WO2006108167A1 - Bioactive stents for type ii diabetics and methods for use thereof - Google Patents
Bioactive stents for type ii diabetics and methods for use thereof Download PDFInfo
- Publication number
- WO2006108167A1 WO2006108167A1 PCT/US2006/013214 US2006013214W WO2006108167A1 WO 2006108167 A1 WO2006108167 A1 WO 2006108167A1 US 2006013214 W US2006013214 W US 2006013214W WO 2006108167 A1 WO2006108167 A1 WO 2006108167A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polymer
- stent
- alkyl
- bioligand
- pecs
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- 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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
- A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
Definitions
- the invention relates generally to implantable medical devices, and in particular to biodegradable polymer coated implantable stents that promote vascular healing in diabetics.
- the stent itself reduces restenosis in a mechanical way by providing a larger lumen. For example, some stents gradually enlarge over time.
- many stents are implanted in a contracted form mounted on a partially expanded balloon of a balloon catheter and then expanded in situ to contact the lumen wall.
- U. S. Patent No. 5,059,211 discloses an expandable stent for supporting the interior wall of a coronary artery wherein the stent body is made of a porous bioabsorbable material.
- U. S. Patent No. 5,662,960 discloses a friction-reducing coating of commingled hydrogel suitable for application to polymeric plastic, rubber or metallic substrates that can be applied to the surface of a stent.
- agents that affect cell proliferation have been tested as pharmacological treatments for stenosis and restenosis in an attempt to slow or inhibit proliferation of smooth muscle cells.
- These compositions have included heparin, coumarin, aspirin, fish oils, calcium antagonists, steroids, prostacyclin, ultraviolet irradiation, and others.
- Such agents may be systemically applied or may be delivered on a more local basis using a drug delivery catheter or a drug eluting stent.
- biodegradable polymer matrices loaded with a pharmaceutical may be implanted at a treatment site. As the polymer degrades, a medicament is released directly at the treatment site.
- U.S. Patent No. 5,342,348 to Kaplan and U.S. Patent No. 5,419,760 to Norciso are exemplary of this technology.
- U.S. Patent 5,766,710 discloses a stent formed of composite biodegradable polymers of different melting temperatures.
- Porous stents formed from porous polymers or sintered metal particles or fibers have also been used for release of therapeutic drugs within a damaged vessel, as disclosed in U. S. Patent No. 5,843,172.
- tissue surrounding a porous stent tends to infiltrate the pores.
- pores that promote tissue ingrowth are considered to be counterproductive because the growth of neointima can occlude the artery, or other body lumen, into which the stent is being placed.
- U.S. Patent 5,766,584 to Edelman et al. describes a method for inhibiting vascular smooth muscle cell proliferation following injury to the endothelial cell lining by creating a matrix containing endothelial cells and surgically wrapping the matrix about the tunica adventitia.
- the matrix, and especially the endothelial cells attached to the matrix secrete products that diffuse into surrounding tissue, but do not migrate to the endothelial cell lining of the injured blood vessel.
- EDRF endothelium-derived relaxing factor
- thrombin factor Xa operates upon factor VII to control thrombus formation and, at the same time stimulates production of PARs (Protease Activated Receptors) by pro-inflammatory monocytes and macrophages.
- PARs Protease Activated Receptors
- Nitric oxide produced endogenously by endothelial cells regulates invasion of the proinflammatory monocytes and macrophages. In the lumen of an artery, this two-phase cycle results in influx and proliferation of healing cells through a break in the endothelium.
- Stabilization of the vascular smooth muscle cell population by this naturally counterbalanced process is required to prevent neointimal proliferation leading to restenosis.
- the absence or scarcity of endogenously produced nitric oxide caused by damage to the endothelial layer in the vasculature is thought to be responsible for the proliferation of vascular smooth muscle cells that results in restenosis following vessel injury, for example following angioplasty.
- Nitric oxide dilates blood vessels (Vallance et al., Lancet, 2:997-1000, 1989), inhibits platelet activation and adhesion (Radomski et al., Br. J Pharmacol, 92:181-187, 1987) and, in vitro, nitric oxide limits the proliferation of vascular smooth muscle cells (Garg et al., J. Clin. Invest. 83:1774-1777, 1986). Similarly, in animal models, suppression of platelet-derived mitogens by nitric oxide decreases intimal proliferation (Ferns et al., Science, 253:1129-1132, 1991).
- Clinical research has strongly implicated the generally impaired healing of the endothelium in patients who suffer from diabetes mellitus as a major contributor to the diminished therapeutic outcome in these patients when an arterial stent has been implanted.
- Impaired glucose tolerance (IGT) is considered a transitional phase to the development of Type II diabetes and many of the changes in health of endothelium found in Type II diabetics are prefigured in IGT. IGT and diabetes are also independently associated with the occurrence of cardiovascular disease. While Type II diabetic patients make up a significant proportion of those patients who experience such treatment failure, all Type II diabetics do not experience stent failure and the reason why some do, and some do not, has not hitherto been studied.
- the present invention is based on the discovery that endogenous endothelial healing processes at a site of vascular damage in patients suffering from Type II diabetes can be promoted by coating stents and other implantable devices with biodegradable, bioactive polymers bearing covalently attached bioligands that specifically capture and activate therapeutic progenitors of endothelial cells from the circulating blood of such patients.
- the polymers which biodegrade over time, may also release one or more bioactive agent that re-establish in patients suffering from Type II diabetes the natural endothelial healing process in an artery by activating PECs.
- the bioactive agent(s) attached to the polymers promote endogenous endothelial processes in arteries of diabetics by specifically recruiting to the stent surface progenitors of endothelial cells from circulating blood at the site of stent or device implantation in the vasculature.
- the polymers e.g., the polymer backbone
- the invention provides bioactive implantable stents including a stent structure with a surface coating of a biodegradable, bioactive polymer, and at least one bioligand that specifically binds to an integral receptor on progenitors of endothelial cells (PECs) in circulating blood present on the surface of the polymer.
- This bioligand may itself be bioactive in also activating the PECs, or it may act in conjunction with another bioactive PEC-activating agent.
- the polymer has a chemical formula described by structural formula
- R 1 is independently selected from (C 2 - C 20 ) alkylene, (C 2 -C 2 o) alkenylene, ⁇ , ⁇ -bis(4-carboxyphenoxy) (Ci-C 8 ) alkane, residues of 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid, or a saturated or unsaturated residue of a therapeutic di-acid;
- the R 3 S in individual n monomers are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Ci 0 ) aryl (C 1 -C 6 ) alkyl and -(CH 2 ) 2 S(CH 3 ); and
- R 4 is independently selected from the group consisting of (C 2 -C 2 o) alky
- R 1 is independently selected from residues of (C 2 - C 20 ) alkylene, (C 2 -Q 20 ) alkenylene, ⁇ , ⁇ -bis(4-carboxyphenoxy) (C]-C 8 ) alkane, 3,3'- (alkanedioyldioxy) dicinnaniic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid, or a saturated or unsaturated residue of a therapeutic di-acid and combinations of thereof; each R 2 is independently hydrogen, (Ci-C 12 ) alkyl, (C 2 -Cs) alkyloxy (C 2 -C20) alkyl, (C 6 -Cio) aryl or a protecting group; the R 3 S in individual m monomers are independently selected from the group consisting
- n ranges from about 5 to about 150; wherein the R 3 S within an individual n monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -C 10 ) aryl (Ci-C 6 ) alkyl and -(CH 2 ) 2 S(CH 3 ); R 4 and R 6 is independently selected from the group consisting of (C 2 -C 2 o) alkylene, (C 2 -C 2 o) alkenylene or alkyloxy, bicyclic-fragments of l,4:3,6-dianhydrohexitols of structural formula (II), or residues of saturated or unsaturated therapeutic diols and combinations thereof; or a PEUR polymer having a chemical structure described by general structural formula (V)
- each R 2 is independently hydrogen, (C 1 -Ci 2 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 2 o) alkyl, (C 6 -Cio) aryl or a protecting group;
- the R 3 S within an individual m monomer are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (Ci-C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 );
- R 4 and R 6 is independently selected from the group consisting Of(C 2 -C 20 ) alkylene, (C 2 - C 2 o) alkenylene or alkyloxy, and bi
- n is about 10 to about 150; the R 3 S within an individual n monomer are independently selected from hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Cio) aryl (C i- C 6 ) alkyl and -(CH 2 ) 2 S(CH 3 ); R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 - C 20 ) alkenylene, (C 2 -Cs) alkyloxy (C 2 -C 2 o) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a l,4:3,6-dianhydrohexitol of structural formula (II); or a PEU having a chemical formula described by structural formula (VII)
- R 2 is independently hydrogen, (Ci-C] 2 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkyl, (C 6 -CiO) aryl or a protecting group; and the R 3 S within an individual m monomer are independently selected from hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Ci 0 ) aryl (Q- C 6 )alkyl and -(CH 2 ) 2 S(CH 3 ); R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 - C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 2 o) alkylene, a residue of a saturated or unsatur
- the invention provides a kit that includes an invention biocompatible implantable stent and instructions for its use.
- the invention stent has a stent structure with a surface coating of a biodegradable, biocompatible polymer with at least one bioligand or first member of a specific binding pair that binds specifically to an integrin receptor on PECs.
- the invention provides a tubular sheath comprising a biodegradable, bioactive polymer having a chemical structure described by structural formulas (I and III- VII), wherein the polymer comprises at least one bioligand present on the surface of the polymer, wherein the bioligand specifically binds to an integrin receptor on PECs in peripheral blood.
- the invention provides implantable medical devices having a biodegradable, bioactive polymer having a chemical structure described by structural formulas (I and III- VII) coated upon at least a portion of a surface. At least one bioligand that specifically binds an integrin receptor on PECs found in peripheral blood is present on the surface of the polymer.
- the invention provides methods for delivering at least one bioligand that specifically binds an integrin receptor on PECs found in peripheral blood to damaged arterial endothelium in heart or limb in a subject having Type II diabetes comprising implanting an invention stent in an artery of the subject having the damaged arterial endothelium to promote natural healing in the artery wall of the subject.
- the invention provides methods for using a polymer having a chemical structure described by structural formulas (I and III-VII) as a medical device, a pharmaceutical, or as a carrier for covalent immobilization of a bioligand or first member of a specific binding pair that specifically attaches to an integrin receptor in PECs in the circulating blood of a subject with Type II diabetes into which the polymer is implanted.
- the bioligand is a polypeptide that binds specifically to an integrin receptor on PECs in circulating blood; b) the bioligand forms a specific binding pair with an antibody that binds specifically to the integrin receptor; or c) the antibody is tagged with a first member of a specific binding pair and the bioligand comprises a second member of the specific binding pair.
- the invention provides methods for promoting natural healing of endothelium damaged by mechanical intervention in an artery of a subject having Type II diabetes by implanting into the artery following the mechanical intervention an invention stent to promote natural healing of the artery.
- FIG. 1 is a schematic cross-section of an invention multilayered polymer- coated stent.
- Fig. 2 is a flow chart describing the PEC isolation protocol.
- Fig. 3 is a flow chart of the protocol for adhesion assays conducted with ECs and SMCs.
- Fig. 4 is a graph summarizing the results of a representative adhesion assay quantitation based on ATP standard curve. At each time point of the adhesion assay, an ATP assay was done to determine the number of adherent cells.
- Fig. 5 shows the chemical structure of dansyl, an acronym for 5 dimethylamino-1 naphthalenesulfonyl, a reactive fluorescent dye, linked to PEA.
- Figs. 6A-B are flowcharts summarizing surface chemistry optimization protocols.
- Fig. 6A shows a flowchart of the surface chemistry for conjugation of peptides to the acid version of the polymers (PEA-H).
- Fig. 6B shows a flowchart of the protocol for surface conjugation of peptides to mixtures of PEA polymers.
- Fig. 7 is a graph showing the rate of phenotypic progression of monocytes-to- macrophages and contact-induced fusion to form multinucleated cells on PEA and other test polymers over three weeks of culture.
- Fig. 8 is a graph showing monocytes secreted over 5 -fold less IL-6 when on PEAs than on the other polymers tested.
- Fig. 9 is a graph showing secretion of IL-Ib by monocytes incubated for 24 hours on PEAs, PLGA 73K and PBMA.
- Fig. 10 is a graph showing secretion of Interleukin-1 receptor antagonist, a naturally occurring inhibitor of IL-Ib, by adherent monocytes incubated on PEAs.
- Fig. 11 is a graph showing growth of human coronary artery endothelial cells (ECs) and aortic smooth muscle cells (SMCs) incubated for 72 hours on PEA, polyethylene-co-vinyl acetate (PEVAc:PBMA), and a gelatin-coated surface.
- PEVAc:PBMA polyethylene-co-vinyl acetate
- the left- hand bar in each pair is ECs and the right-hand bar is SMCs.
- Fig. 12 is a graph showing ATP release of human platelets incubated in polymer-coated (PEA.Ac.Bz or PEA.Ac.TEMPO) or fibrinogen-coated wells for 30 minutes at 37 °C.
- this invention provides stents and methods using such devices to re-establish an endothelial blood/artery barrier in patients suffering from diabetes mellitus, particularly Type II diabetes.
- the invention stents, stent coverings and drug delivery compositions are also designed to promote endothelial healing at a site of damaged vascular endothelium in patients having impaired glucose tolerance, which is considered a transitional phase to the development of Type II diabetes.
- the invention stents comprise a biocompatible, resorbable polymeric sheath that encapsulates the stent structure.
- the stent is placed at the conclusion of an angioplasty procedure, or other medical procedure that damages arterial endothelium, without allowing a lapse of time sufficient for infiltration of inflammatory factors from the blood stream into the artery wall.
- the stent is placed at the location of the damage and preferably immediately covers and protects the area of damaged endothelium so as to prevent infiltration of inflammatory factors from the blood stream into the artery wall, while performing its primary function of gathering therapeutic progenitors of endothelial cells from the patient's circulating blood so that the natural processes of endothelial healing can go forward in the patient suffering from Type II diabetes.
- the invention stents perform as an artificial endothelial layer while promoting the natural cycle of endothelial healing in diabetics as described herein.
- the polymeric sheath may have additional features that contribute to the healing of the artery.
- the invention sheath or covering comprises multiple layers, each of which can perform a distinct function in re-establishing a stable lesion and contributing to healing endothelium of the injured artery wall.
- diabetes and "diabetes mellitus” as used herein mean Type II diabetes as well as impaired glucose tolerance (IGT), which is widely considered a transitional phase to the development of Type II diabetes. Many of the changes in health of endothelium found in Type II diabetics are prefigured in IGT.
- bioactive agent means active agents that activate progenitors of endothelial cells to promote natural processes of endothelialization.
- bioactive agents include bioligands that capture PECs from the blood stream of a subject.
- additional bioactive agent means an active agent other than a “bioactive agent”, which additional bioactive agent affects a biological process in a mammalian individual, such as a human, in a therapeutic or palliative manner when administered to the mammal and that is not incorporated into the polymer backbone.
- Bioactive agents may include, without limitation, small molecule drugs, peptides, proteins, DNA, cDNA, RNA, sugars, lipids and whole cells.
- One or more such bioactive agents may be dispersed in the invention therapeutic polymer compositions.
- EPCs endothelial progenitor cells
- PECs precursor endothelial cells
- examples of bioligands suitable for use in capture of PECs from circulating blood are monoclonal antibodies directed against a known or identified surface marker of therapeutic PECs.
- Complementary determinants (CDs) that have been reported to decorate the surface of endothelial cells include CD31, CD34, CD 102, CD105, CD106, CD109, CDwl30, CD141, CD142, CD143, CD144, CDwl45, CD146, CD147, and CD166.
- CDs 106, 142 and 144 have been reported to mark mature endothelial cells with some specificity.
- CD34 is presently known to be specific for progenitor endothelial cells in non-diabetics and therefore is one of the cell surface markers that is believed to be useful for capturing PECs out of blood circulating in the vessels in a diabetic patient into which the stent is implanted.
- ECM extracellular matrix
- Fibronectin is one of the more ubiquitous members of the ECM. It is a potential ligand for most cell types and is recognized by at least 10 adhesion receptors of the integrin family (Leukemia 1997; 11:822-829 and Blood 1998; 91(9):3230-3238). In particular, CS5 and REDVDY are both found in the Type III connecting segment of fibronectin.
- the sequence for the CS5 peptide is: Gly-Glu-Glu- llQ-Gln-lle-Gly-Ris-IlQ-Pro-Ars-Glu-Asp-Val-Asp-Tyr-Ris-Leu-Twr- ⁇ w (SEQ ID NO.l), which contains REDVDY (underlined) (SEQ ID NO:2). It has been discovered that CS5 and REDVDY peptides bind specifically to integrin receptors on PECs.
- REDV The minimal active cell binding amino acid sequence, REDV , is somewhat related to the RGDs, a major active site in the central cell binding domain of fibronectin.
- REDV is novel in its cell type selectivity.
- the integrin ⁇ 4/31 is known to bind to the REDV sequence and is found on ECs but not on SMCs (JBC (1991) 266(6):3579- 3585; Am. J of Pathology (1994) 145:1070-1081; and Blood (1998) 91(9):3230-32384). This becomes even more important in recruiting PECs versus smooth muscle progenitor cells (SPCs) in peripheral blood.
- SPCs smooth muscle progenitor cells
- Bioligands e.g., peptides and polypeptides
- a biodegradable polymer as described herein for coating at least a portion of the surface of an interventional implantable device, such as a vascular stent, to endow the coating with the property of preferential and specific recruitment of a subpopulation of PECs from the circulating bloodstream of a diabetic patient into which the device is implanted.
- the resulting localized concentration of PECs throughout the stent will enhance endothelial wound healing of the arterial wall of the diabetic patient.
- the bioligand is an antibody, such as a monoclonal antibody, and is specific for an integrin receptor identified on PECs as described above.
- a stent having a polymer coating to which the capture antibody is bound will, when implanted in a Type II diabetic, in turn bind to and hold captured PECs near the polymer surface for activation and subsequent migration.
- an antibody is used in its broadest sense to include polyclonal and monoclonal antibodies, as well as antigen binding fragments of such antibodies.
