MXPA02005769A - Therapeutic compositions and methods for treating periodontitis with antiinflamatory compounds - Google Patents

Abstract

Methods of promoting healing through enhanced regeneration of tissue (e.g. hard tissue or soft tissue) by contacting the tissue or the surrounding tissue with an anti-inflammatory agent. These methods are useful in a variety of dental and orthopedic applications.

Description

METHODS AND THERAPEUTIC CO MPOSITIONS Related Requests This application claims priority to the Provisional Application of E. U. Number 60 / XXXXX, which was filed on December 7, 1999 as the Patent Application of E. U. Serial Number 09 / 455,861 .. for which a request under 37 C. F. R § 1 .53 (c) to convert the non-provisional application to a provisional application was filed on December 6, 2000.

Field of the Invention The present invention relates to the use of anti-inflammatory agents to increase tissue regeneration and healing (e.g., hard tissue and soft tissue).

BACKGROUND OF THE INVENTION Polymers comprising aliphatic or aromatic anhydrides have been studied extensively over the years for a variety of uses. For example, in the 30's the fibers comprising aliphatic polyanhydrides are prepared for use in the textile industry. In the mid-50's, aromatic polyanhydrides are prepared with improved fiber and film-forming properties. More recently, attempts have been made to synthesize the polyanhydrides with enhanced hydrolytic and thermal stability and prolonged drug release properties.

The Patents of E. U. 4, 757, 128 and 4, 997, 904 describe the preparation of polyanhydrides with prolonged drug release properties, improved from isolated, pure prepolymers of diacids and acetic acid. However, these biodegradable and biocompatible aromatic polyhydroxides have aliphatic linkages that result in compounds with slow degradation times as well as relatively insoluble degradation products at least incorporated in a copolymer containing a more aliphatic monomer, such as sebasic acid. The aromatic polyanhydrides described in the patent? 28 and the '904 patent are also insoluble in most organic solvents. A controllable, bioerodible release device produced as a homogeneous polymer matrix of polyanhydrides with aliphatic linkages 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 disclosed in the US Pat. E. U. 4, 888, 1 76. Another bioerodible matrix material for controlled delivery of bioactive compounds comprising polyanhydride polymers with a uniform distribution of aromatic and aliphatic residues is described in the E. OR . 4, 857, 31 1. The biodegradable and biocompatible aromatic polyhydroxides prepared from para-substituted bis-aromatic dicarboxylic acids for use in wound closure devices are described in the E. OR . 5,264, 540. However, these compounds exhibit high glass transition and melting temperatures and reduced solubility, thus making them difficult to process.

The described polyhydric alcohols also comprise aliphatic bonds or radicals that can not be hydrolyzed by water. Polymeric polymer matrices have also been described for use in dental and orthopedic applications. For example, the Patent of E. U. 4,886, 870 discloses a bioerodible article useful for prosthesis and implantation comprising a hydrophobic, biocompatible polyanhydride matrix. The Patent of E. U. 5, 902, 599 also discloses biodegradable polymer networks for use in a variety of orthopedic and dental applications that are formed by polymerizing anhydride prepolymers. Biodegradable and biocompatible aromatic polyanhydrides, as well as developed with improved solubility, processing and degradation properties, as well as therapeutic equipment. As demonstrated herein, the new aromatic polyhydric alcohols are particularly useful for increasing tissue regeneration and healing. In this way, these new polynucleides can be used in a variety of orthopedic and dental applications.

BRIEF DESCRIPTION OF THE INVENTION It has been unexpectedly discovered that the local administration of an anti-inflammatory agent to tissue provides beneficial effects in the healing and growth of tissue in tissues that are soon to be disrupted. According to the above, the invention provides a method for promoting tissue healing which comprises administering an effective amount of an anti-inflammatory agent at or near the tissue. The invention provides a method for promoting hard tissue healing which comprises administering an effective amount of an anti-inflammatory agent to hard tissue or soft tissue near hard tissue. The invention also provides a method for treating periodontal disease comprising administering an effective amount of an anti-inflammatory agent at the site of periodontal disease. The invention also provides a method for treating a bone fracture comprising fixing the fracture with an orthopedic device comprising an anti-inflammatory agent. The invention also provides a method for increasing tissue regeneration comprising administering an effective amount of an anti-inflammatory agent to or near tissue. The invention also provides a method for increasing hard tissue regeneration comprising administering an effective amount of an anti-inflammatory agent to the hard tissue or soft tissue near the hard tissue. The invention also provides a method for reducing 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 for promoting bone healing which comprises contacting the bone and surrounding soft tissue with a polyanhydride comprising a repeat unit having the structure.

OO II II -C-Ar- R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Z i -R i -Z ^ substituted on each Ar ortho to the anhydride group, wherein R is a dysfunctional organic moiety and is a dysfunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates so that the regeneration of the bone is increased. The invention also provides a method for treating periodontal diseases in a patient comprising administering to the patient at the site of periodontal disease an aromatic polyanhydride comprising a repeat unit having the structure: O O II II -C-Ar-R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Zr R i -? T - substituted on each Ar ortho to the anhydride group, wherein R i is a dysfunctional organic portion and? is a dysfunctional portion selected from the group consisting of esters, amides, urethanes, carbamates and carbonates. The invention also provides a method for treating bone fractures in a patient comprising fixed bone fracture with an orthopedic device comprised of or coated with an aromatic polyanhydride comprising a repeat unit having the structure: O O II II -C-Ar-R-Ar-C-O- wherein Ar is a substituted or unsubstituted aromatic ring and R is -? - R i-? T substituted in each Ar ort to the anhydride group, wherein R es is a dysfunctional organic moiety and Z n is a dysfunctional 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 in or near the 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 may also be preferably formulated to provide local release of an effective amount of the agent for a period of up to about 3 months, about 6 months, about 1 year. or about 2 years. The invention also provides the use of an anti-inflammatory agent to prepare a medicament useful for promoting tissue healing by administration to or near the tissue. The invention also provides the use of an anti-inflammatory agent to prepare a medicament useful for reducing bone resorption at a site in the body of a male by administering the or near the site. The invention also provides the use of an anti-inflammatory agent to prepare a medicament useful for increasing tissue regeneration by administration to or near the tissue. The preparation of aromatic polyanhydrides of ortho-substituted bis-aromatic carboxylic acid anhydrides interrupts the crystallinity of the resulting polymer, increasing the solubility and processability, as well as degradation properties. The use of hydrolysable linkages such as esters, amides, urethanes, carbamates and carbonates as opposed to the aliphatic linkages in these compounds further increases these properties.Aromatic polyanhydrides have a repeating unit within the structure of Formula I: OO II II -C-Ar-R-Ar-C-O- (I) wherein Ar is a substituted or unsubstituted aromatic ring and R is a substituted functional portion in each Ar ortho to the anhydride group. Ar and R are preferably selected so that the hydrolysis products of polyanhydrides have 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 -ZI-R ^ Z T, where R i is a dysfunctional moiety and both Z ^ 's are independently either an -C ester. { = 0) 0-. amide - C (= 0) N -, anhydride C (= 0) -0-C (= 0) -, carbonate -0-C (= 0) -0-, urethane -N- C (= 0) -N-, -S- sulfide groups. Ri is preferably an alkylene group containing 1 to 20 carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (-CH2-CH2-0-) m, (CH2- CH2-CH2- 0-) m and (-CH2-CHCH3-0-) m. The ortho-substituted bis-aromatic carboxylic anhydrides of the present invention are used in the preparation of the aromatic polyanhydrides of the present invention. Ortho-substituted bis-aromatic carboxylic acid anhydrides have the structure of Formula I I: O O O O II II II II l H3C-C-0-C-Ar-R-Ar-C-0-C-CH3 (I I) wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I and R is substituted in each Ar ort to the anhydride group. i-s The aromatic polyanhydrides of the present invention satisfy the need for moldable bicompatible biodegradable polymers and are particularly useful in enhancing the healing process of surrounding soft tissue and bone. Accordingly, the present invention relates to compositions and methods for using compositions comprising an aromatic polyanhydride with a repeating unit of Formula I to increase tissue healing (eg, soft tissue). It has been found that these compositions promote healing in hard tissue by inhibiting inflammation and / or pain in the surrounding soft tissue and by increasing the regeneration of the hard tissue by promoting growth and / or reduce bone resorption. In order to use these compositions to increase tissue regeneration, it is preferred that the compositions are incorporated into fibers, films, membranes, pastes or microspheres. For this use, it is also preferred that the compositions comprise poly (anhydride-esters), referred to herein as bioactive polyanhydrides that are degraded into salicylic acid, an analgesic or antipyretic, anti-inflammatory agent. The hard tissue and surrounding soft tissue are contacted directly with the composition so that regeneration and healing is increased. A more complete appreciation of the invention and other proposed advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which describe the principles of the invention and the best modes currently contemplated for carrying them out.

