CA2174072C - Hydrogel-forming, self-solvating absorbable polyester block copolymers, and methods for use thereof - Google Patents
Hydrogel-forming, self-solvating absorbable polyester block copolymers, and methods for use thereof Download PDFInfo
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- CA2174072C CA2174072C CA002174072A CA2174072A CA2174072C CA 2174072 C CA2174072 C CA 2174072C CA 002174072 A CA002174072 A CA 002174072A CA 2174072 A CA2174072 A CA 2174072A CA 2174072 C CA2174072 C CA 2174072C
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Dispersion Chemistry (AREA)
- Neurosurgery (AREA)
- Inorganic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Polyesters Or Polycarbonates (AREA)
- Materials For Medical Uses (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
The present invention provides novel hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon contacting an aqueous environment. Methods of using the novel polyester copolymers of the invention in humans are also disclosed for providing a protective barrier to prevent post-surgical adhesion, treatment of defects in conduits such as blood vessels, and controlled release of a biologically active agent for modulating cellular events such as wound healing and tissue regeneration or therapeutic treatment of diseases such as infection of the periodontium, dry socket, bone, skin, vaginal, and nail infections
Description
H~DROGEL-FORM~NG,SELF~OLVAlnNGABSORBABLEPOLYESTER
COPOLYMERS,ANDMETHODSFORUSEl~REOF
This invention relates generally to biomedical and/or ph~ln~c~u~ applications ofabsorbable or biodegradable polymeric hydrogels. More particularly, the present invention relates to hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon co"~i~cli"g an aqueous env.lun.ne-ll. The invention also discloses methods of using the polyester copolymers of the invention in humans for providing a protective barrier to prevent post-surgical adhesion, a carrier of viable cells or living tissue, treatment of defects in conduits such as blood vessels, and controlled release of a biologically ætive agent for modulating cellular events such as wound healing and tissue regene~ioll or thel~c;u~ic L~L~enl of diseases such as infection of the perio(lontillm, dry socket, bone, skin, vaginal,~and nail infections.
Hydrogels are materials which absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and m~int~in three~lim~ncional networks capable of reversible der~ aLion (Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Publishing Co., T ~n~ster~ PA, 1993; W. Shalaby et al.~ J. Controlled Rel., 19, 131, 1992; and Silberberg, in Molecular Basis of Polymer Networks (Rallmg~rtner, A. & Picot, C.E., Eds.), Spring-Verlag, Berlin, 1989, p. 147).
Covalently croc~link~d networks of hydrophilic polymers, including water-soluble polymers are traditionally denoted as hydrogels (or aquagels) in their hydrated state. Hydrogels have been prepared to be based on crosslinked polymeric chains of methoxy poly(ethylene glycol) monomethacrylate having variable lengths of the polyoxyethylene side chains, and their interaction as hydrogels, with blood components have been studied (Nagaoka, et al., in Polvmers as Biomaterials (Shalaby, S.W., et al., Eds.), Plenum Press, 1983, p. 381). A number of aqueous hydrogels (aquagels) have been used in various biomedical applications, such as, for example, soft contact lenses, wound m~n~g~. .on~ and drug delivery. However, methods used in the p~paL~Llion of these hydrogels, and their conversion to useful articles, are subject to the constraintc associa~d with the nature of their three rl;l"Pl,~;on~l theL"-os~ -g ~llucluL~ and, hence, deprive the users from applying the facile ylocessing t~hniq~les employed in the production of non-crocslin~Pd thermoplastic materials.
This, and the low ~ ~rl~nir~l strength of the hydrated networks, led a number ofinvestig~t()r.c to explore the concept of c~ lbillillg hydrophilic and hydrophobic polymeric components in block (Okano, et al., J. Biomed. Mat. Research, 15, 393, 1981), or graft copolymeric structures (Onishi, et al., in Conlelllpold-y Topics in Polymer Science~ (W.J. Bailey & T. Tsuruta, eds.), Plenum Publ. Co., New York, 1984, p. 149), and blends (Shah, Polymer, 28, 1212 ,1987; and U.S. Pat. No. 4,369,229) to form the hydrophobic-hydrophilic" domain systems, which are suited for thermoplastic p~ssi lg (Shah, Chap. 30, in Water Soluble Polymers (S.W. Shalaby, et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer. Chem. Soc., W~chington, 1991).
The hydrophobic-hydrophilic" domain system (HHDS) undergoes morphological changes which are ~csoci~d with the hydration of the hydrophilic domains and formation of pseudo-crosslinks via the hydrophobic component of the system (Shah, 1991, cited above). Such morphology was considered to be responsible for the enh~ ed biocolllpa~ii,ility and superior m~ni-~l strength of the two-phase HHDS as colll~,~ed to those of covalently crosslinl ~d, hydrophilic polymers. The m.o~h~nicm of gel formation in the present invention parallels that described by Shah, 1991, cited above, for non-absorbable blends of hydrophilic-hydrophobic domain systems (HHDS). However, dirrelellces exist between the copolymers of the present invention, and more particularly, Component "A", and HHDS. In this regard, Component A is based on a water-soluble and water-insoluble block structure (SIBS). This is not a mere physical mixture of two polymers as are the blends described by Shah, 1991, cited above. Additionally, due to the presence of covalent links between the blocks of SIBS, the resulting hydrogel displays higher elasticity compliance and tensile strength while being absorbable. In fact, the SIBS systems are, in some respects, analogous to thermoreversible gels (Shalaby, in Water-Soluble Polymers, (Shalaby, S.W., et al., Eds.), Vol.
467, Chapt. 33, ACS Symp. Ser., Amer. Chem. Soc., Washington, DC, 1991a) in displaying a 2~ 74072 ..
hydration-dehydration equilibrium governing the system ll~r<,.,~ ion, i.e., the gel/liquid equilibrium is driven by the water content of the SIBS. Thus, in the absence of water, the polyoxyalkylene blocks undergo intermolec~ r se.~",~-nli11 mixing with the neighboring hydrophobic blocks to produce a viscous liquid. In the plesellce of water, co"lL~lilion between the water as an e~L~ ic solvent and the polyester block for the polyoxyalkylene (POA) block forces the hydration of the POA, and aggregation or ~c~oci~tion of the polyester blocks to establish pseudo-crosslinks which m~int~in a 3-dimensional illl~lity. Since gel formation takes place in an aqueous environment, the POA block will plere,e"Lidlly migrate to the exterior of the gel and interface with the adjoining tissues to establish an a&esive joint, which prevents gel migration from target site and sustains its intended efficacy. As for example, for periodontal and dry socket applications, post-surgical a&esion prevention and treatment of vaginal and bone inrec~ions, and other applications where predictable' site residence of the gel carmot be compromised.
Synthesis and biomedical and phal",aceutical applications of absorbable or biodegradable hydrogels based on covalently croc~linl~d n~wc,l~ COllly~ g polypeptide or polyester components as the enzymatically or hydrolytically labile components, respectively, have been described by a number of resea~cllel~ (Jarrett, et. al., Trans. Soc. Biomater., Vol. XVIII, 182, 1995; Pathak, et. al., Macromolecules~ 26, 581, 1993; Park, et. al., Biodegradable Hydrogels for Drug Delivery. Technomic Publishing Co., Lancaster, PA, 1993; Park, Bio,na~lials, 2. 435.
1988; and W. Shalaby, et. al., 1992, cited elsewhere herein). The hydrogels most often cited in the lilelalulc; are those made of water-soluble polymers, such as polyvinyl pyrrolidone, which have been crosslink~d with naturally derived biodegradable components such as those based on albumin (Park, et. al., 1993, cited elsewhere herein; and W. Shalaby, et. al., 1992, cited elsewhere herein).
Totally synthetic hydrogels which have been studied for controlled drug release and membranes for the treatment of post-surgical adhesion are based on covalent networks formed by the addition polymerization of acrylic-terminated, water-soluble chains of polyether dl-polylactide block copolymers (Jarrett, et. al., 1995, cited elsewhere herein; and Pathak, et al., 1993, cited elsewhere herein).
2~1 7~0,;~2 .
Polymer solutions which undergo reversible gelation by heating or cooling about certain L~ peldt lres (lower critical solution ~IllpGl~ e, LCSI~ are known as thermoreversible gels.
Theoretical and practical aspects of key forms of the,.--o~eversible gels are des~,il,ed by Shalaby, 1991a, cited elsewhere herein. Among the thermoreversible gels ~i~c~ by Shalaby are those of amorphous N-s~ Li~ ed acrylamides in water and amorphous polystyrene and crystalline poly(4-methyl pentene) in organic-solvents. Prevailing gel formation mP~h~ ",c include molecular clu~L~ g of amorphous polymers and selective cryst~lli7~tion of mixed phases of crystalline materials. Thermodynamic p~u~lleL~l~, (enthalpy and entropy) which favor gel rol---alioll in terms of LCST are ~lisc~l~sed by Shalaby only with respect to the solvent-polymer interaction. Shalaby fails, however, to address self-solvating chains.
U.S. Patent No., 4,911,926, discloses aqueous and non-aqueous compositions comprised of block polyoxyalkylene copolymers that form gels in the biologic environment, for preventing post-surgical ~h~5jon Other gel forming compositions for use in preventing post-surgical adhesion include: (a) chitin derivatives (U.S. Pat. No., 5,093,319); (b) aqueous solutions of xanthan gum (U.S. Pat. No., 4,994,277); (c) chitosan-coagulufn (U.S. Pat. No., 4,532,134); and (d) hyaluronic acid (U.S. Pat. No., 4,14,1,973).
Absorbable polymers, or often referred to a~s biodegradable polymers, have been used clinically in sutures and allied surgical ~l~gment~ )n devices to eliminate the need for a second surgical p~ lure to remove functionally equivalent non-absorbable devices (U.S. Pat. No., 3,991,766, to Schmitt et al.; and Shalaby, in Encyclopedia of Pl.~.na~euLical Technolo~y (J.C.
Boylan & J. Swarbrick, eds.),- Vol. 1, Dekker, New York, 1988, p. 465). Although these devices were designed for repairing soft tissues, interest in using such transient systems, with or without biologically active components, in dental and orthopedic applications has grown significantly over the past few years. Such applications are disclosed in Bhatia, et. al., J. Biomater. Sci., Polym.
Ed., 6(5), 435, 1994; U.S. Pat. No., 5,198,220, to Damani; U.S. Pat. No., 5,198,220, to Wasserman, et. al.; and U.S. Pat. No., 3,991,766, to Schmitt et al.
U.S. Patent No., 3,991,766, to Scllmitt et al., discloses absorbable articles made of polyglycolide acid, such as sutures, clips and storage pallets having medicaments incorporated 21 7~0i72 therein and usable for both their own mPrh~ni-~l properties and delayed release systems of m~lir~mPntc. U.S. Patent No., 5,171,148, to W~se~ et al., discloses the use of ~bs~,l,able polymers made from p-dioxanone or L,lactide and glycolide as dental inserts for the ll~a~"lenl of periodontal disease. Here, a semiporous mesh material with sealed edges is emplaced between the tooth and gingiva. The implant is attached to the tooth by an absu,l ablc ligature material. U.S.
Pat. No., 5,198,220, to Damani, discloses the ~ lne~,l of periodontal disease through the use of a sllct~in~d release col"posilion/device co~ g bioactive agents. The composition/device is in a liquid, semi-solid or solid form suitable for insertion into or around the periodontal pocket.
Damani also teaches the formation of a gel, or paste, co~llL.o~ilion COI si~ g of poly(lactyl-co-glycolide) in an acceptable solvent (such as propylene carbonate), with or without propylene and/or polyethylene glycol, and an al-libiu~ic agent such as tetracycline hydrochloride.
Other in-situ forming biodegradable implants and methods of forming them are described in U.S. Pat. Nos., 5,278,201 ('201 Patent) and 5,077,049 ('049 Patent), to Dunn et al. The Dunn et al., patents disclose methods for ~ cting the l~ol~ioll of periodontal tissue in a periodontal pocket and for retarding migr~tion of epithelial cells along the root surface of a tooth. The ' 0~9 Patent tli~clos~s methods which involve pl~r~m~nt of an in-situ forming biodegradable barrier adjacent to the surface of the tooth. The barrier is microl)oluus and includes pores of defined size and can include biologically active agents. The barrier formation is achieved by placing a liquid solution of a biodegradable polymer, such as poly(dl-lactide-co-glycolide) water-coagulatable, thermoplastic in a water miscible, non-toxic organic solvent such as N-methyl pyrrolidone (i.e., to achieve a typical polymer concelllld~ion of <50%) into the periodontal pocket. The organic solvent di~ipa~es into the periodontal fluids and the biodegradable, water coagulatable polymer forms an in-situ solid biodegradable implant. The ~lissir~tion of solvent creates pores within the solid biodegradable implant to promote cell ingrowth. The '859 Patent likewise discloses methods for the same in~ ns involving the formation of the biodegradable barrier from a liquid mixture of a biodegradable, curable thermosetting prepolymer, curing agent and water-soluble material such as salt, sugar, and water-soluble polymer. The curable thermosetting prepolymer is described as an acrylic-ester terminated absorbable polymer.
The '049 and '859 Patents, as well as U.S. Patent No., 4,938,763 to Dunn et al., disclose polymer compositions primarily consialillg of absorbable ~ .,..oplastic or thermosetting polymer, dissolved in organic solvent. These compositions are also described to produce, in an aqueous environment, solids which can be used as tissue barrier (Fujita, et. al., Trans. Soc. Biomater., Vol.
XVII, 384, 1994) a-lb~ P for tissue gPl,P-~l;on (Dunn, et. al., Poly. Prepr., 35(2), 437, 1994a) or carrier for the controlled delivery of drugs (Sherman, et. al., Pharm. Res., 11(10 5-318, 1994).
Acrylate-endcapped poly(~lola~lo.le) prepolymer was also used as a branched pl~;ulaOI for the in-situ formation of a crosslinl ~d system for potential use in controlled drug release (Moore, et. al., Trans. Soc. Biomater., Vol. XVIII, 186, 1995).
A number of controlled delivery systerns for the treatment of periodontal disease are also described in the li~,~lure. For example, U.S. Patent No., 4,919,939, to Baker, discloses a controlled release de!ivery system for pl~r~m~nt in the periodontal pocket, gingival sulcus, tooth socket, wound or other cavity within the mouth. The system incorporates mie-d~allicles in fluid m~lillm and is effective in the environment of use for up to 30 days. The drug, in 10-50 micron polymer particles, is released at a controlled rate by a combination of diffusion of the drug through the polymer and erosion of the polymer.
U.S. Patent No., 5,135,752, to Snipes, di~r,lose~s a buccal dosage form, which melts in the oral cavity, yet will not ~ol.~neollsly deform at higher le~l.pe~l~es encou~ ed in shipment and storage. This composition co~ es two grades of polyethylene glycol, polyethylene oxide, long-chain saturated fatty acid, and colloidal silica.
U.S. Patent No., 5,366,733, to B- ~oldl~ et al., discloses an oral composition for the local administration of a therapeutic agent to a periodontal pocket coll~ hlg at least one therapeutic agent dispersed in a matrix including a biocompatible and/or biodegradable polymer. The composition is a-lmini~tPred æ a plurality of dry discrete microparticles, which are prepared by a phæe separation process. An oral composition is also described wherein the polymer comprises a block copolymer of polyglycolide, trimethylene carbonate and polyethylene oxide.
Apparatus and methods are also provided for dispensing the dry microparticles to the periodontal pocket, whereby they become tacky and adhere to the involved tissue so as to induce long-term therapeutic effects.
In addition, a number of systems for the controlled delivery of biologically active compounds to a variety of sites are (1i~chced in the literature. For Exarnple, U.S. Patent No., 5,011,692, to Fujioka et al., di~los~s a sllcPined l)uls~wise release ph~ reul;,~l p~ lion which ~lllL,lises drug cont~ining polymeric material layers. The polymeric material layers contain the drug only in a slight amount, or are dn~g free. The ent~e sll~f~ ~L~3~ in a directi~n perpendicular to the layer plane and is coated with a polymeric material which is insoluble in water.
These types of pulsewise-release pharm~ l dosages are suitable for embedding beneath the skin.
U. S. Patent No. 5,366,756, to Chesterfield et al., describes a method for p,cL,aling porous bioabsorbable surgical implant materials. The method comprises providing a quantity of particles of bioabsorbable implant material, and coating particles of bioabsorbable implant material with at least one growth factor. The implant can also contain antimicrobial agents.
