US20100303878A1 - Biodegradable bioactive agent releasing matrices with particulates - Google Patents

Biodegradable bioactive agent releasing matrices with particulates Download PDF

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US20100303878A1
US20100303878A1 US12792309 US79230910A US2010303878A1 US 20100303878 A1 US20100303878 A1 US 20100303878A1 US 12792309 US12792309 US 12792309 US 79230910 A US79230910 A US 79230910A US 2010303878 A1 US2010303878 A1 US 2010303878A1
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biodegradable
bioactive agent
matrix
releasing
aliphatic polyester
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Joram Slager
Robert Hergenrother
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SurModics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591Stabilisation, fragmentation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/005Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/14Post-treatment to improve physical properties
    • A61L17/145Coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/34Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08Materials for coatings
    • A61L29/085Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/256Antibodies, e.g. immunoglobulins, vaccines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624Nanocapsules
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55Fab or Fab'
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/31504Composite [nonstructural laminate]
    • Y10T428/31652Of asbestos
    • Y10T428/31663As siloxane, silicone or silane

Abstract

The present invention is directed to biodegradable polymeric matrices for the controlled release of a hydrophilic bioactive agent. Generally, the biodegradable matrices include an aliphatic polyester copolymer and microparticulates that include the hydrophilic bioactive agent. In some embodiments, the matrix includes a second biodegradable polymer comprising hydrophilic and hydrophobic portions. Exemplary matrix forms are device coatings and medical implants. Matrices of the invention demonstrated high bioactive agent loading, were able to modulate release of the bioactive agent in a therapeutic manner, and also maintained high levels of activity for therapeutically useful large molecule bioactive agents, such as proteins.

Description

    PRIORITY CLAIM
  • This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/217,615 filed Jun. 2, 2009, entitled BIODEGRADABLE BIOACTIVE AGENT RELEASING MATRICES WITH PARTICULATES, the disclosure of which is incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The present invention relates to biodegradable polymeric matrices for hydrophilic drug delivery and related methods. More specifically, the present invention relates to biodegradable polymeric matrices containing particulates and related methods.
  • BACKGROUND OF THE INVENTION
  • In recent years, much attention has been given to site-specific delivery of drugs within a patient. Site-specific drug delivery focuses on delivering the drugs locally, i.e., to the area of the body requiring treatment. One benefit of the local release of bioactive agents is the avoidance of toxic concentrations of drugs that are at times necessary, when given systemically, to achieve therapeutic concentrations at the site where they are required.
  • Site-specific drug delivery can be accomplished by injection and/or implantation of an article or device that releases the drug to the treatment site. Implantation or injection of an article or device that delivers drug to the treatment site can provide improvements with regards to administration, reduced complications (such as reduced infection), and patient comfort. Therapeutic benefits can also be achieved by providing a bioactive agent to a subject in a manner that provides controlled release of the bioactive agent. Controlled release of a bioactive agent can allow the concentration of the bioactive agent at the target tissue site to remain at a more consistent therapeutic level.
  • One technique for providing controlled-release site-specific drug delivery is to use a drug-releasing polymeric matrix system, which can be formed as a coating on a medical device. The coating can serve to control the rate at which the bioactive agent is released. Because the coating is formed on a medical device and because the medical device can be positioned as desired within the body of a patient, the delivery of the bioactive agent can be site-specific. Another technique for providing controlled-release site-specific drug delivery is to use polymeric matrices in the form of implantable or injectable articles (such as polymeric microparticles or other drug-releasing depots in the form of filaments, etc.).
  • The present invention is directed to biodegradable polymeric matrices for hydrophilic drug delivery, wherein the hydrophilic drug is present in the matrix in particulate form and the polymeric matrix includes an aliphatic polyester copolymer. The matrices of the invention have been found to provide one or more of the following: improvements in maintaining activity of therapeutically useful large molecule drugs like proteins; improvements in drug loading in the matrix; and improvements in drug-release characteristics.
  • SUMMARY OF THE INVENTION
  • The present invention generally relates to biodegradable polymeric matrices including a hydrophilic bioactive agent which can be released at a target location following implantation or injection of the matrix in a subject. The invention also relates to methods for preparing these matrices, and using these matrices for the treatment of a medical condition in a subject.
  • Generally, the biodegradable bioactive agent-releasing matrices of the invention include (a) a biodegradable polymer comprising an aliphatic polyester copolymer, and (b) microparticulates, the microparticulates including a hydrophilic bioactive agent. In many cases, the hydrophilic bioactive agent is a “large molecule drug,” such as a therapeutic polypeptide, polynucleotide, or polysaccharide.
  • The hydrophilic bioactive agent, being in the form of microparticulates, can be dispersed throughout the biodegradable matrix in discrete microdomains. The use of microparticulates is advantageous over other matrix-forming processes that may result in the hydrophilic bioactive agent becoming aggregated or grossly non-dispersed in the matrix. Further, using microparticulates, the elution control matrix can have high bioactive agent loading. Finally, the use of bioactive agent in microparticulate form, along with the processing steps described herein, allows the bioactive agent that is incorporated into the matrix to retain most or all of its activity.
  • The matrices of the invention provide desirable properties for use in association with, or in the form of, an implantable or injectable medical article. For example, when used in the form of coating on the surface of an implantable medical device, the matrices demonstrate good adhesion to the device surface, compliance, and durability.
  • In addition, it has been found that the matrices of the invention can include a high load of hydrophilic bioactive. Even at high loads, the hydrophilic bioactive agent was capable of being released from the matrix in a controlled manner. Therefore, following implantation, an initial release burst, which can deplete a substantial amount of bioactive agent from the biodegradable polymeric matrix, can be avoided. In addition, the matrix can be completely degraded, making all of the bioactive agent contained in the matrix available to the subject after a period of implantation. This allows the implants to be useful for the prolonged release of therapeutically effective amounts of bioactive agents to treat medical conditions. For example, the matrices can be used to deliver a hydrophilic bioactive agent requiring a course of treatment for a period of time of greater than a month. Given the prolonged release of bioactive agent, the need for periodic administration of the bioactive agent is not required. This is beneficial as it eliminates or significantly reduces need for patient compliance.
  • In some aspects the implantable or injectable article is formed entirely of the biodegradable polymeric matrix, or is associated with another implant material that is erodable or degradable in the body. In these cases, the implantable or injectable article is entirely degradable after a period of time in the body, and an explantation process does not need to be performed.
  • In one aspect, the invention provides a biodegradable bioactive agent-releasing matrix that includes a biodegradable polymer comprising an aliphatic polyester copolymer, the aliphatic polyester comprising monomeric units of the following formula
  • Figure US20100303878A1-20101202-C00001
  • wherein R1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms (such as a monomeric unit derived from lactide), and wherein the monomeric unit is present in the aliphatic polyester copolymer in an amount of greater than 17% by weight. The biodegradable bioactive agent-releasing matrix also includes microparticulates that comprise a hydrophilic bioactive agent. In an implantable or injectable form, the biodegradable bioactive agent-releasing matrix comprises a surface that is in direct contact with body fluid and/or body tissue. It was found that using this arrangement, polymeric matrices formed using the aliphatic polyester with amounts of lactide greater than 17% by were able to suppress the burst of the hydrophilic bioactive agent, even at high loading levels.
  • In another aspect, the invention provides a biodegradable bioactive agent-releasing matrix that includes at least two biodegradable polymers. The first biodegradable polymer comprises an aliphatic polyester copolymer, the aliphatic polyester comprising a monomeric unit of formula II:
  • Figure US20100303878A1-20101202-C00002
  • wherein R2 is a divalent saturated or unsaturated hydrocarbon group that includes four or five carbon atoms (such as a monomeric unit derived from caprolactone). The monomeric unit of formula II is present in the aliphatic polyester copolymer in an amount of greater than 15% by weight. The second biodegradable polymer comprises hydrophobic and hydrophilic portions. The biodegradable bioactive agent-releasing matrix also includes microparticulates that comprise a hydrophilic bioactive agent.
  • In this embodiment of the invention, it was found that the use of aliphatic polyesters with amounts of a monomeric unit of formula II greater than 15% rendered the matrix very sensitive to the inclusion of second biodegradable polymer and its effect on elution of the hydrophilic bioactive agent. In other words, the aliphatic polyesters comprising the higher caprolactone content, when combined with the second polymer, provided biodegradable matrices that not only showed the ability to suppress the burst of the hydrophilic bioactive agent (even when the bioactive agent was used at high loads), but also revealed remarkable tunability for providing a desired bioactive agent release rate. It was found that the release rate could be readily tuned by adjusting the ratio between the first and second biodegradable polymers in the matrix.
  • In other aspects, the invention provides implantable or injectable medical articles that are formed from, or are associated with, the biodegradable bioactive agent-releasing matrices of the invention that include a biodegradable polymer comprising an aliphatic polyester copolymer, and microparticulates, the microparticulates including a hydrophilic bioactive agent. The invention also provides methods for the treatment of a medical condition using an implantable or injectable medical article formed from, or are associated with, the bioactive agent-releasing matrices of the invention.
  • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing release of Fab from metal coils coated with various poly(lactide-co-glycolide)s and microparticulates.