- An antibody useful in a method of the invention, or an antigen-binding fragment thereof, is characterized, for example, by having specific binding activity for an epitope of a target molecule.
- the antibody for example, includes naturally occurring antibodies as well as non-naturally occurring antibodies, including, for example, single chain antibodies, chimeric, bifunctional and humanized antibodies, as well as antigen-binding fragments thereof.
- non-naturally occurring antibodies can be constructed using solid phase peptide synthesis, can be produced recombinantly or can be obtained, for example, by screening combinatorial libraries consisting of variable heavy chains and variable light chains (see Huse et al., Science 246:1275-1281 (1989)).
- These and other methods of making, for example, chimeric, humanized, CDR-grafted, single chain, and bifunctional antibodies are well known to those skilled in the art (Winter and Harris, Immunol.
- Monoclonal antibodies suitable for use as bioligands may also be obtained from a number of commercial sources. Such commercial antibodies are available against a wide variety of targets.
- Antibody probes can be conjugated to molecular backbones using standard chemistries, as discussed below.
- the term "binds specifically" or "specific binding activity,” when used in reference to an antibody means that an interaction of the antibody and a particular epitope has a dissociation constant of at least about 1 x 10 "6 , generally at least about 1 x 10 "7 , usually at least about 1 x 10 "8 , and particularly at least about 1 x 10 "9 or 1 x 10 "10 or less.
- Fab, F(ab') 2 , Fd and Fv fragments of an antibody that retain specific binding activity for an epitope of an antigen are included within the definition of an antibody.
- a pair of biocompatible specific binding partners can be used to specifically capture PECs from the circulating blood of Type II diabetics.
- one of the specific binding pair acts as the bioligand covalently attached to the polymer coating of the stent or other implantable device.
- the other member of the pair of specific binding partners is attached or allowed to attach to an integrin receptor on the PECs of the diabetic patient to be treated (either ex vivo or in vivo by administration to the blood of the patient).
- a Mab that binds specifically to a PEC cell surface marker such as CD 144
- molecule A a PEC cell surface marker
- streptavidin molecule B
- a Mab that binds specifically to a PEC cell surface marker such as CD 144
- molecule A a PEC cell surface marker
- streptavidin molecule B
- a Mab that binds specifically to a PEC cell surface marker such as CD 144
- the roles of the specific binding partners, A and B can be reversed, with biotin, for example, being attached to the polymer of the stent and streptavidin being attached to a monoclonal antibody administered to the patient for specific attachment to the integrin receptor on the patient's PECs.
- Mab-A conjugates are added to the patient's blood either in vivo (e.g., parenterally) or ex vivo (e.g., by extracorporeal circulation of the patient's blood) either prior to, contemporaneously with, or immediately following installation of the stent or other therapeutic device.
- circulating therapeutic EPC-Mab-A complexes are preferentially recruited to binding partner B, streptavidin, which is covalently attached to the device coating, enhancing the local concentration of therapeutic PECs at the site of intervention and injury.
- a monoclonal antibody administered to the blood of a human is preferably a "humanized monoclonal antibody" and suitable antigen-binding fragments can be commissioned commercially or can readily be produced recombinantly using well known techniques.
- this aspect of the invention is illustrated by reference to specific binding partners, biotin and streptavidin, any biocompatible pair of specific binding partners can be used in an analogous way.
- the biocompatible bioligand can further comprise one member of a specific binding pair, such as a biotin-streptavidin, and the other member of the specific binding pair can be pre-attached to the polymer.
- a specific binding pair such as a biotin-streptavidin
- the bioligand is administered to the patient's blood stream, either in vivo or ex vivo, and allowed to bind to its specific target on therapeutic PECs therein, via a specific binding pair bridge. If the bioligand is administered to the patient's blood stream in vivo (e.g., parenterally), the PECs in the blood stream become bound to the polymer in vivo via the bioligand-specific binding pair-polymer complex.
- small proteinaceous motifs such as the B domain of bacterial Protein A and the functionally equivalent region of Protein G, are known to form a specific binding pair with, and thereby capture Fc-containing antibodies.
- the antibody administered to the diabetic patient's blood is an Fc- containing antibody that is specific for an integrin receptor on PECs in blood and the bioligand attached to the polymer of the stent is a "sticky" peptide or polypeptide, such as Protein A and Protein G, which will capture the antibody and hold it near to the polymer surface of the stent to aid in recruiting PECs to the area of endothelium damage.
- these "sticky" peptides or polypeptides may also capture other circulating, Fc- containing, native antibodies, thereby reducing specificity of the reaction for the therapeutic purposes.
- Protein A is a constituent of staphylococcus A bacteria that binds the Fc region of particular antibodies or immunoglobulin molecules.
- the Protein A bioligand can be or contain the amino acid sequence:
- Protein G is a constituent of group G streptococci bacteria, and displays similar activity to Protein A, namely binding the Fc region of particular antibody or immunoglobulin molecules.
- the Protein G bioligand can be, or contain Protein G having an amino acid sequence:
- Such Protein A and Protein G molecules can be covalently attached as bioligands to the bioactive polymer coatings on the stent structure (e.g., the inner layer of a multilayered stent as described herein) and will act as bioligands to capture out of the patient's circulating blood stream Fc-containing antibodies that have been complexed with the patients' therapeutic PECs.
- Bioligands are selected and conjugated to the polymer backbone while avoiding steric hindrance to binding of the ligand to its biological target.
- bioactive agents that activate the progenitor endothelial cells and are contemplated for attachment to the polymer backbone in the polymer coatings covering the invention medical devices include the bradykinins.
- Bradykinins are vasoactive nonapeptides formed by the action of proteases on kininogens, to produce the decapeptide kallidin (KRPPGFSPFR) (SEQ ID NO:7), which can undergo further C-terminal proteolytic cleavage to yield the bradykinin 1 nonapeptide: (KRPPGFSPF) (SEQ ID NO: 8), or N- terminal proteolytic cleavage to yield the bradykinin 2 nonapeptide: (RPPGFSPFR) (SEQ ID NO: 9).
- KRPPGFSPFR decapeptide kallidin
- Bradykinins 1 and 2 are functionally distinct as agonists of specific bradykinin cell surface receptors Bl and B2 respectively: both kallidin and bradykinin 2 are natural bioligands for the B2 receptor; whereas their C-terminal metabolites (bradykinin 1 and the octapeptide RPPGFSPF (SEQ ID NO: 10) respectively) are bioligands for the Bl receptor.
- a portion of circulating bradykinin peptides can be subject to a further post-translational modification: hydroxylation of the second proline residue in the sequence (Pro3 to Hyp3 in the bradykinin 2 amino acid numbering). Bradykinins are very potent vasodilators, increasing permeability of post-capillary venules, and acting on endothelial cells to activate calmodulin and thereby nitric oxide synthase.
- Bradykinin peptides are incorporated into the bioactive polymers used in the invention stents by attachment at one end of the peptide.
- the unattached end of the bradykinin extends freely from the polymer as a bioligand to contact endothelial cells in the vessel wall as well as progenitor endothelial cells captured from the blood in the vessel into which the stent is implanted. Thereby the endothelial cells with which contact is made become activated.
- the bioactive agent can be a nucleoside, such as adenosine, which is also known to be a potent activator of endothelial cells to produce nitric oxide endogenously. Endothelial cells activated in this way activate further progenitor endothelial cells with which they come into contact. Thus, a cascade of endothelial cell activation at the site of the injury is caused to result in endogenous production of nitric oxide and development of an endothelial lining on the surface of the stent that contacts blood.
- a nucleoside such as adenosine
- the invention stent has a multilayered polymer covering that encapsulates a stent structure.
- Fig. 1 shows a schematic cross-section of an example of an invention stent 11 with stent struts 10 and a multilayered sheath or covering.
- the outer layer 16 of the stent covering or sheath lies directly next to the artery wall.
- Bioactive agents and additional bioactive agents, as described herein, are incorporated into the outer layer of the stent covering or sheath to promote healing of the epithelium.
- An optional diffusion barrier layer 14 can be placed between and in contact with outer layer 16 and inner layer 12.
- the inner layer 12 of the multilayered stent covering is exposed to the circulating blood with its PECs and has bioligands for recruitment of PECs covalently attached thereto.
- a biocompatible polymer of the type specifically described herein e.g., having a chemical structure described by structures I and III- VII herein
- One or more bioligands that bind specifically to PECs such as those having an amino acid sequence as set forth in SEQ ID NOS: 1, 2, or 11, or a member of a specific binding pair for which the other member is contained within or conjugated with a specifically binding bioligand, are covalently attached to the polymer in the inner layer using techniques of covalent attachment described herein.
- streptavidin can be bound to the polymer of the inner layer of the sheath for use with a biotin-tagged antibody that specifically binds the target on PECs in the circulating blood (which biotin- tagged antibody will be administered to the subject's blood stream).
- a biotin-tagged antibody that specifically binds the target on PECs in the circulating blood (which biotin- tagged antibody will be administered to the subject's blood stream).
- one or more "bioactive agent,” as described herein, but not “an additional bioactive agent” can also be covalently bound to the polymer in the inner layer of the invention multilayered stent.
- the bioactive agent is selected to activate PECs attracted to the inner layer of the sheath from the circulating blood of diabetic patients by the bioligands attached to the inner layer of the stent covering.
- the stent takes an active role in the process of re-establishing the natural endothelial cell layer at the site of one or more damaged areas of arterial endothelium.
- the outer layer 16 of the invention multilayered stent comprises a polymer layer loaded with a bioactive agent and/or an additional bioactive agent, or combination thereof, specifically including those that limit cellular proliferation or reduce inflammation as disclosed herein.
- These cellular proliferation limiting and/or inflammation reducing drugs can be solubilized in the polymer solid phase and, hence, are preferably not bound to the polymer of the outer layer. Rather such bioactive agents and additional bioactive agents are loaded into the polymer and sequestered there until the stent is put into place. Once implanted, the bioactive agents in the outer layer 16 are eluted and diffuse into the artery wall.
- Preferred active agents for incorporation into the outer layer of invention multilayered stents include rapamycin and any of its analogs or derivatives, such as everolimus (also known as sirolimus), paclitaxel or any of its analogs or derivatives, and statins, such as simvastatin.
- rapamycin and any of its analogs or derivatives such as everolimus (also known as sirolimus), paclitaxel or any of its analogs or derivatives
- statins such as simvastatin.
- non-covalently bound bioactive agents and/or additional bioactive agents can be dispersed in or "loaded into” any biocompatible biodegradable polymer as is known in the art since the outer layer in this embodiment of the invention does not come into contact with blood, except during placement of the stent.
- a diffusion barrier layer 14 of resorbable polymer that acts as a diffusion barrier to the bioactive agent or additional bioactive agent contained in the outer layer.
- the purpose of this diffusion barrier is to direct elution of the drug/biologic into the artery wall to prevent proliferation of smooth muscle cells, while limiting or preventing passage of the drug/biologic into the inner layer.
- the diffusion barrier layer 14 can accomplish its purpose of partitioning of the drug through hydrophobic/hydrophilic interaction related to the solubility of the bioactive agent in the polymer solid phase.
- the polymer barrier layer is selected to be less hydrophobic than the active agent(s) in the outer layer; if the bioactive agent or additional bioactive agent in the outer layer is relatively hydrophilic, the barrier layer is selected to be more hydrophobic.
- the barrier layer can be selected from such polymers as polyester, ⁇ oly(amino acid), poly(ester amide), poly(ester urethane), polyurethane, polylactone, poly(ester ether), or copolymers thereof, whose charge properties are well known by those of skill in the art.
- the barrier layer 14 is considered optional because the inner layer of the stent may itself prove an effective diffusion barrier, depending upon the properties of the polymers and various active agents contained in the inner and outer layers of the stent.
- the stent structure used in manufacture of the invention multilayered stent as well as the stents comprising a single layer of polymer covering described herein is made of a biodegradable and absorbable material, e.g., a polymer, with sufficient strength and stiffness to replace a conventional stent structure, such as a stainless steel or wire mesh stent structure.
- a cross-linked poly(ester amide), polycaprolactone, or poly(ester urethane) as described herein can be used for this purpose so that the stent structure as well as its covering(s) is completely bioabsorbable, for example, over a period of three months to years.
- each of the layers, and the stent structure as well will be re-absorbed by the body through natural processes, including enzymatic action, allowing the re-established endothelial cell layer to resume its dual function of acting as a blood/artery barrier and providing natural control and stabilization of the intra-cellular matrix within the artery wall through the production of nitric oxide.
- biodegradable means that at least the polymer coating of the invention stent is capable of being broken down into innocuous and biocompatible products in the normal functioning of the body. This is particularly true when the amino acids used in fabrication of the invention polymers are biological L- ⁇ -amino acids.
- the polymers in the invention stents, sheaths and polymer delivery compositions include hydrolyzable ester and enzymatically cleavable amide linkages that provide biodegradability, and are typically chain terminated, predominantly with amino groups.
- the amino termini of the polymers can be acetylated or otherwise capped by conjugation to any other acid-containing, biocompatible molecule, to include without restriction organic acids, bioinactive biologies, and bioactive agents as described herein.
- the entire stent, including the stent structure is biodegradable.
- Biodegradable, biocompatible polymers suitable for use in the practice of the invention of the type specifically described herein bear functionalities that allow for facile covalent attachment of bioactive agents to the polymer.
- a polymer bearing carboxyl groups can readily react with a bioactive agent having an amino moiety, thereby covalently bonding the bioactive agent to the polymer via the resulting amide group.
- the biodegradable, biocompatible polymer and the bioligands and bioactive agents can contain numerous complementary functional groups that can be used to covalently attach the bioactive agent to the biodegradable, biocompatible polymer.
- bioactive agent includes agents that play an active role in the endogenous healing processes at a site of stent implantation, such as the above-described bioligands and members of a specific binding pair, and/or agents, including those specifically described herein, having properties that capture (i.e., "bioligands"), attract and activate captured circulating PECs, and include those contemplated for covalent attachment to the polymers used in coating the invention stents.
- bioactive agents include, but are not limited to, agents that, when freed from the polymer during polymer degradation, promote endogenous production of a therapeutic natural wound healing agent, such as nitric oxide endogenously produced by endothelial cells.
- bioactive agents released from the polymers during degradation may be directly active in promoting natural wound healing processes by endothelial cells while controlling proliferation of smooth muscle cells in the vessel at the locus of the damage.
- bioactive agents can include any agent that donates, transfers, or releases nitric oxide, elevates endogenous levels of nitric oxide, stimulates endogenous synthesis of nitric oxide, or serves as a substrate for nitric oxide synthase or that inhibits proliferation of smooth muscle cells.
- Such agents include, for example, aminoxyls, furoxans, nitrosothiols, nitrates and anthocyanins; nucleosides such as adenosine, and nucleotides such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP); neurotransmitter/neuromodulators such as acetylcholine and 5-hydroxytryptamine (serotonin/5-HT); histamine and catecholamines such as adrenalin and noradrenalin; lipid molecules such as sphingosine-1 -phosphate and lysophosphatidic acid; amino acids such as arginine and lysine; peptides such as the bradykinins, substance P and calcium gene- related peptide (CGRP), and proteins such as insulin, vascular endothelial growth factor (VEGF), and thrombin.
- nucleosides such as adenosine, and nucle
- Additional bioactive agents are optionally dispersed in, e.g., covalently attached, to the polymers used in the coverings of the invention stents, stent covering and devices, and drug delivery compositions.
- Additional bioactive agents include aminoxyls, having the structure:
- aminoxyls include the following compounds:
- An exemplary furoxan is 4-phenyl-3-furoxancarbonitrile, as set forth below:
- Anthocyanins are also contemplated for use as bioactive agents.
- Anthocyanins are glycosylated anthocyanidins and have the structure:
- Bioactive agents for dispersion into and release from the surface coverings of the invention stents and medical devices also include anti-proliferants, rapamycin and any of its analogs or derivatives, paclitaxel or any of its taxene analogs or derivatives, everolimus, Sirolimus, tacrolimus, or any of its -limus named family of drugs, and statins such as simvastatin, atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin, geldanamycins, such as 17AAG ( ⁇ -allylamino- ⁇ -demethoxygeldanamycin); Epothilone D and other epothilones, ly-dimethylammoethylammo-lT-demethoxy-geldanamycin and other polyketide inhibitors of heat shock protein 90 (Hsp90), Cilostazol, and the like.
- statins such as simvastatin, atorvastat
- Polymers contemplated for use in forming the blood-compatible, hydrophilic coating or inner layer in the invention multilayered stents include polyesters, poly(amino acids), polyester amides, polyurethanes, or copolymers thereof.
- biodegradable polyesters include poly( ⁇ -hydroxy Ci -C 5 alkyl carboxylic acids), e.g., polyglycolic acids, poly-L-lactides, and poly-D,L-lactides; poly-3 -hydroxy butyrate; polyhydroxyvalerate; polycaprolactones, e.g., poly( ⁇ -caprolactone); and modified poly( ⁇ - hydroxyacid)homopolymers, e.g., homopolymers of the cyclic diester monomer, 3- (S)[alkyloxycarbonyl)methyl]-l,4-dioxane-2,5-dione which has the formula 4 where R is lower alkyl, depicted in Kimura, Y., "Biocompatible Polymers” in Biomedical Applications of Polymeric Materials, Tsuruta, T., et al, eds., CRC Press, 1993 at page 179.
- biodegradable copolymer polyesters useful in forming the blood- compatible, hydrophilic coating or inner layer in the invention stents include copolyester amides, copolyester urethanes, glycolide-lactide copolymers, glycolide-caprolactone copolymers, poly-3 -hydroxy butyrate-valerate copolymers, and copolymers of the cyclic diester monomer, 3-(S)[(alkyloxycarbonyl)methyl]-l,4-dioxane-2,5-dione, with L-lactide.
- the glycolide-lactide copolymers include poly(glycolide-L-lactide) copolymers formed utilizing a monomer mole ratio of glycolic acid to L-lactic acid ranging from 5:95 to 95:5 and preferably a monomer mole ratio of glycolic acid to L-lactic acid ranging from 45:65 to 95:5.
