Connect public, paid and private patent data with Google Patents Public Datasets

Improvements in polymer compositions for chemotherapy and methods of treatment using the same

Info

Publication number
WO1998007434A1
WO1998007434A1 PCT/US1997/014218 US9714218W WO1998007434A1 WO 1998007434 A1 WO1998007434 A1 WO 1998007434A1 US 9714218 W US9714218 W US 9714218W WO 1998007434 A1 WO1998007434 A1 WO 1998007434A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
agents
block
poly
copolymers
copolymer
Prior art date
Application number
PCT/US1997/014218
Other languages
French (fr)
Inventor
Alexander V. Kabanov
Valery Y. Alakhov
Original Assignee
Supratek Pharma, 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

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Abstract

Improved antineoplastic compositions comprising an antineoplastic agent combined with a pluronic and a water-soluble non-toxic homopolymer resulting in a decrease of toxicity and/or an increase in anti-cancer activity, and methods of treatment using such formulations.

Description

IMPROVEMENTS IN POLYMER COMPOSITIONS FOR CHEMOTHERAPY AND METHODS OF TREATMENT USING THE SAME

The present invention relates to improvements in antmeoplastic formulations and methods of treatment using such improved formulations.

BACKGROUND OF THE INVENTION

A variety of antmeoplastic agents are presently in use in chemotherapy. See generally Cuttings Handbook of Pharmacology, 7th Ed., Chapter 13, Scaky and Barnes. However, because of their often complex structure, antmeoplastic agents are known to exhibit low stability in the bloodstream. Often, chemotherapeutic agents are extremely insoluble, and are thus poorly transported across cell membranes. Additionally, the effective amount of antineoplastic agents can be greatly reduced through binding of such agents with plasmoproteins, as well as other non-specific interactions in the bloodstream occurring prior to the agents reaching the target. Multidrug resistance (MDR) is a further complication observed with such chemotherapeutic agents, resulting in host resistance to structurally different antineoplastic agents.

Certain antineoplastic agents currently in use have demonstrated toxicity in patients. It is thus desirable to either {/} decrease toxicity of these compositions, {»} increase their overall anti-cancer activity, or {Hi} both. It is similarly desirable to overcome MDR in patients receiving chemotherapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

The above difficulties can be overcome by administration of antineoplastic agents incorporated into a composition comprising an amphiphilic block copolymer and a non-toxic water-soluble homopolymer or random copolymer.

The invention thus relates to improved compositions comprising an antineoplastic agent combined with an amphiphilic block copolymer and a water-soluble non-toxic homopolymer or random polymer. It has been found that this combination results in {i} a decrease of toxicity, { } an increase in anti-cancer activity, or { } both. The combinations are further capable of reducing or avoiding MDR in patients suffering from neoplasm.

The advantageous properties of the resultant compositions are achieved through the combination of at least one antineoplastic agent, a water-soluble or random non-toxic polymer, and a hydrophobic copolymer, i.e., where the copolymers contain poly(oxypropylene), or POP, content greater than 50 percent.

In one embodiment, the recited homopolymers are water soluble. These polymers can be ionic or capable of being ionically charged in a pH-dependent manner. The preferred molecular mass range for the nontoxic water-soluble homopolymer or random copolymer is from about 0.5 x 103 to 0.5 x 105. The preferred concentration of these polymers in mixture is from about 1 x 10"4 to about 25% w/v.

Where a homopolymer is used, the homopolymer is preferably poly(ethylene oxide), or

PEO. Where block copolymers are used, the block copolymers are preferably poly(oxyethylene)-poly(oxypropylene) block copolymers. In these POE-POP block copolymers, it has been found that hydrophobe (POP) concentrations greater than 50% are advantageous.

The block copolymers of poly(oxyethylene)-poly(oxypropylene) generally are characterized by one of the following structural formulae:

(I)

or:

(ID

or: CH, CH,

HO- CHCH20" CH2CH20 CHCH20- H y

(HI)

in which each of x and z, independently of one another, has a value of from about 5 to about 100, and y has a value of from about 20 to about 80. Such block copolymers are known. See Schmolka, hoc. Cit., 82(7), 25-30 (1967); Stanton, Am. Perfumer. Cosmet., 72(4), 54-58 (1958); and Nonionic Surfactants, Schick, Ed., 300-371 (Dekker, NY, 1967). A number of these copolymers are commercially available under the generic names of "pluronics" and "poloxamers".

The hydrophobic/hydrophilic properties of a given block copolymer are dependent upon the ratio of oxypropylene groups to the number of oxyethylene groups. Selecting the ratio of oxypropylene groups to oxyethylene groups involves the use of mixtures of different block copolymers of POE-POP to achieve an optimal balance for a given anti-neoplastic agent, or mixture of anti-neoplastic agents, preserving the optimal particle size.

