Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From ketone or ketene reactant
Reexamination Certificate
2001-05-11
2003-07-08
Acquah, Samuel A. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From ketone or ketene reactant
C528S073000, C528S074000, C528S271000, C528S310000, C528S354000, C528S361000, C528S403000, C528S406000, C528S422000, C424S422000, C424S425000, C424S426000, C424S451000, C424S458000, C424S486000
Reexamination Certificate
active
06590059
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application relates to polyorthoesters. In particular, this invention relates to bioerodible polyorthoesters containing new diketene acetals 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-diethoxytetrahydrofuran 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-orthoester 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. No. 5,968,543 (Heller et al.) describes polyorthoesters containing &agr;-hydroxy acid-containing groups. The polyorthoesters are formed from the reaction of a diketene acetal such as 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) with at least 0.1 mol % of an “&agr;-hydroxy acid” diol and 0-99.9 mol % of one or more of a “hard” diol and a “soft” diol (as those terms are used in the patent). These polyorthoesters are stated to have greater bioerodibility than similar polyorthoesters not containing the &agr;-hydroxy acid ester-containing groups, and to have the bioerodibility controllable by variation in the concentration of the &agr;-hydroxy acid ester-containing groups.
U.S. Pat. No. 4,549,010 (Sparer et al.) describes polyorthoesters containing functional groups which produce hydrogen bonding.
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:
where:
R is a bond, —(CH
2
)
a
—, or —(CH
2
)
a
—O—(CH
2
)
a
—; where A is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
R* is a C
1-4
alkyl;
n is an integer of at least 5; and
A is R
1
, R
2
, R
3
, or R
4
, 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 residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.1 mol % of the A units are R
1
.
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, in particular 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 pharmaceutical composition described above.
In a fourth aspect, this invention is methods of using the polyorthoesters of the first aspect of the invention as bioerodible implants.
In a fifth 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.
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 trans-1,4-cyclohexane-dimethanol 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 trans-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 of dif
Heller Jorge
Ng Steven Y.
Acquah Samuel A.
AP Pharma Inc.
Heller Ehrman White & McAuliffe LLP
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