- the glycolide-caprolactone copolymers include glycolide and ⁇ -caprolactone block copolymer, e.g., Monocryl or Poliglecaprone.
- biocompatible polymers in the surface coverings of the invention stents and medical devices have built-in functional groups on side chains, and these built-in functional groups can react with other chemicals and lead to the incorporation of additional functional groups to expand the functionality of the polymer further. Therefore, such polymers used in the invention compositions and methods are ready for reaction with other chemicals having a hydrophilic structure to increase water solubility and with bioactive agents and additional bioactive agents, without the necessity of prior modification.
- polymers used in the invention polymer coated stents and medical devices display minimal hydrolytic degradation when tested in a saline (PBS) medium, but in an enzymatic solution, such as chymotrypsin or CT, a uniform erosive behavior has been observed.
- PBS saline
- the polymer is a PEA having a chemical formula described by structural formula (I),
- R 1 is independently selected from (C 2 - C 2 o) alkylene, (C 2 -C 2 0) alkenylene, ⁇ , ⁇ -bis(4-carboxyphenoxy) (Ci-C 8 ) alkane, residues of 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid, or a saturated or unsaturated residue of a therapeutic di-acid and combinations thereof;
- the R 3 S in individual n monomers are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Ci 0 ) aryl (Ci-C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ); and
- R 4 is independently selected from the group consisting Of (C 2 -C 20 -C 20
- R 1 is independently selected from (C 2 - C 20 ) alkylene, (C 2 -C 20 ) alkenylene, ⁇ , ⁇ -bis(4-carboxyphenoxy) (Ci-Cs) alkane, residues of 3,3'- (alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid, or a saturated or unsaturated residue of a therapeutic di-acid; each R 2 is independently hydrogen, (Ci-C 12 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkyl, (C 6 -Cio) aryl or a protecting group; the R 3 S in individual m monomers are independently selected from the group consisting of hydrogen, (Ci-C 12 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkyl, (C 6
- an effective amount of the residue of at least one therapeutic diol or di-acid can be contained in the polymer backbone.
- at least one R 1 is a residue of ⁇ , ⁇ bis(4-carboxyphenoxy) (Ci-C 8 ) alkane or 4,4'- (alkanedioyldioxy) dicinnamic acid and R 4 is a bicyclic-fragment of a 1,4:3,6- dianhydrohexitol of general formula (II), or a residue of a saturated or unsaturated therapeutic diol.
- R 1 in the PEA polymer is either a residue of ⁇ , ⁇ - bis (4-carboxyphenoxy) (Ci-C 8 ) alkane, or 4,4'-(alkanedioyldioxy)dicinnamic acid, a residue of a therapeutic diacid, and mixtures thereof.
- R 1 is a residue ⁇ , ⁇ -bis(4-carboxyphenoxy) (Ci-C 8 ) alkane, such as 1,3- bis(4-carboxyphenoxy)propane (CPP), or 4,4'-(alkanedioyldioxy)dicinnamic acid and R is a bicyclic-fragment of a l,4:3,6-dianhydrohexitol of general formula (II), such as l,4:3,6-dianhydrosorbitol (DAS).
- CPP 1,3- bis(4-carboxyphenoxy)propane
- R is a bicyclic-fragment of a l,4:3,6-dianhydrohexitol of general formula (II), such as l,4:3,6-dianhydrosorbitol (DAS).
- the polymer is a PEUR having a chemical formula described by structural formula (IV),
- n ranges from about 5 to about 150; wherein the R 3 S within an individual n monomer are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Ci 0 ) aryl (C 1 -C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ); R 4 and R 6 is independently selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 2 o) alkenylene or alkyloxy, and bicyclic-fragments of l,4:3,6-dianhydrohexitols of structural formula (II), a residue of a saturated or unsaturated therapeutic diol, and mixtures thereof; or a PEUR polymer having a chemical structure described by general structural formula (V)
- R 2 is independently hydrogen, (Ci-Ci 2 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkyl, (C 6 -Cio) aryl or a protecting group; the R 3 S within an individual m monomer are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 6 -Ci 0 ) aryl (Ci-C 6 ) alkyl and-(CH 2 ) 2 S(CH 3 ); R 4 and R 6 is independently selected from (C 2 -C 2 o) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic- fragments of l,4:3,6-dianhydrohexitols of
- an effective amount of the residue of at least one therapeutic diol can be contained in the polymer backbone.
- at least one of R 4 or R 6 is a bicyclic fragment of l,4:3,6-dianhydrohexitol, such as 1,4:3,6- dianhydrosorbitol (DAS).
- DAS 1,4:3,6- dianhydrosorbitol
- the invention provides a polymer particle delivery composition in which a therapeutically effective amount of at least one bioactive agent is dispersed in a biodegradable polymer, wherein the polymer is a biodegradable PEU polymer having a chemical formula described by structural formula (VI):
- n is about 10 to about 150; the R 3 S within an individual n monomer are independently selected from hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -Cio) aryl (Ci-C 6 )alkyl and -(CH 2 ) 2 S(CH 3 ); R 4 is independently selected from (C 2 - C 2 o) alkylene, (C 2 -C 2 o) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a 1,4:3,6- dianhydrohexitol of structural formula (II) and mixtures thereof; or PEU polymer having a chemical formula described by structural formula (VII)
- R 2 is independently hydrogen, (Ci-Ci 2 ) alkyl, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkyl, (C 6 -Cio) aryl or a protecting group; and the R 3 S within an individual m monomer are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl and -(CH 2 ) 2 S(CH 3 ); R 4 is independently selected from (C 2 - C 2 o) alkylene, (C 2 -C 2 o) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C
- At least one R 4 is a residue of a saturated or unsaturated therapeutic diol, or a bicyclic fragment of a l,4:3,6-dianhydrohexitol, such as DAS.
- at least one R 4 is a bicyclic fragment of a l,4:3,6-dianhydrohexitol, such as DAS.
- PEU polymers can be fabricated as high molecular weight polymers useful for making the invention polymer particle delivery compositions for delivery to humans and other mammals of a variety of pharmaceutical and biologically active agents.
- the PEUs used in the invention bioactive implantable stents incorporate hydrolytically cleavable ester groups and non-toxic, naturally occurring monomers that contain ⁇ -amino acids in the polymer chains.
- the ultimate biodegradation products of PEUs will be amino acids, diols, and CO 2 .
- the invention PEUs are crystalline or semi-crystalline and possess advantageous mechanical, chemical and biodegradation properties that allow formulation of completely synthetic, and hence easy to produce, crystalline and semi-crystalline polymer particles, for example nanoparticles.
- the PEU polymers used in the invention polymer particle delivery compositions have high mechanical strength, and surface erosion of the PEU polymers can be catalyzed by enzymes present in physiological conditions, such as hydrolases.
- Suitable bicyclic-fragments of 1 ,4:3,6-dianhydrohexitols of general formula (II) can be derived from sugar alcohols, such as D-glucitol, D-mannitol, or L-iditol.
- Dianhydrosorbitol is the presently preferred bicyclic fragment of a 1,4:3,6- dianhydrohexitol for use in the PEA, PEUR and PEU polymers used in fabrication of the invention polymer particle delivery compositions.
- an effective amount of the residue of at least one therapeutic diol can be contained in the polymer backbone used in the invention stents, stent coverings, drug delivery compositions, and the like.
- amino acid and " ⁇ -amino acid” mean a chemical compound containing an amino group, a carboxyl group and a pendent R group, such as the R 3 groups defined herein.
- biological ⁇ -amino acid means the amino acid(s) used in synthesis are selected from phenylalanine, leucine, glycine, alanine, valine, isoleucine, methionine, or a mixture thereof.
- a "therapeutic diol” means any diol molecule, whether synthetically produced, or naturally occurring (e.g., endogenously) that affects a biological process in a mammalian individual, such as a human, in a therapeutic or palliative manner when administered to the mammal.
- the term "residue of a therapeutic diol” means a portion of a therapeutic diol, as described herein, which portion excludes the two hydroxyl groups of the diol.
- the term “residue of a therapeutic di-acid” means a portion of a therapeutic di-acid, as described herein, which portion excludes the two carboxyl groups of the di-acid. The corresponding therapeutic diol or di-acid containing the "residue" thereof is used in synthesis of the polymer compositions.
- the residue of the therapeutic di-acid or diol is reconstituted in vivo (or under similar conditions of pH, aqueous media, and the like) to the corresponding di-acid or diol upon release from the backbone of the polymer by biodegradation in a controlled manner that depends upon the properties of the PEA, PEUR or PEU polymer selected to fabricate the composition, which properties are as known in the art and as described herein.
- bioactive agent means a bioactive agent as disclosed herein that is not incorporated into the polymer backbone.
- bioactive agents may be included in the invention therapeutic polymers.
- the term “dispersed” is used to refer to additional bioactive agents and means that the additional bioactive agent is dispersed, mixed, dissolved, homogenized, and/or covalently bound (“dispersed") in a polymer, for example attached to a functional group in the polymer used in the invention, but not incorporated into the backbone of a PEA, PEUR, or PEU polymer.
- bioactive agent(s) dispersed therapeutic or palliative agents
- bioactive agent(s) may include, without limitation, small molecule drugs, peptides, proteins, DNA, cDNA, RNA, sugars, lipids and whole cells.
- the bioactive agents are administered in polymer particles having a variety of sizes and structures suitable to meet differing therapeutic goals and routes of administration.
- At least one of the ⁇ -amino acids used in fabrication of the invention polymers is a biological ⁇ -amino acid.
- the biological ⁇ -amino acid used in synthesis is L-phenylalanine.
- the polymer contains the biological ⁇ -amino acid, L-leucine.
- R 3 S By varying the R 3 S within monomers as described herein, other biological ce-amino acids can also be used, e.g., glycine (when the R 3 S are H), alanine (when the R 3 S are CH 3 ), valine (when the R 3 S are CH(CH 3 ) 2 ), isoleucine (when the R 3 S are CH(CH 3 )-CH 2 -CH 3 ), phenylalanine (when the R 3 S are CH 2 -C 6 Hs), or methionine (when the R 3 S are -(CH 2 ) 2 -S- CH 3 ) and mixtures thereof.
- all of the various ⁇ - amino acids contained in the polymers used in making the invention polymer particle delivery compositions are biological ⁇ -amino acids, as described herein.
- At least one of the R 3 S further can be -(CH 2 )3-, which cyclizes to form the chemical structure described by structural formula (XIII):
- biodegradable as used herein to describe the polymers used in the invention polymer particle delivery compositions means the polymer is capable of being broken down into innocuous and bioactive products in the normal functioning of the body. In one embodiment, the entire polymer particle delivery composition is biodegradable.
- the biodegradable polymers described herein have hydrolyzable ester and enzymatically cleavable amide linkages that provide the biodegradability, and are typically chain terminated predominantly with amino groups.
- these amino termini can be acetylated or otherwise capped by conjugation to any other acid- containing, biocompatible molecule, to include without restriction organic acids, bioinactive biologies and bioactive compounds such as adjuvant molecules.
- the PEA, PEUR and PEU polymer molecules may also have the bioactive agent or additional bioactive agent attached thereto, optionally via a linker or incorporated into a crosslinker between molecules.
- the polymer is contained in a polymer-bioactive agent conjugate having structural formula VIII:
- R 8 is H or (Ci-C 8 )alkyl; and R 7 is the bioactive agent.
- two molecules of the polymer of structural formula (IX) can be crosslinked to provide an -R 5 -R 7 -R 5 - conjugate.
- the bioactive agent is covalently linked to two parts of a single polymer molecule of structural formula IV through the -R 5 -R 7 -R 5 - conjugate and R 5 is independently selected from the group consisting of-O-, -S-, and - NR 8 -, wherein R 8 is H or (C 1 -Cs) alkyl; and R 7 is the bioactive agent.
- a linker, -X-Y- can be inserted between R 5 and bioactive agent R 7 , in the molecule of structural formula (IV), wherein X is selected from the group consisting Of(C 1 -C 18 ) alkylene, substituted alkylene, (C3-C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -C 18 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6 and Cio aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, substituted arylalken
- two parts of a single macromolecule are covalently linked to the bioactive agent through an -R 5 -R 7 -Y-X- R 5 - bridge (Formula XI):
- X is selected from the group consisting Of (C 1 -C 18 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -Ci 8 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, (C 6 - Cio) aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, substituted arylalkynyl, wherein the substituents are selected from the group consisting of H, F, Cl, Br,
- the polymer composition contains four molecules of the polymer, except that only two of the four molecules omit R 7 and are crosslinked to provide a single -R 5 -X-R 5 - conjugate.
- aryl is used with reference to structural formulae herein to denote a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. In certain embodiments, one or more of the ring atoms can be substituted with one or more of nitro, cyano, halo, trifluoromethyl, or trifiuoromethoxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, and nitrophenyl.
- alkenylene is used with reference to structural formulae herein to mean a divalent branched or unbranched hydrocarbon chain containing at least one unsaturated bond in the main chain or in a side chain.
- alkylene is used with reference to structural formulae herein to mean a branched or unbranched hydrocarbon chain containing no unsaturated bond in the main chain or in a side chain.
- the molecular weights and polydispersities herein are determined by gel permeation chromatography (GPC) using polystyrene standards. More particularly, number and weight average molecular weights (M n and M w ) are determined, for example, using a Model 510 gel permeation chromatography (Water Associates, Inc., Milford, MA) equipped with a high-pressure liquid chromatographic pump, a Waters 486 UV detector and a Waters 2410 differential refractive index detector. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAc) is used as the eluent (1.0 mL/min). Polystyrene or poly(methyl methacrylate) standards having narrow molecular weight distribution were used for calibration.
- GPC gel permeation chromatography
- the bis- ⁇ , ⁇ -diamine is entered into a polycondensation reaction with a di-acid such as sebacic acid, or bis-activated esters, or bis-acy ⁇ chlorides, to obtain the final polymer having both ester and amide bonds (PEA).
- a di-acid such as sebacic acid, or bis-activated esters, or bis-acy ⁇ chlorides
- PDA ester and amide bonds
- an activated diacid derivative e.g., bis-p-nitrophenyl diester
- a biscarbonates of diols such as bis(p-nitrophenyl)-carbonate, can be used as the activated species to obtain polymers containing a residue of a diol.
- R 4 in (I) is -C 4 H 8 - or -CeH 12 -.
- R 1 in (I) is -C 4 H 8 - or -C 8 Hi 6 -.
- the UPEAs can be prepared by solution polycondensation of either (1) di-p- toluene sulfonic acid salt of bis( ⁇ -amino acid) di-ester of unsaturated diol and di-p- nitrophenyl ester of saturated dicarboxylic acid or (2) di-p-toluene sulfonic acid salt of bis ( ⁇ -amino acid) diester of saturated diol and di-nitrophenyl ester of unsaturated dicarboxylic acid or (3) di-p-toluene sulfonic acid salt of bis( ⁇ -amino acid) diester of unsaturated diol and di-nitrophenyl ester of unsaturated dicarboxylic acid.
- Salts of p-toluene sulfonic acid are known for use in synthesizing polymers containing amino acid residues.
- the aryl sulfonic acid salts are used instead of the free base because the aryl sulfonic salts of bis ( ⁇ -amino acid) diesters are easily purified through recrystallization and render the amino groups as unreactive ammonium tosylates throughout workup.
- the nucleophilic amino group is readily revealed through the addition of an organic base, such as triethylamine, so the polymer product is obtained in high yield.
- the di-p-nitrophenyl esters of unsaturated dicarboxylic acid can be synthesized from p-nitrophenyl and unsaturated dicarboxylic acid chloride, e.g., by dissolving triethylamine and p-nitrophenol in acetone and adding unsaturated dicarboxylic acid chloride dropwise with stirring at -78 0 C and pouring into water to precipitate product.
- Suitable acid chlorides included fumaric, maleic, mesaconic, citraconic, glutaconic, itaconic, ethenyl-butane dioic and 2-propenyl- butanedioic acid chlorides.
- each R 5 is independently (C 6 -C 1O ) aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and R 6 is independently (C 2 -C 2 o) alkylene or (C 2 -C 20 ) alkyloxy, or (C 2 -C 2 o) alkenylene.
- Suitable therapeutic diol compounds that can be used to prepare bis( ⁇ -amino acid) diesters of therapeutic diol monomers, or bis(carbonate) of therapeutic di-acid monomers, for introduction into the invention stents, stent covering and drug delivery devices include naturally occurring therapeutic diols, such as 17-j8-estradiol, a natural and endogenous hormone, useful in preventing restenosis and tumor growth (Yang, N.N. ,et al. Identification of an estrogen response element activated by metabolites of 17- ⁇ -estradiol and raloxifene.
- incorpora therapeutic diol into the backbone of a PEA, PEUR or PEU polymer is illustrated, for example, by introduction of active steroid hormone 17-/3- estradiol containing mixed hydroxyls - secondary and phenolic - into the backbone of a PEA polymer.
- active steroid hormone 17-/3- estradiol containing mixed hydroxyls - secondary and phenolic - into the backbone of a PEA polymer.
- PTCA percutaneous transluminal coronary angioplasty
- 17-/3-estradiol is only one example of a diol with therapeutic properties that can be incorporated in the backbone of a PEA, PEUR or PEU polymer in accordance with the invention.
- any bioactive steroid- diol containing primary, secondary or phenolic hydroxyls can be used for this purpose.
- Many steroid esters that can be made from bioactive steroid diols for use in the invention are disclosed in European application EP 0127 829 A2.
- the amount of the therapeutic diol or di-acid incorporated in the polymer backbone can be controlled by varying the proportions of the building blocks of the polymer. For example, depending on the composition of the PEA, loading of up to 40% w/w of 17/3-estradiol can be achieved. Three different regular, linear PEAs with various loading ratios of 17j8-estradiol are illustrated in Scheme 1 below:
- the loading of the therapeutic diol into PEUR and PEU polymer can be varied by varying the amount of two or more building blocks of the polymer.
- synthetic steroid based diols based on testosterone or cholesterol such as 4-androstene-3, 17 diol (4-androstenediol), 5-androstene-3, 17 diol (5-androstenediol), 19-nor5-androstene-3, 17 diol (19-norandrostenediol) are suitable for incorporation into the backbone of PEA, PEUR and PEU polymers according to this invention.
