Bioerodible polyorthoesters containing amine groups

Details Bioerodible polyorthoesters containing amine groups Bioerodible polyorthoesters containing amine groups

2001-11-16

2003-02-25

Acquah, Samuel A. (Department: 1711)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C528S220000, C528S271000, C528S361000, C528S392000, C528S403000, C528S406000, C528S422000, C528S425000, C424S422000, C424S426000, C424S433000, C424S435000, C424S486000, C424S490000, C424S491000, C424S457000, C424S463000, C424S468000, C514S772300, C514S773000

Reexamination Certificate

active

06524606

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This application relates to polyorthoesters. In particular, this invention relates to bioerodible polyorthoesters containing amine groups and &agr;-hydroxy acid-containing groups.
2. Description of the Prior Art
Interest in synthetic biodegradable polymers for the systemic delivery of therapeutic agents began in the early 1970's with the work of Yolles et al.,
Polymer News
1:9-15 (1970) using poly(lactic acid). Since that time, numerous other polymers have been prepared and investigated as bioerodible matrices for the controlled release of therapeutic agents.
U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646 disclose biodegradable or bioerodible polyorthoesters. These polymers are formed by a reaction between an orthoester (or orthocarbonate) such as 2,2-diethoxytetrahydrofaran and a diol such as 1,4-cyclohexanedimethanol. The reaction requires elevated temperature and reduced pressure and a relatively long reaction time. Drugs or other active agents are retained in the polymer matrix to be released as the polymer biodegrades due to hydrolysis of the labile linkages.
U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting a polyol with a polyfunctional ketene acetal. These polymers represent a significant improvement over those of U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceeds readily at room temperature and atmospheric pressure, and the resulting polymers have superior properties.
Further polymers are disclosed in U.S. Pat. No. 4,957,998. These polymers contain acetal, carboxy-acetal and carboxy-ortho ester linkages, and are prepared by a two-step process beginning with the reaction between a polyfunctional ketene acetal and a compound containing a vinyl ether, followed by reaction with a polyol or polyacid.
Still further polymers of a similar type are disclosed in U.S. Pat. No. 4,946,931. The polymers are formed by a reaction between a compound containing a multiplicity of carboxylate functions and a polyfunctional ketene acetal. The resulting polymers have very rapid erosion times.
Despite the ease with which the orthoester linkage hydrolyses, polyorthoesters known in the prior art are extremely stable materials when placed in an aqueous buffer, or when residing in the body. This stability is attributable to the extreme hydrophobicity of the polyorthoesters which severely limits the amount of water that can penetrate the polymer. To achieve useful erosion rates, therefore, acidic excipients must be physically incorporated into the polymer. While this allows control over erosion rates, the physically incorporated acidic excipient can diffuse from the polymer matrix at varying rates, leaving a matrix that is completely depleted of excipient while the polymer still has a very long lifetime remaining.
U.S. Pat. Nos. 4,764,364 and 4,855,132 describe bioerodible polymers, in particular polyorthoesters containing an amine functionality. The polymers are said to erode more rapidly at lower pH than at higher pH in an acidic aqueous environment.
The disclosures of the documents listed in this section and elsewhere throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
In a first aspect, this invention is polyorthoesters of formula I or formula II:
R* is a C
1-4
alkyl;
R is a bond, —(CH
2
)
a
—, or —(CH
2
)
b
—O—(CH
2
)
c
—; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
n is an integer of at least 5; and
A is selected from R
1
, R
2
, R
3
, R
4
, and mixtures thereof, where
R
1
is:
where:
p is an integer of 1 to 20;
R
5
is hydrogen or C
1-4
alkyl; and
R
6
is:
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R
7
is hydrogen or C
1-4
alkyl;
R
2
is:
 R
3
is:
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R
8
is hydrogen or C
1-4
alkyl;
R
9
and R
10
are independently C
1-12
alkylene;
R
11
is hydrogen or C
1-6
alkyl and R
12
is C
1-6
alkyl; or R
11
and R
12
together are C
3-10
alkylene; and
R
4
is the residual of a diol containing at least one amine functionality incorporated therein;
in which at least 0.1 mol % of the A units are R
1
, and at least 0.1 mol % of the A units are R
4
.
In a second aspect, this invention is controlled release pharmaceutical compositions comprising:
(a) an active agent; and
(b) as a vehicle, the polyorthoester described above.
In a third aspect, this invention is a method of treating a disease state treatable by controlled release local administration of an active agent, such as treating pain by administration of a local anesthetic or treating cancer by administration of a chemotherapeutic or antineoplastic agent, comprising locally administering a therapeutically effective amount of the active agent in the form of the controlled release pharmaceutical composition described above.
In a fourth aspect, this invention is methods of preparation of the polyorthoesters of the first aspect of the invention and the controlled release pharmaceutical compositions of the second aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that polyorthoesters useful as orthopedic implants or vehicles for the sequestration and sustained delivery of drugs, cosmetic agents and other beneficial agents can be prepared in such a manner that the rate and degree to which they are hydrolyzed by contact with bodily fluids at normal body temperature and pH can be controlled without addition of exogenous acid. This discovery resides in the incorporation of esters of short-chain &agr;-hydroxy acids such as esters of glycolic acid, lactic acid or glycolic-co-lactic acid copolymer into the polyorthoester chain and variation of the amount of these esters relative to the polyorthoester as a whole.
In the presence of water, these esters, when incorporated into the polyorthoester chain, are readily hydrolyzed at a body temperature of 37° C. and a physiological pH, in particular at a pH of 7.4, to produce the corresponding &agr;-hydroxy acids. The &agr;-hydroxy acids then act as an acidic excipient to control the hydrolysis rate of the polyorthoester. When the polyorthoester is used as a vehicle or matrix entrapping an active agent, the hydrolysis of the polyorthoester causes release of the active agent.
The use in these polyorthoesters of diols containing amine functionalities causes the polyorthoesters to become more pH-sensitive than polyorthoesters not containing such diols, and thus to hydrolyze yet more readily at lower pH than at higher pH. This is particularly so in an acidic aqueous environment, such as is found within animal cells, and enables the polyorthoesters to be relatively stable within the extracellular environment within an animal, such as within the blood, but to hydrolyze rapidly within the intracellular environment. This makes these polyorthoesters particularly suitable for delivery of active agents within the cell.
In addition, the mechano-physical state of the polyorthoester may also be controlled. This is achieved by the inclusion of the residues of certain diols in selected proportions relative to the polyorthoester as a whole. For example, a high content of the residue of 1,4-cyclohexane-dimethanol (as the trans isomer or as a cis/trans isomer mixture) or a similar “hard” diol relative to a “soft” diol (definition of which is given below) produces a relatively rigid polymer chain and a more solid substance, and by decreasing the cyclohexanedimethanol content relative to the “soft” diol, the polyorthoester will change progressively through the stages of a rigid thermoplastic, a soft thermoplastic, a low melting solid to an ointment-like (viscous liquid) material, and any stage in between.
The polyorthoesters of the present invention are prepared by condensation reactions between diketene acetals and polyols, preferably diols, and the variation in mechano-physical state and rate of hydrolysis (bioerodibility) is achieved by the selection and use of combinations

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