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WO2002072166A1 - Compositions destinees a l'administration de medicaments - Google Patents

Compositions destinees a l'administration de medicaments Download PDF

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Publication number
WO2002072166A1
WO2002072166A1 PCT/US2001/028809 US0128809W WO02072166A1 WO 2002072166 A1 WO2002072166 A1 WO 2002072166A1 US 0128809 W US0128809 W US 0128809W WO 02072166 A1 WO02072166 A1 WO 02072166A1
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WO
WIPO (PCT)
Prior art keywords
composition
macromers
active agent
groups
diol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/028809
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English (en)
Inventor
Hassan Chaouk
Troy Holland
Bruktawit T. Asfaw
Stephen D. Goodrich
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Biocure Inc
Original Assignee
Biocure Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2001/007941 external-priority patent/WO2001068721A1/fr
Priority claimed from PCT/US2001/007940 external-priority patent/WO2001068720A1/fr
Application filed by Biocure Inc filed Critical Biocure Inc
Publication of WO2002072166A1 publication Critical patent/WO2002072166A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the invention relates to compositions for use in drug delivery and to methods for drug delivery. More specifically, the invention relates to compositions including crosslinkable macromonomers (referred to herein as macromers) that form hydrogels useful in drug delivery and methods of using these compositions for drug delivery.
  • macromers crosslinkable macromonomers
  • U.S. Patent No. 5,410,016 to Hubbell et al. discloses hydrogels useful for drug delivery made from photopolymerizable macromers having a biodegradable region, preferably hydrolyzable under in vivo conditions, a water soluble region (preferably polyethylene glycol), and at least two polymerizable regions.
  • U.S. Patent No. 6,166,130 to Rhee et al. discloses crosslinked polymer compositions formed from a first synthetic polymer containing multiple nucleophihc groups crosslinked using a second synthetic polymer containing multiple electrophilic groups, allegedly useful for drug delivery.
  • U.S. Patent No. 6,201,072 to Rathi et al. discloses thermosensitive biodegradable triblock polymers based on biodegradable polyester and polyethylene glycol(PEG) blocks. The polymers exist as clear solutions at, or about, 5 °C to 25 °C in water but, when the temperature is raised to about body temperature (typically 37 °C for humans), they spontaneously interact to form semisolid hydrogels.
  • Atrix Laboratories has developed the Atrigel drug delivery system, which is based on a biodegradable polymer that can be presented as a liquid, gel, paste, or putty. This polymer solidifies when it comes into contact with body fluids, and forms a biodegradable implant that can be used for drug delivery. Summary of the Invention
  • compositions for drug delivery comprising macromers having a backbone of a polymer containing units with a 1,2-diol and/or 1,3-diol structure.
  • Such polymers include polyvinyl alcohol (PNA) and hydrolyzed copolymers of vinyl acetate, for example, copolymers with vinyl chloride, ⁇ -vinylpyrrolidone, etc.
  • PNA polyvinyl alcohol
  • the backbone polymer contains pendant chains bearing crosslinkable groups and, optionally, other modifiers.
  • the macromers fonn hydrogels advantageous for use in drug delivery.
  • the invention also relates to methods for drug delivery wherein the compositions described above are fonned into a hydrogel in situ, which releases a drug over a period of time.
  • the drug can be formulated into the hydrogel in a number of ways.
  • the methods for using the compositions as in situ forming drug delivery devices include the step of delivering the macromers to the intended site using a delivery device such as a catheter or syringe.
  • the macromers are then crosslinked into a hydrogel, generally upon exposure to a crosslinking initiator.
  • the macromers are dissolved in a biocompatible solution prior to administration.
  • the macromers are exposed to the crosslinking initiator before they are administered to the intended site.
  • the invention relates to compositions for use in drug delivery comprising macromers having a backbone of a polymer containing units with a 1,2-diol and/or 1,3-diol structure and having at least two pendant chains including a crosslinkable group, and optionally, pendant chains containing modifiers.
  • the macromers form a hydrogel when crosslinked.
  • the macromers are exposed to a polymerization initiator upon or after administration to the intended site.
  • the macromers are exposed to the initiator prior to delivery and complete crosslinking is delayed until the composition is in place.
  • the compositions can be produced very simply and efficiently due to a number of factors. Firstly, the starting materials, such as polyhydroxy polymer backbones, are inexpensive to obtain or prepare.
  • the macromers are stable, so that they can be subjected to very substantial purification.
  • the crosslinking can therefore be carried out using a macromer that is highly pure, containing substantially no unpolymerized constituents.
  • the crosslinking can be carried out in purely aqueous solutions. Aldehyde is not required.
  • the Macromer Backbone The macromers have a backbone of a polymer comprising units having a 1 ,2-diol or 1 ,3- diol structure, such as polyhydroxy polymers.
  • polyvinyl alcohol (PVA) or copolymers of vinyl alcohol contain a 1,3-diol skeleton.
  • the backbone can also contain hydroxyl groups in the form of 1 ,2-glycols, such as copolymer units of 1 ,2-dihydroxyethylene. These can be obtained, for example, by alkaline hydrolysis of vinyl acetate-vinylene carbonate copolymers.
  • Other polymeric diols can be used, such as saccharides.