- therapeutic diol compounds suitable for use in preparation of the invention polymer particle delivery compositions include, for example, amikacin; amphotericin B; apicycline; apramycin; arbekacin; azidamfenicol; bambermycin(s); butirosin; carbomycin; cefpiramide; chloramphenicol; chlortetracycline; clindamycin; clomocycline; demeclocycline; diathymosulfone; dibekacin, dihydrostreptomycin; dirithromycin; doxycycline; erythromycin; fortimicin(s); gentamycin(s); glucosulfone solasulfone; guamecycline; isepamicin; josamycin; kanamycin(s); leucomycin(s); lincomycin; lucensomycin; lymecycline; meclocycline; methacycline; micronomycin; midecamycin(s
- Suitable naturally occurring and synthetic therapeutic di-acids that can be used to prepare an amide linkage in the PEA polymer compositions of the invention include, for example, bambermycin(s); benazepril; carbenicillin; carzinophillin A; cefixime; cefminox cefpimizole; cefodizime; cefonicid; ceforanide; cefotetan; ceftazidime; ceftibuten; cephalosporin C; cilastatin; denopterin; edatrexate; enalapril; lisinopril; methotrexate; moxalactam; nifedipine; olsalazine; penicillin N; ramipril; quinacillin; quinapril; temocillin; ticarcillin; Tomudex® (N-[[5-[[(l,4-Dihydro-2-methyl-4-
- the di-aryl sulfonic acid salts of diesters of ⁇ -amino acid and unsaturated diol can be prepared by admixing ⁇ -amino acid, e.g., p-aryl sulfonic acid monohydrate and saturated or unsaturated diol in toluene, heating to reflux temperature, until water evolution is minimal, then cooling.
- the unsaturated diols include, for example, 2-butene- 1,3-diol and l,18-octadec-9-en-diol.
- Saturated di-p-nitrophenyl esters of dicarboxylic acid and saturated di-p-toluene sulfonic acid salts of bis- ⁇ -amino acid esters can be prepared as described in U.S. Patent No. 6,503,538 Bl.
- UPEAs unsaturated poly(ester-amide)s
- UPEAs having the structural formula (I) can be made in similar fashion to the compound (VII) of U. S. Patent No. 6,503,538 Bl, except that R 4 of (III) of 6,503,538 and/or R 1 of (V) of 6,503,538 is (C 2 -C 20 ) alkenylene as described above.
- the reaction is carried out, for example, by adding dry triethylamine to a mixture of said (III) and (IV) of 6,503,538 and said (V) of 6,503,538 in dry N,N-dimethylacetamide, at room temperature, then increasing the temperature to 80 0 C and stirring for 16 hours, then cooling the reaction solution to room temperature, diluting with ethanol, pouring into water, separating polymer, washing separated polymer with water, drying to about 30 0 C under reduced pressure and then purifying up to negative test on p-nitrophenol and p-toluene sulfonate.
- a preferred reactant (IV) of 6,503,538 is p-toluene sulfonic acid salt of Lysine benzyl ester, the benzyl ester protecting group is preferably removed from (II) to confer biodegradability, but it should not be removed by hydrogenolysis as in Example 22 of U.S. Patent No. 6,503,538 because hydrogenolysis would saturate the desired double bonds; rather the benzyl ester group should be converted to an acid group by a method that would preserve unsaturation.
- the lysine reactant (IV) of 6,503,538 can be protected by a protecting group different from benzyl that can be readily removed in the finished product while preserving unsaturation, e.g., the lysine reactant can be protected with t-butyl (i.e., the reactant can be t-butyl ester of lysine) and the t-butyl can be converted to H while preserving unsaturation by treatment of the product (II) with acid.
- t-butyl i.e., the reactant can be t-butyl ester of lysine
- a working example of the compound having structural formula (I) is provided by substituting p-toluene sulfonic acid salt of bis(L-phenylalanine) 2-butene-l,4-diester for (III) in Example 1 of 6,503,538 or by substituting di-p-nitrophenyl fumarate for (V) in Example 1 of 6,503,538 or by substituting the p-toluene sulfonic acid salt of bis(L- phenylalanine) 2-butene-l,4-diester for III in Example 1 of 6,503,538 and also substituting bis-p-nitrophenyl fumarate for (V) in Example 1 of 6,503,538.
- an amino substituted aminoxyl (N-oxide) radical bearing group e.g., 4- amino TEMPO
- carbonyldiimidazol or suitable carbodiimide
- Bioactive agents as described herein, can be attached via the double bond functionality. Hydrophilicity can be imparted by bonding to poly(ethylene glycol) diacrylate.
- the biodegradable PEA, PEUR and PEU polymers can contain from one to multiple different ⁇ -amino acids per polymer molecule and preferably have weight average molecular weights ranging from 10,000 to 125,000; these polymers and copolymers typically have intrinsic viscosities at 25 0 C, determined by standard viscosimetric methods, ranging from 0.3 to 4.0, for example, ranging from 0.5 to 3.5.
- PEA and PEUR polymers contemplated for use in the practice of the invention can be synthesized by a variety of methods well known in the art.
- tributyltin (IV) catalysts are commonly used to form polyesters such as poly(e- caprolactone), poly(glycolide), poly(lactide), and the like.
- a wide variety of catalysts can be used to form polymers suitable for use in the practice of the invention.
- Such poly(caprolactones) contemplated for use have an exemplary structural formula (XIV) as follows:
- Poly(glycolides) contemplated for use have an exemplary structural formula (XV) as follows:
- hydroxy terminated polymer chains can then be capped with maleic anhydride to form polymer chains having structural formula (XVIII):
- 4-amino-2,2,6,6-tetramethylpiperidine-l-oxy can be reacted with the carboxylic end group to covalently attach the aminoxyl moiety to the copolymer via the amide bond which results from the reaction between the 4-amino group and the carboxylic acid end group.
- the maleic acid capped copolymer can be grafted with polyacrylic acid to provide additional carboxylic acid moieties for subsequent attachment of further aminoxyl groups.
- an amino substituted aminoxyl (N-oxide) radical bearing group e.g., 4-amino TEMPO
- carbonyldiimidazole or suitable carbodiimide
- Additional bioactive agents, and the like, as described herein, optionally can be attached via the double bond functionality provided that the therapeutic diol residue in the polymer composition does not contain a double or triple bond.
- the invention high molecular weight semi-crystalline PEUs having structural formula (VI) can be prepared inter-facially by using phosgene as a bis- electrophilic monomer in a chloroform/water system, as shown in the reaction scheme (2) below:
- the ⁇ -amino acid can be converted into a bis( ⁇ -amino acid)- ⁇ , ⁇ -diol- diester monomer, for example, by condensing the ⁇ -amino acid with a diol HO-R ⁇ -OH. As a result, ester bonds are formed.
- acid chloride of carbonic acid (phosgene, diphosgene, triphosgene) is entered into a polycondensation reaction with a di-p- toluenesulfonic acid salt of a bis( ⁇ -amino acid) -alkylene diester to obtain the final polymer having both ester and urea bonds.
- at least one therapeutic diol can be used in the polycondensation protocol.
- the unsaturated PEUs can be prepared by interfacial solution condensation of di- p-toluenesulfonate salts of bis( ⁇ -amino acid)-alkylene diesters, comprising at least one double bond in R 1 .
- Unsaturated diols useful for this purpose include, for example, 2- butene-l,4-diol and l,18-octadec-9-en-diol.
- Unsaturated monomer can be dissolved prior to the reaction in alkaline water solution, e.g. sodium hydroxide solution.
- the water solution can then be agitated intensely, under external cooling, with an organic solvent layer, for example chloroform, which contains an equimolar amount of monomelic, dimeric or trimeric phosgene.
- an organic solvent layer for example chloroform, which contains an equimolar amount of monomelic, dimeric or trimeric phosgene.
- An exothermic reaction proceeds rapidly, and yields a polymer that (in most cases) remains dissolved in the organic solvent.
- the organic layer can be washed several times with water, dried with anhydrous sodium sulfate, filtered, and evaporated. Unsaturated PEUs with a yield of about 75%-85% can be dried in vacuum, for example at about 45°C.
- L-Leu based PEUs such as l-L-Leu-4 and 1- L-Leu-6
- L-Leu based PEUs can be fabricated using the general procedure described below. Such procedure is less successful in formation of a porous, strong material when applied to L-Phe based PEUs.
- reaction solution or emulsion (about 100 mL) of PEU in chloroform, as obtained just after interfacial polycondensation, is added dropwise with stirring to 1,000 mL of about 80 0 C -85 0 C water in a glass beaker, preferably a beaker made hydrophobic with dimethyldichlorsilane to reduce the adhesion of PEU to the beaker's walls.
- the polymer solution is broken in water into small drops and chloroform evaporates rather vigorously. Gradually, as chloroform is evaporated, small drops combine into a compact tar-like mass that is transformed into a sticky rubbery product.
- This rubbery product is removed from the beaker and put into hydrophobized cylindrical glass-test-tube, which is thermostatically controlled at about 80 0 C for about 24 hours. Then the test-tube is removed from the thermostat, cooled to room temperature, and broken to obtain the polymer. The obtained porous bar is placed into a vacuum drier and dried under reduced pressure at about 80 0 C for about 24 hours.
- any procedure known in the art for obtaining porous polymeric materials can also be used.
- a glass transition temperature in the range from about 30 C° to about 90 C°, for example, in the range from about 35 C° to about 70 C°; 2.
- a film of the polymer with average thickness of about 1.6 cm will have tensile stress at yield of about 20 Mpa to about 150 Mpa, for example, about 25 Mpa to about 60 Mpa;
- a film of the polymer with average thickness of about 1.6 cm will have a percent elongation of about 10 % to about 200%, for example about 50 % to about 150%;
- a film of the polymer with average thickness of about 1.6 cm will have a Young's modulus in the range from about 500 MPa to about 2000 MPa.
- dispensersed means at least one bioactive agent as disclosed herein is dispersed, mixed, dissolved, homogenized, and/or covalently bound (“dispersed") in a polymer particle, for example attached to the surface of the particle.
- bioactive agents can be dispersed within the polymer matrix without chemical linkage to the polymer carrier, it is also contemplated that the bioactive agent or covering molecule can be covalently bound to the biodegradable polymers via a wide variety of suitable functional groups.
- the carboxyl group chain end can be used to react with a complimentary moiety on the bioactive agent or covering molecule, such as hydroxy, amino, thio, and the like.
- a complimentary moiety on the bioactive agent or covering molecule such as hydroxy, amino, thio, and the like.
- a bioactive agent can be linked to the PEA, PEUR or PEU polymers described herein through an amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl, disulfide linkage.
- Such a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art.
- a polymer can be linked to the bioactive agent via an end or pendent carboxyl group (e.g., COOH) of the polymer.
- carboxyl group e.g., COOH
- a compound of structures III, V and VII can react with an amino functional group or a hydroxyl functional group of a bioactive agent to provide a biodegradable polymer having the bioactive agent attached via an amide linkage or carboxylic ester linkage, respectively.
- the carboxyl group of the polymer can be benzylated or transformed into an acyl halide, acyl anhydride/"mixed" anhydride, or active ester.
- the free -NH 2 ends of the polymer molecule can be acylated to assure that the bioactive agent will attach only via a carboxyl group of the polymer and not to the free ends of the polymer.
- the molecular weights of PEG molecules on a single particle can be substantially any molecular weight in the range from about 200 to about 200,000, so that the molecular weights of the various PEG molecules attached to the particle can be varied.
- the bioactive agent or covering molecule can be attached to the polymer via a linker molecule, for example, as described in structural formulas (VIII-XI).
- a linker may be utilized to indirectly attach the bioactive agent to the biodegradable polymer.
- the linker compounds include poly(ethylene glycol) having a molecular weight (MW) of about 44 to about 10,000, preferably 44 to 2000; amino acids, such as serine; polypeptides with repeat number from 1 to 100; and any other suitable low molecular weight polymers.
- the linker typically separates the bioactive agent from the polymer by about 5 angstroms up to about 200 angstroms.
- alkyl refers to a straight or branched chain hydrocarbon group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
- alkenyl refers to straight or branched chain hydrocarbyl groups having one or more carbon-carbon double bonds.
- alkynyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond.
- aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms.
- the linker may be a polypeptide having from about 2 up to about 25 amino acids.
- Suitable peptides contemplated for use include poly-L-glycine, poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L- ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L- lysine-L-phenylalanine, poly-L-arginine, poly-L-lysine-L-tyrosine, and the like.
- the bioactive agent can covalently crosslink the polymer, i.e. the bioactive agent is bound to more than one polymer molecule. This covalent crosslinking can be done with or without additional polymer-bioactive agent linker.
- bioactive agent molecule can also be incorporated into an intramolecular bridge by covalent attachment between two polymer molecules.
- a linear polymer polypeptide conjugate is made by protecting the potential nucleophiles on the polypeptide backbone and leaving only one reactive group to be bound to the polymer or polymer linker construct. Deprotection is performed according to methods well known in the art for deprotection of peptides (Boc and Fmoc chemistry for example).
- a polypeptide bioactive agent is presented as retro-inverso or partial retro-inverso peptide.
- the bioactive agent is mixed with a photocrosslinkable version of the polymer in a matrix, and after crosslinking the material is dispersed (ground) to an average diameter in the range from about 0.1 to about lO ⁇ m.
- the linker can be attached first to the polymer or to the bioactive agent or covering molecule.
- the linker can be either in unprotected form or protected form, using a variety of protecting groups well known to those skilled in the art.
- the unprotected end of the linker can first be attached to the polymer or the bioactive agent or covering molecule.
- the protecting group can then be de-protected using PdZH 2 hydrogenolysis, mild acid or base hydrolysis, or any other common de-protection method that is known in the art.
- the de-protected linker can then be attached to the bioactive agent or covering molecule, or to the polymer [0175]
- An exemplary synthesis of a biodegradable polymer according to the invention (wherein the molecule to be attached is an aminoxyl) is set forth as follows.
- a polyester can be reacted with an amino-substituted aminoxyl (N-oxide) radical bearing group, e.g., 4-amino-2,2,6,6-tetramethylpiperidine-l-oxy, in the presence of N 9 N'- carbonyldiimidazole to replace the hydroxyl moiety in the carboxyl group at the chain end of the polyester with an amino-substituted aminoxyl-(N-oxide) radical bearing group, so that the amino moiety covalently bonds to the carbon of the carbonyl residue of the carboxyl group to form an amide bond.
- N-oxide amino-substituted aminoxyl
- the N,N'-carbonyl diimidazole or suitable carbodiimide converts the hydroxyl moiety in the carboxyl group at the chain end of the polyester into an intermediate product moiety which will react with the aminoxyl, e.g., 4- amino-2,2,6,6-tetramethylpiperidine-l-oxy.
- the aminoxyl reactant is typically used in a mole ratio of reactant to polyester ranging from 1:1 to 100: 1.
- the mole ratio of N,N'- carbonyl diimidazole to aminoxyl is preferably about 1:1.
- a typical reaction is as follows.
- a polyester is dissolved in a reaction solvent and reaction is readily carried out at the temperature utilized for the dissolving.
- the reaction solvent may be any in which the polyester will dissolve.
- the polyester is a polyglycolic acid or a poly(glycolide-L-lactide) (having a monomer mole ratio of glycolic acid to L-lactic acid greater than 50:50), highly refined (99.9+% pure) dimethyl sulfoxide at 115 0 C to 130 0 C or DMSO at room temperature suitably dissolves the polyester.
- polyester is a poly-L-lactic acid
- a poly-DL-lactic acid or a poly(glycolide-L- lactide) having a monomer mole ratio of glycolic acid to L-lactic acid 50:50 or less than 50:50
- tetrahydrofuran tetrahydrofuran
- dichloromethane DCM
- chloroform at room temperature to 40 ⁇ 50 0 C suitably dissolve the polyester.
- the polymers used to make the invention stents, stent coatings and sheath, and drug delivery compositions as described herein have one or more bioactive agent directly linked to the polymer.
- the residues of the polymer can be linked to the residues of the one or more bioactive agents.
- one residue of the polymer can be directly linked to one residue of the bioactive agent.
- the polymer and the bioactive agent can each have one open valence.
- more than one bioactive agent, multiple bioactive agents, or a mixture of bioactive agents having different therapeutic or palliative activity can be directly linked to the polymer.
- the residue of each bioactive agent can be linked to a corresponding residue of the polymer, the number of residues of the one or more bioactive agents can correspond to the number of open valences on the residue of the polymer.
- a "residue of a polymer” refers to a radical of a polymer having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the polymer (e.g., on the polymer backbone or pendant group) of the present invention can be removed to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent. Additionally, any synthetically feasible functional group (e.g., carboxyl) can be created on the polymer (e.g., on the polymer backbone or pendant group) to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent. Based on the linkage that is desired, those skilled in the art can select suitably functionalized starting materials that can be derived from the polymer of the present invention using procedures that are known in the art.
- a "residue of a compound of structural formula (*)” refers to a radical of a compound of polymer formulas (I) and (III- VII) as described herein having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the compound (e.g., on the polymer backbone or pendant group) can be removed to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent.
- any synthetically feasible functional group e.g., carboxyl
- any synthetically feasible functional group can be created on the compound of formulas (I) and (III- VII) (e.g., on the polymer backbone or pendant group) to provide the open valance, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent.
- suitably functionalized starting materials that can be derived from the compound of formulas (I) and III— VII) using procedures that are known in the art.
- Such a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art. Based on the linkage that is desired, those skilled in the art can select suitably functional starting material that can be derived from a residue of a compound of structural formula (I) or (III- VII) and from a given residue of a bioactive agent or adjuvant using procedures that are known in the art. The residue of the bioactive agent or adjuvant can be linked to any synthetically feasible position on the residue of a compound of structural formula (I) or (III- VII). Additionally, the invention also provides compounds having more than one residue of a bioactive agent or adjuvant bioactive agent directly linked to a compound of structural formula (I) or (III-VII).
