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WO2000078285A1 - Liberation regulee d'agents therapeutiques au moyen du piegeage in situ par reticulation de matrice - Google Patents

Liberation regulee d'agents therapeutiques au moyen du piegeage in situ par reticulation de matrice Download PDF

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Publication number
WO2000078285A1
WO2000078285A1 PCT/US2000/016881 US0016881W WO0078285A1 WO 2000078285 A1 WO2000078285 A1 WO 2000078285A1 US 0016881 W US0016881 W US 0016881W WO 0078285 A1 WO0078285 A1 WO 0078285A1
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WIPO (PCT)
Prior art keywords
polymer
cross
matrix
therapeutic agent
thiol groups
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PCT/US2000/016881
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English (en)
Inventor
Stanley Stein
Bo Qiu
Guobao Zhang
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University Of Medicine And Dentistry Of New Jersey
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Publication date
Application filed by University Of Medicine And Dentistry Of New Jersey filed Critical University Of Medicine And Dentistry Of New Jersey
Priority to EP00942957A priority Critical patent/EP1194119A1/fr
Priority to AU57501/00A priority patent/AU5750100A/en
Publication of WO2000078285A1 publication Critical patent/WO2000078285A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to a method for preparing and pharmaceutical compositions
  • PEG 19 glycol
  • Protein encapsulation processes that require the use of organic solvents or heating potentially physically modify, i.e. denature, a protein drug.
  • a process for preparing protein mi croparticles by heating in the presence of polymers is described by Woiszwillo et al. (U. S. Patent 5,849,884).
  • a process in which the protein drug is contacted with an organic solvent is described by Zale et al. (U.S. Patent 5,716,644).
  • Encapsulation processes that require chemical bond formation among the encapsulation reagents might have reactions that unintentionally chemically modify the protein.
  • this latter method is less favored, since for the example of proteins, which are typically composed of amino acids having a variety of side chain functional groups, chemical modification may impair the pharmacological activity. The same impairment may be imparted to other therapeutic agents.
  • the present invention is directed to compositions and methods for preparing a cross-linked matrix physically entrapping at least one therapeutic agent comprising the steps of preparing a solution comprising the at least one therapeutic agent and at least one polymer comprising thiol groups; and then incubating the solution under conditions that cause cross-linking of the thiol groups to form a matrix physically entrapping the at least one therapeutic agent.
  • the matrix comprising the at least one therapeutic agent has at least one controlled release in-vivo kinetic profile, and may have additional profiles for the same agent.
  • the matrix may also comprise more than one therapeutic agent, and each additional therapeutic agent may have one or more controlled release in-vivo kinetic profile.
  • the therapeutic agent entrapped in the matrix of the present invention is a compound capable of being entrapped and then released in a controlled manner from the matrix.
  • the therapeutic agent is a compound capable of being entrapped and then released in a controlled manner from the matrix.
  • the therapeutic agent may be, by way of non-limiting example, a small- molecule drug, protein, peptide, polysaccharide, polynucleotide, or any other compound that may be entrapped in the matrix of the present invention and subjected to controlled delivery in vivo.
  • proteins include insulin, erythropoietin, ⁇ -interferon, growth hormone, or an antibody or antibody fragment.
  • the protein may be a recombinant protein.
  • Non-limiting examples of polysaccharides include sulfated polysaccharides, such as heparin or calcium spirulan.
  • polynucleotide therapeutic agents may be antisense oligonucleotides.
  • Other examples include antibiotics, hormones, enzymes, receptors, ligands and cytokines.
  • Vaccines are also embraced by the present invention.
  • a non-limiting example of a small molecule drug includes an anticancer drug, a cardiovascular drug, an antibiotic, an antifungal, an antiviral drug, an AIDS drug, an HIV-1 protease inhibitor, a reverse transcriptase inhibitor, an antinociceptive drug, a hormone, a vitamin, an anti-inflammatory drug, an angiogenesis l drug, and an anti-angiogenesis drug.
  • the therapeutic agent may be derivatized to
  • the derivatization may be, by way of non-limiting example, polymerization or conjugation to
  • the cross-linking of the polymer on which at least two thiol groups are present may include
  • the thiol groups in the o thiol-containing polymer may also be present in a protected and/or activated form, such as the i S-2-thiopyridine derivative. 2 3
  • the polymer may be a homopolymer or a copolymer.
  • 4 suitable polymers which may be derivatized or chemically modified to comprise thiol s groups, or functional groups to which a thiol group may be attached, include a polyalkylene 6 oxide such as poly(ethylene glycol) [also known as polyethylene glycol or PEG, polyethylene
  • a polymer of the present invention is derived from a poly(ethylene
  • PEG glycol
  • the polymer comprising thiol groups may be, for example, a polymer of ⁇ , ⁇ -diamino-poly(ethylene glycol) and thiomalic acid; a polymer of ⁇ , ⁇ -dihydroxy-poly(ethylene glycol) and thiomalic acid; or a polymer of ⁇ , ⁇ -dicarboxy-PEG subunits and lysine wherein the free carboxy groups on the lysine residues are derivatized to form thiol groups.
  • a poly(ethylene glycol) subunit size for the polymer may be from about 200 to about 20,000 Da; preferably, the subunit size is from about 600 to about 5,000 Da.
  • the polymer of the present invention has from 2 to about 20 thiol groups; preferably from about 3 to about 20 thiol groups, and most preferably, from about 3 to about 8 thiol groups.
  • the thiol groups on the polymer are sterically hindered, such as is provided when thiomalic acid is used.
  • Conditions that cause cross-linking of the thiol groups involves reaction of the polymer on which at least two thiol groups are present in the presence of an oxidizing agent, such as by way of non-limiting example, in the presence of molecular oxygen, hydrogen peroxide, dimethylsulfoxide, or molecular iodine.