  • the macromers can also contain small proportions, for example, up to 20%, preferably up to 5%, of comonomer units of ethylene, propylene, acrylamide, methacrylamide, dimethacrylamide, hydroxyethyl methacrylate, alkyl methacrylates, alkyl methacrylates which are substituted by hydrophilic groups, such as hydroxyl, carboxyl or amino groups, methyl acrylate, ethyl acrylate, vmylpyrrolidone, hydroxyethyl acrylate, allyl alcohol, styrene, polyalkylene glycols, or similar comonomers usually used.
  • hydrophilic groups such as hydroxyl, carboxyl or amino groups, methyl acrylate, ethyl acrylate, vmylpyrrolidone, hydroxyethyl acrylate, allyl alcohol, styrene, polyalkylene glycols, or similar comonomers usually used.
  • Polyvinyl alcohols that can be used as macromer backbones include commercially available PVAs, for example Vinol ® 107 from Air Products (MW 22,000 to 31,000, 98 to 98.8% hydrolyzed), Polysciences 4397 (MW 25,000, 98.5% hydrolyzed), BF 14 from Chan Chun, Elvanol ® 90-50 from DuPont and UF-120 from Umtika. Other producers are, for example,
  • copolymers of hydrolyzed or partially hydrolyzed vinyl acetate which are obtainable, for example, as hydrolyzed ethylene-vinyl acetate (EVA), or vinyl chloride-vinyl acetate, N-vinylpyrrolidone-vinyl acetate, and maleic anhydride-vinyl acetate.
  • EVA hydrolyzed ethylene-vinyl acetate
  • vinyl chloride-vinyl acetate vinyl chloride-vinyl acetate
  • N-vinylpyrrolidone-vinyl acetate N-vinylpyrrolidone-vinyl acetate
  • maleic anhydride-vinyl acetate maleic anhydride-vinyl acetate.
  • the macromer backbones are, for example, copolymers of vinyl acetate and vmylpyrrolidone
  • commercially available copolymers for example the commercial products available under the name Luviskol ® from BASF.
  • Polyvinyl alcohols that can be derivatized as described herein preferably have a molecular weight of at least about 2,000.
  • the PVA may have a molecular weight of up to 1,000,000.
  • the PVA has a molecular weight of up to 300,000, especially up to approximately 130,000, and especially preferably up to approximately 60,000.
  • the PVA usually has a poly(2-l_ydroxy)ethylene structure.
  • the PVA derivatized in accordance with the disclosure may, however, also comprise hydroxy groups in the fonn of 1,2- glycols.
  • the PVA system can be a fully hydrolyzed PVA, with all repeating groups being -CH 2 - CH(OH), or a partially hydrolyzed PVA with varying proportions (1% to 25%>) of pendant ester groups.
  • PVA with pendant ester groups have repeating groups of the structure CH 2 -CH(OR) where R is COCH 3 group or longer alkyls, as long as the water solubility of the PVA is preserved.
  • the ester groups can also be substituted by acetaldehyde or butyraldehyde acetals that impart a certain degree of hydrophobicity and strength to the PVA.
  • the commercially available PVA can be broken down by NaIO 4 -KMnO 4 oxidation to yield a small molecular weight (2000 to 4000) PVA.
  • the PVA is prepared by basic or acidic, partial or virtually complete hydrolysis of polyvinyl acetate.
  • the PVA comprises less than 50% of vinyl acetate units, especially less than about 25% of vinyl acetate units.
  • the macromers have at least two pendant chains containing groups that can be crosslinked.
  • the term group includes single polymerizable moieties, such as an acrylate, as well as larger crosslinkable regions, such as oligomeric or polymeric regions.
  • the crosslinkers are desirably present in an amount of from approximately 0.01 to 10 milliequivalents of crosslinker per gram of backbone (meq/g), more desirably about 0.05 to 1.5 meq/g.
  • the macromers can contain more than one type of crosslinkable group.
  • the pendant chains are attached via the hydroxyl groups of the polymer backbone.
  • the pendant chains having crosslinkable groups are attached via cyclic acetal linkages to the 1 ,2-diol or 1,3-diol hydroxyl groups.
  • Crosslinking of the macromers may be via any of a number of means, such as physical crosslinking or chemical crosslinking.
  • Physical crosslinking includes, but is not limited to, complexation, hydrogen bonding, desolvation, Van der wals interactions, and ionic bonding.
  • Chemical crosslinking can be accomplished by a number of means including, but not limited to, chain reaction (addition) polymerization, step reaction (condensation) polymerization and other methods of increasing the molecular weight of polymers/ oligomers to very high molecular weights.
  • Chain reaction polymerization includes, but is not limited to, free radical polymerization (thermal, photo, redox, atom transfer polymerization, etc.), cationic polymerization (including onium), anionic polymerization (including group transfer polymerization), certain types of coordination polymerization, certain types of ring opening and metathesis polymerizations, etc.
  • Step reaction polymerizations include all polymerizations which follow step growth kinetics including but not limited to reactions of nucleophiles with electrophiles, certain types of coordination polymerization, certain types of ring opening and metathesis polymerizations, etc.
  • Other methods of increasing molecular weight of polymers/oligomers include but are not limited to polyelectrolyte formation, grafting, ionic crosslinking, etc.
  • hydrogels can be formed by the ionic interaction of divalent cationic metal ions (such as Ca +2 and Mg +2 ) with ionic polysaccharides such as alginates, xanthan gums, natural gum, agar, agarose, canageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust beam gum, arabinogalactan, pectin, and amylopectin.