  • FIG. 2 is a graph showing release of Fab from metal coils coated with various poly(lactide-co-glycolide)s and microparticulates and having topcoats.
  • FIG. 3A-3D are micrographs of metal coils coated with various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • FIG. 4A-4D are micrographs of metal coils coated with various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • FIG. 5A-5D are micrographs of metal coils coated with various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • FIG. 6 is a graph showing release of Fab from metal coils coated with a combination of various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • FIG. 7 is a graph showing release of Fab from metal coils coated with a combination of various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • FIG. 8 is a graph showing release of Fab from metal coils coated with a combination of various poly(lactide-co-glycolide)s and PEG1000-45PBT-55 mixtures, and microparticulates.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The embodiments of the present invention described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices of the present invention.
  • All publications and patents mentioned herein are hereby incorporated by reference. The publications and patents disclosed herein are provided solely for their disclosure. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate any publication and/or patent, including any publication and/or patent cited herein.
  • The present invention generally relates to microparticulate-containing biodegradable polymeric matrices for the controlled release of a hydrophilic bioactive agent. Generally, the matrix is configured for placement in contact with body tissue or fluid (an “elution environment”) in which the hydrophilic bioactive agent becomes released from the matrix and available to a subject. The release of the bioactive agent can be site specific, and used to treat a medical condition. As used herein, the polymeric “matrix” refers to a three dimensional material structure which is based on one or more types of polymeric material(s) which form such a structure. The polymeric matrix can be in a particular form, such as a coating, and can have properties typical and/or desirable for desirable for that particular matrix form. The matrix can also include secondary, tertiary, etc., components, but that may not necessarily be a structural (polymeric) component of the matrix. For example, the matrix includes non-structural components, such as the microparticulates that include the hydrophilic bioactive agent. Other, optional, non-structural components can be included in the matrix.
  • The biodegradable bioactive agent-releasing matrices can be in any one or more various forms that provide an effective vehicle for release of the bioactive agent. In some aspects, the matrix is present in the form of a coating on the surface of an implantable medical device. Many particular compositions of the invention are suitable for forming biodegradable matrices in the form of coatings having desirable properties, such as strength, compliance, durability, etc. The biodegradable bioactive agent-releasing matrices can also be in other forms. For example, the matrix can be formed within a medical device, such as within an inner space (e.g., a lumen) of a device, with the device arranged so that the bioactive agent can be released through a part of the device, such as an aperture or a membrane that is associated with the device.
  • In another form, the biodegradable bioactive agent-releasing matrix can be fabricated as an implant itself. For example, the matrix can be in the form of an implant, such as a filament, coil, or prosthesis. The matrix in the form of an implant can serve as reservoir for release of the hydrophilic bioactive agent, or may also include some structure that (in addition to its drug releasing capability) can be placed in a subject to provide a mechanical feature.
  • Given the use of degradable polymers for the matrix, bioactive agent release is not dependent solely on the process of the bioactive agent diffusing through the matrix. Portions of the matrix that erode (e.g., through bulk or surface erosion) are able to contribute to the release of the bioactive agent into the local environment.
  • The term “degradable” as used herein with reference to polymers, shall refer to those natural or synthetic polymers that break down under physiological conditions (such as by enzymatic or non-enzymatic processes) into constituent components over a period of time. The terms “erodible,” “bioerodible,” and “biodegradable,” shall be used herein interchangeably with the term “degradable”.
  • Degradable polymers (including aliphatic polyester copolymers, such as those described herein) include those having hydrolyzable linkages between some or all of the monomeric units of the polymeric backbone. These linkages can be broken without requiring enzymatic assistance and are referred to as non-enzymatic hydrolyzable linkages (or “hydrolyzable linkages” for short). The cleavage of these hydrolyzable linkages leads to degradation of the polymer. Other degradable polymers can include enzymatically cleavable linkages that can be cleaved by enzymes in the body, leading to degradation of the polymer. Polymers that can be used in the biodegradable bioactive agent-releasing matrix of the invention can have both enzymatically cleavable linkages and non-enzymatic hydrolyzable linkages.
  • In a first matrix embodiment of the invention, the biodegradable bioactive agent-releasing matrix includes at least two components. One component is a biodegradable polymer comprising an aliphatic polyester copolymer. The aliphatic polyester copolymer comprises monomeric units of formula I which are present in the copolymer in an amount of greater than 17% (wt). This biodegradable aliphatic polyester copolymer can form all, or at least part of the polymeric matrix in which the microparticulates are present. Another component is a set of microparticulates comprising hydrophilic bioactive agent. The microparticulates, which are immobilized by the matrix, release hydrophilic bioactive agent when the matrix is implanted at or injected into a target location in the body. The matrix is arranged so that its surface is in direct contact with the environment (e.g., body fluid or tissue) that causes bioactive agent release when in use. In a second matrix embodiment of the invention, the biodegradable bioactive agent-releasing polymeric matrix includes at least three components: a first biodegradable polymer, a second biodegradable polymer, and microparticulates. The polymeric matrix in which the microparticulates are present is formed from at least the first and second biodegradable polymers. The first polymer comprises a biodegradable aliphatic polyester copolymer, the aliphatic polyester comprising a monomeric unit of formula II in an amount of greater than 15% by weight. The second biodegradable polymer comprises hydrophobic and hydrophilic portions. The microparticulates, which are immobilized by the matrix, release hydrophilic bioactive agent when the matrix is implanted at or injected into a target location in the body. The matrix is arranged so that its surface is in direct or indirect contact with the environment (e.g., body fluid or tissue) that causes bioactive agent release when in use.
  • The biodegradable bioactive agent-releasing matrix can contain one or more bioactive agents. The hydrophilic bioactive agent is provided in the microparticulates. In the biodegradable bioactive agent-releasing matrix, the microparticulates of the invention are, in essence, microdomains of hydrophilic bioactive agent. The use of hydrophilic bioactive agent in the form of microparticulates is advantageous because it allows bioactive agent to be included in the matrix without necessarily having to dissolve the bioactive agent in a solvent that dissolves the one or more polymeric materials used to form the matrix. In this regard, the microparticulate form can preserve bioactive agent activity because, in theory, within the microparticulate the bioactive agent is not subject to the same structurally altering forces as it would be if it were simply solvated in the solvent or in an emulsion with the solvent. Bioactive agent in microparticulate form also allows for the preparation of matrices with a desired distribution of bioactive agent in the matrix. The use of microparticulates, in combination with the biodegradable matrix materials described herein, provides an advantageous system for the controlled release of hydrophilic bioactive agents.
  • Aspects of the microparticulate may affect release of the bioactive agent from the biodegradable matrix. These aspects may include the size of the microparticulate, the presence or absence of other optional components in the microparticulate such as an optional polymer, an additive, or a solvent, the erosion characteristics of the material in the microparticulate, the structural features of the microparticulate including porosity, overcoats and the like.
  • The term “microparticulate” as used herein shall refer to non-dissolved particulate matter having a size of less than 1 mm in diameter (when observed as individual, discrete microparticulates). The term “microparticulate” also encompasses nanoparticles.
  • In many aspects, the biodegradable bioactive agent-releasing matrix includes particles that are spherical or substantially spherical in shape (also referred to as “microspheres”). In a spherical particle, distances from the center (of the microsphere) to the outer surface of the microsphere will about the same for any point on the surface of the microsphere. A substantially spherical microparticulate is where there may be a difference in radii, but the difference between the smallest radii and the largest radii is generally not greater than about 40% of the smaller radii, and more typically less than about 30%, or less than 20%.
  • In specific aspects, the biodegradable bioactive agent-releasing matrix includes a set of microparticulates having an average diameter (“dn”, number average) from about 10 nm to about 100 μm. In some more specifically aspects, the biodegradable bioactive agent-releasing matrix comprises a set of microparticulates is used having an average diameters from about, from about 100 nm to about 25 μm, from about 500 nm to about 15 μm, or even more specifically from about 1 μm to about 10 μm. In an embodiment, microparticulates are equal to or less than about 5 μm.
  • In some aspects of the invention, a microparticulate set having a smaller average diameter is used to prepare the biodegradable bioactive agent-releasing matrix. The use of smaller diameter microparticulates may improve control over release of the hydrophilic bioactive agent, such as in terms of rate and duration of release from the matrix. The use of smaller diameter microparticulates can also improve aspects of matrix formation. For example, smaller microparticulates can provide smoother coatings and are also less likely to clog coating equipment. In some aspects the small microparticulates have a diameter of less than about 10 μm.
  • The microparticles of the biodegradable bioactive agent-releasing matrix comprise a hydrophilic bioactive agent. The hydrophilic bioactive agent can have a solubility of at least 1 part agent per 50 parts water. In more specific aspects, the hydrophilic bioactive agent may be soluble (having a solubility of at least 1 part agent per from 10 to 30 parts water), freely soluble (having a solubility of at least 1 part agent per from 1 to 10 parts water), or very soluble (having a solubility of greater than 1 part agent per 1 part water). These descriptive terms for solubility are standard terms used in the art (see, for example, Remington: The Science and Practice of Pharmacy, 20th ed. (2000), Lippincott Williams & Wilkins, Baltimore Md.).