A variety of copolymers are suitable for use in the present invention. The present compositions can utilize, but are not limited to, the following copolymers:

Pluronic Hydrophobe Weight Hydrophobe Percentage

L31 950 90%

F35 950 50%

L42 1200 80%

L43 1200 70%

L44 1200 60%

L61 1750 90%

L62 1750 80%

L63 1750 70%

L64 1750 60%

P65 1750 50%

F68 1750 20%

L72 2050 80%

P75 2050 50%

L81 2250 90%

P84 2250 60%

P85 2250 50%

F87 2250 30%

F88 2250 20%

L92 2750 80%

F98 2750 20%

L101 3250 90%

P103 3250 70%

P104 3250 60%

PI05 3250 50%

F108 3250 20%

L121 4000 90%

L122 4000 80%

L123 4000 70%

F127 4000 30%

10R5 1000 50%

10R8 1000 20%

12R3 1200 70%

17R2 1700 80%

17R1 1700 90%

17R2 1700 80%

17R4 1700 60%

17R8 1700 20%

22R4 2200 60%

25R1 2500 90%

25R2 2500 80%

25R4 2500 60%

25R5 2500 50%

25R8 2500 50%

31R1 3100 90%

31R2 3100 80%

31R4 3100 60% It has been found that the effectiveness of the block copolymers of the instant invention in enhancing the potency of chemotherapeutic drugs, decreasing toxicity, and/or in reducing or reversing MDR depend upon the hydrophobe percentage and the hydrophobe weight. Overall effectiveness of the compositions has been found to increase with an increase in either hydrophobe weight, hydrophobe percentage, or both. It has been found for example that L61 is more effective than P85 which in turn is more effective than F108, which in turn is more effective than F68. One skilled in the art, however, can readily determine the most preferable copolymer based upon the specific circumstances of its intended use.

In accordance with the present invention, the preferred homopolymer is poly(ethylene oxide), or PEO, represented by the formula:

wherein n is such that the molecular mass range of PEO is from about 0.5 x 10 to about 0.5 x 105. More preferred is from about 1 x 103 to about .2 x 105, and most preferred is from about 1.5 x l03 to about .l5 x l05.

The present application is not, however, limited to the use of PEO. Other water-soluble polymers will work in accordance with the present invention. Suitable water-soluble polymers include without limitation: N-(2-hydroxypropyl)-methacrylamide copolymers, poly(ortho esters), poly(vinyl pyrrolidone), poly(vinyl alcohol), polysaccharides and their derivatives, including dextrane and heparin.

In a most preferred embodiment, the composition comprises doxorubicin as the antineoplastic agent, Pluronic L61 as the block copolymer, and PEO. Other anthracycline antibiotics such as daunorubicin and epirubicin are similarly most preferred. Pluronic L61 is characterized by hydrophobe (POP) content of at least about 90%. It will be appreciated, however, that the present invention is not limited to the recited hydrophobic pluronic polymers.

A variety of antineoplastic agents are suitable for use in accordance with the present invention. These include, but are not limited to, alkaloids such as vinblastine, colchicine, and demecoline; anthracycline antibiotics, including those of the rhodomycin group (e.g., daunorubicin, doxorubicin or epirubicin), those of the mitomycin group (e.g., mitomycin C and N-methylmitomycin C), those of the bleomycin group (e.g., bleomycin A2), and antifolates (including methotrexate. aminopteran. and dideazatetrahydrofolic acid). Mixtures of several of these agents is contemplated within the scope of the invention.

It will be appreciated that the invention is not directed to the underlying anti-neoplastic activity of these agents, but rather to an improvement in the manifestation of this activity through formulation. The present compositions can be administered parenterally in aqueous formulations, alone or in combination with other therapeutic agents, including other antineoplastic agents, steroids, etc., to a mammal suffering from neoplasm and in need of treatment. Such parenteral routes of administration include intramuscular, intrathecal, intraperitoneal, intravenous, and intra-arterial. Isotonic micellular solutions of one or more block copolymers incorporating one or more antineoplastic agents can be used for parenteral administration. Dosages typically are those associated with the specific antineoplastic agent, although the regimen must be titrated to the particular neoplasm, the condition of the patient, and the specific response. Thus, the specific dosage will be determined by the attending physician or caretaker, based upon the individual circumstances of the patient. For example, an isotonic micellular solution of daunorubicin is administered to provide about 1 mg of daunorubicin per kg of body weight. In contrast, vinblastine is administered in a similar fashion, but in accordance with conventional usage at lower dosages from about 0.1 to 0.2 mg per kg of body weight.

The following examples will serve to further typify the nature of the invention, but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.

Example 1

Preparation of Three-Component Composition Comprising Pluronic L61, Doxorubicin, and PEO

Doxorubicin (Sigma, St. Louis) was dissolved at different concentrations in sterilized water (Prep. A). Polyethylene oxide (PEG 8000, Sigma, St. Louis) was then dissolved in PBS at a concentration of 10% w/v, and Pluronic L61 (BASF) (0.2% w/v) was added. The mixture obtained was stirred at 4°C until optically transparent (about 45 minutes), (Prep. B). Prep. B was then sterilized by filtration through a 0.2 μM filter. Prep. A and Prep. B were then mixed together in equal proportions (Prep. C) and incubated at 37°C for 30 minutes.

Example 2 In Vitro Evaluation of Anticancer Activity on

Lewis Lung Carcinoma (3LL) Cell Line

A highly metastatic clonal Lewis Lung Carcinoma cell subline H-59 (3LL) was used to evaluate cytotoxic activity of Prep. C and compare it with that of doxorubicin. To this end, the cells were suspended in RPMI 1640 medium supplemented with 10% fetal calf serum, and plated at 2000-3000 cells/well into 96-well microtiter plates. Prep. C in which doxorubicin final concentrations varied from 1 to 10,000 ng/ml was added to the cells and incubated for 2 hours at 37°C and 5% CO2. The cells were then washed three times with RPMI 1640 and cultured for 4 days. Drug cytotoxicity was determined by a standard XTT assay. To this end, sterile 1 mg/ml XTT solution in RPMI 1640 containing 5 μl/ml of 1.54 μg/ml phenazine methasulfate solution in sterile PBS was added to the cells (100 μl/well) and incubated for 4 to 16 hours at 37°C and 5% CO2. The absorbance at λ420 was determined using a microplate reader. All the experiments were carried out in triplicate. SEM values were less than 10% (PO.05). the concentrations of free doxorubicin and doxorubicin in Prep. C producing 50% inhibition of cell growth (IC50) are presented in Table 1.