  • divalent cationic metal ions such as Ca +2 and Mg +2
  • ionic polysaccharides such as alginates, xanthan gums, natural gum, agar, agarose, canageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum traga
  • Multifunctional cationic polymers such as poly(l-lysine), poly(allylamine), poly(ethyleneimine), poly(guanidine), poly(vinyl a ine), which contain a plurality of amine functionalities along the backbone, may be used to further induce ionic crosslinks.
  • Block and graft copolymers of water soluble and insoluble polymers exhibit such effects, for example, poly(oxyethylene)-poly(oxypropylene) block copolymers, copolymers of poly(oxyethylene) with poly(styrene), poly(caprolactone), poly(butadiene), etc.
  • Desirable crosslinkable groups include (meth)acrylamide, (meth)acrylate, styryl, vinyl ester, vinyl ketone, vinyl ethers, etc. Particularly desirable are ethylenically unsaturated functional groups.
  • Ethylenically unsaturated groups can be crosslinked via free radical initiated polymerization, including via photoinitiation, redox initiation, and thermal initiation. Systems employing these means of initiation are well known to those skilled in the art.
  • a two part redox system is employed.
  • One part of the system contains a reducing agent such as a ferrous salt.
  • Various fenous salts can be used, such as, for example, ferrous gluconate dihydrate, fenous lactate dihydrate, or fenous acetate.
  • the other half of the solution contains an oxidizing agent such as hydrogen peroxide.
  • Either or both of the redox solutions can contain macromer, or it may be in a third solution. The two solutions are combined to initiate the crosslinking.
  • reducing agents can be used, such as, but not limited to, cuprous salts, cerous salts, cobaltous salts, permanganate, and manganous salts.
  • Ascorbate for example, can be used as a coreductant to recycle the reductant and reduce the amount needed. This can reduce the toxicity of a fenous based system.
  • Other oxidizing agents that can be used include, but are not limited to, t-butyl hydroperoxide, t-butyl peroxide, benzoyl peroxide, cumyl peroxide, etc.
  • R is a linear or branched C ⁇ -C 8 alkylene or a linear or branched C ⁇ -C 12 alkane.
  • Suitable alkylene examples include octylene, hexylene, pentylene, butylene, propylene, ethylene, methylene, 2-propylene, 2-butylene and 3-pentylene.
  • Preferably lower alkylene R has up to 6 and especially preferably up to 4 carbon atoms. The groups ethylene and butylene are especially prefened.
  • Alkanes include, in particular, methane, ethane, n- or isopropane, n-, sec- or tert- butane, n- or isopentane, hexane, heptane, or octane.
  • Prefened groups contain one to four carbon atoms, in particular one carbon atom.
  • R 3 is an olefinically unsaturated electron attracting copolymerizable radical having up to 25 carbon atoms. In one embodiment, R 3 has the structure
  • R and R 7 independently of one another, are hydrogen, a linear or branched C ⁇ -C 8 alkyl, aryl or cyclohexyl, for example one of the following: octyl, hexyl, pentyl, butyl, propyl, ethyl, methyl, 2-propyl, 2-butyl or 3-pentyl.
  • Re is preferably hydrogen or the CH 3 group
  • R 7 is preferably a C ⁇ -C 4 alkyl group.
  • R 6 and R 7 as aryl are preferably phenyl.
  • R 3 is an olefinically unsaturated acyl group of formula R 8 -CO-, in which R 8 is an olefinically unsaturated copolymerizable group having from 2 to 24 carbon atoms, preferably from 2 to 8 carbon atoms, especially preferably from 2 to 4 carbon atoms.
  • R 9 and Rio are each independently lower alkylene having from 2 to 8 carbon atoms, arylene having from 6 to 12 carbon atoms, a saturated divalent cycloaliphatic group having from 6 to 10 carbon atoms, arylenealkylene or alkylenearylene having from 7 to 14 carbon atoms or arylenealkylenearylene having from 13 to 16 carbon atoms, and
  • R 8 is as defined above.
  • Lower alkylene R 9 or Rio preferably has from 2 to 6 carbon atoms and is especially straight-chained. Suitable examples include propylene, butylene, hexylene, dimethylethylene and, especially preferably, ethylene.
  • Arylene R 9 or Rio is preferably phenylene that is unsubstituted or is substituted by lower alkyl or lower alkoxy, especially 1,3 -phenylene or 1,4-phenylene or methyl- 1,4-phenylene.
  • a saturated divalent cycloaliphatic group R 9 or Rio is preferably cyclohexylene or cyclohexylene-lower alkylene, for example cyclohexylenemethylene, that is unsubstituted or is substituted by one or more methyl groups, such as, for example, trimethylcyclohexylenemethylene, for example the divalent isophorone radical.
  • the arylene unit of alkylenearylene or arylenealkylene R or Rio is preferably phenylene, unsubstituted or substituted by lower alkyl or lower alkoxy, and the alkylene unit thereof is preferably lower alkylene, such as methylene or ethylene, especially methylene.
  • Such radicals R 9 or Rio are therefore preferably phenylenemethylene or methylenephenylene.
  • Arylenealkylenearylene R 9 or Rio is preferably phenylene-lower alk lene-phenylene having up to 4 carbon atoms in the alkylene unit, for example phenyleneethylenephenylene.