BRIEF DESCRIPTION OF THE FIGURE Figure 1 illustrates a perspective view of a bioactive implant as constructed in accordance with one embodiment.

DETAILED DESCRIPTION OF THE INVENTION The applicant has discovered that local administration of an anti-inflammatory agent in or near hard tissue, such as bone or tooth, increases the growth and regeneration of hard tissue and the surrounding soft tissue. Preferably, the anti-inflammatory agent is administered in a form that provides controlled release of the agent in or near the soft tissue for a period of days or months. Numerous controlled release mechanisms are known in the art (for example, see R. Langer, 1990, Science I, 249, 1527-1533) Any controlled release mechanism can be used in conjunction with the methods of the invention, stipulated that controlled release of the anti-inflammatory agent at or near the tissue site A preferred method for providing controlled release of an anti-inflammatory agent is to incorporate the agent into a polymer (eg, a biodegradable polymer). Through the polymer matrix, they can be attached to the polymer structure, or can be incorporated directly into a biodegradable polymer structure Typically, any anti-inflammatory agent can be dispersed through a polymer matrix to provide a suitable controlled release formulation However, the ability of an agent to attach to or incorporate into a polymer may depend on the functional groups present in the agent. Preferred anti-inflammatory agents that can be attached to or incorporated into a polymer to provide a suitable controlled release formulation are described in greater detail below. Anti-inflammatory agent Anti-inflammatory agents are a well-known class of pharmaceutical agents that reduce inflammation by triggering on body mechanisms (Stedman's Medical Dictionary 26 ed., Williams and Wilkins, (1995); Physicians Desk Reference 51 ed. , Medical Economics, (1997)).

