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WO1994020089A1 - Compositions a base de taxol a activite biologique accrue - Google Patents

Compositions a base de taxol a activite biologique accrue Download PDF

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Publication number
WO1994020089A1
WO1994020089A1 PCT/US1994/002441 US9402441W WO9420089A1 WO 1994020089 A1 WO1994020089 A1 WO 1994020089A1 US 9402441 W US9402441 W US 9402441W WO 9420089 A1 WO9420089 A1 WO 9420089A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
composition
polyalkylene oxide
substituted
oxide derivative
Prior art date
Application number
PCT/US1994/002441
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English (en)
Inventor
Richard B. Greenwald
Robert G. L. Shorr
Original Assignee
Enzon, 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
Application filed by Enzon, Inc. filed Critical Enzon, Inc.
Priority to AU63612/94A priority Critical patent/AU6361294A/en
Publication of WO1994020089A1 publication Critical patent/WO1994020089A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Definitions

  • compositions having an anti-microtubule activity relate to compositions having an anti-microtubule activity.
  • the invention relates to modified taxol-based compositions, which, in certain cases, demonstrate prolonged anti- neoplastic activity.
  • Taxol is a plant product derived in minute quantities from the needles and bark of the western pacific yew, Taxus brevifolia.
  • Taxol is known as an anti-microtubule agent and is thought to inhibit cell mitosis through the enhancement of the rate of microtubular assembly and prevention of microtubular depolymerization.
  • Numerous studies performed to date indicate that taxol has a wide spectrum of activity against several malignancies. To date, the use of taxol, however, has been severely limited by, among other things, its short supply, poor water solubility and immunogenicity.
  • the pacific yew is a rare, slow-growing tree which is not typically cultivated.
  • Hypersensitivity reactions from taxol administration are known. See, for example, J. Clin Oncol 8:1263-1268 (1990). Indeed, since taxol is extracted from a natural plant source, hypersensitivity reactions in a portion of the population are expected. Moreover, certain non- aqueous vehicles which have been suggested to deliver taxol in vivo have also been implicated in causing hypersensitivity reactions in mammals. Finally, although taxol holds much promise as an anti-neoplastic agent, certain neoplasms have demonstrated resistance against it's activity. It would be highly desirable to provide novel anti-microtubule compositions with effectiveness against a wider range of In view of the foregoing, it is an object of the present invention to address the shortcomings set forth above.
  • the present invention includes biologically active compositions having a taxol-like activity.
  • the compositions have the structure:
  • R 4 alkyl, substituted alkyl, phenyl or substituted phenyl, or an ⁇ -substituted polyalkylene oxide derivative
  • R 3 one of H, CH 3 , alkyl, cycloalkyl, aryl, aralkyl or an en-substituted polyalkylene oxide derivative.
  • R 2 and R 3 are (are) ⁇ -substituted polyalkylene oxide derivatives
  • the derivatives are in a functionalized or activated form.
  • One preferred activated polymer is monomethoxy-polyethylene glycol or MPEG.
  • the present invention also includes methods of making the compositions described herein.
  • the methods include reacting suitable taxol-based moieties with an activating reagent under conditions sufficient to form the biologically active composition.
  • suitable reagents include:
  • compositions of the present invention are based on the premise that taxol and taxol-like molecules can be modified in the 7 position to provide improved variations of the naturally occurring alkaloids.
  • the compositions are further described as having an anti-microtubule activity in vivo, especially as such action pertains to oncologic or anti-neoplastic activity as such activity is understood by those of ordinary skill in the art.
  • the compositions in some instances will demonstrate the ability to preferentially bind to and stabilize microtubules, thus interrupting cell mitosis. While applicants are not bound by theory, it is believed that other anti-microtubule or oncolytic effects may also be observed in vivo with one or more of the compositions described herein.
  • the taxol component of the novel compositions can be selected from a wide variety of materials in addition to taxol per se harvested from naturally-occurring pacific yews and available from, for example, Calbiochem Corp. of San Diego, CA or ESCAgenetics Corp. of San Carlos, CA.
  • taxol will be understood to include all naturally occurring alkaloids as well as all synthetic and related moieties.