- bioactive agents that can be linked to the polymer molecule can typically depend upon the molecular weight of the polymer. For example, for a compound of structural formula (I), wherein n is about 5 to about 150, preferably about 5 to about 70, up to about 150 bioactive agent molecules (i.e., residues thereof) can be directly linked to the polymer (i.e., residue thereof) by reacting the bioactive agent with side groups of the polymer. In unsaturated polymers, the bioactive agents can also be reacted with double (or triple) bonds in the polymer.
- the polymer covering in the invention bioactive stents, and other surgical devices plays an active role in the treatment processes at the site of local administration, e.g., by implant, by holding the bioactive agent at a site of implant.
- the polymer with dispersed bioactive agent can be injected or implanted in an agglomeration or polymer depot at a local site and will remain at the site while the polymer biodegrades. In either case, the polymer remains for a period of time sufficient to allow the subject's endogenous processes to slowly release bioactive agents from the polymer covering or from the agglomeration.
- bioactive agents can be dispersed within the polymer matrix without chemical linkage to the polymer carrier, it is also contemplated that the bioactive agent or additional bioactive agent can be covalently bound to the biodegradable polymers via a wide variety of suitable functional groups.
- the carboxyl group chain end can be used to react with a complimentary moiety on the bioactive agent or additional bioactive agent, such as hydroxy, amino, thio, and the like.
- a complimentary moiety on the bioactive agent or additional bioactive agent such as hydroxy, amino, thio, and the like.
- a bioactive agent can be linked to any of the polymers of structures (I and III- VII) through an amino, hydroxyl (alcohol) or thiol linkage.
- a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art.
- a polymer can be linked to the bioactive agent or additional bioactive agent via a carboxyl group (e.g., COOH) of the polymer.
- a carboxyl group e.g., COOH
- a compound of structures (I) and (III) can react with an amino functional group or a hydroxyl functional group of a bioactive agent to provide a biodegradable polymer having the bioactive agent attached via an amide linkage or carboxylic ester linkage, respectively.
- the carboxyl group of the polymer can be benzylated or transformed into an acyl halide, acyl anhydride/"mixed" anhydride, or active ester.
- the free -NH 2 ends of the polymer molecule can be acylated to assure that the bioactive agent will attach only via a carboxyl group of the polymer and not to the free ends of the polymer.
- the bioactive agent or additional bioactive agent can be attached to the polymer via a linker molecule, for example, as described in structural formulae (VIII - X).
- a linker may be utilized to indirectly attach the bioactive agent and/or adjuvant to the biodegradable polymer.
- the linker compounds include poly(ethylene glycol) having a molecular weight (MW) of about 44 to about 10,000, preferably 44 to 2000; amino acids, such as serine; polypeptides with repeat number from 1 to 100; and any other suitable low molecular weight polymers.
- the linker typically separates the bioactive agent from the polymer by about 5 angstroms up to about 200 angstroms.
- alkyl refers to a straight or branched chain hydrocarbon group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-buryl, n-hexyl, and the like.
- alkenyl refers to straight or branched chain hydrocarbyl groups having one or more carbon-carbon double bonds.
- alkynyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond.
- aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms.
- the linker may be a polypeptide having from about 2 up to about 25 amino acids.
- Suitable peptides contemplated for use include poly-L-glycine, poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L- ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L- lysine-L-phenylalanine, poly-L-arginine, poly-L-lysine-L-tyrosine, and the like.
- the bioactive agent can covalently crosslink the polymer, i.e. the bioactive agent is bound to more than one polymer molecule. This covalent crosslinking can be done with or without additional polymer-bioactive agent linker.
- the bioactive agent molecule can also be incorporated into an intramolecular bridge by covalent attachment between two polymer molecules.
- a linear polymer polypeptide conjugate is made by protecting the potential nucleophiles on the polypeptide backbone and leaving only one reactive group to be bound to the polymer or polymer linker construct. Deprotection is performed according to methods well known in the art for deprotection of peptides (Boc and Fmoc chemistry for example).
- a polypeptide bioactive agent is presented as retro-inverso or partial retro-inverso peptide.
- the terms "peptide” and "polypeptide,” as used herein, include peptides, wholly peptide derivatives (such as branched peptides) and covalent hetero- (such as glyco- and lipo- and glycolipo-) derivatives of peptides.
- the peptides described herein can be synthesized using any technique as is known in the art.
- the peptides and polypeptides can also include "peptide mimetics.”
- Peptide analogs are commonly used in the pharmaceutical industry as non-peptide bioactive agents with properties analogous to those of the template peptide. These types of non- peptide compound are termed "peptide mimetics" or "peptidomimetics.” Fauchere, J. (1986) Adv. Bioactive agent Res., 15:29; Veber and Freidinger (1985) TINSp. 392; and Evans et al. (1987) J. Med. Chem., 30: 1229; and are usually developed with the aid of computerized molecular modeling.
- Such peptide mimetics may have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others.
- substitution of one or more amino acids within a peptide or polypeptide may be used to generate more stable peptides and peptides resistant to endogenous proteases.
- the synthetic peptide or polypeptide e.g., covalently bound to the biodegradable polymer, can also be prepared from D-amino acids, referred to as inverso peptides.
- inverso peptides When a peptide is assembled in the opposite direction of the native peptide sequence, it is referred to as a retro peptide.
- peptides prepared from D-amino acids are very stable to enzymatic hydrolysis.
- the linker can be attached first to the polymer or to the bioactive agent or additional bioactive agent.
- the linker can be either in unprotected form or protected form, using a variety of protecting groups well known to those skilled in the art.
- the unprotected end of the linker can first be attached to the polymer or the bioactive agent or additional bioactive agent.
- the protecting group can then be de-protected using PdZH 2 hydrogenation for saturated polymers, mild acid or base hydrolysis for unsaturated polymers, or, any other common de-protection method that is known in the art.
- the de-protected linker can then be attached to the bioactive agent or additional bioactive agent, or to the polymer
- a polyester can be reacted with an amino substituted aminoxyl (N-oxide) radical bearing group, e.g., 4-amino-2,2,6,6-tetramethylpiperidine-l-oxy, in the presence of N 5 N 1 - carbonyldiimidazole or suitable carbodiimide to replace the hydroxyl moiety in the carboxyl group at the chain end of the polyester with an amino substituted aminoxyl (N- oxide) radical bearing group, so that the amino moiety covalently bonds to the carbon of the carbonyl residue of the carboxyl group to form an amide bond.
- N-oxide amino substituted aminoxyl
- the N 5 N'- carbonyldiimidazole or suitable carbodiimide converts the hydroxyl moiety in the carboxyl group at the chain end of the polyester into an intermediate activated moiety which will react with the aminoxyl, e.g., 4-amino-2,2,6,6-tetramethylpiperidine-l-oxy.
- the aminoxyl reactant is typically used in a mole ratio of reactant to polyester ranging from 1:1 to 100:1.
- the mole ratio of N,N'-carbonyldiimidazole to aminoxyl is preferably about 1:1.
- a typical reaction is as follows.
- a polyester is dissolved in a reaction solvent and reaction is readily carried out at the temperature utilized for the dissolving.
- the reaction solvent may be any in which the polyester will dissolve; this information is normally available from the manufacturer of the polyester.
- the polyester is a polyglycolic acid or a poly(glycolide-L-lactide) (having a monomer mole ratio of glycolic acid to L- lactic acid greater than 50:50), highly refined (99.9+% pure) dimethyl sulfoxide at 115 0 C to 130 0 C or DMSO at room temperature suitably dissolves the polyester.
- polyester is a poly-L-lactic acid
- a poly-DL-lactic acid or a poly(glycolide-L-lactide) having a monomer mole ratio of glycolic acid to L-lactic acid 50:50 or less than 50:50
- tetrahydrofuran tetrahydrofuran
- dichloromethane DCM
- chloroform at room temperature to 40 ⁇ 50 0 C suitably dissolve the polyester.
- the reaction is typically carried out to substantial completion in 30 minutes to 5 hours.
- a polyglycolic acid or a poly(glycolide-L-lactide) from a glycol-rich monomer mixture constitutes the polyester, 2 to 3 hours of reaction time is preferred.
- a poly-L-lactic acid is the polyester, the reaction is readily carried out to substantial completion at room temperature for one hour.
- the reaction is preferably carried out under an inert atmosphere with dry nitrogen purging so as to drive the reaction towards completion.
- the product may be precipitated from the reaction mixture by adding cold non- solvent for the product.
- cold non- solvent for the product For example, aminoxyl-containing polyglycolic acid and aminoxyl-containing poly(glycolide-L-lactide) formed from glycolic acid-rich monomer mixture are readily precipitated from hot dimethylsulfoxide by adding cold methanol or cold acetone/methanol mixture and then recovered, e.g., by filtering.
- the product and solvent may be separated by using vacuum techniques.
- aminoxyl- containing poly-L-lactic acid is advantageously separated from solvent in this way.
- the recovered product is readily further purified by washing away water and by-products (e.g.
- urea with a solvent which does not dissolve the product, e.g., methanol in the case of the modified polyglycolic acid, polylactic acid and poly(glycolide-L-lactide) products herein. Residual solvent from such washing may be removed using vacuum drying.
- a solvent which does not dissolve the product e.g., methanol in the case of the modified polyglycolic acid, polylactic acid and poly(glycolide-L-lactide) products herein. Residual solvent from such washing may be removed using vacuum drying.
- the polymers used to make the surface covering for the invention stents and other medical devices as described herein have one or more bioactive agent directly linked to the polymer.
- the residues of the polymer can be linked to the residues of the one or more bioactive agents.
- one residue of the polymer can be directly linked to one residue of the bioactive agent.
- the polymer and the bioactive agent can each have one open valence.
- bioactive agent more than one bioactive agent, multiple bioactive agents, or a mixture of bioactive agents and additional bioactive agents having different therapeutic or palliative activity can be directly linked to the polymer.
- residue of each bioactive agent can be linked to a corresponding residue of the polymer, the number of residues of the one or more bioactive agents can correspond to the number of open valences on the residue of the polymer.
- a "residue of a polymer” refers to a radical of a polymer having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the polymer (e.g., on the polymer backbone or pendant group) of the present invention can be removed to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent. Additionally, any synthetically feasible functional group (e.g., carboxyl) can be created on the polymer (e.g., on the polymer backbone or pendant group) to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent. Based on the linkage that is desired, those skilled in the art can select suitably functionalized starting materials that can be derived from the polymer of the present invention using procedures that are known in the art.
- a "residue of a compound of structural formula (*)” refers to a radical of a compound of polymer formulas (I and III- VII) as described herein having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the compound (e.g., on the polymer backbone or pendant group) can be removed to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent.
- any synthetically feasible functional group e.g., carboxyl
- any synthetically feasible functional group can be created on the compound of formulas (I and III- VII) (e.g., on the polymer backbone or pendant group) to provide the open valance, provided bioactivity is substantially retained when the radical is attached to a residue of a bioactive agent.
- those skilled in the art can select suitably functionalized starting materials that can be derived from the compound of formulas (I - VII) using procedures that are known in the art.
- Such a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art. Based on the linkage that is desired, those skilled in the art can select suitably functional starting material that can be derived from a residue of a compound of structural formula (I or III - VII) and from a given residue of a bioactive agent or adjuvant using procedures that are known in the art. The residue of the bioactive agent or adjuvant can be linked to any synthetically feasible position on the residue of a compound of structural formula (I or III - VII). Additionally, the invention also provides compounds having more than one residue of a bioactive agent or adjuvant bioactive agent directly linked to a compound of structural formula (I and III - VII).
- the number of bioactive agents that can be linked to the polymer molecule can typically depend upon the molecular weight of the polymer. For example, for a compound of structural formula (I), wherein n is about 5 to about 150, preferably about 5 to about 70, up to about 150 bioactive agent molecules (i.e., residues thereof) can be directly linked to the polymer (i.e., residue thereof) by reacting the bioactive agent with side groups of the polymer. In unsaturated polymers, the bioactive agents can also be reacted with double (or triple) bonds in the polymer.
- Stents according to the invention are typically cylindrical in shape.
- the walls of the stent structure can be formed of metal or polymer with openings therein, e.g., a mesh.
- the stent is implanted into a body lumen, such as a blood vessel, where it stays permanently or biodegrades, to keep the vessel open and to improve blood flow to the heart muscle and promote natural wound healing processes at a location of damaged endothelium.
- Stents can also be positioned in vasculature in other parts of the body, such as the peripheral limbs, the kidneys or the brain.
- the stenting procedure is fairly common, and various types of stents have been developed and used as is known in the art.
- the polymers described herein can be coated onto the surface of a porous stent structure or other medical device as described here in many ways, such as dip-coating, spray-coating, ionic deposition, and the like, as is well known in the art.
- care must be taken not to occlude the pores in the stent structure, which are needed to allow access and migration from the interior of the vessel to the vessel wall of blood borne progenitor endothelial cells and other blood factors that participate in the natural biological process of wound healing.
- the polymer coating on the surface of the stent structure can be formed as a polymer sheath that is applied over the stent structure.
- the sheath serves as a partial physical barrier to macrophages so that a relatively small number of smooth muscle cells are activated to cause neointimal proliferation.
- the sheath can be laser ablated to form openings in the polymer coating.
- the stent structure can be moved while the laser is held stationary to ablate the structure into a pattern, or alternatively, the laser can be programmed to move along a predetermined pattern by a method known to artisans. A combination of both, i.e. moving both the laser and the structure, is also possible. In the present invention, even a coated stent having a complex stent pattern can be made with high precision.
- the stent structure can be formed of any suitable substance, such as is known in the art, that can be processed (e.g., molded, stamped, woven, etc.) to contain the porous surface features described herein.
- the stent body can be formed from a biocompatible metal, such as stainless steel, tantalum, nitinol, elgiloy, and the like, as well as suitable combinations thereof.
- metal stent structures can be formed of a material comprising metallic fibers uniformly laid to form a three-dimensional non-woven matrix and sintered to form a labyrinth structure exhibiting high porosity, typically in a range from about 50 percent to about 85 percent, preferably at least about 70 percent.
- the metal fibers typically have a diameter in the range from about 1 micron to 25 microns.
- Pores in the stent structure can have an average diameter in the range from about 30 microns to about 65 microns.
- the stent structure should be made of 100% stainless steel, with fully annealed stainless steel being a preferred metal.
- the stent structure can be of the type that is balloon expandable, as is known in the art.
- the stent structure is itself entirely biodegradable, being made of cross-linkable "star structure polymers", or dendrimers, which are well known to those skilled in the art.
- the stent structure is formed from biodegradable cross- linked poly(ester amide), polycaprolactone, or poly(ester urethane) as described herein.
- the stent structure i.e., the "stent struts" is preferably biodegradable and hence is made of such cross-linkable polymers or dendrimers.
- Residues of the polymers described herein can be formed employing any suitable reagents and reaction conditions. Suitable reagents and reaction conditions are disclosed, e.g., in Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Carey and Sundberg (1983); Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Second Edition, March (1977); and Comprehensive Organic Transformations, Second Edition, Larock (1999).
- an “additional bioactive agent” refers to a therapeutic or diagnostic agent other than the above described “bioactive” agents, which promote the natural wound healing process of re-endothelialization of vessels as disclosed herein.
- additional bioactive agents for example wound healing agents, antibiotics, and the like, can also be attached to polymer coatings on the surface of the invention stents or to polymers used for coating other types of insertable or implantable medical or therapeutic devices having different treatment aims as are known in the art, wherein contact of the polymer coating with a treatment surface or blood borne cell or factor, or release from the polymer coating by biodegradation is desirable.
- additional bioactive agents are not used in the inner layer of the invention multilayered stents, which contain only the "bioactive agents” that promote the natural wound healing process of re- endothelialization of vessels.
- such additional bioactive agent can include, but is not limited to, one or more of: polynucleotides, polypeptides, oligonucleotides, gene therapy agents, nucleotide analogs, nucleoside analogs, polynucleic acid decoys, therapeutic antibodies, abciximab, anti-inflammatory agents, blood modifiers, anti-platelet agents, anticoagulation agents, immune suppressive agents, anti-neoplastic agents, anti-cancer agents, anti-cell proliferation agents, and nitric oxide releasing agents.
- the polynucleotide can include deoxyribonucleic acid (DNA), ribonucleic acid (RNA), double stranded DNA, double stranded RNA, duplex DNA/RNA, antisense polynucleotides, functional RNA or a combination thereof.
- the polynucleotide can be RNA.
- the polynucleotide can be DNA.
- the polynucleotide can be an antisense polynucleotide.
- the polynucleotide can be a sense polynucleotide.
- the polynucleotide can include at least one nucleotide analog.
- the polynucleotide can include a phosphodiester linked 3'-5' and 5'-3' polynucleotide backbone.
- the polynucleotide can include non-phosphodiester linkages, such as phosphotioate type, phosphoramidate and peptide-nucleotide backbones.
- moieties can be linked to the backbone sugars of the polynucleotide. Methods of creating such linkages are well known to those of skill in the art.
- the polynucleotide can be a single-stranded polynucleotide or a double-stranded polynucleotide.
- the polynucleotide can have any suitable length. Specifically, the polynucleotide can be about 2 to about 5,000 nucleotides in length, inclusive; about 2 to about 1000 nucleotides in length, inclusive; about 2 to about 100 nucleotides in length, inclusive; or about 2 to about 10 nucleotides in length, inclusive.
- An antisense polynucleotide is typically a polynucleotide that is complimentary to an mRNA that encodes a target protein.
- the mRNA can encode a cancer promoting protein i.e., the product of an oncogene.
- the antisense polynucleotide is complimentary to the single-stranded mRNA and will form a duplex and thereby inhibit expression of the target gene, i.e., will inhibit expression of the oncogene.
- the antisense polynucleotides of the invention can form a duplex with the mRNA encoding a target protein and will disallow expression of the target protein.
- a "functional RNA” refers to a ribozyme or other RNA that is not translated.
- a "polynucleic acid decoy” is a polynucleic acid that inhibits the activity of a cellular factor upon binding of the cellular factor to the polynucleic acid decoy.
- the polynucleic acid decoy contains the binding site for the cellular factor.
- cellular factors include, but are not limited to, transcription factors, polymerases and ribosomes.