Anti-inflammatory agents useful in the methods of the invention include Non-Steroidal Anti-Inflammatory Agents (N SAI DS). NSAI DS typically inhibits the body's ability to synthesize prostaglandins. Prostaglandins are a family of chemicals such as hormones, some of which are made in response to cell injury. Specific NSADIS approved for administration to humans include naproxen sodium, diclofenac, sulindac, oxaprozin, diflunisal, aspirin, piroxicam, indomethocin, etodolac, ibuprofen, fenoprofen, acetoprofen, mefenamic acid, nabumetone, tolmetin sodium and acetorolac tromethamine. Other anti-inflammatory agents useful in the methods of the invention include salicylates, such as, for example, salicylic acid, salicylic acid acetyl, choline salicylate, magnesium salicylate, sodium salicylate, olsalazine, finally sauce. Other anti-inflammatory agents useful in the methods of the invention include cyclooxygenase (COX) inhibitors. COX catalyzes the conversion of arachidonate into prostaglandin H2 (PGH2); A COX inhibitor inhibits this reaction. COX is also known as prostaglandin H synthase, or PG H synthase. Two genes Cox, Cox-1 and Cox-2 have been isolated in several pieces. COX-2 is tightly regulated in most tissues and is usually only induced under abnormal conditions, such as inflammation, osteo or rheumatic arthritis, kidney disease and osteoporosis. It is believed that COX-1 is constitutively expressed to maintain kidney and platelet function and integral homeostasis. Typical COX inhibitors useful in the methods of the invention include endolac, celebrex, meloxicam, piroxicam, nimeulide, nabumotenoa and rofecoxib. Preferred anti-inflammatory agents that can be incorporated into a polymer matrix for administration in the methods of the invention include: Isonixin, Amtolmetin Guacil, Proglumetacin, Piketoprofen, Diphenamizola, Epirizola, Apazona, Feprazone, Morazona, Phenylbutazone, Pipebuzone, Propifenazone, Ramifenazone, Tiazolinobutazone, Aspirin, Benyrolate, Calcium Acetylsalicylate, Etersalate, Imidazole Salicylate, Lysine Acetylsalicylate, Morpholine Salicylate, 1-Nitric Salicylate, Lysine Acetylsalicylate, Morpholine Salicylate, 1 -Nacyl Salicylate, Phenyl Acetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine, Amixetrine, Benzydamine, Bucolome, Difenpyramide, Emorfazone, Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase, and Tenidap. Preferred anti-inflammatory agents that can be attached to a polymer for administration in the methods of the invention include: Etofenamate, Talniflumate Terofenamate, Acemetacin, Alclofenac, Bufexamac, Cinmetacin, Clopirac, Felbinac, Fenclic Acid, Fentiazac, Ibufenac, Indometacin, Isofezolac , Isoxepac, Lonazolac, Metiazinic Acid, Mofezolac, Oxametacin, Pirazolac, Sulindac, Tiaramide, Tolmetin, Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac, Ketorolac, Tinoridin, Benoxaprofen, Bermoprofen, Bucilloxic Acid, Fenoprofen, Flunoxaprofen, Flurbiprofen , Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen, Pranoprofen, Protizinic Acid, Suprofen, Thiaprofenic Acid, Zaltoprofen, Benzpiperilon, Mofebutazone, Oxifenbutazone, Suxibuzone, Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide, Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam, Acetomaidocaproic Acid, Bendazac, α-Bisabolol, Paraniline, Perisoxal, and Zileuton. Preferred anti-inflammatory agents that can be incorporated into a polymer structure for administration in the methods of the invention include: Enfenamic Acid, Aceclofenac, Glucametacin, Alminoprofen, Carprofen, Ximoprofen, Salsalate, 3-Amino-4-hydroxybutyric acid, Ditazole , Fepradinol and Oxaceprol. Preferred anti-inflammatory agents possessing ortho functionality suitable for incorporation into the structure of a polymer of the formula (I) as described herein include. Flufenamic Acid, Eclophenamic Acid, Mefenamic Acid, Niflumic Acid, Tolfenamic Acid, Amfenac, Bromfenac, Diclofenac Sodium, Etodolac: Bromosaligenin, Diflunisal, Fendosal, Gentisic Acid, Glycol Salicylate, Salicylic Acid, Mesalamine, Olsalazine, Salicylamide Acetic Acid-O , Sulfasalazine. For any anti-inflammatory agent referred to herein by a trademark it is understood that any commercially branded product or active ingredient possessing the anti-inflammatory activity of the product can be used. Additionally, the preferred agents identified herein for incorporation into a polymer structure may also be preferentially attached to a polymer or may be incorporated into a polymer matrix. Preferred agents which can be attached or incorporated into a polymer matrix. Preferred agents that can be attached to a polymer can also be preferably incorporated into a polymer matrix. Definitions As used herein, the term "hard tissue" includes tissue that has been mineralized, such as, for example, bone, cartilage and teeth. As used herein, the administration of an agent "to or near the tissue" means administering the agent so that it is in direct contact with the tissue or administering the agent to a location close to the tissue, so that the agent can produce the fixed or desired therapeutic effect. As used herein, "administering an anti-inflammatory agent to hard tissue" means applying the agent so that it is in direct contact with the hard tissue. As used herein, "administering an anti-inflammatory agent to the soft tissue near the hard tissue" means applying the agent to the soft tissue close to the hard tissue, so that the agent can produce the fixed or desired therapeutic effect. As used in the term, "formulated for controlled release" means that the agent is formulated so that it will be released for an extended period of time when administered according to the methods of the invention. For example, the agent can be conveniently formulated so that it will be released over a period of at least about 2, about 5, about 10, approximately 20 or approximately 40 days. Preferably, the agent is formulated so that it is released for at least about 5 or about 10 days. The agent can also be preferably formulated so that it is released over a period of about 30 to about 90 days. For the treatment of hard tissue, the agent is preferably formulated so that it is released for a period of about 30 to about 90 days. For the treatment of soft tissue, the agent is preferably formulated so that it is released for a period of about 1 to about 30 days, more preferably about 2 to about 25 days. As used herein, an agent is "attached" to a polymer when the agent binds to the polymer as a side chain or side group, but is not part of the polymer structure. Preferably, the agent is bound to the polymer through a bond that is suitable for releasing the agent when the polymer is administered according to the methods of the invention. For example, the agent can be covalently linked to a polymer through a hydrolysable linkage such as an ester or anhydride bond. As used herein, the term "dispersed through the polymer matrix" means that an anti-inflammatory agent is located within the matrix of a polymer so that it can be released in a controlled manner within the body. Preferably, the polymer matrix comprises a biodegradable polymer. As used herein, the term "at the site of the Periodontal disease "means at a site that is on or near the site of periodontal disease, so that when an agent is administered to the site, the agent can produce a beneficial effect and improve one or more of the symptoms of periodontal disease. As used herein, the term "gingival fissure" means the space between the soft tissue of the gum and the tooth.As used herein, the term "fix the fracture" means keeping the fractured pieces together or stabilizing the fracture. Fracture As used herein, the term "enhancing hard tissue regeneration" means allowing or facilitating the growth of hard tissue in a normal manner As used herein, "administering an anti-inflammatory agent at the site" means applying the agent so that it is in direct contact with the site.As used herein, "administering an anti-inflammatory agent near the site" means apl icar the agent near the site, so that the agent can produce the fixed or desired therapeutic effect (for example, reduce the resorption of bone in the site). As used herein, the term "periodontal disease" includes any abnormality, whether inflammatory or degenerative, of the tissue around the tooth. As used in the present "cure" means restoration in normal health. Aromatic polyanhydrides with improved degeneracy and processability properties have now been developed. These compounds have repeating units with the structure of the Formula I: O O II II -C-Ar-R-Ar-C-O- (I) wherein Ar is a substituted or unsubstituted aromatic ring and R is a substituted dysfunctional organic moiety in 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 pharmaceutically active materials, particularly salicylates such as aspirin, phenyl propionate or naphthyl non-spheroidal anti-inflammatories such as ibuprofen, acetoprofen, naproxen and the like, and other anti-inflammatory aromatic compounds such as indomethacin, indoprofen, and the like. In particular, Ar is preferably a phenyl group and R is preferably -ZrRrZr, where R ,, is a dysfunctional moiety and both Z s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. is preferably an alkylene group containing 1 to 20 carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (-CH2-CH2-0-) m, (CH2-CH2-CH2-0 -) my (-CH2-CHCH3-0-) mo Ri can have the structure -R2-Z2-R3-1 wherein R2 and R3 are independently alkylene groups containing from 1 to 19 carbon atoms or groups having 2 to 18 carbon atoms having a structure selected from (-CH2-CH2-0-) m,. { CH2-CH2-CH2-0-) m and (-CH2-CHCH3-0-) m, and Z2 is selected from the dysfunctional moieties described above with respect to? .

Ar can be an alkylaryl group, in which a dysfunctional organic moiety is placed between each anhydride carbonyl group and the corresponding aromatic ring. Preferably, however, each carbonyl group is directly substituted in the corresponding aromatic ring. Preferred polymers of the present invention have repeating units with the structure of Formula I in which Ar is a phenyl ring and R is selected from -Z ^ -. { -C 2-) nZ ^ -, -Z1 - (- CH2-CH2-0-) mZ, -, -Z1 - (- CH2-CH2-CH2-0-) m-Z1-, and -Z1 - (- CH2-CHCH3-0-) m-Z1-, wherein Z, is an amide or ester group and n is from 1 to 20 inclusive, and preferably is 6, and m is selected such that R has from 20 to 20, and preferably 6, carbon atoms. O O II II -C-Ar-R-Ar-C-O- (I) wherein Ar is a substituted or unsubstituted aromatic ring and R is a dysfunctional organic moiety. R are preferably selected from -Z, -RrZr, wherein R1t is a dysfunctional moiety and both Z s independently are an ester -C (= 0) 0-, amide -C (= 0) N-, anhydride C (= 0 ) -0-C (= 0) -, carbonate -0-C (= 0) -0-: urethane -NC (= 0) -N-: or thioester - (C = 0) S-. R- is preferably an alkylene group containing from 1 to 20 carbon atoms. The aromatic polyanhydrides of the present invention can be prepared by the method described in Conix, Macromol, Synth, 2, 95-99 (1996), in which the dicarboxylic acids are acetylated in an excess of acetic anhydride followed by melting condensation of the anhydride. from carboxylic acid resulting at 1 80 ° C for 2-3 hours. The resulting polymers are isolated by precipitation from methylene chloride dithylether. The process described is essentially the conventional method for polymerizing bis-aromatic dicarboxylic acid anhydrides in aromatic polyanhydrides. The aromatic polyhydrates according to the present invention have average molecular weights of about 1 500 daltons, up to about 50,000 daltons, calculated by Gel Permeation Chromatography (G PC) relative to narrow molecular weight polystyrene standards. Preferred aromatic polyanhydrides have average molecular weights of about 1 500 daltons, up to about 35,000 daltons. The aromatic polyhydric acids of the present invention are produced from ortho-substituted bis-aromatic carboxylic acid anhydrides having the structure of Formula I I. O O O O II II II II H3C-C-0-C-Ar-R-Ar-C-0-C-CH3 (I I) wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I. As noted above, ortho-substituted bis-aromatic carboxylic acid anhydrides are prepared by acetylation of the corresponding ortho-substituted bis-aromatic carboxylic acids in an excess of acetic anhydride. Dicarboxylic acids have the structure of formula I I I O O II II HO-C-Ar-R-Ar-C-OH (I I I). wherein Ar, R and the preferred species thereof are the same as described above with respect to Formula I. The dicarboxylic acids are prepared by reacting a stoichiometric ratio of aromatic carboxylic acid having the structure Z3-Ar-COOH and a compound having a structure Z4-R-Z4 wherein Ar is a substituted or unsubstituted aromatic ring in which Z3 ortho is substituted in the carboxylic acid group, R is a dysfunctional organic moiety and Z3 and Z4 are functional groups selected to provide the desired linkage between the dysfunctional organic moiety and the two aromatic rings. Suitable functional groups Z3 and Z4, and the manner in which they can be reacted to produce the bis-aromatic dicarboxylic acids of the present invention, can be readily determined by those of ordinary skill in the art without undue experimentation. For example, aromatic polyanhydrides having the structure of Formula I in which Ar is a phenyl group and R is -0- (CH2-) 6-0-, the ortho-substituted bis-aromatic dicarboxylic acid starting material may Prepare by reacting o-salicylic acid with 1,6-dibromohexane. For aromatic polyanhydrides having the structure of Formula I in which Ar is a phenyl group and R is -0-C (= O) - (CH2-) 6-C (= O) -0-, the initial material of ortho-substituted bis-aromatic dicarboxylic acid can be prepared by reacting o-salicylic acid with 1,6-dioctanoic acid.

