JP2003501379A - Use of Drug-Filled Nanoparticles for Cancer Treatment - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of drug-loaded nanoparticles for the preparation of a medicament for the treatment of cancer, in particular for the treatment of cancer in the brain, more particularly for the treatment of human brain tumors. The invention also relates to a method for treating brain tumors, in particular for treating human brain tumors, by administering an effective amount of nanoparticles comprising a substance having an effect or having immunosuppressive properties in the treatment of cancer. About the process.

Description

Detailed Description of the Invention

The present invention relates to the use of drug-loaded nanoparticles as pharmaceutical preparations for the treatment of cancer, preferably for the treatment of cancer in the brain, more preferably for the treatment of brain tumors in humans. The present invention also relates to a method of treating a brain tumor, preferably a human brain tumor, by administering an effective amount of nanoparticles containing a substance having an effect in treating cancer or an immunosuppressive effect.

US Patent No. 08 / 203,326 and International Patent Application No. PCT / EP95
/ 00724 (corresponding to WO 95/22963), the drug is transferred to the mammalian body, preferably the human body, and the drug is complexed (incorporated, adsorbed or absorbed) and a suitable interface It has been reported that nanoparticles surrounded by a coating with an active agent are transported across the blood-brain barrier (also called "bbb"). Similar technology is available in pending international patent application number PCT /
It can be found in EP 97/03099. In both of the above applications, it is described that the drug has an immunosuppressive effect or an anticancer drug. Examples of suitable surfactants include, for example, common commercial surfactants useful as R Polysorbate 80 (Polysorbate ^R 80) or R Tween 80 (Tween ^R 80) are described a number.

Non-invasive treatment of cancer in the mammalian brain, preferably the human brain, is for example
It is generally known that one must resort to very small amounts of immunosuppressive or anti-cancer drugs or agents that are delivered to desired targets such as brain tumors. In particular, anticancer agents known to show high effects in anticancer treatment are
It is effective only when it does not pass through the blood-brain barrier (bbb) at all or in a sufficiently effective amount, but directly into the brain. However, such a transfer step means transfer into the skull at a suitable point, which is a very complicated and sometimes dangerous surgical procedure.

As used herein, the term brain blood barrier (bbb) refers to bbb in a strict sense, for example, the meaning of this term is the spinal blood barrier or the blood retina barrier. ), As is commonly used by those skilled in the medical arts.

Surprisingly, the nanoparticles prepared according to the prior art, in particular according to the above-mentioned two patent applications, are effective for substances which are effective in the treatment of cancer (in particular in the treatment of brain cancer, for example in humans). Loaded and then the drug-loaded nanoparticles pass across bbb to transfer the effective drug to the site that exerts anti-cancer and / or immunosuppressive activity. , Found to be coated with a suitable surfactant. In particular, proper selection of drug / surfactant binding provides for the effective use of such drug-loaded and surfactant-coated nanoparticles in the treatment of cancer, especially in the brain. I knew that.

From here, the present invention relates to the use of nanoparticles made of polymeric material, wherein said nanoparticles are said polymeric material, one or more substances that have a physiological effect in the treatment of cancer by transfer to a mammal, said mammal. One or more stabilizers for the nanoparticles that enable the physiologically effective substance to attack a specific site inside an animal, and / or a surfactant that coats the nanoparticles, the nanoparticles comprising: , In a physiologically acceptable carrier and / or diluent, which enables the transfer of the nanoparticles to a target inside the mammal after administration for the manufacture of a medicament for the treatment of cancer in the mammal. Is being supplied to.

In a preferred form of the invention said cancer treatment is brain cancer treatment. In a more preferred form, the brain tumor treatment is for humans. The terms cancer and tumor (s) are used synonymously in the specification and claims.

The nanoparticles for cancer treatment used in the present invention are nanoparticles mainly composed of three main components. For example, a drug or a substance having a physiological effect is incorporated into or Said polymeric material used to form adsorbed or adsorbed walls (for example, on its surface), said physiologically effective substance or substances contained within or on said nanoparticles, and One stabilizer or more than one stabilizer for passing the nanoparticles through bbb.

The above-mentioned three components and the combination thereof are basically not limited as long as the intended purpose can be achieved, but the present invention, as one of the preferred modes, Use of said nanoparticles comprising particles of said polymeric material with a diameter of 1000 nm or less, preferably 1-1000 nm.