  • the groups R 9 and Rio are each independently preferably lower alkylene having from 2 to 6 carbon atoms, phenylene, unsubstituted or substituted by lower alkyl, cyclohexylene or cyclohexylene-lower alkylene, unsubstituted or substituted by lower alkyl, phenylene-lower alkylene, lower alkylene-phenylene or phenylene-lower alkylene-phenylene.
  • the group -R 9 -NH-CO-O- is present when q is one and absent when q is zero.
  • Macromers in which q is zero are prefened.
  • the group -CO-NH-(R 9 -NH-CO-O) q -R ⁇ o-O- is present when p is one and absent when p is zero. Macromers in which p is zero are prefened.
  • Macromers in which p is one, q is zero, and Rio is lower alkylene are especially prefened.
  • All of the above groups can be monosubstituted or polysubstituted, examples of suitable substituents being the following: C ⁇ -C 4 alkyl, such as methyl, ethyl or propyl, -COOH, -OH, - SH, C ⁇ -C 4 alkoxy (such as methoxy, ethoxy, propoxy, butoxy, or isobutoxy), -NO 2 , -NH 2 , - NH(C ⁇ -C 4 ), -NH-CO-NH 2 , -N(C ⁇ -C 4 alkyl) 2 , phenyl (unsubstituted or substituted by, for example, -OH or halogen, such as Cl, Br or especially I), -S(C ⁇ -C alkyl), a 5- or 6-membered heterocyclic ring, such as, in particular, indole or imidazole, -NH-C(NH)-NH 2 , phenoxyphenyl (unsubstituted
  • Preferred substituents are lower alkyl, which here, as elsewhere in this description, is preferably C ⁇ -C 4 allyl, C ⁇ -C 4 alkoxy, COOH, SH, -NH 2 , -NH(C ⁇ -C 4 alkyl), -N(C ⁇ -C 4 alkyl) 2 or halogen. Particular preference is given to Ci-C alkyl, C ⁇ -C alkoxy, COOH and SH.
  • cycloalkyl is, in particular, cycloalkyl
  • aryl is, in particular, phenyl, unsubstituted or substituted as described above.
  • the macromers can include further modifier groups and crosslinkable groups. Some such groups are described in U.S. Patent Nos. 5,508,317, 5,665,840, 5,807,927, 5,849,841, 5,932,674, 5,939,489, and 6,011,077.
  • Crosslinkable groups and the optional further modifier groups can be bonded to the macromer backbone in various ways, for example through a certain percentage of the 1,3-diol units being modified to give a 1,3-dioxane, which contains a crosslinkable group, or a further modifier, in the 2-position.
  • Modifiers that might be attached to the backbone include those to modify the hydrophobicity, active agents or groups to allow attachment of active agents, photoinitiators, modifiers to enhance or reduce adhesiveness, modifiers to impart thermoresponsiveness, modifiers to impart other types of responsiveness, modifiers to promote targeting of the drug delivery devices, and additional crosslinking groups. These modifiers may be attached to the hydroxyl groups in the backbone, or to other monomeric units included in the backbone.
  • Attaching a cellular adhesion promoter to the macromers can enhance cellular attachment or adhesiveness of the drug delivery implants formed by the compositions.
  • These agents are well known to those skilled in the art and include carboxymethyl dextran, proteoglycans, collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, and natural or synthetic biological cell adhesion agents such as RGD peptides.
  • Having pendant ester groups that are substituted by acetaldehyde or butyraldehyde acetals, for example, can increase the hydrophobicity of the macromers and the formed hydrogel.
  • Hydrophobic groups can desirably be present in an amount from about 0 to 25%.
  • a molecule that allows visualization of the formed hydrogel examples include dyes and molecules visualizable by magnetic resonance imaging.
  • the macromers can form a hydrogel that is degradable. Suitable degradable systems are described in the co-owned application WO 01/44307. In the degradable systems described in that application, the macromers include a degradable region in the backbone or on a pendant chain. The degradable region is preferably degradable under in vivo conditions by hydrolysis. The degradable region can be enzymatically degradable.
  • the degradable region may be polymers or oligomers of glycolide, lactide, ⁇ -caprolactone, other hydroxy acids, and other biologically degradable polymers mat yield materials that are non-toxic or present as normal metabolites in the body.
  • Prefened poly( ⁇ -hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid).
  • Other useful materials include poly(amino acids), poly(anhydrides), poly(orthoesters), poly(phosphazines), and poly(phosphoesters).
  • Polylactones such as poly( ⁇ -caprolactone), poly( ⁇ -caprolactone), poly( ⁇ -valerolactone) and poly( ⁇ - butyrolactone), for example, are also useful.
  • Enzymatically degradable linkages include poly(amino acids), gelatin, chitosan, and carbohydrates.
  • the biodegradable regions may have a degree of polymerization ranging from one up to values that would yield a product that was not substantially water soluble. Thus, monomeric, dimeric, trimeric, oligomeric, and polymeric regions may be used.
  • the biodegradable region could, for example, be a single methacrylate group.
  • Biodegradable regions can be constructed from polymers or monomers using linkages susceptible to biodegradation, such as ester, acetal, carbonate, peptide, anhydride, orthoester, phosphazine, and phosphoester bonds.
  • the biodegradable regions may be arranged within the macromers such that the formed hydrogel has a range of degradability, both in terms of extent of degradation, whether complete or partial, and in terms of time to complete or partial degradation.
  • the macromers can be made by general synthetic methods known to those skilled in the art.