Table 1

Preparation IC50, ng ml doxorubicin

Prep. C 40

Doxorubicin 110

Example 3 Effect of Three Component Composition on Metastasis Development

A highly metastatic clonal subline H59 of Lewis Lung, Carcinoma (3LL-H59) was used as a model. This cell line was established using the s.c. grafting of a rare spontaneous lung metastasis detected in a mouse bearing a 3LLc s.c. tumor in the axillary region. Previous studies showed that this cell line exhibits a good pattern of organ-selective metastasis. These cells were cultured in D-MEM supplemented with 10% FCS at 37°C in a humidified atmosphere with 5% CO2. After 7 to 10 passes in culture, the cells in their logarithmic growth phase were harvested with trypsin for the following experiments.

Animals. Female C57BL/6 mice were obtained from Charles River Canada Inc. (St. Constant, Quebec, Canada) and used at 6 to 7 weeks of age. Animals were grouped five per cage with air filter cover under a light (12-h light/dark cycle, light on at 06h00) and temperature-controlled environment (22 ± 1°C). All manipulations of animals were performed under a sterilized laminar. The animals had ad libitum access to Purina Mouse Chow (Pro Lab PMH 4018, Trademark of Agway, Syracuse, New York) and water. Animal studies were conducted according to the "Guidelines for Care and Use of Experimental Animals."

The animals were injected .v. with the cells (5 x 10 cells/animal) and were randomly divided into the four groups (10 animals per group). The animals received the following treatments: 1) Control (isotonic solution), 2) Dox (5.0mg/kg), 3) Dox/L61 [(5.0mg/kg)/(0.25%w/v)], 4) Dox/L61 PEG8000 [(5.0mg kg)/(0.25%w/v)/(l%w/v)]. Injection volumes were lOOul per animal for all experimental groups. The treatments were performed 3 times at Day 1, Day 4 and Day 7 after tumor inoculation.

At Day 16 after tumor inoculation, the animals were sacrificed and subjected to routine metastasis inspection. All organs were routinely screened, although metastatic formations were normally detected only in the lung. Metastatic colonies on the organ surface were enumerated immediately following removal of the organs. Where the number of metastatic nodules on the organ surface was equal to or greater than 50, the animal was considered to have 50 metastasis sites. The results are presented in Table 2. The data are expressed as means ± SEM for the number of metastatic sites and as the percentage of the animals having metastasis for the incidence of metastasis development. Statistical significance was calculated according to the multiple range test of Duncan-Kramer. Analysis of the incidence of metastasis development was done using the Fisher's exact test. Iahje_2

Example 4 Effect of Compositions on WBC Count

Cells. The same as in Example 3.

Animals. The same as in Example 3.

The animals were injected i.v. with the cells (5 x 105 cells) and randomly divided into four groups (10 animals per group). The animals received the following treatments: 1) Control (isotonic solution), 2) Dox (5.0mg/kg), 3) Dox/Lόl [(5.0mg/kg)/0.25%w/v)], 4) Dox Lόl /PEG8000 [(5.0mg kg)/(0.25%w/v)/(l%w/v)]. The injection volumes were lOOul per animal, for all experimental groups. The treatments were performed 3 times at Day 1, Day 4 and Day 7 after tumor inoculation.

At Day 16 after tumor inoculation, the blood samples (20 ul) were collected from the lateral tail vein. Each sample was supplemented with 400 ul of 3% acetic acid, incubated for 20 minutes, and the number of leukocytes was counted (WBC per ml blood).

The results are presented in Table 3. The data were treated by Student's criteria and expressed as means ± SEM. Table

Group WBC count per ml of blood ±SEM

Control 12346±834

Dox 2134±321

Dox/Lόl 5478±235

Dox/Lόl /PEG 10358±978

Claims

What is claimed:
1. In a pharmaceutical composition comprising an anti-neoplastic agent, the improvement in which said agent is incorporated into micelles of at least one amphiphilic block copolymer and at least one of a water-soluble homopolymer and random copolymer.
2. A composition according to claim 1 wherein the block copolymer comprises poly(oxyethylene)-poly(oxypropylene).
3. A composition according to claim 2 wherein the poly (oxypropylene) portion of said block copolymer comprises at least 50% by weight of the block copolymer.
4. A composition according to claim 1 wherein the molecular mass range for the nontoxic water-soluble homopolymer or random copolymer is from about 0.5 x 103 to about 0.5 x 105.
5. A composition according to claim 1 wherein the nontoxic water-soluble polymer concentration is from about lxl 0"4 to about 25% w/v.
6. A composition according to claim 5 wherein the nontoxic water-soluble polymers are selected from the group consisting of jV-(2-hydroxypropyl)-methacrylamide copolymers, poly(ortho esters), poly(vinyl pyrrolidone), poly(vinyl alcohol), polysaccha- rides and derivatives thereof.
7. A composition according to claim 1 wherein the water- soluble nontoxic homopolymer is poly(ethylene oxide).
8. A composition according to claim 1 wherein said anti-neoplastic agent is an anthracycline antibiotic.
9. A composition according to claim 8 wherein the anthracycline antibiotic is selected from the group consisting of doxorubicin, daunorubicin, and epirubicin.
10. A composition according to claim 1 wherein said antineoplastic agent is doxorubicin, said block copolymer is Pluronic L61 and said homopolymer is PEO.
11. A method of treating a mammal suffering from neoplasm comprising administering to said mammal a therapeutic amount of a composition according to claim 1.
PCT/US1997/014218 1996-08-16 1997-08-13 Improvements in polymer compositions for chemotherapy and methods of treatment using the same WO1998007434A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/698,570 1996-08-16
US08698570 US6060518A (en) 1996-08-16 1996-08-16 Polymer compositions for chemotherapy and methods of treatment using the same