In a further preferred embodiment, in the present invention, the polymer material forming the nanoparticles is polyacrylate, polymethacrylate, polycyanoacrylate, polyacrylamide, polyactates, polyglycolate, polyanhydrate. , Polyorthoester, gelatin, polysaccharides, albumin, polystyrene, polyvinyl, polyacrooein
in), polyglutaraldehyde and derivatives, copolymers and mixtures thereof, for use of said nanoparticles. of course,
The particular material of the nanoparticles is not limited as long as it allows or facilitates the physiologically effective substance or substances to be effectively transported or passed across the bbb.

In the present use of the nanoparticles according to the invention, one or more substances having a physiological effect in the treatment of cancer by transfer to a mammal are bound to (bound to, absorbed within, or on the nanoparticles. Supplied and / or adsorbed). The substance may be a single substance, or two or more substances that act on the human body in separate or linked or synergistic pathways.

In a preferred use according to the invention, said physiologically effective substance to be delivered to a mammal is used for the treatment of cancer, in particular for the treatment of cancer in the brain of said mammal, as well as in the human body (eg brain). ) Includes one or more chemotherapeutic agents for the treatment of cancer. The transfer of such an anti-cancer drug to the human brain has been extremely difficult in the prior art in which the effective amount of the chemotherapeutic drug that can be supplied to the site of action is important.
Surprisingly, the use of the present invention can provide such a substance to its site of action effectively and in a controllable amount in an easily administrable composition.

According to the invention, said chemotherapeutic anti-cancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural anti-cancer products, hormones, metal coordination complexes and mixtures thereof, such It is preferable to use the nanoparticles. There is no limitation with regard to the administration of one single group of substances or one or more groups of said groups. It is merely necessary that the nanoparticles used in the present invention be stably incorporated inside, or adsorbed and absorbed, and that each does not interfere during such use.

Specific substances used according to the preferred embodiment of the present invention include the substances shown below, but are not limited to the invention using the substances shown below. -Nitrogen mustards such as cyclophosphamide, Trofosfamide, Ifosfamide and chlorambucil (
Chlorambucil) -nitrosourea, eg, Carmustine (BCNU), Lomustine (CCNU), Semustine (methyl CCNU)
And Nimustine (ACNU) -ethyleneimine and methylmelamine, such as Thiotepa-folate analogs, such as Methotrexate-pyrimidine analogs, such as 5-fluorouracil and cytarabine (Cyt).
arabine) -purine analogs such as mercaptopurine and azathioprine
prine) -vinica alkaloids such as vinblastine, vincristine and vindesine-epipodophyllotoxins such as etoposide
oposide) and teniposide-antibiotics such as dactinomycin, daunorubicin, doxorubicin, epirubicin, bleomycin A2, mitomycin C and mitoxantrone-estrogen, eg diethylstilbestrol (Diethyl stilbest)
rol) -gonadotropin-releasing hormone analogs, such as leuprolide
, Buserelin and Goserelin-antiestrogens, such as tamoxifen, aminoglutethimide (Aminogl)
utethimide) -androgens, such as Testolactone and Drostanolonproprionate; and-Platinum complexes, such as Cisplatin and Carboplatin.

According to the invention, mixtures of the substances mentioned above can also be used, so long as they result in an effective treatment of cancers (in particular brain tumors) in mammals such as humans. More preferred in the use of nanoparticles of the invention, the administration of these substances with nanoparticles results in an effective anti-cancer treatment, in particular an effective brain tumor treatment in eg mammals such as humans. Is doxorubicin and / or mitoxantrone. In particular, the passage of bbb by the substance in a therapeutically effective amount was observed, which is known to those skilled in the art who are concerned with the prior art problem of delivering a therapeutically effective amount of anti-cancer agents in the brain. It's totally amazing.

The critical components of the nanoparticles used in the present invention are:
It is a stabilizer. In a preferred use, only one stabilizer is used, which allows the passage of bbb by the nanoparticles loaded with anti-cancer agent in an efficient manner. And, the anti-cancer agent in the nanoparticles directly acts on the tumor site of the brain at a high concentration. This was not yet possible in the prior art. As a result, the treatment of brain tumors has improved considerably and the success rate of treatment has increased as well.