  • suitable taxol-based moieties are described in Biochem. Biophys. Res. Comm. 124, 329 (1984); J. Med. Chem. 35, 145 (1992); J. of Nat'l Prod. 51, 298 (1988); J. Med. Chem. .32., 788 (1989) and S.B. Horowitz, et al Annals NY Acad. of Sci. 466, 733 (1986).
  • 2' taxol esters can also be used. Since esters hydrolyze in the acidic environment of cancer cells, 2' taxol esters are useful as a prodrug. See J. Med. Chem. 32, 788 (1989). While such pro-drug modifications are desirable in certain situations, it has been surprisingly found that the modifications described herein which are realized by conversion of the 7 OH to relatively stable carbamates provides novel compositions which are chemotherapeutically active. Moreover, 2 ' taxol esters can be modified in the 7 position if desired, to provide compositions which display both the prodrug and 1- carbamate features.
  • one of R 2 and R 3 is an ⁇ -substituted polyalkylene oxide derivative.
  • both R 2 and R 3 are ⁇ -substituted polyalkylene oxide derivatives.
  • the compositions have one or more of the following attributes:
  • the attachment of the polymeric materials to taxol is preferably via a covalent linkage, and most preferably via a carbamate (urethane) linkage.
  • linkages are preferred due to their stability, especially in aqueous based systems.
  • linkage can be achieved via any suitable linking group containing at least one atom capable of joining the taxol moiety covalently to the polymeric material while substantially maintaining the activity of the taxol- containing substance.
  • Alternative linking groups also include ethers. While it is preferred that at least one of R 2 , and R 3 is covalently attached to the taxol moiety, one or both may also be attached using reversible and/or ionic or non-covalent chemistries.
  • the polymers are activated in order to effect such linkages.
  • activation it is understood by those of ordinary skill in the art that the polymer is functionalized to include the desired reactive group. See, for example, U.S. Patent Nos. 4,179,337 and 5,122,614, wherein the hydroxyl end-groups of polyalkylene glycols, are converted and activated into reactive functional groups to modify proteins and/or enzymes.
  • the disclosure of each of the '337 and '614 patents is hereby incorporated by reference. These references, however, are directed to modifying enzymes and/or proteins via epsilon amino acid lysines. The differences in structure, function and effect between these materials and taxol-based moieties are so substantial that the references are of little predictive value for the purposes of the present invention.
  • Alternative activated polymers include isocyanates as set forth in the parent U.S. patent application Serial Number 07/934,131, filed August 21, 1992 or the hydrazines set forth in commonly assigned PCT patent application bearing Publication No. W092/16555.
  • Polyethylene glycols are particularly preferred polymeric materials. Although polyethylene glycols come in a variety of molecular weights, molecular weight ranges of from about 200 to about 10,000, are usually selected for the purposes of the present invention.
  • Molecular weights of from about 2,000 to about 7,500 are preferred while molecular weights of about 5,000 are particularly preferred.
  • alkyl-capped polyethylene oxides such as methoxypolyethylene glycols (MPEG) and bis-polyethylene oxides are also contemplated.
  • polymeric substances included herein are also preferably water-soluble at room temperature.
  • a non- limiting list of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers maintained.
  • PAO based polymers effectively non-antigenic materials such as dextran, polyvinyl pyrrolidone, polyacrylamides polyvinyl alcohols, carbohydrate-based polymers and the like.
  • dextran polyvinyl pyrrolidone
  • polyacrylamides polyvinyl alcohols
  • carbohydrate-based polymers and the like.
  • polymeric materials are also effectively non- antigenic in mammals.
  • "effectively non-antigenic” means all polymeric materials understood in the art as being nontoxic and not eliciting an appreciable immunogenic response in mammals.
  • the taxol-polymer conjugates retain at least a substantial portion of the anti-microtubule activity of the taxol moiety prior to conjugation.
  • the modified compositions demonstrate equipotent and even synergistic activity against certain neoplastic cells. See Examples below.
  • substantially portion of the activity means that at least therapeutic effectiveness is maintained. While the conjugate may have less activity than the unmodified taxol-moiety in certain situations, the therapeutic effectiveness is nonetheless maintained. In any event, the advantageous properties of high aqueous solubility, substantially longer circulating life, and reduced antigenicity, either alone or in combination outweigh any decrease in activity in those situations where decreased but nonetheless therapeutically effective compositions result.
