or “hydrolytically cleavable”, “auto-cleavable', or linked prodrugs half-life Versus the hydrogel degradation “self-cleavage”, “self-cleavable', “transient’ or “temporary’ kinetics. refer within the context of the present invention to bonds and 0193 To introduce the hydrolytically cleavable bonds into linkages which are non-enzymatically hydrolytically degrad the hydrogel carrier of the invention, the backbone moieties able under physiological conditions (aqueous buffer at pH can be directly linked to each other by means of biodegrad 7.4, 37° C.) with half-lives ranging from one hour to three able bonds. months, include, but are not limited to, aconityls, acetals, 0.194. In one embodiment, the backbone moieties of the carboxylic anhydrides, esters, imines, hydrazones, maleamic biodegradable hydrogel carrier may be linked together acid amides, ortho esters, phosphamides, phosphoesters, directly, i.e. without crosslinker moieties. The hyperbranched phosphosilyl esters, silyl esters, Sulfonic esters, aromatic car dendritic moieties of two backbone moieties of such biode bamates, combinations thereof, and the like. Preferred biode gradable hydrogel may either be directly linked through an US 2015/0202317 A1 Jul. 23, 2015
interconnected functional group that connects the two hyper (0203 Preferably, the crosslinker moieties are PEG based, branched dendritic moieties. Alternatively, two hyper preferably represented by only one PEG based molecular branched dendritic moieties of two different backbone moi chain. Preferably, the poly(ethylene glycol) based crosslink eties may be interconnected through two spacer moieties ers are hydrocarbon chains comprising ethylene glycol units, connected to a backbone moiety and on the other side con optionally comprising further functional groups, wherein the nected to a crosslinking moiety separated by an intercon poly(ethylene glycol) based crosslinker moieties comprise at nected functional groups. least each methylene glycol units, wherein m is an integer in (0195 Preferably, backbone moieties may be linked the range of from 3 to 100, preferably from 10 to 70. Prefer together through crosslinker moieties, each crosslinker moi ably, the poly(ethylene glycol) based crosslinkers have a ety being terminated by at least two of the hydrolytically molecular weight in the range of from 0.5 kDa to 5 kDa. degradable bonds. In addition to the terminating degradable 0204. In a preferred embodiment of the present invention bonds, the crosslinker moieties may contain further biode the crosslinker moiety consists of a PEG chain, which is gradable bonds. Thus, each end of the crosslinker moiety symmetrically connected through ester bonds to two alpha, linked to a backbone moiety shows a hydrolytically degrad omega-aliphatic dicarboxylic spacers provided by backbone able bond, and additional biodegradable bonds may option moieties through permanent amide bonds. ally be present in the crosslinker moiety. 0205 The dicarboxylic acids of the spacer moieties con 0196. The hydrogel may contain one or more different nected to the backbone moiety and on the other side con types of crosslinker moieties, preferably one. The crosslinker nected to a crosslinking moiety consists of 3 to 12 carbon moiety may be a linear or branched molecule and preferably atoms, most preferably between 5 and 8 carbon atoms and is a linear molecule. In a preferred embodiment of the inven may be substituted at one or more carbon atom. Preferred tion, the crosslinker moiety is connected to backbone moi Substituents are alkyl groups, hydroxy groups or amido eties by at least two biodegradable bonds. groups or Substituted amino groups. One or more of the 0197) If present in a hydrogel used as carrier in the pro aliphatic dicarboxylic acids methylene groups may option drugs according to the invention as degradable intercon ally be substituted by O or NH or alkyl-substituted N. Pre nected functional group, preferred biodegradable linkages ferred alkyl is linear or branched alkyl with 1 to 6 carbon are carboxylic esters, carboxylic anhydrides, carbonates, atOmS. phosphoesters and Sulfonic acid esters; more preferably car 0206 Preferably, there is a permanent amide bond boxylic esters, carbonates, phosphoesters and Sulfonic acid between the hyperbranched dendritic moiety and the spacer moiety connected to a backbone moiety and on the other side esters and most preferred are carboxylic esters or carbonates. is connected to a crosslinking moiety. 0198 In one embodiment, a crosslinker moiety consists of a polymer. Preferably, crosslinker moieties have a molecular 0207. One preferred crosslinker moiety is shown below: weight in the range of from 0.5kDa to 5 kDa, more preferably, dashed lines indicate interconnecting biodegradable linkages from 1 kDa to 4 kDa, even more preferably from 1 kDa to 3 to backbone moieties: kDa. 0199. In addition to oligomeric or polymeric crosslinking moieties, low-molecular weight crosslinking moieties may be used, especially when hydrophilic high-molecular weight N-N-N-N-1O a No1 , backbone moieties are used for the hydrogel formation. 0200 Preferably, the polyethyleneglycol based crosslinker moieties are hydrocarbon chains comprising eth wherein q is an integer of from 5 to 50. ylene glycol units, optionally comprising further functional 0208 Preferably, the hydrogel carrier is composed of groups, wherein the poly(ethylene glycol) based crosslinker backbone moieties interconnected by hydrolytically degrad moieties comprise at least each methylene glycol units, able bonds. wherein m is an integer in the range of from 3 to 100, prefer 0209 More preferably, the backbone moieties comprise a ably from 10 to 70. Preferably, the poly(ethylene glycol) branching core of the following formula: based crosslinker moieties have a molecular weight in the range of from 0.5 kDa to 5 kDa. 0201 If used in reference to a crosslinker moiety or a PEG-based polymeric chain connected to a branching core, the term "PEG-based refers to a crosslinker moiety or PEG based polymeric chain comprising at least 20 weight 96 eth ylene glycol moieties. wherein the dashed line indicates attachment to the remainder 0202 In one embodiment, monomers constituting the polymeric crosslinker moieties are connected by biodegrad of the backbone moiety. able bonds. Such polymeric crosslinkers may contain up to 0210 More preferably, the backbone moieties comprise a 100 biodegradable bonds or more, depending on the molecu structure of the following formula: lar weight of the crosslinker moiety and the molecular weight of the monomer units. Examples for Such crosslinkers are polylactic acid or polyglycolic acid based. It is understood that such polylactic acid) or poly(glycolic acid) chain may be terminated or interrupted by alkyl oraryl groups and that they C -h. O1N-"Nu-N pi NT - , may optionally be substituted with heteroatoms and chemical functional groups. US 2015/0202317 A1 Jul. 23, 2015 26 wherein n is an integer of from 5 to 50 and the dashed line wherein one of the dashed lines indicates attachment to the indicates attachment to the remainder of the backbone moi hyperbranched moiety Hyp and the second dashed line indi ety. cates attachment to the rest of the molecule; and wherein mis 0211 Preferably, backbone moiety comprises a hyper an integer of from 2 to 4. branched moiety Hyp. 0215 Preferably, the backbone moieties are linked 0212 More preferably, the backbone moiety comprises a together through crosslinker moieties having the following hyperbranched moiety Hyp of the following formula: Structure
Y& O1n-N-N O >1',
wherein q is an integer from 3 to 100. 0216. More preferably, the backbone moieties of the hydrogel are linked together through moieties of the follow ing formula:
O O O O
, w O 1n-on-1sO F ?
