Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2000-12-07
2004-02-03
Page, Thurman K. (Department: 1609)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S426000, C424S444000, C424S501000, C424S078370
Reexamination Certificate
active
06685928
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of anti-inflammatory agents to enhance the regeneration and healing of tissue (e.g. hard tissue and soft tissue).
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 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 on 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 cannot 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 aromatic polyanhydrides have now been developed with improved degradation, processing and solubility properties, as well as therapeutic utilities. As demonstrated herein, the new aromatic polyanhydrides are particularly useful in enhancing regeneration and healing of tissue. Thus, these new polyanhydrides can be used in a variety of dental and orthopedic applications.
SUMMARY OF THE INVENTION
It has unexpectedly been discovered that the local administration of an anti-inflammatory agent to tissue provides beneficial effects on the healing and growth of the tissue and on proximally located tissues.
Accordingly, the invention provides a method to promote healing of tissue comprising administering an effective amount of an anti-inflammatory agent to or near the tissue.
The invention provides a method to promote healing of hard tissue comprising administering an effective amount of an anti-inflammatory agent to the hard tissue or to soft tissue near the hard tissue.
The invention also provides a method of treating periodontal disease comprising administering an effective amount of an anti-inflammatory agent at the site of the periodontal disease.
The invention also provides a method of treating a bone fracture comprising fixing the fracture with an orthopedic device comprising an anti-inflammatory agent.
The invention also provides a method to enhance regeneration of tissue comprising administering an effective amount of an anti-inflammatory agent to or near the tissue.
The invention also provides a method to enhance regeneration of hard tissue comprising administering an effective amount of an anti-inflammatory agent to the hard tissue or to soft tissue near the hard tissue.
The invention also provides a method to decrease bone resorption at a site in the body of a patient comprising administering an effective amount of an anti-inflammatory agent at or near the site.
The invention also provides a method to promote healing of bone comprising contacting the bone and surrounding soft tissue with an aromatic polyanhydride comprising a repeating unit having the structure:
wherein Ar is a substituted or unsubstituted aromatic ring and R is —Z
1
—R
1
—Z
1
— substituted on each Ar ortho to the anhydride group, wherein R
1
is a difunctional organic moiety and Z
1
is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates so that regeneration of bone is enhanced.
The invention also provides a method of treating periodontal diseases in a patient comprising administering to the patient at the site of the periodontal disease an aromatic polyanhydride comprising a repeating unit having the structure:
wherein Ar is a substituted or unsubstituted aromatic ring and R is —Z
1
—R
1
—Z
1
— substituted on each Ar ortho to the anhydride group, wherein R
1
is a difunctional organic moiety and Z
1
is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
The invention also provides a method of treating bone fractures in a patient comprising fixing the bone fracture with an orthopedic device comprised of or coated with an aromatic polyanhydride comprising a repeating unit having the structure:
wherein Ar is a substituted or unsubstituted aromatic ring and R is —Z
1
—R
1
—Z
1
— substituted on each Ar ortho to the anhydride group, wherein R
1
is a difunctional organic moiety and Z
1
is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
The invention also provides pharmaceutical compositions comprising an anti-inflammatory agent and a pharmaceutically acceptable carrier, which are formulated to provide controlled release of the agent at or near tissue (e.g. hard or soft tissue). Preferably, the compositions are formulated to provide local release of an effective amount of the agent over a period of at least about 2, about 5, about 10, about 20, or about 40 days. The compositions can also preferably be formulated to provide local release of an effective amount of the agent over a period of up to about 3 months, about 6 months, about 1 year, or about 2 years.
The preparation of aromatic polyanhydrides from ortho-substituted bis-aromatic carboxylic acid anhydrides 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 aliphatic bonds in these compounds further enhances these properties.
These aromatic polyanhydrides have 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 the chemical structure of an anti-inflammatory agent, particularly salicylates such as aspirin, non-steroidal anti-inflammatory compounds, or other aromatic anti-inflammatory compounds. 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 —C(═O)O—, amide —C(═O)N—, anhydride —C(═O)—O—C(&
Macedo Braz
Uhrich Kathryn E.
Fubara Blessing
Page Thurman K.
Rutgers The State University of New Jersey
Schwegman Lundberg Woessner & Kluth P.A.
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