  • an oxidizing agent such as by way of non-limiting example, in the presence of molecular oxygen, hydrogen peroxide, dimethylsulfoxide, or molecular iodine.
  • the cross-linking may be carried out by reaction with a bifunctional disulfide-forming cross-linking agent, or reaction with a bifunctional thioether- forming cross-linking agent.
  • the cross-linking agent may have a molecular weight of about 00 to about 5,000 Da, and may be a polymeric cross-linking agent.
  • a suitable cross-linking agent may be a non-polymeric agent such as l,4-di-[3',2'-pyridyldithio(propionamido)-butane]; or polymeric cross-linking agents such as ⁇ , ⁇ -di-O-pyridyldisulf ⁇ dyl-poly(ethylene glycol); ⁇ , ⁇ -divinylsulfone-poly(ethylene glycol); or ⁇ , ⁇ -diiodoacetamide-poly(ethylene glycol).
  • the matrix of the present invention may be provided in a form such as, but not limited to, a gel, microparticles, and nanoparticles.
  • a method for the controlled release of a therapeutic agent in an animal comprising administration to the animal a therapeutically effective amount of the therapeutic agent physically entrapped within a matrix prepared as described above.
  • the matrix may have more than one therapeutic agent, and each therapeutic agent may have one or more controlled release in-vivo kinetic profiles.
  • the matrix may be administered by a route such as but not limited to subcutaneous, oral, intravenous, intraperitoneal, intradermal, subdermal, intratumor, intraocular, intravisceral, intraglandular, intravaginal, intrasinus, intraventricular, intrathecal, intramuscular, and intrarectal.
  • the controlled release of the therapeutic agent from the matrix occurs as a consequence of diffusion from and/or biodegradation of the matrix by one or more in-vivo degradation pathways such as reducing agents, reductases, S-transferases, esterases, peptidases, proteases, non-enzymatic hydrolysis, and thioesterases.
  • in-vivo degradation pathways such as reducing agents, reductases, S-transferases, esterases, peptidases, proteases, non-enzymatic hydrolysis, and thioesterases.
  • the therapeutic agent in the above-described matrix is prepared in accordance with the above methods and the matrix is formed immediately prior to or during administration to the animal.
  • the present invention is directed to a compositions and pharmaceutical composition consisting of a matrix comprising a therapeutic agent exhibiting at least one first controlled release in-vivo kinetic profile, the matrix comprising at least one cross-linked thiol-containing polymer physically entrapping at least one therapeutic agent.
  • the therapeutic agent in the aforementioned matrix has at least one second controlled release in-vivo kinetic profile.
  • the polymer or cross-linking agent may additionally comprise a functional group, such as an amino or carboxyl group.
  • the functional group may be derivatized to provide on the polymer or cross-linking agent a moiety such as but not limited to a label, for example, a contrast/imaging agent, radionuclide, chromophore, fluorophore, or nonradioactive isotope, such that the matrix may be readily located within the body, or the label may be used to monitor degradation of the matrix by detecting a metabolically stable moiety in the urine.
  • the polymer or cross-linking agent may additionally comprise a functional group for linking a therapeutic agent that will be released in a delayed manner requiring considerable matrix degradation, in comparison to a therapeutic agent not having a covalent linkage to the matrix itself.
  • Figure 2 shows the release of the chemokine RANTES from a thiol-containing polymer
  • the present invention concerns pharmaceutical compositions and methods for their o preparation which are capable of physically entrapping a therapeutic agent and releasing the i therapeutic agent with a controlled release kinetic profile in vivo, such as zero order, pseudo 2 zero order, or first order.
  • the pharmaceutical composition comprises a polymer matrix 3 prepared from polymers bearing thiol moieties, such that the thiol moieties are cross-linked 4 by any of a number of processes to physically entrap the therapeutic agent.
  • the polymer on which at least two thiol groups are present is cross- 6 linked in the presence of the therapeutic agent, thus forming a cross-linked polymer with the 7 therapeutic agent entrapped therein.
  • sulfur chemistry is the basis of the cross-linking used in this i invention, disulfide bonds already present in a particular protein would be non-reactive under 2 the cross-linking conditions. Also, the sulfur atom in the thioether side chain of methionine 3 residues in the protein drug would be nonreactive.
  • proteins containing free thiol 4 groups might not be suitable for use in their native form in this invention, and may need to be derivatized or otherwise protected during the entrapment process. Similar considerations are given to other non-protein therapeutic agents which are used in the present invention.
  • the present invention provides a sustained release depot formulation with the following characteristics: (1) the process used to prepare the matrix does not chemically or physically damage the therapeutic agent, in particular proteins, thereby avoiding protein inactivation or rendering the protein immunogenic; (2) the matrix maintains the stability of a therapeutic agent against denaturation or other metabolic conversion by protection within the matrix until release, which is important for very long sustained release; (3) the entrapped therapeutic agent is released from the depot at a substantially uniform rate, following a kinetic profile, and furthermore, a particular therapeutic agent can be prepared with two or more kinetic profiles, for example, to provide a loading dose and then a sustained release dose; (4) the desired release profile can be selected by varying the components and the process by which the matrix is prepared; and (5) the matrix is nontoxic and degradable.
  • the cross-linked matrix of the present invention entrapping at least one therapeutic agent is prepared by cross-linking a polymer on which at least two thiol groups are present, by any one of various means, in the presence of the therapeutic agent to be entrapped.
  • a polymer on which at least two thiol groups are present are suitable for the use herein.