  • the specific macromers discussed above can be made as described in U.S. Patent Nos. 5,508,317, 5,665,840, 5,807,927, 5,849,841, 5,932,674, 5,939,489, and 6,011,077.
  • the specific macromers described above are extraordinarily stable. Spontaneous crosslinking by homopolymerization does not typically occur.
  • the macromers can furthermore be purified in a manner known per se, for example by precipitation with organic solvents, such as acetone, extraction in a suitable solvent, washing, dialysis, filtration, or ultrafiltration.
  • Ultrafiltration is especially prefened.
  • the macromers can be obtained in extremely pure form, for example in the form of concentrated aqueous solutions that are free, or at least substantially free, from reaction products, such as salts, and from starting materials.
  • the prefened purification process for the macromers of the invention can be carried out in a manner known per se. It is possible for the ultrafiltration to be carried out repeatedly, for example from two to ten times. Alternatively, the ultrafiltration can be canied out continuously until the selected degree of purity is attained.
  • the selected degree of purity can in principle be as high as desired.
  • a suitable measure for the degree of purity is, for example, the sodium chloride content of the solution, which can be determined simply in a known manner, such as by conductivity measurements.
  • the macromers are crosslinkable in an extremely effective and controlled manner.
  • Vinylic Comonomers are crosslinkable in an extremely effective and controlled manner.
  • the process for polymerization of the macromers may comprise, for example, crosslinking a macromer comprising units of formula I, especially in substantially pure form, that is to say, for example, after single or repeated ultrafiltration, preferably in solution, especially in aqueous solution, in the absence or presence of an additional vinylic comonomer.
  • the vinylic comonomer may be hydrophilic or hydrophobic, or a mixture of a hydrophobic and a hydrophilic vinylic monomer. Generally, approximately from 0.01 to 80 units of a typical vinylic comonomer react per unit of formula I, especially from 1 to 30 units per unit of formula I, and especially preferably from 5 to 20 units per unit of formula I.
  • hydrophobic vinylic comonomer or a mixture of a hydrophobic vinylic comonomer with a hydrophilic vinylic comonomer, the mixture comprising at least 50 percent by weight of a hydrophobic vinylic comonomer.
  • hydrophobic vinylic comonomers and conventional hydrophilic vinylic comonomers are suitable for copolymerization with the macromer.
  • Suitable hydrophobic vinylic comonomers include, without the list being exhaustive, C ⁇ - C ⁇ 8 alkyl acrylates and methacrylates, C 3 -C ⁇ 8 alkyl acrylamides and methacrylamides, acrylonitrile, methacrylonitrile, vinyl-C ⁇ -C ⁇ 8 alkanoates, C 2 -C ⁇ 8 alkenes, C 2 -C ⁇ 8 haloalkenes, styrene, C ⁇ -C 6 alkylstyrene, vinyl alkyl ethers, in which the alkyl moiety contains from 1 to 6 carbon atoms, C 2 -C ⁇ o perfluoroalkyl acrylates and methacrylates or correspondingly partially fluorinated acrylates and methacrylates, C 3 -C ⁇ 2 perfluoroalkyl-ethylthiocarbonylaminoethyl acrylates and methacrylates, acryloxy- and methacryloxy-alkyls
  • Suitable hydrophobic vinylic comonomers include methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, cyclohexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride, vinylidene chloride, acrylonitrile, 1- butene, butadiene, methacrylonitrile, vinyltoluene, vinyl ethyl ether, perfluorohexylethylthiocarbonylaminoethyl methacrylate, isobornyl methacrylate, trifluoroethyl methacrylate, hexafluoroisopropyl methacrylate, hexafluorobutyl meth
  • Suitable hydrophilic vinylic comonomers include, without the list being exhaustive, hydroxy-substituted lower alkyl acrylates and methacrylates, acrylamide, methacrylamide, lower alkyl acrylamides and methacrylamides, ethoxylated acrylates and methacrylates, hydroxy- substituted lower alkyl acrylamides and methacrylamides, hydroxy-substituted lower alkyl vinyl ethers, sodium ethylenesulfonate, sodium styrenesulfonate, 2-acrylamido-2- methylpropanesulfonic acid (AMPS® monomer from Lubrizol Corporation), N-vinylpynole, N- vinylsuccinimide, N-vinylpynolidone, 2- or 4-vinylpyridine, acrylic acid, methacrylic acid, amino- (the term "amino" also including quaternary ammonium), mono-lower alkylamino- or di- lower alkylamin
  • Active Agents An effective amount of one or more biologically active agents is included in the composition and delivered from the farmed hydrogel.
  • a wide variety of active agents can be incorporated into the hydrogel. Release of the incorporated additive from the hydrogel is achieved by diffusion of the agent from the hydrogel, degradation of the hydrogel, and/or degradation of a chemical link coupling the agent to the polymer.
  • an "effective amount" refers to the amount of active agent required to obtain the desired effect.
  • Biologically active agents that can be delivered using the compositions include prophylactic, therapeutic, and diagnostic agents including naturally occurring agents, synthetic organic molecules, inorganic molecules (collectively refened to herein as an "active agent” or “drug”).
  • Naturally occurring agents include cells, proteins, peptides, carbohydrates, lipids, and nucleic acids.
  • Active agents also include antibiotics, antineoplastic agents, local anesthetics, antiangiogenic agents, vasoactive agents, anticoagulants, immunomodulators, cytotoxic agents, antiviral agents, antibodies, neurotransmitters, psychoactive drugs, and radiation delivery devices, such as radioactive seeds for brachytherapy.