U.S. Patent No., 5,385,738, to Yamahira et al., discloses a sllct~in~-d-release injection system, COlll~ illg a suspension of a powder col--~, ised ~f an active ingredient and a pharm~r~uti~lly acceptable biodegradable carrier (e.g., proteins, polysaccharides, and synthetic high molecular weight compounds, preferably collagen, atelo collagen, gelatin, and a mixture thereofl in a viscous solvent (e.g., vegetable oils, polyethylene glycol, propylene glycol, silicone oil, and medium-chain fatty acid triglycerides) for injection. The active ingredient in the pharmaceutical formulation is incorporated into the biodegradable carrier in the following state: (i) the active ingredient is chemically bound to the carrier matrix; (ii) the active ingredient is bound to the carrier matrix by intermolecular action; or (iii) the active ingredient is physically embraced within the carrier matrix.
Furthermore, a common complication which is encountered by many surgeons following tootll extraction is dry socket. Dry socket occurs following three to four percent of routine extractions (Field, et. al., J. Oral Maxillofac. Surg., 23(6), 419, 1985), and its etiology appears to be multifactorial (Westerholm, Gen. Dent., July-Aug., 306, 1988). Over the years, dry socket has 2*i 740-72 been referred to as alveoloalgia, alveolitis sicca dolorosa, avascular socket, localized osteitis, fibrinolytic alveolitis and localiæd acute alveolar osteomyelitis (Shafer, et al., A Textbook of Oral Patholo~y. 4th Ed., W.B. S~llndPrs Co., Philadelphia, 1974, p. 605, 1974; and Birn, Int. J. Oral Surg., ~, 211, 1973). Although many chelllolllel~ellLic prevention Illeasul~s or management have been pursued, none have s;g,,iri~ y reduced the in~i~enre of dry socket (Birn, 1973, cited above;
Field, et. al., 1985, cited above). Arnong such approaches to the therapeutic treatment of dry socket, with limited success, are those based on systemic administration of antibiotics (Wes~rhc)lm, 1988, cited above) or direct pl~rem~nt of powdered sulf~ 7in~ or sl~lf~thi~701e into the socket (Elwell, J. Amer. Dent. Assoc., 31, 615, 1944).
To date, the known HHDS and thermoreversible gels can be classified as non-absorbable materials and are expected not to absorb through chain dissociation in the biological environment.
Meanwhile, there is a growing interést in developing absorbable sutures and allied surgical devices such as transient implants, which are degraded to bioabsoll,able, safe by-products and leave no residual mass at the surgical site, as well as frequently cited clinical advantages (Shalaby, Chap. 3 in High Technology Fibers (M. Lewin & J. Preston, eds.), Dekker, New York, 1985; Shalaby, 1988, cited elsewhere herein; Shalaby, Polym. News. L~, 238, 1991; Shalaby. J. Appl.
Biomater., 3, 73, 1992; Shalaby, Biomedical Polymers: Designed to Degrade Systems, Hanser Publ., New York, 1994; and Shalaby, et al, eds. Polymers of Biological & Biomedical Si~nifir~nre, Vol. 520, ACS-Symp. Ser., Amer. Chem. Soc., Washington, 1993) have justified the need for novel absorbable hydrogel formulations.
Moreover, such systems as those previously described in the literature, for example, such as by Dunn, et al, (U.S. Pat. No. 4,938,763), teach in-situ formations of biodegradable, microporous, solid implants in a living body through coagulation of a solution of a polymer in an organic solvent such as N-methyl-2-pyrrolidine. However, the use of solvents, including those of low rnolecular organic ones, facilitates migration of the solution from the application site thereby causing damage to living tissue including cell dehydration and necrosis. Loss of the solvent mass can lead to shrinkage of the coagulum and separation from surrounding tissue.
..
Furthermore, currently available drug delivery systems deal with solid implants which can elicit mechanical incompatibility and, hence, patient discomfort. The present invention provides novel, hydrogel-forming copolymers, which in contrast to those systems previously described, are absorbable, do not require the use of solvents, and are compliant, swollen, mechanically compatible gels, which adhere to surrounding tissue.
The present invention provides a hydrogel-forming, self-solvating, absorbable polyester copolymer capable of selective, segmental association into a compliant hydrogel mass on contact with an aqueous environment. The copolymer can optionally comprise a biologically active agent or a low molecular weight component.
The present invention is able to provide such a copolymer capable of the controlled-release of a biologically active agent/drug for modulating cellular events, such as, wound healing and tissue regeneration. Further, the copolymers described herein are capable of the controlled-release of a biologically active agent/drug for therapeutic treatment of diseases, such as, infection of the oral cavity, dry socket, bone, skin, vaginal and nail infections.
Preferred embodiments of copolymers made according to the invention are capable of being extruded or injected into living tissue, or onto the surface thereof, for providing a protective barrier for treating conditions, such as, post-surgical adhesion. Also preferred copolymers described herein can be used for constituting or constructing a carrier of vaccines, living cells, or viable tissue for sust~;ning biological functions both in vitro and in vivo.
Preferred versions of copolymers described herein are capable of acting as a blocking agent or sealant for treating defects in conduits.
2~ ~0i~2 Accordingly, the present invention provides hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, se~mP-nt~l ~ccoci~tion into a compliant hydrogel mass on contact with an aqueous en~ ol""e"l. In a pier~"ed e--~l)o~ of the invention, the copolymer colll~lises a base colll~ol~e~ si~ Cullll)o~ A" herein. As used herein, the terms "Component A" and Ucopolymer(s)" are "IL~ ge~le and refer to the basic ~ clul~ of the copolymers of the invention. Co",pol~"L A ~o".~ es a molecular chain having a hydrophilic block, ~ n~tPd "yn herein, and a relatively hydlophobic polyester block, d~sign~tPd "X" herein.
Hydrophobic block X and hydrophilic block Y more pl~r~l~bly comprise a molecular SlluGlult~
having the following formula: X-Y-X or (X-Y)n, and branched ~LI~lclulcs thereof. Most preferably, hydrophobic block X collly~ es a polyester forrned by grafting a glycolide, lactide, ~-caprolactone, p-dioxanone, trimethylene carbonate or combina'tions thereof, onto the hydroxylic or amino groups of a hydrophilic polyrner precursor i.e., Y; hydrophilic block Y con~ es a polyoxyethylene, poly(oxyethylene-b-oxypropylene), polypeptide polyalkylene o,~a,-,~, a polysaccharide, and derivatives thereof; or a liquid, high molecul~r weight polyether glycol interlinked with an oxalate or ~uccinale functionalities in linear or branched form.
Component A optionally co"l~,i;,es carboxylic end-groups formed by any known technique in the art, such as, for example, end-group succinylation. This facilitates ionically binding a biologically active agent or drug to Co~nl ollelll A, such that, drug release can be modulated. The biologically active agent or drug is preferably present on Co~pollent A in an insoluble form, such as, (1) a mic,opa"iculate dispersion, (2) a surface-deposited coating onto an absorbable microporous microparticles, and/or (3) ionically bound molecules onto the surfaces of absorbable microporous mic,~licles.
In another embodiment of the invention, Component A optionally comprises an absorbable carrier associated therewith and, designated "Component B" herein. As used herein, the term aassociated therewith" refers to any chemical and/or physical means known in the art for combining components together. The function of Component B is to carry the biologically active agent. This is preferably desirable for medications which call for an initial drug burst and prolonged release thereafter and, thus, highly regulated availability of drugs at the biological site.
2 1 74 U~
In a further embodiment of the invention, Compol1enl A, with or without component B
and/or the biologically active agent, optionally colnpllses a similarly con.~Lil~ d low molecular weight block copolyester ~sor~ d therewith. The low lc'~ r weight coplyester p~ bly is a plasticizer and, more plt;r~,~ly, the pl~ Pr is df~ nA~d "Colllpollel~ C" herein.
It is u. l.l~ ~ûd that ColllL~ol~elll A, with or without the biologically active agent/drug and/or c~ oSi~ionS of Cc~ ollell~ A, B, C, the biologically active agent, and variations thereof, can provide a wide range of plu~el~ics for treating a host of ~ e~cPs, including, but not limited to, dental, orthopeAi~ and vascular applications. For example, the copolymers of the invention can:
(1) be extruded or injected into living tissue or onto the surface of living tissues to provide a protective barrier to prevent post-surgical adhesion; (2) act as a blocking agent or sealant for treatment of defect in conduits such as blood vessels; (3) facilitate the controlled-release of a biologically active agent/drug for modlll~tin~ cellular events such as wound healing and tissue regeneration or theldp~u~ic Ll~a~lllent of diseases such as infection of the periodontium, dry socket, bone, skin, vaginal, and nail i~ ions; and (4) f~.ilit~tP, the sll~t~inP,d in vinO or in vivo growth of viable cells and/or llving tissues for the purpose of tissue en~in~p-ring.
The term Hydrophobic Block(s)" as used herein, refers to absorbable polyester chain block(s) or segment(s) of variable length which is present in an isolated form, will produce practically amorphous (with less than 5 % crystallinity) or totally amorphous material having a Tg of less than 25C, and preferably, is a viscous liquid at room tell~peia~lre. Hydrophobic block(s) X
comprises copolymeric segments of known chemistries in the art, such as, those comprised from cyclic lactones (e.g., glycolide, I-lactide, dl-lactide, ~-caprolactone, p dioxanone, trimethylene carbonate), polyalkylene oxalate, and the like, as described by Shalaby, 1988, cited elsewhere herein. More ~l~r~ y~ l-ydlvl-hnbic __ L(s) or blDck(s) X
lactide/glycolid~ copolymer (with 51 to 80% 1- or dl-lactide).
The term "Hydrophilic Block(s)" as used herein, refers to polymeric blocks or segments which, if present in an isolated form, will be water soluble. Hydrophilic block(s) or segment(s) Y
co~ i.es poly(oxyethylene), with or without a minor component of a higher homolog, such as, poly(oxypropylene)--polypeptide, polyalkylene oxamate (Shalaby et al., 1980, cited elsewhere herein), a poly~ , or derivaties U ~.~L. The length of the lly.l.~)hil;~ block and its weight fractions can be varied to nLdulate the rate of gel rc"ll~ion, its mod~ c~ its water content, diffusivity of bioactive drug through it, its adhesiveness to surrounding tissue, and bioal)s~ll,ability.
The term UHydrogel'' or Hydrogel Mass" as used herein, refers to materials which have a high tendency for water absorption and/or retention, and m~int~in m~rh~ni~l integrity through physical crosslin'ks which are reversible in nature.
The term Physical Crosslinks as used herein, refers to a three~lim~ncion~ c~ule which is held together by physical quasi or pseudo crosslinks, or ionic bonds, as colllpa~ed to covalently crocclin~d. These physical crosslinks facilitate the reversibility of the hydrogel. This reversibility property can be influenced by external factors, such as, solvent or heat.
The term Self-Solvating" as used herein, refers to components of chains which in the absence of external factors i.e., solvents, have greater affinity for physical interaction such that the components are capable of forming a virtually one phase system.
The term Compliant" as used herein, refers to a material having a low modulus and which is easily deformable.
The term "Biologically Active Agent" as used herein broadly includes any composition or compound of matter which when dispensed in the chosen environment of use produces a predetermined, beneficial and useful result.
The term Drug" or Agent" as used herein broadly includes physiologically or pharmacologically active subst~n~s for producing a localiæd effect at the administration site or a systemic effect at a site remote from the ~llmini~tration site.
The term "Plasticizer" as used herein, refers to an absorbable polyester composition with hydrophilic and hydrophobic components similar, or identical to, those of Component A, with the exception of having a higher hydrophilic/hydrophobic ratio in Component C than Component A.
21 7~072 The present invention ~liccl-)ses novel hydrogel-forming, self-solvating, absorbable polyester copolymers, which upon hydration results in a hydrogel mass. The hydrogel mass is stabilized by pseudo-crosslinks provided by a hydrophobic polyester cû.l.ponenL, such as those co.~ ed from cyclic lactones e.g., glycolide, I-lactide, dl-lactide, ~-caprolactone, p dioxanone, l~ hylene c~bo~ , polyalkylene oxalate, derivatives thereof and the like, covalently linked to a hydrophilic co~ onelll co~ ed of blocks, such as those derived from a polyethylene glycol, polypeptide, polyalkylene oY~m~tP (U.S. Pat. Nos. 4,209,607 and 4,æ6,243, to Shalaby et al.
or poly~ and derivaties U~ L. me polyester copolynErs with or without modifying additives, undergo hydration in the biologic environment leading to selective segmental associalioll thereby forming compliant hydrogels at the application site.
These copolymers are ~speci~lly useful for localized, controlled delivery of biologically active agents/drugs and prola~ling or aug~llellli-lg damaged, colllplolllised, and/or tr~llm~ti7P,d tissues. More particularly applications of the novel copolymers of the invention include: (a) the en~ of periodontal disease, wherein a tetracycline- or chlorhexidine-containing hydrogel-former is injected in the periodontal pocket to form an adhesive gel or semi-solid mass in the pocket for the controlled release of such antimicrobial drugs over a period of 2 to 45 days. Near the practical exhaustion of the drug, the polymer will comm~nre to absorb ~b~ lly as it undergoes advanced stages of degradation; ~b) the prevention and Ll~.lenl of dry socket with formulations similar to those of Component A; (c) providing a hydrogel barrier with or without non-steroidal anti-infl~mm~tory drugs on ~ rd tissue to prevent post-surgical adhesion; (d) applications as an antimicrobial hydrogel for the treatment of vaginal infections; (e) treatment of bone diseases such as osteomyelitis, with injectable formulations colllplisillg antibiotics including gentamicin and vancomycin; (f) accelerating tissue regenerating in ~IIlL)lulllised soft and hard tissue, e.g., fractured bone, ulcers, burns, by employing formulations comprising growth promoters, such as growth factors or their oligomeric analogs; and, (g) treatment of diseases such as psoriasis and infected nails using formulations comprising antimicrobial agents. Other applications of the hydrogel-forming copolymers of the invention include (a) blood vessel sealant; (b) vascular 2 1 7407~
..
blocking agent; (c) carrier for injectable anti~ y formulations in the treatrnent of joint ~i~e,.ces; and (d) active carrier of viable cells or living tissue.
The copolymers of the invention CO~ G a primary or base cc .-.~nenl ~ sign, t~d "Co---pone--L A" herein. Co~ o~ A colnl.l.sGs mol~c~ r chains having a hydrophilic block, ;gl~ i "Y" herein, and a relatively l~y~ hobic polyester block, clf ~;glli-lr~l "X" herein. The mOllfl~Ul~ r ~ll U~;~ulG of hydrophobic block X and hydrophilic block Y prefel~bly co-~l-ses one of the following formulas: X-Y-X or (X~Y)n~ and branched structures thereof. More preferably, hydrophobic block X COII~ GS a polyester formed by grafting a glycolide, lactide, ~-caprolactone, p-dioxanone, trimethylene ~I~OI~IG or combinations thereof, onto the hydroxylic or amino-end groups of a hydrophilic polymer precursor i.e., Y. Hydrophilic block Y preferably Colllpli~Gs a polyoxyethylene, poly(oxyethylene-b-oxypropylene), polypeptide, polyalkylene oxamate, a polysaccharide, or derivatives thereof, or a liquid, high molecular weight polyether glycol interlinked with oxalate or ~UCCil)~G functionalities in linear or branched form.
In a plerellGd embodiment, Co---pollelll A co-ll~ es a polyethylene glycol having a molecular weight of about 400 Daltons which is pre-interlinked with succi.~e or oxalate bridges to increase the length of the hydrophilic block and, thus, th'e moleclll~r weight of A without favoring its cryst, 11i7~tion. That is, the hydrophilic prepolymer "Y" having hydroxylic end-groups, is end-grafted with a mixture 60/40 dl-lactide/glycolide to produce a block copolymer having a hydrophilic block fraction "Y" of about 0.25. To render Component A more receptive to basic drugs, its end-groups can optionally be carboxylated, for instance, by their acylation with succinic anhydride. Component A, with or without a biologically active agent, is introduced to a biological target site using conventional means and, thereafter, undergoes selective-segmental segregation to form a flexible, compliant, reversible gel which adheres to the surrounding tissues and acquires the configuration of the site. Component A of the invention more preferably comprises an inherent viscosity at 25C in chloroform ranging between 0.03 to 0.80 dL/g and can be present as a liquid at room temperature, or practically amorphous material (with .
lecs than 5 % crystallinity) with a Tg of less than 25C, which can be extruded through a die or -lminictered through a syringe needle.
Col,~onelll A coll~ P~ copolymeric chains with self-solvating comL,onellL~, (analogous to phase mixing of two cullll~onellL miccibl~ blends) to allow its e~ ,Lence as a viscous, extrudable material at room l~ 7 and its ~l~L-,r,l IIIA~;Ol1 to a flexible reversible hydrogel upon lministr~tion to a biological site. These hydrogels adhere tenaciously to adjacent tissues and acquire the shape of the site. The present copolymers are mt~r.h~nin~lly colllL)~Iible in highly sensitive sites and can mediate external l~rl~Anical stresses or shockc. As such, the copolymers of the invention can be applied easily without incorporating a major extrincic water-soluble, potentially cytotoxic organic solvent in order to facilitate upon ~minictration in-situ coagulation to a solid mass.
