Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
1999-04-15
2001-06-26
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S486000, C514S002600, C525S054100, C560S159000
Reexamination Certificate
active
06251382
ABSTRACT:
TECHNICAL FIELD
The present invention relates to new types of biodegradable, terminally activated polymers which are useful in forming conjugates of bioactive materials. In particular, the invention relates to biodegradable, polymeric-based conjugates having increased therapeutic payloads and methods of preparing the same.
BACKGROUND OF THE INVENTION
Over the years, several methods of administering biologically-effective materials to mammals have been proposed. Many medicinal agents are available as water-soluble salts and can be included in pharmaceutical formulations relatively easily. Problems arise when the desired medicinal agent is either insoluble in aqueous fluids or is rapidly degraded in vivo. Alkaloids are often especially difficult to solubilize.
One way to solubilize medicinal agents is to include them as part of a soluble prodrug. Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, eventually liberate the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent in vivo and can modify the transportation, distribution or solubility of a drug in the body. Furthermore, prodrug formulations often reduce the toxicity and/or otherwise overcome difficulties encountered when administering pharmaceutical preparations. Typical examples of prodrugs include organic phosphates or esters of alcohols or thioalcohols. See
Remington's Pharmaceutical Sciences
, 16th Ed., A. Osol, Ed. (1980), the disclosure of which is incorporated by reference herein.
Prodrugs are often biologically inert or substantially inactive forms of the parent or active compound. The rate of release of the active drug, i.e. the rate of hydrolysis, is influenced by several factors but especially by the type of bond joining the parent drug to the modifier. Care must be taken to avoid preparing prodrugs which are eliminated through the kidney or reticular endothelial system, etc. before a sufficient amount of hydrolysis of the parent compound occurs.
Incorporating a polymer as part of a prodrug system has been suggested to increase the circulating life of a drug. However, it has often been determined that when only one or two polymers of less than about 10,000 daltons each are conjugated to certain biologically active substances such as alkaloid compounds, the resulting conjugates are often rapidly eliminated in vivo, especially if a somewhat hydrolysis-resistant linkage is used. In fact, such conjugates can be so rapidly cleared from the body that even if a hydrolysis-prone ester linkage is used, not enough of the parent molecule is regenerated in vivo to be therapeutic.
As an outgrowth of the work in the prodrug field, it has been thought that it would be beneficial in some situations to increase the payload of the polymeric transport form. This technique was offered as an alternative to the many approaches in which a single molecule of a therapeutic moiety containing a substitutable hydroxyl moiety is attached to a terminal group found on the polymer. For example, commonly-assigned PCT publication WO96/23794 describes bis-conjugates in which one equivalent of the hydroxyl-containing drug is attached to each terminal of the polymer. In spite of this advance, techniques which would further increase the payload of the polymer have been sought. In addition, technologies for forming prodrugs of therapeutic moieties having a substitutable amino group have also been sought. The present invention addresses these needs.
SUMMARY OF THE INVENTION
The present invention includes compounds of the formula:
(D)
n
—M—(R
1
)
m
(I)
wherein
(m) and (n) independently selected positive integers, preferably from about 1 to about 6 each;
D is a residue of a biologically active moiety:
M is a multifunctional linker/spacer moiety; and
R
1
is a polymer residue.
Methods of preparing the same and methods of treatment using the same are also included as part of the present invention.
With respect to the linking of the polymer strands, the artisan is provided with higher total molecular weight polymers which are useful in providing therapeutic conjugates with relatively long T
½
's. There are several advantages associated with these types of polymers. For example, depending upon the linkages used to attach the polymer strands to the multifunctional spacer groups, the artisan can design relatively high molecular weight polymeric transport systems which will predictably biodegrade into polymers of relatively low molecular weight which are more readily eliminated from the body than the singular polymer of higher molecular weight. Secondly, because relatively small molecular weight polymers are used to build the biodegradable transport form, the polydispersity associated with some single strand high moleulcar weight polymers such as when PEG has a molecular weight of over 40 kDa is substantially avoided.
Additional advantages associated with using the multifunctional spacers in the polymers of the present invention is that there is a large number of multifunctional moieties readily available. Thus, the artisan can prepare polymeric prodrug systems having high degrees of loading, i.e. 3-6 or more molecules of active drug per transport system. A still further advantage of the multifunctional spacers of polymeric systems of the present invention is that the artisan can form prodrugs of almost any therapeutic molecule. For example, the multifunctional spacer can be designed to include the capability of accommodating a linker for attaching to hydroxyl residues, amine residues, sulfhydryl residues, etc. found on organic molecules, proteins, peptides, eyes, etc. Another advantage is that the linkers can be selected to achieve a proper balance between the rate of parent drug-polymer linkage hydrolysis on the one hand and the rate of clearance of prodrug from the body on the other which is caused by lower molecular weight polymer portions being released from the transport system. The linkages between the polymer and the parent compounds, also referred to herein as a biologically-active nucleophiles, hydrolyze at a rate which allows a sufficient amount of the parent molecules to be released in vivo before clearance of the prodrug from the plasma or body.
The high payload polymeric conjugates of the present invention are thus unique delivery systems which can contain up to several molecules of a drug per unit.
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Benaglia, Maurizio. Synthesis of New Poly (ethyleneglycol)s with a High Loading Capacity, J. Org. Chem. 1998, 63, 8628-8629.
Gao, Yong. Stereoselective Synthesis of meso-2,6-Diaminopimelic Acid and its Selectively Protected Derivatives, J. Org. Chem. 1998, 63, 2133-2143.
Williams, Robert M. Asymmetric Synthesis of Differentially Protected 2,7-Diaminosuberic Acid, a Ring-Clsure Metathesis Approach, J. Org. Chem. 1998, 63, 2130-2132.
Sigma Catalog, p. 1715, 1991.
Choe Yun H.
Greenwald Richard B.
Martinez Anthony J.
Pendri Annapurna
Enzon Inc.
Low Christopher S. F.
Lukton David
Roberts & Mercanti LLP
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