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP51080898A JP2000516246A (en) 1996-08-16 1997-08-13 Polymer composition improved in chemotherapy and treatment method using the same
CA 2263754 CA2263754A1 (en) 1996-08-16 1997-08-13 Improvements in polymer compositions for chemotherapy and methods of treatment using the same
EP19970937219 EP0939640A4 (en) 1996-08-16 1997-08-13 Improvements in polymer compositions for chemotherapy and methods of treatment using the same

Publications (1)

Publication Number Publication Date
WO1998007434A1 true true WO1998007434A1 (en) 1998-02-26

Family

ID=24805815

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/014218 WO1998007434A1 (en) 1996-08-16 1997-08-13 Improvements in polymer compositions for chemotherapy and methods of treatment using the same

Country Status (5)

Country Link
US (1) US6060518A (en)
JP (1) JP2000516246A (en)
CA (1) CA2263754A1 (en)
EP (1) EP0939640A4 (en)
WO (1) WO1998007434A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049848A1 (en) * 1998-04-01 1999-10-07 Rtp Pharma Inc. Anticancer compositions
WO2002072150A2 (en) * 2001-03-13 2002-09-19 Angiotech Pharmaceuticals Inc. Micellar drug delivery vehicles and uses thereof
WO2002085337A1 (en) * 2001-04-20 2002-10-31 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs
EP1991239A1 (en) * 2006-02-22 2008-11-19 Supratek Pharma Inc. Doxorubicin formulations for anti-cancer use
WO2009117333A1 (en) * 2008-03-17 2009-09-24 University Of Utah Research Foundation Dithiocarbamate metal chelates and methods of making and using thereof
US7829616B2 (en) 2003-02-12 2010-11-09 Syncera, Inc. Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer
US8524784B2 (en) 2009-04-30 2013-09-03 Intezyne Technologies, Incorporated Polymer micelles containing anthracylines for the treatment of cancer
US8524783B2 (en) 2009-04-30 2013-09-03 Intezyne Technologies, Incorporated Polymer micelles containing anthracylines for the treatment of cancer