wherein the dashed lines indicate attachment to a backbone moiety, respectively, and wherein n is 45. 0217. In an alternative preferred embodiment, the back bone moieties of the hydrogel are linked together through moieties of the following formula:
wherein the dashed lines indicate attachment to the rest of the wherein the dashed lines indicate attachment to a backbone molecule and carbon atoms marked with asterisks indicate in moiety, respectively, and wherein n is 22. a preferred embodiment S-configuration. 0218. The hydrolysis rate of the biodegradable bonds 0213 However, it is understood that hyperbranched moi between backbone and crosslinker moieties is influenced or eties Hyp as shown above may also be in R-confirmation or determined by the number and type of connected atoms adja cent to the PEG-ester carboxy group. For instance, by select may be racemic. ing from Succinic, adipic or glutaric acid for PEG ester for 0214 Preferably, the backbone moieties are attached to at mation it is possible to vary the degradation half-lives of the least one spacer of the following formula: biodegradable hydrogel carrier. 0219. The hydrogel-linked prodrug of the present inven tion can be prepared starting from the hydrogel of the present
invention by convenient methods known in the art. It is clear to a practitioner in the art that several routes exist. For example, the prodrug linker mentioned above to which the biologically active moiety is covalently attached can be reacted with the reactive functional groups of the hydrogel of the present invention with or with the prodrug linker already bearing the active moiety in part or as whole. US 2015/0202317 A1 Jul. 23, 2015 27
0220. In a preferable method of preparation, the hydrogel 2000 to 5000 Da. To such multi-arm PEG-derivatives, lysine is generated through chemical ligation reactions. The hydro residues are coupled sequentially to form the hyperbranched gel may be formed from two macromolecular educts with backbone reagent. It is understood that the lysines can be complementary functionalities which undergo a reaction partially or fully protected by protective groups during the Such as a condensation or addition. One of these starting coupling steps and that also the final backbone reagent may materials is a crosslinker reagent with at least two identical contain protective groups. A preferred building block is bis functional groups and the other starting material is a homo boc lysine. Alternatively, instead of sequential additions of multifunctional backbone reagent. Suitable functional groups lysine residues, a dendritic poly-lysine moiety may be present on the crosslinker reagent include terminal amino, carboxylic acid and derivatives, maleimide and other alpha, assembled first and subsequently coupled to the 4-arm PEG beta unsaturated Michael acceptors like vinylsulfone, thiol, tetra amine or 8-arm PEG octa amine. It is desirable to obtain hydroxyl groups. Suitable functional groups present in the backbone reagent carrying 32 amino groups, consequently backbone reagent include but are not limited to amino, car seven lysines would be attached to each arm of a 4-arm PEG, boxylic acid and derivatives, maleimide and other alphabeta or three lysines would be attached to each arm of a 8-arm unsaturated Michael acceptors like vinylsulfone, thiol, PEG. In another embodiment, the multi-arm PEG derivative hydroxyl groups. is a tetra- or octa carboxy PEG. In this case, the dendritic 0221) If the crosslinker reagent's reactive functional moieties may be generated from glutaric or aspartic acid, and groups are used substoichiometrically with respect to back the resulting backbone reagent would carry 32 carboxy bone reactive functional groups, the resulting hydrogel will groups. It is understood that all or a fraction of the backbone be a reactive hydrogel with free reactive functional groups reagents functional groups may be present in a free form, as attached to the backbone structure. salts or conjugated to protecting groups. It is understood that 0222 Optionally, the prodrug linker may be first conju due to practical reasons the backbone reagent's number of gated to the biologically active agent and the resulting pro lysines per PEG-arm will be between six and seven, more drug linker conjugate may then react with the hydrogels preferably approximately seven. reactive functional groups. Alternatively, after activation of 0225. A preferred backbone reagent is shown below:
is O1 NH NH2 NH2
O O O HN N H C O H NH2 N N-1-on- H NH2 O O
N H HN NH2
O
in N 28 NH2 one of the functional groups of the prodrug linker, the linker 0226 Synthesis of the crosslinker reagent starts from a hydrogel conjugate may be contacted with biologically active linear PEG chain with a molecular weight ranging from 0.2 to agent in the second reaction step and excess biologically 5 kDa, more preferably from 0.6 to 2 kDa, which is esterified active agent may be removed by filtration after conjugation of the biologically active agent to the hydrogel-bound prodrug with a half ester of a dicarboxylic acid, preferably adipic acid linker. or glutaric acid. A preferred protecting group for half ester 0223) A preferred process for the preparation of a prodrug formation is the benzylic group. The resulting bis dicarboxy according to the present invention is as follows: lic acid PEG half esters are converted into more reactive 0224. A preferred starting material for the backbone carboxy compounds, such as acyl chlorides or active esters, reagent synthesis is a 4-arm PEG tetra amine or 8-arm PEG eg pentafluorophenyl or N-hydroxySuccinimide esters, most octa amine, with the PEG reagent having a molecular weight preferred N-hydroxysuccinimde esters, of which a preferred ranging from 2000 to 10000 Dalton, most preferably fom selected structure is shown below. US 2015/0202317 A1 Jul. 23, 2015 28
O O O O O O
N-O ---iii. O1--N-1N O ---iii. O-N
O O wherein each mindependently is an integer ranging from 2 to linker reagents, carrying a reactive thiol group on the linker 4, and q is an integer of from 3 to 100. moiety to form hydrogel-linked prodrugs according to the 0227. More preferred is the following structure: present invention.