- An example of a polynucleic acid decoy for use as a transcription factor decoy will be a double-stranded polynucleic acid containing the binding site for the transcription factor.
- the polynucleic acid decoy for a transcription factor can be a single-stranded nucleic acid that hybridizes to itself to form a snap-back duplex containing the binding site for the target transcription factor.
- An example of a transcription factor decoy is the E2F decoy.
- E2F plays a role in transcription of genes that are involved with cell-cycle regulation and that cause cells to proliferate. Controlling E2F allows regulation of cellular proliferation. For example, after injury (e.g., angioplasty, surgery, stenting) smooth muscle cells proliferate in response to the injury. Proliferation may cause restenosis of the treated area (closure of an artery through cellular proliferation).
- modulation of E2F activity allows control of cell proliferation and can be used to decrease proliferation and avoid closure of an artery.
- examples of other such polynucleic acid decoys and target proteins include, but are not limited to, promoter sequences for inhibiting polymerases and ribosome binding sequences for inhibiting ribosomes. It is understood that the invention includes polynucleic acid decoys constructed to inhibit any target cellular factor.
- a "gene therapy agent” refers to an agent that causes expression of a gene product in a target cell through introduction of a gene into the target cell followed by expression.
- An example of such a gene therapy agent would be a genetic construct that causes expression of a protein, such as insulin, when introduced into a cell.
- a gene therapy agent can decrease expression of a gene in a target cell.
- An example of such a gene therapy agent would be the introduction of a polynucleic acid segment into a cell that would integrate into a target gene and disrupt expression of the gene. Examples of such agents include viruses and polynucleotides that are able to disrupt a gene through homologous recombination. Methods of introducing and disrupting genes with cells are well known to those of skill in the art.
- An oligonucleotide of the invention can have any suitable length. Specifically, the oligonucleotide can be about 2 to about 100 nucleotides in length, inclusive; up to about 20 nucleotides in length, inclusive; or about 15 to about 30 nucleotides in length, inclusive.
- the oligonucleotide can be single-stranded or double-stranded. In one embodiment, the oligonucleotide can be single-stranded.
- the oligonucleotide can be DNA or RNA. In one embodiment, the oligonucleotide can be DNA. In one embodiment, the oligonucleotide can be synthesized according to commonly known chemical methods.
- the oligonucleotide can be obtained from a commercial supplier.
- the oligonucleotide can include, but is not limited to, at least one nucleotide analog, such as bromo derivatives, azido derivatives, fluorescent derivatives or a combination thereof. Nucleotide analogs are well known to those of skill in the art.
- the oligonucleotide can include a chain terminator.
- the oligonucleotide can also be used, e.g., as a cross-linking reagent or a fluorescent tag. Many common linkages can be employed to couple an oligonucleotide to another moiety, e.g., phosphate, hydroxyl, etc.
- a moiety may be linked to the oligonucleotide through a nucleotide analog incorporated into the oligonucleotide.
- the oligonucleotide can include a phosphodiester linked 3'-5' and 5'-3' oligonucleotide backbone.
- the oligonucleotide can include non-phosphodiester linkages, such as phosphotioate type, phosphoramidate and peptide-nucleotide backbones.
- moieties can be linked to the backbone sugars of the oligonucleotide. Methods of creating such linkages are well known to those of skill in the art.
- Nucleotide and nucleoside analogues are well known in the art.
- nucleoside analogs include, but are not limited to, Cytovene® (Roche Laboratories), Epivir® (Glaxo Wellcome), Gemzar® (Lilly), Hivid® (Roche Laboratories), Rebetron® (Schering), Videx® (Bristol-Myers Squibb), Zerit® (Bristol-Myers Squibb), and Zovirax® (Glaxo Wellcome). See, Physician 's Desk Reference, 2005 Edition.
- Polypeptides acting as additional bioactive agents attached to the polymers in the invention stent coverings and other medical devices can have any suitable length.
- the polypeptides can be about 2 to about 5,000 amino acids in length, inclusive; about 2 to about 2,000 amino acids in length, inclusive; about 2 to about 1,000 amino acids in length, inclusive; or about 2 to about 100 amino acids in length, inclusive.
- the additional bioactive agent polypeptide attached to the polymer coatings for the invention medical devices can be an antibody.
- the antibody can bind to a cell adhesion molecule, such as a cadherin, integrin or selectin.
- the antibody can bind to an extracellular matrix molecule, such as collagen, elastin, fibronectin or laminin.
- the antibody can bind to a receptor, such as an adrenergic receptor, B-cell receptor, complement receptor, cholinergic receptor, estrogen receptor, insulin receptor, low-density lipoprotein receptor, growth factor receptor or T-cell receptor.
- Antibodies attached to polymers (either directly or by a linker) in the invention medical devices can also bind to platelet aggregation factors (e.g., fibrinogen), cell proliferation factors (e.g., growth factors and cytokines), and blood clotting factors (e.g., fibrinogen).
- an antibody can be conjugated to an active agent, such as a toxin.
- the antibody can be Abciximab (ReoProR)).
- Abciximab is an Fab fragment of a chimeric antibody that binds to beta(3) integrins.
- Abciximab is specific for platelet glycoprotein Ilb/IIIa receptors, e.g., on blood cells.
- Human aortic smooth muscle cells express alpha(v)beta(3) integrins on their surface. Treating beta(3) expressing smooth muscle cells may prohibit adhesion of other cells and decrease cellular migration or proliferation, thus reducing restenosis following percutaneous coronary interventions (CPI) e.g., stenosis, angioplasty, stenting.
- CPI percutaneous coronary interventions
- Abciximab also inhibits aggregation of blood platelets.
- the peptide can be a glycopeptide.
- glycopeptide refers to oligopeptide (e.g. heptapeptide) antibiotics, characterized by a multi-ring peptide core optionally substituted with saccharide groups, such as vancomycin. Examples of glycopeptides included in this definition may be found in "Glycopeptides Classification, Occurrence, and Discovery," by Raymond C. Rao and Louise W. Crandall, ("Bioactive agents and the Pharmaceutical Sciences” Volume 63, edited by Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.). Additional examples of glycopeptides are disclosed in U.S. Patent Nos.
- glycopeptides include those identified as KAIl, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimyein, Chloroorientiein, Chloropolysporin, Decaplanin, -demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin, UK-68597, UD-69542, UK-720
- glycopeptide or "glycopeptide antibiotic” as used herein is also intended to include the general class of glycopeptides disclosed above on which the sugar moiety is absent, i.e. the aglycone series of glycopeptides. For example, removal of the disaccharide moiety appended to the phenol on vancomycin by mild hydrolysis gives vancomycin aglycone. Also included within the scope of the term “glycopeptide antibiotics" are synthetic derivatives of the general class of glycopeptides disclosed above, included alkylated and acylated derivatives.
- glycopeptides that have been further appended with additional saccharide residues, especially aminoglycosides, in a manner similar to vancosamine.
- lipidated glycopeptide refers specifically to those glycopeptide antibiotics that have been synthetically modified to contain a lipid substituent.
- lipid substituent refers to any substituent contains 5 or more carbon atoms, preferably, 10 to 40 carbon atoms.
- the lipid substituent may optionally contain from 1 to 6 heteroatoms selected from halo, oxygen, nitrogen, sulfur, and phosphorous. Lipidated glycopeptide antibiotics are well known in the art. See, for example, in U.S. Patent Nos.
- Anti-inflammatory agents useful for attachment to polymer coatings of the invention stents and other medical devices, or for loading into the outer layer of the invention multilayered stents include, e.g. analgesics (e.g., NSAIDS and salicyclates), antirheumatic agents, gastrointestinal agents, gout preparations, hormones (glucocorticoids), nasal preparations, ophthalmic preparations, otic preparations (e.g., antibiotic and steroid combinations), respiratory agents, and skin & mucous membrane agents. See, Physician 's Desk Reference, 2005 Edition.
- the antiinflammatory agent can include dexamethasone, which is chemically designated as (1 l ⁇ , 16I)-9-fiuro- 11,17,21 -trihydroxy- 16-methylpregna- 1 ,4-diene-3 ,20-dione.
- the anti-inflammatory agent can include sirolimus (rapamycin), which is a triene macrolide antibiotic isolated from Steptomyces hygroscopicus.
- Anti-platelet or anti-coagulation agents include, e.g., Coumadin® (DuPont), Fragmin® (Pharmacia & Upjohn), Heparin® (Wyeth-Ayerst), Lovenox®, Normiflo®, Orgaran ® (Organon), Aggrastat® (Merck), Agrylin® (Roberts), Ecotrin® (Smithkline Beecham), Flolan® (Glaxo Wellcome), Halfprin® (Kramer), Integrillin® (COR Therapeutics), Integrillin® (Key), Persantine® (Boehringer Ingelheim), Plavix® (Bristol- Myers Squibb), ReoPro® (Centecor), Ticlid® (Roche), Abbokinase® (Abbott), Activase® (Genentech), Eminase® (Roberts), and Strepase® (Astra).
- Coumadin® DuPont
- Fragmin® Pulg.
- the anti-platelet or anti-coagulation agent can include trapidil (avantrin), cilostazol, heparin, hirudin, or ilprost.
- Trapidil is chemically designated as N,N-dimethyl-5-methyl-[l,2,4]triazolo[l,-5- a]pyrimidin-7-amine.
- Cilostazol is chemically designated as 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)- butoxy]-3,4-dihydro-2(lH)-quinolinone.
- Heparin is a glycosaminoglycan with anticoagulant activity; a heterogeneous mixture of variably sulfonated polysaccharide chains composed of repeating units of D- glucosamine and either L-iduronic or D-glucuronic acids.
- Hirudin is an anticoagulant protein extracted from leeches, e.g., Hirudo medicinalis.
- Iloprost is chemically designated as 5-[Hexahydro-5-hydroxy-4-(3-hydroxy-4- methyl- 1 -octen-6-ynyl)-2( 1 H)-pentalenylidene]pentanoic acid.
- the immune suppressive agent can include, e.g., Azathioprine® (Roxane), BayRho-D® (Bayer Biological), CellCept® (Roche Laboratories), Imuran® (Glaxo Wellcome), MiCRhoGAM® (Ortho-Clinical Diagnostics), Neoran® (Novartis), Orthoclone OKT3® (Ortho Biotech), Prograf® (Fujisawa), PhoGAM® (Ortho-Clinical Diagnostics), Sandimmune® (Novartis), Simulect® (Novartis), and Zenapax® (Roche Laboratories).
- the immune suppressive agent can include rapamycin or thalidomide.
- Rapamycin is a triene macrolide isolated from Streptomyces hygroscopicus.
- Thalidomide is chemically designated as 2-(2,6-dioxo-3-piperidinyl)-lH-iso- indole-l,3(2H)-dione.
- Anti-cancer or anti-cell proliferation agents that can be used as an additional bioactive agent, for example, in the outer layer of the invention multilayered stents include, e.g., nucleotide and nucleoside analogs, such as 2-chloro-deoxyadenosine, adjunct antineoplastic agents, alkylating agents, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, hormonal agonists/antagonists, androgens, antiandrogens, antiestrogens, estrogen & nitrogen mustard combinations, gonadotropin releasing hormone (GNRH) analogues, progestrins, immunomodulators, miscellaneous antineoplastics, photosensitizing agents, and skin and mucous membrane agents.
- nucleotide and nucleoside analogs such as 2-chloro-deoxyadenosine, adjunct antineoplastic agents, alkylating agents, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, hormonal
- Suitable adjunct antineoplastic agents include Anzemet® (Hoeschst Marion Roussel), Aredia® (Novartis), Didronel® (MGI), Diflucan® (Pfizer), Epogen® (Amgen), Ergamisol® (Janssen), Ethyol® (Alza), Kytril® (SmithKline Beecham), Leucovorin® (Immunex), Leucovorin® (Glaxo Wellcome), Leucovorin® (Astra), Leukine® (Immunex), Marinol® (Roxane), Mesnex® (Bristol-Myers Squibb Oncology/Immunology), Neupogen (Amgen), Procrit® (Ortho Biotech), Salagen® (MGI), Sandostatin® (Novartis), Zinecard® (Pharmacia and Upjohn), Zofran® (Glaxo Wellcome) and Zyloprim® (Glaxo Wellcome).
- Anzemet® Hoe
- Suitable miscellaneous alkylating agents include Myleran® (Glaxo Wellcome), Paraplatin® (Bristol-Myers Squibb Oncology/Immunology), Platinol® (Bristol-Myers Squibb Oncology/Immunology) and Thioplex® (Immunex).
- Suitable nitrogen mustards include Alkeran® (Glaxo Wellcome), Cytoxan® (Bristol-Myers Squibb Oncology/Immunology), Ifex® (Bristol-Myers Squibb Oncology/Immunology), Leukeran® (Glaxo Wellcome) and Mustargen® (Merck).
- Suitable nitrosoureas include BiCNU® (Bristol-Myers Squibb Oncology/Immunology), CeeNU® (Bristol-Myers Squibb Oncology/Immunology), Gliadel® (Rhone-Poulenc Rover) and Zanosar® (Pharmacia and Upjohn).
- Suitable antibiotics include Adriamycin PFS/RDF® (Pharmacia and Upjohn), Blenoxane® (Bristol-Myers Squibb Oncology/Immunology), Cerubidine® (Bedford), Cosmegen® (Merck), DaunoXome® (NeXstar), Doxil® (Sequus), Doxorubicin Hydrochloride® (Astra), Idamycin® PFS (Pharmacia and Upjohn), Mithracin® (Bayer), Mitamycin® (Bristol-Myers Squibb Oncology/Immunology), Nipen® (SuperGen), Novantrone® (Immunex) and Rubex® (Bristol-Myers Squibb Oncology/Immunology).
- Suitable antimetabolites include Cytostar-U® (Pharmacia and Upjohn), Fludara® (Berlex), Sterile FUDR® (Roche Laboratories), Leustatin® (Ortho Biotech), Methotrexate® (Immunex), Parinethol® (Glaxo Wellcome), Thioguanine® (Glaxo Wellcome) and Xeloda® (Roche Laboratories).
- Suitable androgens include Nilandron® (Hoechst Marion Roussel) and Teslac® (Bristol-Myers Squibb Oncology/Immunology).
- Suitable antiandrogens include Casodex® (Zeneca) and Eulexin® (Schering).
- Suitable antiestrogens include Arimidex® (Zeneca), Fareston® (Schering), Femara® (Novartis) and Nolvadex® (Zeneca).
- Suitable estrogen and nitrogen mustard combinations include Emcyt® (Pharmacia and Upjohn).
- Suitable estrogens include Estrace® (Bristol-Myers Squibb) and Estrab® (Solvay).
- Suitable gonadotropin releasing hormone (GNRH) analogues include Leupron Depot® (TAP) and Zoladex® (Zeneca).
- Suitable progestins include Depo-Provera® (Pharmacia and Upjohn) and Megace® (Bristol-Myers Squibb Oncology/Immunology).
- Suitable immunomodulators include Erganisol® (Janssen) and Proleukin® (Chiron Corporation).
- Suitable miscellaneous antineoplastics include Camptosar® (Pharmacia and Upjohn), Celestone® (Schering), DTIC-Dome® (Bayer), Elspar® (Merck), Etopophos® (Bristol-Myers Squibb Oncology/Immunology), Etopoxide® (Astra), Gemzar® (Lilly), Hexalen® (U.S.
- Suitable photosensitizing agents include Photofrin® (Sanofi).
- the anti-cancer or anti-cell proliferation agent can include Taxol® (paclitaxol), a nitric oxide-like compound, or NicOX (NCX-4016).
- Taxol® paclitaxol
- a nitric oxide-like compound or NicOX (NCX-4016).
- Taxol® paclitaxol
- N-benzoyl-3-phenylisoserine is chemically designated as 5 ⁇ ,20-Epoxy-l,2 ⁇ 4,7 ⁇ s 10 ⁇ ,13 ⁇ -hexahydroxytax-ll-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
- a nitric oxide-like agent includes any bioactive agent that contains a nitric oxide releasing functional group.
- Suitable nitric oxide-like compounds are S-nitrosothiol derivative (adduct) of bovine or human serum albumin and as disclosed, e.g., in U.S. Patent No. 5,650,447. See, e.g., David Marks et al., "Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide," JCUn. Invest. ⁇ 995) 96:2630-2638.
- NCX-4016 is chemically designated as 2-acetoxy-benzoate 2-(nitroxymethyl)-phenyl ester, and is an antithrombotic agent.
- bioactive agent or additional bioactive agent useful in the present invention is the bioactive substance present in any of the bioactive agents or agents disclosed above.
- Taxol® is typically available as an injectable, slightly yellow viscous solution.
- the bioactive agent is a crystalline powder with the chemical name 5 ⁇ ,20-Epoxy- l,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexahydroxytax-ll-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Physician 's Desk Reference (PDR), Medical Economics Company (Montvale, NJ), (53rd Ed.), pp. 1059-1067.
- a "residue of a bioactive agent” or “residue of an additional bioactive agent” is a radical of such bioactive agent as disclosed herein having one or more open valences. Any synthetically feasible atom or atoms of the bioactive agent can be removed to provide the open valence, provided bioactivity is substantially retained when the radical is attached to a residue of a polymer described herein. Based on the linkage that is desired, those skilled in the art can select suitably functionalized starting materials that can be derived from a bioactive agent using procedures that are known in the art.
- the residue of a bioactive agent or additional bioactive agent, as described herein, can be formed employing any suitable reagents and reaction conditions.
- suitable reagents and reaction conditions are disclosed, e.g., in Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Carey and Sundberg (1983); Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Second Edition, March (1977); and Comprehensive Organic Transformations, Second Edition, Larock (1999).
- the/>o/>r ⁇ er-bioactive agent linkage can degrade to provide a suitable and effective amount of free bioactive agent.
- the bioactive agent attached to the polymer performs its therapeutic effect while still attached to the polymer, such as is the case with the "sticky" polypeptides Protein A and Protein G, known herein as "bioligands", which function while attached to the polymer to hold a target molecule close to the polymer, and the bradykinins and antibodies, which function by contacting (e.g., bumping into) a receptor on a target molecule.