Component A, with or without a non-steroidal anti-infl~ll III~A10l y drug (NSAID) or active polypeptide, can be used as a protective barrier, a blocking agent of vascular defects caused by needle puncturing, a sealant of damaged surfaces for preventing post-surgical adhesion or as a carrier of imm~nl~stim~ ntc or viable cells. Component A, mixed with an antimicrobial agent/drug, can be injected or applied topically with a suitable known applicator for the treatment of bone, cartilage, nail, skin, and vaginal infectionc.
In another embodiment of the invention, Compollell~ A optionally includes a biologically active agent/drug, such as, an antimicrobial agent, anesthetic agent, antibiotic, and/or a peptide or protein, for regulating cellular events. The biologically active agent/drug can comprise by way of illustration, antifungal agents, ~ntihacterial agents, antibiotics, anti-infl~mm~t~ry agents, immllnoSu~ple~sive agents, immnnostim~ tory agents, dental densi~i~els, odor masking agents, immune reagents, anesthetics, antiseptics, nutritional agents, antioxidants, lipopolysaccharide complexing agents, peroxides, tissue growth factors, a mixture of any of the foregoing, and the like. The agent/drug can be deposited, wholly or in part, on Component A, with or without carboxy-terminated ends. In an alternative embodiment, the biologically active agent/drug can be deposited, wholly or in part, on a solid carrier, designated "Component B" herein. Component B
preferably is an absorbable, powder prior to mixing with Component A and, more preferably, ....
Component B is an absorbable, mic.~olo~ls low molcc~ r weight polyester which is highly crystalline and practically insoluble in Co--~ponen~ A.
A prer~ t;d f~rm~ tion of Co-"~o,le"~ A/B co",~l~es a mixture of 20/80 B/A, with B
being a low molec~ r, micr~uluus polyglycolide with 0.70 to 0.95 solid fraction, average particle size of 0.5-200 micron and c~ul,uAyl-bearing chains. High concel,llalioll of carboxylic groups on the chains can be achieved by pl~i~lg Compon~nt B using di- or poly-carboAylic acid as iniLialol~. The deposited agent on Component B can exhibit a release profile which can be multiphasic, inrlllrling (a) simple, fast diffusion of soluble free drug through gel A; (b) slow diffusion of soluble free drug housed in the pores of B; and, (c) drug release at the surface (bod exterior and pore) of B or the chain ends of carboxylated A chains by ion exchange of ionically bound molecules. By varying the collre~ ;QIl of Component B in Component A, the flow ch~r~ lics and release profile of the agent can be modulated. This is important because in certain applications, the flow chd~ ic or properties of Component A/B formulations can determine the clinical efficacy, particularly in cases of treating periodontal disease, nail infection and bone illf~;~ion where high vi~coel~stir-ity (due to the high weight fraction of the mi~lop~i~;ulate dispersed phase and its physicom~r,h~ni~l interlocking with viscous liquid continuous pha~se A) of the gel composite is pertinent to assure merh~nir~l stability at the target site.
Component A optionally includes an absorbable low molecular weight component. This component can modulate the rheological properties, gel-formation time, and mechanical disposition of Component A at the target site. The low molecular weight component preferably is a plasticizer and, more preferably, the pla~ic~;L is designated "Component C" herein. Component C can (a) aid the dispersion of Component B in Component A; (b) reduce the overall system viscosity of Component A/B formulation, (c) reducing the viscosity and facilitating the injectability of Component B if used alone or with a biologically active compound, and/or (d) increase the rate of hydration or gel formation. The absorbable pla~ici~er, such as Component C, is capable of modulating the viscosity and/or gel-formation rate of Component A, with or without Component B, thereby broadening its applicability. Highly viscous forms of Component A can be easily plasticized with a low mnlecul~r weight (inherent viscosity of 0.03 - 0.15) polye ter copolymer Component C, that is made of the same ch~mi~l entities as Component A, (but dirrelen hydrophilic weight fraction) to produce easily i~jPct~l lP- liquid systems.
In a more preferred embodiment, Coll,pol~elll A is formed by end-grafting a polyethylene glycol having a m~ r weight of about 400-900 Dalton with a mixture of glycolide and l- or dl-lactide in the pl~sence of sku~ octoate as a catalyst to produce a block copolymer with (a) ether/ester ma s ratios of 2049/80-51, p~rel~ly 2540/75-SS and, most preferably 3040/70-60;
(b) having an inherent viscosity in chloroform.at 25C from about 0.03 to 0.80, preferably from about 0.1 to 0.6, more p-~r~ldbly from about 0.15 to O.S, and most preferably from about 0.2 to 0.4 dL/g; and (c) is in the form of an extrudable, P.c.cenfi~lly amorphous, semi-solid having a Tg of less than 25C, preferably an amorphous material having a Tg of less than 37C, and more preferably a viscous liquid at room temperature that can be easily ~mini.ctered through a syringe needle.
In a still more preferred embodiment, copolymer Component A is formed by end-grafting an oxalate- or ~uccu~t~-interlinked liquid polyethylene glycol having a molecular weight of more than 1200 Dalton with a mixture of glycolide and l- or d¦-lactide in the presence of stannous octoate as a catalyst to produce a block copolymer with (a) ether/ester mass ratio of 2~49/80-51 and preferably 25-40/75-SS but most preferably 30-40/70-60; (bj having an inherent viscosity in chloroform at 25C of about 0.03 to 0.80, p.~re.dbly 0.1 to 0.60, more preferably, 0.15 to 0.50, and most preferably, 0.2 to 0.4 dL/g; and (c) in the form of extrudable, essentially amorphous semi-solid having a Tg of less than 25C and preferably an amorphous material having a Tg of less than 25C and, more preferably, a viscous liquid at room temperature that can be easily administered through a syringe needle.
Formulations comprised of the polyester c~nnlvmers of the invention are suitable carriers of biologically active agents/drugs at typical loading of 0.001% to 30%. The chain of C~ .,L
A or Component C can be succinylated to provide acidic end-groups for ionic binding of the agents/drugs. Liquid compositions made of Component A or Components A/C, with or without agent/drug, can form hydrogels upon contactillg a liquid environment. This is achieved through the hydration of the hydrophilic block of the copolymeric chains leading to intramolecular conrc,~ lio~al changes and ~oci~lion of the hydrophobic blocks as pseudo-crosslinks in a reversible, hydrophilic/ hydrophobic hydrogel system.
For copolymer form~ tions colll~"i,illg the agent, such morphology provides a suitable en~d,~ llell~ for the controlled release of the agent. The agent can be present in a soluble or dispersed form. Preferably, the agent is de~o.,i~d on a micronized powder, more L"~r~,~ably a microporous abso,l,able powder and, most preferably, a powder (Component B) which offers an ion-binding, high surface area for ionically immobilizing part of the soluble agent to control its release and, thus, produce copolymers with a multiphasic release profile over a period of 1 to 90 days.
More specifically, the biologically active agents can be present as (a) a solute in Component A; (b) a dispersed solid in Component A; (c) a coating on Component B; (d) ionically bound molecules on Components A and/or B; and/or (e) m~ nically held within the pores of Component B. Each of these forms of drug will have its own release pathway and, thus, bio-availability at the site. D~en~ g on the concell~a~ion of Component B, the hydrogel-forming formulation can be made to have a broad range of plupe~lies and gel-formation kinetics to allow its use in many applications.
Component A with a biologically active agent and/or Components B and/or C, is used for treatment of periodontal disease, osteomyalitis, and dry socket. While a ~liccuccion follows for using the copolymers of the invention for ~lllent of periodontal disease, it is understood that this discussion is for purposes of illustration only and, not limitation, and the copolymers of the invention have broad applications of use. Periodontal disease, as used herein, is a general term for a number of diseases that affect the periodontal tissue. These diseases are characterized by a range of symptoms including infl~mm~fion, bleeding, exudation of pus from the gingival sulcus, deepening of the sulcus to form periodontal pockets, tissue lesions, loss of connective tissue, alveolar bone loss, and ultimately tooth loosening and loss. The primary cause of periodontal disease is now believed to be bacterial infection of the plaque that forms on tooth surfaces below the gingival margin. The copolymer formulations of the present invention are useful for prolonged, 2~ 74~7~
controlled ~lis~ensil~g of a range of drugs and agents, such as, for exarnple: (a) prophylactic prolonged application of minerals and ions, such as calcium or fluoride ion; (b) prolonged controlled t;A~o~ure to local an~i~lics, including, chlorhexidine and ~ oniu-" iodide; (c) controlled antibiotic delivery, including such antibiotics as aminoglycosides, macrolides such as y~ro~lycin, penicillins, cephalosporins and the like; (d) ~n~sth~tic/analgesic delivery pre- or post surgery or to treat other mouth pain using such agents as amide-type local ~npsth~tir-s like li(lor~in~, mepivacaine, pyrrocaine, bupivacaine, prilocaine, etidoc~in~, or the like; and (e) local controlled delivery of non-steriodal anti-infl~mm~tory drugs such as ketorolac, naproxen, diclofenac sodium and fluribiprofen. It is recognized that in certain forms of therapy, combinations of agents/drugs in the same delivery system i.e., copolymer of the invention, can be useful in order to obtain an optimal effect. Thus, for example, an ~ntibartPrial and an ~ntiinfl~mm~tory agent may be combined in a single copolymer to provide combined effectiveness.
It has also been recently shown that regrowth and repair of periodontal connective tissue can be encouraged with the aid of polypeptide mitogenic growth factors. See, for exarnple, V.P.
Terranova et al., BiochPmir~lly Medicated Periodontal Regeneration, J. Periodont. Res., 22, pages 248-251. The c~po1yn~s of the pr~sent inv~tion can be esi~n~d to release a~pru~lia~e encapsulated, or uncapsulated, growth factors, including, epidermal growth factors, human platelet derived TGF-B, endothelial cell growth factors, thymocyte-activating factors, platelet derived growth factors, fibroblast growth factor, fibronectin or laminin.
The drug/agent can be used at a level of from about 0.1% to about 70 %, preferably fmn about 1% to about 50 %, most preferably f}~n about 2 % to about 30 % . The copolymers of the invention can be designed to release drug to provide a steady state number average concentrations of from about 1 llg to about 2000 llg, preferably f~m about 20 llg to about 1200 llg, most preferably from about 50 ~g to about 800 ~lg per milliliter of the gingival crevicular fluid of a treated periodontal pocket. The steady state release rates can be altered by varying component ratios of the copolymer formulations. The steady state conditions are preferably used since initial bursts are accounted for as well as delays in release For example, in the case of a ten (lO) day therapy, steady state is generally reached in about one to two days More preferably, a forlnulatio for treating periodontal disease comprises 20/80 Co~ B/A, c~nt~inin~ 1-3 % of an active drug such as chlorh~Yi~in~ or tetracycline.
In addition to the agent/drug, the copolymer formulations of the present invention can include a variety of optional co---~olle-l~. Such co,l-~ol~el-~ include, but are not limited to, surfactants, viscosity controlling agents, m~li~in~l agents, cell growth mod~ tnrs, dyes, complexing agents, ~ntin~ ntc, other polymers such as carboxymethly cellulose, gums such as guar gum, waxes/oils such as castor oil, glycerol, dibutyl phthalate and di(2-ethylhexyl) phthalate as well as many others. If used, such optior~ L~ I , ~e fron about 0.1% to about 20 %, preferably from about 0.5 % to about 5 % of the total copolymer formulation The copolymers of the invention can be inserted into the periodontal pocket or gingival region, and can be ~1minictered in the form of a particle, film or sheet. The size, shape and thi~kn~o55 can be changed according to the condition of the disease to be treated. Ordinarily, the size, shape and thirkn~ss are changed according to the size of the periodontal pocket of the patient or the condition of the gingiva.
In another embodiment of the invention, there is contemplated phal"l~re~ l r~l",.,~ ol.c ~ _ F~. arl injectable visoous fluid of C _ L A, C~ _ Ls A/B, C _ L~A/B/C ~n~/or ~( _ Ls A/C, aontA;ning about 0.001% to 30% agents/drugs and, mDre ~ r~ y about 0.1% to 10% of agents/drugs. The rp~ e of the agent/drug is over a period of 1 to 90 days and, more ~l~r~ ~ ly 2 to 45 d~ys. m e drugs/agents can ;nnll~P one or I n~tions of the foll~ . ng: aul ~rbk;Al agents (e.g. nhl.. ~ ;nP, L~Llauy~line and/or duAy~y~line), ant;ho~;P-s (e.g., i n;n, v ,uin, and/or l~ in), antivn~xLL agents (e.g., acyclovir, 3TC tT vu~ine] and/or inl~r~N~)~ v~nr;np~ (e.g. ricin toxoid and deglyoosylated A-chain ricin D), anti-epileptic and anti-oonvulsant drugs (e.g.,_ nP and di~k~ly~-ydkulLuin), a~ uæLic agents (e.g., Le~ ~;n ~uL~ILal~i1, L~lLallyl, and l;~nr~;nP), and ~ _ ' which can A~cPlPrAte wound hPAl;ng An~ tissue ~J~ Lion, L~v~L post-surgical A~hP~;nn, n~nrlA~tic formation, and ~v~lL or A~pl~r~te blood clotting.
In another embodiment of the phal ~ formulation, the eopolymer ~ol-lpl ises part or all of the bioaetive agent deposited on a microporous and/or finely divided absorbable powder, sueh as, those eonsisting of low molecular weight erystalline polyglyeolide or copolyglyeolide. The powder is formed by low to moderate conversion (that is 60-95 %) ring-opening polymerization of glycolide or a mixture made predomillantly of glycolide and small amounts of other lactones. Tlle 2 1 7~072 .
pol~ 7.~tion is ~rr;~ out in the presenoe of ~ octoate as a catalyst and ~lff;~;~nt con~lL dLion of glycolic acid as an initiator to prcduoe a mass. Upon ~l~nrh;n~, ~rin~in~, r~ll llin~ (or jet llin~) in an inert medium, and ~xL,d~Lion with water, 2-~1u~Yulol, mi~ u~s particles are produced having (a) 1 to 200,u ~ and, more preferably 10-150,u; (b) an inherent viscosity in hexafluoro-2-propanol at 25C of ~0.03 to 0.3 and, more preferably <0.05 to 0.2 dL/g; (c) contain less than 2% residual monomer; and (d) have 0.03 to 0.35 and, more preferably 0.05 to 0.25 pore fraction.
An important difference between conventional formulations in the art and the novel copolymers of the invention, is that the present copolymers do not include the use of organic solvents. Such solvents can compromise the copolymers shelf-stability, as in the case of a polyester in a basic solvent such as N-methyl-pyrrolidine, which can catalyze chain dissociation in the presence of traoe amounts of moisture. The prior art formulations also teach the use of other reactive solvents such as propylene glycol (which degrades the polyester chain through alcoholysis), or trimethylene carbonate (which can copolymerize with the polyester chain). Moreover, should the prior art formulations be radiation sterilized, the presence of a solvent can lead to the generation of new ch~mi~l species origin~ting from the solvent as well as in combination with the bioactive ingredient. In effect, organic solvents described in the prior art can compromise the purity and efficacy of both the drug (optional) and polymer which can, in turn, be associated with unsafe use.
Another feature of the novel copolymers of the invention, is that when administered to a biological site the copolymers do not experience discernible reduction in organic mass, as is the case of prior art compositions which coagulate in-situ by le~f~.hing out a major water-soluble component. Leaching out major water-soluble components can be associated with shrinkage and separation from the surrounding tissue and, in some instances, uncontrolled formation of microporous mass. Because the copolymers of the invention are comprised of copolymeric chains, the copolymers can be easily tailored to modulate its viscosity without the intervention of a new chemical species, such as, an organic solvent.
A further feature of the novel copolymers of the invention, is that sinGe the copolymers are comprised of self-solvatillg molecules, its conversion to a llydrogel about a drug provides a uniform distribution of the therapeutic agent, and thus, more reproducible release profile, in contrast with prior art systems where complex physical events prevail due to the presence of leachable solvents.
The following Examples are provided to further illustrative the present invention, and should not be construed as limit~tion.c thereof:
EXAMPLE I
PREPARATION OF COMPONENT "A"
1. ~pa-~Lion of 79/21 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 A suitable flask was thoroughly cleaned, flame-dried, and charged dry with polyethylene glycol (MW - 400; Sg, 0.0125 mole), dl-lactide (12 g, 0.083 mole), glycolide (6.4 g, 0.056 mole), stannous octoate catalyst (0.4 M in toluene; 34.7 ~lL, 0.014 mmole), and a magnetic stirrer under nitrogen condition. The reactor was placed in an oil bath and heated to 170C under a positive nitrogen pressure for 16 hours. The flask was removed and stored open in a vacuum oven. The inherent viscosity (IV) of the composition was determined using a 50 capillary viscometer (Ostwald type) at a cûncenll~tion Qf 0.1 g/100 mL in chloroform. In a constant temperature bath set at 30C, the IV was determined to ~e 0.13 dL/g. A DuPont 990 Differential Sc~nning Calorimeter (DSC) was used to determine glass transition (Tg) of the material. Applu~ lla~ly 4 mg of the sample was heated at 10C/min from -50C in a nitrogen environment. Tg = -41C.