  • R 1 and/or R 2 are not ⁇ -substituted polyalkylene oxide derivatives, that is, R 1 and/or R 2 is hydrogen, an alkyl, cycloalkyl, aryl, aralkyl, other 7 carbamate taxols are formed. While these compositions have utility in their own right, they can be further functionalized to include other moieties which would enhance the anti-microtubule composition. For example, the artisan can enhance aqueous solubility by adding moieties such as carboxylic, sulfonic, phosphonic acids or amines or other salt formers.
  • R 4 alkyl, substituted alkyl, phenyl or substituted phenyl
  • Y OH, NH 2 or CHO
  • these functional groups are added initially in a protected form such as a tetrahydropyranyl ether of the alcohol, carbobenzyloxy for the amine and dialkylacetal for the aldehydes.
  • an ⁇ -substituted polyalkylene oxide derivative can attached via an alkyl spacer to produce an active, highly water soluble anti-microtubule or cytotoxic composition
  • compositions are further modified to include a targeting moiety that enhances accumulation of the taxol-based moiety in a desired location such as a tumor.
  • suitable targeting moieties include peptide sequences, mono- or polyclonal antibodies, single chain antigens (sFv's), fusion proteins or the like.
  • sFv's single chain antigens
  • a DNA binding peptide can be attached to the compositions via a properly functionalized R 2 and/or R 3 under conditions known to those of ordinary skill in the art.
  • the taxol-based compositions are prepared by reacting a taxol-based moiety depicted below as (II) or one of those described above with an activating reagent out under conditions which are sufficient to effect the desired 7 position modification yet maintain at least a portion of the therapeutic effect of the moiety.
  • R 1 alkyl, haloalkyl, substituted alkyl or aryl.
  • R 2 NH 2 where R 2 is one of H, CH 3 , alkyl, cycloalkyl, aryl, aralkyl or an ⁇ -substituted polyalkylene oxide derivative; 3) R 2 R 3 NH where R 2 and R 3 are independently one of CH 3 , alkyl, cycloalkyl, aryl, aralkyl or an ⁇ -substituted polyalkylene oxide derivative; or
  • R 2 R 3 NCOCl where R 2 and R 3 are independently one of CH 3 , alkyl, cycloalkyl, aryl, aralkyl or an ⁇ -substituted polyalkylene oxide derivative.
  • the conditions under which the anti-microtubule moiety and the activating reagent are reacted include: the use of nonhydroxylic solvents such as anhydrous toluene, tetrahydrofuran, 1,2-dichloroethane, CHCl 3 ,
  • Another aspect of the present invention provides methods of treatment for various medical conditions in mammals.
  • the methods include administering an effective amount of a taxol-based conjugate as described herein to the mammal.
  • the compositions are useful for, among other things, treating neoplastic disease, reducing tumor burden, preventing metastasis of neoplasms and preventing recurrences of tumor / neoplastic growths.
  • the amount of taxol-based conjugate used in the methods described herein may generally be described as that amount which effectively achieves the desired therapeutic result in mammals.
  • the dosages of the various taxol conjugates will vary somewhat depending upon the taxol-based moiety and the non-antigenic polymer selected for conjugation.
  • the conjugate may be administered in amounts ranging from about 5 to about 500 mg/m 2 per day, based the amount of the active taxol moiety in the conjugate.
  • the range set forth above is illustrative and those skilled in the art will determine the optimal dosing of the conjugate selected based on clinical experience and the treatment indication.
  • the conjugates of the present invention can be included in one or more suitable pharmaceutical compositions for administration to mammals.
  • the pharmaceutical compositions may be in the form of a solution, suspension, tablet, capsule or the like, prepared according to methods well known in the art. It is also contemplated that administration of such compositions may be by the oral and/or parenteral routes depending upon the needs of the artisan.
  • mPEG-NCO was prepared in situ by placing 515 mg (0.010 mmol) of mPEG-NH 2 in a 100 ml round bottom flask and undergoing drying by azeotropic toluene distillation followed by conversion to mPEG-NCO as described in the parent application.
  • the FTIR showed the isocyanate peak at 2263 cm -1 .
  • the reaction mixture was cooled to room temperature before adding 60 mg of 2 ' - acetyltaxol prepared as described in Biochem. Biophys. R.S. Commun. 124, 329-336 (1984) and 10 mg Sn(II) octoate.