O O O O O O
N - O ---* O 1-S-1NO ---* O-N s
O O q ~ 45 wherein r is either 1 or 2, preferably 1. 0233. After loading the drug-linker conjugate to the func 0228. Alternatively, the bis-dicarboxylic acid PEG half tionalized maleimido group-containing hydrogel, all remain esters may be activated in the presence of a coupling agent ing functional groups are capped with a suitable blocking such as DCC or HOBt or PyBOP. reagent, such as mercaptoethanol, to prevent undesired side reactions. 0229. In an alternative embodiment, the backbone reagent 0234. A particularly preferred method for the preparation carries carboxy groups and the corresponding crosslinker of a prodrug of the present invention comprises the steps of reagent would be selected from ester-containing amino-ter 0235 (a) reacting a compound of formula C(A-X1), minated PEG-chains. wherein A-X1 represents Abefore its binding to Hyp or 0230 Backbone reagent and crosslinker reagent may be a precursor of Hyp and X1 is a Suitable functional group, polymerized to form the hydrogel according to the invention with a compound of formula Hyp'-X2, wherein Hyp'-X2 using inverse emulsion polymerization. After selecting the represents Hyp before its binding to A or a precursor of desired stoichiometry between backbone and crosslinker Hyp and X2 is a suitable functional group to react with functional groups, backbone and crosslinker are dissolved in X1; DMSO and a suitable emulgator with an appropriately 0236 (b) optionally reacting the resulting compound selected HLB value, preferably Arlacel P135, is employed to from step (a) in one or more further steps to yield a forman inverse emulsion using a mechanical stirrer and con compound of formula C(A-Hyp) having at least four trolling the stirring speed. Polymerization is initiated by the functional groups; addition of a suitable base, preferably by N.N.N',N'-tetram 0237 (c) reacting the at least four functional groups of ethylene diamine. After stirring for an appropriate amount of the resulting compound from step (b) with a polyethyl time, the reaction is quenched by the addition of an acid, Such eneglycol based crosslinker precursor, wherein the as acetic acid and water. The beads are harvested, washed, and crosslinker precursor is used in a Sub-stoichiometric fractionated according to particle size by mechanical sieving. amount compared to the total number of functional Optionally, protecting groups may be removed at this stage. groups of C(A-Hyp) to yield a hydrogel; 0231. In an alternative embodiment of this invention, 0238 (d) reacting remaining un-reacted functional multi-functional moieties are coupled to the reactive func groups (representing the reactive functional groups of tional groups of the polymerized reactive hydrogel to increase the backbone comprised in the hydrogel) in the hydrogel the number of functional groups which allows increasing the backbone of step (c) with a covalent conjugate of bio drug load of the hydrogel. Such multi-functional moieties logically active moiety and transient prodrug linker or may be provided by suitably substituted derivatives of lysine, first reacting the un-reacted functional groups with the dilysine, trilysine, tetralysine, pentalysine, hexalysine, hep transient prodrug linker and Subsequently with the bio talysine, or oligolysine, low-molecular weight PEI. Prefer logically active moiety; ably, the multi-functional moiety is lysine. 0239 (e) optionally capping remaining un-reacted 0232 Further, such hydrogel according to the invention functional groups to yield a prodrug of the present inven may be functionalized with a spacer carrying a different reac tion. tive functional group than provided by the hydrogel. For 0240 Such hydrogel is preferably comminuted by instance maleimide reactive functional groups may be intro mechanical processes such as stirring, crushing, cutting duced into the hydrogel by coupling a suitable heterobifunc pressing, or milling, and optionally sieving. For emulsion tional spacer such as Mal-PEG6-NHS to the hydrogel. Such polymerization, the reaction mixture is comprised of the dis functionalized hydrogel can be further conjugated to drug persed phase and the continuous phase. US 2015/0202317 A1 Jul. 23, 2015 29
0241 For the dispersed phase, backbone reagent and the reactive hydrogel is a shaped article Such as a mesh or a crosslinker reagent are mixed in a ratio aminefactive ester of stent. Most preferably, the hydrogel is formed into micropar 5:1 to 1.05:1, preferably of 2:1 to 1.05:1 and are dissolved in ticulate beads which can be administered as Subcutaneous or DMSO to give a to give a solution with a concentration of 5 to intramuscular injectably by means of a standard Syringe. 50 g per 100 mL, preferably 7 to 30 g per 100 ml, more Such soft beads may have a diameter of between 1 and 500 preferably 7.5 to 20g per 100 ml and most preferably 10 to 20 micrometer. g per 100 ml. 0249 Preferably, such beaded carrier-linked hydrogel 0242. The continuous phase is any solvent, that is not prodrugs have a diameter of between 10 and 100 micrometer miscible with DMSO, not basic, aprotic and shows a viscosity if suspended in an isotonic aqueous formulation buffer, most lower than 10 Pas. Preferably, the solvent is not miscible preferably a diameter of between 20 and 100 micrometer, with DMSO, not basic, aprotic, shows a viscosity lower than most preferably a diameter of between 25 and 80 micrometer. 2 Pas and is non-toxic. More preferably, the solvent is a 0250 Preferably, such beaded carrier-linked hydrogel saturated linear or branched hydrocarbon with 5 to 10 carbon prodrugs can be administered by injection through a needle atoms. Most preferably, the solvent is n-heptane. smaller than 0.6 mm inner diameter, preferably through a 0243 To form an emulsion of the dispersed phase in the needle smaller than 0.3 mm inner diameter, more preferably continuous phase, an emulsifier is added to the continuous through a needle small than 0.25 mm inner diameter, even phase before adding the dispersed phase. The amount of more preferably through a needle smaller than 0.2 mm inner emulsifier is 2 to 50 mg per mL dispersed phase, more pref diameter, and most preferably through a needle Small than erably 5 to 20 mg per mL dispersed phase, most preferably 10 0.16 mm inner diameter. mg per mL dispersed phase. 