2. Pl~alation of 60/40 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW = 400; 4.1 g, 0.01 mole), dimethyl oxalate (3.1 g, 0.025 mole), and stannous octoate catalyst (0.4 M in toluene; 883 IlL, 0.035 mmole) were mixed in a dry glass reactor containing a magnetic stirrer and heated to 150C under a nitrogen atmosphere for 4 hours.
A vacuum of less than 0.1 mm Hg was applied to remove the condensate (methanol) and excess dimethyl oxalate. The reactor was then cooled to approximately 50C and PEG (MW = 400; 8.3 g, 0.021 mole) was added. The reactants \~ere heated to 150C for 3 hours before applyh-g 2~ 74072 ~. .
vacuum and cooling to room temperature. dl-Lactide (13.3 g, 0.093 mole), glycolide (7.2 g, 0.062 mole) were added under dry conditions to the reactor. The flask was heated to 150C under a positive nitrogen pressure for 12 hours. Next, the temperature was increased to 170C for 3.5 hours and vacuum was applied for 2 hours as the flask cooled to room L~r,~e.a~ . The polymer was isolated and stored under vacuum.
IV in CHCl3 = 0.11 dL/g 3. Preparation of 78/22 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW = 400; 2.0 g, 0.005 mole), dimethyl oxalate (1.77 g, 0.015 mole), and stannous octoate catalyst (0.2 M in toluene; 90.5 IlL, 0.036 mmole) were mixed in a dry glass reactor containing a m~gnPtic stirrer and heated to 140C under a nitrogen atmosphere for 2 hours. A vacuum of less than 0.1 rnm Hg was applied to remove the condensate (methanol) and excess dimethyl oxalate. The reactor was then cooled to approximately 50 and PEG (MW = 400;
COPOLYMERS,ANDMETHODSFORUSEl~REOF
This invention relates generally to biomedical and/or ph~ln~c~u~ applications ofabsorbable or biodegradable polymeric hydrogels. More particularly, the present invention relates to hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon co"~i~cli"g an aqueous env.lun.ne-ll. The invention also discloses methods of using the polyester copolymers of the invention in humans for providing a protective barrier to prevent post-surgical adhesion, a carrier of viable cells or living tissue, treatment of defects in conduits such as blood vessels, and controlled release of a biologically ætive agent for modulating cellular events such as wound healing and tissue regene~ioll or thel~c;u~ic L~L~enl of diseases such as infection of the perio(lontillm, dry socket, bone, skin, vaginal,~and nail infections.
Hydrogels are materials which absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and m~int~in three~lim~ncional networks capable of reversible der~ aLion (Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Publishing Co., T ~n~ster~ PA, 1993; W. Shalaby et al.~ J. Controlled Rel., 19, 131, 1992; and Silberberg, in Molecular Basis of Polymer Networks (Rallmg~rtner, A. & Picot, C.E., Eds.), Spring-Verlag, Berlin, 1989, p. 147).
Covalently croc~link~d networks of hydrophilic polymers, including water-soluble polymers are traditionally denoted as hydrogels (or aquagels) in their hydrated state. Hydrogels have been prepared to be based on crosslinked polymeric chains of methoxy poly(ethylene glycol) monomethacrylate having variable lengths of the polyoxyethylene side chains, and their interaction as hydrogels, with blood components have been studied (Nagaoka, et al., in Polvmers as Biomaterials (Shalaby, S.W., et al., Eds.), Plenum Press, 1983, p. 381). A number of aqueous hydrogels (aquagels) have been used in various biomedical applications, such as, for example, soft contact lenses, wound m~n~g~. .on~ and drug delivery. However, methods used in the p~paL~Llion of these hydrogels, and their conversion to useful articles, are subject to the constraintc associa~d with the nature of their three rl;l"Pl,~;on~l theL"-os~ -g ~llucluL~ and, hence, deprive the users from applying the facile ylocessing t~hniq~les employed in the production of non-crocslin~Pd thermoplastic materials.
This, and the low ~ ~rl~nir~l strength of the hydrated networks, led a number ofinvestig~t()r.c to explore the concept of c~ lbillillg hydrophilic and hydrophobic polymeric components in block (Okano, et al., J. Biomed. Mat. Research, 15, 393, 1981), or graft copolymeric structures (Onishi, et al., in Conlelllpold-y Topics in Polymer Science~ (W.J. Bailey & T. Tsuruta, eds.), Plenum Publ. Co., New York, 1984, p. 149), and blends (Shah, Polymer, 28, 1212 ,1987; and U.S. Pat. No. 4,369,229) to form the hydrophobic-hydrophilic" domain systems, which are suited for thermoplastic p~ssi lg (Shah, Chap. 30, in Water Soluble Polymers (S.W. Shalaby, et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer. Chem. Soc., W~chington, 1991).
The hydrophobic-hydrophilic" domain system (HHDS) undergoes morphological changes which are ~csoci~d with the hydration of the hydrophilic domains and formation of pseudo-crosslinks via the hydrophobic component of the system (Shah, 1991, cited above). Such morphology was considered to be responsible for the enh~ ed biocolllpa~ii,ility and superior m~ni-~l strength of the two-phase HHDS as colll~,~ed to those of covalently crosslinl ~d, hydrophilic polymers. The m.o~h~nicm of gel formation in the present invention parallels that described by Shah, 1991, cited above, for non-absorbable blends of hydrophilic-hydrophobic domain systems (HHDS). However, dirrelellces exist between the copolymers of the present invention, and more particularly, Component "A", and HHDS. In this regard, Component A is based on a water-soluble and water-insoluble block structure (SIBS). This is not a mere physical mixture of two polymers as are the blends described by Shah, 1991, cited above. Additionally, due to the presence of covalent links between the blocks of SIBS, the resulting hydrogel displays higher elasticity compliance and tensile strength while being absorbable. In fact, the SIBS systems are, in some respects, analogous to thermoreversible gels (Shalaby, in Water-Soluble Polymers, (Shalaby, S.W., et al., Eds.), Vol.
467, Chapt. 33, ACS Symp. Ser., Amer. Chem. Soc., Washington, DC, 1991a) in displaying a 2~ 74072 ..
hydration-dehydration equilibrium governing the system ll~r<,.,~ ion, i.e., the gel/liquid equilibrium is driven by the water content of the SIBS. Thus, in the absence of water, the polyoxyalkylene blocks undergo intermolec~ r se.~",~-nli11 mixing with the neighboring hydrophobic blocks to produce a viscous liquid. In the plesellce of water, co"lL~lilion between the water as an e~L~ ic solvent and the polyester block for the polyoxyalkylene (POA) block forces the hydration of the POA, and aggregation or ~c~oci~tion of the polyester blocks to establish pseudo-crosslinks which m~int~in a 3-dimensional illl~lity. Since gel formation takes place in an aqueous environment, the POA block will plere,e"Lidlly migrate to the exterior of the gel and interface with the adjoining tissues to establish an a&esive joint, which prevents gel migration from target site and sustains its intended efficacy. As for example, for periodontal and dry socket applications, post-surgical a&esion prevention and treatment of vaginal and bone inrec~ions, and other applications where predictable' site residence of the gel carmot be compromised.
Synthesis and biomedical and phal",aceutical applications of absorbable or biodegradable hydrogels based on covalently croc~linl~d n~wc,l~ COllly~ g polypeptide or polyester components as the enzymatically or hydrolytically labile components, respectively, have been described by a number of resea~cllel~ (Jarrett, et. al., Trans. Soc. Biomater., Vol. XVIII, 182, 1995; Pathak, et. al., Macromolecules~ 26, 581, 1993; Park, et. al., Biodegradable Hydrogels for Drug Delivery. Technomic Publishing Co., Lancaster, PA, 1993; Park, Bio,na~lials, 2. 435.
1988; and W. Shalaby, et. al., 1992, cited elsewhere herein). The hydrogels most often cited in the lilelalulc; are those made of water-soluble polymers, such as polyvinyl pyrrolidone, which have been crosslink~d with naturally derived biodegradable components such as those based on albumin (Park, et. al., 1993, cited elsewhere herein; and W. Shalaby, et. al., 1992, cited elsewhere herein).
Totally synthetic hydrogels which have been studied for controlled drug release and membranes for the treatment of post-surgical adhesion are based on covalent networks formed by the addition polymerization of acrylic-terminated, water-soluble chains of polyether dl-polylactide block copolymers (Jarrett, et. al., 1995, cited elsewhere herein; and Pathak, et al., 1993, cited elsewhere herein).
2~1 7~0,;~2 .
Polymer solutions which undergo reversible gelation by heating or cooling about certain L~ peldt lres (lower critical solution ~IllpGl~ e, LCSI~ are known as thermoreversible gels.
Theoretical and practical aspects of key forms of the,.--o~eversible gels are des~,il,ed by Shalaby, 1991a, cited elsewhere herein. Among the thermoreversible gels ~i~c~ by Shalaby are those of amorphous N-s~ Li~ ed acrylamides in water and amorphous polystyrene and crystalline poly(4-methyl pentene) in organic-solvents. Prevailing gel formation mP~h~ ",c include molecular clu~L~ g of amorphous polymers and selective cryst~lli7~tion of mixed phases of crystalline materials. Thermodynamic p~u~lleL~l~, (enthalpy and entropy) which favor gel rol---alioll in terms of LCST are ~lisc~l~sed by Shalaby only with respect to the solvent-polymer interaction. Shalaby fails, however, to address self-solvating chains.
U.S. Patent No., 4,911,926, discloses aqueous and non-aqueous compositions comprised of block polyoxyalkylene copolymers that form gels in the biologic environment, for preventing post-surgical ~h~5jon Other gel forming compositions for use in preventing post-surgical adhesion include: (a) chitin derivatives (U.S. Pat. No., 5,093,319); (b) aqueous solutions of xanthan gum (U.S. Pat. No., 4,994,277); (c) chitosan-coagulufn (U.S. Pat. No., 4,532,134); and (d) hyaluronic acid (U.S. Pat. No., 4,14,1,973).
Absorbable polymers, or often referred to a~s biodegradable polymers, have been used clinically in sutures and allied surgical ~l~gment~ )n devices to eliminate the need for a second surgical p~ lure to remove functionally equivalent non-absorbable devices (U.S. Pat. No., 3,991,766, to Schmitt et al.; and Shalaby, in Encyclopedia of Pl.~.na~euLical Technolo~y (J.C.
Boylan & J. Swarbrick, eds.),- Vol. 1, Dekker, New York, 1988, p. 465). Although these devices were designed for repairing soft tissues, interest in using such transient systems, with or without biologically active components, in dental and orthopedic applications has grown significantly over the past few years. Such applications are disclosed in Bhatia, et. al., J. Biomater. Sci., Polym.
Ed., 6(5), 435, 1994; U.S. Pat. No., 5,198,220, to Damani; U.S. Pat. No., 5,198,220, to Wasserman, et. al.; and U.S. Pat. No., 3,991,766, to Schmitt et al.
U.S. Patent No., 3,991,766, to Scllmitt et al., discloses absorbable articles made of polyglycolide acid, such as sutures, clips and storage pallets having medicaments incorporated 21 7~0i72 therein and usable for both their own mPrh~ni-~l properties and delayed release systems of m~lir~mPntc. U.S. Patent No., 5,171,148, to W~se~ et al., discloses the use of ~bs~,l,able polymers made from p-dioxanone or L,lactide and glycolide as dental inserts for the ll~a~"lenl of periodontal disease. Here, a semiporous mesh material with sealed edges is emplaced between the tooth and gingiva. The implant is attached to the tooth by an absu,l ablc ligature material. U.S.
Pat. No., 5,198,220, to Damani, discloses the ~ lne~,l of periodontal disease through the use of a sllct~in~d release col"posilion/device co~ g bioactive agents. The composition/device is in a liquid, semi-solid or solid form suitable for insertion into or around the periodontal pocket.
Damani also teaches the formation of a gel, or paste, co~llL.o~ilion COI si~ g of poly(lactyl-co-glycolide) in an acceptable solvent (such as propylene carbonate), with or without propylene and/or polyethylene glycol, and an al-libiu~ic agent such as tetracycline hydrochloride.
Other in-situ forming biodegradable implants and methods of forming them are described in U.S. Pat. Nos., 5,278,201 ('201 Patent) and 5,077,049 ('049 Patent), to Dunn et al. The Dunn et al., patents disclose methods for ~ cting the l~ol~ioll of periodontal tissue in a periodontal pocket and for retarding migr~tion of epithelial cells along the root surface of a tooth. The ' 0~9 Patent tli~clos~s methods which involve pl~r~m~nt of an in-situ forming biodegradable barrier adjacent to the surface of the tooth. The barrier is microl)oluus and includes pores of defined size and can include biologically active agents. The barrier formation is achieved by placing a liquid solution of a biodegradable polymer, such as poly(dl-lactide-co-glycolide) water-coagulatable, thermoplastic in a water miscible, non-toxic organic solvent such as N-methyl pyrrolidone (i.e., to achieve a typical polymer concelllld~ion of <50%) into the periodontal pocket. The organic solvent di~ipa~es into the periodontal fluids and the biodegradable, water coagulatable polymer forms an in-situ solid biodegradable implant. The ~lissir~tion of solvent creates pores within the solid biodegradable implant to promote cell ingrowth. The '859 Patent likewise discloses methods for the same in~ ns involving the formation of the biodegradable barrier from a liquid mixture of a biodegradable, curable thermosetting prepolymer, curing agent and water-soluble material such as salt, sugar, and water-soluble polymer. The curable thermosetting prepolymer is described as an acrylic-ester terminated absorbable polymer.
The '049 and '859 Patents, as well as U.S. Patent No., 4,938,763 to Dunn et al., disclose polymer compositions primarily consialillg of absorbable ~ .,..oplastic or thermosetting polymer, dissolved in organic solvent. These compositions are also described to produce, in an aqueous environment, solids which can be used as tissue barrier (Fujita, et. al., Trans. Soc. Biomater., Vol.
XVII, 384, 1994) a-lb~ P for tissue gPl,P-~l;on (Dunn, et. al., Poly. Prepr., 35(2), 437, 1994a) or carrier for the controlled delivery of drugs (Sherman, et. al., Pharm. Res., 11(10 5-318, 1994).
Acrylate-endcapped poly(~lola~lo.le) prepolymer was also used as a branched pl~;ulaOI for the in-situ formation of a crosslinl ~d system for potential use in controlled drug release (Moore, et. al., Trans. Soc. Biomater., Vol. XVIII, 186, 1995).
A number of controlled delivery systerns for the treatment of periodontal disease are also described in the li~,~lure. For example, U.S. Patent No., 4,919,939, to Baker, discloses a controlled release de!ivery system for pl~r~m~nt in the periodontal pocket, gingival sulcus, tooth socket, wound or other cavity within the mouth. The system incorporates mie-d~allicles in fluid m~lillm and is effective in the environment of use for up to 30 days. The drug, in 10-50 micron polymer particles, is released at a controlled rate by a combination of diffusion of the drug through the polymer and erosion of the polymer.
U.S. Patent No., 5,135,752, to Snipes, di~r,lose~s a buccal dosage form, which melts in the oral cavity, yet will not ~ol.~neollsly deform at higher le~l.pe~l~es encou~ ed in shipment and storage. This composition co~ es two grades of polyethylene glycol, polyethylene oxide, long-chain saturated fatty acid, and colloidal silica.
U.S. Patent No., 5,366,733, to B- ~oldl~ et al., discloses an oral composition for the local administration of a therapeutic agent to a periodontal pocket coll~ hlg at least one therapeutic agent dispersed in a matrix including a biocompatible and/or biodegradable polymer. The composition is a-lmini~tPred æ a plurality of dry discrete microparticles, which are prepared by a phæe separation process. An oral composition is also described wherein the polymer comprises a block copolymer of polyglycolide, trimethylene carbonate and polyethylene oxide.
Apparatus and methods are also provided for dispensing the dry microparticles to the periodontal pocket, whereby they become tacky and adhere to the involved tissue so as to induce long-term therapeutic effects.
In addition, a number of systems for the controlled delivery of biologically active compounds to a variety of sites are (1i~chced in the literature. For Exarnple, U.S. Patent No., 5,011,692, to Fujioka et al., di~los~s a sllcPined l)uls~wise release ph~ reul;,~l p~ lion which ~lllL,lises drug cont~ining polymeric material layers. The polymeric material layers contain the drug only in a slight amount, or are dn~g free. The ent~e sll~f~ ~L~3~ in a directi~n perpendicular to the layer plane and is coated with a polymeric material which is insoluble in water.