  • In some aspects the hydrophilic bioactive agent is a macromolecule. Hydrophilic macromolecules are exemplified by compounds such as polypeptides, polynucleotides, and polysaccharides. The hydrophilic macromolecules can have a molecular weight of about 1000 Da or greater, 5,000 Da or greater, or 10,000 Da or greater.
  • In some specific aspects, the microparticulate comprises a polypeptide. A polypeptide refers to an oligomer or polymer including two or more amino acid residues, and is intended to encompass compounds referred to in the art as proteins, polypeptides, oligopeptides, peptides, and the like. By way of example, peptides can include antibodies (both monoclonal and polyclonal), antibody derivatives (including diabodies, F(ab) fragments, humanized antibodies, etc.), cytokines, growth factors, receptor ligands, enzymes, and the like. Polypeptides can also include those that are modified with, or conjugated to, another biomolecule or biocompatible compound. For example, the polypeptide can be a peptide-nucleic acid (PNA) conjugate, polysaccharide-peptide conjugates (e.g., glyosylated polypeptides; glycoproteins), a poly(ethyleneglycol)-polypeptide conjugate (PEG-ylated polypeptides).
  • In some modes of practice, the microparticulates are prepared from polypeptides having a molecular weight of about 10,000 Da or greater, or about 20,000 Da or greater; more specifically in the range of about 10,000 Da to about 100,000 Da, or in the range of about 25,000 Da to about 75,000 Da.
  • One class of polypeptides that can be formed into the microparticulates includes antibodies and antibody fragments. A variety of antibody and antibody fragments are commercially available, obtainable by deposit or deposited samples, or can be prepared by techniques known in the art. For example, monoclonal antibodies (mAbs) can be obtained by any technique that provides for the production of antibody molecules by continuous cell lines in culture. These include, for example, the hybridoma technique (Kohler and Milstein, Nature, 256:495-497 (1975)); the human B-cell hybridoma technique (Kosbor et al., Immunology Today, 4:72 (1983); and the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96 (1985)). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • Fab or Fab′2 fragments can be generated from monoclonal antibodies by standard techniques involving papain or pepsin digestion, respectively. Kits for the generation of
  • Fab or Fab′2 fragments are commercially available from, for example, Pierce Chemical (Rockford, Ill.).
  • Examples of antibodies and antibody fragments that can be used to prepare the microparticulates include, but are not limited to, therapeutic antibodies such as trastuzumab (Herceptin™), a humanized anti-HER2 monoclonal antibody (mAb); alemtuzumab (Campath™), a humanized anti-CD52 mAb; gemtuzumab (Mylotarg™), a humanized anti-CD33 mAb; rituximab (Rituxan™), a chimeric anti-CD20 mAb; ibritumomab (Zevalin™), a murine mAb conjugated to a beta-emitting radioisotope; tositumomab (Bexxar™), a murine anti-CD20 mAb; edrecolomab (Panorex™), a murine anti-epithelial cell adhesion molecule mAb; cetuximab (Erbitux™), a chimeric anti-EGFR mAb; bevacizumab (Avastin™), a humanized anti-VEGF mAb, Ranibizumab (Lucentis™), an anti-vascular endothelial growth factor mAb fragment, satumomab (OncoScint™) an anti-pancarcinoma antigen (Tag-72) mAb, pertuzumab (Omnitarg™) an anti-HER2 mAb, and daclizumab (Zenapax™) an anti IL-2 receptor mAb.
  • The polypeptide can also be selected from cell response modifiers. Cell response modifiers include chemotactic factors such as platelet-derived growth factor (PDGF), pigmented epithelium-derived factor (PEDF), neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, SIS (small inducible secreted) proteins, platelet factor, platelet basic protein, melanoma growth stimulating activity, epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived endothelial cell growth factor, insulin-like growth factor, nerve growth factor, vascular endothelial growth factor, bone morphogenic proteins, and bone growth/cartilage-inducing factor (alpha and beta). Other cell response modifiers are the interleukins, interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10; interferons, including alpha, beta and gamma; hematopoietic factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; tumor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1, beta-2, beta-3, inhibin, and activin.
  • The polypeptide can also be selected from therapeutic enzymes, such as proteases, phospholipases, lipases, glycosidases, cholesterol esterases, and nucleases.
  • Specific examples include recombinant human tissue plasminogen activator (alteplase), RNaseA, RNaseU, chondroitinase, pegaspargase, arginine deaminase, vibriolysin, sarcosidase, N-acetylgalactosamine-4-sulfatase, glucocerebrocidase, α-galactosidase, and laronidase.
  • In some aspects, the microparticulate is composed predominantly of, or entirely of, hydrophilic bioactive agent. For example, the microparticulate polypeptide can include hydrophilic bioactive agent in an amount of about 50% wt or greater, about 60% wt or greater, about 70% wt or greater, or even about 90% wt or greater. This can be important in many therapeutic methods, as the amount of hydrophilic bioactive agent that is available to a subject following implantation or injection of the biodegradable bioactive agent-releasing matrix is maximized.
  • In some preparations, the biodegradable bioactive agent-releasing matrix comprises microparticulates composed predominantly of polypeptides. For example, polypeptide microparticulates can be formed as described in commonly owned U.S. patent application Ser. No. 12/215,504, and published as US2009/0028956, entitled “Polypeptide Microparticulates.” Generally, these microparticulates are formed in a solution, by coalescing polypeptides with a nucleating agent to form polypeptide nuclei; mixing a phase separation agent with the solution to further coalesce polypeptide around the polypeptide nuclei, thereby forming a mixture; cooling the mixture to form polypeptide microparticulates; and removing all or part of the phase separation agent from the polypeptide microparticulates. This method has been found to be particularly advantageous for the preparation of microparticulates formed predominantly of antibody or antibody fragments, and provides microparticulate sets having microparticulates of desired sizes, with low size polydispersity, and which maintains good polypeptide activity.
  • Optionally, the microparticulate can include a component that is different than the hydrophilic bioactive agent. In some aspects, the microparticulate includes a hydrophilic bioactive agent and a bioactive agent-stabilizing compound. The stabilizing compound can be of a type and present in an amount in the microparticulate useful for a particular bioactive agent. Exemplary stabilizing compounds include, but are not limited to, small carbohydrate sugars, such as trehalose, glucose, fructose, sucrose, lactose, maltose, and raffinose, with trehalose being a particularly effective stabilizing compound for polypeptides. In some cases an amount of bioactive agent to stabilizing agent is present in the microparticulate in a range of about 5:1 to about 1:1 (w:w), such as about a 2:1 polypeptide to trehalose. Other components such as biocompatible surfactants can be present in the microparticulate, such as poloxamer (polyoxypropylene-polyoxyethylene block copolymers) surfactants and polysorbate (polyoxyethylene sorbitan fatty acid ester) surfactants.
  • Optionally, the microparticulate can include a component can provide an additional control over the release of the bioactive agent, or protection of the bioactive agent in the microparticulate. This component can be a polymer, and can be different than, or the same as, the one or more polymers that are used to form polymer of the degradable matrix.
  • If used, the optional polymer is degradable and further selected based on various factors including compatibility with the bioactive agent, degradation characteristics, and compatibility or incompatibility with solvents used to form the matrix.
  • In some embodiments, the microparticulates used are substantially monodisperse. In other embodiments, the microparticulates used are polydisperse. In some applications, the use of substantially monodisperse microparticulates is advantageous because elution rates from substantially monodisperse microparticulates can be more consistent than those from polydisperse microparticulates.
  • Optionally, one or more additional bioactive agents that are different than the hydrophilic bioactive agent can be present in the elution control matrix. For example, one or more additional hydrophilic bioactive agents can be present in the microparticulate, such as two different polypeptides.
  • The aliphatic polyester copolymer provides desirable properties when the elution control matrix is provided in certain forms. For example, when the matrix is in the form of a coating, the aliphatic polyester copolymer can provide one or more properties of durability, compliance, and adherence in association with a substrate surface, an in the context of biodegradable coatings. As used herein, the term “durability” refers to the wear resistance of a polymer coating, or the ability of a coating to adhere to an article surface when subjected to forces typically encountered during use (for example, normal force, shear force, and the like). A more durable coating is less easily removed from a substrate by abrasion. A compliant coating is one that it shapes well to the article to which is has been coated and that conforms to the changes in the shape of the article without introducing any substantial physical deformities.
  • As a general matter, in both first and second matrix embodiments of the invention, the aliphatic polyester copolymers are formed from two or more aliphatic polyester-forming monomers. Exemplary aliphatic polyester-forming monomers include lactide, glycolide, dioxanone, tartronic acid, hydroxyvalerate, hydroxybutyrate, malonic acid, valerolactone, and caprolactone. Exemplary aliphatic polyester-forming monomers also include different enantiomeric forms of these monomers.
  • Aliphatic polyester copolymers suitable for use in both matrix embodiments of the invention can be obtained commercially. For example, aliphatic polyester copolymers having levels of lactide and caprolactone falling within the scope of the invention can be obtained from Lakeshore Pharmaceuticals (Birmingham, Ala.). Alternatively, suitable aliphatic polyester copolymers can be obtained through the polymerization of aliphatic polyester-forming monomers using known techniques. Such techniques commonly include direct condensation and ring opening polymerization techniques. For example, see Jacobson, S., et al. Polymer Engineering and Science, 39:1311-1319 (1999).
