Micelle encapsulation of a combination of therapeutic agents

• US 8,529,917 B2
• Filed: 02/26/2013
• Issued: 09/10/2013
• Est. Priority Date: 09/25/2009
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Kwon, Glen S.
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US13/777,377
• Publication Number:
  US 20130171207A1
• Time in Patent Office: 196 Days
• Field of Search: 424/400, 514/449, 514/27, 514/291, 514/183
• US Class Current: 424/400
• 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 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/124 characterised by the propellant
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10S 977/788 Of specified organic or carbon-based composition
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

The invention provides active agents, such as paclitaxel, rapamycin, or 17-DMAG, encapsulated by safe poly(ethylene glycol)-block-poly(lactic acid) (“PEG-b-PLA”) micelles. The compositions provide effective solubilization of drug combinations, such as paclitaxel, rapamycin, and 17-DMAG, as well as others described herein. A significant advantage of PEG-b-PLA as a carrier is that it is less toxic than Cremophor® EL or DMSO, which are used in currently known compositions. Additionally, PEG-b-PLA micelles are easier to handle than DMSO and they do not possess a foul odor, which is a problem with formulations currently in clinical trials. Accordingly, the invention provides stable and biocompatible drug formulations that improve bioavailability without causing toxicity. It was also found that larger doses of individual drugs in micelle formulations can be administered compared to non-micelle formulations.

Claims

1. A composition comprising micelles encapsulating three drugs, wherein

the three drugs are non-covalently encapsulated in the interior of the micelles;

the micelles comprise poly(ethylene glycol)-block-poly(lactic acid) polymers where the hydrophobic poly(lactic acid) block of the polymers orient toward the interior of each micelle, and the hydrophilic poly(ethylene glycol) block of the polymers orient toward the exterior of each micelle;

a first drug of the three drugs encapsulated in the micelles is geldanamycin or 17-DMAG;

a second drug of the three drugs encapsulated in the micelles is paclitaxel or docetaxel;

a third drug of the three drugs encapsulated in the micelles is rapamycin, deforolimus, temsirolimus, everolimus, etoposide, or teniposide;

the drug loading of the micelles is about 1 wt. % to about 50 wt. % with respect to the mass of the micelles; and

the composition is substantially free of ethanol, dimethyl sulfoxide, castor oil, and castor oil derivatives.

2. The composition of claim 1 wherein the combined drug loading in the micelles is about 10 wt. % to about 40 wt. %.

3. The composition of claim 1 further comprising an aqueous vehicle, wherein the concentration of the drugs is about 0.6 mg/mL to about 40 mg/mL, with respect to the volume of the aqueous vehicle.

4. The composition of claim 1 wherein the encapsulated drugs have an aqueous solubility of about 1 mg/mL to about 20 mg/mL when contacted with an aqueous environment.

5. The composition of claim 1 wherein the composition comprises less than about 2 wt. % of ethanol, dimethyl sulfoxide, castor oil, and castor oil derivatives.

6. The composition of claim 1 wherein the molecular weight of the poly(ethylene glycol) block is about 1,000 to about 35,000 g/mol and the molecular weight of the poly(lactic acid) block is about 1,000 to about 15,000 g/mol.

7. The composition of claim 6 wherein the molecular weight of the poly(ethylene glycol) block is about 1,500 to about 14,000 g/mol, the molecular weight of the poly(lactic acid) block is about 1,500 to about 7,000 g/mol.

8. The composition of claim 1 wherein the average diameter of the micelles is about 30 nm to about 50 nm.

9. The composition of claim 1 wherein each of the drugs are incorporated together into individual PEG-PLA micelles.

10. The composition of claim 1 wherein the each drug is incorporated separately into PEG-PLA micelles and the micelles are combined in a single aqueous vehicle.

11. A composition for the delayed release of a three drug combination comprising a composition of claim 1 and an aqueous carrier, wherein less than 50 wt. % of the drugs are released from the micelles after exposure to an aqueous environment or to the body fluid of a mammal for about two hours.

12. A pharmaceutical composition comprising the composition of claim 1 and an aqueous carrier, wherein the composition is formulated for intravenous or intraperitoneal administration and the aqueous carrier comprises saline or an aqueous carbohydrate solution.

13. A method of inhibiting or killing cancer cells comprising contacting the cells with an effective inhibitory or lethal amount of a composition of claim 1.

14. The method of claim 13 wherein the contacting is in vivo.

15. The method of claim 13 wherein the contacting is in vitro.

16. The method of claim 13 wherein the cancer cells are brain tumor cells, breast cancer cells, colon cancer cells, head and neck cancer cells, lung cancer cells, lymphoma cells, melanoma cells, neuroblastoma cells, ovarian cancer cells, pancreatic cancer cells, prostate cancer cells, or leukemia cells.

17. The method of claim 13 wherein the cancer cells are breast cancer cells.

18. The method of claim 13 wherein the cancer cells are lung cancer cells.

19. A composition comprising micelles encapsulating three drugs, wherein the micelles are poly(ethylene glycol)-block-poly(lactic acid) polymers;

the hydrophobic poly(lactic acid) block of the polymers orient toward the interior of each micelle, and the hydrophilic poly(ethylene glycol) block of the polymers orient toward the exterior of each micelle;

a first drug of the three drugs encapsulated in the micelles is geldanamycin or 17-DMAG;

a second drug of the three drugs encapsulated in the micelles is paclitaxel;

a third drug of the three drugs encapsulated in the micelles is rapamycin, deforolimus, temsirolimus, everolimus, etoposide, or teniposide;

the drug loading of the micelles is about 5 wt. % to about 50 wt. % with respect to the mass of the micelles;

the composition comprises less than about 1 wt. % of ethanol, dimethyl sulfoxide, castor oil, and castor oil derivatives.

20. A composition comprising micelles encapsulating three drugs, wherein the micelles are poly(ethylene glycol)-block-poly(lactic acid) polymers;

the hydrophobic poly(lactic acid) block of the polymers orient toward the interior of each micelle, and the hydrophilic poly(ethylene glycol) block of the polymers orient toward the exterior of each micelle;

a first drug of the three drugs encapsulated in the micelles is geldanamycin or 17-DMAG;

a second drug of the three drugs encapsulated in the micelles is docetaxel;

a third drug of the three drugs encapsulated in the micelles is rapamycin, deforolimus, temsirolimus, everolimus, etoposide, or teniposide;

the drug loading of the micelles is about 5 wt. % to about 50 wt. % with respect to the mass of the micelles;

the composition comprises less than about 1 wt. % of ethanol, dimethyl sulfoxide, castor oil, and castor oil derivatives.

21. A composition comprising micelles encapsulating three drugs,

wherein the micelles are poly(ethylene glycol)-block-poly(lactic acid) polymers;

the hydrophobic poly(lactic acid) block of the polymers orient toward the interior of each micelle, and the hydrophilic poly(ethylene glycol) block of the polymers orient toward the exterior of each micelle;

a first drug of the three drugs encapsulated in the micelles is geldanamycin or 17-DMAG;

a second drug of the three drugs encapsulated in the micelles is paclitaxel or docetaxel;

a third drug of the three drugs encapsulated in the micelles is rapamycin, or etoposide;

the drug loading of the micelles is about 5 wt. % to about 50 wt. % with respect to the mass of the micelles;

the composition comprises less than about 1 wt. % of ethanol, dimethyl sulfoxide, castor oil, and castor oil derivatives.