FULVESTRANT NANOSPHERE/MICROSPHERE AND PREPARATIVE METHOD AND USE THEREOF

• US 20110318420A1
• Filed: 08/31/2009
• Published: 12/29/2011
• Est. Priority Date: 08/31/2009
• Status: Active Grant

• Current Assignee: Xi'an Libang Pharmaceutical Co.,Ltd.
• Original Assignee: Xi'an Libang Pharmaceutical Co.,Ltd.
• Inventors: Hu, Renle, Wang, Jiucheng, Jiao, Yaqi, Liang, Hua, Ding, Duohao
• Granted Patent: US 8,586,092 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis

Abstract

Fulvestrant nanosphere/microsphere and preparation method and use thereof are provided in the present invention. The carrier material of the fulvestrant nanosphere/microsphere is methoxy ended polyethylene glycol-polylactic acid block copolymer. The nanosphere/microsphere is prepared by solvent-nonsolvent method, in-liquid drying method and/or spray drying method, and has the features of high drug loading and high encapsulation efficiency, controllable release of medicine and no irritant to application site or blood vessel. The fulvestrant nanosphere/microsphere can be used to treat metastatic advanced breast cancer in post-menopausal woman.

Claims

1. Fulvestrant nanosphere or microsphere, comprising:

a. fulvestrant or pharmaceutically acceptable salt or solvate thereof and

b. a methoxy ended polyethylene glycol-polylactic acid block copolymer.

2. The fulvestrant nanosphere or microsphere according to claim 1, comprising 0.01%˜

50% weight of fulvestrant or pharmaceutically acceptable salt or solvate thereof based on the amount of fulvestrant, preferably 5%˜

50% weight, more preferably 10%˜

30% weight, and most preferably 20%˜

30% weight.

3. The fulvestrant nanosphere or microsphere according to claim 1, wherein the methoxy ended polyethylene glycol-polylactic acid block copolymer is composed of hydrophilic fragment polyethylene glycol and lipophilic fragment polylactic acid;

preferably, the structural formula of the methoxy ended polyethylene glycol-polylactic acid block copolymer is

4. The fulvestrant nanosphere or microsphere according to claim 1, wherein the particle size of the fulvestrant nanosphere is 0.1 μ

m˜

1 μ

um, preferably 0.3 μ

m˜

0.8 μ

m;

the particle size of the fulvestrant microsphere is 10 μ

m˜

1 mm, preferably 10˜

500 μ

m.

5. A method of preparing for the fulvestrant nanosphere or microsphere according to claim 1, wherein the method is selected from the group consisting of solvent-nonsolvent method, in-liquid drying method and spray drying method.

6. The method according to claim 5, wherein the solvent-nonsolvent method includes the steps of:

a. dispersing or dissolving the fulvestrant in the solvent system containing dissolved methoxy ended polyethylene glycol-polylactic acid block copolymer;

b. added into nonsolvent system to form nanosphere or microsphere;

c. solidifying, collecting, washing and drying;

preferably, the solvent of the methoxy ended polyethylene glycol-polylactic acid block copolymer is one or more of dichloromethane, trichloromethane, methylhydrofuran, ethanol, and ethyl acetate;

preferably, the concentration of the methoxy ended polyethylene glycol-polylactic acid block copolymer in the solvent system is 0.1%-50% (g/ml);

preferably, the concentration of the fulvestrant in the solvent system which contains dissolved methoxy ended polyethylene glycol-polylactic acid block copolymer is 0.01%˜

80% (g/ml);

preferably, the nonsolvent system is ether, petroleum ether, n-hexane, cyclohexane, acetone;

preferably, the volume ratio of the solvent system to the nonsolvent system is 10;

1˜

1;

10; and

/or

preferably, the nonsolvent system further comprises antisticking agent;

more preferably, the antisticking agent is one or more of polyisobutyl ester, polyethylene, and butyl rubber;

further preferably, the mass ratio of the antisticking agent to the methoxy ended polyethylene glycol-polylactic acid block copolymer is 0;

10˜

2;

10.