  • the polymer on which at least two thiol groups are present may be prepared, for example, by the reaction or derivatization of a particular polymer that does not contain thiol groups, with a thiol-containing compound, or a compounds to which thiol moieties may be attached.
  • a polymer may be prepared which has reactive terminal ends or functional groups on the ends of the polymer chain which may be subsequently derivatized to attach thiol groups.
  • a copolymer may be prepared with repeating or alternately repeating thiol groups or functional groups which may be subsequently derivatized to have thiol groups. The extent of derivatization to provide thiol groups may be tailored to the requirements of the matrix to be formed.
  • suitable polymers is not intended to be limiting, but to be illustrative of the varieties of polymers and polymer derivatives that may be used in the practice of the invention.
  • the polymer has at least two thiol groups to participate in the formation of cross-links.
  • the polymer on which at least two thiol groups are present may have from 2 to about 20 thiol moieties.
  • the polymer has from 3 to about 20 thiol moieties, and in a most preferred embodiment, the thiol containing polymer has from 3 to about 8 thiol moieties.
  • suitable subunit polymer backbones for the preparation of the polymer on which at least two thiol groups are present include both homopolymers or copolymers.
  • suitable polymer backbones which may be chemically modified to comprise thiol groups, include a polyalkylene oxide such as poly(ethylene glycol) [also known as polyethylene glycol or PEG, polyethylene oxide or PEO], carboxymethylcellulose, dextran, polyvinyl alcohol, N-(2-hydroxypropyl)methacrylamide, polyvinyl pyrrolidone, poly-l,3-dioxolane, poly-l,3,6-trioxane, polypropylene oxide, copolymers of ethylene/maleic anhydride copolymer, polylactide/polyglycolide copolymers, polyaminoacids, copolymer of polyethylene glycol and an amino acid, or polypropylene oxide/ethylene oxide copolymers.
  • poly(ethylene glycol) also known as polyethylene glycol or
  • a polymer of the present invention may be derived from a poly(ethylene glycol) (PEG) derivative, for example, ⁇ , ⁇ -dihydroxy-PEG or ⁇ , ⁇ -diamino-PEG, but other derivatives are embraced herein.
  • PEG poly(ethylene glycol)
  • the polymer comprising thiol groups may be, for example, a polymer of ⁇ , ⁇ -diamino-poly(ethylene glycol) and thiomalic acid; a polymer of ⁇ , ⁇ -dihydroxy-poly(ethylene glycol) and thiomalic acid; or a polymer of ⁇ , ⁇ -dicarboxy-PEG subunits and lysine wherein the free carboxy groups on the lysine residues are derivatized to form thiol groups.
  • These polymers are only examples of possible choices, as the skilled artisan will be aware of numerouse alternatives.
  • a product of the invention may comprise more than one polymer component in order to provide two or more different release characteristics.
  • more than one therapeutic agent may be included.
  • a polymer of the present invention is derived from a poly(ethylene glycol) (PEG) derivative, for example, ⁇ , ⁇ -dihydroxy-PEG or ⁇ , ⁇ -diamino-PEG, but other derivatives are embraced herein.
  • PEG poly(ethylene glycol)
  • Examples of such polymers with particular molecular weights include ⁇ , ⁇ -dihydroxy-PEG 3 400 ; ⁇ , ⁇ -dihydroxy-PEG ! 000 ; ⁇ , ⁇ -diamino-PEG 3 400 ; and ⁇ , ⁇ -diamino-PEG, 000 PEG is known to be a particularly nontoxic polymer.
  • These derivatized PEG subunit polymers are used to prepare the polymer on which 1 at least two thiol groups are present by derivatization with thiomalic acid. As will be shown
  • thiomalic acid may be replaced with dimercaptosuccinic acid, lo thereby doubling the number of sites available for cross-linking. Doubling the number of ⁇ sites for cross-linking results in a gel with smaller pores.
  • a polymer of ⁇ , ⁇ -dicarboxy-PEG and lysine may be prepared, and
  • the poly(ethylene glycol) subunit size for the polymer may 2i be from about 200 to about 20,000 Da; preferably, the subunit size is from about 600 to about
  • the polymer of the present invention has from 2 to about 20
  • thiol groups preferably from about 3 to about 20 thiol groups, and most preferably, from
  • the thiol groups on the polymer on which at least two thiol groups are present may be sterically hindered. It has been found that a polymer on which at least two thiol groups are present with sterically hindered thiol groups tends to be nonreactive with disulfide bonds in the therapeutic agent, particularly a protein, and thus does not interfere with the intramolecular disulfide bonds in the protein. Furthermore, steric hindrance governs the rate at which reductive cleavage of the polymer occurs in vivo.
  • a polymer on which at least two thiol groups are present sterically hindered thiol groups may be preferred.
  • Such sterically hindered thiol groups are also preferred when increased resistance to reductive cleavage is desired, for example in a longer controlled release formulation.
  • the skilled artisan will be able to design a matrix with the desired characteristics. Examples of such sterically hindered thiol groups include thiomalate, as used in the above example.
  • the matrix of the present invention is prepared by cross-linking the polymer on which at least two thiol groups are present in the presence of the therapeutic agent.
  • the cross-linking of the polymer on which at least two thiol groups are present may include disulfide bonds, thioether bonds, and combinations thereof.
  • Other means of covalent bond formation of thiol groups in the thiol-containing polymer to effect cross-linking will be known to the skilled artisan and are considered within the scope and spirit of this invention.
  • reaction of the polymer on which at least two thiol groups are present in the presence of an oxidizing agent forms disulfide cross-links.
  • This may be achieved by molecular oxygen, hydrogen peroxide, dimethyl sulfoxide (DMSO), or molecular iodine.