- bioactive agent can be released and will typically depend, e.g., on the specific polymer, bioactive agent, and polymer/bioactive agent linkage chosen. Typically, up to about 100% of the bioactive agent can be released from the polymer by degradation of the polymer/bioactive agent linkage. Specifically, up to about 90%, up to 75%, up to 50%, or up to 25% of the bioactive agent can be released from the polymer. Factors that typically affect the amount of the bioactive agent that is released from the polymer is the type of polymer/bioactive agent linkage, and the nature and amount of additional substances present in the formulation.
- the polymer-bioactive agent linkage can degrade over a period of time to provide time release of a suitable and effective amount of bioactive agent. Any suitable and effective period of time can be chosen. Typically, the suitable and effective amount of bioactive agent can be released in about twenty-four hours, in about seven days, in about thirty days, in about ninety days, or in about one hundred and twenty days. Factors that typically affect the length of time in which the bioactive agent is released from the polymer-bioactive agent include, e.g., the nature and amount of polymer, the nature and amount of bioactive agent, the nature of the polymer/bioactive agent linkage, and the nature and amount of additional substances present in the formulation.
- Polymer Intermixed -with Bioactive Agent or Additional Bioactive Agent In addition to being linked to one or more bioactive agents, either directly or through a linker, a polymer used for coating a medical device or making a sheath for a stent structure as described herein can be physically intermixed with one or more bioactive agents or additional bioactive agents to provide a polymer formulation that is used for coating a medical device or a stent structure.
- a "formulation” refers to a polymer as described herein in which one or more bioactive agents or additional bioactive agents is dispersed.
- the formulation includes such a polymer having one or more bioactive agents present on the surface of the polymer, partially embedded in the polymer, or completely embedded in the polymer. Additionally, the formulation includes a polymer as described herein and a bioactive agent forming a homogeneous composition (i.e., a homogeneous formulation).
- multilayered stents in the outer layer non-covalently bound bioactive agents and/or additional bioactive agents can be dispersed within or "loaded into” any biocompatible biodegradable polymer as is known in the art since the outer layer in this embodiment of the invention does not come into contact with blood.
- the inner layer of the multilayered stent has only bioactive agents covalently attached to a hydrophilic, blood-compatible polymer as described herein.
- any suitable amount of polymer and bioactive agent can be employed to provide the formulation.
- the polymer can be present in about 0.1 wt.% to about 99.9 wt.% of the formulation. Typically, the polymer can be present above about 25 wt.% of the formulation; above about 50 wt.% of the formulation; above about 75 wt.% % of the formulation; or above about 90 wt.% of the formulation.
- the bioactive agent can be present in about 0.1 wt.% to about 99.9 wt.% of the formulation. Typically, the bioactive agent can be present above about 5 wt.% of the formulation; above about 10 wt.% of the formulation; above about 15 wt.% of the formulation; or above about 20 wt.% of the formulation.
- the polymer coating having a bioactive agent dispersed therein can be applied as a polymeric film onto at least a portion of the surface of any medical device to be implanted into a diabetic that is exposed to blood and upon which it is desirable to establish an endothelial layer (e.g., a heart valve, a synthetic bypass artery, or a dialysis shunt).
- the polymeric film can have any suitable thickness on the medical device.
- the thickness of the polymeric film on the medical device can be about 1 to about 50 microns thick or about 5 to about 20 microns thick.
- each of the layers can be from 0.1 micron to 50 microns thick, for example from 0.5 micron to 5 microns in thickness.
- the polymeric film can effectively serve as a bioactive agent-eluting polymeric coating on a medical device, such as a stent structure.
- This bioactive agent-eluting polymeric coating can be created on the medical device by any suitable coating process, e.g., dip coating, vacuum depositing, or spray coating the polymeric film, on the medical device.
- the bioactive agent eluting polymer coating can be applied onto the surface of a stent, a vascular delivery catheter, a delivery balloon, a separate stent cover sheet configuration, or a stent sheath (i.e., a bioactive agent delivery sheath), as described herein to create a type of local bioactive agent delivery system.
- the polymer When the polymer is used as a cover sheath for a stent, the polymer can be processed, for example by extrusion or spinning as is known in the art, to form a woven sheet or mat of fine polymer fibers to which the bioactive agent, e.g., a bioligand, is covalently attached, either directly or by means of a linker, as described herein.
- the bioactive agent e.g., a bioligand
- the bioactive agent-eluting polymer coated stents and other medical devices can be used in conjunction with, e.g., hydrogel-based bioactive agent delivery systems.
- the above-described polymer coated stents and medical devices can be coated with an additional formulation layer applied over the polymer coated stent surface as a sandwich type of configuration to deliver to the blood vessels bioactive agents that promote natural re-endothelialization processes and prevent or reduce in-stent restenosis.
- Such an additional layer of hydrogel-based drug release formulation can comprise various bioactive agents mixed with hydrogels (see, U.S. Patent No. 5,610,241, which is incorporated by reference herein in its entirety) to provide an elution rate different than that of the polymer-active agent coating on the stent structure or medical device surface.
- any suitable size of polymer and bioactive agent can be employed to provide such a formulation.
- the polymer can have a size of less than about 1 x 10 '4 meters, less than about 1 x 10 "5 meters, less than about 1 x 10 "6 meters, less than about 1 x 10 "7 meters, less than about 1 x 10 "8 meters, or less than about 1 x 10 ⁇ 9 meters.
- the formulation can degrade to provide a suitable and effective amount of the bioactive agents. Any suitable and effective amount of bioactive agent can be released and will typically depend, e.g., on the specific formulation chosen. Typically, up to about 100% of the bioactive agent can be released from the formulation. Specifically, up to about 90%, up to 75%, up to 50%, or up to 25% of the bioactive agent can be released from the formulation. Factors that typically affect the amount of the bioactive agent that is released from the formulation include, e.g., the nature and amount of polymer, the nature and amount of bioactive agent, and the nature and amount of additional substances present in the formulation.
- the formulation can degrade over a period of time to provide the suitable and effective amount of bioactive agent. Any suitable and effective period of time can be chosen. Typically, the suitable and effective amount of bioactive agent can be released in about twenty-four hours, in about seven days, in about thirty days, in about ninety days, or in about one hundred and twenty days. Factors that typically affect the length of time in which the bioactive agent is released from the formulation include, e.g., the nature and amount of polymer, the nature and amount of bioactive agent, and the nature and amount of additional substances present in the formulation.
- the present invention also provides for an invention stent coated with a formulation that includes a polymer as described herein physically intermixed with one or more bioactive agents.
- the polymer that is present in the formulation can also be linked, either directly or through a linker, to one or more (e.g., 1, 2, 3, or 4) bioactive agents.
- the polymer can be intermixed with one or more (e.g., 1, 2, 3, or 4) bioactive agents and can be linked, either directly or through a linker, to one or more (e.g., 1, 2, 3, or 4) bioactive agents.
- a polymer used in making an invention stent or covering for an implantable surgical device can have the one or more bioactive agents dispersed therein.
- the polymer is physically intermixed with one or more bioactive agents.
- the polymer is linked to one or more bioactive agents, either directly or through a linker.
- the polymer is linked to one or more bioactive agents, either directly or through a linker, and the resulting polymer can also be physically intermixed with one or more bioactive agents.
- a polymer used in making an invention stent, stent sheath, or covering for an implantable surgical device for use in a subject suffering from diabetes can also be used in medical therapy or medical diagnosis.
- the polymer can be used in the manufacture of a medical device.
- Suitable medical devices include, e.g., artificial joints, artificial bones, cardiovascular medical devices, stents, dialysis shunts, medical devices useful in angioplastic therapy, artificial heart valves, artificial by-passes, sutures, artificial arteries, vascular delivery catheters, drug delivery balloons, separate tubular stent cover sheet configurations referred to herein as "sheaths", and bioactive agent or "drug" delivery compositions for local bioactive agent delivery systems.
- the invention provides methods for delivering a bioactive agent to damaged endothelium in a subject suffering from diabetes by implanting an invention stent in the vessel at the locus of damage and allowing the bioactive agent in the stent covering to interact with blood components within the vessel as an aid to activating PECs in the subject's blood stream, thereby enhancing healing of the damaged endothelium.
- the invention may further comprise testing a blood sample from the diabetic patient to determine the amount of therapeutic PECs in the sample as compared with a parallel sample of blood from a healthy non-diabetic individual to detect a decrease in the amount of therapeutic PECs in the blood from the diabetic patient.
- Such testing may be conducted prior to implantation of an invention stent to determine whether the diabetic patient has a decreased amount or concentration of PECs as compared with the normal concentration in healthy non-diabetic patients. Detection of a decrease in the amount of PECs in the blood of the diabetic patient will indicate that the patient is particularly in need of treatment that includes implantation of the invention bioactive stent.
- the PEA-OSu product may be isolated by precipitation, or used without further purification, in which case the PEA-OSu solution is transferred to a round bottom flask, diluted to the desired concentration, and cooled to O 0 C.
- a solution of the free amine-containing bioactive agent — the nucleophile, specifically, 4-Amino- Tempo ⁇ in CH 2 Cl 2 is added in a single shot at O 0 C.
- the nucleophile may be revealed in situ by treating the ammonium salt of the bioactive agent with a hindered base, preferably a tertiary amine, such as like triethylamine or, diisopropylethylamine, in a suitable aprotic solvent, such as dichloromethane (DCM)).
- a hindered base preferably a tertiary amine, such as like triethylamine or, diisopropylethylamine
- a suitable aprotic solvent such as dichloromethane (DCM)
- DCM dichloromethane
- TLC dichloromethane
- Work-up for the polymer involves customary precipitation of the reaction solution into a mixture of non-solvent, such as hexane/ethyl acetate.
- Solvent is then decanted, polymer residue is resuspended in a suitable solvent, filtered, concentrated by roto-evaporation, cast onto a clean teflon tray, and dried under vacuum to furnish the PEA-bioactive agent conjugate, specifically, PEA-4-Amino-Tempo.
- Aminium/Uronium Salt and Phosphonium Salt Mediated Couplings Two effective catalysts for this type of coupling include: HBTU, O-(benzotriazol-l-yl)-l, 1,3,3- teramethyluronium hexafluorophosphate, and BOP, l-benzotriazolyoxytris(dimethyl- amino)phosphonium hexafluorophosphate (Castro's Reagent); These reagents are employed in the presence of equimolar amounts of the carboxyl group of the polymer and the amino functional group of the bioactive agent (neutral or as the ammonium salt), with a tertiary amine such as diisopropylethylamine, N-methylmorpholine, or dimethyl- substituted pyridines (DMAP), in solvents such as DMF, THF, or acetonitrile.
- HBTU O-(benzotriazol-l-yl)-l
- Ester Bond Formation - This example illustrates coupling of a carboxyl group of a polymer with a hydroxyl functional group of the bioactive agent, or equally, coupling of a carboxyl group of the bioactive agent with a hydroxyl functional group of a polymer.
- PEC Isolations To establish the protocol for isolating the progenitor endothelial cells (PECs) from peripheral blood, blood from healthy, normal donors was used.
- a literature review generated multiple PEC isolation protocols (J.C.I. (2000) 105: 71-77; Ore. (2003) 107:143-149; Ore. (2003) 107:1164-1169; Plast. Reconstruc. Surgr. (2004) 113:284; and Am. J. Physiol. Heart Ore. Physiol. (2004) 286:H1985-H1993).
- preliminary attempts required modification of the known protocols to ensure successful isolations.
- the flow chart in Fig. 2 presents a modified protocol followed in isolation of PECs.
- Table 2 below indicates the isolation methods and the PEC isolation outcome for PEC isolation from various donors. Initially, both a mononuclear cell Ficoll gradient protocol (designed to isolate human mononuclear cells from peripheral blood) and a CD133+ magnetic bead purification step were used to ensure the isolation of PECs. It did not appear that the CD133+ purification step was increasing the isolation of PECs, so this step was omitted from the last two donors.
- Cells were plated either in 12- well or 6- well fibronectin-coated plates and monitored daily, over a span of about 28-30 days.
- the culture media used in the PEC isolations was Endothelial Basal Medium plus SingleQuot Kit (Cambrex Corporation, East Rutherford, New Jersey, a mixture of hydrocortisone, hEGF, FBS, VEGF, hFGF-B, R3-IGF-1, ascorbic acid and heparin. Generally from 10-15 days in culture after the isolation were required before a monolayer became apparent.
- LDL Di- acetylated-Low Density Lipoprotein
- the human LDL complex delivers cholesterol to cells via receptor-mediated endocytosis.
- the acetylated form of LDL is not taken up by the LDL receptor, but is taken up by macrophages and endothelial cells via a "scavenger" receptor specific for the modified LDL.
- Decreased uptake by endothelial cells as compared with macrophages was determined by microscope and photographed (10Ox magnification). The monolayer remains actively growing for a few months. Cells were replated and reformed the monolayer for several passages (about 30 days in culture) before becoming senescent.
- Fig. 3 shows the flow chart of the protocol followed for this assay.
- the attachment factor in a phosphate buffered saline (PBS) solution, was coated onto a non- tissue culture dish and allowed to adsorb overnight at 4 0 C. The following day the plate was blocked for 1 hour at room temperature with heat-inactivated, 0.2% bovine serum albumin (BSA) solution (in PBS) to prevent non-specific attachment.
- BSA bovine serum albumin
- a timed adhesion assay was then conducted.
- the assay includes negative control wells coated only with PBS and positive control wells coated with fibronectin. So far, none of the adhesion factors tested has surpassed the cell adhesion and cell spreading induced by fibronectin. In addition to adhesion, spreading is also an important consideration in determining the suitability of a substrate. If the cells are not able to spread, it is unlikely that the cells will proliferate on that surface.
- CS5 whose amino acid sequence is Gly-Glu-Glu-Ile-Gln-Ile-Gly-His-Ile- Yxo-Ars-Glu-Asv- F ⁇ /- ⁇ p-7Vr-His-Leu-Tvr-Pro (SEQ ID NO: 1).
- CS5 is found in the Type III connecting segment of fibronectin, an extracellular matrix protein known to bind many different cells, including ECs.
- the sequence for the CS5 peptide contains the amino acid sequence REDVDY (underlined) (SEQ ID NO:2); and
- GREDVDY (SEQ ID NO: 11), which includes a G linker placed on the REDVDY sequence.)
- ATP assay In addition to microscopic observations, cell adhesion was quantitated using an ATP assay. Data of a representative adhesion assay quantitation by ATP standard curve is shown in the graph in Fig. 4, which illustrates the comparative results obtained at 2, 4 and 6 hours into the assay.
- the assay can identify the number of cells that are adhered to a specific substrate; however, it does not take into consideration cell spreading.
- the cell spreading determined in microscopic observations may indicate that cell spreading can increase the overall degree of cell adhesion since more space is occupied by a well spread cell than by an adhered cell that has not spread on the surface, due to timing of data points or appropriateness of the substrate used.
- the ATP data are useful to support the observational findings of the adhesion assay but cannot replace the adhesion assay.
- the biodegradable polymer is a poly(ester amide) (PEA) containing Lysine residues
- the carboxyl groups from the Lysine residues can be used to react with a complementary moiety on the peptide, such as an hydroxy, amino, thio moiety, and the like(5).
- the PEA-H polymer with free COOH reacts with water soluble carbodiimide (WSC) and N-Hydroxysuccinimide (HOSu) to produce an activated ester, which, in turn, reacts with an amino functional group of a peptide to provide an amide linkage (Fig. 6B).
- WSC water soluble carbodiimide
- HOSu N-Hydroxysuccinimide
- Fig. 6B By using a fluorescent dansyl- lysine (Fig.
- PEA copolymers are their ability to promote a natural healing response.
- PEA was compared to non-degradable and other biodegradable polymers in a series of in vitro assays to examine blood and cellular responses to the polymers that are important for healing of the vasculature after placement of a drug eluting stent.
- Tissue compatibility was measured by exposing human peripheral blood monocytes to PEA, PEA-TEMPO, 50:50 poly(D,L-lactide-co-glycolide) (PLGA), poly(n- butyl methacrylate) (PBMA) and tissue culture-treated polystyrene (TCPS).
- PEA poly(D,L-lactide-co-glycolide)
- PBMA poly(n- butyl methacrylate)
- TCPS tissue culture-treated polystyrene
- PLGAs Human peripheral blood monocytes were isolated by density centrifugation and magnetic separation (Miltenyi). PLGAs of 34,000 and 73,000 MW were purchased from Boehringer-Ingelheim. PBMA was purchased from Polysciences. TCPS plates (Falcon) with or without fibronectin, fibrinogen, heparin, or gelatin (Sigma) coatings were used as controls.
- the monocytes differentiated into macrophages as judged by an increase in cell size to greater than 20 ⁇ m in diameter and increased granularity.
- Interleukin-1 receptor antagonist is a naturally occurring inhibitor of IL-Ib that competitively binds the receptors for IL-I and blocks pro-inflammatory signaling.
- PEA was also assayed for hemocompatibility. Platelet aggregation, used as a marker of polymer hemocompatibility, was visualized using human platelets (purchased from the San Diego blood bank) that were exposed to PEAs and a fibrinogen-coated surface for 30 minutes.
