Chemotherapeutic composition using nanocrystalline calcium phosphate paste

• US 20060240121A1
• Filed: 03/30/2006
• Published: 10/26/2006
• Est. Priority Date: 10/16/1996
• Status: Active Grant

• Current Assignee: Life Science Enterprises , INC.
• Original Assignee: Life Science Enterprises , INC.
• Inventors: Aiolova, Maria, Lee, Dosuk D.
• Granted Patent: US 8,728,536 B2
• Time in Patent Office: Days
• US Class Current: 424/603
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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

Abstract

A method and composition are provided for treating cancer in a mammal. The method includes administering to a tumor site of the mammal an anticancer composition comprising a mixture of an anticancer agent and a nanocrystalline or poorly crystalline calcium phosphate paste, said paste comprised of one or more calcium phosphates and a physiologically acceptable fluid, the paste having an injectable or formable consistency at the time of administration and hardenable at the tumor

Claims

1. An anticancer composition comprising a mixture of an anticancer agent and a calcium phosphate paste, said paste comprised of one or more nanocrystalline or poorly crystalline calcium phosphates and a physiologically acceptable fluid, the paste having an injectable or formable consistency at the time of administration and hardenable at the tumor site.

2. The composition of claim 1, wherein each calcium phosphate has a Ca/P ratio of less than or equal to 1.7.

3. The composition of claim 1, wherein the anticancer agent is selected from the group consisting of methotrexate, cisplatin, prednisone, hydroxyprogesterone, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, testosterone propionate, fluoxymesterone, vinblastine, vincristine, vindesine, hydroxyurea, procarbazine, aminoglutethimide, mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, carmustine, lomustine, dacarbazine (DTIC, dimethyltriazenomideazolecarboxamide), procarbozine, 5-fluorouracil, cytarabine, cytosine arabinoside, 6-mercaptopurine, tamoxifen, paclitaxel, etoposide, vinorelbine, gemcitabine, leuprolide, flutamide, goserelin acetate, thioguanine, and mixtures thereof.

4. The composition of claim 3, wherein said anticancer agent is cisplatin.

5. The composition of claim 1, wherein the anticancer composition is of a consistency administrable to the tumor site by cannula or by injection.

6. The composition of claim 1, wherein the nanocrystalline or poorly crystalline calcium phosphate cement comprises a calcium phosphate selected from the group consisting of amorphous calcium phosphate, poorly crystalline apatitic (PCA) calcium phosphates (PCA), dicalcium phosphates, such as dicalcium phosphate dihydrate (DCPD) and dicalcium phosphate anhydrous (DCPA), tricalcium phosphates (TCP), monetite, monocalcium phosphate monohydrate (MCPM), hetpacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, octacalcium phosphates (OCP), hydroxyapatites (HA).

7. The composition of claim 6, wherein at least one of the nanocrystalline or poorly crystalline calcium phosphates is selected from the group consisting of amorphous calcium phosphate and poorly crystalline apatitic calcium phosphate.

8. The composition of claim 1, wherein each of the said one or more nanocrystalline or poorly crystalline calcium phosphates has a calcium to phosphate ratio in the range of 1.3 to 1.67.

9. The composition of claim 1, wherein nanocrystalline or poorly crystalline calcium phosphate paste comprises a physiologically acceptable fluid in an amount sufficient to produce a paste having injectable or formable consistency for at least five minutes.

10. The composition of claim 1, wherein nanocrystalline or poorly crystalline calcium phosphate paste comprises a physiologically acceptable fluid in an amount sufficient to produce a paste having injectable or formable consistency for at least twenty minutes.

11. The composition of claim 1, wherein the nanocrystalline or poorly crystalline calcium phosphate paste is hardenable into an apatitic calcium phosphate.

12. The composition of claim 1, wherein a therapeutically effect amount of anticancer agent is released from the composition for a time greater than one week.

13. The composition of claim 1, wherein a therapeutically effect amount of anticancer agent is released from the composition for a time greater than two weeks.

14. The composition of claim 1, wherein a therapeutically effect amount of anticancer agent is released from the composition for a time greater than one month.

15. The composition of claim 1, wherein a therapeutically effect amount of anticancer agent is released from the composition for a time greater than three months.

16. The composition of claim 1, wherein delivery of the anticancer therapy to the tumor site is sufficient to at least prevent increase of tumor mass without significant weight loss of the mammal.

17. The composition of claim 1, wherein delivery of the anticancer therapy to the tumor site is sufficient to promote a decrease in tumor mass without significant weight loss in the mammal.

19. A method for treating cancer in a mammal, said method comprising administering to a tumor site of the mammal the anticancer composition of claim 1.

18. An anticancer composition comprising cisplatin admixed with a calcium phosphate paste, said paste comprised of one or more nanocrystalline or poorly crystalline calcium phosphates and a physiologically acceptable fluid, the paste having an injectable or formable consistency at the time of administration and hardenable at the tumor site.

20. A method for treating cancer in a mammal, said method comprising administering to a tumor site of the mammal the anticancer composition of claim 18.

21. A kit for use in preparing a flowable anticancer composition that remains injectable for at least about 20 minutes, said kit comprising:

(a) dry ingredients comprising a nanocrystalline or poorly crystalline calcium phosphate and a second calcium phosphate in a proportion of about 1;

10 to 10;

1 by weight;

(b) a physiologically acceptable aqueous lubricant in an amount sufficient to produce a flowable product upon combination with said dry ingredients; and

(c) an anticancer agent in an amount ranging from about 0.01 to 10 wt. % of said dry ingredients.

22. The kit of claim 21, further comprising a means of mixing the dry ingredients and the lubricant.

23. The kit of claim 21, further comprising injecting means.