  • the cross-linking may be carried out by reaction with a bifunctional disulfide-forming cross-linking agent, or reaction with a bifunctional thioether- forming cross- linking agent.
  • Such cross-linking agents may have a molecular weight of about 100 to about 5,000 Da, and may be a polymeric cross-linking agent.
  • the PEG-thiomalate polymer described above may be cross-linked with the non- polymeric cross-linking agent l,4-di-[3',2'-pyridyldithio(propionamido)-butane].
  • a polymeric cross-linking agent such as ⁇ , ⁇ -di-O-pyridyldisulf ⁇ dyl-poly(ethylene glycol); ⁇ , ⁇ -divinylsulfone-poly(ethylene glycol); or ⁇ , ⁇ -diiodoacetamide-poly(ethylene glycol) may be used.
  • cross-linking reaction examples include the following agents capable for forming the suitable matrix.
  • the selection of the cross-linking agent is guided by the desired characteristics of the matrix product, i.e., the controlled release kinetic profile and the duration of release. These factors, as well as the potential reactivity of the cross-linking agent with reactive moieties on the therapeutic agent, must be taken into consideration in selecting the appropriate polymer, and cross-linking agent in the preparation of the product.
  • the therapeutic agent entrapped in the matrix of the present invention is a compound capable of being entrapped and then released in a controlled manner from the matrix.
  • a wide variety of both high molecular weight and low molecular weight compounds are suitable, and as will be noted below, a compound not suitable because of its small size may be made suitable by appropriate modification by for example, polymerization or conjugation to a polymer.
  • the therapeutic agent may be a protein, peptide, polysaccharide, polynucleotide, or any other compound that may be entrapped in the matrix of the present invention and subjected to controlled delivery in vivo. It is noted that a further advantage of the present invention is that the matrix protects the therapeutic agent from degradation or other metabolic processing.
  • the agents may be for the prophylaxis or treatment of a condition or disease, or for the purpose of providing controlled delivery of any suitable agent.
  • suitable therapeutic agents are proteins. This includes proteins, peptides, modified proteins and peptides, and conjugates between proteins or peptides and other macromolecules.
  • the protein may be a recombinant protein.
  • candidate agents include erythropoietin, ⁇ -interferon, growth hormone and antibodies. Erythropoietin is administered over long periods to promote the formation of red blood cells, such as in conditions including renal failure or cancer therapy-induced anemia.
  • -Interferon is used to treat certain viral diseases (e.g. hepatitis) and cancers(e.g. hairy cell leukemia). Growth hormone is used for pituitary dwarfism. These compounds are therapeutically effective for certain indications when administered at low doses over an extended period of time, making them good candidates for controlled delivery from a depot administration as described herein, as they otherwise are administered by injection.
  • Suitable protein agents are antibodies and antibody fragments, such as those directed against tumor-specific antigens and against inflammatory response proteins such as tumor necrosis factor and interleukin 1, are additional examples of proteins that may be used in the practice of the present invention.
  • a matrix with an antibody delivered by controlled release provides convenience. The antibody is protected from biodegradative machinery while in the matrix.
  • polysaccharides examples include sulfated polysaccharides, such as heparin or calcium spirulan.
  • Heparin is an anticoagulant for which long-term therapy is indicated in various hypercoagulation disorders and for prophylactic use. Chronic anticoagulation therapy is indicated, for example, postoperatively to prevent stroke and pulmonary embolism, and in deep vein thrombosis.
  • Calcium spirulan is a potent antiviral agent against both HIV-1 and HSV-1 (herpes simplex virus) (Hayashi et al., 1996, AIDS Research & Human Retroviruses. 12(15):1463-71).
  • polynucleotides such as antisense oligonucleotides. These may be delivered to a particular site within the body using the methods described herein, for sustained delivery to target cells or tissues.
  • antibiotics include antibiotics, hormones, enzymes, receptors, ligands and cytokines.
  • Another example of a therapeutic agent embraced by the invention herein is a vaccine.
  • I I targeted delivery to a particular site within the body, and furthermore, allow a higher
  • therapeutic agent is administered systemically.
  • administration of an agent is administered systemically.
  • the therapeutic agent may be derivatized to
  • the derivatization may be, by way of non-limiting example, polymerization or conjugation to 22 poly(ethylene glycol). Such methods are known to the skilled artisan.
  • the matrix of the present invention may be provided in a form such as, but not limited to, a l gel, microparticles, and nanoparticles.
  • 6 matrix may contain more than one therapeutic agent, and an animal may be administered a
  • the matrix of the present invention is performed to locate the matrix at a i desired site for controlled delivery of the therapeutic agent. This may be to a particular body 2 compartment to which the therapeutic agent has a desired targeted effect, or the matrix may 3 be administered to a particular location wherein controlled release may provide the 4 therapeutic agent for distribution throughout the body or to another site from which the s administered site drains. Where a number of appropriate sites are possible, one may be 6 selected from which the matrix may be easily removed. The particular site will be 7 determined by the desired effect of the therapeutic agent. 8
  • Non- limiting examples of possible sites for administration of the matrix includes 0 subcutaneous, oral, intravenous, intraperitoneal, intradermal, subdermal, intratumor, i intraocular, intravisceral, intraglandular, intravaginal, intrasinus, intraventricular, intrathecal, 2 intramuscular, and intrarectal. It will be seen that certain of these sites provides a site from
  • Certain sites may be selected to provide a target tissue or organ to which the therapeutic agent's efficacy is desired, such as intratumor, intravaginal, intraglandular, intrathecal, intraventricular, and intraocular.
  • a target tissue or organ such as intratumor, intravaginal, intraglandular, intrathecal, intraventricular, and intraocular.
  • an antitumor agent may be entrapped in the matrix of the present invention and implanted in or near a tumor, for targeted delivery to the tumor.