Another essential component of the nanoparticles used in the present invention is the surfactant material of the coating, which is a material that belongs to the same group of compounds as described above. The stabilizer may be present in the nanoparticles used according to the invention as a result of a small amount remaining in the manufacturing process and also forms a coating that allows passage of the effective substance across the bbb. May be. Also, separate coatings may be provided. As a result, the outer walls of the nanoparticles used in the present invention are coated with said material which allows the passage of bbb. The provision of coatings or the provision of stabilizers on such nanoparticles is basically described in the specification of the above-mentioned international patent application incorporated herein by reference.

In a preferred form of use of the present invention, said material of said stabilizer / surfactant is such that said nanoparticles comprising said physiologically effective substance pass across said mammalian blood-brain barrier. Releasing a physiologically effective substance from the nanoparticles, and separating the nanoparticles from the nanoparticles to allow the substance to pass across the blood brain barrier. Selected from the group consisting of stabilizers / surfactants. More preferably, the stabilizer / surfactant is polysorbate, dextran, carboxylic acid ester of multifunctional alcohol, polyoxamer, polyoxamine, alkoxylated ether, alkoxylated ester, alkoxylated mono-, di- and triglyceride, alkoxyl. Selected from the group consisting of derivatized phenols and diphenols, registered Genapol ^R and registered Bauki ^R substances, metal salts of carboxylic acids, metal salts of sulphate alcohols, metal salts of sulfosuccinic acid and mixtures of two or more of the above substances. Contains substances.

Specific examples of the stabilizer and / or surfactant used for coating the nanoparticles are described below. It is not limited to the above compounds or the groups of compounds shown below. Preferably, the stabilizer / surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 8
0, polysorbate 81, polysorbate 85, dextran 12,000, dextran 70,000, fatty acid esters of glycerol and sorbitol such as glycerol monostearate, sorbitan monostearate and sorbitan monooleate, polyoxamer 188 (Pluronic R F68.
(Pluronic R F68)), ethoxylated ethers, ethoxylated esters, ethoxylated triglycerides, ethoxylated phenols and diphenols, fatty acids and metal salts of lipid sulfate alcohols, more preferably sodium salts of fatty acids and lipid alcohol sulfates, and More preferred are sodium stearate and sodium lauryl sulphate and mixtures of two or more of said substances.

The most preferred stabilizer / surfactant materials are polysorbate 80, polysorbate 85, dextran 12,000, dextran 70,000 and mixtures thereof, and mixtures of said stabilizers with other stabilizers. . The latter compounds are capable of achieving excellent use of nanoparticles in anti-cancer therapy, especially in the treatment of human brain tumors.

[0021] In the further preferred nanoparticles, the carrier and / or diluent used for administration of the nanoparticles used in the present invention is water,
It is selected from the group consisting of physiologically acceptable aqueous solutions containing salts and / or buffers, and other solutions acceptable for administration to mammals.

In the present invention, the nanoparticles to be supplied are the polymer material, one or more substances having a physiological effect in cancer treatment by transfer to a mammal, and the physiological effect to specific sites inside the mammal. One or more stabilizers to the nanoparticles that enable attack of certain substances, and / or a surfactant that coats the nanoparticles, the nanoparticles being for the treatment of cancer in the mammal. , Optionally provided in a physiologically acceptable carrier and / or diluent, which allows transfer of the nanoparticles to a target inside the mammal after administration.

In another aspect of the invention, a process for treating cancer, particularly brain tumor, in a mammal, the process comprising administering to the mammal nanoparticles made of a polymeric material, the nanoparticles comprising: 1 for the polymeric material, one or more substances that have a physiological effect in the treatment of cancer by transfer to a mammal, and 1 for the nanoparticles that allow the physiologically effective substance to attack specific sites inside the mammal The above stabilizers and / or surfactants for coating the nanoparticles are included, and the nanoparticles enable transfer of the nanoparticles to a target inside the mammal after administration, physiologically. In an acceptable carrier and / or diluent, in an amount effective for treating cancer, It is being supplied to you.

In the preferred process according to the invention, said administration is intravenous. Particularly preferably, the treatment is, for example, treatment of brain tumors in mammals such as humans.

The present invention is further illustrated by the examples that follow, which should not be understood as limited thereto.

