Drug – bio-affecting and body treating compositions – Digestive system regulator containing solid synthetic...
Reexamination Certificate
1999-10-21
2002-10-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Digestive system regulator containing solid synthetic...
C424S078190, C424S078170, C424S078370
Reexamination Certificate
active
06468519
ABSTRACT:
FIELD OF THE INVENTION
Biocompatible polyanhydrides having improved degradation properties and processability with useful degradation products have now been developed. In one embodiment, the polyanhydrides are ortho-substituted aromatic polyanhydrides produced from ortho-substituted bis-aromatic carboxylic acid anhydrides which degrade into biologically active materials such as salicylates. In another embodiment, the polyanhydrides are aliphatic in structure and degrade into alpha-hydroxy acids. Salicylates are used routinely as anti-inflammatory, antipyretic, analgesic, and anti-oxidant agents, while alpha-hydroxy acids are incorporated into many skin moisturizers, cleansers, lotions, creams shampoos, tanning products and lipsticks to promote smoother, clearer skin with fewer wrinkles. Thus, the biocompatible polyanhydrides of the present invention can be administered to a host via a variety of routes including, but not limited to orally, subcutaneously, intramuscularly, intradermally and topically, depending upon the degradation product of the polyanhydride and the selected use for the degradation product.
BACKGROUND OF THE INVENTION
Polymers comprising aromatic or aliphatic anhydrides have been studied extensively over the years for a variety of uses. For example, in the 1930s fibers comprising aliphatic polyanhydrides were prepared for use in the textile industry. In the mid 1950s, aromatic polyanhydrides were prepared with improved film and fiber forming properties. More recently, attempts have been made to synthesize polyanhydrides with greater thermal and hydrolytic stability and sustained drug release properties.
U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparation of polyanhydrides with improved sustained drug release properties from pure, isolated prepolymers of diacids and acetic acid. However, these biocompatible and biodegradable aromatic polyanhydrides have radical or aliphatic bonds resulting in compounds with slow degradation times as well as relatively insoluble degradation products unless incorporated into a copolymer containing a more hydrophilic monomer, such as sebacic acid. The aromatic polyanhydrides disclosed in the '128 Patent and the '904 Patent are also insoluble in most organic solvents. A bioerodible controlled release device produced as a homogenous polymeric matrix from polyanhydrides with aliphatic bonds having weight average molecular weights greater than 20,000 and an intrinsic velocity greater than 0.3 dL/g and a biologically active substance is also described in U.S. Pat. No. 4,888,176. Another bioerodible matrix material for controlled delivery of bioactive compounds comprising polyanhydride polymers with a uniform distribution of aliphatic and aromatic residues is disclosed in U.S. Pat. No. 4,857,311.
Biocompatible and biodegradable aromatic polyanhydrides prepared from para-substituted bis-aromatic dicarboxylic acids for use in wound closure devices are disclosed in U.S. Pat. No. 5,264,540. However, these compounds exhibit high melt and glass transition temperatures and decreased solubility, thus making them difficult to process. The disclosed polyanhydrides also comprise radical or aliphatic bonds which can not be hydrolyzed by water.
Polyanhydride polymeric matrices have also been described for use in orthopedic and dental applications. For example, U.S. Pat. No. 4,886,870 discloses a bioerodible article useful for prosthesis and implantation which comprises a biocompatible, hydrophobic polyanhydride matrix. U.S. Pat. No. 5,902,599 also discloses biodegradable polymer networks for use in a variety of dental and orthopedic applications which are formed by polymerizing anhydride prepolymers.
Biocompatible and biodegradable polyanhydrides have now been developed with improved degradation, processing and solubility properties, as well as utilities based upon their degradation products.
SUMMARY OF THE INVENTION
An object of the present invention is to provide biocompatible and biodegradable polyanhydrides which degrade into biologically active products. In one embodiment, aromatic polyanhydrides which degrade into biologically active salicylates are prepared from ortho-substituted bis-aromatic carboxylic acid anhydrides. Ortho substitution disrupts the crystallinity of the resulting polymer, enhancing solubility and processability, as well as degradation properties. The use of hydrolyzable bonds such as esters, amides, urethanes, carbamates and carbonates as opposed to radical or aliphatic bonds in these compounds further enhances these properties. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula I:
wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, non-steroidal anti-inflammatory naphthyl or phenyl propionates such as ibuprofen, ketoprofen, naproxen, and the like, or other aromatic anti-inflammatory compounds such as indomethacin, indoprofen, and the like. Ar is preferably a phenyl group and R is preferably —Z
1
—R
1
—Z
1
-in which R
1
, is a difunctional moiety and both Z
1
s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. R
1
is preferably an alkylene group containing from 1 to carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (—CH
2
—CH
2
—O—)
m
, (CH
2
—CH
2
—CH
2
—O—)
m
and (—CH
2
—CHCH
3
—O—)
m
.
Ortho-substituted bis-aromatic carboxylic acid anhydrides are used in the preparation of the aromatic polyanhydrides of the present invention. The ortho-substituted bis-aromatic carboxylic acid anhydrides have the structure of Formula II:
wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I and R is substituted on each Ar ortho to the anhydride group.
In another embodiment, polyanhydrides which degrade into biologically active alpha-hydroxy acids are prepared from bis-carboxylic acid anhydrides. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula III:
wherein, R is preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling an alpha-hydroxy acid. In this embodiment, R is preferably an alkylene group containing from 1 to 20 carbon atoms, —(CH
2
)
x
— wherein x is from 1 to 20, or
wherein x is from 1 to and Z
1
and Z
2
are OH so that the R group contains from 1 to 40 hydroxyl groups.
The present invention relates to compositions and methods of using compositions comprising polyanhydrides of Formula (I) or (III) in applications wherein delivery of a salicylate or an alpha-hydroxy acid to a host is desired. By “host” it is meant to include both animals and plants.
A more complete appreciation of the invention and other intended advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out.
DETAILED DESCRIPTION OF THE INVENTION
Polyanhydrides which degrade into useful biologically active products such as salicylates and alpha-hydroxy acids have now been developed. Compounds comprising these polyanhydrides are useful in a variety of applications wherein delivery of a salicylate or alpha-hydroxy acid is desired.
In one embodiment, the polyanhydride comprises repeating units with the structure of Formula I:
wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. In this embodiment, Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, nonste
Fubara Blessing
Page Thurman K.
Rutgers The State University of New Jersey
Schwegman Lundberg Woessner & Kluth P.A.
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