The aromatic polyanhydrides used in the present invention can be isolated by known methods commonly used in the field of synthetic polymers to produce a variety of useful articles with valuable chemical and physical properties. The new polymers can be easily processed in pastes, and gels or solvent mold to produce films, membranes, coatings, microspheres, chips and fibers with different geometrical shapes for the design of various medical implants and can be processed by compression and extrusion molding. Medical implant applications include the use of aromatic polyanhydrides to form shaped articles such as vascular grafts and micro-scaffolds, bone plates, sutures, implantable sensors, implantable drug delivery devices, micro-scaffolds for tissue regeneration, scaffolding to support new cell growth and other items that break down without damage within a known period of time. For the present invention, it is preferred that the polyanhydride is incorporated into films, membranes, pastes, gels, microspheres, chips or fibers useful in orthopedic and dental applications. It has now been demonstrated that polymers comprising these aromatic polyanhydrides having a repeating unit with the structure of Formula I in which Ar and R are selected to provide aromatic polyanhydrides that hydrolyze to form therapeutically useful salicylates, are particularly useful for increase tissue regeneration. Examples of therapeutically useful salicylates include, but are not limited to, thymotic acid, 4.4- sulfinildinaili na, 4-sulfanilamidosalicílico acid, sulfanilic acid, sulfanilbencilamina, sulfalóxico acid, succisulfona, salicils sulfuric acid, salsalate, salicylic alcohol, salicylic acid, orthocarna, mesalamine, gentisic acid, acetylsalicylic acid, and the like. The identification of the portions of Ar and R that provide aromatic polyhydric acids that hydrolyze to form such therapeutically useful salicylates can be readily determined by those of ordinary skill in the art without undue experimentation. A preferred salicylate for incorporation into the polymers of the formula (I) is salicylic acid, thymotic acid, 4-sulfanylamidosalicylic acid, gentisic acid, enfenamic acid, cresotic acid, or aminosalicylic acid. The amount of aromatic polyhydric acid that is hydrolyzed to form an effective amount of therapeutic salicylate to alleviate inflammation and promote bone healing can be readily determined by those of ordinary experience without undue experimentation. The amount corresponds essentially stoichiometrically to the amount of known salicylate to produce an effective treatment. Oral dosage forms of aromatic polyanhydrides that are hydrolyzed to form other therapeutic non-steroidal anti-inflammatory compounds and other therapeutic compounds are prepared and administered in a similar manner. Absorbent or more degradable devices for dental or orthopedic applications cause local inflammation. In the present invention, however, the use of com positions such as films, membranes, fibers, pastes, gels and microspheres comprising an aromatic polyanhydride that hydrolyzes to form a therapeutically useful salicylate in dental and orthopedic applications currently reduces local inflammation and / or pain. These compositions can also be incorporated into matrices to provide adaptive or preformed scaffolding for cellular inner growth. In addition, it has been found that the use of these compositions promotes the healing process of the tissue (e.g., bone) through the increased regeneration of these tissues. The selection of the form of the composition to be used is routinely performed by those of experience in the field based on the type of injury and tissue healing to be promoted. Compositions comprising an aromatic polyanhydride can be used to coat orthopedic devices for the fixation of bone fractures such as pins or screws, thus reducing local inflammation and bone resorption associated with these devices. Films comprising an aromatic polyanhydride are also supplied as being useful as orthopedic devices to enhance the healing process of bone fractures. The fibers useful as suture materials can also be compressed from the aromatic polyanhydride. For example, polymer fibers are frequently used in oral surgery to suture the palate of the fissure. The use of an aromatic polyanhydride that degrades in a therapeutic salicylate would increase tissue regeneration through the sutures while reducing the pain and inflammation associated with surgery through the degradation products.

The films, membranes, pastes, gels, microplates and microspheres comprising the aromatic polyanhydrides can also be used to reduce tooth pain and promote healing within a tooth, in the pulp chamber and root canal. The films or membranes comprising the aromatic polyanhydrides can also be used in guided tissue or bone regeneration. After surgery, especially dental or oral surgery, proper healing of the wound requires both regeneration of soft tissue and bone. However, it is well known that bone heals more slowly than surrounding tissues such as gums. In fact, several times the inferior growth of other tissues in the area prevents the required bone regeneration. For example, removal of a substantial portion of the tooth root due to reabsorption or disease leaves a cavity that frequently fills rapidly with connective tissue. This inferior growth of connective tissue effectively prevents bone regeneration. According to the above, a procedure referred to as a guided regeneration of bone or tissue has been developed to overcome this difficulty. In this method, a membrane is surgically inserted around the periphery of the wound cavity. The membrane prevents or inhibits the invasion of the wound cavity by unwanted cell types and allows the preferred cells to grow in the cavity, thereby healing the wound. This procedure also uses regenerating the bone around the teeth and at endothelial nozzle edges in association with implant reconstruction.