  • the active agent is one or more chemotherapeutic agents, such as 5-fluorouracil, cisplatin, adriamycin, or mitamycin.
  • Natural and recombinant peptides and proteins can be delivered, such as, but not limited to, hormones, growth factors, angiogenesis inhibitors, angiogenesis activators, and antibodies.
  • Nucleic acids that can be incorporated include genes, cDNAs encoding proteins, expression vectors, antisense molecules that bind to complementary nucleic acid sequences to inhibit transcription or translation, and ribozymes.
  • genes for the treatment of diseases such as cystic fibrosis can be administered.
  • Polysaccharides, such as heparin can also be administered.
  • Exemplary diagnostic agents include gases and other commercially available imaging agents that are used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, X-ray, fluoroscopy, and magnetic resonance imaging (MRI).
  • Suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper and chromium chelates. Examples of materials useful for CAT and X-rays include iodine based materials.
  • Cells can be incorporated into the compositions, including cells to encourage tissue growth or cells to secrete a desired active agent.
  • cells that can be incorporated include fibroblasts, endothelial cells, muscle cells, stem cells, etc.
  • Cells can be modified to secrete active agents such as growth factors.
  • Active agents can be incorporated into the liquid compositions simply by mixing the agent with the composition prior to or upon administration. The active agent will then be entrapped in the hydrogel that is formed upon administration of the composition.
  • the active agent can be in compound form or can be in the form of degradable or nondegradable nano or microspheres. It some cases, it may be possible and desirable to attach the active agent to the macromer.
  • the active agent may be released from the macromer or hydrogel over time or in response to an environmental condition.
  • the active may be attached by a degradable linkage, such as a linkage susceptible to degradation via hydrolysis or enzymatic degradation. The linkage may be one which is susceptible to degradation at a certain pH, for example.
  • the active agent can be encapsulated in liposomes, which are then entrapped in the hydrogel.
  • the only limitation as to how much active agent(s) can be loaded into the compositions is one of functionality, namely, the drug load may be increased until the crosslinking of the macromers is adversely affected to an unacceptable degree, or until the properties of the formulation are adversely affected to such a degree as to make administration of the formulation unacceptably difficult.
  • the active agent will make up between about 0.01 to 20% by weight of the formulation with ranges of between about 0.01 to 10% being highly common.
  • a contrast agent is a biocompatible (non-toxic) material capable of being monitored by, for example, radiography.
  • the contrast agent can be water soluble or water insoluble.
  • water soluble contrast agents include metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine.
  • Iodinated liquid contrast agents include Omnipaque®, Visipaque®, and Hypaque-76®.
  • water insoluble contrast agents are tantalum, tantalum oxide, barium sulfate, gold, tungsten, and platinum. These are commonly available as particles preferably having a size of about 10 ⁇ m or less.
  • the contrast agent can be added to the composition prior to administration. Both solid and liquid contrast agents can be simply mixed with a solution of the liquid compositions or with the solid articles. Liquid contrast agent can be mixed at a concentration of about 10 to 80 volume percent, more desirably about 20 to 50 volume percent. Solid contrast agents are desirably added in an amount of about 10 to 40 weight percent, more preferably about 20 to 40 weight percent.
  • peroxide stabilizer it may be desirable to include a peroxide stabilizer in redox initiated systems.
  • peroxide stabilizers are Dequest® products from Solutia Inc., such as for example Dequest® 2010 and Dequest® 2060S. These are phosphonates and chelants that offer stabilization of peroxide systems.
  • Dequest® 2060S is diethylenetriamine penta(methylene phosphonic acid).
  • fillers in the compositions, such as fillers that leach out of the formed hydrogel over a period of time and cause the hydrogel to become porous.
  • Appropriate fillers include calcium salts, for example.
  • Excipients may be selected that can, in some applications, enhance stability of a protein drug.
  • the excipient may be, e.g., human serum albumin (HSA), bulking agents such as carbohydrates, amino acids, peptides, pH adjusters or buffers, and salts.
  • Additional excipients include zinc, ascorbic acid, mannitol, sucrose, trehalose, cyclodextrans, polyethylene glycol, and other commonly used pharmaceutical excipients, including those described in The United States Pharmacopeia, published by the United States Pharmacopeia Convention, Inc., 1995 (see, e.g., pp. 2205-2207).
  • Exemplary carbohydrates include monosaccharides, such as galactose, and disaccharides such as lactose.
  • the excipients are used as carriers; i.e., they are used to modulate the release rate of the active substances.
  • mannitol can be used to accelerate or delay release.
  • Additives can be included in the composition by being mixed in or by being attached to the macromer itself.
  • the compositions are highly versatile. A number of characteristics can be easily modified, making the compositions suitable for a number of applications.
  • the polymer backbones can include comonomers to add desired properties, such as, for example, thermoresponsiveness, degradability, gelation speed, and hydrophobicity.
  • Modifiers can be attached to the polymer backbone (or to pendant groups) to add desired properties, such as, for example, thermoresponsiveness, degradability, hydrophobicity, and adhesiveness.
  • Active agents can also be attached to the polymer backbone using the free hydroxyl groups, or can be attached to pendant groups.
  • the gelation time of the liquid compositions can be varied from about 0.5 seconds to as long as 10 minutes, and longer if desired.