0251. It is understood that the terms “can be administered 0244. The emulsifier has an HLB-value of 3 to 8. Prefer by injection”, “injectable' or “injectability” refer to a com ably, the emulsifier is a triester of sorbitol and a fatty acid or bination of factors such as a certain force applied to a plunger an poly(hydroxyl fatty acid)-poly(ethylene glycol) conju of a syringe containing the carrier-linked hydrogel prodrugs gate. More preferably, the emulsifier is an poly(hydroxy-fatty according to the invention Swollen in a liquid at a certain acid)-polyethylene glycol conjugate, with a linear poly(eth concentration (w/v) and at a certain temperature, a needle of ylene glycol) of a molecular weight in the range of from 0.5 a given inner diameter connected to the outlet of such syringe, kDa to 5 kDa and poly(hydroxy-fatty acid) units of a molecu and the time required to extrude a certain volume of the lar weight in the range of from 0.5 kDa to 3 kDa on each end carrier-linked hydrogel prodrugs according to the invention of the chain. Most preferably, the emulsifier is poly(ethylene from the syringe through the needle. glycol) dipolyhydroxy stearate, Cithrol DPHS (Cithrol 0252. In order to provide for injectability, a volume of 1 DPHS, former Arlacel P135, Croda International Plc). mL of the carrier-linked hydrogel prodrugs swollen in water 0245 Droplets of the dispersed phase are generated by to a concentration of at least 5% (w/v) and contained in a stirring with an axial flow impeller with a geometry similar to Syringe holding a plunger of a diameter of 4.7 mm can be stirrers such as Isojet, Intermig, Propeller (EKATO Ruhr- and extruded at room temperature within 10 seconds by applying Mischtechnik GmbH, Germany), most preferably similar to a force of less than 60 Newton, such as less than 50 Newton, Isojet or Propeller with a diameter of 50 to 90% of the reactor preferably by applying a force of less than 40 Newton. diameter. Preferably, stirring is initated before addition of the 0253 Preferably injectability measurement is carried out dispersed phase. Stirrer speed is set to 0.6 to 2.4 m/s, such as for the carrier-linked hydrogel prodrugs of the present inven 0.8 to 2.3 m/s, preferably to 0.6 to 1.7 m/s. The dispersed tion swollen in water to a concentration of ca. 15% (w/v). phase is added at room temperature, and the concentration of 0254. By consequence, the prodrugs according to the the disperse phase is 2% to 70%, preferably 5 to 50%, more present invention show the beneficial effect of a controlled preferably 10 to 40%, and most preferably 20 to 35% of the release rate in respect of the released drug D-H. Preferably, a total reaction Volume. The mixture of dispersed phase, emul Sustained release rate is obtained. Sustained release means sifier and continuous phase is stirred for 5 to 60 min before that the administration intervals of the respective prodrug are adding the base to the effect polymerization. expanded. For example, prodrugs according to the present 0246 5 to 10 equivalents (referred to each amide bond to invention which are based on drugs commonly applied once beformed) of a base are added to the mixture of dispersed and or several times a day provide therapeutically effective levels continuous phase. The base is aprotic, non nucleophilic and for at least three days, more preferably for at least one week soluble in the disperse phase. Preferably, the base is aprotic, and even more preferably for at least one month. non nucleophilic, well soluble in both disperse phase and 0255. The prodrug according to the present invention DMSO. More preferably, the base is aprotic, non nucleo show excellent in vivo/invitro correlation of linker cleavage, philic, well soluble in both disperse phase and DMSO, an a high degree of enzyme independence and show a higher amine base and non-toxic. Most preferably, the base is N.N. stability at lower pH, resulting in a pH dependent cleavage. N',N'-tertramethylethylene diamine (TMEDA). Stirring in 0256 A strong in vivo/in vitro correlation is observed, if the presence of base is continued for 1 to 16 h. the release kinetics exhibited by a carrier-linked prodrug con 0247 During stirring, droplets of dispersed phase are jugate according to the invention in Vivo has a half-life that is hardened to become crosslinked hydrogel beads according to not smaller than half the value exhibited by the same carrier the invention which can be collected and fractionation linked prodrug conjugate in aqueous buffer of pH 7.4 at 37° according to size is performed on a vibrational continuous C., wherein the release kinetics in vivo is measured as plasma sieving machine with a 75 um and a 32 um deck to give levels of free drug. It is understood that in the case of soluble hydrogel microparticles according to the invention. carriers, release kinetics may be recorded as hydrolysis kinet 0248. The hydrogel for the prodrug of the present inven 1CS tion can be obtained from the preparation methods inform of 0257 Another aspect of the present invention are pharma micro-particles. In a preferred embodiment of the invention, ceutical compositions of the carrier-linked prodrugs US 2015/0202317 A1 Jul. 23, 2015 30 described before. Such pharmaceutical compositions contain with sorbitol or sorbitol may be used as the sole protectant. one or more excipients, selected from the groups consisting Starch or starch derivatives may also be used. of: 0264 (vii) Oxidation protection agents: antioxidants such 0258 (i) Buffering agents: physiologically tolerated buff as ascorbic acid, ectoine, methionine, glutathione, mono ers to maintain pH in a desired range. Such as sodium phos thioglycerol, morin, polyethylenimine (PEI), propyl gallate, phate, bicarbonate, Succinate, histidine, citrate and acetate, Vitamin E. chelating agents such aus citric acid, EDTA, Sulphate, nitrate, chloride, pyruvate. Antacids such as hexaphosphate, thioglycolic acid. Mg(OH) or ZnCO may be also used. Buffering capacity may be adjusted to match the conditions most sensitive to pH 0265 (viii) Viscosifiers or viscosity enhancers: retard set stability. tling of the particles in the vial and Syringe and are used in order to facilitate mixing and resuspension of the particles 0259 (ii) Isotonicity modifiers: to minimize pain that can and to make the Suspension easier to inject (i.e., low force on result from cell damage due to osmotic pressure differences at the