Two membranes commonly used in tissue guided regeneration include a synthetic non-resorptive polytetrafluoroethylene membrane such as GORETEX and synthetic membranes formed from glycolide and lactide copolymers. The Patent of E. U. 5,837,278 also discloses a resorbable collagen membrane for use in guided tissue regeneration. It is believed that films comprising aromatic polyanhydrides would also be useful in this process. Compositions comprising an aromatic polyanhydride that hydrolyzes to form a therapeutically useful salicylate are believed to be particularly useful in the treatment of periodontal diseases. Periodontal diseases, including a group of chronic inflammatory-related mycrobial disorders and a disorder referred to as periodontal disease, destroy the tissue that supports the teeth. These diseases can result in the loss of normal hard and soft tissue architectures at sites adjacent to the affected teeth. The incorporation of these compositions into films, membranes, pastes, fibers or microspheres for use in the treatment of periodontal diseases is expected to accelerate the recovery / restoration of healthy new periodontal architecture while reducing post-operative pain after periodontal surgery. In addition, the lower pH environment resulting from degradation in salicylates is unfavorable for the growth of some periodontal bacteria. In this way, the use of these compositions is also expected to reduce infections in procedures Periodontal In vivo studies are conducted to compare the effects of a polymer system of the present invention (referred to herein as the implant or bioactive polymer) and a similar chemical polyanhydride system (referred to herein as the control polyanhydride) in the healing process. The only chemical difference between these two systems is the replacement of the ether linkage in the polyanhydride of the bioactive polymer with an ester linkage thus resulting in degradation in salicylic acid compared to a non-active component in the control polyanhydride. In these experiments, polymers are compression molded into films with thicknesses of 0.1, 0.2 and 0.3 mm and cut into 0.5 mm wide tapes. In these experiments, mice (m = 10) were anesthetized and the gingival mucosa of the palate adjacent to the maxillary first molar was reflected to expose the alveolar bone and palate. A polymer film is then placed in the bone adjacent to the tooth. The tissue is replaced and the procedure is repeated on the side against the side. The polymer films are placed randomly (left to right) with each mouse carrying both polymers. The mice are fed a diet of soil and water ad libitum and weigh each week. Mice are sacrificed at 1, 4 and 20 days after surgical insertion. The visual intraoral examination of the mucosa covering the implantation sites is carried out with a dissector microscope under optimal light. The magnification is varied from 5 to 40 times the normal size. The photographs are taken to record the observed morphological changes.

The polymer membranes with thicknesses of 0. 1 and 2.0 mm were not visible under the microscope at 4 and 20 days after insertion. However, the thicker membranes (0.3 mm) were still observable after 20 days. For control polyanhydride films, the mucosa is red and thin sow of the implant with the surrounding tissue inflamed on days 1 and 4. By day 14, the tissue swells slightly in three animals while the tissue is within the the normal limits for the 5 remaining animals. In contrast, the tissue surrounding the bioactive polymer implants swells slightly after day 1 but within the normal limits in all animals by day 4. In addition, considerable bedding is observed on the side that carries the polyanhydride. of alcohol, while the side with the bioactive polymer showed a progressively normal mucosa. The tissue surrounding the control polyanhydride swells slowly and is white, while the tissue adjacent to the bioactive implant swells less and is normal in color. The three salients of the maxillary molar palate (anterior, middle and posterior) were clearly visible. However, the projections, anterior and medial, collide due to swelling and whitening on the side of the control fluid. This effect was pronounced more on day 13. On days 1 5 and 20, the whitening and swelling on the control polyanhydride side decreases considerably. Histological tissue examination of the mice is also performed. After sacrifice, the tissues are fixed in 10% formalin, decalcified, embedded in paraffin, sectioned serially in 4 μp thickness, and stained with hematoxilkin and eosin. The sections are subject to evaluation microscopic and histomérica valuation using 4, 10 and 20X magnifications. Histopathological examination correlates well with visual observations. A mouse is sacrificed 24 hours after implantation. Histology showed heavy infiltration of polymorphonuclear leukocytes (PM N) and erythrocytes. The 0.1 mm films are mostly dissolved during the tissue processing process. The bone is stripped from the periosteum and the polymer is in direct contact. The gingival epithelium and connective tissue below the subcular epithelium rupture. The coronal part of the periodontal ligament that connects the alveolar bone to the coronal cement is mostly intact. The method to reflect the palatal mucosa was effective in not damaging the periodontal ligament below the bone level and coronal cement. There was no significant difference between the control and bioactive side for the reduction in swelling on the bioactive side. Two mice were sacrificed four days after implantation. At this point, some polymeric material remains in all places. The 0.1 mm film is in direct contact with the palate bone. A thin, extensive layer of palatal epithelium is observed surrounding the portions of the polymer specimens. The degree of epithelium along the membrane was greater for the control polyanhydride site as bioactive. Similarly, the inflammatory infiltration of PMN cells was greater on the control polyanhydride side than on the bioactive polymer side. The infiltrate was dense below the epithelium adjacent to the membrane. The infiltrate along the bone of the Palate was much less. Six mice are sacrificed twenty days after implantation. At this time, the small remnants of a 0.3 mm film in only one specimen is presented; all other specimens are stripped of the polymer. The gingival epithelium that includes subcular and union are restored essentially in all sites. Two specimens showed external resorption including cement and dentin on the control polyanhydride side. Tissue specimens with bioactive polymer showed no alvelar bone, cement and dentin resorption. However, a significant amount of new bone could be observed coronally to inverse lines at sites that carry bioactive films. New bone is also found at the control polyanhydride sites, but in significant amounts compared to the bioactive polymer side. The inflammatory cell infiltrate occurs and consists mainly of PMN cells and macrophages. No erythrocyte is observed except within the vasculature. The intensity of the infiltrate was lower in the bioactive polymer sites. Quantitative analyzes are also performed through electronic images taken from tissue sections using a Kodak MDS-120 camera attached to an Olympus CH trinocular microscope at 4X magnifications. 10X and 40X. Using N I H 1 .61 software images, the area of the bone, connective tissue, epithelium and artifacts at the lower magnification is determined. Perpendicular to the nacho part of the tooth, a square box is drawn with sides of 575 pixels in length. The areas of bone, connective tissue, epithelium and artifacts are determined by the number of pixels within the defined box. All images are analyzed dry. Sections were taken from mice sacrificed after 20 days of membranes that were either 0.3 or 2 mm thick. The results are shown in the following table.