These types of pulsewise-release pharm~ l dosages are suitable for embedding beneath the skin.
U. S. Patent No. 5,366,756, to Chesterfield et al., describes a method for p,cL,aling porous bioabsorbable surgical implant materials. The method comprises providing a quantity of particles of bioabsorbable implant material, and coating particles of bioabsorbable implant material with at least one growth factor. The implant can also contain antimicrobial agents.
U.S. Patent No., 5,385,738, to Yamahira et al., discloses a sllct~in~-d-release injection system, COlll~ illg a suspension of a powder col--~, ised ~f an active ingredient and a pharm~r~uti~lly acceptable biodegradable carrier (e.g., proteins, polysaccharides, and synthetic high molecular weight compounds, preferably collagen, atelo collagen, gelatin, and a mixture thereofl in a viscous solvent (e.g., vegetable oils, polyethylene glycol, propylene glycol, silicone oil, and medium-chain fatty acid triglycerides) for injection. The active ingredient in the pharmaceutical formulation is incorporated into the biodegradable carrier in the following state: (i) the active ingredient is chemically bound to the carrier matrix; (ii) the active ingredient is bound to the carrier matrix by intermolecular action; or (iii) the active ingredient is physically embraced within the carrier matrix.
Furthermore, a common complication which is encountered by many surgeons following tootll extraction is dry socket. Dry socket occurs following three to four percent of routine extractions (Field, et. al., J. Oral Maxillofac. Surg., 23(6), 419, 1985), and its etiology appears to be multifactorial (Westerholm, Gen. Dent., July-Aug., 306, 1988). Over the years, dry socket has 2*i 740-72 been referred to as alveoloalgia, alveolitis sicca dolorosa, avascular socket, localized osteitis, fibrinolytic alveolitis and localiæd acute alveolar osteomyelitis (Shafer, et al., A Textbook of Oral Patholo~y. 4th Ed., W.B. S~llndPrs Co., Philadelphia, 1974, p. 605, 1974; and Birn, Int. J. Oral Surg., ~, 211, 1973). Although many chelllolllel~ellLic prevention Illeasul~s or management have been pursued, none have s;g,,iri~ y reduced the in~i~enre of dry socket (Birn, 1973, cited above;
Field, et. al., 1985, cited above). Arnong such approaches to the therapeutic treatment of dry socket, with limited success, are those based on systemic administration of antibiotics (Wes~rhc)lm, 1988, cited above) or direct pl~rem~nt of powdered sulf~ 7in~ or sl~lf~thi~701e into the socket (Elwell, J. Amer. Dent. Assoc., 31, 615, 1944).
To date, the known HHDS and thermoreversible gels can be classified as non-absorbable materials and are expected not to absorb through chain dissociation in the biological environment.
Meanwhile, there is a growing interést in developing absorbable sutures and allied surgical devices such as transient implants, which are degraded to bioabsoll,able, safe by-products and leave no residual mass at the surgical site, as well as frequently cited clinical advantages (Shalaby, Chap. 3 in High Technology Fibers (M. Lewin & J. Preston, eds.), Dekker, New York, 1985; Shalaby, 1988, cited elsewhere herein; Shalaby, Polym. News. L~, 238, 1991; Shalaby. J. Appl.
Biomater., 3, 73, 1992; Shalaby, Biomedical Polymers: Designed to Degrade Systems, Hanser Publ., New York, 1994; and Shalaby, et al, eds. Polymers of Biological & Biomedical Si~nifir~nre, Vol. 520, ACS-Symp. Ser., Amer. Chem. Soc., Washington, 1993) have justified the need for novel absorbable hydrogel formulations.
Moreover, such systems as those previously described in the literature, for example, such as by Dunn, et al, (U.S. Pat. No. 4,938,763), teach in-situ formations of biodegradable, microporous, solid implants in a living body through coagulation of a solution of a polymer in an organic solvent such as N-methyl-2-pyrrolidine. However, the use of solvents, including those of low rnolecular organic ones, facilitates migration of the solution from the application site thereby causing damage to living tissue including cell dehydration and necrosis. Loss of the solvent mass can lead to shrinkage of the coagulum and separation from surrounding tissue.
..
Furthermore, currently available drug delivery systems deal with solid implants which can elicit mechanical incompatibility and, hence, patient discomfort. The present invention provides novel, hydrogel-forming copolymers, which in contrast to those systems previously described, are absorbable, do not require the use of solvents, and are compliant, swollen, mechanically compatible gels, which adhere to surrounding tissue.
The present invention provides a hydrogel-forming, self-solvating, absorbable polyester copolymer capable of selective, segmental association into a compliant hydrogel mass on contact with an aqueous environment. The copolymer can optionally comprise a biologically active agent or a low molecular weight component.
The present invention is able to provide such a copolymer capable of the controlled-release of a biologically active agent/drug for modulating cellular events, such as, wound healing and tissue regeneration. Further, the copolymers described herein are capable of the controlled-release of a biologically active agent/drug for therapeutic treatment of diseases, such as, infection of the oral cavity, dry socket, bone, skin, vaginal and nail infections.
Preferred embodiments of copolymers made according to the invention are capable of being extruded or injected into living tissue, or onto the surface thereof, for providing a protective barrier for treating conditions, such as, post-surgical adhesion. Also preferred copolymers described herein can be used for constituting or constructing a carrier of vaccines, living cells, or viable tissue for sust~;ning biological functions both in vitro and in vivo.
Preferred versions of copolymers described herein are capable of acting as a blocking agent or sealant for treating defects in conduits.
2~ ~0i~2 Accordingly, the present invention provides hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, se~mP-nt~l ~ccoci~tion into a compliant hydrogel mass on contact with an aqueous en~ ol""e"l. In a pier~"ed e--~l)o~ of the invention, the copolymer colll~lises a base colll~ol~e~ si~ Cullll)o~ A" herein. As used herein, the terms "Component A" and Ucopolymer(s)" are "IL~ ge~le and refer to the basic ~ clul~ of the copolymers of the invention. Co",pol~"L A ~o".~ es a molecular chain having a hydrophilic block, ~ n~tPd "yn herein, and a relatively hydlophobic polyester block, d~sign~tPd "X" herein.
Hydrophobic block X and hydrophilic block Y more pl~r~l~bly comprise a molecular SlluGlult~
having the following formula: X-Y-X or (X-Y)n, and branched ~LI~lclulcs thereof. Most preferably, hydrophobic block X collly~ es a polyester forrned by grafting a glycolide, lactide, ~-caprolactone, p-dioxanone, trimethylene carbonate or combina'tions thereof, onto the hydroxylic or amino groups of a hydrophilic polyrner precursor i.e., Y; hydrophilic block Y con~ es a polyoxyethylene, poly(oxyethylene-b-oxypropylene), polypeptide polyalkylene o,~a,-,~, a polysaccharide, and derivatives thereof; or a liquid, high molecul~r weight polyether glycol interlinked with an oxalate or ~uccinale functionalities in linear or branched form.
Component A optionally co"l~,i;,es carboxylic end-groups formed by any known technique in the art, such as, for example, end-group succinylation. This facilitates ionically binding a biologically active agent or drug to Co~nl ollelll A, such that, drug release can be modulated. The biologically active agent or drug is preferably present on Co~pollent A in an insoluble form, such as, (1) a mic,opa"iculate dispersion, (2) a surface-deposited coating onto an absorbable microporous microparticles, and/or (3) ionically bound molecules onto the surfaces of absorbable microporous mic,~licles.
In another embodiment of the invention, Component A optionally comprises an absorbable carrier associated therewith and, designated "Component B" herein. As used herein, the term aassociated therewith" refers to any chemical and/or physical means known in the art for combining components together. The function of Component B is to carry the biologically active agent. This is preferably desirable for medications which call for an initial drug burst and prolonged release thereafter and, thus, highly regulated availability of drugs at the biological site.
2 1 74 U~
In a further embodiment of the invention, Compol1enl A, with or without component B
and/or the biologically active agent, optionally colnpllses a similarly con.~Lil~ d low molecular weight block copolyester ~sor~ d therewith. The low lc'~ r weight coplyester p~ bly is a plasticizer and, more plt;r~,~ly, the pl~ Pr is df~ nA~d "Colllpollel~ C" herein.
It is u. l.l~ ~ûd that ColllL~ol~elll A, with or without the biologically active agent/drug and/or c~ oSi~ionS of Cc~ ollell~ A, B, C, the biologically active agent, and variations thereof, can provide a wide range of plu~el~ics for treating a host of ~ e~cPs, including, but not limited to, dental, orthopeAi~ and vascular applications. For example, the copolymers of the invention can:
(1) be extruded or injected into living tissue or onto the surface of living tissues to provide a protective barrier to prevent post-surgical adhesion; (2) act as a blocking agent or sealant for treatment of defect in conduits such as blood vessels; (3) facilitate the controlled-release of a biologically active agent/drug for modlll~tin~ cellular events such as wound healing and tissue regeneration or theldp~u~ic Ll~a~lllent of diseases such as infection of the periodontium, dry socket, bone, skin, vaginal, and nail i~ ions; and (4) f~.ilit~tP, the sll~t~inP,d in vinO or in vivo growth of viable cells and/or llving tissues for the purpose of tissue en~in~p-ring.
The term Hydrophobic Block(s)" as used herein, refers to absorbable polyester chain block(s) or segment(s) of variable length which is present in an isolated form, will produce practically amorphous (with less than 5 % crystallinity) or totally amorphous material having a Tg of less than 25C, and preferably, is a viscous liquid at room tell~peia~lre. Hydrophobic block(s) X
comprises copolymeric segments of known chemistries in the art, such as, those comprised from cyclic lactones (e.g., glycolide, I-lactide, dl-lactide, ~-caprolactone, p dioxanone, trimethylene carbonate), polyalkylene oxalate, and the like, as described by Shalaby, 1988, cited elsewhere herein. More ~l~r~ y~ l-ydlvl-hnbic __ L(s) or blDck(s) X
lactide/glycolid~ copolymer (with 51 to 80% 1- or dl-lactide).
The term "Hydrophilic Block(s)" as used herein, refers to polymeric blocks or segments which, if present in an isolated form, will be water soluble. Hydrophilic block(s) or segment(s) Y
co~ i.es poly(oxyethylene), with or without a minor component of a higher homolog, such as, poly(oxypropylene)--polypeptide, polyalkylene oxamate (Shalaby et al., 1980, cited elsewhere herein), a poly~ , or derivaties U ~.~L. The length of the lly.l.~)hil;~ block and its weight fractions can be varied to nLdulate the rate of gel rc"ll~ion, its mod~ c~ its water content, diffusivity of bioactive drug through it, its adhesiveness to surrounding tissue, and bioal)s~ll,ability.
The term UHydrogel'' or Hydrogel Mass" as used herein, refers to materials which have a high tendency for water absorption and/or retention, and m~int~in m~rh~ni~l integrity through physical crosslin'ks which are reversible in nature.
The term Physical Crosslinks as used herein, refers to a three~lim~ncion~ c~ule which is held together by physical quasi or pseudo crosslinks, or ionic bonds, as colllpa~ed to covalently crocclin~d. These physical crosslinks facilitate the reversibility of the hydrogel. This reversibility property can be influenced by external factors, such as, solvent or heat.
The term Self-Solvating" as used herein, refers to components of chains which in the absence of external factors i.e., solvents, have greater affinity for physical interaction such that the components are capable of forming a virtually one phase system.
The term Compliant" as used herein, refers to a material having a low modulus and which is easily deformable.
The term "Biologically Active Agent" as used herein broadly includes any composition or compound of matter which when dispensed in the chosen environment of use produces a predetermined, beneficial and useful result.
The term Drug" or Agent" as used herein broadly includes physiologically or pharmacologically active subst~n~s for producing a localiæd effect at the administration site or a systemic effect at a site remote from the ~llmini~tration site.
The term "Plasticizer" as used herein, refers to an absorbable polyester composition with hydrophilic and hydrophobic components similar, or identical to, those of Component A, with the exception of having a higher hydrophilic/hydrophobic ratio in Component C than Component A.
21 7~072 The present invention ~liccl-)ses novel hydrogel-forming, self-solvating, absorbable polyester copolymers, which upon hydration results in a hydrogel mass. The hydrogel mass is stabilized by pseudo-crosslinks provided by a hydrophobic polyester cû.l.ponenL, such as those co.~ ed from cyclic lactones e.g., glycolide, I-lactide, dl-lactide, ~-caprolactone, p dioxanone, l~ hylene c~bo~ , polyalkylene oxalate, derivatives thereof and the like, covalently linked to a hydrophilic co~ onelll co~ ed of blocks, such as those derived from a polyethylene glycol, polypeptide, polyalkylene oY~m~tP (U.S. Pat. Nos. 4,209,607 and 4,æ6,243, to Shalaby et al.
or poly~ and derivaties U~ L. me polyester copolynErs with or without modifying additives, undergo hydration in the biologic environment leading to selective segmental associalioll thereby forming compliant hydrogels at the application site.
These copolymers are ~speci~lly useful for localized, controlled delivery of biologically active agents/drugs and prola~ling or aug~llellli-lg damaged, colllplolllised, and/or tr~llm~ti7P,d tissues. More particularly applications of the novel copolymers of the invention include: (a) the en~ of periodontal disease, wherein a tetracycline- or chlorhexidine-containing hydrogel-former is injected in the periodontal pocket to form an adhesive gel or semi-solid mass in the pocket for the controlled release of such antimicrobial drugs over a period of 2 to 45 days. Near the practical exhaustion of the drug, the polymer will comm~nre to absorb ~b~ lly as it undergoes advanced stages of degradation; ~b) the prevention and Ll~.lenl of dry socket with formulations similar to those of Component A; (c) providing a hydrogel barrier with or without non-steroidal anti-infl~mm~tory drugs on ~ rd tissue to prevent post-surgical adhesion; (d) applications as an antimicrobial hydrogel for the treatment of vaginal infections; (e) treatment of bone diseases such as osteomyelitis, with injectable formulations colllplisillg antibiotics including gentamicin and vancomycin; (f) accelerating tissue regenerating in ~IIlL)lulllised soft and hard tissue, e.g., fractured bone, ulcers, burns, by employing formulations comprising growth promoters, such as growth factors or their oligomeric analogs; and, (g) treatment of diseases such as psoriasis and infected nails using formulations comprising antimicrobial agents. Other applications of the hydrogel-forming copolymers of the invention include (a) blood vessel sealant; (b) vascular 2 1 7407~
..
blocking agent; (c) carrier for injectable anti~ y formulations in the treatrnent of joint ~i~e,.ces; and (d) active carrier of viable cells or living tissue.
The copolymers of the invention CO~ G a primary or base cc .-.~nenl ~ sign, t~d "Co---pone--L A" herein. Co~ o~ A colnl.l.sGs mol~c~ r chains having a hydrophilic block, ;gl~ i "Y" herein, and a relatively l~y~ hobic polyester block, clf ~;glli-lr~l "X" herein. The mOllfl~Ul~ r ~ll U~;~ulG of hydrophobic block X and hydrophilic block Y prefel~bly co-~l-ses one of the following formulas: X-Y-X or (X~Y)n~ and branched structures thereof. More preferably, hydrophobic block X COII~ GS a polyester formed by grafting a glycolide, lactide, ~-caprolactone, p-dioxanone, trimethylene ~I~OI~IG or combinations thereof, onto the hydroxylic or amino-end groups of a hydrophilic polymer precursor i.e., Y. Hydrophilic block Y preferably Colllpli~Gs a polyoxyethylene, poly(oxyethylene-b-oxypropylene), polypeptide, polyalkylene oxamate, a polysaccharide, or derivatives thereof, or a liquid, high molecular weight polyether glycol interlinked with oxalate or ~UCCil)~G functionalities in linear or branched form.
In a plerellGd embodiment, Co---pollelll A co-ll~ es a polyethylene glycol having a molecular weight of about 400 Daltons which is pre-interlinked with succi.~e or oxalate bridges to increase the length of the hydrophilic block and, thus, th'e moleclll~r weight of A without favoring its cryst, 11i7~tion. That is, the hydrophilic prepolymer "Y" having hydroxylic end-groups, is end-grafted with a mixture 60/40 dl-lactide/glycolide to produce a block copolymer having a hydrophilic block fraction "Y" of about 0.25. To render Component A more receptive to basic drugs, its end-groups can optionally be carboxylated, for instance, by their acylation with succinic anhydride. Component A, with or without a biologically active agent, is introduced to a biological target site using conventional means and, thereafter, undergoes selective-segmental segregation to form a flexible, compliant, reversible gel which adheres to the surrounding tissues and acquires the configuration of the site. Component A of the invention more preferably comprises an inherent viscosity at 25C in chloroform ranging between 0.03 to 0.80 dL/g and can be present as a liquid at room temperature, or practically amorphous material (with .
lecs than 5 % crystallinity) with a Tg of less than 25C, which can be extruded through a die or -lminictered through a syringe needle.