Syringe plunger). Suitable viscosifiers or viscosity the injection depot. Glycerin and Sodium chloride are enhancers are, for example, carbomer viscosifiers like Car examples. Effective concentrations can be determined by bopol 940, Carbopol Ultrez, 10, cellulose derivatives like osmometry using an assumed osmolality of 285-315 mCs hydroxypropylmethylcellulose (hypromellose, HPMC) or mol/kg for serum. diethylaminoethyl cellulose (DEAE or DEAE-C), colloidal 0260 (iii) Preservatives and/or antimicrobials: multidose magnesium silicate (Veegum) or sodium silicate, hydroxya parenteral preparations may require the addition of preserva patite gel, tricalcium phosphate gel, Xanthans, carrageenans tives at a Sufficient concentration to minimize the risk of like Satia gum UTC 30, aliphatic poly(hydroxy acids), such patients becoming infected upon injection and corresponding as poly(D.L- or L-lactic acid) (PLA) and poly(glycolic acid) regulatory requirements have been established. Typical pre (PGA) and their copolymers (PLGA), terpolymers of D.L- servatives include m-cresol, phenol, methylparaben, ethylpa lactide, glycolide and caprolactone, poloxamers, hydrophilic raben, propylparaben, butylparaben, chlorobutanol, benzyl poly(oxyethylene) blocks and hydrophobic poly(oxypropy alcohol, phenylmercuric nitrate, thimerosol, Sorbic acid, lene) blocks to make up a triblock of poly(oxyethylene)-poly potassium Sorbate, benzoic acid, chlorocresol, and benzalko (oxypropylene)-poly(Oxyethylene) (e.g. Pluronic R), poly nium chloride. etherester copolymer, Such as a polyethylene glycol 0261 (iv) Stabilizers: Stabilisation is achieved by terephthalate/polybutylene terephthalate copolymer, Sucrose strengthening of the protein-stabilising forces, by destabili acetate isobutyrate (SAIB), dextran or derivatives thereof, sation of the denatured stater, or by direct binding of excipi combinations of dextrans and PEG, polydimethylsiloxane, ents to the protein. Stabilizers may be amino acids such as collagen, chitosan, polyvinyl alcohol (PVA) and derivatives, alanine, arginine, aspartic acid, glycine, histidine, lysine, pro polyalkylimides, poly (acrylamide-co-diallyldimethyl line, Sugars such as glucose, Sucrose, trehalose, polyols such ammonium (DADMA)), polyvinylpyrrolidone (PVP), gly as glycerol, mannitol, Sorbitol, salts such as potassium phos cosaminoglycans (GAGs) such as dermatan Sulfate, chon phate, sodium Sulphate, chelating agents such as EDTA, droitin Sulfate, keratan Sulfate, heparin, heparan Sulfate, hexaphosphate, ligands Such as divalent metal ions (Zinc, hyaluronan, ABA triblock or AB block copolymers com calcium, etc.), other salts or organic molecules Such as phe posed of hydrophobic A-blocks, such as polylactide (PLA) or nolic derivatives. In addition, oligomers or polymers such as poly(lactide-co-glycolide) (PLGA), and hydrophilic cyclodextrins, dextran, dendrimers, PEG or PVP or prota B-blocks, such as polyethylene glycol (PEG) or polyvinyl mine or HSA may be used. pyrrolidone. Such block copolymers as well as the above 0262 (v) Anti-adsorption agents: Mainly ionic or inon mentioned poloxamers may exhibit reverse thermal gelation ionic Surfactants or other proteins or soluble polymers are behavior (fluid state at room temperature to facilitate admin used to coat or adsorb competitively to the inner surface of the istration and gel state above sol-gel transition temperature at composition’s container, e.g. poloxamer (Pluronic F-68), body temperature after injection). PEG dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, 0266 (ix) Spreading or diffusing agent: modifies the per polyethylene glycol, PEG-polyhistidine, BSA and HSA and meability of connective tissue through the hydrolysis of com gelatines. Chosen concentration and type of excipient ponents of the extracellular matrix in the intrastitial space depends on the effect to be avoided but typically a monolayer Such as, but not limited to, hyaluronic acid, a polysaccharide of surfactant is formed at the interface just above the CMC found in the intercellular space of connective tissue. A spread value. ing agent such as, but not limited to, hyaluronidase tempo 0263 (vi) Lyo- and/or cryoprotectants: During freeze- or rarily decreases the viscosity of the extracellular matrix and spray drying, excipients may counteract the destabilising promotes diffusion of injected drugs. effects caused by hydrogenbond breaking and water removal. 0267 (X) Other auxiliary agents: Such as wetting agents, For this purpose, Sugars and polyols may be used, but corre Viscosity modifiers, antibiotics, hyaluronidase. Acids and sponding positive effects have also been observed for surfac bases such as hydrochloric acid and sodium hydroxide are tants, amino acids, non-aqueous solvents, and other peptides. auxiliary agents necessary for pH adjustment during manu Trehalose is particulary efficient at reducing moisture-in facture. duced aggregation and also improves thermal stability poten tially caused by exposure of protein hydrophobic groups to 0268. The composition of a prodrug according to the water. Mannitol and Sucrose may also be used, either as sole invention may be provided as a liquid composition, a Suspen lyo/cryoprotectant or in combination with each other where sion composition or as a dry composition. higher ratios of mannitol:Sucrose are known to enhance 0269. In one embodiment, the pharmaceutical composi physical stability of a lyophilized cake. Mannitol may also be tion of a prodrug according to the invention is a dry compo combined with trehalose. Trehalose may also be combined sition. Suitable methods of drying are, for example, spray US 2015/0202317 A1 Jul. 23, 2015 drying and lyophilization (freeze-drying). Preferably, the 0279 (ii) transferring amounts of the liquid or suspen pharmaceutical composition of prodrug is dried by lyo sion composition equivalent to single or multiple doses philization. into Suitable containers, and 0270 Preferably, the prodrug is sufficiently dosed in the 0280 (iii) sealing the containers. composition to provide therapeutically effective amounts of 0281 Another aspect of the present invention is the biologically active agent for at least 12 hours in one applica method of manufacturing a dry composition of carrier-linked tion. More preferably, one application of prodrug is sufficient prodrug. In one embodiment, Such composition is made by for at least one day, more preferably for at least 3 days, more 0282 (i) admixing the carrier-linked prodrug with one preferably for at least 1 week and most preferably for at least or more excipients, 4 weeks. 