  • As described herein, in the first matrix embodiment, the biodegradable bioactive agent-releasing matrix includes at least one polymeric component and a microparticulate component. The polymeric component is a biodegradable polymer comprising an aliphatic polyester copolymer comprising monomeric units of the following formula I
  • Figure US20100303878A1-20101202-C00003
  • wherein R1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms (such as monomeric units derived from lactide), and wherein the monomeric unit is present in the aliphatic polyester copolymer in an amount of greater than 17% by weight. Exemplary R1 groups include divalent saturated hydrocarbon groups that include two carbon atoms. For example, the aliphatic polyester copolymer can have monomeric units with one or both of the following structures:
  • Figure US20100303878A1-20101202-C00004
  • Structure (a) is a monomeric unit derived from the polymerization of lactide or lactic acid, and (b) a monomeric unit derived from the polymerization of butyric acid.
  • In more specific aspects of the first matrix embodiment, the biodegradable aliphatic polyester copolymer comprises monomeric units of formula I in an amount in the range of greater than 17% to about 99% wt, in the range of about 20% to about 85% wt, in the range of about 25% to about 85% wt, in the range of about 35% to about 85% wt, in the range of about 50% to about 85% wt, or in the range of about 65% to about 85% wt. In some aspects the biodegradable aliphatic polyester copolymer includes an amount of lactic acid monomeric units in these ranges.
  • A lactide copolymer includes lactide monomeric units, the lactide monomeric units being derived from the polymerization of a monomer mixture that includes lactide or lactic acid. Lactic acid has one asymmetric carbon atom and is a chiral molecule. Accordingly, lactide is available in two different optical isomeric forms (enantiomeric forms), D-lactic acid and L-lactic acid (also known as R and S enantiomers, respectively). The cyclic dimer lactide is formed by the combination of two lactic acid molecules. The cyclic lactidc dimer can exist is three possible stereoisomer forms, (a) a cyclic dimer of two D-lactic acid moieties, (b) a cyclic dimer of two L-lactic acid moieties, or (c) a cyclic dimer of D-lactic acid and L-lactic acid moieties. The aliphatic polyester copolymer comprising lactide that is used to form the matrix of the invention can be formed from the lactide dimers (a), (b), or (C), or a mixture thereof. As such, the lactide portion of the aliphatic polyester copolymer can include monomeric units formed from D-lactic acid, L-lactic acid, or combinations thereof.
  • In some preparations, the aliphatic polyester copolymer comprising lactide is formed substantially or entirely from L-lactide. The use of L-lactide is advantageous because its degradation product is a naturally occurring stereoisomer that can be readily metabolized by the body.
  • The biodegradable aliphatic polyester copolymer including monomeric units of formula I can include one or more other co-monomers that, when included in the copolymer, provide an aliphatic polyester copolymer capable of being degraded in vivo. For example, the lactide copolymer can be a random copolymer and can include one or more other aliphatic polyester-forming monomers. In more specific aspects of the first matrix embodiment, the aliphatic polyester copolymer comprises monomeric units of one of formula I in an amount of greater than 17% by weight, and a monomeric unit of formula II:
  • Figure US20100303878A1-20101202-C00005
  • wherein R2 is a divalent saturated or unsaturated hydrocarbon group that includes four or five carbon atoms. Exemplary R2 groups include divalent saturated linear or branched hydrocarbon groups that include four or five carbon atoms. In some aspects, R2 group is a divalent saturated linear hydrocarbon group that includes five carbon atoms, which can be provided by the ring opening and polymerization of caprolactone into the aliphatic polyester copolymer. In some aspects, R2 is a divalent saturated linear hydrocarbon group that includes four carbon atoms, which can be provided by the ring opening and polymerization of valerolactone into the aliphatic polyester copolymer.
  • In more specific aspects of the first matrix embodiment, the biodegradable aliphatic polyester copolymer comprises a monomeric unit of formula I in an amount in the range of greater than 17% to about 99% wt and a monomeric unit of formula II in an amount in the range of about 1% to less than 83% wt; a monomeric unit of formula I in an amount in the range of about 20% to about 85% wt and a monomeric unit of formula II in an amount in the range of about 15% to about 80% wt; a monomeric unit of formula I in an amount in the range of about 25% to about 85% wt and a monomeric unit of formula II in an amount in the range of about 15% to about 75% wt; a monomeric unit of formula I in an amount in the range of about 35% to about 85% wt and a monomeric unit of formula II in an amount in the range of about 15% to about 65% wt; a monomeric unit of formula I in an amount in the range of about 50% to about 85% wt and a monomeric unit of formula II in an amount in the range of about 15% to about 50% wt; or a monomeric unit of formula I in an amount in the range of about 65% to about 85% wt and a monomeric unit of formula II in an amount in the range of about 15% to about 35% wt.
  • For example, an exemplary biodegradable aliphatic polyester copolymer of the first matrix embodiment includes monomeric units formed from lactide in an amount in the range of about 25% to about 85% wt, and caprolactone in an amount in the range of about 15% to about 75%.
  • In the second matrix embodiment, the biodegradable bioactive agent-releasing matrix includes at least two polymeric components (a first biodegradable polymer, a second biodegradable polymer) and a microparticulate component. The polymeric matrix in which the microparticulates are present is formed from at least the first and second biodegradable polymers. The first polymer comprises a biodegradable aliphatic polyester copolymer, the aliphatic polyester comprising a monomeric unit of formula II:
  • Figure US20100303878A1-20101202-C00006
  • wherein R2 is as described herein, and the monomeric unit is present in the biodegradable aliphatic polyester copolymer in an amount of greater than 15% by weight. The second biodegradable polymer comprises hydrophobic and hydrophilic portions. The microparticulates are immobilized by the matrix.
  • In more specific aspects of the second matrix embodiment, the biodegradable aliphatic polyester copolymer comprises monomeric units of formula II (such as caprolactone) in an amount in the range of greater than 15% to about 99% wt, in the range of about 20% to about 83% wt, in the range of about 25% to about 83% wt, in the range of about 35% to about 83% wt, in the range of about 50% to about 83% wt, or in the range of about 75% to about 83% wt.
  • In more specific aspects of the second matrix embodiment, the biodegradable aliphatic polyester copolymer comprises a monomeric unit of formula II in an amount in the range of greater than 15% to about 99% wt and a monomeric unit of formula I in an amount in the range of about 1% to less than 85% wt; a monomeric unit of formula II in an amount in the range of about 20% to about 83% wt and a monomeric unit of formula I in an amount in the range of about 17% to about 80% wt; a monomeric unit of formula II in an amount in the range of about 25% to about 83% wt and a monomeric unit of formula I in an amount in the range of about 17% to about 75% wt; a monomeric unit of formula II in an amount in the range of about 35% to about 83% wt and a monomeric unit of formula I in an amount in the range of about 17% to about 65% wt; a monomeric unit of formula II in an amount in the range of about 50% to about 83% wt and monomeric unit of formula I in an amount in the range of about 17% to about 50% wt; a monomeric unit of formula II in an amount in the range of about 75% to about 83% wt and a monomeric unit of formula I in an amount in the range of about 17% to about 25% wt.
  • For example, an exemplary biodegradable aliphatic polyester copolymer of the second embodiment of the invention includes caprolactone in an amount in the range of about 20% to about 83% wt, and monomeric units derived from lactide in an amount in the range of about 17% to about 80%.
  • In the second matrix embodiment, the biodegradable matrix also includes a second biodegradable polymer. The second biodegradable polymer includes hydrophilic and hydrophobic portions. The presence of the second biodegradable polymer modulates release of the hydrophilic bioactive agent from the matrix. It was shown that the rate of release of the bioactive agent from the matrix was very sensitive to the relative amounts of the first and second biodegradable polymers in the matrix. In addition, the matrices formed from the first and second biodegradable polymers were able to suppress the burst of the hydrophilic bioactive agent at high loading levels.
  • In some aspects the second biodegradable polymer includes hydrophilic and hydrophobic portions, and the portions are in the form of polymeric blocks. For example, the second biodegradable polymer includes hydrophilic polymeric blocks and hydrophobic polymeric blocks, with one or both blocks including degradable linkages. In some aspects, the second biodegradable polymer includes a hydrophobic polymeric blocks that are degradable, and hydrophilic polymeric blocks including a biocompatible polymer.
  • Exemplary degradable hydrophobic polymeric blocks also include those that are blocks of copolymers having a hydrophobic property. Such hydrophobic copolymeric blocks can be formed from formed from polyester-forming monomers such as glycolic acid, glycolide, lactic acid, lactide, dioxanone, caprolactone, 3-hydroxybutyrate, 3-hydroxyvalerate, valerolactone, tartronic acid, β-malonic acid, propylene fumarate, and butylene terephthalate.
  • Exemplary degradable hydrophobic polymeric blocks include those that are formed from degradable polyesters such as poly(glycolic acid), poly(lactic acid), poly(lactic-co-glycolic acid), poly(dioxanone), poly(caprolactone), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(valerolactone), poly(tartronic acid), poly(β-malonic acid), polypropylene fumarate), and poly(butylene terephthalate).