  • reaction was followed by HPLC on a C 8 reverse phase column with 3:1 methanol-H 2 O as eluent.
  • the reaction appeared to be complete when about 75% of 2 '-acetyltaxol was converted to the corresponding PEG- derivative.
  • the reaction product was evaporated to near dryness and precipitated with ether. Most of the unreacted 2'-acetyltaxol and any 2', 7-diacetyltaxol present remained in the ether phase.
  • the ether was decanted, and the precipitate was recrystallized from 20 ml of 2-propanol.
  • the 7-carbamate-PEG derivative was isolated by centrifugation, washing with two 20 milliliter portions of 2-propanol, and finally drying under high vacuum to obtain 508 mg of product with less than 1% 2'-acetyltaxol and some non-functionalized PEG.
  • the FTIR spectrum of the purified compound had all the characteristic peaks of PEG in addition to peaks at 1748.6, 1741.2, 1726.5, 1663 cm -1 which are characteristic of the 2'-acetyltaxol molecule.
  • the mixture was concentrated to near dryness, precipitated with 25 ml of hexane, and then centrifuged. The supernatant contained only a very small amount of the desired product.
  • the precipitate was dried under high vacuum and further purified by HPLC on a preparative C 8 column to yield 50 mg of product which was characterized by NMR.
  • the product was subjected to hydrolysis by NaHCO 3 (20 mg) in 3:1 methanol-water (8 ml). After 30 minutes at room temperature, a new peak of lower retention time began to appear in the HPLC trace which corresponded to the hydrolysis of 2'-acetyl group (II).
  • 2'-acetyltaxol (78mg, 89 ⁇ mol) was dissolved in 2 ml of dry 2-dichloroethane, and to this solution were added 13.2 mg of triphosgene (44.5 mmol) and 7.6 mg of pyridine (96.8 /xmol) 7.6 mg.
  • the reaction was followed by HPLC using the disappearance of 2'-acetyltaxol and appearance of a new peak with higher retention time. More triphosgene and pyridine were added until this conversion to chloroformate was greater than 80%. At this time one equivalent each of mPEGNH 2 and pyridine were added to complete the reaction.
  • Example 3 the procedure of Example 3 was repeated except that N-methyl-PEG-amine was employed instead of the mPEGNH 2 to yield the N-methyl-carbamate derivative of taxol.
  • compositions A, B and C were dissolved in DMSO prior to dilution for cell testing.
  • the inhibitory concentrations (IC 50 ) were determined using standard procedures and after 72 hours, the results were reported. All cell lines are obtained from the ATCC.
  • A549 HUMAN LUNG CARCINOMA
  • A375 HUMAN MALIGNANT MELANOMA IC 50 MICROMOLAR QUANTITIES OF TAXOL DERIVATIVES
  • Example 6 the same taxol derivatives A-F described above in Example 6 were evaluated in two more malignant cell lines.
  • Cell line P388/0 is a doxorubicin- sensitive mouse lymphoid neoplasm
  • P388/ADR is a doxorubicin-resistant mouse lymphoid neoplasm. Both were obtained from the Southern Research Institute, Birmingham, AL. The results are set forth below in Table II.

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Abstract

Cette invention concerne des compositions à base de taxol fondées sur la formation de 7 carbamates. Ces compositions se caractérisent par le fait qu'elles renferment du polyéthylène glycol, qu'elles circulent plus longtemps dans les cellules des mammifères, qu'elles sont fortement solubles dans l'eau et sensiblement nonantigéniques. Des procédés de préparation de ces compositions et de traitement à l'aide de ces dernières sont également décrits.