0283 (ii) transferring amounts equivalent to single or 0271 In one embodiment of the present invention, the multiple doses into Suitable containers, composition of prodrug is provided as a single dose, meaning 0284 (iii) drying the composition in said containers, that the container in which it is Supplied contains one phar and maceutical dose. 0285 (iv) sealing the containers. 0272. In another embodiment, the composition is pro 0286 Suitable containers are vials, syringes, dual-cham vided as a multiple dose composition, meaning that it con ber Syringes, ampoules, and cartridges. tains more than one therapeutic dose. Preferably, a multiple 0287 Another aspect is a kit of parts. For liquid and sus dose composition contains at least 2 doses. Such multiple pension compositions, and when the administration device is dose composition of prodrug can either be used for different simply a hypodermic syringe, the kit may comprise the patients in need thereof or is intendend for use in one patient, Syringe, a needle and a container comprising the carrier wherein the remaining doses are stored after the application linked prodrug composition for use with the Syringe. In case of the first dose until needed. of a dry composition, the container may have one chamber 0273. In another aspect of the present invention the pro containing the dry carrier-linked prodrug composition, and a drug composition is comprised in a container. For liquid or second chamber comprising a reconstitution solution. In Suspension compositions, the container is preferably a single more preferred embodiments, the injection device is other chamber syringe. For dry compositions, preferably the con than a simple hypodermic syringe and so the separate con tainer is a dual-chamber Syringe. The dry composition tainer with carrier-linked prodrug composition is adapted to according to the present invention is provided in a first cham engage with the injection device Such that in use the liquid or ber of the dual-chamber Syringe and reconstitution solution is Suspension or reconstituted dry composition in the container provided in a second chamber of the dual-chamber syringe. is in fluid connection with the outlet of the injection device. 0274 Prior to applying the dry composition of prodrug to Examples of administration devices include but are not lim a patient in need thereof, the dry composition is reconstituted. ited to hypodermic syringes and pen injector devices. Particu Reconstitution can take place in the containerin which the dry larly preferred injection devices are the pen injectors, in composition of prodrug is provided, such as in a vial, Syringe, which case the container is a cartridge, preferably a dispos dual-chamber Syringe, ampoule, and cartridge. Reconstitu able cartridge. tion is done by adding a predefined amount of reconstitution 0288 A preferred kit of parts comprises a needle and a Solution to the dry composition. Reconstitution solutions are container containing the dry carrier-linked prodrug composi sterile liquids, such as water or buffer, which may contain tion according to the present invention and optionally further further additives, such as preservatives and/orantimicrobials, containing a reconstitution solution, the container being such as, for example, benzylalcohol and cresol. Preferably, adapted for use with the needle. Preferably, the container is a the reconstitution solution is sterile water. dual-chamber syringe. 0275 A further aspect is a method of preparing a recon 0289. In another aspect, the invention provides a cartridge stituted composition comprising a therapeutically effective containing a composition of carrier-linked prodrug as here amount of prodrug, and optionally one or more pharmaceu inbefore described for use with a pen injector device. The tically acceptable excipients, the method comprising the step cartridge may contain a single dose or multiplicity of doses of of contacting the composition of the present invention with a carrier-linked prodrug. reconstitution solution. 0290. In one embodiment of the present invention the sus pension composition of carrier-linked prodrug does not only 0276 Another aspect is a reconstituted composition com comprise a carrier-linked prodrug and one or more excipients, prising a therapeutically effective amount of a prodrug but also other biologically active agents, either in their free according to the invention, and optionally one or more phar form or as prodrugs or carrier-linked prodrugs such as PEG maceutically acceptable excipients. prodrugs or hydrogel prodrugs. Preferably, Such additional 0277 Another aspect of the present invention is the one or more biologically active agent is a prodrug, more method of manufacturing a liquid or Suspension composition preferably a PEG or hydrogel prodrug. of carrier-linked prodrug. In one embodiment, such compo 0291. In an alternative embodiment, the carrier-linked sition is made by prodrug composition according to the present invention is 0278 (i) admixing the carrier-linked prodrug with one combined with a second biologically active compound in or more excipients, Such way that the carrier-linked prodrug composition accord US 2015/0202317 A1 Jul. 23, 2015 32 ing to the invention is administered to a patient in need thereof 0298 Y is a leaving group. Such leaving groups are known first, followed by the administration of the second compound. to a person skilled in the art. Preferably, Y is chloride, bro Alternatively, the carrier-linked prodrug composition is mide, fluoride, nitrophenoxy, imidazolyl. N-hydroxysuccin administered to a patient in need thereof after another com imidyl, N-hydroxybenzotriazolyl, N-hydroxyazobenzotriaz pound has been administered to the same patient. olyl, pentafluorophenoxy, 2-thiooxo-thiazolidinyl, or 0292 Yet another aspect of the present invention is a car N-hydroxysulfosuccinimidyl. rier-linked prodrug of the present invention or a pharmaceu 0299. In case the synthesis of a carrier-linked prodrug tical composition of the present invention for use as a medi according to the present invention is carried out by employing Cament. a precursor L'-Y, a drug linker intermediate (L-D) is 0293 Yet another aspect of the present invention is a car obtained by reacting L'-Y with the biologically active drug rier-linked prodrug of the present invention or a pharmaceu D-H by forming an amide bond. In such case, said drug linker tical composition of the present invention for use in a method intermediate L'-D is reacted further to obtain the drug linker of treating or preventing diseases or disorders which can be conjugate D-L by adding the moiety L and the carrier group treated by the biologically active moiety released from the Z to said drug linker intermediate L'-D. It has to be indicated carrier-linked prodrug according to the present invention. that the addition of L and/or Z to L'-D may be performed in 0294. Another subject of the present invention is a method several steps by preparing further intermediate compounds for the synthesis of a carrier-linked prodrug or a pharmaceu prior to obtaining the drug linker conjugate D-L. tically acceptable salt thereof as defined above. Carrier 0300 Alternatively, a prodrug precursor L*-Y may be linked prodrugs or precursors of carrier-linked prodrugs employed instead of L'-Y, wherein L* is selected from a according to the present invention may be prepared by known fragment of L', L' containing at least one protecting group or methods or in accordance with the reaction sequences L' additionally containing precursors of L and/or Z. described below. The starting materials used in the prepara 0301 Another subject of the present invention is the use of tion (synthesis) of prodrugs of the invention or precursors prodrugs or a pharmaceutically acceptable salt thereof com thereof are known or commercially available, or can be pre prising a drug linker conjugate D-L as pharmaceuticals or pared by known methods or as described below. medicaments, respectively. With respect of the definitions of 0295 All reactions for the synthesis of the carrier-linked the drug linker conjugate D-L as well as further Substituents prodrugs according to the present invention including precur Such as L' the same explanations as laid out above in the sors such as the moiety L'according to the formula (I) are per context of the prodrug as Such apply. se well-known to the skilled person and can be carried out under Standard conditions according to or analogously to EXAMPLES procedures described in the literature, for example in Houben-Weyl, Methoden der Organischen Chemie (Methods Example 1 of Organic Chemistry). Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. Depending on the Synthesis of Linker Reagent Intermediate (1) circumstances of the individual case, in order to avoid side 0302) reactions during the synthesis of a carrier-linked prodrug or a precursor thereof, it can be necessary or advantageous to temporarily block functional groups by introducing protec tive groups and to deprotect them in a later stage of the O synthesis, or introduce functional groups in the form of pre cursor groups which in a later reaction step are converted into OH the desired functional groups. Such synthesis strategies and N protective groups and precursor groups which are Suitable in O an individual case are known to the skilled person. If desired, the carrier-linked prodrugs or precursors can be purified by Nws customary purification procedures, for example by recrystal boy lization or chromatography. 0296. The carrier-linked prodrugs according to the present invention or a pharmaceutically acceptable salt thereof may be prepared by a method comprising the step of reacting a prodrug precursor L-Y with a biologically active drug D-H to NH obtain the drug linker conjugate D-L by forming an amide ind bond, wherein Y is a leaving group. 0297. In respect of the prodrug precursor L-Y, L has the 0303 Fmoc-5,5-dimethyl-L-proline (0.9 mmol) is loaded same meaning as indicated above in connection with the drug onto 2-chlorotrityl resin (0.6 mmol) according to manufac linker conjugate D-L. The same holds true for the analogous turer's instructions. After finnoc removal, a solution of boc employment of the prodrug precursor L'-Y in respect of the Lys(fmoc)-OH (3 mmol), HATU (3 mmol), and collidine (6 moiety L' represented by formula (I). mmol) is added to the resin and incubated for 30 min. This US 2015/0202317 A1 Jul. 23, 2015 procedure is repeated once. Intermediate 1 is cleaved from Example 3 resin according to the following procedure: Synthesis of PEG-Linker-Exendin-4 Conjugate (3) 0304. The resin is washed with DCM, dried in vacuo and treated two times for 30 minutes with 6/4 (v/v) DCM/HFIP. 0309 Eluates are combined, Volatiles are removed under a nitrogen 3 stream and product 1 is purified by RP-HPLC and analyzed O by RP-HPLC-MS. oHis N-Exendin H Example 2 N O Synthesis of Exendin-4 Linker Intermediate (2) H.N." 0305
2 O ois NH N-Exendin H O N O
H.N." iPEG40kDa
0310 2 (12 mg) is dissolved in 500 ul of 1/1 acetonitrile/ water and 120 mg 40 kDa methoxy poly(ethylene glycol) maleimido-propionamide in 1 ml of 1/1 acetonitrile/water are NH added. 300 ul of 0.25 M sodium phosphate buffer pH 7.0 are added and solution is acidified after 10 min with 300 ulacetic acid. 3 is purified by cation exchange chromatography, O desalted, and then lyophilized.
SH Example 4
Exendin-4 Release In Vitro 0311 Release of exendin from 3 is effected by hydrolysis in 50 mM sodium phosphate buffer at pH 7.4 and 37° C. (0306 1 (0.10 mmol), PyBOP (0.10 mmol), and DIEA Unmodified native exendin-4 is released as assessed by RP (0.20 mmol) are dissolved in 2 ml of dry DME Mixture is HPLC/MS. added to 250 mg side-chain protected Exendin-4 (J. Enget al., J. Biol.Chem. 1992, 267, 11, 7402-7405) on-resin (25umol; Example 5 synthesized by Fmoc-strategy on Rink amide resin) and agi tated for 30 min at room temperature. Resin is washed with Synthesis of Linker Reagent Intermediate (4) DMF (10 times) and DCM (10 times). Fmoc-group is 0312 removed by agitating the resin with 2/2/96 (v/v/v) piperidine/ DBU/DMF (two times, 10 min each) and washing with DMF 4 (ten times). Trt-mercaptopropionic acid (0.1 mmol), PyBOB O (0.1 mol), and DIEA (0.2 mmol) in DMF are added to the 't resin and agitated for 30 minatroom temperature. 2 is cleaved N from resin according to the following procedure: OH boc1 t , O 0307. The resin is washed with DCM, dried in vacuo and treated with 2 ml of TFA cleavage cocktail (TFA/TES/Water/ DTT 95/2/2/1) per 100 mg resin for 60 min at room tempera ture. Volatiles are removed under a nitrogen stream. Nonpolar side products and protecting groups are removed by precipi tating peptide from diethyl ether. Precipitate is dried in vacuo. NH fmoc 0308 Crude 2 is dissolved in acetonitrile/water 1/1 and purified by RP-HPLC. US 2015/0202317 A1 Jul. 23, 2015 34