  • Exemplary biocompatible hydrophilic polymeric blocks include those that are formed from hydrophilic biocompatible polymers such as poly(ethylene oxide) (PEO), poly(ethyloxazoline), poly(ethylene glycol) (PEG), PEG-PPO (copolymers of polyethylene glycol and polypropylene oxide), tetraethylene glycol, triethylene glycol, trimethylolpropane ethoxylate, or pentaerythritol ethoxylate, hydrophilic segmented urethanes, and polyvinyl alcohol.
  • In some aspects the hydrophilic polymeric blocks of the second biodegradable polymer have a molecular weight in the range of about 250 Da to about 5000 Da.
  • The hydrophilic and hydrophobic portions of the second biodegradable polymer can also be defined in terms of their weight ratios in the polymer. For example, in some aspects, the weight ratio of the hydrophilic portion to the hydrophobic portions can be in the range of about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1 to about 1:1.5.
  • Specific examples of degradable polymers having hydrophilic and hydrophobic blocks include poly(ether ester) multiblock copolymers. Exemplary poly(ether ester) multiblock copolymers are based on poly(ethylene glycol) (PEG) and poly(butylene terephthalate) (PBT) that can be described by the following general structure:

  • [—(OCH2CH2)n—O—C(O)—C6H4—C(O)—]x[—O—(CH2)4—O—C(O)—C6H4—C(O)—]y,
  • where —C6H4— designates the divalent aromatic ring residue from each esterified molecule of terephthalic acid, n represents the number of ethylene oxide units in each hydrophilic PEG block, x represents the number of hydrophilic blocks in the copolymer, and y represents the number of hydrophobic blocks in the copolymer. n can be selected such that the molecular weight of the PEG block is between about 300 and about 4000. X and y can be selected so that the multiblock copolymer contains from about 55% up to about 80% PEG by weight. For example a (poly(butyleneterephthalate-co-ethylene glycol) copolymer with 45 wt. % polyethylene glycol (having an average molecular weight of 1000 kD) and 55 wt. % butyleneterephthalate, would have a weight ratio of hydrophilic portion to hydrophobic portion of about 1:1.22. Examples of these types of multiblock copolymers are described in, for example, U.S. Pat. No. 5,980,948. PEG/PBT polymers are also commercially available from Octoplus BV, under the trade designation PolyActive™.
  • Another example of a degradable polymer having hydrophilic and hydrophobic blocks are those including PEG and polylactic acid (PLA) blocks. These include PEG-PLA AB-block and ABA-triblock copolymers, which can be linear or star shaped. See, for example, U.S. Pat. Nos. 4,745,160 and 6,004,573, and Li Y., et al. (1998) Synthesis, characteristics and in vitro degradation of star-block copolymers consisting of L-lactide, glycolide, and branched multi-arm poly(ethylene oxide), Polymer 39:4421-4427.
  • Another type of poly(ether ester) block copolymers suitable as the second polymer are those composed of various pre-polymer building blocks of different combinations of DL-lactide, glycolide, ε-caprolactone and polyethylene glycol (PEG). These are referred to herein as PEG-aliphatic polyester block copolymers. Exemplary PEG-aliphatic polyester block copolymers can have a formula as shown below:
  • Figure US20100303878A1-20101202-C00007
  • wherein,
  • m and p are each independently glycolide;
  • n is polyethylene glycol, Mw 300-1000;
  • o is ε-caprolactone; and
  • q is DL-lactide.
  • These PEG-aliphatic polyester block copolymers can degrade completely via hydrolysis into non-toxic degradation products which are metabolized and/or excreted through the urinary pathway. Consequently, there can be no accumulation of biomaterials, thereby minimizing the chance of long-term foreign body reactions.
  • PEG-aliphatic polyester block copolymers are described in, for example, WO 2005/068533.
  • The multi-block copolymers can specifically include two hydrolysable segments having a different composition, linked by a multifunctional, specifically an aliphatic chain-extender, and which are specifically essentially completely amorphous under physiological conditions (moist environment, body temperature, which is approximately 37° C. for humans).
  • The resulting multi-block copolymers can specifically have a structure according to any of the formulas (1)-(3):

  • [—R8-Q1—R11-Q2-]x—[R9-Q3—R11-Q4-]y—[R10-Q5-—R11-Q6-]x-  (1)

  • [—R8—R2—R8-Q1—R11-Q2-]x—[R10-Q2—R11-Q1]x-  (2)

  • [—R9—R8 1—R9-Q1—R11-Q2-]x—[R10-Q2—R11-Q1]z-  (3)
  • wherein
  • R8 and R9 can be amorphous polyester, amorphous poly ether ester or amorphous polycarbonate; or an amorphous pre-polymer that is obtained from combined ester, ether and/or carbonate groups. R8 and R9 can contain polyether groups, which can result from the use of these compounds as a polymerization initiator, the polyether being amorphous or crystalline at room temperature. However, the polyether thus introduced will become amorphous at physiological conditions. R8 and R9 are derived from amorphous pre-polymers or blocks A and B, respectively, and R8 and R9 are not the same. R8 and R9 can contain a polyether group at the same time. In a specific embodiment, only one of them will contain a polyether group;
  • z is zero or a positive integer;
  • R10 is a polyether, such as poly(ethylene glycol), and may be present (z≠0) or not (z=0). R10 will become amorphous under physiological conditions;
  • R11 is an aliphatic C2-C8 alkylene group, optionally substituted by a Ci-C1-C10 alkylene, the aliphatic group being linear or cyclic, wherein R11 can specifically be a butylene, —(CH2)4— group, and the C1-C10 alkylene side group can contain protected S, N, P or O moieties;
  • x and y are both positive integers, which can both specifically be at least 1, whereas the sum of x and y (x+y) can specifically be at most 1000, more specifically at most 500, or at most 100. Q1-Q6 are linking units obtained by the reaction of the pre-polymers with the multifunctional chain-extender. Q1-Q6 are independently amine, urethane, amide, carbonate, ester or anhydride. The event that all linking groups Q are different being rare and not preferred.
  • Typically, one type of chain-extender can be used with three pre-polymers having the same end-groups, resulting in a copolymer of formula (1) with six similar linking groups. In case pre-polymers R8 and R9 are differently terminated, two types of groups Q will be present: e.g. Q1 and Q2 will be the same between two linked pre-polymer segments R8, but Q1 and Q2 are different when R8 and R9 are linked. Obviously, when Q1 and Q2 are the same, it means that they are the same type of group but as mirror images of each other.
  • In copolymers of formula (2) and (3) the groups Q1 and Q2 are the same when two pre-polymers are present that are both terminated with the same end-group (which is usually hydroxyl) but are different when the pre-polymers are differently terminated (e.g. PEG which is diol terminated and a di-acid terminated ‘tri-block’ pre-polymer). In case of the tri-block pre-polymers (R8R9R8 and R9R8R9), the outer segments should be essentially free of PEG, because the coupling reaction by ring opening can otherwise not be carried out successfully. Only the inner block can be initiated by a PEG molecule.
  • The examples of formula (1), (2) and (3) show the result of the reaction with a di-functional chain-extender and di-functional pre-polymers.
  • With reference to formula (1) the polyesters can also be represented as multi-block or segmented copolymers having a structure (ab)n with alternating a and b segments or a structure (ab)r with a random distribution of segments a and b, wherein ‘a’ corresponds to the segment R8 derived from pre-polymer (A) and ‘b’ corresponds to the segment R9 derived from pre-polymer (B) (for z=0). In (ab)r, the ail) ratio (corresponding to x/y in formula (1)) may be unity or away from unity. The pre-polymers can be mixed in any desired amount and can be coupled by a multifunctional chain extender, viz. a compound having at least two functional groups by which it can be used to chemically link the pre-polymers. Specifically, this is a di-functional chain-extender. In case z≠0, then the presentation of a random distribution of all the segments can be given by (abc)r were three different pre-polymers (one being e.g. a polyethylene glycol) are randomly distributed in all possible ratio's. The alternating distribution is given by (abc)n. In this particular case, alternating means that two equally terminated pre-polymers (either a and c or b and c) are alternated with a differently terminated pre-polymer b or a, respectively, in an equivalent amount (a+c=b or b+c=a). Those according to formula (2) or (3) have a structure (aba)n and (bab)n wherein the aba and bab ‘triblock’ pre-polymers are chain-extended with a di-functional molecule.
  • The method to obtain a copolymer with a random distribution of a and b (and optionally c) is far more advantageous than when the segments are alternating in the copolymer such as in (ab)n with the ratio of pre-polymers a and b being 1. The composition of the copolymer can then only be determined by adjusting the pre-polymer lengths. In general, the a and b segment lengths in (ab)n alternating copolymers are smaller than blocks in block-copolymers with structures ABA or AB.