  • a subject in whom administration of the pharmaceutical composition of the present invention is preferably a human, but can be any animal.
  • the methods and pharmaceutical compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.
  • the controlled release of the therapeutic agent from the matrix is believed to occur as a consequence of the diffusion from and/or biodegradation of the matrix by one or more in- vivo degradation pathways. While not wishing to be bound by theory, and by which the inventors herein have no duty to disclose, it is believed that degradation of the matrix is achieved by local factors at the site of administration such as reducing agents, for example, glutathione; reductases, S-transferases, esterases, peptidases, proteases, non-enzymatic hydrolysis, and thioesterases.
  • reducing agents for example, glutathione
  • the varied presence of these various degradation agents in particular compartments in the body provides further guidance on selecting the appropriate site for administration, and also in the preparation of a matrix to provide the desired release l kinetics in the presence of the particular degradative machinery at the
  • the present invention is directed to a pharmaceutical composition s consisting of a matrix comprising a therapeutic agent exhibiting at least one first controlled 6 release in-vivo kinetic profile, the matrix comprising at least one cross-linked polymer on
  • the therapeutic agent in the aforementioned matrix has at least one
  • Controlled release in vivo kinetic profiles 0 refer to the particular release characteristics of the therapeutic agent from the matrix to
  • i provide therapeutically effective delivery of the therapeutic agent to the body.
  • the pharmaceutical composition is prepared by cross-linking a polymer on which at least two
  • thiol groups are present, by any one of various means, in the presence of the therapeutic agent to be entrapped.
  • Various polymer on which at least two thiol groups are present are suitable for the use herein.
  • the polymer on which at least two thiol groups are present may be prepared, for example, by the polymerization of a particular polymer subunit that does not contain thiol groups, with a thiol-containing compound, thus forming a larger polymer.
  • the polymer on which at least two thiol groups are present has at least two thiol groups per polymer to participate in the formation of cross-links.
  • the polymer on which at least two thiol groups are present may have from 2 to about 20 thiol moieties.
  • the polymer has from 3 to about 20 thiol moieties, and in a most preferred embodiment, the thiol containing polymer has from 3 to about 8 thiol moieties.
  • suitable subunit polymers for the preparation of the polymer on which at least two thiol groups are present include both homopolymers or copolymers.
  • suitable polymers which may be chemically modified to comprise thiol groups, include poly(ethylene glycol) [also known as polyethylene glycol or PEG, polyethylene oxide or PEO], carboxymethylcellulose, dextran, polyvinyl alcohol, N-(2- hydroxypropyl)methacrylamide, polyvinyl pyrrolidone, poly-l,3-dioxolane, poly-l,3,6-trioxane, polypropylene oxide, copolymers of ethylene/maleic anhydride copolymer, polylactide/polyglycolide copolymers, polyaminoacids, copolymer of polyethylene glycol and an amino acid, or polypropylene oxide/ethylene oxide copolymers.
  • Such polymers are then derivatized or further polymerized to introduce thiol groups;
  • chemical modification of the polymer may be necessary as a step prior to the further
  • the polymer comprising thiol groups may be, for
  • a polymer of ⁇ , ⁇ -diamino-poly(ethylene glycol) and thiomalic acid a polymer of ⁇ , ⁇ -dihydroxy-poly(ethylene glycol) and thiomalic acid; or a polymer of ⁇ , ⁇ -dicarboxy-PEG subunits and lysine wherein the free carboxy groups on the lysine residues are derivatized to form thiol groups.
  • These polymers are only examples of possible choices, as the skilled artisan will be aware of numerous alternatives.
  • the selection of the polymer, or combinations thereof will be guided by the desired properties of the final product, particularly the duration of release of the therapeutic agent and the release kinetics.
  • a product of the invention may comprise more than one polymer component in order to provide two or more different release characteristics. Of course, more than one therapeutic agent may be included.
  • a polymer of the present invention is derived from a poly(ethylene glycol) (PEG) derivative, for example, ⁇ , ⁇ -dihydroxy-PEG or ⁇ , ⁇ -diamino-PEG, but other derivatives are embraced herein.
  • PEG poly(ethylene glycol)
  • PEG is known to be a particularly nontoxic polymer.
  • the thiol group of thiomalic acid is first protected by reaction with trityl chloride, to produce trityl-thiomalic acid. Subsequently, the polymer on which at least two thiol groups are present is prepared from the trityl-thiomalic acid and, for example, ⁇ , ⁇ -dihydroxy-PEG. Under suitable conditions, a carbodiimide compound is used to condense the ⁇ , ⁇ -dihydroxy-PEG with the protected thiomalic acid. After condensation, the trityl group is removed by treatment with trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • a polymer of ⁇ ,co-dicarboxy-PEG and lysine may be prepared, and subsequently the free carboxy groups on the lysine residues are derivatized to form thiol groups
  • thiol groups Huang, S.-Y., Pooyan, S., Wang, J., Choudhury, I., Leibowitz, M. J. and Stein, S. A Polyethylene Glycol Copolymer for Carrying and Releasing Multiple Copies of Cysteine-Containing Peptides. Bioconjugate Chemistry 9, 612-617, 1998.
  • the poly(ethylene glycol) subunit size for the polymer may be from about 200 to about 20,000 Da; preferably, the subunit size is from about 600 to about 5,000 Da.
  • the polymer of the present invention has from 2 to about 20 thiol groups; preferably from about 3 to about 20 thiol groups, and most preferably, from about 3 to about 8 thiol groups.
  • the thiol groups on the polymer on which at least two thiol groups are present may be sterically hindered. It has been found that a polymer on which at least two thiol groups are
  • the therapeutic agent particularly a protein, and thus does not interfere with the
  • thiol groups are present with a sterically hindered thiol groups may be preferred.
