Abstract: A method for rendering water-insoluble materials water-soluble is provided. The method is useful for solubilizing substantially water-insoluble bioactive materials such as drugs. This is accomplished by forming a non-covalently bonded complex between the drug and a polymer which is soluble in both water and an organic solvent. This is carried out by combining the desired medicinal agent with the polymer is an organic solvent, removing the solvent and dissolving the complex in water or aqueous buffer. When the organic solvent is evaporated, a solid complex is recovered which is water-soluble. Methods of treatment with the complexes are also provided.

Abstract: The present invention is directed to conjugates such as polymeric prodrugs of aromatic, hydroxyl-containing compounds and methods of making and using the same. These polymeric prodrugs are preferably esters of hydroxyl-containing aromatic compounds and are formed by reacting a desired aromatic, hydroxyl-containing compound with a substantially non-antigenic polymer so as to produce a transport form having an ester linkage between the aromatic compound and the polymer. Preferred aromatic hydroxyl-containing compositions include 10- and 11-hydroxycamptothecin derivatives. Methods of treatment are also disclosed.

Abstract: A process for preparing .alpha.-interferon-polymer conjugates having high levels of retained interferon activity and relatively long circulating lives in vivo is disclosed. The process includes forming substantially non-antigenic .alpha.-interferon-polymer conjugates, combining the .alpha.-interferon-polymer conjugates with a sufficient amount of an acid to reduce the pH of the conjugates to a level which is sufficient to cleave the polymer linkages in an active site area of the interferon and thereafter adjusting the .alpha.-interferon-polymer conjugates to a physiologically-acceptable pH. Methods of treating interferon-susceptible conditions with the compositions of the present invention are also disclosed.

Abstract: The present invention is directed compositions of the formula: ##STR1## wherein: D is a residue of biologically active moiety;X is an electron withdrawing group;Y and Y' are independently O or S;(n) is zero (0) or a positive integer, preferably from 1 to about 12;wherein: R.sub.1 and R.sub.2 are independently selected from the group consisting of H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C.sub.1-6 alkyls;wherein: R.sub.3 is a substantially non-antigenic polymer, C.sub.1-12 straight or branched alkyl or substituted allyl, C.sub.5-8 cycloalkyl or substituted cycloalkyl, carboxyalkyl, carboalkoxy alkyl, dialkylaminoalkyl, phenylalkyl, phenylaryl or ##STR2## wherein: R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls, and substituted C.sub.1-6 alkyls or jointly form a cyclic C.sub.5 -C.sub.7 ring.

Abstract: The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula: ##STR1## wherein: B is a leaving group or a residue of an amine-containing target moiety;G is ##STR2## or CH.sub.2 ; Y.sub.1-2 are independently O or S;M is X or Q; where X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(.dbd.Y.sub.2);R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and R.sub.13 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.3-12 branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted alkyls, C.sub.3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.sub.1-6 heteroalkyls, substituted C.sub.1-6 heteroalkyls;R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.1-6 alkoxy, phenoxy, C.sub.1-8 heteroalkyls, C.sub.

Abstract: Branched, substantially non-antigenic polymers are disclosed. Conjugates prepared with the polymers and biologically active molecules such as proteins and peptides demonstrate extended circulating life in vivo. Substantially fewer sites on the biologically active material are used as attachment sites. Methods of forming the polymer, conjugating the polymers with biologically active moieties and methods of using the conjugates are also disclosed.

Abstract: Substantially non-antigenic polymers containing pI and/or pH optimum modulating moieties are disclosed. The polymers are useful as intermediates for synthesis of amine-based polymers and in the formation of activated polymers for conjugation with nucleophiles. Conjugates and methods of preparation and treatment with the conjugates are also disclosed.

Abstract: High molecular weight, water-soluble prodrugs of the formula: ##STR1## wherein: D is a biologically active moiety;M is X or Q;X is an electron withdrawing group;Q is a moiety containing a free electron pair positioned five or six atoms from Y';Y and Y' are oxygen or sulfur;R is a polyalkylene oxide; andZ is OH, C.sub.1-4 all moieties or ##STR2## are disclosed. In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.

Abstract: The present invention is directed compositions of the formula: ##STR1## wherein: D is a biologically active moiety;X is an electron withdrawing group;Y and Y' are independently O or S;R.sub.1 is selected from the group consisting of H, C.sub.1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C.sub.1-6 alkyls;(n) is an integer from 1 to about 12; andR.sub.2 is a polyalkylene oxide.In preferred embodiments, the prodrugs contain a polyethylene glycol having a molecular weight of at least about 20,000.