  • The pre-polymers of which the a and b (and optionally c) segments are formed in (ab)r, (abc)r, (ab)n and (abc)n are linked by the di-functional chain-extender. This chain-extender can specifically be a diisocyanate chain-extender, but can also be a diacid or diol compound. In case all pre-polymers contain hydroxyl end-groups, the linking units will be urethane groups. In case (one of) the pre-polymers are carboxylic acid terminated, the linking units are amide groups. Multi-block copolymers with structure (ab)r and (abc)r can also be prepared by reaction of di-carboxylic acid terminated pre-polymers with a diol chain extender or vice versa (diol terminated pre-polymer with diacid chain-extender) using a coupling agent such as DCC (dicyclohexyl carbodiimide) forming ester linkages. In (aba)n and (bab)n the aba and bab pre-polymers are also specifically linked by an aliphatic di-functional chain-extender, more specifically, a diisocyanate chain-extender.
  • The term “randomly segmented” copolymers refers to copolymers that have a random distribution (i.e. not alternating) of the segments a and b: (ab)r or a, b and c: (abc)r.
  • Other exemplary second biodegradable polymers include those of copolymers containing both hydrophilic poly(alkylene oxides) (PAO) and degradable sequences, wherein the hydrocarbon portion of each PAO unit contains from 1 to 4 carbon atoms, or 2 carbon atoms (i.e., the PAO is poly(ethylene oxide)). For example, useful degradable polymeric materials can be made of block copolymers containing PAO and amino acids or peptide sequences and contain one or more recurring structural units independently represented by the structure —L—R3—L—R4—, wherein R3 is a poly(alkylene oxide), L is —O— or —NH—, and R4 is an amino acid or peptide sequence containing two carboxylic acid groups and at least one pendent amino group.
  • Other useful degradable polymeric materials are composed of polyarylate or polycarbonate random block copolymers that include tyrosine-derived diphenol monomeric units and poly(alkylene oxide), such as the polycarbonate shown below:
  • Figure US20100303878A1-20101202-C00008
  • wherein R5 is —CH═CH— or (—CH2—)j, in which j is 0 to 8; R6 is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and optionally containing at least one ether linkage, and derivatives of biologically and pharmaceutically active compounds covalently bonded to the copolymer; each R7 is independently selected from alkylene groups containing 1 to 4 carbon atoms; y is between 5 and about 3000; and f is the percent molar fraction of alkylene oxide in the copolymer and ranges from about 0.01 to about 0.99.
  • In some embodiments, pendent carboxylic acid groups can be incorporated within the polymer bulk for polycarbonates, polyarylates, and/or poly(alkylene oxide) block copolymers thereof, to further control the rate of polymer backbone degradation and resorption.
  • The biodegradable bioactive agent-releasing matrix can also be discussed in terms of the amounts of the components of the matrix (at particular percentages by weight solids), or amounts of components in the formed matrix, in relation to one another.
  • The first and second biodegradable polymers can be present in the second matrix embodiment of the invention at a desired ratio. For example the second biodegradable polymer can be present and have an affect on the modulation of bioactive agent release in amounts as little as 10% or about 15%, and up to about 85% or about 90% (by weight) of the total polymeric material that is used to form the matrix. For example, the ratio of the first biodegradable polymer to the second biodegradable polymer can be in the range of about 1:10 to about 10:1, or about 1.5:10 to about 10:1.5.
  • In some aspects, the biodegradable bioactive agent-releasing matrix has an amount of microparticulates (i.e., the amount of microparticulates as a percentage of the total weight of the coating) of up to about 50% wt, such as in the range of about 1% wt to about 50% wt, about 10% wt to about 45% wt, or about 20% wt to about 40% wt.
  • In some aspects, the elution control matrix has an amount of total polymeric content (i.e., the amount of first polymer, second polymer, and any additional polymer as a percentage of the total weight of the elution control matrix) of greater than 30% wt, in the range of about 30% wt to about 70% wt, about 40% wt to about 70% wt, or about 50% wt to about 70% wt.
  • The bioactive agent-releasing matrix can be provided in certain forms, and one or more processing steps can be carried out to prepare the matrix in the desired form. Generally, the process includes obtaining or preparing a composition, the composition including the one or more polymeric components used to form the matrix and microparticulates. In many modes of practice, the composition includes a liquid component, with the one or more polymeric material(s) microparticulates present as dissolved or suspended solids in the liquid component, and the microparticulates present as dispersed, suspended, or suspendable material in the liquid. Such a liquid composition can be used, for example, in a coating process to prepare the biodegradable matrix in the form of a coating on the surface of a device, or in a solvent casting process to form an article.
  • For the first matrix embodiment, the composition includes at least the biodegradable polymer comprising an aliphatic polyester copolymer, the aliphatic polyester comprising a monomeric unit of formula I in an amount greater than 17% by weight, and microparticulates comprising hydrophilic bioactive agent.
  • For the second matrix embodiment, the composition includes at least the biodegradable polymer comprising an aliphatic polyester copolymer, the aliphatic polyester comprising a monomeric unit of formula II in an amount greater than 17% by weight, a second biodegradable polymer including hydrophobic and hydrophilic portions, and microparticulates comprising a hydrophilic bioactive agent.
  • In some modes of preparation, once the microparticulates are produced or obtained, they are mixed with a solvent and one or more polymeric material(s) that will form the biodegradable matrix. An appropriate solvent, or solvent system, can be chosen for preparation of the composition. Different types of solvents can be used depending on the properties of the particles and the properties of the one or more matrix polymer(s). Suitable solvents include those that do not cause substantial or any dissolution of the microparticulates during the process.
  • Examples of solvents suitable for dissolution of the aliphatic polyester copolymer include halogenated alkanes such as methylene chloride and chloroform. Halogenated alkanes are preferred solvents when the microparticulates include or are formed from polypeptides. Other solvents that can be used include, but are not limited to, toluene and xylene, ethers such as tetrahydrofuran; and amides such as dimethylformamide (DMF). Combinations of one or more of these or other solvents can also be used.
  • In some modes of practice, a composition is formed by dissolving the one or more biodegradable polymers used to form the matrix in a solvent, and then dispersing the microparticulates in the composition. However, the components of the composition can be added to the solvent in any particular order, or can be combined all at once. In many modes of practice the components are added with agitation to keep the microparticulates dispersed and/or suspended. The microparticulates can be provided to the composition in dry (e.g., lyophilized form) or alternatively can be provided in a solvent used in the microparticulate formation process. For example, it is noted that solvents useful for extraction of phase separation agents in the microparticulate formation process can also be useful as solvents during the matrix formation (e.g., coating) process.
  • The one or more polymer components of the matrix (i.e., in either the first or second matrix embodiments of the invention) can be added to the composition to provide a concentration of suitable for forming and holding the microparticulates in place after the matrix forms, and providing a matrix with desired bioactive agent release properties. The total polymer content can be at least the first polymer; the first and second polymers; or the first, second, and any additional polymers.
  • In the second matrix embodiment, the composition is prepared including the second biodegradable polymer that has hydrophilic and hydrophobic portions, such as a poly(ethylene glycol)-based block copolymer. Exemplary concentrations of the second biodegradable polymer in the solvent can be in the range of up to 20 mg/mL, such as in the range of about 1 mg/mL to about 20 mg/mL. The first and second biodegradable polymers can be used at concentrations to provide a desired ratio of these materials in the formed matrix.
  • The amount of microparticulates incorporated into the matrix can be chosen based on various factors, including the type and amount of hydrophilic bioactive agent intended to be incorporated into the matrix, and the desired release rate and duration of release of the bioactive agent from the matrix, and the type and amount of the polymeric material(s) to be used to form the matrix. There is no particular lower limit of amount of microparticulates to be dispersed in the composition. In many aspects, the amount of microparticulates in the composition per volume is less than the amount of polymeric material per the same volume.
  • In some modes of practice, the composition is used in a coating process so the biodegradable matrix is in the form of a coating on the surface of a device. In a coating process, the composition can be applied to a substrate, and then the solvent is allowed to evaporate from the surface. This leaves the polymeric material or materials deposited on the surface with the microparticulates partially and/or full embedded in the polymeric material, thereby forming a coated layer that is the biodegradable matrix.
  • A coating process can be performed with a single application of the coating composition, or multiple applications of a coating composition. For example, the composition may be repeatedly applied to the surface build up the coating and increase the amount of solids. Methods forming the matrix can be quite variable, and suited to provide a coating with desired characteristics, such as a desired amount of bioactive agent and a desired thickness of the coating material.
  • After all the components of the matrix-forming composition have been combined, the composition can then be processed to produce a suspension that is substantially homogenous. Depending on the nature of the composition components, this may be done using a sonication apparatus, homogenizer, stirring apparatus, or the like. In some instances, the composition forms a suspension that is stable over a period of time of about five minutes to about twenty-four hours. In other instances, the composition is not stable and must be stirred or otherwise agitated to maintain the homogeneity of the suspension. In some embodiments, other agents may be added to the suspension. If desired, antiflocculation agents can be added to the composition.
  • The coating composition is then applied onto the substrate using any one of a variety of coating techniques including dip-coating, spray-coating (including both gas-atomization and ultrasonic atomization), fogging, brush coating, press coating, blade coating, and the like. The coating composition may be applied under conditions where atmospheric characteristics such as relative humidity, temperature, gaseous composition, and the like are controlled.