  • sterically hindered thiol groups are also preferred when increased resistance to reductive
  • cleavage is desired, for example in a longer controlled release formulation.
  • a therapeutic agent for example in a longer controlled release formulation.
  • the skilled artisan will be able to design a matrix with the desired characteristics.
  • sterically hindered thiol groups include thiomalate, as used in the above example.
  • the matrix of the present invention is prepared by cross-linking the polymer on which at least two thiol groups are present in the presence of the therapeutic agent.
  • the cross-linking of the polymer on which at least two thiol groups are present may include disulfide bonds, thioether bonds, and combinations thereof.
  • reaction of the polymer on which at least two thiol groups are present in the presence of an oxidizing agent forms disulfide cross-links. This may be achieved by molecular oxygen, hydrogen peroxide, dimethylsulfoxide, or molecular iodine.
  • the cross-linking may be carried out by reaction with a bifunctional disulfide-forming cross-linking agent, or reaction with a bifunctional thioether-forming cross-linking agent.
  • Such cross-linking agents may have a molecular weight of about 100 to about 5,000 Da, and may be a polymeric cross-linking agent.
  • the PEG-thiomalate polymer described above may be cross-linked with the cross-linking agent l,4-di-[3',2'-pyridyldithio(propionamido)-butane].
  • a polymeric cross-linking agent such as ⁇ , ⁇ -di-O-pyridyldisulfidyl-poly( ethyl ene glycol); ⁇ , ⁇ -divinylsulfone-poly(ethylene glycol); or , ⁇ -diiodoacetamide-poly(ethylene glycol) may be used.
  • cross-linking reaction examples include the following agents capable of forming the suitable matrix.
  • the selection of the cross-linking agent is guided by the desired characteristics of the matrix product, i.e., the controlled release kinetic profile and the duration of release. These factors, as well as the potential reactivity of the cross-linking agent with reactive moieties on the therapeutic agent, must be taken into consideration in selecting the appropriate polymer, and cross-linking agent in the preparation of the product.
  • the therapeutic agent entrapped in the matrix of the present invention is a compound capable of being entrapped and then released in a controlled manner from the matrix.
  • a wide variety of both high molecular weight and low molecular weight compounds are suitable, and as will be noted below, a compound not suitable because of its size may be made suitable by appropriate modification by for example, polymerization or conjugation to a polymer.
  • the therapeutic agent may be a protein, peptide, polysaccharide, polynucleotide, or any other compound that may be entrapped in the matrix of the present invention and subjected to controlled delivery in vivo. It is noted that a further advantage of the present invention is that the matrix protects the therapeutic agent from degradation and other metabolic processing.
  • suitable therapeutic agents is proteins. This includes proteins, peptides, modified proteins and peptides, and conjugates between proteins or peptides and other macromolecules.
  • the protein may be a recombinant protein, or one prepared synthetically, such as by solid phase synthesis.
  • candidate agents include erythropoietin, ⁇ -interferon, and growth hormone. Each of these examples is described above. These compounds are therapeutically effective for certain indications when administered at low doses over an extended period of time, making them good candidates for controlled delivery from a depot administration as described herein, as they otherwise are administered by injection.
  • Another group of suitable agents are antibodies and antibody fragments, such as polyclonal, monoclonal, chimeric, single chain, and Fab fragments. Non- l limiting examples are as described above.
  • Another example of a class of therapeutic agents are polysaccharides. Examples include
  • suitable therapeutic agents is polynucleotides, such as transgenic
  • vectors include, for example, an attenuated or defective 4 DNA virus, such as but not limited to herpes simplex virus (HSV), papillomavirus, Epstein s Barr virus (EBV), adenovirus, adeno-associated virus (AAV), and the like, including
  • HSV herpes simplex virus
  • EBV Epstein s Barr virus
  • AAV adeno-associated virus
  • Defective virus is not infective after introduction into a cell.
  • Use of defective viral is vectors allows for administration to cells in a specific, localized area, without concern that the 19 vector can infect other cells. Thus, a particular tissue can be specifically targeted.
  • agents including vaccines, are those as described above.
  • the therapeutic agent may be derivatized to
  • the derivatization may be, by way of non- limiting example, polymerization or conjugation to poly(ethylene glycol).
  • a suitable drug carrier may be constructed, for example, from linear poly(ethylene glycol) (PEG) subunits linked by amino acid subunits. The side chains of the amino acid subunits may be used for attachment of multiple copies of the drug (and other groups as well, such as a label) to the polymer.
  • PEG-based polymers have been found to be biocompatible. Such methods are known to one skilled in the art.
  • the polymer or cross-linking agent may additionally comprise a functional group, such as an amino or carboxyl group.
  • the functional group may be derivatized to provide on the polymer or cross-linking agent a moiety such as a label, for example, a contrast/imaging agent, a radionuclide, a chromophore, a fluorophore, or a nonradioactive isotope, such that the matrix may be readily located within the body, or the label may be used to monitor degradation of the matrix by detecting a metabolically stable moiety in the urine.
  • a label for example, a contrast/imaging agent, a radionuclide, a chromophore, a fluorophore, or a nonradioactive isotope
  • the label may be chemically attached to the functional group by, for example, carbodiimide activation or use of a homobifunctional or heterobifunctional cross-linking agent.
  • contrast/imaging agents include F-19 for MRI, 1-126 for X-ray and Tc-99m for radioscintigraphy.
  • the first step is the synthesis of a polymer on which at least two thiol groups are present.