Families Citing this family (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7682647B2 (en) * 1999-09-03 2010-03-23 Advanced Cardiovascular Systems, Inc. Thermal treatment of a drug eluting implantable medical device
US6219804B1 (en) * 1998-08-05 2001-04-17 International Business Machines Corporation Debugging client server programs from third party workstations
US6790228B2 (en) 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US7807211B2 (en) 1999-09-03 2010-10-05 Advanced Cardiovascular Systems, Inc. Thermal treatment of an implantable medical device
US8435550B2 (en) 2002-12-16 2013-05-07 Abbot Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US7682648B1 (en) 2000-05-31 2010-03-23 Advanced Cardiovascular Systems, Inc. Methods for forming polymeric coatings on stents
US6451373B1 (en) * 2000-08-04 2002-09-17 Advanced Cardiovascular Systems, Inc. Method of forming a therapeutic coating onto a surface of an implantable prosthesis
US6953560B1 (en) 2000-09-28 2005-10-11 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US7807210B1 (en) 2000-10-31 2010-10-05 Advanced Cardiovascular Systems, Inc. Hemocompatible polymers on hydrophobic porous polymers
US6824559B2 (en) * 2000-12-22 2004-11-30 Advanced Cardiovascular Systems, Inc. Ethylene-carboxyl copolymers as drug delivery matrices
US6663662B2 (en) * 2000-12-28 2003-12-16 Advanced Cardiovascular Systems, Inc. Diffusion barrier layer for implantable devices
US6780424B2 (en) * 2001-03-30 2004-08-24 Charles David Claude Controlled morphologies in polymer drug for release of drugs from polymer films
US6712845B2 (en) * 2001-04-24 2004-03-30 Advanced Cardiovascular Systems, Inc. Coating for a stent and a method of forming the same
US6656506B1 (en) * 2001-05-09 2003-12-02 Advanced Cardiovascular Systems, Inc. Microparticle coated medical device
US6743462B1 (en) 2001-05-31 2004-06-01 Advanced Cardiovascular Systems, Inc. Apparatus and method for coating implantable devices
US6939564B2 (en) 2001-06-08 2005-09-06 Labopharm, Inc. Water-soluble stabilized self-assembled polyelectrolytes
US6695920B1 (en) 2001-06-27 2004-02-24 Advanced Cardiovascular Systems, Inc. Mandrel for supporting a stent and a method of using the mandrel to coat a stent
US8741378B1 (en) 2001-06-27 2014-06-03 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device
US7682669B1 (en) 2001-07-30 2010-03-23 Advanced Cardiovascular Systems, Inc. Methods for covalently immobilizing anti-thrombogenic material into a coating on a medical device
US8303651B1 (en) 2001-09-07 2012-11-06 Advanced Cardiovascular Systems, Inc. Polymeric coating for reducing the rate of release of a therapeutic substance from a stent
US7989018B2 (en) 2001-09-17 2011-08-02 Advanced Cardiovascular Systems, Inc. Fluid treatment of a polymeric coating on an implantable medical device
US7223282B1 (en) 2001-09-27 2007-05-29 Advanced Cardiovascular Systems, Inc. Remote activation of an implantable device
US6592899B2 (en) 2001-10-03 2003-07-15 Macromed Incorporated PLA/PLGA oligomers combined with block copolymers for enhancing solubility of a drug in water
US6709514B1 (en) * 2001-12-28 2004-03-23 Advanced Cardiovascular Systems, Inc. Rotary coating apparatus for coating implantable medical devices
US7018655B2 (en) 2002-03-18 2006-03-28 Labopharm, Inc. Amphiphilic diblock, triblock and star-block copolymers and their pharmaceutical compositions
US7919075B1 (en) 2002-03-20 2011-04-05 Advanced Cardiovascular Systems, Inc. Coatings for implantable medical devices
US20070032853A1 (en) 2002-03-27 2007-02-08 Hossainy Syed F 40-O-(2-hydroxy)ethyl-rapamycin coated stent
US7794743B2 (en) 2002-06-21 2010-09-14 Advanced Cardiovascular Systems, Inc. Polycationic peptide coatings and methods of making the same
US8506617B1 (en) 2002-06-21 2013-08-13 Advanced Cardiovascular Systems, Inc. Micronized peptide coated stent
US7056523B1 (en) 2002-06-21 2006-06-06 Advanced Cardiovascular Systems, Inc. Implantable medical devices incorporating chemically conjugated polymers and oligomers of L-arginine
US7033602B1 (en) 2002-06-21 2006-04-25 Advanced Cardiovascular Systems, Inc. Polycationic peptide coatings and methods of coating implantable medical devices
US7217426B1 (en) 2002-06-21 2007-05-15 Advanced Cardiovascular Systems, Inc. Coatings containing polycationic peptides for cardiovascular therapy
US7160551B2 (en) * 2002-07-09 2007-01-09 The Board Of Trustees Of The University Of Illinois Injectable system for controlled drug delivery
US7087263B2 (en) * 2002-10-09 2006-08-08 Advanced Cardiovascular Systems, Inc. Rare limiting barriers for implantable medical devices
US6982004B1 (en) 2002-11-26 2006-01-03 Advanced Cardiovascular Systems, Inc. Electrostatic loading of drugs on implantable medical devices
US7776926B1 (en) 2002-12-11 2010-08-17 Advanced Cardiovascular Systems, Inc. Biocompatible coating for implantable medical devices
US7758880B2 (en) 2002-12-11 2010-07-20 Advanced Cardiovascular Systems, Inc. Biocompatible polyacrylate compositions for medical applications
US7074276B1 (en) 2002-12-12 2006-07-11 Advanced Cardiovascular Systems, Inc. Clamp mandrel fixture and a method of using the same to minimize coating defects
US7563483B2 (en) * 2003-02-26 2009-07-21 Advanced Cardiovascular Systems Inc. Methods for fabricating a coating for implantable medical devices
US6926919B1 (en) 2003-02-26 2005-08-09 Advanced Cardiovascular Systems, Inc. Method for fabricating a coating for a medical device
US7279174B2 (en) * 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
US20040258754A1 (en) * 2003-06-18 2004-12-23 Valery Alakhov Compositions for oral administration of camptothecin and its analogs
US7285304B1 (en) 2003-06-25 2007-10-23 Advanced Cardiovascular Systems, Inc. Fluid treatment of a polymeric coating on an implantable medical device
US20050021127A1 (en) * 2003-07-21 2005-01-27 Kawula Paul John Porous glass fused onto stent for drug retention
US7682603B2 (en) * 2003-07-25 2010-03-23 The Trustees Of The University Of Pennsylvania Polymersomes incorporating highly emissive probes
US7056591B1 (en) * 2003-07-30 2006-06-06 Advanced Cardiovascular Systems, Inc. Hydrophobic biologically absorbable coatings for drug delivery devices and methods for fabricating the same
US7785512B1 (en) 2003-07-31 2010-08-31 Advanced Cardiovascular Systems, Inc. Method and system of controlled temperature mixing and molding of polymers with active agents for implantable medical devices
US7645474B1 (en) 2003-07-31 2010-01-12 Advanced Cardiovascular Systems, Inc. Method and system of purifying polymers for use with implantable medical devices
US7431959B1 (en) * 2003-07-31 2008-10-07 Advanced Cardiovascular Systems Inc. Method and system for irradiation of a drug eluting implantable medical device
US7441513B1 (en) 2003-09-26 2008-10-28 Advanced Cardiovascular Systems, Inc. Plasma-generated coating apparatus for medical devices and a method of coating deposition
US7318932B2 (en) * 2003-09-30 2008-01-15 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices comprising hydrolitically stable adducts of poly(ethylene-co-vinyl alcohol) and methods for fabricating the same
US7198675B2 (en) 2003-09-30 2007-04-03 Advanced Cardiovascular Systems Stent mandrel fixture and method for selectively coating surfaces of a stent
US7704544B2 (en) * 2003-10-07 2010-04-27 Advanced Cardiovascular Systems, Inc. System and method for coating a tubular implantable medical device
US7329413B1 (en) 2003-11-06 2008-02-12 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices having gradient of hydration and methods for fabricating thereof
US9114198B2 (en) 2003-11-19 2015-08-25 Advanced Cardiovascular Systems, Inc. Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
US8192752B2 (en) 2003-11-21 2012-06-05 Advanced Cardiovascular Systems, Inc. Coatings for implantable devices including biologically erodable polyesters and methods for fabricating the same
US7560492B1 (en) * 2003-11-25 2009-07-14 Advanced Cardiovascular Systems, Inc. Polysulfone block copolymers as drug-eluting coating material
US7807722B2 (en) * 2003-11-26 2010-10-05 Advanced Cardiovascular Systems, Inc. Biobeneficial coating compositions and methods of making and using thereof
US20050118344A1 (en) 2003-12-01 2005-06-02 Pacetti Stephen D. Temperature controlled crimping