These experiments demonstrate that the implantation of a film comprising an aromatic polyanhydride that hydrolyzes to form a therapeutically useful salicylate results in less swelling in tissues adjacent to the film and a reduction in the density of inflammatory cells compared to other polyanhydride films. In addition, little or no bone resorption is observed in the regions near the film as indicated by the increased thickness of the palate. In fact, the quantitative analysis data are indicative of compositions used in the present invention either promoting the growth of the bone or reducing the reabsorption of bone relative to the polyanhydride composition. Accordingly, the use of compositions comprising an aromatic polyanhydride that hydrolyzes to form a therapeutically useful salicylate in dental and occlusal applications increases the bone healing process compared to other polymer systems routinely used in these Applications. The invention also provides bioactive implants that are useful for treating periodontal disease. As shown in Figure 1, a bioactive implant 100 comprises a film of material that is dimensioned and shaped to be received at or near the gingival fissure. For example, the film has a height 102 of about 1 -2 mm, a width 104 of about 1 -5 mm, and a thickness 106 of about 0.1 -2.0 mm. It should be noted, however, that other suitably sized films can be configured to be received at or near the gingival fissure. Other examples for the bioactive implant 100 include, but are not limited to membranes, pastes, gels, microplates or microspheres. The bioactive agent further includes an anti-inflammatory agent, for example, any of the agents discussed above. Options for the anti-inflammatory agent include, but are not limited to, coatings, agents molded into or with a polymer matrix, or agents embedded in a polymer. The following non-limiting examples set forth below illustrate certain aspects of the invention. All parts and percentages are by weight unless otherwise noted and all temperatures are in degrees Celsius. Except for acetic anhydride and ethyl ether (Fischer Scientific), all solvents and reagents are obtained from Aldrich Chemical. All solvents were grade H PLC. All other reagents were analytical grade and purified by distillation or recrystallization. All compounds are characterized by a spectroscopy of proton nuclear magnetic resonance (NMR), infrared spectroscopy (IR), gel permeation chromatography (G PC), high performance liquid chromatography (H PLC), differential scanning calorimetry (DSC), and thermal gravimetric analysis ( TGA). Infrared spectroscopy is performed on an FTI R ATI Mattson Genesis Spectrophotometer (M 100). Samples are prepared by melting solvent in NaCl plates. 1 H and 13 C N M R spectroscopy is obtained on a spectrometer Varied 200 M Hz or Varied 400 M HZ in solutions of C DCI3 or DMSO-d6 with solvent as the internal reference. GPC is performed on a Perkin-Elmer Advanced LC Sample Processor (ISS 200) with PE Series 200 LC pump and a PE Series LC Retractive Index Detector to determine molecular weight and polydispersity. In data analysis, it is carried out using Turbochrom 4 software on a DEC Celebris 466 computer. The samples are dissolved in tetrahydrofuran and eluted through a mixed bed column (PE PL gel)., 5 μ ?? of mixed bed) at a flow rate of 0.5 m L / minute. Samples (approximately 5 mg / mL) are dissolved in tetrahydrofuran and filtered using 0.5 μp syringe filters. PTFE before the column injection. Molecular weights are determined relative to narrow molecular weight polystyrene standards (Polysciences, I nc.). The thermal analysis is performed in a Perkin-Elmer system consisting of a TGA 7 thermal gravimetric analyzer equipped with a PE A D-4 autobalance and Pyris Venturis 51 00 analyzer. For DSC, an average sample weight of 5-10 mg is heated at 1 0 ° C / minute to a flow of 30 psi of N2. For TGA, an average sample weight of 10 mg is heated to 20 ° C / minute under a flow of 8 psi of N2. The measurements of the contact angle of sessile fall are obtained with a Goniometer NRL (Rame-hart) using distilled water. The polymer solutions in methylene chloride (10% w / v) are coated in glass slides, at 5,000 rpm for 30 seconds. Example 1: Preparation of 1,6-Bis Dicarboxylic Acid (o-Carboxyphenoxyhexane To a mixture of salicylic acid (77.12 g, 0.5580 mol) and distilled water (84 mL) of sodium hydroxide (44.71 g, 1120 mol) is added. The reaction is brought to reflux temperature before the 1,6-dibromohexane (45.21 g, 0.2790 mol) is added dropwise.The reflux is continued for 23 hours after which the additional sodium hydroxide (11.17 g, 0.2790 g. mol) is added The mixture is refluxed for a further 16 hours, cooled, filtered, and rinsed with methanol The product was 48.8% Example 2: Preparation of 116-Bis (o-Carboxyphenoxy) Hexane monomer (o-CPI) The dicarboxylic acid of Example 1 is acetylated in an excess of acetic anhydride at reflux temperature The resulting monomer is precipitated with methylene chloride in an excess of diethyl ether The product was 66.8% Example 3: Preparation of Polid , 6-Bis (o-Carboxyphenoxy) Hexane) (Poly (o-CPH)) The monomer of Example 2 is p Olimerizes in a condensation of fusion carried out at 180 ° C for 3 hours under vacuum in a reaction vessel with a lateral arm. The polymerization vessel is rinsed with nitrogen at frequent intervals. The polymer is isolated by precipitation from diethyl ether of methylene chloride. The product was quantitative. All compounds are characterized by nuclear magnetic resonance spectroscopy, GPC, differential scanning calorimetry (DSC), thermal gravimetric analysis, contact angle measurements, UV spectroscopy, mass spectroscopy, elemental analysis and high pressure liquid chromatography (H PLC ). The o-CPH monomer is polymerized by melt polycondensation for 60 minutes at temperatures ranging from 100 ° C to 300 ° C. The analysis of the resulting polymers by GPC indicates that the highest molecular weight, coupled with the lowest polydispersity index occurs at 260 ° C. Poly (o-CPH) is generally soluble in methylene chloride and chloroform, while poly (p-CPH) does not. Poly (o-CPH) was slightly soluble in tetrahydrofuran, acetone and ethyl acetate. Discs of poly (o-CPH), poly (pC PH) and, as a reference, poly (lactic acid, glycolic acid) are prepared and placed in 0. 1 of phosphate buffer solution at 37 ° C for 4 weeks . The degradation medium is periodically replaced. The degradation profile was linear up to the time of three weeks. In the polyanhydride systems of the prior art, the aromatic groups are para-substituted. This substitution pattern results in temperatures of glass transition and fusion high and reduced solubility, thus making these para-substituted polymers difficult to process. Poly (o-CPH), different from poly (p-CPH), has both a lower melting point (65 ° C vs. 143 ° C) and vitreous transition temperature (35 ° C vs. 47 ° C). It is also possible to place molten poly (o-CPH) in solution using low boiling solvents while poly (p-CPH) is relatively insoluble in most organic and aqueous solvents. This structural modification gives a polymer whose hydrolysis products are chemically similar to aspirin. Aspirin is an anti-inflammatory agent derived from salicylic acid, which is one of the reagents used to synthesize the inventive polyanhydrides. Therefore, the degradation products of this polymer currently aid in the recovery of the patient. Due to the flexibility and ease of processing, the aromatic polyanhydrides of the present invention have greater potential as polymer scaffolds to heal the wound. Example 4: Preparation of acid 1, 3-bis (o-carboxyphenoxy) propane dicarboxylic 1,3-dibromopropane (14.7 mL 0. 145 mol) is added to a mixture of salicylic acid (40.0 g, 0.290 mol), distilled water (44 mL) and sodium hydroxide. (23.2 g, 0.580 mol) using the method described in Example 1. After 4 hours, the additional sodium hydroxide (5.79 g, 0.145 mol) is added to the reaction mixture. The reflux is continued for another 4 hours, after which the mixture is cooled, filtered and rinsed using the methods described in Example 1. The product was 37.7%.

