Strictly alternating poly(alkylene oxide ether) copolymers

Details Strictly alternating poly(alkylene oxide ether) copolymers Strictly alternating poly(alkylene oxide ether) copolymers

2000-06-26

2003-08-05

Pryor, Alton N. (Department: 1616)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

C424S078170, C521S030000

Reexamination Certificate

active

06602497

ABSTRACT:

TECHNICAL FIELD
The present invention relates to strictly alternating poly(alkylene oxide ether) copolymers that self-assemble in aqueous media to form micelles that are useful for the delivery of hydrophobic drugs.
BACKGROUND ART
Many important drugs are hydrophobic, particularly the anti-neoplastic agents, such as daunomycin and adriamycin. To date, the delivery of hydrophobic drugs has been problematic. Hydrophobic drugs are not effectively absorbed into the blood stream by the stomach or small intestine, making oral delivery impractical, if not impossible. Instead, hydrophobic drugs are usually delivered parenterally, intravenously or intramuscularly.
Even when delivered by one of these methods, the hydrophobic drug must be uniformly distributed in a biocompatible, typically aqueous medium. This requires the use of a surfactant. The surfactants are amphiphilic molecules that form micellar structures having hydrophobic interiors into which the hydrophobic drug is incorporated and hydrophilic exterior which maintain a stable dispersion in aqueous media.
Repulsion between similar charges keeps the micelles dispersed. Dispersion stability therefore depends upon micellar concentration. Every surfactant has a minimum micellar concentration (MC), below which the micelles fall apart.
Many surfactants are unsuitable for hydrophobic drug delivery because the dilution that occurs upon injection into the blood stream causes the MC to drop below the minimum concentration. Many other surfactants are unsuitable because they produce side-effects in the patient. Many times interferences and interactions produced by administering surfactant stabilized aqueous dispersions of hydrophobic drugs are caused by the surfactant, rather than by the drug itself.
Biocompatibility is also essential in order to avoid toxicity, as well as to prevent rapid clearance of the micelles from the patient's bloodstream. The reduction of the clearance rate by administering the drug in a more biocompatible form also increases the dose efficiency, so that the amount of the drug that is administered may be reduced. This also reduces the occurrence of toxic side-effects.
The ideal surfactant is therefore biocompatible and has a minimum MC below the concentration produced by dilution upon injection into the patient's bloodstream. A class of surfactants with low minimum MC's are the polymeric surfactants, or polysoaps. Shin et al.
J.Control Rel
., 51, 1-11 (1998) discloses a polymeric surfactant that is a diblock copolymer of methoxy polyethylene glycol and e caprolactone. This polymer, however, does not self-assemble into micelles in aqueous solution, complicating the preparation of aqueous dispersions for drug delivery.
U.S. Pat. No. 5,219,564 discloses polyamide and polyetherurethane copolymers of polyethylene glycol and lysine having pendent chains to which drugs may be covalently attached for delivery. The disclosed polymers are highly hydrophilic and do not assemble into micellar structures when a hydrophilic drug is attached to them.
There remains a need for biocompatible polymeric surfactants with sufficiently low minimum MC's to withstand dilution upon injection into a patient that also self-assemble into micelles in aqueous solution.
SUMMARY OF THE INVENTION
This need is met by the present invention. Polyethers copolymerized from poly(alkylene oxides) and aromatic diols have now been discovered that self-assemble to form micelles in aqueous solution. The present invention incorporates the discovery that the aqueous micelle self-assembly is determined by the hydrophilic/hydrophobic ratio of the polyether. Both the poly(alkylene oxides) and the aromatic diols may be selected to obtain a polyether capable of aqueous micelle self-assembly occurs.
Therefore, according to one aspect of the present invention, a polyether comprising strictly alternating poly(alkylene oxide) and aromatic diol monomeric repeating units is provided wherein the combination of repeating units is effective to provide the polymer with a hydrophilic/hydrophobic ratio at which micelle self-assembly will occur in aqueous solution. Aromatic diols are defined as including diphenols.
The polyethers of the present invention possess broad utility beyond medical or pharmaceutical uses. Accordingly, it is not essential that the polyether be non-toxic or biocompatible. However, biocompatible polymers are preferred for medical uses.
In preferred polyethers according to the present invention, the poly(alkylene oxide) and aromatic diol form a repeating segment having the structure of Formula I:
wherein R
1
is selected from alkyl, aryl, and alkylaryl groups containing up to 18 carbon atoms; R
7
is selected from alkylene groups containing from 1 to 4 carbon atoms; m is between about 5 and about 3,000; X
2
is independently an iodine or bromine atom; and Y2 is between 0 and 2, inclusive. Preferably, R
1
contains as part of its structure a pendent carboxylic acid group or an ester or amide thereof, wherein the ester or amide is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms, in addition to the rest of the R
1
structure and derivatives of biologically and pharmaceutically active compounds. The pendent carboxylic acid group permits substitution of monomer repeating units with hydrophilic or hydrophobic moieties to attenuate the hydrophilic/hydrophobic character of the polyether. The side chain also permits the covalent attachment to the polymer of the drug to delivered, if desired. Because of the hydrophobic nature of the aromatic diol, conjugation reactions with hydrophobic drugs are not disfavored. R
1
can also contain non-carbon atoms such as iodine, bromine, nitrogen and oxygen.
Formula I preferably is a structure related to derivatives of tyrosine joined by way of an amide linkage to a &agr;, &bgr; or &ggr;-hydroxy acid or derivative thereof, having the structure of Formula II:
wherein R
5
and R
6
are each independently selected from H, Br, I and straight and branched alkyl groups having up to 18 carbon atoms; R
0
is (—CH
2
—)
d
, —CH═CH— or (—CHJ
1
—CHJ
2
—), R
15
are (—CH
2
—)
c
, —CH═CH— or (—CHJ
1
—CHJ
2
—), wherein J
1
and J
2
are independently selected from Br and I; c and d are between 0 and 8, inclusive; and Z is H, a free carboxylic acid group, or an ester or amide thereof. Z preferably is a pendent group having a structure according to Formula III:
wherein L is selected from hydrogen and straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds.
Z can also be a pendent group having a structure according to Formula IIIa:
wherein M is selected from —OH, —NH—NH
2
, —O—R
8
—NH
2
, —O—R
8
—OH, —NH—R
8
—NH
2
, —NH—R
8
—OH,
a C-terminus protecting group and a derivative of a biologically or pharmaceutically active compound covalently bonded to the pendent functional group by means of an amide bond in the case when in the underivatized biologically or pharmaceutically active compound a primary or secondary amine is present in the position of the amide bond in the derivatives, or an ester bond in the case when in the underivatized biologically or pharmaceutically active compound a hydroxyl or thiol is present in the position of the ester bond in the derivative. Z can also be a pendent group having a structure represented by Formula IIIb:
wherein M is a derivative of a biologically or pharmaceutically active compound covalently bonded to the pendent functional group by means of R
3
, wherein R
3
is a linkage selected from —NH—NH— in the case when in the underivatized biologically or pharmaceutically active compound an aldehyde or ketone is present at the position linked to the pendent functional group by means of R
3
; and —NH—NH—, —NH—R
8
—NH, —O—R
8
—NH—, —O—R
8
—O— or —NH—R
8
—O— in the case when in the underivatized biologically or pharmaceutically active compound a carboxylic acid is present in the position linked to the pendent functional group by means of X;

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