PCT/US1994/002441 1993-03-09 1994-03-08 Compositions a base de taxol a activite biologique accrue WO1994020089A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63612/94A AU6361294A (en) 1993-03-09 1994-03-08 Taxol-based compositions with enhanced bioactivity

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US2874393A 1993-03-09 1993-03-09
US08/028,743 1993-03-09

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025728A1 (fr) * 1994-03-18 1995-09-28 Pharmacia S.P.A. Derives taxanes possedant une activite dirigee contre les tumeurs
EP0807115A4 (fr) * 1995-01-30 1998-10-07 Enzon Inc Promedicaments a base de polymeres ayant un poids moleculaire eleve
US5886026A (en) * 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
EP0727992A4 (fr) * 1993-10-20 2001-01-31 Enzon Inc Substances taxoides substituees en position 2' et/ou 7'
EP1427407A4 (fr) * 2001-03-23 2005-05-11 Luitpold Pharm Inc Conjugues a base d'amines gras et d'agents pharmaceutiques
EP2014307A2 (fr) 2001-03-13 2009-01-14 Angiotech International Ag Vecteurs de délivrance de médicament micellaires et leurs utilisations
EP2108390A2 (fr) 2008-03-31 2009-10-14 Cordis Corporation Dispositif pour administration locale et/ou régionale utilisant des agents thérapeutiques sous forme liquide
EP1683520A3 (fr) * 1996-03-12 2009-11-18 PG-TXL Company, L.P. Bioprécurseurs de paclitaxel solubles dans l'eau
EP2123312A2 (fr) 2008-05-19 2009-11-25 Cordis Corporation Extraction de solvants de réservoirs en polymère contenant des médicaments
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US7846940B2 (en) 2004-03-31 2010-12-07 Cordis Corporation Solution formulations of sirolimus and its analogs for CAD treatment
US7875677B2 (en) 2001-04-20 2011-01-25 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs
US7989490B2 (en) 2004-06-02 2011-08-02 Cordis Corporation Injectable formulations of taxanes for cad treatment
EP2380606A1 (fr) 2006-06-30 2011-10-26 Cook Incorporated Procédés de fabrication et de modification de revêtements de taxane pour dispositifs médicaux implantables
US8314077B2 (en) 1996-05-22 2012-11-20 Luitpold Pharmaceuticals, Inc. Fatty acid-pharmaceutical agent conjugates
US8313521B2 (en) 1995-06-07 2012-11-20 Cook Medical Technologies Llc Method of delivering an implantable medical device with a bioabsorbable coating
WO2012162010A1 (fr) 2011-05-25 2012-11-29 Cordis Corporation Dispositifs expansibles revêtus d'une composition de paclitaxel
WO2012162007A1 (fr) 2011-05-25 2012-11-29 Cordis Corporation Dispositifs expansibles revêtus d'une composition de rapamycine
US8409601B2 (en) 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
WO2014004760A1 (fr) 2012-06-28 2014-01-03 Covidien Lp Traitement postérieur d'un dispositif médical pour en contrôler la morphologie et les propriétés mécaniques
US8642063B2 (en) 2008-08-22 2014-02-04 Cook Medical Technologies Llc Implantable medical device coatings with biodegradable elastomer and releasable taxane agent
WO2017053920A1 (fr) 2015-09-25 2017-03-30 Zy Therapeutics Inc. Formulation médicamenteuse à base de particules comprenant un conjugué polysaccharide-vitamine
CN110862410A (zh) * 2018-08-27 2020-03-06 深圳福山生物科技有限公司 三氟甲基硒化合物及其用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840900A (en) * 1993-10-20 1998-11-24 Enzon, Inc. High molecular weight polymer-based prodrugs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4534899A (en) * 1981-07-20 1985-08-13 Lipid Specialties, Inc. Synthetic phospholipid compounds
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US5059699A (en) * 1990-08-28 1991-10-22 Virginia Tech Intellectual Properties, Inc. Water soluble derivatives of taxol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4534899A (en) * 1981-07-20 1985-08-13 Lipid Specialties, Inc. Synthetic phospholipid compounds
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US5059699A (en) * 1990-08-28 1991-10-22 Virginia Tech Intellectual Properties, Inc. Water soluble derivatives of taxol

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
EUROPEAN POLYMER JOURNAL, Volume 19, No. 12, issued 1983, ZALIPSKY et al., "Attachment of Drugs to Polyethylene Glycols", see pages 1177-1183. *