Example 5: Preparation of polyd, 3-bis (o-carboxyphenoxy) propane) The dicarboxylic acid of Example 4 is acetylated using the methods of Example 2. The acetylated dicarboxylic acid is then polymerized using the methods described in Example 3. The polymer The resultant has an Mw of 8,500 daltons and a polydispersity of 2.3. Contact angle measurements in solvent melt films demonstrated that the hexyl chain of the polymer of Example 3 increases the hydrophobicity of the relative surface to the shorter propyl chain of the polymer of Example 5. A comparison of the thermal characteristics emphasized the effects of lengthening the alkyl chain. In particular, the polymer of Example 3 has a Tg of 34 ° C and a Td of 410 ° C, while the polymer of Example 5 has a Tg of 50 ° C and a Td of 344 ° C. In this way, the hexyl chain reduces the transition temperature (Tg) relative to the propyl chain, reflecting the increased flexibility of the polymer chain. The trend is observed for the decomposition temperatures (Td), with the larger alkyl chain increasing the Td. Optimal polycondensation conditions are determined by the polymer of Example 3. Optimal conditions are defined as those that produce a crude polymer with the highest molecular weight and highest Tg. The higher reaction temperatures reduced the Mw values (measured by GPC) with a concurrent increase in polydispersity. As expected for a condensation polymerization, the longer reaction times produced polymers with higher molecular weights. However, during times of longer reactions, a subsequent reduction in Tg appears. Based on these results, optimal conditions are defined as temperatures of 220 ° C for 150 minutes under vacuum. Example 6: Preparation of 1,8-bis- (benzylcarboxy) carboxyphenyloctane dicarboxylic acid ester The initial synthesis of poly (anhydride-ester) dicarboxylic acid monomers is attempted using the same methodology used for poly (anhydride-ether) monomers dicarboxylics of Example 3. However, it was found that the reactivity of the phenol is increased by benzylation of the carboxylic acid group. In addition, the solubility of benzyl salicylate in organic media increased the ability of the reaction to move forward. In this manner, the benzyl salicylate (1.530 g, 6.720 mmol) and distilled tetrahydrofuran are combined under an inert atmosphere in a reaction flask. A cold salt bath is placed under the reaction flask and follows the addition of 60% sodium hydride (0.4840 g, 12.10 mmol). After one hour, sebacoyl chloride (0.7850 g, 3.280 mmol) is added dropwise to the reaction mixture at 0 ° C. After 30 minutes, the reaction mixture is filtered under vacuum, the collected filtrate and the solvent are removed to yield the free carboxylate as a white solid residue. The purification is performed using a chromatron with ethyl acetate / methylene chloride (20/80) as the solvent system. The product was 43%. Example 7: Polymerization of Polid, 8-bis (o-dicarboxyphenyl) octane) To remove the benzyl protecting groups, the ester of 1, 8-bis [(benzylcarboxy) -carboxyphenyl] octane dicarboxylic acid from Example 6 (0.06000 g, 0.9620 mmol) is dissolved in methylene chloride in a reaction flask (60.00 ml_). The Pd-C catalyst (10%, 1.200 g) is added to the reaction mixture and hydrogen bubbles through the solution. After 30 minutes, the reaction is complete. The reaction mixture is filtered and the solvent is removed to yield the free dicarboxylic acid as a white solid residue which is recrystallized using petroleum ether and methylene chloride. The product was 45%. The dicarboxylic acid is acetylated using the methods described in Example 2 and the acetylated dicarboxylic acid is then polymerized using the methods described in Example 3. The resulting polymer has an Mw of 3., 000 daltons and a polydispersity of 1 .40. Subsequent polymerizations produced polymers with Mw's ranging from 2,000 to 5,000 daltons with corresponding polydispersities of approximately 1 .40. The poly (anhydride esters) of Example 7 were compression molded into circular discs and placed in phosphate buffered saline under acid, neutral, and basic conditions. During the course of a three-week degradation study, the polymers in the acidic and neutral solutions showed no observable changes, while the polymer in the basic medium showed significant morphological changes over time. Example 8: Preparation of copolymers of polyfd. 8-bis (o-dicarboxyphenyl) octane) - (6-bis (p-carboxyphenoxy) hexane 1 The 1,8-bis (o-dicarboxyphenyl) octane of Example 2 is copolymerizes with 1,6-bis (p-carboxyphenoxy) hexane using the methods described in Example 3. In an in vivo mouse study, each mouse is implanted with 2 polymers, the copolymer of Example 8 and poly (1, 6-bis (p-carboxyphenoxy) hexane). Each polymer is compression molded for 1 to 5 minutes at 1 to 20 K psi depending on the thickness of the polymer needed. The polymer is placed under the gingival mucosa of the palate adjacent to the first molar jaws. All publications, patents and patent documents (including Requests of E. U. Serial Nos. 09 / 455,861 and 09/508, 21 7, as well as International Patent Application PCT / US98 / 1 8816) are they are incorporated herein by reference, as taught to be individually incorporated herein. The invention has been described with reference to various preferred and specific techniques and modalities. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims (47)