  • In some embodiments, the coating solution is applied using a spray technique. Exemplary spray coating equipment that can be used to apply coatings of the invention can be found in U.S. Pat. Nos. 6,562,136; 7,077,910; 7,192,484; 7,125,577; U.S. Published Patent Applications 2006/0088653, and 20051019424; and U.S. application Ser. Nos. 11/102,465 and 60/736,995.
  • The spray technique can be performed by spraying the composition on the surface of a substrate. Generally, an amount of solvent will evaporate during spray coating and after the composition has been applied to the surface. The composition can be repeatedly sprayed on the surface to provide a coating with desired properties, such as thickness and amount of bioactive agent per unit area on the surface. The coating evaporates from the applied composition, leaving a coating of solids on the surface. The process can be carried out to provide a coating with desired features.
  • The coating can have certain dimensions, such as thickness. In many aspects the thickness will be relatively uniform over the entire coating on the surface. A coating process can be carried out to provide a coating that is at least based on the size of the microparticulates that are included in the coating. In many aspects, the thickness of the coating is greater than the diameter of the microparticulates present in the coating. For example, the thickness of the coating can be greater than about 5 μm, greater than about 10 μm. Exemplary coatings have thicknesses in the range of about 40 μm to about 50 μm.
  • In other modes of practice, the coating process is carried out wherein components used to form the coating are separately sprayed on the substrate, using two or more sprayed solutions. For example, the coating process can be carried out using a spray coating apparatus with a dual spray head as described in U.S. Published Patent Application No, 2007/0128343, entitled “Apparatus and Methods for Applying Coatings.” To exemplify this method, and with reference to the second embodiment of the invention, one composition including the first polymer and microparticulates is sprayed from a first spray head, and another composition including the second polymer is sprayed from a second spray head. The spray patterns from both spray heads are directed at the same location on the surface of the substrate, and the components can mix during the coating process to form the coating.
  • Other types of processes can be used to form a biodegradable bioactive agent-releasing matrix. The matrix can be in the form of a mass within an implantable article, such as a lumen of an implantable article. The composition can be disposed in the lumen, with the removal of solvent during the process, to form a matrix within the lumen of the article. Following formation and implantation, the matrix can be contacted with a body fluid through a portion of the article, such as an aperture, which causes the bioactive agent to be released from the matrix through the aperture and degradation of the polymeric material of the matrix.
  • In another mode of practice, the biodegradable bioactive agent-releasing matrix is prepared in the form of an implant, which is composed of the matrix itself. The implant can be in the form of a filament, coil, or prosthesis, such that when the implant is placed in a subject, the bioactive agent can be released from the matrix. In one mode of preparation, the implant is formed by disposing the composition in a mold, performing solvent removal and solidification of the matrix, and then removing the formed implant from the mold.
  • Embodiments of the invention can be used to form elution control matrices in association with many different types of devices, including medical devices, including many different types of substrates. Medical devices can include both implantable devices (chronically and transiently implantable) and non-implantable medical devices. In many aspects, a composition used to form the elution control matrix can be formed into a device as described herein.
  • Embodiments of the invention can be used with implantable, or transitorily implantable, devices including, but not limited to, vascular devices such as grafts (e.g., abdominal aortic aneurysm grafts, etc.), stents (e.g., self-expanding stents typically made from nitinol, balloon-expanded stents typically prepared from stainless steel, degradable coronary stents, etc.), catheters (including arterial, intravenous, blood pressure, stent graft, etc.), valves (e.g., polymeric or carbon mechanical valves, tissue valves, valve designs including percutaneous, sewing cuff, and the like), embolic protection filters (including distal protection devices), vena cava filters, aneurysm exclusion devices, artificial hearts, cardiac jackets, and heart assist devices (including left ventricle assist devices), implantable defibrillators, electro-stimulation devices and leads (including pacemakers, lead adapters and lead connectors), implanted medical device power supplies (e.g., batteries, etc.), peripheral cardiovascular devices, atrial septal defect closures, left atrial appendage filters, valve annuloplasty devices (e.g., annuloplasty rings), mitral valve repair devices, vascular intervention devices, ventricular assist pumps, and vascular access devices (including parenteral feeding catheters, vascular access ports, central venous access catheters); surgical devices such as sutures of all types, staples, anastomosis devices (including anastomotic closures), suture anchors, hemostatic barriers, screws, plates, clips, vascular implants, tissue scaffolds, cerebro-spinal fluid shunts, shunts for hydrocephalus, drainage tubes, catheters including thoracic cavity suction drainage catheters, abscess drainage catheters, biliary drainage products, and implantable pumps; orthopedic devices such as joint implants, acetabular cups, patellar buttons, bone repair/augmentation devices, spinal devices (e.g., vertebral disks and the like), bone pins, cartilage repair devices, and artificial tendons; dental devices such as dental implants and dental fracture repair devices; drug delivery devices such as drug delivery pumps, implanted drug infusion tubes, drug infusion catheters, and intravitreal drug delivery devices; ophthalmic devices including orbital implants, glaucoma drain shunts and intraocular lenses; urological devices such as penile devices (e.g., impotence implants), sphincter, urethral, prostate, and bladder devices (e.g., incontinence devices, benign prostate hyperplasia management devices, prostate cancer implants, etc.), urinary catheters including indwelling (“Foley”) and non-indwelling urinary catheters, and renal devices; synthetic prostheses such as breast prostheses and artificial organs (e.g., pancreas, liver, lungs, heart, etc.); respiratory devices including lung catheters; neurological devices such as neurostimulators, neurological catheters, neurovascular balloon catheters, neuro-aneurysm treatment coils, and neuropatches; ear nose and throat devices such as nasal buttons, nasal and airway splints, nasal tampons, ear wicks, ear drainage tubes, tympanostomy vent tubes, otological strips, laryngectomy tubes, esophageal tubes, esophageal stents, laryngeal stents, salivary bypass tubes, and tracheostomy tubes; biosensor devices including glucose sensors, cardiac sensors, intra-arterial blood gas sensors; oncological implants; and pain management implants.
  • In some aspects, embodiments of the invention can be utilized in connection with ophthalmic devices. Suitable ophthalmic devices in accordance with these aspects can provide bioactive agent to any desired area of the eye. In some aspects, the devices can be utilized to deliver bioactive agent to an anterior segment of the eye (in front of the lens), and/or a posterior segment of the eye (behind the lens). Suitable ophthalmic devices can also be utilized to provide bioactive agent to tissues in proximity to the eye, when desired.
  • In some aspects, embodiments of the invention can be utilized in connection with an ophthalmic device configured for placement at an external or internal site of the eye. Suitable external devices can be configured for topical administration of bioactive agent. Such external devices can reside on an external surface of the eye, such as the cornea (for example, contact lenses) or bulbar conjunctiva. In some embodiments, suitable external devices can reside in proximity to an external surface of the eye.
  • Devices configured for placement at an internal site of the eye can reside within any desired area of the eye. In some aspects, the ophthalmic devices can be configured for placement at an intraocular site, such as the vitreous. Illustrative intraocular devices include, but are not limited to, those described in U.S. Pat. Nos. 6,719,750 B2 (“Devices for Intraocular Drug Delivery,” Varner et al.) and 5,466,233 (“Tack for Intraocular Drug Delivery and Method for Inserting and Removing Same,” Weiner et al.); U.S. Patent Publication Nos. 2005/0019371 A1 (“Controlled Release Bioactive Agent Delivery Device,” Anderson et al.), 2004/0133155 A1 (“Devices for Intraocular Drug Delivery,” Varner et al.), 2005/0059956 A1 (“Devices for Intraocular Drug Delivery,” Varner et al.), and 2003/0014036 A1 (“Reservoir Device for Intraocular Drug Delivery,” Varner et al.); and U.S. Patent Publication Nos. 2005/0276837 A1 (filed Dec. 15, 2005, Anderson et al.), 2004/0271706 A1 (filed Dec. 8, 2005, Anderson et al.), 20050287188 A1 (filed Dec. 29, 2005, Anderson et al.), 2008/0271703 A1 (filed Dec. 8, 2005, Anderson et al.), 2005/0281863 A1 (filed Dec. 22, 2005, Anderson et al.); and related applications.
  • Suitable ophthalmic devices can be configured for placement within any desired tissues of the eye. For example, ophthalmic devices can be configured for placement at a subconjunctival area of the eye, such as devices positioned extrasclerally but under the conjunctiva, such as glaucoma drainage devices and the like. In other aspects, the ophthalmic devices can be configured for placement at a subretinal area within the eye.
  • The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.
  • EXAMPLE 1 Controlled Delivery of Nonspecific Fab from Poly(Lactide-Co-Caprolactone) Microparticulate Coatings
  • The controlled release characteristics and capacity of coatings formed from various poly(lactide-co-caprolactone) copolymers were investigated using high protein loadings (˜40% w/w).
  • Helical intravitreal coil implants constructed from MP-35 alloy (see commonly assigned U.S. Pub. No. 2005/0019371) were used as the medical device on which the coatings were formed.
  • Poly(lactide-co-caprolactone; pDLCL), prepared using various DL:CL ratios, was synthesized by Lakeshore Biomaterials (Birmingham, Ala. 35211). The pDLCL polymers used were pDLCL17/83 8E (IV=0.73), pDLCL 25/75 8E (IV=0.75), pDLCL 65/35 4A (IV=0.43) and pDLCL 85/15 (8E IV-0.81).