Abstract: Taxane-based compositions of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of aryls, substituted aryls, aralkyls, substituted aralkyls, alkyls and substituted alkyls;R.sub.2 is an aryl or substituted aryl, preferably phenyl;R.sub.3 is H, a C.sub.1-10 alkoxy, SiEt.sub.3 or ##STR2## Y is O or S; (n) is zero or a positive integer;X is oxygen, S, SO.sub.2 or NL, where L is selected from the group consisting of H, C.sub.1-8 alkyls, aryls and aralkyls;R.sub.4 is H or an aroyl of the formula: ##STR3## wherein Ar is an aromatic, substituted aromatic or heteroaromatic group; R.sub.5 is H, CH.sub.3 CO or a substituted acetic acid derivative;Z is H or OR.sub.6 where R.sub.6 is selected from the group consisting of H, C.sub.1-8 alkyls, C.sub.1-8 substituted alkyls, C.sub.1-8 aralkyls, substituted aryls, aralkyls, substituted aralkyls, C.sub.1-10 alkoxy, SiEt.sub.3, ##STR4## P is O or OH; R.sub.8 is one of H, S(CH.sub.3).sub.3, Si(C.sub.2 H.sub.5).sub.3, CH.sub.

Abstract: The present invention is directed to methods of preparing high purity polyalkylene oxide carboxylic acids. The methods include reacting a polyalkylene oxide such as polyethylene glycol with a t-butyl haloacetate in the presence of a base followed by treatment with an acid such as trifloroacetic acid. The resultant polymer carboxylic acids are of sufficient plurty so that expensive and time consuming purification steps required for pharmaceutical grade polymers are avoided.

Abstract: Interferon-polymer conjugate containing compositions having high levels of retained interferon activity and relatively long circulating lives in vivo are disclosed. The compositions contain a mixture of mono-interferon-polymer conjugates and bis-interferon-polymer conjugates, with both species containing substantially a single polymer strand. The conjugate compositions are prepared by reacting about 1 mole of an interferon with from about 0.125 to about 1 mole of a bis-activated substantially non-antigenic polymer under conditions sufficient to effect covalent conjugation of the interferon and polymer. Methods of treating interferon-susceptible conditions with the compositions of the present invention are also disclosed.

Abstract: Substantially non-antigenic polymers containing pI and/or pH optimum modulating moieties are disclosed. The polymers are useful as intermediates for synthesis of amine-based polymers and in the formation of activated polymers for conjugation with nucleophiles. Conjugates and methods of preparation and treatment with the conjugates are also disclosed.

Abstract: A method for rendering water-insoluble materials water-soluble is provided. The method is useful for solubilizing substantially water-insoluble bioactive materials such as drugs. This is accomplished by forming a non-covalently bonded complex between the drug and a polyalkylene oxide polymer end capped with an alkyl or olefinic group which is soluble in both water and an organic solvent. This is carried out by combining the desired medicinal agent with the polymer is an organic solvent, removing the solvent and dissolving the complex in water or aqueous buffer. When the organic solvent is evaporated, a solid complex is recovered which is water-soluble. Methods of treatment with the complexes are also provided.

Abstract: The present invention is directed to methods of preparing high purity polyalkylene oxide carboxylic acids. The methods include reacting a polyalkylene oxide such as polyethylene glycol with a t-butyl haloacetate in the presence of a base followed by treatment with an acid such as trifluoroacetic acid. The resultant polymer carboxylic acids are of sufficient purity so that expensive and time containing purification steps required for pharmaceutical grade polymers are avoided.

Abstract: Branched, substantially non-antigenic polymers are disclosed. Conjugates prepared with the polymers and biologically active molecules such as proteins and peptides demonstrate extended circulating life in vivo. Substantially fewer sites on the biologically active material are used as attachment sites. Methods of forming the polymer, conjugating the polymers with biologically active moieties and methods of using the conjugates are also disclosed.

Abstract: Water-soluble aryl imidate activated polyalkylene oxides having improved hydrolytic stability and conjugates of the aryl imidate activated polyalkylene oxides with biologically active nucleophiles are disclosed. Methods of preparing the activated polyalkylene oxides and conjugates thereof are also disclosed.

Abstract: 2'- and/or 7'- substituted taxoid derivatives having improved water-solubility and/or enhanced therapeutic activity and methods of making the same are disclosed.

Abstract: Water-soluble prodrugs of the formula: ##STR1## wherein: D is a biologically active nucleophile;M is X or Q;x is an electron withdrawing group;Q is a moiety containing a free electron pair positioned five or six atoms from Y';Y and Y' are oxygen or sulfur;R is a polyalkylene oxide; andZ is OH, C.sub.1-4 alkyl moieties or ##STR2## are disclosed.

Abstract: The present invention is directed to methods of preparing high purity polyalkylene oxide carboxylic acids. The methods include reacting a polyalkylene oxide such as polyethylene glycol with a t-butyl haloacetate in the presence of a base followed by treatment with an acid such as trifluoroacetic acid. The resultant polymer carboxylic acids are of sufficient purity so that expensive and time consuming purification steps required for pharmaceutical grade polymers are avoided.