The anti-tumor effect of doxorubicin preparation is that neuroglioblastoma 101
/ 8 was tested in transplanted rats. This tumor is known to have substantial amounts of receptors for epidermal growth factor.

The mice were treated with doxorubicin 1.5 mg / kg × 3 so that the total course dose was 4.5 mg / kg (usually the total dose for mice was 7-8 mg / kg). .

The drug was intravenously administered 2 days (48 hours after tumor implantation), 5 days, and 8 days after tumor implantation.

The experiment started on December 9-13, 1998 and was not completed by May 20, 1999 because some of the mice are still alive.

The pharmaceutical preparations can, as usual, administered in saline or 1% Tween ^R 80. For coating the nanoparticles loaded with doxorubicin, with stirring, it was added 1% Tween ^R 80 in suspension. The mixture was incubated for 2 hours.

As clearly shown in the table below in the case where doxorubicin was administered (Dox), the rats died after a given time (hours, h) in column 1 of the above table. Most rats died when the drug was administered with Tween80. As a first case, all rats died after administration of nanoparticles coated with Tween 80 and nanoparticles coated with uncoated doxorubicin (columns 3 and 4 in the table above).
Only in the case of nanoparticles loaded with Tween 80-coated doxorubicin, 3 out of 8 survived.

From this result, the surfactant-coated nanoparticles are suitable for facilitating the passage of an effective dose of the anticancer drug doxorubicin across bbb for effective anticancer treatment. Is.

The survival rate of rats with glioblastoma 101/8 after administration of doxorubicin preparation (day) control Dox Dox NP Dox-NP Dox- NP + + + Tween80 Tween80 Tween80 9 11 13 9 13 22 11 13 13 11 13 13 22 12 14 23 23 11 15 22 22 13 14 38 12 15 23 23 13 14 51 18 17 17 37 13 15 Survival 19 38 Survival 14 20 40 Survival 17 21 50 Survival 17 23

Prolongation of survival time MST Intermediate value of survival number (MST, day)% Up to 60 days Control 13.2 Dox 16.1 220/9 Dox-NP 25.1 90 0/8 Dox + Tween 27.6 112 1/6 Dox-NP + Tween 25.1 91 3/8 NP + Tween 13.3 0 0/6

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/18 A61K 47/18 47/40 47/40 A61P 35/00 A61P 35/00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA ( AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LV, MD, MG, MK, MN, MW, MX , NZ, PL, RO, RU, SD, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Gelperina, Svetlana Russia , 117647, Moscow, 113-3, Prov Soyuznaya Youel, apartment number 719 (72) Inventor Schroeder, Ulrike Germany, De-39171 Dodendorf, Am Zürzehang 7 F-term (reference) 4C076 AA22 AA65 BB13 BB21 CC27 DD07F DD39F DD39F DD39Q DD46F DD46Q EE38F EE38Q FF06 FF43 GG21 4C086 AA01 AA02 EA10 MA01 MA05 MA08 MA09 MA23 MA37 MA56 MA66 NA11 ZB26 4C206 AA01 AA02 FA31 MA02 MA05 MA43 MA57 MA76 MA86 NA11 ZB26

Claims (14)