- Platelets did not readily adhere to or aggregate on PEAs as evidenced by the very small number of platelets observed on the surface by microscopy. Moreover, the platelets that did adhere were identified as individual platelets by size, indicating that the platelets did not aggregate together. In contrast, significant numbers of platelets adhered to the fibrinogen control, and the very large complexes of platelets demonstrated a large degree of aggregation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Vascular Medicine (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Prostheses (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06749606A EP1868656A4 (en) | 2005-04-04 | 2006-04-04 | Bioactive stents for type ii diabetics and methods for use thereof |
JP2008505615A JP2008538302A (en) | 2005-04-04 | 2006-04-04 | Bioactive stent for type II diabetic patients and method of use thereof |
US11/885,791 US20080288057A1 (en) | 2004-04-05 | 2006-04-04 | Bioactive Stents For Type II Diabetics and Methods for Use Thereof |
AU2006232486A AU2006232486A1 (en) | 2005-04-04 | 2006-04-04 | Bioactive stents for type ll diabetics and methods for use thereof |
CA002602090A CA2602090A1 (en) | 2005-04-04 | 2006-04-04 | Bioactive stents for type ii diabetics and methods for use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/098,891 | 2005-04-04 | ||
US11/098,891 US8163269B2 (en) | 2004-04-05 | 2005-04-04 | Bioactive stents for type II diabetics and methods for use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006108167A1 true WO2006108167A1 (en) | 2006-10-12 |
Family
ID=37073816
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/013214 WO2006108167A1 (en) | 2004-04-05 | 2006-04-04 | Bioactive stents for type ii diabetics and methods for use thereof |
Country Status (8)
Country | Link |
---|---|
US (1) | US8163269B2 (en) |
EP (1) | EP1868656A4 (en) |
JP (1) | JP2008538302A (en) |
KR (1) | KR20080000635A (en) |
CN (1) | CN101155601A (en) |
AU (1) | AU2006232486A1 (en) |
CA (1) | CA2602090A1 (en) |
WO (1) | WO2006108167A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007038246A2 (en) | 2005-09-22 | 2007-04-05 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
US8133436B2 (en) | 2008-08-05 | 2012-03-13 | Howmedica Osteonics Corp. | Polyethylene cross-linked with an anthocyanin |
US9102830B2 (en) | 2005-09-22 | 2015-08-11 | Medivas, Llc | Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use |
US9517203B2 (en) | 2000-08-30 | 2016-12-13 | Mediv As, Llc | Polymer particle delivery compositions and methods of use |
CN107456296A (en) * | 2016-09-14 | 2017-12-12 | 四川蓝光英诺生物科技股份有限公司 | Lumen organization's construct, the preparation method of lumen organization's construct and preparation facilities |
US9873764B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Particles comprising polyesteramide copolymers for drug delivery |
US9873765B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Biodegradable polyesteramide copolymers for drug delivery |
US10434071B2 (en) | 2014-12-18 | 2019-10-08 | Dsm Ip Assets, B.V. | Drug delivery system for delivery of acid sensitivity drugs |
Families Citing this family (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7850676B2 (en) | 2004-04-19 | 2010-12-14 | The Invention Science Fund I, Llc | System with a reservoir for perfusion management |
US7998060B2 (en) | 2004-04-19 | 2011-08-16 | The Invention Science Fund I, Llc | Lumen-traveling delivery device |
US8361013B2 (en) | 2004-04-19 | 2013-01-29 | The Invention Science Fund I, Llc | Telescoping perfusion management system |
US9011329B2 (en) | 2004-04-19 | 2015-04-21 | Searete Llc | Lumenally-active device |
US8512219B2 (en) | 2004-04-19 | 2013-08-20 | The Invention Science Fund I, Llc | Bioelectromagnetic interface system |
US8019413B2 (en) | 2007-03-19 | 2011-09-13 | The Invention Science Fund I, Llc | Lumen-traveling biological interface device and method of use |
US8092549B2 (en) | 2004-09-24 | 2012-01-10 | The Invention Science Fund I, Llc | Ciliated stent-like-system |
US7857767B2 (en) | 2004-04-19 | 2010-12-28 | Invention Science Fund I, Llc | Lumen-traveling device |
US8337482B2 (en) | 2004-04-19 | 2012-12-25 | The Invention Science Fund I, Llc | System for perfusion management |
US8353896B2 (en) | 2004-04-19 | 2013-01-15 | The Invention Science Fund I, Llc | Controllable release nasal system |
US8318973B2 (en) * | 2005-10-21 | 2012-11-27 | Bezwada Biomedical, Llc | Functionalized sinapic acid and methyl sinapate |
JP2009524584A (en) * | 2005-12-07 | 2009-07-02 | メディバス エルエルシー | Method for building a polymer-biologic delivery composition |
US20080058788A1 (en) | 2006-04-12 | 2008-03-06 | Searete Llc., A Limited Liability Corporation Of The State Of Delaware | Autofluorescent imaging and target ablation |
US20120035438A1 (en) | 2006-04-12 | 2012-02-09 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Path selection by a lumen traveling device in a body tub tree based on previous path |
JP5445130B2 (en) * | 2006-05-02 | 2014-03-19 | メディバス エルエルシー | Delivery of ophthalmic drugs to the exterior or interior of the eye |
JP5196498B2 (en) * | 2006-05-09 | 2013-05-15 | メディバス エルエルシー | Biodegradable water-soluble polymer |
US7794495B2 (en) * | 2006-07-17 | 2010-09-14 | Advanced Cardiovascular Systems, Inc. | Controlled degradation of stents |
JP2010502822A (en) * | 2006-09-05 | 2010-01-28 | メディバス エルエルシー | Polymer stabilized liposome compositions and methods of use |
EP2091474B1 (en) * | 2006-12-07 | 2010-07-07 | Mallinckrodt Inc. | Medical devices for localized drug delivery |
CA2709412A1 (en) * | 2007-07-24 | 2009-01-29 | Medivas, Llc | Biodegradable cationic polymer gene transfer compositions and methods of use |
US8217134B2 (en) | 2007-08-30 | 2012-07-10 | Bezwada Biomedical, Llc | Controlled release of biologically active compounds |
US8026285B2 (en) * | 2007-09-04 | 2011-09-27 | Bezwada Biomedical, Llc | Control release of biologically active compounds from multi-armed oligomers |
US8048980B2 (en) * | 2007-09-17 | 2011-11-01 | Bezwada Biomedical, Llc | Hydrolysable linkers and cross-linkers for absorbable polymers |
US8053591B2 (en) * | 2007-09-26 | 2011-11-08 | Bezwada Biomedical, Llc | Functionalized biodegradable triclosan monomers and oligomers for controlled release |
DE102007050668A1 (en) * | 2007-10-24 | 2009-04-30 | Biotronik Vi Patent Ag | Stent with a base made of a bioinert metallic implant material |
US8367747B2 (en) * | 2008-05-23 | 2013-02-05 | Bezwada Biomedical, Llc | Bioabsorbable polymers from bioabsorbable polyisocyanates and uses thereof |
DE102008027095A1 (en) * | 2008-06-06 | 2009-12-17 | Siemens Aktiengesellschaft | Intervention device for collecting biological material and method for its production |
CA2733686A1 (en) * | 2008-08-13 | 2010-02-18 | Medivas, Llc | Aabb-poly(depsipeptide) biodegradable polymers and methods of use |
US20100305688A1 (en) * | 2009-05-26 | 2010-12-02 | Mallinckrodt Inc. | Medical Devices for Localized Drug Delivery |
CA2774036C (en) * | 2009-10-16 | 2018-04-03 | Dsm Ip Assets B.V. | Coatings comprising bis-(alpha-amino-diol-diester) containing polyesteramide |
EP2555751B8 (en) * | 2010-04-03 | 2018-02-14 | Praful Doshi | Methods of coating a contact lens |
CA2846436A1 (en) * | 2011-09-23 | 2013-03-28 | Universitat Stuttgart | Serum half-life extension using immunoglobulin binding domains |
US9220584B2 (en) | 2012-03-30 | 2015-12-29 | Abbott Cardiovascular Systems Inc. | Treatment of diabetic patients with a stent and locally administered adjunctive therapy |
US10538864B2 (en) | 2012-10-24 | 2020-01-21 | Dsm Ip Assets, B.V. | Fibers comprising polyesteramide copolymers for drug delivery |
EP2737894A1 (en) * | 2012-12-03 | 2014-06-04 | Debiotech S.A. | Smart coating for implantable devices |
WO2014096339A1 (en) * | 2012-12-20 | 2014-06-26 | Dsm Ip Assets B.V. | Coating comprising polyesteramide copolymers for drug delivery |
KR101850778B1 (en) * | 2016-08-12 | 2018-04-20 | 서울대학교산학협력단 | The Nectin-2 stent coating composition for capturing and proliferating outgrowth endothelial cell and stent using thereof |
CN107411844B (en) * | 2016-09-14 | 2020-06-30 | 四川蓝光英诺生物科技股份有限公司 | Lumen tissue construct, and preparation method and preparation device thereof |
CN110547897B (en) * | 2019-09-04 | 2021-04-23 | 中国人民解放军总医院 | Blood vessel support device |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050019366A1 (en) * | 2002-12-31 | 2005-01-27 | Zeldis Jerome B. | Drug-coated stents and methods of use therefor |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5599352A (en) * | 1992-03-19 | 1997-02-04 | Medtronic, Inc. | Method of making a drug eluting stent |
US7041785B1 (en) * | 1996-08-19 | 2006-05-09 | UNIVERSITé DE SHERBROOKE | B1-bradykinin receptor antagonists and use thereof |
KR100188987B1 (en) * | 1996-09-06 | 1999-06-01 | 박원훈 | Multi-channel acoustic-optic modulator, the aperture of each modulating cell connected in one row |
US6982249B1 (en) * | 1997-04-23 | 2006-01-03 | The Regents Of The University Of Michigan | Bradykinin analogs as selective inhibitors of cell activation |
US6703040B2 (en) * | 2000-01-11 | 2004-03-09 | Intralytix, Inc. | Polymer blends as biodegradable matrices for preparing biocomposites |
US20070055367A1 (en) * | 2000-03-15 | 2007-03-08 | Orbus Medical Technologies, Inc. | Medical device with coating that promotes endothelial cell adherence and differentiation |
EP1263484B1 (en) * | 2000-03-15 | 2007-05-16 | OrbusNeich Medical, Inc. | Coating which promotes endothelial cell adherence |
US9522217B2 (en) * | 2000-03-15 | 2016-12-20 | Orbusneich Medical, Inc. | Medical device with coating for capturing genetically-altered cells and methods for using same |
US20070141107A1 (en) * | 2000-03-15 | 2007-06-21 | Orbusneich Medical, Inc. | Progenitor Endothelial Cell Capturing with a Drug Eluting Implantable Medical Device |
US20070191932A1 (en) * | 2000-03-15 | 2007-08-16 | Orbusneich Medical, Inc. | Medical device with coating for capturing genetically-altered cells and methods for using same |
US20030229393A1 (en) * | 2001-03-15 | 2003-12-11 | Kutryk Michael J. B. | Medical device with coating that promotes cell adherence and differentiation |
US20050271701A1 (en) * | 2000-03-15 | 2005-12-08 | Orbus Medical Technologies, Inc. | Progenitor endothelial cell capturing with a drug eluting implantable medical device |
US6663863B2 (en) * | 2000-03-17 | 2003-12-16 | Millennium Pharmaceuticals, Inc. | Method of inhibiting stenosis and restenosis |
US6503538B1 (en) * | 2000-08-30 | 2003-01-07 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
US7304122B2 (en) * | 2001-08-30 | 2007-12-04 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
EP1427829A4 (en) * | 2001-08-31 | 2005-10-12 | Abmaxis Inc | Multivalent protein conjugate with multiple ligand-binding domains of receptors |
RU2004124387A (en) * | 2002-01-10 | 2005-06-10 | Новартис АГ (CH) | MEDICINES ADMINISTRATION SYSTEMS CONTAINING RAPAMICIN AND ITS DERIVATIVES THAT ARE INTENDED FOR THE PREVENTION AND TREATMENT OF VASCULAR DISEASES |
WO2003062298A1 (en) | 2002-01-17 | 2003-07-31 | Polyrava Llc | Co-poly(ester amide) and co-poly(ester urethane) compositions which exhibit biodegradability, methods for making same and uses for same |
EP1471853B1 (en) * | 2002-02-06 | 2017-03-22 | OrbusNeich Medical, Inc. | Medical device with coating that promotes endothelial cell adherence and differentiation |
WO2003073993A2 (en) * | 2002-03-01 | 2003-09-12 | Colb Mark A | Binding of red blood cell to exposed subendothelial surfaces to impede platelet deposition thereon and/or for use in targeted drug delivery thereto |
EP1603485A4 (en) * | 2003-02-26 | 2011-03-30 | Medivas Llc | Bioactive stents and methods for use thereof |
JP2007532185A (en) * | 2004-04-05 | 2007-11-15 | メディバス エルエルシー | Bioactive stent for type II diabetes and method of use thereof |
KR20070008714A (en) * | 2004-04-30 | 2007-01-17 | 오르버스네이치 메디칼 인코포레이티드 | Medical device with coating for capturing genetically-altered cells and methods of using same |
US20050271700A1 (en) * | 2004-06-03 | 2005-12-08 | Desnoyer Jessica R | Poly(ester amide) coating composition for implantable devices |
US7166680B2 (en) * | 2004-10-06 | 2007-01-23 | Advanced Cardiovascular Systems, Inc. | Blends of poly(ester amide) polymers |
US7214759B2 (en) | 2004-11-24 | 2007-05-08 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on polyesters and methods for fabricating the same |
KR100696125B1 (en) * | 2005-03-30 | 2007-03-22 | 엘지전자 주식회사 | A fixed scroll for scroll compressor |
-
2005
- 2005-04-04 US US11/098,891 patent/US8163269B2/en not_active Expired - Fee Related
-
2006
- 2006-04-04 CA CA002602090A patent/CA2602090A1/en not_active Abandoned
- 2006-04-04 JP JP2008505615A patent/JP2008538302A/en active Pending
- 2006-04-04 WO PCT/US2006/013214 patent/WO2006108167A1/en active Application Filing
- 2006-04-04 KR KR1020077025554A patent/KR20080000635A/en not_active Application Discontinuation
- 2006-04-04 CN CNA2006800110448A patent/CN101155601A/en active Pending
- 2006-04-04 EP EP06749606A patent/EP1868656A4/en not_active Withdrawn
- 2006-04-04 AU AU2006232486A patent/AU2006232486A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050019366A1 (en) * | 2002-12-31 | 2005-01-27 | Zeldis Jerome B. | Drug-coated stents and methods of use therefor |
Non-Patent Citations (1)
Title |
---|
See also references of EP1868656A4 * |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9517203B2 (en) | 2000-08-30 | 2016-12-13 | Mediv As, Llc | Polymer particle delivery compositions and methods of use |
EP1933881B1 (en) * | 2005-09-22 | 2019-03-13 | Medivas, LLC | Solid polymer delivery compositions and methods for use thereof |
WO2007038246A2 (en) | 2005-09-22 | 2007-04-05 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
US8652504B2 (en) | 2005-09-22 | 2014-02-18 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
US9102830B2 (en) | 2005-09-22 | 2015-08-11 | Medivas, Llc | Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use |
US8439975B2 (en) | 2008-08-05 | 2013-05-14 | Howmedica Osteonics Corp. | Polyethylene cross-linked with an anthocyanin |
US8133436B2 (en) | 2008-08-05 | 2012-03-13 | Howmedica Osteonics Corp. | Polyethylene cross-linked with an anthocyanin |
US8303657B2 (en) | 2008-08-05 | 2012-11-06 | Howmedica Osteonics Corp. | Polyethylene cross-linked with an anthocyanin |
US9873765B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Biodegradable polyesteramide copolymers for drug delivery |
US9896544B2 (en) | 2011-06-23 | 2018-02-20 | Dsm Ip Assets, B.V. | Biodegradable polyesteramide copolymers for drug delivery |
US9963549B2 (en) | 2011-06-23 | 2018-05-08 | Dsm Ip Assets, B.V. | Biodegradable polyesteramide copolymers for drug delivery |
US9873764B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Particles comprising polyesteramide copolymers for drug delivery |
US10434071B2 (en) | 2014-12-18 | 2019-10-08 | Dsm Ip Assets, B.V. | Drug delivery system for delivery of acid sensitivity drugs |
US10888531B2 (en) | 2014-12-18 | 2021-01-12 | Dsm Ip Assets B.V. | Drug delivery system for delivery of acid sensitivity drugs |
US11202762B2 (en) | 2014-12-18 | 2021-12-21 | Dsm Ip Assets B.V. | Drug delivery system for delivery of acid sensitivity drugs |
CN107456296A (en) * | 2016-09-14 | 2017-12-12 | 四川蓝光英诺生物科技股份有限公司 | Lumen organization's construct, the preparation method of lumen organization's construct and preparation facilities |
Also Published As
Publication number | Publication date |
---|---|
CA2602090A1 (en) | 2006-10-12 |
US8163269B2 (en) | 2012-04-24 |
JP2008538302A (en) | 2008-10-23 |
EP1868656A1 (en) | 2007-12-26 |
US20050238689A1 (en) | 2005-10-27 |
CN101155601A (en) | 2008-04-02 |
KR20080000635A (en) | 2008-01-02 |
EP1868656A4 (en) | 2011-11-02 |
AU2006232486A1 (en) | 2006-10-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2006108167A1 (en) | Bioactive stents for type ii diabetics and methods for use thereof | |
US20080288057A1 (en) | Bioactive Stents For Type II Diabetics and Methods for Use Thereof | |
US20060013855A1 (en) | Bioactive stents for type II diabetics and methods for use thereof | |
US20060188486A1 (en) | Wound care polymer compositions and methods for use thereof | |
EP1737379A2 (en) | Bioactive stents for type ii diabetics and methods for use thereof | |
CA2566713C (en) | Wound healing polymer compositions and methods for use thereof | |
JP2006520217A (en) | Bioactive stent and method of use thereof | |
US8445627B2 (en) | Alkylene-dicarboxylate-containing biodegradable poly(ester-amides) and methods of use | |
US8765164B2 (en) | Poly(ester urea) polymers and methods of use | |
US20070292476A1 (en) | Delivery of ophthalmologic agents to the exterior or interior of the eye | |
US20060286064A1 (en) | Therapeutic polymers and methods | |
JP2008518666A (en) | Bioactive wound dressings and implantable devices and methods of use | |
EP1933881A2 (en) | Solid polymer delivery compositions and methods for use thereof | |
JP2008542393A (en) | Therapeutic polymers and methods of use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680011044.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006232486 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2602090 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7265/DELNP/2007 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 2006232486 Country of ref document: AU Date of ref document: 20060404 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006749606 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2008505615 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12007502175 Country of ref document: PH |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020077025554 Country of ref document: KR |
|
NENP | Non-entry into the national phase |
Ref country code: RU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1200702320 Country of ref document: VN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11885791 Country of ref document: US |