  • the thiomalic acid is first protected as (S-trityl)-thiomalic acid, as follows. Equimolar quantities of ⁇ , ⁇ -diamino-PEG (MW 3,400, Shearwater Polymers) and (S-trityl)-thiomalic acid were dissolved in methylene 1 chloride, and 3.5 equivalents of 1,3-diisopropylcarbodiimide (DIPC, Aldrich) was added to
  • a preferred cross-linking reagent is ⁇ , ⁇ -divinylsulfone-PEG
  • vinylsulfone functional group reacts readily and specifically with 2i thiol groups on the matrix-forming polymer, but will not react with disulfide bonds, such as
  • any disulfide bond in the therapeutic agent can be minimized or essentially prevented by
  • Another factor influencing the release rate of the therapeutic agent is the size and the shape of the matrix depot.
  • the selection of the size and shape of the matrix will be readily determinable by a skilled artisan based on desired characteristics of release of the particular therapeutic agent.
  • the matrix may be administered just after mixing the polymer on which at least two thiol groups are present with the cross-linking agent, in the presence of the therapeutic agent, such that the mixture may be injected in liquid form but the matrix solidifies into the cross-linked form soon thereafter.
  • a dual-syringe pump may be used for making and administering the mixture.
  • one syringe will be filled with 0.5 ml of matrix-forming polymer and the therapeutic agent, while the other syringe will be filled with 0.5 ml of the cross-linker solution (or the therapeutic agent may be mixed in this syringe), both at the equivalent normality.
  • the concentrations selected for these two solutions will be that appropriate to create the matrix with the appropriate controlled release kinetic profile.
  • the pump will be set at a constant flow rate (e.g. 0.1 ml/min).
  • the two solutions will be mixed in a tee-fitting and the mixture will be injected.
  • the mixture becomes viscous as it flows through teflon tubing for a specified time.
  • the mixed solution may be injected to the site of administration, whereupon the solution polymerizes into a hydrogel matrix.
  • This rate may be controlled by the type of
  • the fluid would be a partially cross-linked viscous
  • microparticles perhaps
  • variables for the protein solution include but are not limited to protein concentration, pH, salt content and presence of other excipients and stabilizers.
  • the protein may be modified, such as by pegylation, to increase its size and, thereby, decrease its release rate.
  • a particular release rate may be achieved using a mixture of two or more starting polymer subunits to prepare the thiol-containing polymer or using a mixture of two or more polymers during the cross-linking/entrapment process.
  • a delayed release product may be prepared by first entrapping the protein using an ester- type polymer, followed by coating or encapsulating these resulting particles using an amide-type polymer.
  • the desired release kinetics for the final product may be achieved by administering to the patient a blend of two or more differently and separately cross-linked, entrapped protein preparations.
  • the release rate must be determined empirically in vivo, since it is dependent on many factors, including the size of the protein, diffusion from the matrix and the rate of degradation of the cross-linked polymer matrix due to the action of esterases, peptidases and reducing agents at the site of the depot. What is essential to and definitive of the present invention is that gel formation proceeds in situ without any chemical reactions occurring with the therapeutic agent.
  • reaction mixture was loaded onto a silica gel column and the eluted fractions containing
  • the polymer was treated with 100% trifluoroacetic acid (TFA) for 2 hours to remove the
  • the deprotected polymer was precipitated in cold ethyl ether, washed 5 times with ether and dried under vacuum. The molecular weight of the resulting PEG-thiomalic acid polymer was measured by size
  • Example 3 Preparation of an ester-linked-thiol-protected thiol-containing polymer Polymerization of thiol-protected thiomalic acid with ⁇ , ⁇ -dihydroxy-PEG.
  • bovine serum albumin (BSA, Sigma, St. Louis, MO) is dissolved in 5 mL 0.2 M
  • entrapment of fluorescein-BSA by cross-linking of amide-linked polymers using a polymeric cross-linking agent Three mg polymer prepared in Example 1 and 1 mg BSA are dissolved in 90 ⁇ L PBS, pH 7.4. Six ⁇ L of FITC-BSA (about 100 ug) is added, with mixing. Three mg ⁇ , ⁇ -di-O-pyridyldisulfidyl-poly(ethylene glycol) [PEG-(OPD) 2 ] (MW 3,400 Da; Shearwater Polymers, Inc., Huntsville, AL) is added to the solution. The mixture is allowed to stand at room temperature (25 °C) until hydrogel forms, entrapping the FITC-B S A.
  • Example 6 Entrapment of fluorescein-bovine serum albumin in cross-linked hydrogel.
  • Example 2 Two mg polymer on which at least two thiol groups are present as prepared in Example 1 is dissolved in 50 mL of PBS, pH 7.4. 0.6 mg PEG-(VS) 2 (MW 2000 Da, Shearwater Polymers, Inc., Huntsville, AL) is dissolved in 40 mL of PBS, pH 7.4 and 10 mL of fluorescein-BSA (about 200 mg). The two solutions are mixed thoroughly. The final concentration of the polymer on which at least two thiol groups are present solution before the hydrogel formation was 2% w/v (2 mg in 100 microliters). The mixture was allowed to stand at room temperature (25 °C) until the hydrogel forms. The amount of the protein entrapped in the hydrogel was about 93%, based on fluorescence measurement.
  • Example 7 Entrapment of fluorescein-bovine serum albumin in a densely cross-linked hydrogel.