0313 Fmoc-5,5-dimethyl-D-proline (0.9 mmol) was 0318. To a solution of 5 (1.4 mg) in 50 L of DMSO were loaded onto 2-chlorotrityl resin (0.6 mmol) according to added a solution of 63 mg 20 kDa methoxy poly(ethylene manufacturers instructions. After finnoc removal, a Solution glycol)NHS ester in 500 uL ml of DMSO and 7uL of DIPEA. of boc-Lys(fmoc)-OH (3 mmol), HATU (3 mmol), and colli After incubation at 22° C. for 30 min, the reaction mixture dine (6 mmol) was added to the resin and incubated for 30 was frozen and lyophilized. min. This procedure was repeated once. Intermediate 4 was 0319 Dry samples were treated with TFA/DCM 1:1(v/v) cleaved from resin according to the following procedure: for 20 min, diluted with MeCN and purified by RP-HPLC. 0314. The resin was washed with DCM, dried in vacuo and Example 8 treated two times for 30 minutes with 6/4 (v/v) DCM/HFIP. Eluates were combined, volatiles were removed underanitro Amoxapine Release In Vitro gen stream and product 4 was purified by RP-HPLC and 0320 Release of amoxapine from 6 was effected by analyzed by RP-HPLC-MS. hydrolysis in 50 mM sodium phosphate buffer at pH 7.4 and Example 6 37° C. Unmodified amoxapine is released as assessed by RP-HPLC/MS. 0321) t—1.75 h. Synthesis of Amoxapine Linker Intermediate (5) 0322. While this invention has been described in conjunc 0315 tion with the specific embodiments outlined above, it is evi dent that many alternatives, modifications, and variations will 5 be apparent to those skilled in the art. Accordingly, the pre ferred embodiments of the invention as set forth above are >C) “utié O intended to be illustrative, not limiting. Various changes may --, be made without departing from the spirit and scope of the N inventions as defined in the following claims. boc1 '. O ABBREVIATIONS C 0323 Boc t-butyloxycarbonyl N 0324 DBU 1,3-diazabicyclo[5.4.0]undecene 0325 DCM dichloromethane 2 0326 DIEA diisopropylethylamine 0327 DMF N,N-dimethylformamide 0328 DMSO dimethylsulfoxide 0329 DTT dithiothreitol 0330 Fmoc 9-fluorenylmethoxycarbonyl NH2 C 0331 HATU O-(7-AZabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate 0316 5 (26 umol), PyBOP (32 umol), and DIEA (63 0332 HFIP hexafluoroisopropanol umol) were dissolved in 250 uL of anhydrous DME Amox 0333 MeCN acetonitrile apine (36 umol) was added, and the mixture was stirred at 0334 MS mass spectrometry room temperature for 50 min. Piperidine (63 uL) was added 0335 PEG poly(ethylene glycol) and stirring was continued for 20 minutes. The crude product 0336 PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino was purified by RP-HPLC. Yield 83%. phosphonium hexafluorophosphate 0337 RP-HPLC reversed-phase high performance liq Example 7 uid chromatography 0338 TES triethylsilane Synthesis of PEG-Linker-Amoxapine Conjugate (6) 0339 TFA trifluoroacetic acid 1. A prodrug or a pharmaceutically acceptable salt thereof 0317 comprising: a drug linker conjugate D-L: wherein D is a biologically active moiety containing an aliphatic amine containing group; and wherein L is a non-biologically active linker containing: i) a moiety L' represented by formula (I):
(I)
PEG-2OkDA-OMe US 2015/0202317 A1 Jul. 23, 2015
wherein the dashed line indicates the attachment of L' ii) a moiety Lif, which is a chemical bond or a spacer, and to the aliphatic amine group of D by forming an L is bound to a carrier group Z: amide bond; wherein L' is substituted with one to four Li moieties; wherein X is selected from O, S, and CH-R'': wherein Z is a water-soluble polymer selected from the wherein R' and R'' are independently selected from group consisting of polyalkyloxy polymers, hyalu ronic acid and derivatives thereof, polyvinyl alcohols, H, OH, and CH: polyoxazolines, polyanhydrides, poly(ortho esters), wherein R. R. R', and R* are independently polycarbonates, polyurethanes, polyacrylic acids, Selected from H and C alkyl; polyacrylamides, polyacrylates, polymethacrylates, wherein R and Rare independently selected from polyorganophosphaZenes, polysiloxanes, polyvi H, C, alkyl, and R. and nylpyrrolidone, polycyanoacrylates, and polyesters; wherein R is selected from: and wherein, optionally, L is further substituted. 2. The prodrug according to claim 1: wherein L is a chemical bond. 3. The prodrug according to claim 1: wherein the carrier group Z is a polymer with a molecular weight-500 g/mol. c 4. A pharmaceutical composition comprising: a prodrug of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. -(o- 5. The pharmaceutical composition according to claim 4: wherein the pharmaceutical composition is dry. 6. The pharmaceutical composition according to claim 4: wherein the prodrug is sufficiently dosed in the composi tion to provide a therapeutically effective amount of biologically active agent for at least 12 hours in one NH application. 7. A kit of parts comprising: a needle; and a container containing: reconstitution Solution; and the dry composition according to claim 5 configured for use with the needle. 8. The kit of parts according to claim 7: wherein the container is a dual-chamber Syringe, and wherein one of the two-chambers of the dual-chamber Syringe contains the dry pharmaceutical composition and the second chamber of said dual-chamber Syringe contains the reconstitution solution. NH 9. The prodrug according to claim 1: wherein the prodrug is configured for use as pharmaceuti cal. 10. A method for the synthesis of a prodrug or a pharma and ceutically acceptable salt thereof according to claim 1, com wherein, optionally, one or more of the pairs R/R', prising: R/R“, and R/R may independently form one or a step of reacting a prodrug precursor L-Y or L'-Y with a more cyclic fragments selected from C-7 biologically active drug D-H, to obtain the drug linker cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to conjugate D-L or a drug linker intermediate D-L' by 11 membered heterobicyclyl; and forming an amide bond; wherein, optionally, R. R. R', and R“ are further wherein Y is a leaving group. Substituted; and k k k k k