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 16, No. 5, issued 1973, WEINER et al., "Polyethylene Glycol Derivatives of Procaine", see pages 573-574. *
POLYMER PREPRINTS, Vol. 31, issued 1990, NATHAN et al., "Polyethylene Glycol-Lysine Copolymers: New Biocompatible Polymers for Biomedical Applications", see pages 213-214. *
TETRAHEDRON LETTERS, No. 31, issued 1974, BRANDSTETTER et al., "Neue Polymer-Schutzgruppe in der Oligonucleolidsynthese 2-Hydroxy-Athylphenylthioather von Polyathylenglycol", pages 2705-2708. *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5886026A (en) * 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
EP0727992A4 (fr) * 1993-10-20 2001-01-31 Enzon Inc Substances taxoides substituees en position 2' et/ou 7'
WO1995025728A1 (fr) * 1994-03-18 1995-09-28 Pharmacia S.P.A. Derives taxanes possedant une activite dirigee contre les tumeurs
EP0807115A4 (fr) * 1995-01-30 1998-10-07 Enzon Inc Promedicaments a base de polymeres ayant un poids moleculaire eleve
US8313521B2 (en) 1995-06-07 2012-11-20 Cook Medical Technologies Llc Method of delivering an implantable medical device with a bioabsorbable coating
EP1683520A3 (fr) * 1996-03-12 2009-11-18 PG-TXL Company, L.P. Bioprécurseurs de paclitaxel solubles dans l'eau
US8314077B2 (en) 1996-05-22 2012-11-20 Luitpold Pharmaceuticals, Inc. Fatty acid-pharmaceutical agent conjugates
EP2014307A2 (fr) 2001-03-13 2009-01-14 Angiotech International Ag Vecteurs de délivrance de médicament micellaires et leurs utilisations
EP1427407A4 (fr) * 2001-03-23 2005-05-11 Luitpold Pharm Inc Conjugues a base d'amines gras et d'agents pharmaceutiques
US7875677B2 (en) 2001-04-20 2011-01-25 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US8003122B2 (en) 2004-03-31 2011-08-23 Cordis Corporation Device for local and/or regional delivery employing liquid formulations of therapeutic agents
US7846940B2 (en) 2004-03-31 2010-12-07 Cordis Corporation Solution formulations of sirolimus and its analogs for CAD treatment
US8557272B2 (en) 2004-03-31 2013-10-15 Cordis Corporation Device for local and/or regional delivery employing liquid formulations of therapeutic agents
US7932265B2 (en) 2004-03-31 2011-04-26 Cordis Corporation Solution formulations of sirolimus and its analogs for CAD treatment
US9402804B2 (en) 2004-06-02 2016-08-02 CARDINAL HEALTH SWITZERLAND 515 GmbH Injectable formulations of taxanes for cad treatment
US7989490B2 (en) 2004-06-02 2011-08-02 Cordis Corporation Injectable formulations of taxanes for cad treatment
EP2380606A1 (fr) 2006-06-30 2011-10-26 Cook Incorporated Procédés de fabrication et de modification de revêtements de taxane pour dispositifs médicaux implantables
EP2108390A2 (fr) 2008-03-31 2009-10-14 Cordis Corporation Dispositif pour administration locale et/ou régionale utilisant des agents thérapeutiques sous forme liquide
US8409601B2 (en) 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
US8871240B2 (en) 2008-03-31 2014-10-28 Cordis Corporation Rapamycin coated expandable devices
EP2123312A2 (fr) 2008-05-19 2009-11-25 Cordis Corporation Extraction de solvants de réservoirs en polymère contenant des médicaments
US8273404B2 (en) 2008-05-19 2012-09-25 Cordis Corporation Extraction of solvents from drug containing polymer reservoirs
US8642063B2 (en) 2008-08-22 2014-02-04 Cook Medical Technologies Llc Implantable medical device coatings with biodegradable elastomer and releasable taxane agent
WO2012162007A1 (fr) 2011-05-25 2012-11-29 Cordis Corporation Dispositifs expansibles revêtus d'une composition de rapamycine
WO2012162010A1 (fr) 2011-05-25 2012-11-29 Cordis Corporation Dispositifs expansibles revêtus d'une composition de paclitaxel
WO2014004760A1 (fr) 2012-06-28 2014-01-03 Covidien Lp Traitement postérieur d'un dispositif médical pour en contrôler la morphologie et les propriétés mécaniques
US9956385B2 (en) 2012-06-28 2018-05-01 The Spectranetics Corporation Post-processing of a medical device to control morphology and mechanical properties
WO2017053920A1 (fr) 2015-09-25 2017-03-30 Zy Therapeutics Inc. Formulation médicamenteuse à base de particules comprenant un conjugué polysaccharide-vitamine
CN110862410A (zh) * 2018-08-27 2020-03-06 深圳福山生物科技有限公司 三氟甲基硒化合物及其用途

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