USRE45744E1 (en) 2003-12-01 2015-10-13 Abbott Cardiovascular Systems Inc. Temperature controlled crimping
US7435788B2 (en) 2003-12-19 2008-10-14 Advanced Cardiovascular Systems, Inc. Biobeneficial polyamide/polyethylene glycol polymers for use with drug eluting stents
US8309112B2 (en) * 2003-12-24 2012-11-13 Advanced Cardiovascular Systems, Inc. Coatings for implantable medical devices comprising hydrophilic substances and methods for fabricating the same
US8685431B2 (en) 2004-03-16 2014-04-01 Advanced Cardiovascular Systems, Inc. Biologically absorbable coatings for implantable devices based on copolymers having ester bonds and methods for fabricating the same
US20050208093A1 (en) * 2004-03-22 2005-09-22 Thierry Glauser Phosphoryl choline coating compositions
US8551512B2 (en) 2004-03-22 2013-10-08 Advanced Cardiovascular Systems, Inc. Polyethylene glycol/poly(butylene terephthalate) copolymer coated devices including EVEROLIMUS
US8778014B1 (en) 2004-03-31 2014-07-15 Advanced Cardiovascular Systems, Inc. Coatings for preventing balloon damage to polymer coated stents
US7820732B2 (en) 2004-04-30 2010-10-26 Advanced Cardiovascular Systems, Inc. Methods for modulating thermal and mechanical properties of coatings on implantable devices
US8293890B2 (en) 2004-04-30 2012-10-23 Advanced Cardiovascular Systems, Inc. Hyaluronic acid based copolymers
US9561309B2 (en) 2004-05-27 2017-02-07 Advanced Cardiovascular Systems, Inc. Antifouling heparin coatings
US7563780B1 (en) 2004-06-18 2009-07-21 Advanced Cardiovascular Systems, Inc. Heparin prodrugs and drug delivery stents formed therefrom
US20050287184A1 (en) 2004-06-29 2005-12-29 Hossainy Syed F A Drug-delivery stent formulations for restenosis and vulnerable plaque
US20060002968A1 (en) * 2004-06-30 2006-01-05 Gordon Stewart Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
US7758881B2 (en) 2004-06-30 2010-07-20 Advanced Cardiovascular Systems, Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US7494665B1 (en) 2004-07-30 2009-02-24 Advanced Cardiovascular Systems, Inc. Polymers containing siloxane monomers
US8357391B2 (en) 2004-07-30 2013-01-22 Advanced Cardiovascular Systems, Inc. Coatings for implantable devices comprising poly (hydroxy-alkanoates) and diacid linkages
US7648727B2 (en) 2004-08-26 2010-01-19 Advanced Cardiovascular Systems, Inc. Methods for manufacturing a coated stent-balloon assembly
US7244443B2 (en) 2004-08-31 2007-07-17 Advanced Cardiovascular Systems, Inc. Polymers of fluorinated monomers and hydrophilic monomers
US8110211B2 (en) 2004-09-22 2012-02-07 Advanced Cardiovascular Systems, Inc. Medicated coatings for implantable medical devices including polyacrylates
US8603634B2 (en) 2004-10-27 2013-12-10 Abbott Cardiovascular Systems Inc. End-capped poly(ester amide) copolymers
US7390497B2 (en) 2004-10-29 2008-06-24 Advanced Cardiovascular Systems, Inc. Poly(ester amide) filler blends for modulation of coating properties
US7214759B2 (en) * 2004-11-24 2007-05-08 Advanced Cardiovascular Systems, Inc. Biologically absorbable coatings for implantable devices based on polyesters and methods for fabricating the same
US8609123B2 (en) 2004-11-29 2013-12-17 Advanced Cardiovascular Systems, Inc. Derivatized poly(ester amide) as a biobeneficial coating
US7588642B1 (en) 2004-11-29 2009-09-15 Advanced Cardiovascular Systems, Inc. Abluminal stent coating apparatus and method using a brush assembly
US7892592B1 (en) 2004-11-30 2011-02-22 Advanced Cardiovascular Systems, Inc. Coating abluminal surfaces of stents and other implantable medical devices
US7604818B2 (en) 2004-12-22 2009-10-20 Advanced Cardiovascular Systems, Inc. Polymers of fluorinated monomers and hydrocarbon monomers
US7419504B2 (en) 2004-12-27 2008-09-02 Advanced Cardiovascular Systems, Inc. Poly(ester amide) block copolymers
US8007775B2 (en) 2004-12-30 2011-08-30 Advanced Cardiovascular Systems, Inc. Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same
US7795467B1 (en) 2005-04-26 2010-09-14 Advanced Cardiovascular Systems, Inc. Bioabsorbable, biobeneficial polyurethanes for use in medical devices
US8778375B2 (en) 2005-04-29 2014-07-15 Advanced Cardiovascular Systems, Inc. Amorphous poly(D,L-lactide) coating
US7823533B2 (en) 2005-06-30 2010-11-02 Advanced Cardiovascular Systems, Inc. Stent fixture and method for reducing coating defects
US8021676B2 (en) 2005-07-08 2011-09-20 Advanced Cardiovascular Systems, Inc. Functionalized chemically inert polymers for coatings
US7785647B2 (en) 2005-07-25 2010-08-31 Advanced Cardiovascular Systems, Inc. Methods of providing antioxidants to a drug containing product
US7735449B1 (en) 2005-07-28 2010-06-15 Advanced Cardiovascular Systems, Inc. Stent fixture having rounded support structures and method for use thereof
US7976891B1 (en) 2005-12-16 2011-07-12 Advanced Cardiovascular Systems, Inc. Abluminal stent coating apparatus and method of using focused acoustic energy
US7867547B2 (en) 2005-12-19 2011-01-11 Advanced Cardiovascular Systems, Inc. Selectively coating luminal surfaces of stents
US20070196428A1 (en) 2006-02-17 2007-08-23 Thierry Glauser Nitric oxide generating medical devices
US7713637B2 (en) 2006-03-03 2010-05-11 Advanced Cardiovascular Systems, Inc. Coating containing PEGylated hyaluronic acid and a PEGylated non-hyaluronic acid polymer
US8304012B2 (en) 2006-05-04 2012-11-06 Advanced Cardiovascular Systems, Inc. Method for drying a stent
US8069814B2 (en) 2006-05-04 2011-12-06 Advanced Cardiovascular Systems, Inc. Stent support devices
US7985441B1 (en) 2006-05-04 2011-07-26 Yiwen Tang Purification of polymers for coating applications
US7775178B2 (en) 2006-05-26 2010-08-17 Advanced Cardiovascular Systems, Inc. Stent coating apparatus and method
US9561351B2 (en) 2006-05-31 2017-02-07 Advanced Cardiovascular Systems, Inc. Drug delivery spiral coil construct
US8568764B2 (en) * 2006-05-31 2013-10-29 Advanced Cardiovascular Systems, Inc. Methods of forming coating layers for medical devices utilizing flash vaporization
US8703167B2 (en) 2006-06-05 2014-04-22 Advanced Cardiovascular Systems, Inc. Coatings for implantable medical devices for controlled release of a hydrophilic drug and a hydrophobic drug
US8778376B2 (en) 2006-06-09 2014-07-15 Advanced Cardiovascular Systems, Inc. Copolymer comprising elastin pentapeptide block and hydrophilic block, and medical device and method of treating
US8603530B2 (en) 2006-06-14 2013-12-10 Abbott Cardiovascular Systems Inc. Nanoshell therapy
US8114150B2 (en) 2006-06-14 2012-02-14 Advanced Cardiovascular Systems, Inc. RGD peptide attached to bioabsorbable stents
US8048448B2 (en) 2006-06-15 2011-11-01 Abbott Cardiovascular Systems Inc. Nanoshells for drug delivery
US8017237B2 (en) 2006-06-23 2011-09-13 Abbott Cardiovascular Systems, Inc. Nanoshells on polymers
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
US8685430B1 (en) 2006-07-14 2014-04-01 Abbott Cardiovascular Systems Inc. Tailored aliphatic polyesters for stent coatings
US8703169B1 (en) 2006-08-15 2014-04-22 Abbott Cardiovascular Systems Inc. Implantable device having a coating comprising carrageenan and a biostable polymer
WO2008035229A3 (en) * 2006-09-22 2009-08-13 Labopharm Barbados Ltd Compositions and methods for ph targeted drug delivery
US8597673B2 (en) 2006-12-13 2013-12-03 Advanced Cardiovascular Systems, Inc. Coating of fast absorption or dissolution
US8147769B1 (en) 2007-05-16 2012-04-03 Abbott Cardiovascular Systems Inc. Stent and delivery system with reduced chemical degradation
US9056155B1 (en) 2007-05-29 2015-06-16 Abbott Cardiovascular Systems Inc. Coatings having an elastic primer layer
US8109904B1 (en) 2007-06-25 2012-02-07 Abbott Cardiovascular Systems Inc. Drug delivery medical devices
US8048441B2 (en) 2007-06-25 2011-11-01 Abbott Cardiovascular Systems, Inc. Nanobead releasing medical devices
CA2775747A1 (en) 2009-10-07 2011-04-14 Sanford Burnham Medical Research Institute Methods and compositions related to clot-binding lipid compounds
US20110237686A1 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc Formulations and methods of use
US8912215B2 (en) 2011-12-13 2014-12-16 Everon Biosciences, Inc. Rapamycin composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4769250A (en) * 1985-10-15 1988-09-06 Vestar, Inc. Antracycline antineoplastic agents encapsulated in phospholipid vesicle particles and methods for using same for tumor therapy