Col,~onelll A coll~ P~ copolymeric chains with self-solvating comL,onellL~, (analogous to phase mixing of two cullll~onellL miccibl~ blends) to allow its e~ ,Lence as a viscous, extrudable material at room l~ 7 and its ~l~L-,r,l IIIA~;Ol1 to a flexible reversible hydrogel upon lministr~tion to a biological site. These hydrogels adhere tenaciously to adjacent tissues and acquire the shape of the site. The present copolymers are mt~r.h~nin~lly colllL)~Iible in highly sensitive sites and can mediate external l~rl~Anical stresses or shockc. As such, the copolymers of the invention can be applied easily without incorporating a major extrincic water-soluble, potentially cytotoxic organic solvent in order to facilitate upon ~minictration in-situ coagulation to a solid mass.
Component A, with or without a non-steroidal anti-infl~ll III~A10l y drug (NSAID) or active polypeptide, can be used as a protective barrier, a blocking agent of vascular defects caused by needle puncturing, a sealant of damaged surfaces for preventing post-surgical adhesion or as a carrier of imm~nl~stim~ ntc or viable cells. Component A, mixed with an antimicrobial agent/drug, can be injected or applied topically with a suitable known applicator for the treatment of bone, cartilage, nail, skin, and vaginal infectionc.
In another embodiment of the invention, Compollell~ A optionally includes a biologically active agent/drug, such as, an antimicrobial agent, anesthetic agent, antibiotic, and/or a peptide or protein, for regulating cellular events. The biologically active agent/drug can comprise by way of illustration, antifungal agents, ~ntihacterial agents, antibiotics, anti-infl~mm~t~ry agents, immllnoSu~ple~sive agents, immnnostim~ tory agents, dental densi~i~els, odor masking agents, immune reagents, anesthetics, antiseptics, nutritional agents, antioxidants, lipopolysaccharide complexing agents, peroxides, tissue growth factors, a mixture of any of the foregoing, and the like. The agent/drug can be deposited, wholly or in part, on Component A, with or without carboxy-terminated ends. In an alternative embodiment, the biologically active agent/drug can be deposited, wholly or in part, on a solid carrier, designated "Component B" herein. Component B
preferably is an absorbable, powder prior to mixing with Component A and, more preferably, ....
Component B is an absorbable, mic.~olo~ls low molcc~ r weight polyester which is highly crystalline and practically insoluble in Co--~ponen~ A.
A prer~ t;d f~rm~ tion of Co-"~o,le"~ A/B co",~l~es a mixture of 20/80 B/A, with B
being a low molec~ r, micr~uluus polyglycolide with 0.70 to 0.95 solid fraction, average particle size of 0.5-200 micron and c~ul,uAyl-bearing chains. High concel,llalioll of carboxylic groups on the chains can be achieved by pl~i~lg Compon~nt B using di- or poly-carboAylic acid as iniLialol~. The deposited agent on Component B can exhibit a release profile which can be multiphasic, inrlllrling (a) simple, fast diffusion of soluble free drug through gel A; (b) slow diffusion of soluble free drug housed in the pores of B; and, (c) drug release at the surface (bod exterior and pore) of B or the chain ends of carboxylated A chains by ion exchange of ionically bound molecules. By varying the collre~ ;QIl of Component B in Component A, the flow ch~r~ lics and release profile of the agent can be modulated. This is important because in certain applications, the flow chd~ ic or properties of Component A/B formulations can determine the clinical efficacy, particularly in cases of treating periodontal disease, nail infection and bone illf~;~ion where high vi~coel~stir-ity (due to the high weight fraction of the mi~lop~i~;ulate dispersed phase and its physicom~r,h~ni~l interlocking with viscous liquid continuous pha~se A) of the gel composite is pertinent to assure merh~nir~l stability at the target site.
Component A optionally includes an absorbable low molecular weight component. This component can modulate the rheological properties, gel-formation time, and mechanical disposition of Component A at the target site. The low molecular weight component preferably is a plasticizer and, more preferably, the pla~ic~;L is designated "Component C" herein. Component C can (a) aid the dispersion of Component B in Component A; (b) reduce the overall system viscosity of Component A/B formulation, (c) reducing the viscosity and facilitating the injectability of Component B if used alone or with a biologically active compound, and/or (d) increase the rate of hydration or gel formation. The absorbable pla~ici~er, such as Component C, is capable of modulating the viscosity and/or gel-formation rate of Component A, with or without Component B, thereby broadening its applicability. Highly viscous forms of Component A can be easily plasticized with a low mnlecul~r weight (inherent viscosity of 0.03 - 0.15) polye ter copolymer Component C, that is made of the same ch~mi~l entities as Component A, (but dirrelen hydrophilic weight fraction) to produce easily i~jPct~l lP- liquid systems.
In a more preferred embodiment, Coll,pol~elll A is formed by end-grafting a polyethylene glycol having a m~ r weight of about 400-900 Dalton with a mixture of glycolide and l- or dl-lactide in the pl~sence of sku~ octoate as a catalyst to produce a block copolymer with (a) ether/ester ma s ratios of 2049/80-51, p~rel~ly 2540/75-SS and, most preferably 3040/70-60;
(b) having an inherent viscosity in chloroform.at 25C from about 0.03 to 0.80, preferably from about 0.1 to 0.6, more p-~r~ldbly from about 0.15 to O.S, and most preferably from about 0.2 to 0.4 dL/g; and (c) is in the form of an extrudable, P.c.cenfi~lly amorphous, semi-solid having a Tg of less than 25C, preferably an amorphous material having a Tg of less than 37C, and more preferably a viscous liquid at room temperature that can be easily ~mini.ctered through a syringe needle.
In a still more preferred embodiment, copolymer Component A is formed by end-grafting an oxalate- or ~uccu~t~-interlinked liquid polyethylene glycol having a molecular weight of more than 1200 Dalton with a mixture of glycolide and l- or d¦-lactide in the presence of stannous octoate as a catalyst to produce a block copolymer with (a) ether/ester mass ratio of 2~49/80-51 and preferably 25-40/75-SS but most preferably 30-40/70-60; (bj having an inherent viscosity in chloroform at 25C of about 0.03 to 0.80, p.~re.dbly 0.1 to 0.60, more preferably, 0.15 to 0.50, and most preferably, 0.2 to 0.4 dL/g; and (c) in the form of extrudable, essentially amorphous semi-solid having a Tg of less than 25C and preferably an amorphous material having a Tg of less than 25C and, more preferably, a viscous liquid at room temperature that can be easily administered through a syringe needle.
Formulations comprised of the polyester c~nnlvmers of the invention are suitable carriers of biologically active agents/drugs at typical loading of 0.001% to 30%. The chain of C~ .,L
A or Component C can be succinylated to provide acidic end-groups for ionic binding of the agents/drugs. Liquid compositions made of Component A or Components A/C, with or without agent/drug, can form hydrogels upon contactillg a liquid environment. This is achieved through the hydration of the hydrophilic block of the copolymeric chains leading to intramolecular conrc,~ lio~al changes and ~oci~lion of the hydrophobic blocks as pseudo-crosslinks in a reversible, hydrophilic/ hydrophobic hydrogel system.
For copolymer form~ tions colll~"i,illg the agent, such morphology provides a suitable en~d,~ llell~ for the controlled release of the agent. The agent can be present in a soluble or dispersed form. Preferably, the agent is de~o.,i~d on a micronized powder, more L"~r~,~ably a microporous abso,l,able powder and, most preferably, a powder (Component B) which offers an ion-binding, high surface area for ionically immobilizing part of the soluble agent to control its release and, thus, produce copolymers with a multiphasic release profile over a period of 1 to 90 days.
More specifically, the biologically active agents can be present as (a) a solute in Component A; (b) a dispersed solid in Component A; (c) a coating on Component B; (d) ionically bound molecules on Components A and/or B; and/or (e) m~ nically held within the pores of Component B. Each of these forms of drug will have its own release pathway and, thus, bio-availability at the site. D~en~ g on the concell~a~ion of Component B, the hydrogel-forming formulation can be made to have a broad range of plupe~lies and gel-formation kinetics to allow its use in many applications.
Component A with a biologically active agent and/or Components B and/or C, is used for treatment of periodontal disease, osteomyalitis, and dry socket. While a ~liccuccion follows for using the copolymers of the invention for ~lllent of periodontal disease, it is understood that this discussion is for purposes of illustration only and, not limitation, and the copolymers of the invention have broad applications of use. Periodontal disease, as used herein, is a general term for a number of diseases that affect the periodontal tissue. These diseases are characterized by a range of symptoms including infl~mm~fion, bleeding, exudation of pus from the gingival sulcus, deepening of the sulcus to form periodontal pockets, tissue lesions, loss of connective tissue, alveolar bone loss, and ultimately tooth loosening and loss. The primary cause of periodontal disease is now believed to be bacterial infection of the plaque that forms on tooth surfaces below the gingival margin. The copolymer formulations of the present invention are useful for prolonged, 2~ 74~7~
controlled ~lis~ensil~g of a range of drugs and agents, such as, for exarnple: (a) prophylactic prolonged application of minerals and ions, such as calcium or fluoride ion; (b) prolonged controlled t;A~o~ure to local an~i~lics, including, chlorhexidine and ~ oniu-" iodide; (c) controlled antibiotic delivery, including such antibiotics as aminoglycosides, macrolides such as y~ro~lycin, penicillins, cephalosporins and the like; (d) ~n~sth~tic/analgesic delivery pre- or post surgery or to treat other mouth pain using such agents as amide-type local ~npsth~tir-s like li(lor~in~, mepivacaine, pyrrocaine, bupivacaine, prilocaine, etidoc~in~, or the like; and (e) local controlled delivery of non-steriodal anti-infl~mm~tory drugs such as ketorolac, naproxen, diclofenac sodium and fluribiprofen. It is recognized that in certain forms of therapy, combinations of agents/drugs in the same delivery system i.e., copolymer of the invention, can be useful in order to obtain an optimal effect. Thus, for example, an ~ntibartPrial and an ~ntiinfl~mm~tory agent may be combined in a single copolymer to provide combined effectiveness.
It has also been recently shown that regrowth and repair of periodontal connective tissue can be encouraged with the aid of polypeptide mitogenic growth factors. See, for exarnple, V.P.
Terranova et al., BiochPmir~lly Medicated Periodontal Regeneration, J. Periodont. Res., 22, pages 248-251. The c~po1yn~s of the pr~sent inv~tion can be esi~n~d to release a~pru~lia~e encapsulated, or uncapsulated, growth factors, including, epidermal growth factors, human platelet derived TGF-B, endothelial cell growth factors, thymocyte-activating factors, platelet derived growth factors, fibroblast growth factor, fibronectin or laminin.
The drug/agent can be used at a level of from about 0.1% to about 70 %, preferably fmn about 1% to about 50 %, most preferably f}~n about 2 % to about 30 % . The copolymers of the invention can be designed to release drug to provide a steady state number average concentrations of from about 1 llg to about 2000 llg, preferably f~m about 20 llg to about 1200 llg, most preferably from about 50 ~g to about 800 ~lg per milliliter of the gingival crevicular fluid of a treated periodontal pocket. The steady state release rates can be altered by varying component ratios of the copolymer formulations. The steady state conditions are preferably used since initial bursts are accounted for as well as delays in release For example, in the case of a ten (lO) day therapy, steady state is generally reached in about one to two days More preferably, a forlnulatio for treating periodontal disease comprises 20/80 Co~ B/A, c~nt~inin~ 1-3 % of an active drug such as chlorh~Yi~in~ or tetracycline.
In addition to the agent/drug, the copolymer formulations of the present invention can include a variety of optional co---~olle-l~. Such co,l-~ol~el-~ include, but are not limited to, surfactants, viscosity controlling agents, m~li~in~l agents, cell growth mod~ tnrs, dyes, complexing agents, ~ntin~ ntc, other polymers such as carboxymethly cellulose, gums such as guar gum, waxes/oils such as castor oil, glycerol, dibutyl phthalate and di(2-ethylhexyl) phthalate as well as many others. If used, such optior~ L~ I , ~e fron about 0.1% to about 20 %, preferably from about 0.5 % to about 5 % of the total copolymer formulation The copolymers of the invention can be inserted into the periodontal pocket or gingival region, and can be ~1minictered in the form of a particle, film or sheet. The size, shape and thi~kn~o55 can be changed according to the condition of the disease to be treated. Ordinarily, the size, shape and thirkn~ss are changed according to the size of the periodontal pocket of the patient or the condition of the gingiva.
In another embodiment of the invention, there is contemplated phal"l~re~ l r~l",.,~ ol.c ~ _ F~. arl injectable visoous fluid of C _ L A, C~ _ Ls A/B, C _ L~A/B/C ~n~/or ~( _ Ls A/C, aontA;ning about 0.001% to 30% agents/drugs and, mDre ~ r~ y about 0.1% to 10% of agents/drugs. The rp~ e of the agent/drug is over a period of 1 to 90 days and, more ~l~r~ ~ ly 2 to 45 d~ys. m e drugs/agents can ;nnll~P one or I n~tions of the foll~ . ng: aul ~rbk;Al agents (e.g. nhl.. ~ ;nP, L~Llauy~line and/or duAy~y~line), ant;ho~;P-s (e.g., i n;n, v ,uin, and/or l~ in), antivn~xLL agents (e.g., acyclovir, 3TC tT vu~ine] and/or inl~r~N~)~ v~nr;np~ (e.g. ricin toxoid and deglyoosylated A-chain ricin D), anti-epileptic and anti-oonvulsant drugs (e.g.,_ nP and di~k~ly~-ydkulLuin), a~ uæLic agents (e.g., Le~ ~;n ~uL~ILal~i1, L~lLallyl, and l;~nr~;nP), and ~ _ ' which can A~cPlPrAte wound hPAl;ng An~ tissue ~J~ Lion, L~v~L post-surgical A~hP~;nn, n~nrlA~tic formation, and ~v~lL or A~pl~r~te blood clotting.
In another embodiment of the phal ~ formulation, the eopolymer ~ol-lpl ises part or all of the bioaetive agent deposited on a microporous and/or finely divided absorbable powder, sueh as, those eonsisting of low molecular weight erystalline polyglyeolide or copolyglyeolide. The powder is formed by low to moderate conversion (that is 60-95 %) ring-opening polymerization of glycolide or a mixture made predomillantly of glycolide and small amounts of other lactones. Tlle 2 1 7~072 .
pol~ 7.~tion is ~rr;~ out in the presenoe of ~ octoate as a catalyst and ~lff;~;~nt con~lL dLion of glycolic acid as an initiator to prcduoe a mass. Upon ~l~nrh;n~, ~rin~in~, r~ll llin~ (or jet llin~) in an inert medium, and ~xL,d~Lion with water, 2-~1u~Yulol, mi~ u~s particles are produced having (a) 1 to 200,u ~ and, more preferably 10-150,u; (b) an inherent viscosity in hexafluoro-2-propanol at 25C of ~0.03 to 0.3 and, more preferably <0.05 to 0.2 dL/g; (c) contain less than 2% residual monomer; and (d) have 0.03 to 0.35 and, more preferably 0.05 to 0.25 pore fraction.
An important difference between conventional formulations in the art and the novel copolymers of the invention, is that the present copolymers do not include the use of organic solvents. Such solvents can compromise the copolymers shelf-stability, as in the case of a polyester in a basic solvent such as N-methyl-pyrrolidine, which can catalyze chain dissociation in the presence of traoe amounts of moisture. The prior art formulations also teach the use of other reactive solvents such as propylene glycol (which degrades the polyester chain through alcoholysis), or trimethylene carbonate (which can copolymerize with the polyester chain). Moreover, should the prior art formulations be radiation sterilized, the presence of a solvent can lead to the generation of new ch~mi~l species origin~ting from the solvent as well as in combination with the bioactive ingredient. In effect, organic solvents described in the prior art can compromise the purity and efficacy of both the drug (optional) and polymer which can, in turn, be associated with unsafe use.
Another feature of the novel copolymers of the invention, is that when administered to a biological site the copolymers do not experience discernible reduction in organic mass, as is the case of prior art compositions which coagulate in-situ by le~f~.hing out a major water-soluble component. Leaching out major water-soluble components can be associated with shrinkage and separation from the surrounding tissue and, in some instances, uncontrolled formation of microporous mass. Because the copolymers of the invention are comprised of copolymeric chains, the copolymers can be easily tailored to modulate its viscosity without the intervention of a new chemical species, such as, an organic solvent.
A further feature of the novel copolymers of the invention, is that sinGe the copolymers are comprised of self-solvatillg molecules, its conversion to a llydrogel about a drug provides a uniform distribution of the therapeutic agent, and thus, more reproducible release profile, in contrast with prior art systems where complex physical events prevail due to the presence of leachable solvents.