[Claims] 1. Use of nanoparticles made of a polymeric material, wherein the nanoparticles are the polymeric material, one or more substances having a physiological effect in the treatment of cancer by transfer to the mammal, inside the mammal. One or more stabilizers for the nanoparticles that enable the physiologically effective substance to attack specific sites, and / or a surfactant that coats the nanoparticles, wherein the nanoparticles are Optionally provided in a physiologically acceptable carrier and / or diluent that allows for the transfer of the nanoparticles to a target within the mammal after administration for the manufacture of a medicament for treating cancer in an animal. Use of said nanoparticles. 2. The use according to claim 1 for the treatment of brain tumors in said mammal. 3. Use according to claim 1 or 2, wherein the nanoparticles comprise particles of the polymeric material with a diameter of 1000 nm or less, preferably 1-1000 nm in diameter. 4. The polymer material is polyacrylate, polymethacrylate, polycyanoacrylate, polyacrylamide, polyactate.
s), polyglycolates, polyanhydrates, polyorthoesters, gelatins, polysaccharides, albumins, polystyrenes, polyvinyls, polyacrooein, polyglutaraldehydes and derivatives, copolymers and mixtures thereof. Use according to any of claims 1 to 3, selected from 5. The use according to any of claims 1 to 4, wherein the nanoparticles contain the physiologically effective substance to be transferred to the mammal in a form adsorbed, absorbed and / or incorporated therein. . 6. The physiologically effective substance transferred to the mammal comprises one or more chemotherapeutic agents for treating cancer, preferably an alkylating agent, an antimetabolite, a natural anticancer product, Including hormones, metal coordination complexes and mixtures thereof,
More preferably, nitrogen mustard, nitroso ureas,
Ethyleneimine and methylmelamine, folic acid analogs, pyrimidine analogs, purine analogs, vinyla alkaloids, epipodophyllotoxins
), Antibiotics, estrogens, gonadotropin-releasing hormone analogues, antiestrogens, androgens, platinum complexes and mixtures thereof, particularly preferably doxorubicin and / or mitoxantrone. Use according to any one of. 7. A stabilizing agent and / or a surfactant coating material enables the nanoparticles containing the physiologically effective material to pass across the mammalian blood-brain barrier. A stabilizing agent / surfactant, and releasing the physiologically effective substance from the nanoparticles, and allowing the substance to separate from the nanoparticles and pass across the blood brain barrier. Is selected from the group consisting of stabilizers / surfactants, preferably polysorbates, dextran, carboxylic acid esters of multifunctional alcohols, polyoxamers, polyoxamines, alkoxylated ethers, alkoxylations. Ester, alkoxylated mono-, di- and triglycerides, alkoxy Silylated phenols and diphenols, registered trademark Gena
pol ^R and Bauki ^R- based substances, metal salts of carboxylic acids, metal salts of sulphate alcohols, metal salts of sulfosuccinic acid and substances selected from the group consisting of two or more of the above substances, more preferably, The stabilizer / surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,
Polysorbate 81, polysorbate 85, dextran 12,000, dextran 70,000, fatty acid esters of glycerol and sorbitol such as glycerol monostearate, sorbitan monostearate and sorbitan monooleate, polyoxamer 188 (Pluronic R F68 (Pl
uronic R F68)), ethoxylated ethers, ethoxylated esters, ethoxylated triglycerides, ethoxylated phenols and diphenols, fatty acids and metal salts of lipid sulfate alcohols, more preferably fatty acid and sodium salts of lipid alcohol sulfates, Preference is given to sodium stearate and sodium lauryl sulphate and mixtures of two or more of said substances, even more preferably polysorbate 80, polysorbate 85,
Dextran 12,000 or Dextran 70,000, and mixtures thereof and mixtures of said stabilizers / surfactants with other stabilizers / surfactants. use. 8. A group of carriers and / or diluents consisting of water, physiologically acceptable aqueous solutions containing salts and / or buffers, and other solutions acceptable for administration to mammals. Use according to any of claims 1 to 7, selected from 9. Use according to any of claims 1 to 8, wherein said administration is intravenous (iv) administration. 10. Use according to any of claims 1 to 9, wherein the mammal is a human. 11. Nanoparticles made of a polymeric material, wherein the nanoparticles are the polymeric material, one or more substances having physiological effects in cancer treatment by transfer to a mammal, and specific sites in the mammal. One or more stabilizers for the nanoparticles, which allow attack of the physiologically effective substance on the nanoparticles,
And / or comprising a surfactant coating said nanoparticles, said nanoparticles enabling transfer of said nanoparticles to a target within said mammal after administration for the treatment of cancer in said mammal. , Nanoparticles of polymeric material, optionally provided in a physiologically acceptable carrier and / or diluent. 12. A process for the treatment of cancer in a mammal, in particular for treating brain tumors, which comprises the step of administering to said mammal nanoparticles of polymeric material,
The nanoparticles enable attack of the polymeric material, one or more substances that have a physiological effect in treating cancer by transfer to a mammal, and a specific site inside the mammal with the physiological effect. One or more stabilizers for the nanoparticles, and / or a surfactant coating the nanoparticles, the nanoparticles allowing transfer of the nanoparticles to a target inside the mammal after administration. Optionally, provided in a physiologically acceptable carrier and / or diluent in an amount effective for the treatment of cancer. 13. The process of claim 12, wherein said administration is intravenous (iv) or intraperitoneal (ip) administration. 14. The process according to claim 12 or 13, wherein the treatment is treatment of brain tumor.