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0619730T3 (en) * 1992-10-08 2001-01-29 Supratek Pharma Inc Compositions of antineoplastic agents incorporated in the micelles
KR100239799B1 (en) * 1995-01-21 2000-02-01 손경식 Cyclosporin a solid micelle dispersion for oral administration, the preparation method thereof and its solid dosage form

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4769250A (en) * 1985-10-15 1988-09-06 Vestar, Inc. Antracycline antineoplastic agents encapsulated in phospholipid vesicle particles and methods for using same for tumor therapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KABANOV A. V., ET AL.: "A NEW CLASS OF DRUG CARRIERS: MICELLES OF POLY(OXYETHYLENE)-POLY(OXYPROPYLENE) BLOCK COPOLYMERS AS MICROCONTAINERS FOR DRUG TARGETING FROM BLOOD IN BRAIN 1.", JOURNAL OF CONTROLLED RELEASE., ELSEVIER, AMSTERDAM., NL, vol. 22., no. 02., 1 October 1992 (1992-10-01), NL, pages 141 - 157., XP000291644, ISSN: 0168-3659, DOI: 10.1016/0168-3659(92)90199-2 *
See also references of EP0939640A4 *
VENNE A, ET AL.: "HYPERSENSITIZING EFFECT OF PLURONIC L61 ON CYTOTOXIC ACTIVITY, TRANSPORT, AND SUBCELLULAR DISTRIBUTION OF DOXORUBICIN IN MULTIPLE DRUG-RESISTANT CELLS", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 56, 15 August 1996 (1996-08-15), US, pages 3626 - 3629, XP002946773, ISSN: 0008-5472 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049848A1 (en) * 1998-04-01 1999-10-07 Rtp Pharma Inc. Anticancer compositions
EP2014307A3 (en) * 2001-03-13 2010-12-08 Angiotech International Ag Micellar drug delivery vehicles and uses thereof
WO2002072150A3 (en) * 2001-03-13 2004-02-05 Angiotech Pharm Inc Micellar drug delivery vehicles and uses thereof
WO2002072150A2 (en) * 2001-03-13 2002-09-19 Angiotech Pharmaceuticals Inc. Micellar drug delivery vehicles and uses thereof
WO2002085337A1 (en) * 2001-04-20 2002-10-31 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs
EP1800670A1 (en) * 2001-04-20 2007-06-27 The University of British Columbia Micellar drug delivery systems for hydrophobic drugs
US7875677B2 (en) 2001-04-20 2011-01-25 The University Of British Columbia Micellar drug delivery systems for hydrophobic drugs
US8124687B2 (en) 2003-02-12 2012-02-28 Syncera, Inc. Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer with bioactive agent
US7829616B2 (en) 2003-02-12 2010-11-09 Syncera, Inc. Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer
EP1991239A1 (en) * 2006-02-22 2008-11-19 Supratek Pharma Inc. Doxorubicin formulations for anti-cancer use
EP1991239A4 (en) * 2006-02-22 2012-09-19 Supratek Pharma Inc Doxorubicin formulations for anti-cancer use
WO2009117333A1 (en) * 2008-03-17 2009-09-24 University Of Utah Research Foundation Dithiocarbamate metal chelates and methods of making and using thereof
US8524784B2 (en) 2009-04-30 2013-09-03 Intezyne Technologies, Incorporated Polymer micelles containing anthracylines for the treatment of cancer
US8524783B2 (en) 2009-04-30 2013-09-03 Intezyne Technologies, Incorporated Polymer micelles containing anthracylines for the treatment of cancer
US8629186B2 (en) 2009-04-30 2014-01-14 Intezyne Technologies, Inc. Polymer micelles containing anthracyclines for the treatment of cancer