The following Examples are provided to further illustrative the present invention, and should not be construed as limit~tion.c thereof:
EXAMPLE I
PREPARATION OF COMPONENT "A"
1. ~pa-~Lion of 79/21 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 A suitable flask was thoroughly cleaned, flame-dried, and charged dry with polyethylene glycol (MW - 400; Sg, 0.0125 mole), dl-lactide (12 g, 0.083 mole), glycolide (6.4 g, 0.056 mole), stannous octoate catalyst (0.4 M in toluene; 34.7 ~lL, 0.014 mmole), and a magnetic stirrer under nitrogen condition. The reactor was placed in an oil bath and heated to 170C under a positive nitrogen pressure for 16 hours. The flask was removed and stored open in a vacuum oven. The inherent viscosity (IV) of the composition was determined using a 50 capillary viscometer (Ostwald type) at a cûncenll~tion Qf 0.1 g/100 mL in chloroform. In a constant temperature bath set at 30C, the IV was determined to ~e 0.13 dL/g. A DuPont 990 Differential Sc~nning Calorimeter (DSC) was used to determine glass transition (Tg) of the material. Applu~ lla~ly 4 mg of the sample was heated at 10C/min from -50C in a nitrogen environment. Tg = -41C.
2. Pl~alation of 60/40 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW = 400; 4.1 g, 0.01 mole), dimethyl oxalate (3.1 g, 0.025 mole), and stannous octoate catalyst (0.4 M in toluene; 883 IlL, 0.035 mmole) were mixed in a dry glass reactor containing a magnetic stirrer and heated to 150C under a nitrogen atmosphere for 4 hours.
A vacuum of less than 0.1 mm Hg was applied to remove the condensate (methanol) and excess dimethyl oxalate. The reactor was then cooled to approximately 50C and PEG (MW = 400; 8.3 g, 0.021 mole) was added. The reactants \~ere heated to 150C for 3 hours before applyh-g 2~ 74072 ~. .
vacuum and cooling to room temperature. dl-Lactide (13.3 g, 0.093 mole), glycolide (7.2 g, 0.062 mole) were added under dry conditions to the reactor. The flask was heated to 150C under a positive nitrogen pressure for 12 hours. Next, the temperature was increased to 170C for 3.5 hours and vacuum was applied for 2 hours as the flask cooled to room L~r,~e.a~ . The polymer was isolated and stored under vacuum.
IV in CHCl3 = 0.11 dL/g 3. Preparation of 78/22 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW = 400; 2.0 g, 0.005 mole), dimethyl oxalate (1.77 g, 0.015 mole), and stannous octoate catalyst (0.2 M in toluene; 90.5 IlL, 0.036 mmole) were mixed in a dry glass reactor containing a m~gnPtic stirrer and heated to 140C under a nitrogen atmosphere for 2 hours. A vacuum of less than 0.1 rnm Hg was applied to remove the condensate (methanol) and excess dimethyl oxalate. The reactor was then cooled to approximately 50 and PEG (MW = 400;
4.2 g, 0.011 mole) was added. The e~c~ls were heated to 155C for 1 hour under slight vacuum before h~ g the ~ el~lure to 160C for 2 hours under increased vacuum. l-Lactide (14.4 g, 0.1 mole), glycolide (7.7 g, 0.066 mole) were added under dry conditions to the reactor. The flask was heated to 150C under a positive nitrogen pressure for 15 hours. Next, the temperature was lowered to 130C and vacuum was applied. The material bubbled violently, in(~ tin,~ the presence of monomer. A strong vacuum was applied as the material cooled to room temperature. The final product was washed with 2-propanol at 40C for about 20 minutes to remove the excess monomer before drying under vacuum at room ~r..pela~ lre.
The weight average molecular weight (MWW) and polydispersity-index (PDI) of the material was determined using a Waters Gel Permeation Chromatography (GPC) apparatus. The instrument consisted of a 600E control Module and Solvent Delivery System, a U6K injector, three Syragel HT linear columns in series, a 401 Differential Refractometer detector, and a 746 Data Module. Chloroform was used as the mobile phase at a flow rate of 1 mL/min. and polystyrene molecular weight standards were used to calibrate the system. MWW: 5723; PDI: 2.42 - 21 ~0~2 -4. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW--400; 15 g, 0.0375 mole), dl-lactide (21 g, 0.146 mole),glycolide (11.3 g, 0.097 mole), and s~m~ous octoate catalyst (0.2M in toluene; 243 IlL, 0.049 mmole) were added under dry conditions to a glass reactor c~nt~ining a magnetic stirrer. The reactor was placed in an oil bath and heated to 150C under a positive nitrogen pl~u~e for 1 hour, then to 160C for 6 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg and placed in a vacuum oven.
MWW: 1670; PDI: 1.46 5. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW--400; 160 g, 0.4 mole), dimethyl oxalate (47.2 g, 0.4 mole) and stannous octoate catalyst (0.2 M in toluene; 200 IlL, 0.04 mmole) were mixed under a dry nitrogen environment and heated to 150C for 1 hour. The temperature was increased to 160C for 2 hours before applying a vacuum of 1 mm Hg and allowing to cool to approximately 50C. Then, 5 g of PEG 400 were added and the reaction was continuéd at 160 for 0.5 hours. Finally, 15 g of the interlinked PEG were mixed with dl-lactide (21 g, 0.146 mole), glycolide (11.3 g, 0.097 mole), and stannous octoate catalyst (0.2 M in toluene; 243 ~L, 0.049 mmole were added under dry conditions to a glass reactor containing a magnetic stirrer. The reactor was heated to 150C
under a positive nitrogen pressure for 1 hour, then to 160C for 6 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg and stored in a vacuum oven.
MWW: 4713; PDI: 2.41 6. Preparation of 73/27 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW 400; 12.5 g), dl-lactide (22.5 g, 0.156 mole), glycolide (12.1 g, 0.101 mole), and stannous octoate catalyst (0.2 M in toluene 260 IlL, 0.052 mmole) were added to a dry glass reactor containing a magnetic stirrer. The reactor was heated to 150C under a positi~e 2 ~ 740 72 nitrogen pressure for 18 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven. MWW: 2172; PDI: 1.53 7. Plepdl~lion of 73/27 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities Interlinked PEG (12.5 g, described in Example 5), dl-lactide (æ.s g, 0.156 moie), glycolide (12.1 g, 0.104 mole), and ~ OUS octoate catalyst (0.2 M in toluene; 260 11L, 0.052 mmolej were added to a dry glass reactor containing a m~gnPtic stirrer. The reactor was heated to 150C under a positive nitrogen pressure for 18 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven.
MWW: 5723; PDI: 2.41 8. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities Interlinked PEG (15 g, described in Example 5), dl-lactide (21 g, 0.146 mole), glycolide (11.3 g, 0.097 mole2, and stannous octoate catalyst (0.2 M in toluene; 243 IlL, 0.049 mmole) were added to a dry glass reactor containing a m~gnPtit~ stirrer. The reactor was heated to 150C under a positive nitrogen pressure for 3 hours and then 160C fof 3 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven.
MWW: 3582; PCI: 2.08 EXAMPLE II
PREPARATION OF COMPONENT "B"
1. Preparation of Polyglycolide ('PG) Drug Carrier Glycolic acid (0.46 g, 0.006 mole), glycolide (34.8 g, 0.30 mole), and stannous octoate catalyst (0.4 M in toluene; 150 ~lL, 0.06 mmole) were mixed in a dry flask equipped with a magnetic stirrer under a dry nitrogen atmosphere. The reactants were slowly heated to 170C
(approx. 20 min.) under agitation. At this time, the reactants formed an opaque mixture and the temperature was increased again to 200C. When the temperature reached 176C, the material was translucent and the viscosity was very higll. The flask was then removed from heat and quencl1ecl 2 1 7407~
with liquid nitrogen for about 2 minnt~s. The glassware was broken and removed and the reactants were dropped in the liquid nitrogen to terminate the reaction completely. The resulting PG solid was dried in a vacuum oven at 35C overnight. Using a Wiley mill with a 60 mesh sieve, the PG
was ground to a fine powder. The e~ ~ped monomer was extracted using anhydrous acetone at 35C resulting in porous particles of PG.
2. Addition of Chlorhexidine Diacetate to PG Carrier Chlorhexidine (li~reptP (8.7 g) was dissolved in aL)~ro~ ately 500 mL of isopropyl alcohol in a roto-evaporator at 38C. The extracted PG powder (25.6 g) (Example II-1) was added to the solution and the mixture was agitated for 6 hours under a slight vacuum. The temperature was increased to 40C and a stronger vacuum was applied to distill 2-propanol and acetic acid. When all of the 2-propanol had displaced, the temperature was decreased to 35C and the agitation was continued for another 2 hours. The resulting white powder was scraped from the containing flask and placed in a vacuum oven at 35C overnight. The powder was then mixed with mineral oil (1:2) and treated in~ 3-roll mill for about 5 min. -The oil was removed using heptane and the dry particles were shown to have an average diameter of 16 micron.
3. Pl~d~ion of Drug Carrier B-Polyglycolide Sarne as in Example II-1, except using the following polymerization charge and scheme:
Charge: Glycolide 34.8 g (0.3 mole) Glycolic acid 2.28 g (0.03 mole) Stannous octoate 0.06 - mmole Scheme: The polymerization charge was heated to 160C and m~int~in~d at that temperature with stirring for 15 minutes when the polymer crysPlli7P,A The product was cooled, isolated, broken into small pieces, and ground using a Wiley mill.
Tlle ground polymer was mixed with about 2 parts mineral oil and roll-milled to achieve the desired particle si_e (about 5 min). The particles were isolated from the mineral oil as described in Example 10 and were shown to have an average diameter of 50 micron. The micronized polymer was then extracted with 2-propanol as described in Example II-1. Dry weight data hldicated a 7%
weight loss. Titration of the accessible carboxylic group of the particle reflects a value of 0.3 mmole/g.
4. T ~ing Carrier B with Chlorhexidine One grarn of Carrier B from Example II-3 was stirred with deionized water for 20 min., filtered, and air dried. Solid B particles were mixed with 150 mg of chlorhexidine (li~re~ in 80%
aqueous acetone at 25C for 1 hour and 40C for 1 hour, cooled and then filtered. Analysis of the filtrate (using UV spectrophotometry) in~i~t~, that 80% of the drug is retained by the carrier.
EXAMPLE m PREPARATION OF COMPONENT "C"
1. Preparation of 14/86 (by weight) of Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW = 400; 20 g, 0.05 mole), dl-lactide (2.12 g, 0.015 mole), glycolide (1.14 g, 0.010 mole), and ~,~mous octoate catalyst (0.4 M in toluene; 25 IlL, 0.05 mmole) were added under dry conditions to a glass rector containing a magnetic stirrer. The reactor was heated to 130C to melt the reactants and then increased to 170C to start the reaction.
After 5 hours, the system was cooled and stored in a vacuum oven.
MW~,: 503; PDI: 1.23 2. Preparation of 14/86 (by weight) of Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities PEG 400 was interlinked with dimethyl oxalate (as described in Example 5) prior to the addition of dl-lactide and glycolide. Interlinked PEG (85 g), dl-lactide (9.0 g, 0.0625 mole), glycolide (4.83 g, 0.0417 mole), and stannous octoate catalyst (0.2 M in toluene; 105 ~uL, 0.05 mmole) were added to a dry glass reactor and heated to 150C for 1 hours. The temperature was increased to 160C for 4 more hours before removillg the reactants from heat and applying a vacuum of less than 0.1 mm Hg as the material cooled to room temperature. ~he polymer was isolated and stored under vacuum.
EXAMPLE IV
PREPARATION OF CHLORHEXIDINE (C~) DELIVERY SYSTEM
Exarnple 1: P~ion of Drug Delivery System (1.0:0.09:0.31:0.01. A:B:C:CHX by weight) Component C (1.20 g-Example III [1]) and Component B (0.40 g--Example II[2]) were added to 4.3 g of Colllpoilelll A (Example I[1]). The materials were mixed at slightly elevated temperatures (ay~ro~ill~ly 40C) to obtain a uniform distribution. Chlorhe~itlin~ (0.04* g) wæ
added to the mixture to make a final coll~osi~ion consi~lillg of 70.5 % A, 6.5 % B, 22% C, and 1%
free drug. [* Based on the weight of ~i~r~l~le salt].
Example 2: Preparation of Drug Delivery System (1.0:0.1:0.25:0.01. A:B:C:CHX by weight) Component C (1.67 g--Example III[1]) and Component B (0.51 g^-Example II[y) wereadded to 4.77 g of Component A (Example I[3]) and mixed to obtain a uniform distribution.
Chlorhexidine (0.05 g) was mixed into the system to make up the following composition by weight:
68% A, 7% B, 24% C, and 1% freedrug.
EXAMPLE V
DRUG RELEASE FORMULATION
Samples of drug carrier (Component B) loa~led with ~h~ xi(l;nP as ~ in Example II[4] were mixed with gel-former Component A from Examples I [4] and [5]. Another set of formulations were made of drug-bearing B, gel-former A, and plasticizer C (Example III[1]).
All formulations were roll-milled for 1 to 3 minutes, transferred to a syringe, and into a 21 gauge needle. The formulations were then injected into water for subjective comparative assessment of their rate of gel formation texture and m~ch~nir~l integrity. A rating of 1 to 5 was adapted for this evaluation with 1 being the fastest. A summary of these-formulation compositions and ratings is provided in Table 1.
2 1 7~0 72 Table 1. Co~ osilion and Gel-Formation of Drug Delivery Formulations Source of A Source of B Source of C Gel-Formation D Number Ex. 4. % Ex. 5. % Ex. 12. % Ex. 13. % Rating EXAMPLE VI: Preparation of Interferon/Acyclovir Delivery System General Procedure Liquid polymers X, Y and Z were mixed at a ratio of 61,9~X, l9.1~Y, and l9.0~Z. The composition of these polymers were as follows: Polyethylene glycol 400-60/40 dl-lactide-glycolide segments ~weight ratio).
X Y Z
Step 1: Liquid polymer of the above composition was mechanically mixed with interferon to produce a composition that contains 50,000 U/ml liquid polymer.
Step 2: The mixture of Step 1 (5.6g) was loaded with (1.4g)B
(a polyglycolide that is acid terminated) previously treated with an alcohol/water solution comprising 668.3 mg of acyclovir sodium and then dried under vacuum.
2~ 7407~
. ,.
Step 3: The procedure of Step 2 was repeated with 77.6 mg acyclovir sodium.
Compositions of Steps 1, 2 and 3 are use for the controlled release of acyclovir and/or interferon over a period of 1 to 3 weeks.
It is understood that the Examples described herein are for purposes of illustration only and, not limitation, and that various modifications and/or changes that may suggest themselves to one skilled in the art are intended to be included within the spirit of this application and the scope of the appended claims.
The weight average molecular weight (MWW) and polydispersity-index (PDI) of the material was determined using a Waters Gel Permeation Chromatography (GPC) apparatus. The instrument consisted of a 600E control Module and Solvent Delivery System, a U6K injector, three Syragel HT linear columns in series, a 401 Differential Refractometer detector, and a 746 Data Module. Chloroform was used as the mobile phase at a flow rate of 1 mL/min. and polystyrene molecular weight standards were used to calibrate the system. MWW: 5723; PDI: 2.42 - 21 ~0~2 -4. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW--400; 15 g, 0.0375 mole), dl-lactide (21 g, 0.146 mole),glycolide (11.3 g, 0.097 mole), and s~m~ous octoate catalyst (0.2M in toluene; 243 IlL, 0.049 mmole) were added under dry conditions to a glass reactor c~nt~ining a magnetic stirrer. The reactor was placed in an oil bath and heated to 150C under a positive nitrogen pl~u~e for 1 hour, then to 160C for 6 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg and placed in a vacuum oven.
MWW: 1670; PDI: 1.46 5. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionality Polyethylene glycol (MW--400; 160 g, 0.4 mole), dimethyl oxalate (47.2 g, 0.4 mole) and stannous octoate catalyst (0.2 M in toluene; 200 IlL, 0.04 mmole) were mixed under a dry nitrogen environment and heated to 150C for 1 hour. The temperature was increased to 160C for 2 hours before applying a vacuum of 1 mm Hg and allowing to cool to approximately 50C. Then, 5 g of PEG 400 were added and the reaction was continuéd at 160 for 0.5 hours. Finally, 15 g of the interlinked PEG were mixed with dl-lactide (21 g, 0.146 mole), glycolide (11.3 g, 0.097 mole), and stannous octoate catalyst (0.2 M in toluene; 243 ~L, 0.049 mmole were added under dry conditions to a glass reactor containing a magnetic stirrer. The reactor was heated to 150C
under a positive nitrogen pressure for 1 hour, then to 160C for 6 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg and stored in a vacuum oven.