7. The method according to claim 5, wherein the in-liquid drying method includes the steps of:

a. dissolving the fulvestrant and the methoxy ended polyethylene glycol-polylactic acid block copolymer in the organic solvent to make an oil phase;

b. adding the oil phase in the aqueous phase and emulsifying to get the oil-in-water O/W type emulsion;

c. stirring and heating up the O/W type emulsion to completely volatilize the organic solvent in the O/W type emulsion;

d. filtering, washing, collecting and drying;

preferably, the solvent of the methoxy ended polyethylene glycol-polylactic acid block copolymer is one or more of dichloromethane, trichloromethane, methylhydrofuran, ethanol, and ethyl acetate;

preferably, the mass ratio of the fulvestrant to the methoxy ended polyethylene glycol-polylactic acid block copolymer is 1;

50˜

1;

3;

preferable concentration of the methoxy ended polyethylene glycol-polylactic acid block copolymer in the oil phase is 1%˜

50% (g/ml);

preferably, the aqueous phase is one or more mixed solution of surfactant solution, mono- or polysaccharides solution, polyol solution, cellulose solution, and colloid solution, the concentration of the solute in the aqueous phase is 0.01%˜

50% (g/ml), and the pH value of aqueous phase is in the range of 3.0˜

10.5;

preferably, the pH adjusting agent used in the aqueous phase is selected from the group consisting of inorganic acid, organic acid, inorganic base, organic base and buffer salt; and

/or preferably, the volume ratio of the oil phase to the aqueous phase is 1;

300˜

1;

5.

8. The method according to claim 5, wherein the spray drying method include the steps of:

a. dissolving or dispersing the fulvestrant in the solvent system containing dissolved methoxy ended polyethylene glycol-polylactic acid block copolymer;

b. spraying into the drying tower of spray drying equipments in the form of spray, and drying, isolating, collecting;

preferably, the solvent of the methoxy ended polyethylene glycol-polylactic acid block copolymer is one or more of dichloromethane, trichloromethane, methylhydrofuran, ethanol, and ethyl acetate;

preferably, the concentration of the methoxy ended polyethylene glycol-polylactic acid block copolymer in the solvent system is 0.1%˜

50% (g/ml);

preferably, the concentration of the dissolved or dispersed fulvestrant in the solvent system containing solved methoxy ended polyethylene glycol-polylactic acid block copolymer is 0.01%˜

50% (g/ml);

preferably, the inlet air temperature of the drying tower is 30°

C.˜

80°

C.;

preferably, the solvent system further comprises plasticizer, more preferably, the plasticizer is one or more of dimethyl benzoate, diethyl benzoate, dibutyl benzoate, dibutyl sebacate, tributyl citrate, acetyl tributyl citrate, and glyceryl triacetate;

further preferably, the mass percent of the plasticizer to the methoxy ended polyethylene glycol-polylactic acid block copolymer is 0%˜

50%; and

/or

preferably, the solvent system further comprises antisticking agent, the antisticking agent is one or more of cholesterol, glycerol monostearate, talc powder, silica gel, and magnesium stearate, more preferably, the mass percent of the antisticking agent to the methoxy ended polyethylene glycol-polylactic acid block copolymer is 0%˜

100%.

9. The use of the fulvestrant nanosphere or microsphere according to claim 1 in the preparation of the drugs for treating breast cancer;

preferably, the breast cancer is advanced breast cancer, more preferably, the breast cancer is the metastatic advanced breast cancer in post-menopausal woman with ineffective, progressed or hormone receptor-positive after treating with antiestrogen therapy.

10. A pharmaceutical composition for treating breast cancer, comprising the fulvestrant nanosphere or microsphere according to claim 1.

11. The use of the fulvestrant nanosphere or microsphere according to claim 1 in the treatment of breast cancer;

preferably, the breast cancer is advanced breast cancer, more preferably, the breast cancer is the metastatic advanced breast cancer in post-menopausal woman with ineffective, progressed or hormone receptor-positive after treating with antiestrogen therapy.

12. A method of treating breast cancer, especially the advanced breast cancer, wherein administering to the patient in need thereof a pharmaceutically acceptable effective amount of the fulvestrant nanosphere or microsphere according to claim 1;

preferably, the fulvestrant nanosphere or microsphere or the pharmaceutical composition are administered every 1 to 3 months;

more preferably, the administration route is subcutaneous or intravenous injection.

13. The use of the fulvestrant nanosphere or microsphere according to the pharmaceutical composition according to claim 10 in the treatment of breast cancer;

preferably, the breast cancer is advanced breast cancer, more preferably, the breast cancer is the metastatic advanced breast cancer in post-menopausal woman with ineffective, progressed or hormone receptor-positive after treating with antiestrogen therapy.

14. A method of treating breast cancer, especially the advanced breast cancer, wherein administering to the patient in need thereof a pharmaceutically acceptable effective amount of the pharmaceutical composition according to claim 10;

preferably, the fulvestrant nanosphere or microsphere or the pharmaceutical composition are administered every 1 to 3 months;

more preferably, the administration route is subcutaneous or intravenous injection.