  • the desired gelation time will depend upon whether it is desired to form a plug near the catheter or syringe tip or to form a more diffuse network.
  • the gelation time will generally be affected by, and can be modified by changing at least the following variables: the initiator system, crosslinker density, macromer molecular weight, macromer concentration (solids content), and type of crosslinker.
  • a higher crosslinker density will provide faster gelation time; a lower molecular weight will provide a slower gelation time.
  • a higher solids content will provide faster gelation time.
  • the gelation time can be designed by varying the concentrations of the redox components. Higher reductant and higher oxidant will provide faster gelation, higher buffer concentration and lower pH will provide faster gelation.
  • the firmness of the formed hydrogel will be determined in part by the hydrophilic/ hydrophobic balance, where a higher hydrophobic percent provides a firmer hydrogel. The firmness will also be determined by the crosslinker density (higher density provides a firmer hydrogel), the macromer molecular weight (lower MW provides a firmer hydrogel), and the length of the crosslinker (a shorter crosslinker provides a firmer hydrogel).
  • the swelling of the hydrogel is inversely proportional to the crosslinker density. Generally, no or minimal swelling is desired, desirably less than about 10 percent.
  • Elasticity of the formed hydrogel can be increased by increasing the size of the backbone between crosslinks and decreasing the crosslinker density. Incomplete crosslinking will also provide a more elastic hydrogel.
  • the elasticity of the hydrogel substantially matches the elasticity of the tissue to which the composition is to administered.
  • an effective amount of the composition in an aqueous solvent is administered to the site where active agent is needed.
  • the composition includes the macromers, the active agent(s), initiators, if needed, and other desired components.
  • the term "effective amount", as used herein, means the quantity of composition needed to deliver the active agent for the effective period of time.
  • the effective amount of composition administered to a particular patient will vary depending upon a number of factors, including the sex, weight, age, and general health of the patient, the type, concentration, and consistency of the macromers and the hydrogel that results from crosslinking, and the particular site and condition being treated, as well as the effective dosage of the active agent.
  • the composition may be administered over a number of treatment sessions.
  • the combination of the macromers is preferably canied out in a substantially aqueous solution.
  • the criterion that the macromer is soluble in water denotes in particular that the macromer is soluble in a concentration of approximately from 3 to 90 percent by weight, preferably approximately from 5 to 60 percent by weight, in a substantially aqueous solution.
  • macromer concentrations of more than 90 percent are also included in accordance with the invention.
  • substantially aqueous solutions of the macromer comprise especially solutions of the macromer in water, in aqueous salt solutions, especially in aqueous solutions that have an osmolarity of approximately from 200 to 450 milliosmol per 1000 ml (mOsm/1), preferably an osmolarity of approximately from 250 to 350 mOsm/1, especially approximately 300 mOsm/1, or in mixtures of water or aqueous salt solutions with physiologically tolerable polar organic solvents, such as, for example, glycerol.
  • Solutions of the macromer in water or in aqueous salt solutions are prefened.
  • the viscosity of the solution of the macromer in the substantially aqueous solution is, within wide limits, not critical, but the solution should preferably be a flowable solution that can be delivered through an appropriately sized catheter or syringe.
  • the desired amounts of the components will be determined by concerns related to gelation speed, toxicity, extent of gelation desired, and stability.
  • concentration of iron will be about 20 to 2000 ppm
  • concentration of hydrogen peroxide will be about 10 to 2000 ppm
  • the pH will be about 3 to 7
  • the buffer concentration will be about 10 to 400 mM
  • ascorbate concentration will be about 10 to 100 mM.
  • composition may be desirable, if initiator is added to the composition before administration, to use a system that provides delayed crosslinking so that the composition does not gel too early. Moreover, using delayed curing, the composition can assume or be formed into a desired shape before complete curing has occurred.
  • the composition should be injected before substantial crosslinking of the macromers has occuned. This allows the macromers to continue crosslinking in situ and prevents blockage of the syringe needle or catheter with gelled polymer.
  • in situ crosslinking may allow anchoring of the hydrogel to host tissue by covalently bonding with collagen molecules present within the host tissue.
  • compositions preferably comprise no undesired low-molecular-weight constituents
  • crosslinked hydrogel products also comprise no such constituents.
  • the implants obtainable by the compositions are therefore distinguished, in an advantageous embodiment, by the fact that they are extremely clean. Delivery Devices
  • compositions can be delivered to the intended site of implantation using delivery devices generally known to those skilled in the art.
  • a catheter or syringe is used.
  • a dual syringe having a mixing chamber is used to deliver the liquid composition.
  • a syringe for example, can be used to deliver the composition containing one or more chemotherapeutic agents directly into a tumor, such as a tumor of the spine, or a brain tumor.
  • a multi-lumen catheter is used to deliver the liquid composition to the intended site of administration.
  • a two or three lumen catheter will be used, wherein the components of the composition which crosslink or initiate crosslinking are maintained in separate lumens until the time of administration.
  • one solution containing the reducing agent is delivered through a first lumen while a solution containing the oxidizing agent is delivered through a second lumen.
  • the macromer can be in one or both of the solutions.
  • a third lumen can be used to deliver contrast agent or the contrast agent can be in either or both of the redox solutions.
  • a guidewire can be inserted through any of the lumens, and removed prior to delivery of a solution through that lumen.
  • the catheter includes a mixing chamber at its delivery tip.
