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Publication numberWO1998007434 A1
Publication typeApplication
Application numberPCT/US1997/014218
Publication date26 Feb 1998
Filing date13 Aug 1997
Priority date16 Aug 1996
Also published asCA2263754A1, EP0939640A1, EP0939640A4, US6060518
Publication numberPCT/1997/14218, PCT/US/1997/014218, PCT/US/1997/14218, PCT/US/97/014218, PCT/US/97/14218, PCT/US1997/014218, PCT/US1997/14218, PCT/US1997014218, PCT/US199714218, PCT/US97/014218, PCT/US97/14218, PCT/US97014218, PCT/US9714218, WO 1998/007434 A1, WO 1998007434 A1, WO 1998007434A1, WO 9807434 A1, WO 9807434A1, WO-A1-1998007434, WO-A1-9807434, WO1998/007434A1, WO1998007434 A1, WO1998007434A1, WO9807434 A1, WO9807434A1
InventorsAlexander V. Kabanov, Valery Y. Alakhov
ApplicantSupratek Pharma, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Improvements in polymer compositions for chemotherapy and methods of treatment using the same
WO 1998007434 A1
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.
Claims  (OCR text may contain errors)
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.
Description  (OCR text may contain errors)

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 4C 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 37C 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 37C 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 37C 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 37C 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 1C). 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 12346834

Dox 2134321

Dox/Lόl 5478235

Dox/Lόl /PEG 10358978

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4769250 *26 Oct 19876 Sep 1988Vestar, Inc.Antracycline antineoplastic agents encapsulated in phospholipid vesicle particles and methods for using same for tumor therapy
Non-Patent Citations
Reference
1 *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
2 *See also references of EP0939640A4
3 *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
Referenced by
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WO1999049848A1 *30 Mar 19997 Oct 1999Rtp Pharma Inc.Anticancer compositions
WO2002072150A2 *13 Mar 200219 Sep 2002Angiotech Pharmaceuticals Inc.Micellar drug delivery vehicles and uses thereof
WO2002072150A3 *13 Mar 20025 Feb 2004Angiotech Pharm IncMicellar drug delivery vehicles and uses thereof
WO2002085337A1 *22 Apr 200231 Oct 2002The University Of British ColumbiaMicellar drug delivery systems for hydrophobic drugs
WO2009117333A1 *16 Mar 200924 Sep 2009University Of Utah Research FoundationDithiocarbamate metal chelates and methods of making and using thereof
EP1800670A1 *22 Apr 200227 Jun 2007The University of British ColumbiaMicellar drug delivery systems for hydrophobic drugs
EP1991239A1 *8 Feb 200719 Nov 2008Supratek Pharma Inc.Doxorubicin formulations for anti-cancer use
EP1991239A4 *8 Feb 200719 Sep 2012Supratek Pharma IncDoxorubicin formulations for anti-cancer use
EP2014307A3 *13 Mar 20028 Dec 2010Angiotech International AgMicellar drug delivery vehicles and uses thereof
US78296168 Jun 20099 Nov 2010Syncera, Inc.Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer
US787567718 Aug 200825 Jan 2011The University Of British ColumbiaMicellar drug delivery systems for hydrophobic drugs
US812468715 Sep 201028 Feb 2012Syncera, Inc.Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer with bioactive agent
US852478330 Apr 20103 Sep 2013Intezyne Technologies, IncorporatedPolymer micelles containing anthracylines for the treatment of cancer
US852478429 Oct 20103 Sep 2013Intezyne Technologies, IncorporatedPolymer micelles containing anthracylines for the treatment of cancer
US862918625 Jul 201314 Jan 2014Intezyne Technologies, Inc.Polymer micelles containing anthracyclines for the treatment of cancer
Classifications
International ClassificationA61P35/00, A61K31/704, A61K47/34, A61K9/107
Cooperative ClassificationA61K9/1075, A61K31/704
European ClassificationA61K9/107D, A61K31/704
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