1. CLAIMS 1. The use of an anti-inflammatory agent to prepare a medicine useful for treating periodontal disease by the administration at the site of periodontal disease.
2. 2. The use according to claim 1, characterized in that the agent is a salicylate.
3. 3. The use according to claim 1, characterized in that the agent is a non-steroidal anti-inflammatory compound.
4. 4. The use according to claim 1, characterized in that the agent is an aromatic anti-inflammatory compound.
5. 5. The use according to claim 1, characterized in that the agent is a cyclooxygenase inhibitor.
6. 6. The use according to claim 1, characterized in that the agent is a cyclooxygenase-1 inhibitor.
7. The use according to claim 1, characterized in that the agent is a cyclooxygenase-2 inhibitor.
8. 8. The use according to claim 1, characterized in that the agent is etodolac, celebrex, meloxicam, piroxicam, nimesulide, nabumetone or rofecoxib.
9. The use according to claim 1, characterized in that the agent is formulated for controlled release at the site of periodontal disease.
10. The use according to claim 9, characterized in that the agent is incorporated in the matrix of a biodegradable polymer. eleven .
11. The use according to claim 10, characterized in that the agent is Isonixin, Amtolmetin Guacil, Proglumetacin, Piketoprofen, Diphenamizole, Epirizola, Apazona, Feprazone, Morazona, Phenylbutazone, Pipebuzone, Propifenazone, Ramifenazone, Tiazolinobutazone, Aspirin, Benyrolate, Calcium Acetylsalicylate, Etersalate, Imidazole Salicylate, Lysine Acetylsalicylate, Morpholine Salicylate, 1-Naphthyl Salicylate, Lysine Acetylsalicylate, Morpholine Salicylate, 1-Naphthyl Salicylate, Phenyl Acetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine, Amixetrine, Benzydamine, Bucolome, Difenpyramide, Emorfazone, Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase, or Tenidap.
12. 12. The use according to claim 10, characterized in that the polymer comprises anhydride bonds in the polymer structure.
13. The use according to claim 10, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O II II -C-Ar-R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Zi-R1-Z1- substituted on each Ar ortho to the anhydride group, wherein R-, is a dysfunctional organic portion and ?? is a dysfunctional portion selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
14. The use according to claim 9, characterized in that the agent is attached to a biodegradable polymer.
15. 15. The use according to claim 14, characterized in that the agent is Etofenamate, Talniflumate Terofenamate, Acemetacin, Alclofenac, Bufexamac, Cinmetacin, Clopirac, Felbinac, Acid Fenclózico, Fentiazac, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Metiazinic Acid, Mofezolac, Oxametacin, Pirazolac, Sulindac, Tiaramide, Tolmetin, Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac, Ketorolac, Tinoridin, Benoxaprofen, Bermoprofen, Bucilloxic Acid, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen, Pranoprofen, Acid Protizin, Suprofen, Thiaprofenic Acid, Zaltoprofen, Benzpiperilon, Ofebutazone, Oxifenbutazone, Suxibuzone, Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide, Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam: Acetamidocaproic Acid, Bendazac, a-Bisabolol, Paraniline , Perisoxal, or Zileuton.
16. 16. The use according to claim 1, characterized in that the agent is administered after periodontal surgery.
17. 17. The use according to claim 14, characterized in that it comprises anhydride bonds in the polymer structure.
18. 18. The use according to claim 14, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O wherein Ar is a substituted or unsubstituted aromatic ring and R is -? - R 1 -Z 1 - substituted in each Ar ortho anhydride group, wherein R 1 is a dysfunctional organic moiety and is a dysfunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
19. The use according to claim 9, characterized in that the agent is incorporated into the structure of a biodegradable polymer.
20. The use according to claim 19, characterized in that the agent is Enfenamic Acid, Aceclofenac, Glucametacin, Alminoprofen, Carprofen, Ximoprofen, Salsalate, 3-Amino-4-hydroxybutyric acid, Ditazole, Fepradinol or Oxaceprol. twenty-one .
21. The use according to claim 19, characterized in that the polymer comprises anhydride bonds in the polymer structure.
22. 22. The use according to claim 19, characterized in that the polymer is an aromatic polyanhydride.
23. 23. The use according to claim 1, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O II II -C-Ar-R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Zr R i -Z ^ substituted on each Ar ortho to the anhydride group, wherein R i is a portion dysfunctional organic and Z, is a dysfunctional portion selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
24. 24. The use according to claim 1 9, characterized in that Ar is Flufenamic Acid, Meclofenamic Acid, Efenamic Acid, Niflumic Acid, Tolfenamic Acid, Amfenac, Bromfenac, Diclofenac Sodium, Etodolac, Bromosaligenin, Diflunisal, Fendosal, Gentisic Acid, Glycol Salicylate, Salicylic Acid, Mesalamine, Olsalazine, Salicylamide, Acetic Acid -O, Sulfasalazine.
25. 25. The use according to claim 19, characterized in that the polymer is incorporated in a film, paste, gel, fiber, chip, microsphere or scaffold for cellular interior growth.
26. 26. The use according to claim 23, characterized in that each is an ester.
27. 27. An orthopedic device comprising an anti-inflammatory agent that is formulated for controlled release.
28. 28. The device according to claim 27, characterized in that the agent is incorporated in the matrix of a biodegradable polymer.
29. 29. The device according to claim 28, characterized in that the agent is Isonixin, Amtolmetin Guacil, Proglumetacin, Piketoprofen, Diphenamizola, Epirizola, Apazone, Feprazone, Morazona, Phenylbutazone, Pipebuzone, Propifenazone, Ramifenazone, Thiazolinobutazone, Aspirin, Benyrolate, Calcium Acetylsalicylate. , Etersalate, Imidazole Salicylate, Usin Acetylsalicylate .. Morpholine Salicylate, 1-N-Phyllose Salicylate, Lysine Acetylsalicylate, Morpholine Salicylate, 1-N-Phyllacrylate, Phenyl Acetylsalicylate, Ampiroxicam, Droxicam, S-Adenosylmethionine, Amixethrin, Benzydamine, Bucolome, Difenpyramide, Emorfazone, Guaiazulene, Nabumetone, Nimesulide, Proquazone, Superoxide Dismutase, or Tenidap.
30. 30. The device according to claim 28, characterized in that the polymer comprises anhydride bonds in the polymer structure.
31. 31. The device according to claim 28, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O II II -C-Ar-R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Z, -R1-Z1- substituted on each Ar ortho to the anhydride group, wherein R is a portion dysfunctional organic and Z1 is a dysfunctional portion selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
32. 32. The device according to claim 28, characterized in that the agent is attached to a biodegradable polymer.
33. The device according to claim 32, characterized in that the agent is Etofenamate, Talniflumate Terofenamate, Acemetacin, Alclofenac, Bufexamac, Cinmetacin, Clopirac, Felbinac, Phencologic Acid, Fentiazac, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Methiazine Acid, Mofezolac , Oxametacin, Pirazolac, Sulindac, Tiaramide, Tolmetin, Tropesin, Zomepirac, Bumadizon, Butibufen, Fenbufen, Xenbucin, Clidanac, Ketorolac, Tinoridin, Benoxaprofen, Bermoprofen, Bucilloxic Acid, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Oxaprozin, Pirprofen, Pranoprofen, Protizinic Acid, Suprofen, Thiaprofenic Acid, Zaltoprofen, Benzpiperilon, Mofebutazone, Oxifenbutazone, Suxibuzone, Acetaminosalol, Parsalmide, Phenyl Salicylate, Salacetamide, Salicylsulfuric Acid, Isoxicam, Lomoxicam, Piroxicam, Tenoxicam, Acetomaidocaproic Acid, Bendazac, α-Bisabolol, Paraniline, Perisoxal, or Zileuton.
34. 34. The device according to claim 32, characterized in that the polymer comprises anhydride bonds in the polymer structure.
35. 35. The device according to claim 32, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O I! II -C-Ar-R-Ar-C-O- wherein Ar is a substituted or unsubstituted aromatic ring and R is -? - substituted in each Ar ort to the anhydride group, wherein Ri is a dysfunctional organic moiety and Zi is a dysfunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
36. 36. The device according to claim 28, characterized in that the agent is incorporated into the structure of a biodegradable polymer.
37. 37. The device according to claim 36, characterized in that the agent is Enfenámico Acid, Aceclofenac, Glucametacin, Alminoprofen, Carprofen, Ximoprofen, Salsalato, 3-Amino-4-acid hydroxybutyric, Ditazol, Fepradinol and Oxaceprol.
38. 38. The device according to claim 36, characterized in that the polymer comprises anhydride bonds in the polymer structure.
39. 39. The device according to claim 36, characterized in that the polymer is an aromatic polyanhydride.
40. 40. The device according to claim 36, characterized in that the polymer is a polyanhydride comprising a repeating unit having the structure: O O II II -C-Ar-R-Ar-CO- wherein Ar is a substituted or unsubstituted aromatic ring and R is -Zi-R ^ -Z ^ - substituted on each Ar ortho to the anhydride group, where is a portion dysfunctional organic and is a dysfunctional portion selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
41. 41. The device according to claim 40, characterized in that Ar is Flufenamic Acid, Meclofenamic Acid, Mefenamic Acid, Niflumic Acid, Tolfenamic Acid, Amfenac, Bromfenac, Diclofenac Sodium, Etodolac, Bromosaligenin, Diflunisal, Fendose L, Gentisic Acid, Glycol Salicylate, Salicylic acid .. Mesalamine, Olsalazine, Salicylamide Acetic Acid-O, Sulfasalazine.
42. 42. The device according to claim 36, characterized in that the polymer is incorporated in a film, paste, gel, fiber, chip, microsphere or scaffold for an internal growth of the cell
43. 43. The device according to claim 40, characterized in that each Z is an ester.
44. 44. The device according to claim 27, characterized in that the agent augments bone growth.
45. 45. A bioactive implant comprising: a polymer film configured to be received at or near the gingival fissure, the film including an anti-inflammatory agent.
46. 46. The bioactive implant according to claim 45, characterized in that the film has a thickness of about 0. 1 - 2.0 mm, a width of about 1 -5 mm, and a height of about 1 -2 mm.
47. 47. The bioactive implant according to claim 45, characterized in that the film is configured to be placed adjacent to a bone. RESU MEN Methods for promoting healing through increased tissue regeneration (e.g., hard tissue or soft tissue) by contacting the surrounding tissue or tissue with an anti-inflammatory agent. These methods are useful in a variety of orthopedic and dental applications.