  • Nonspecific Fab spray-dried particles containing 70% nonspecific Fab, 30% trehalose, and 0.1% Tween-80™ were obtained from SurModics Pharmaceuticals (Birmingham, Ala. 35211).
  • Coating compositions were prepared by dispersing 20 mg of Fab protein particles (40% w/w) in 5 mL of chloroform containing 30 mg of polymer (pDLCL copolymers).
  • Eight coils per group were spray-coated on four-up. Spray coating was performed using an Ultrasonic Spray Coater as described U.S. Published Application 2004/0062875, or an IVEK Coater having a syringe pump connected to an IVEK gas atomization spray system (DIgispense™ 2000 Model #4065, IVEK, North Springfield, Vt.) as described in U.S. Published Application 2005/0244453.
  • pDLCL base coatings were formed on the coils that contained the protein particles with a target amount of lmg of coating material. Subsequently, four coils of the group were topcoated with the same pDLCL polymer solution used in the base coat minus the protein particles. The coated coils were dried overnight at room temperature.
  • Upon inspection, all coatings appeared very sticky in nature.
  • Coated coils were placed in 1 mL of elution medium (PBS, pH 7.4) in 96-deep well plates, capped with tight fitting cover and shaken at 37° C. At prescribed times, 100 μL of eluent of the samples was transferred into a black 96-well plate. The remainder of the eluent buffer was aspirated and discarded. Fab concentrations were determined by adding 100 uL of guanidine HCl 12M to each sample, incubating at −20° C. for 10 minutes and reading at λex=290, λcm=370.
  • The results of the elution studies are shown in FIG. 1 (various DL:CL ratios, no top coats) and FIG. 2 (various DL:CL ratios, with top coats). After 24 hours, no burst was measured from any of the formulations without topcoats. When used in combination with the microparticle-containing based coats, the topcoats tended to increase the burst release.
  • EXAMPLE 2 Controlled Delivery of Nonspecific Fab from Poly(Lactide-Co-Caprolactone)/PEG1000-45PBT-55 Microparticulate Coatings
  • The controlled release characteristics and capacity of coatings formed from various poly(lactide-co-caprolactone) copolymers along with a biodegradable poly(butyleneterephthalate-co-ethylene glycol) copolymer were investigated using high protein loadings (˜40% w/w).
  • Helical intravitreal coil implants, pDLCL copolymers, and nonspecific Fab spray-dried particles, as described in Example 1, were used to prepare the coatings. The polymer PEG1000-45PBT-55 is a copolymer of poly(butyleneterephthalate-co-ethylene glycol) copolymer with 45 wt. % polyethylene glycol having an average molecular weight of 1000 kD and 55 wt. % butyleneterephthalate. PEG1000-45PBT-55 is commercially available from OctoPlus (Leiden, Netherlands) under the product name PolyActive™.
  • Coating compositions were prepared by dispersing 20 mg of Fab protein particles in 5 mL of chloroform containing 30 mg of polymer (pDLCL copolymers, 60% w/w). pDLCL copolymers and PEG1000-45PBT-55 were blended at ratios 60/0, 50/10, 30/30 or 10/50, respectively.
  • Coatings were performed as described in Example 1.
  • Upon inspection, none of the coatings appeared sticky in nature, but many of the coatings containing PEG1000-45PBT-55 were found to have a rougher texture as shown in the micrographs of FIGS. 3A-3D (85/15 DL:CL ratio, various DLCL:PEG1000-45PBT-55 ratios), 4A-4D (65/35 DL:CL ratio, various DLCL:PEG1000-45PBT-55 ratios), and 5A-5D (25/75 DL:CL ratio, various DLCL:PEG1000-45PBT-55 ratios).
  • The results of the elution studies are shown in FIG. 6 (85/15 DL:CL ratio, various DLCL:PEG1000-45PBT-55 ratios), FIG. 7 (65/35 DL:CL ratio, various DLCL:PEG1000-45PBT-55 ratios), and FIG. 8 (25/75 DL:CL ratio, various DLCK:PEG1000-45PBT-55 ratios).

Claims (24)

  1. 1. A biodegradable bioactive agent-releasing matrix, comprising a polymeric matrix comprising:
    a biodegradable aliphatic polyester copolymer comprising monomeric units of formula I:
    Figure US20100303878A1-20101202-C00009
    wherein R1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms, and wherein the monomeric units of formula I are present in the biodegradable aliphatic polyester copolymer in an amount of greater than 17% by weight; and
    a plurality of microparticles dispersed within the matrix; wherein the microparticles comprise a hydrophilic bioactive agent,
    wherein the biodegradable bioactive agent-releasing matrix comprises a surface that is placed in direct contact with body fluid and/or body tissue.
  2. 2. A biodegradable bioactive agent-releasing matrix, comprising a polymeric matrix comprising:
    a first biodegradable copolymer comprising a biodegradable aliphatic polyester copolymer comprising monomeric units of formula II:
    Figure US20100303878A1-20101202-C00010
    wherein R2 is a divalent saturated or unsaturated hydrocarbon group that includes four or five carbon atoms, and wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount of greater than 15% by weight;
    a second biodegradable copolymer comprising hydrophobic and hydrophilic portions; and
    a plurality of microparticles dispersed within the matrix; wherein the microparticles comprise a hydrophilic bioactive agent.
  3. 3. The biodegradable bioactive agent-releasing matrix of claim 2, wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 15% to 80% by weight.
  4. 4. The biodegradable bioactive agent-releasing matrix of claim 3, wherein the monomeric units of formula I are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 25% to 75% by weight.
  5. 5. The elution control matrix of claim 2, wherein the monomeric units of formula II are derived from the polymerization of caprolactone.
  6. 6. The biodegradable bioactive agent-releasing matrix of claim 2, wherein the biodegradable aliphatic polyester copolymer further comprises monomeric units of formula I:
    Figure US20100303878A1-20101202-C00011
    wherein R1 is a divalent saturated or unsaturated hydrocarbon group that includes two carbon atoms.
  7. 7. The biodegradable bioactive agent-releasing matrix of claim 6, wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 20% to 85% by weight.
  8. 8. The biodegradable bioactive agent-releasing matrix of claim 7, wherein the monomeric units of formula II are present in the biodegradable aliphatic polyester copolymer in an amount in the range of 25% to 75% by weight.
  9. 9. The biodegradable bioactive agent-releasing matrix of claim 6, wherein the monomeric units of formula I are derived from the polymerization of lactide.
  10. 10. The biodegradable bioactive agent-releasing matrix of claim 2, wherein the first biodegradable polymer and second biodegradable polymer are present in the matrix in a ratio in the range of 1:10 to 10:1 by weight.
  11. 11. The biodegradable bioactive agent-releasing matrix of claim 10, wherein the first biodegradable polymer and second biodegradable polymer are present in the matrix in a ratio in the range of 1.5:10 to 10:1.5 by weight.
  12. 12. The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable polymer includes hydrophilic polymeric blocks and hydrophobic polymeric blocks, with one or both blocks including degradable linkages
  13. 13. The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable polymer includes polyethylene glycol blocks.
  14. 14. The biodegradable bioactive agent-releasing matrix of claim 2 wherein the second biodegradable copolymer comprises a polyether ester copolymer.
  15. 15. The biodegradable bioactive agent-releasing matrix of claim 14 wherein the second biodegradable copolymer comprises a poly(ether ester) block copolymer comprising poly(ethylene glycol) (PEG) and poly(butylene terephthalate) (PBT) blocks.
  16. 16. The biodegradable bioactive agent-releasing matrix of claim 14 wherein the second biodegradable copolymer comprises a block copolymer comprising poly(ethylene glycol) (PEG) and poly(lactic acid) (PLA) blocks.
  17. 17. The biodegradable bioactive agent-releasing matrix of claim 2 wherein the microparticles are present in the matrix in an amount in the range of 1% to 50% by weight of a total solids content of the matrix.
  18. 18. The biodegradable bioactive agent-releasing matrix of claim 16 wherein the microparticles are present in the matrix in an amount in the range of 20% to 40% by weight of a total solids content of the matrix.
  19. 19. The biodegradable bioactive agent-releasing matrix of claim 2 wherein the microparticles comprise a polypeptide.
  20. 20. The biodegradable bioactive agent-releasing matrix of claim 19, wherein the microparticles comprises a polypeptide that is an antibody or fragment thereof.
  21. 21. The biodegradable bioactive agent-releasing matrix of claim 20, wherein the microparticles comprises a Fab fragment.
  22. 22. The biodegradable bioactive agent-releasing matrix of claim 2, wherein the microparticles are formed predominantly of the hydrophilic bioactive agent.
  23. 23. The biodegradable bioactive agent-releasing matrix of claim 2, which is in the form of a coating on an implantable medical device.
  24. 24. A method for affecting a condition in a subject comprising the steps of introducing the biodegradable bioactive agent-releasing matrix of claim 2 in a subject, and allowing hydrophilic bioactive agent to be released from the elution control matrix which affects the condition in a subject.
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