Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2001-06-22
2004-11-30
Weber, Jon P. (Department: 1653)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C514S248000, C514S283000, C546S047000, C546S070000, C525S054100, C525S054200, C530S323000
Reexamination Certificate
active
06824766
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 biological y-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 Science
, 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 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 rapidly eliminated in vivo, especially if a somewhat hydrolysis-resistant linkage is used. In fact, such conjugates are 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 formulae (X) and (XI):
wherein:
R
31
is a linear or branched polymer residue;
Y
10
and Y
11
are independently O, S, or NR
40
;
R
32
-R
40
, R
50
and R
51
are independently selected from the group consisting of hydrogen, C
1-6
alkyls, C
3-12
branched alkyls, C
3-8
cycloalkyls, C
1-6
substituted alkyls, C
3-8
substituted cycloalkyls, aryls, substituted aryls, aralkyls, C
1-6
heteroalkyls and substituted C
1-6
heteroalkyls;
a, b and e are each independently selected positive integers, preferably from about 1 to about 6;
X
1
and X
2
are independently O, S or NR
41
;
wherein R
41
is selected from the same group as that which defines R
40
;
L is an amino acid residue or a bifunctional linker.
X
3
is
wherein Y
12
and Y
13
are independently O, S, or NR
40
;
Z is selected from the group consisting of a bond, a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
D
1
and D
2
are independently one of OH a residue of a hydroxyl-containing moiety, a residue of an amine-containing moiety or a leaving group; and
y
1
and y
2
are each independently a positive integer.
In preferred aspects of the above embodiment,
R
31
preferably a PEG residue;
Y
11
and Y
12
are both O;
R
22
-R
40
, R
50
, and R
51
are each hydrogen or a C
1-4
alkyl;
a and b hare each 1;
y
1
and y
2
are both one; and
D
1
and D
2
are both residues of either a hydroxyl- or amine-containing moiety such as one having biological activity as defined herein.
With regard to L in formulae (X) and (XI), a non-limiting list of suitable amino acid residues include those of the formula:
wherein X
4
is O, S or NR
42
, Y
14
is O, S, or NR
45
; where R
42
, R
45
and R
52
-R
53
are selected from the same group which defines R
40
; and (f) is a positive integer, preferably from about 1 to about 2. Alternatively, a non-limiting list of suitable bifunctional linkers include:
wherein X
5
is O, S or NR
43
;
Y
15
is O, S, or NR
44
;
R
43
, R
44
and R
54
-R
58
are selected from the same group which defines R
40
; and g is a positive integer, preferably from about 1 to about 2.
With regard to (Z), it will be understood that in addition to being a covalent bond, Z is covalently linked to [D]
y
, so that Z is a moiety that is actively transported into a target cell, a hydrophobic moiety or a combination thereof. Optionally, Z is monovalent, multivalent, or more preferably, bivalent, wherein (y) is 1 or 2. Z itself optionally includes an amino acid residue, a sugar residue, a fatty acid residue, a peptide residue, a C
1-18
alkyl, a substituted aryl, a heteroaryl, —C(═O), —C(═S), and —C(═NR
42
), where R
42
is selected from the same group which defines R
40
.
When Z includes at least one amino acid residue, the amino acid is, e.g., alanine, valine, leucine, isoleucine, glycine, serine, threonine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine, proline, and/or a combination thereof, to name but a few. When Z includes a peptide, the peptide ranges in size, for instance, from about 2 to about 10 amino acid residues. In one preferred embodiment, the peptide is Gly-Phe-Leu-Gly or Gly-Phe-Leu.
Methods of preparing and using the same are also disclosed.
In more general aspects, the invention includes compounds of the formula:
(D)
n
-M-(R
1
)
m
(I)
wherein
(m) and (n) are 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.
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
1/2
'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 molecular polymers such as when PE
Greenwald Richard B.
Zhao Hong
Desai Anand
Enzon Inc.
Muserlian Lucas and Mercanti
Weber Jon P.
LandOfFree
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