  • a side by side "double D" lumen can be used, wherein the interior wall has been removed at the distal end to form an area where the two solutions combine before they are injected into the lumen or void.
  • a coaxial catheter can be used, where one of the inner or outer lumens extends further than the other.
  • Other types of multi-lumen catheters are disclosed in the art.

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Abstract

L'invention concerne des compositions renfermant des macromères possédant un squelette comprenant un squelette polymère renfermant des motifs à structure 1,2-diol ou 1,3-diol, tel qu'un alcool polyvinylique, ainsi que des chaînes latérales porteuses de groupes réticulables et, éventuellement, d'autres modificateurs. La composition comprend un principe actif ou le principe actif est ajouté au cours de l'administration de la composition. Lorsque les macromères sont réticulés, ils forment des hydrogels possédant des propriétés présentant un caractère avantageux pour une utilisation de ceux-ci comme agents d'administration de médicaments.
PCT/US2001/028809 2001-03-13 2001-09-12 Compositions destinees a l'administration de medicaments Ceased WO2002072166A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PCT/US2001/007941 WO2001068721A1 (fr) 2000-03-13 2001-03-13 Compositions de revetement et de gonflement des tissus
USPCT/US01/07941 2001-03-13
USPCT/US01/07940 2001-03-13
PCT/US2001/007940 WO2001068720A1 (fr) 2000-03-13 2001-03-13 Compositions anti-embolie

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076500A1 (fr) * 2003-02-28 2004-09-10 Novartis Ag Copolymeres comprenant des biomolecules
WO2008016490A3 (fr) * 2006-07-31 2008-10-30 Abbott Cardiovascular Systems Systèmes modifiés de gélification à deux composants, et leurs procédés d'utilisation et de fabrication
US7641643B2 (en) 2003-04-15 2010-01-05 Abbott Cardiovascular Systems Inc. Methods and compositions to treat myocardial conditions
US9005672B2 (en) 2006-11-17 2015-04-14 Abbott Cardiovascular Systems Inc. Methods of modifying myocardial infarction expansion
US9242005B1 (en) 2006-08-21 2016-01-26 Abbott Cardiovascular Systems Inc. Pro-healing agent formulation compositions, methods and treatments
US9539410B2 (en) 2005-04-19 2017-01-10 Abbott Cardiovascular Systems Inc. Methods and compositions for treating post-cardial infarction damage
US9687630B2 (en) 2005-04-19 2017-06-27 Abbott Cardiovascular Systems Inc. Methods and compositions for treating post-cardial infarction damage

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US5508317A (en) * 1993-08-06 1996-04-16 Ciba-Geigy Corporation Photocrosslinked polymers
WO1999003454A1 (fr) * 1997-07-18 1999-01-28 Infimed, Inc. Macromeres biodegradables permettant de liberer de maniere regulee des substances biologiquement actives
WO2001044307A2 (fr) * 1999-11-15 2001-06-21 Biocure, Inc. Hydrogels d'alcool polyvinylique degradable
WO2001068721A1 (fr) * 2000-03-13 2001-09-20 Biocure, Inc. Compositions de revetement et de gonflement des tissus
WO2001068720A1 (fr) * 2000-03-13 2001-09-20 Biocure, Inc. Compositions anti-embolie

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5508317A (en) * 1993-08-06 1996-04-16 Ciba-Geigy Corporation Photocrosslinked polymers
WO1999003454A1 (fr) * 1997-07-18 1999-01-28 Infimed, Inc. Macromeres biodegradables permettant de liberer de maniere regulee des substances biologiquement actives
WO2001044307A2 (fr) * 1999-11-15 2001-06-21 Biocure, Inc. Hydrogels d'alcool polyvinylique degradable
WO2001068721A1 (fr) * 2000-03-13 2001-09-20 Biocure, Inc. Compositions de revetement et de gonflement des tissus
WO2001068720A1 (fr) * 2000-03-13 2001-09-20 Biocure, Inc. Compositions anti-embolie

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076500A1 (fr) * 2003-02-28 2004-09-10 Novartis Ag Copolymeres comprenant des biomolecules
US7772286B2 (en) 2003-02-28 2010-08-10 Eyesense Ag Polyvinyl alcohol copolymers comprising biomolecules
US7641643B2 (en) 2003-04-15 2010-01-05 Abbott Cardiovascular Systems Inc. Methods and compositions to treat myocardial conditions
US9539410B2 (en) 2005-04-19 2017-01-10 Abbott Cardiovascular Systems Inc. Methods and compositions for treating post-cardial infarction damage
US9687630B2 (en) 2005-04-19 2017-06-27 Abbott Cardiovascular Systems Inc. Methods and compositions for treating post-cardial infarction damage
WO2008016490A3 (fr) * 2006-07-31 2008-10-30 Abbott Cardiovascular Systems Systèmes modifiés de gélification à deux composants, et leurs procédés d'utilisation et de fabrication
US9242005B1 (en) 2006-08-21 2016-01-26 Abbott Cardiovascular Systems Inc. Pro-healing agent formulation compositions, methods and treatments
US9005672B2 (en) 2006-11-17 2015-04-14 Abbott Cardiovascular Systems Inc. Methods of modifying myocardial infarction expansion
US9775930B2 (en) 2006-11-17 2017-10-03 Abbott Cardiovascular Systems Inc. Composition for modifying myocardial infarction expansion

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