  • Example 2 Four mg of the polymer on which at least two thiol groups are present prepared in Example 1 is dissolved in 50 mL of PBS, pH 7.4. 0.6 mg of ⁇ , ⁇ -divinylsulfone-PEG [PEG-(VS) 2] (MW 2000 Da, Shearwater Polymers, Inc., Huntsville, AL) is dissolved in 40 mL of PBS, pH 7.4 and 10 mL of fluorescein-BSA (about 200 mg). The two solutions are mixed thoroughly. The final concentration of the polymer on which at least two thiol groups are present solution before the hydrogel formation was 4% w/v (4 mg in 100 microliters). The mixture is allowed to stand at room temperature (25 °C) until hydrogel forms. The amount of the protein entrapped in the hydrogel was about 97%, based on fluorescence measurement of the excess liquid after hydrogel formation.
  • Example 8 Release of fluorescein-bovine serum albumin from a hydrogel polymer on which at least two thiol groups are present
  • Example 6 The hydrogel formed in Example 6 (2% hydrogel) or Example 7 (4% hydrogel) was first washed with 3x200 mL of PBS, pH 7.4 to remove any non-entrapped proteins. To conduct the release study, 200 mL of PBS, pH 7.4 was added and allowed to incubate with the hydrogel for pre-selected time period. The supernatant was removed from the hydrogel for fluorescence measurement, and fresh PBS added for next incubation.
  • Example 9 Entrapment and in vivo release study of chemokine from thiol containing polymer hydrogel in rabbits.
  • SC subcutaneously
  • a round-shaped polymer depot with chemokine entrapped is formed in situ at the

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Abstract

La présente invention concerne des compositions pharmaceutiques et un procédé de préparation de compositions pharmaceutiques dans lequel une matrice réticulée piège physiquement au moins un agent thérapeutique. Pour préparer la matrice on fait incuber une solution contenant au moins l'agent thérapeutique et au moins un polymère sur lequel au moins deux groupes thiol sont présents dans des conditions qui provoquent la réticulation des groupes thiol pour former une matrice qui piège le ou les agents thérapeutiques. La matrice contenant le ou les agents thérapeutiques présente un profil cinétique de libération régulée in vivo et peut présenter des profils additionnels pour le même agent. La matrice peut également comprendre plus d'un agent thérapeutique, et chaque agent thérapeutique additionnel peut présenter un ou plusieurs profils cinétiques de libération régulée in vivo.
PCT/US2000/016881 1999-06-18 2000-06-19 Liberation regulee d'agents therapeutiques au moyen du piegeage in situ par reticulation de matrice WO2000078285A1 (fr)

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AU57501/00A AU5750100A (en) 1999-06-18 2000-06-19 Controlled release of therapeutics by in-situ entrapment by matrix cross-linking

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WO2014169708A1 (fr) * 2013-04-18 2014-10-23 The Hong Kong University Of Science And Technology Hydrogel biocompatible in situ
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6822086B1 (en) 1999-08-09 2004-11-23 The General Hospital Corporation Drug-carrier complexes and methods of use thereof
US8106098B2 (en) 1999-08-09 2012-01-31 The General Hospital Corporation Protein conjugates with a water-soluble biocompatible, biodegradable polymer
US8247383B2 (en) 1999-08-09 2012-08-21 The General Hospital Corporation Drug-carrier complexes and methods of use thereof
WO2001010468A3 (fr) * 1999-08-09 2002-01-17 Gen Hospital Corp Complexes vecteurs de medicament et technique d'utilisation de ceux-ci
WO2001097865A3 (fr) * 2000-06-19 2003-03-27 Univ New Jersey Med Compositions reticulees a phases multiples et utilisations de ces dernieres
US20100028445A1 (en) * 2006-09-29 2010-02-04 The University Of Nottingham Polymer
US8404223B2 (en) * 2006-09-29 2013-03-26 The University Of Nottingham Polymer
US8524215B2 (en) 2010-08-02 2013-09-03 Janssen Biotech, Inc. Absorbable PEG-based hydrogels
EP2720722A1 (fr) * 2011-06-16 2014-04-23 The Hong Kong University of Science and Technology Molécule contenant de multiples groupes vinylsulfone
US9592251B2 (en) 2011-06-16 2017-03-14 The Hong Kong University Of Science And Technology Multi-vinylsulfone containing molecule
WO2012171335A1 (fr) * 2011-06-16 2012-12-20 The Hong Kong University Of Science And Technology Molécule contenant de multiples groupes vinylsulfone
CN103687622A (zh) * 2011-06-16 2014-03-26 香港科技大学 含有多个乙烯砜的分子
EP2720722A4 (fr) * 2011-06-16 2014-12-03 Univ Hong Kong Science & Techn Molécule contenant de multiples groupes vinylsulfone
CN105209075A (zh) * 2013-04-18 2015-12-30 香港科技大学 生物相容性原位水凝胶
WO2014169708A1 (fr) * 2013-04-18 2014-10-23 The Hong Kong University Of Science And Technology Hydrogel biocompatible in situ
US9844597B2 (en) 2013-04-18 2017-12-19 The Hong Kong University Of Science And Technology Biocompatible in situ hydrogel
CN105209075B (zh) * 2013-04-18 2019-12-13 香港科技大学 生物相容性原位水凝胶
JP2016519198A (ja) * 2013-05-14 2016-06-30 ダウ グローバル テクノロジーズ エルエルシー ジカルボン酸を用いたエステル化セルロースエーテル
WO2020015737A1 (fr) * 2018-07-20 2020-01-23 The Hong Kong University Of Science And Technology Compositions et méthodes pour la libération contrôlée d'un agent cible
CN112702992A (zh) * 2018-07-20 2021-04-23 香港科技大学 用于靶试剂的受控释放的组合物和方法
US20210220266A1 (en) * 2018-07-20 2021-07-22 The Hong Kong University Of Science And Technology Compositions and methods for controlled release of target agent
US12109307B2 (en) * 2018-07-20 2024-10-08 The Hong Kong University Of Science And Technology Compositions and methods for controlled release of target agent

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