Also Published As

Publication number Publication date Type
EP0939640A4 (en) 2001-09-12 application
EP0939640A1 (en) 1999-09-08 application
JP2000516246A (en) 2000-12-05 application
CA2263754A1 (en) 1998-02-26 application
US6060518A (en) 2000-05-09 grant

Similar Documents

Publication Publication Date Title
Vermillion et al. Jaundice associated with bacteremia
Saffran et al. A new approach to the oral administration of insulin and other peptide drugs
Shuai et al. Micellar carriers based on block copolymers of poly (ε-caprolactone) and poly (ethylene glycol) for doxorubicin delivery
Mu et al. The effects of mixed MPEG–PLA/Pluronic® copolymer micelles on the bioavailability and multidrug resistance of docetaxel
Yadav et al. Development and characterization of hyaluronic acid–anchored PLGA nanoparticulate carriers of doxorubicin
Yokoyama et al. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood
US4795436A (en) Bioadhesive composition and method of treatment therewith
Liu et al. Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent
US5710183A (en) Laxative/antidiarrheal composition comprising polyethylene glycol and fiber bulking agent
Kirsh et al. An emulsion formulation of amphotericin B improves the therapeutic index when treating systemic murine candidiasis
Le Garrec et al. Poly (N-vinylpyrrolidone)-block-poly (D, L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation
Bodey The emergence of fungi as major hospital pathogens
Einzig et al. Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: the Eastern Cooperative Oncology Group (ECOG) results of protocol E1293
US4615697A (en) Bioadhesive compositions and methods of treatment therewith
Toshio et al. Specific delivery of mitomycin c to the liver, spleen and lung: Nano-and m1crospherical carriers of gelatin
US6960563B2 (en) Spontaneous emulsions containing cyclosporine
Batrakova et al. Distribution kinetics of a micelle-forming block copolymer Pluronic P85
US6649702B1 (en) Stabilization and acoustic activation of polymeric micelles for drug delivery
US4983392A (en) Bioadhesive compositions and methods of treatment therewith
Wong-Beringer et al. Lipid formulations of amphotericin B: clinical efficacy and toxicities
Koo et al. Camptothecin in sterically stabilized phospholipid micelles: a novel nanomedicine
Rapoport Stabilization and activation of Pluronic micelles for tumor-targeted drug delivery
Rapoport et al. Micellar delivery of doxorubicin and its paramagnetic analog, ruboxyl, to HL-60 cells: effect of micelle structure and ultrasound on the intracellular drug uptake
Alakhov et al. Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials
Sharma et al. Alginate-based oral drug delivery system for tuberculosis: pharmacokinetics and therapeutic effects

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase in:

Ref country code: CA

Ref document number: 2263754

Kind code of ref document: A

Format of ref document f/p: F

Ref document number: 2263754

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1997937219

Country of ref document: EP

ENP Entry into the national phase in:

Ref country code: JP

Ref document number: 1998 510808

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1997937219

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997937219

Country of ref document: EP