MWW: 4713; PDI: 2.41 6. Preparation of 73/27 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW 400; 12.5 g), dl-lactide (22.5 g, 0.156 mole), glycolide (12.1 g, 0.101 mole), and stannous octoate catalyst (0.2 M in toluene 260 IlL, 0.052 mmole) were added to a dry glass reactor containing a magnetic stirrer. The reactor was heated to 150C under a positi~e 2 ~ 740 72 nitrogen pressure for 18 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven. MWW: 2172; PDI: 1.53 7. Plepdl~lion of 73/27 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities Interlinked PEG (12.5 g, described in Example 5), dl-lactide (æ.s g, 0.156 moie), glycolide (12.1 g, 0.104 mole), and ~ OUS octoate catalyst (0.2 M in toluene; 260 11L, 0.052 mmolej were added to a dry glass reactor containing a m~gnPtic stirrer. The reactor was heated to 150C under a positive nitrogen pressure for 18 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven.
MWW: 5723; PDI: 2.41 8. Preparation of 68/32 (by weight) Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities Interlinked PEG (15 g, described in Example 5), dl-lactide (21 g, 0.146 mole), glycolide (11.3 g, 0.097 mole2, and stannous octoate catalyst (0.2 M in toluene; 243 IlL, 0.049 mmole) were added to a dry glass reactor containing a m~gnPtit~ stirrer. The reactor was heated to 150C under a positive nitrogen pressure for 3 hours and then 160C fof 3 hours. The flask was cooled under a vacuum of less than 0.1 mm Hg for 0.5 hours and stored in a vacuum oven.
MWW: 3582; PCI: 2.08 EXAMPLE II
PREPARATION OF COMPONENT "B"
1. Preparation of Polyglycolide ('PG) Drug Carrier Glycolic acid (0.46 g, 0.006 mole), glycolide (34.8 g, 0.30 mole), and stannous octoate catalyst (0.4 M in toluene; 150 ~lL, 0.06 mmole) were mixed in a dry flask equipped with a magnetic stirrer under a dry nitrogen atmosphere. The reactants were slowly heated to 170C
(approx. 20 min.) under agitation. At this time, the reactants formed an opaque mixture and the temperature was increased again to 200C. When the temperature reached 176C, the material was translucent and the viscosity was very higll. The flask was then removed from heat and quencl1ecl 2 1 7407~
with liquid nitrogen for about 2 minnt~s. The glassware was broken and removed and the reactants were dropped in the liquid nitrogen to terminate the reaction completely. The resulting PG solid was dried in a vacuum oven at 35C overnight. Using a Wiley mill with a 60 mesh sieve, the PG
was ground to a fine powder. The e~ ~ped monomer was extracted using anhydrous acetone at 35C resulting in porous particles of PG.
2. Addition of Chlorhexidine Diacetate to PG Carrier Chlorhexidine (li~reptP (8.7 g) was dissolved in aL)~ro~ ately 500 mL of isopropyl alcohol in a roto-evaporator at 38C. The extracted PG powder (25.6 g) (Example II-1) was added to the solution and the mixture was agitated for 6 hours under a slight vacuum. The temperature was increased to 40C and a stronger vacuum was applied to distill 2-propanol and acetic acid. When all of the 2-propanol had displaced, the temperature was decreased to 35C and the agitation was continued for another 2 hours. The resulting white powder was scraped from the containing flask and placed in a vacuum oven at 35C overnight. The powder was then mixed with mineral oil (1:2) and treated in~ 3-roll mill for about 5 min. -The oil was removed using heptane and the dry particles were shown to have an average diameter of 16 micron.
3. Pl~d~ion of Drug Carrier B-Polyglycolide Sarne as in Example II-1, except using the following polymerization charge and scheme:
Charge: Glycolide 34.8 g (0.3 mole) Glycolic acid 2.28 g (0.03 mole) Stannous octoate 0.06 - mmole Scheme: The polymerization charge was heated to 160C and m~int~in~d at that temperature with stirring for 15 minutes when the polymer crysPlli7P,A The product was cooled, isolated, broken into small pieces, and ground using a Wiley mill.
Tlle ground polymer was mixed with about 2 parts mineral oil and roll-milled to achieve the desired particle si_e (about 5 min). The particles were isolated from the mineral oil as described in Example 10 and were shown to have an average diameter of 50 micron. The micronized polymer was then extracted with 2-propanol as described in Example II-1. Dry weight data hldicated a 7%
weight loss. Titration of the accessible carboxylic group of the particle reflects a value of 0.3 mmole/g.
4. T ~ing Carrier B with Chlorhexidine One grarn of Carrier B from Example II-3 was stirred with deionized water for 20 min., filtered, and air dried. Solid B particles were mixed with 150 mg of chlorhexidine (li~re~ in 80%
aqueous acetone at 25C for 1 hour and 40C for 1 hour, cooled and then filtered. Analysis of the filtrate (using UV spectrophotometry) in~i~t~, that 80% of the drug is retained by the carrier.
EXAMPLE m PREPARATION OF COMPONENT "C"
1. Preparation of 14/86 (by weight) of Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Polyethylene glycol (MW = 400; 20 g, 0.05 mole), dl-lactide (2.12 g, 0.015 mole), glycolide (1.14 g, 0.010 mole), and ~,~mous octoate catalyst (0.4 M in toluene; 25 IlL, 0.05 mmole) were added under dry conditions to a glass rector containing a magnetic stirrer. The reactor was heated to 130C to melt the reactants and then increased to 170C to start the reaction.
After 5 hours, the system was cooled and stored in a vacuum oven.
MW~,: 503; PDI: 1.23 2. Preparation of 14/86 (by weight) of Block Copolymer of 60/40 dl-Lactide/Glycolide and Polyethylene Glycol 400 Interlinked with Oxalate Functionalities PEG 400 was interlinked with dimethyl oxalate (as described in Example 5) prior to the addition of dl-lactide and glycolide. Interlinked PEG (85 g), dl-lactide (9.0 g, 0.0625 mole), glycolide (4.83 g, 0.0417 mole), and stannous octoate catalyst (0.2 M in toluene; 105 ~uL, 0.05 mmole) were added to a dry glass reactor and heated to 150C for 1 hours. The temperature was increased to 160C for 4 more hours before removillg the reactants from heat and applying a vacuum of less than 0.1 mm Hg as the material cooled to room temperature. ~he polymer was isolated and stored under vacuum.
EXAMPLE IV
PREPARATION OF CHLORHEXIDINE (C~) DELIVERY SYSTEM
Exarnple 1: P~ion of Drug Delivery System (1.0:0.09:0.31:0.01. A:B:C:CHX by weight) Component C (1.20 g-Example III [1]) and Component B (0.40 g--Example II[2]) were added to 4.3 g of Colllpoilelll A (Example I[1]). The materials were mixed at slightly elevated temperatures (ay~ro~ill~ly 40C) to obtain a uniform distribution. Chlorhe~itlin~ (0.04* g) wæ
added to the mixture to make a final coll~osi~ion consi~lillg of 70.5 % A, 6.5 % B, 22% C, and 1%
free drug. [* Based on the weight of ~i~r~l~le salt].
Example 2: Preparation of Drug Delivery System (1.0:0.1:0.25:0.01. A:B:C:CHX by weight) Component C (1.67 g--Example III[1]) and Component B (0.51 g^-Example II[y) wereadded to 4.77 g of Component A (Example I[3]) and mixed to obtain a uniform distribution.
Chlorhexidine (0.05 g) was mixed into the system to make up the following composition by weight:
68% A, 7% B, 24% C, and 1% freedrug.
EXAMPLE V
DRUG RELEASE FORMULATION
Samples of drug carrier (Component B) loa~led with ~h~ xi(l;nP as ~ in Example II[4] were mixed with gel-former Component A from Examples I [4] and [5]. Another set of formulations were made of drug-bearing B, gel-former A, and plasticizer C (Example III[1]).
All formulations were roll-milled for 1 to 3 minutes, transferred to a syringe, and into a 21 gauge needle. The formulations were then injected into water for subjective comparative assessment of their rate of gel formation texture and m~ch~nir~l integrity. A rating of 1 to 5 was adapted for this evaluation with 1 being the fastest. A summary of these-formulation compositions and ratings is provided in Table 1.
2 1 7~0 72 Table 1. Co~ osilion and Gel-Formation of Drug Delivery Formulations Source of A Source of B Source of C Gel-Formation D Number Ex. 4. % Ex. 5. % Ex. 12. % Ex. 13. % Rating EXAMPLE VI: Preparation of Interferon/Acyclovir Delivery System General Procedure Liquid polymers X, Y and Z were mixed at a ratio of 61,9~X, l9.1~Y, and l9.0~Z. The composition of these polymers were as follows: Polyethylene glycol 400-60/40 dl-lactide-glycolide segments ~weight ratio).
X Y Z
Step 1: Liquid polymer of the above composition was mechanically mixed with interferon to produce a composition that contains 50,000 U/ml liquid polymer.
Step 2: The mixture of Step 1 (5.6g) was loaded with (1.4g)B
(a polyglycolide that is acid terminated) previously treated with an alcohol/water solution comprising 668.3 mg of acyclovir sodium and then dried under vacuum.
2~ 7407~
. ,.
Step 3: The procedure of Step 2 was repeated with 77.6 mg acyclovir sodium.
Compositions of Steps 1, 2 and 3 are use for the controlled release of acyclovir and/or interferon over a period of 1 to 3 weeks.
It is understood that the Examples described herein are for purposes of illustration only and, not limitation, and that various modifications and/or changes that may suggest themselves to one skilled in the art are intended to be included within the spirit of this application and the scope of the appended claims.
Claims (46)
1. A hydrogel-forming, self-solvating absorbable polyester copolymer capable of selective, segmental association into a compliant hydrogel mass on contact with an aqueous environment.
2. The copolymer of claim 1 wherein said copolymer comprises a hydrophobic polyester block X covalently bonded to a hydrophilic block Y.
3. The copolymer of claim 1, wherein said copolymer is carboxy-terminated.
4. A composition comprising:
the copolymer according to claim 1; and at least one biologically active agent associated with said copolymer.
the copolymer according to claim 1; and at least one biologically active agent associated with said copolymer.
5. The composition of claim 4 wherein said at least one agent is at least partially deposited on an absorbable, microparticulate solid carrier.
6. The composition of claim 4 wherein said at least one agent is bonded to said copolymer.
7. The composition of claim 5 wherein the carrier is a microporous carrier.
8. The copolymer of claim 2 wherein said blocks X and Y are covalently bonded together in an arrangement selected from the group consisting of X-Y-X, (X-Y)n, and branched structures thereof.
9. The copolymer of claim 8 wherein said hydrophilic block Y comprises less than 50% of the mass of said copolymer.
10. The copolymer of claim 9 wherein said hydrophilic block Y comprises oxyethylene or a combination of oxyethylene and oxypropylene sequences.
11. The copolymer of claim 8 wherein said hydrophobic block X comprises greater than 50% of the mass of said copolymer.
12. The copolymer of claim 11 wherein said hydrophobic block is derived from ring opening polymerization of lactones or step-growth formation of alkylene oxalates.
13. The copolymer of claim 1 wherein said copolymer is extrudable.
14. The copolymer of claim 13 wherein said extrudable copolymer is a liquid.
15. The copolymer of claim 14 wherein said liquid is capable of being injectable into a biological site.
16. The copolymer of claim 14 wherein said liquid is obtained by combining a high molecular weight sample of said copolymer with a lower molecular weight component.
17. The copolymer of claim 16 wherein said lower molecular weight component is a plasticizer.
18. The copolymer of claim 17 wherein said plasticizer comprises said polymer wherein the hydrophilic block Y to hydrophobic block X ratio is greater than 1.
19. A composition comprising:
the copolymer of claim 17; and at least one biologically active agent associated with said copolymer.
the copolymer of claim 17; and at least one biologically active agent associated with said copolymer.
20. The composition of claim 19 wherein said copolymer is carboxy-terminated.
21. The composition of claim 19 wherein said at least one biologically active agent is deposited on an absorbable, microparticulate solid carrier.
22. The composition of claim 21 wherein said carrier is a microporous carrier.
23. A composition comprising:
a copolymer according to claim 1; and an absorbable, microparticulate, solid carrier associated with said copolymer, said carrier having at least one biologically active agent deposited thereon.
a copolymer according to claim 1; and an absorbable, microparticulate, solid carrier associated with said copolymer, said carrier having at least one biologically active agent deposited thereon.
24. The composition of claim 23 wherein said copolymer comprises a hydrophobic polyester block X covalently bonded to a hydrophilic block Y.
25. The composition of claim 23 or 24 wherein said at least one agent is a therapeutic agent.
26. The composition of claim 23 or 24 wherein said carrier is a microporous carrier.
27. A composition comprising:
a copolymer according to claim 1;
a low molecular weight component associated with said copolymer; and an absorbable, microparticulate solid carrier associated with said copolymer and said component, said carrier having at least one biologically active agent deposited thereon.
a copolymer according to claim 1;
a low molecular weight component associated with said copolymer; and an absorbable, microparticulate solid carrier associated with said copolymer and said component, said carrier having at least one biologically active agent deposited thereon.
28. The composition of claim 27 wherein said copolymer comprises a hydrophobic polyester block X covalently bonded to a hydrophilic block Y.
29. The composition of claim 27 or 28 wherein said at least one agent is a therapeutic agent.
30. The composition of claim 27 wherein said low molecular weight component is a plasticizer.
31. The composition of claim 30 wherein said plasticizer comprises said polymer wherein the hydrophilic block Y to hydrophobic block X ratio is greater than 1.
32. The copolymer of claim 1 wherein said hydrogel mass is reversible into a liquid.
33. A pharmaceutical formulation comprising a copolymer according to any one of claims 1, 4, 17, 19, 23 and 27;
and a pharmaceutically acceptable carrier.
and a pharmaceutically acceptable carrier.
34. A vaccine formulation comprising the pharmaceutical formulation of claim 33 and a pharmaceutically acceptable carrier.
35. A biomedical barrier for use in tissue regeneration; in postsurgical adhesion; in the treatment of vaginal infections; in the treatment of defects in blood vessels;
in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the copolymer according to any one of claims 1-3 and 8-18.
in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the copolymer according to any one of claims 1-3 and 8-18.
36. A biomedical barrier comprising the copolymer according to claim 1.
37. A biomedical barrier for use in tissue regeneration; in post surgical adhesion;
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier being made from the copolymer according to claim 1.
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier being made from the copolymer according to claim 1.
38. The biomedical burner of any one of claims 35 to 37, wherein said biomedical barrier is a sterilized biomedical barrier.
39. A biomedical barrier for use in tissue regeneration; in post surgical adhesion;
in the treatment of vaginal infections; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the composition according to any one of claims 4 to 7 and 19 to 31.
in the treatment of vaginal infections; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the composition according to any one of claims 4 to 7 and 19 to 31.
40. A biomedical barrier comprising the composition according to any one of claims 4, 19, 23 and 27.
41. A biomedical barrier for use in tissue regeneration; in post surgical adhesion;
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier being made from the composition according to any one of claims 4, 19, 23 and 27.
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier being made from the composition according to any one of claims 4, 19, 23 and 27.
42. A biomedical burner according to any one of claims 39 to 41, wherein said biomedical barrier is a sterilized biomedical burner.
43. A biomedical barrier comprising the copolymer according to claim 17.
44. A biomedical burner for use in tissue regeneration; in post surgical adhesion;
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the copolymer according to claim 17.
in the treatment of vaginal infections; in the treatment of defects in blood vessels; in the treatment of tissue wounds; or in the treatment of diseases of the periodontium, dry socket, bone and skin, the biomedical barrier comprising the copolymer according to claim 17.
45. The biomedical barrier of claim 43 or 44 wherein said barrier is a sterilized barrier.
46. A carrier for anti-epileptic agents, anaesthetic agents and vaccines, comprising the copolymer according to any one of claims 1 to 3.
Applications Claiming Priority (2)
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US08/421,222 | 1995-04-12 | ||
US08/421,222 US5612052A (en) | 1995-04-13 | 1995-04-13 | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
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CA2174072C true CA2174072C (en) | 2003-05-27 |
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US (2) | US5612052A (en) |
EP (1) | EP0737703B1 (en) |
JP (1) | JP3107514B2 (en) |
AT (1) | ATE243720T1 (en) |
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Cited By (2)
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CN117511851A (en) * | 2024-01-03 | 2024-02-06 | 中国肉类食品综合研究中心 | Application of hydrogel scaffold in preparation of cell culture meat |
CN117511851B (en) * | 2024-01-03 | 2024-03-26 | 中国肉类食品综合研究中心 | Application of hydrogel scaffold in preparation of cell culture meat |
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EP0737703A3 (en) | 1998-10-28 |
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EP0737703A2 (en) | 1996-10-16 |
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