Compositions comprising polymeric micelles for drug delivery

• US 8,299,128 B2
• Filed: 12/07/2010
• Issued: 10/30/2012
• Est. Priority Date: 04/01/2005
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Sill, Kevin N., Skaff, Habib, Breitenkamp, Kurt, Breitenkamp, Rebecca
• Primary Examiner(s): Dickinson, Paul
• Application Number:
  US12/962,052
• Publication Number:
  US 20110091534A1
• Time in Patent Office: 693 Days
• Field of Search: None
• US Class Current: 514/772.1
• 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 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• 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 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08G 69/40 Polyamides containing oxygen in the form of ether groups C08G69/12, C08G69/32 take precedence
• CPC Class Codes: C08G 73/028 Polyamidoamines
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same.

Claims

1. A composition comprising a drug-loaded micelle and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the micelle comprises a multiblock copolymer, wherein said micelle has a drug-loaded inner core, a non-crosslinked outer core, and a hydrophilic shell, wherein the multiblock copolymer is of formula I:

2. The composition according to claim 1, wherein the amino acid is aspartic acid or glutamic acid.

3. The composition according to claim 1, wherein the amino acid is histidine.

4. The composition according to claim 1, wherein said micelle is a mixed micelle.

5. The composition according to claim 1, wherein R¹ is

6. The composition according to claim 1, wherein R^2a is selected from the group consisting of:

7. The composition according to claim 1, wherein R^y is a hydrophobic amino acid side-chain selected from a phenylalanine side-chain, alanine side-chain, benzyl or alkyl glutamate side chain, a benzyl or alkyl aspartate side chain, or leucine side-chain, and optionally one or more of tyrosine side-chain, serine side-chain, threonine side-chain, glutamic acid, or aspartic acid such that the overall poly(amino acid) block is hydrophobic.

8. The composition according to claim 7, wherein R^y is a hydrophobic amino acid side-chain selected from a mixture of phenylalanine and tyrosine or a mixture of leucine and tyrosine, such that the overall poly(amino acid) block is hydrophobic.

9. The composition according to claim 1, wherein:

n is about 200 to about 300;

m is 5-25;

m′

is 10-50; and

R^2a is —

NHC(O)CH₃.

10. The composition according to claim 1, wherein the micelle encapsulates a hydrophobic chemotherapeutic drug selected from Abarelix, Aldesleukin, Aldesleukin, Alemtuzumab, Alitretinoin, Allopurinol, Altretamine, Amifostine, Anastrozole, Arsenic trioxide, Asparaginase, Azacitidine, BCG Live, Bevacuzimab, Avastin, Fluorouracil, Bexarotene, Bleomycin, Bortezomib, Busulfan, Calusterone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dactinomycin, Darbepoetin alfa, Daunorubicin, Denileukin, Dexrazoxane, Docetaxel, Doxorubicin, Doxorubicin hydrochloride, Dromostanolone Propionate, Epirubicin, Epoetin alfa, Erlotinib, Estramustine, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, floxuridine fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histrelin acetate, Hydroxyurea, Ibritumomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon alfa-2a, Interferon alfa-2b, Irinotecan, Lenalidomide, Letrozole, Leucovorin, Leuprolide Acetate, Levamisole, Lomustine, Megestrol Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxsalen, Mitomycin C, Mitotane, Mitoxantrone, Nandrolone, Nelarabine, Nofetumomab, Oprelvekin, Oxaliplatin, Paclitaxel, Palifermin, Pamidronate, Pegademase, Pegaspargase, Pegfilgrastim, Pemetrexed Disodium, Pentostatin, Pipobroman, Plicamycin, Porfimer Sodium, Procarbazine, Quinacrine, Rasburicase, Rituximab, Sargramostim, Sorafenib, Streptozocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testolactone, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, ATRA, Uracil Mustard, Valrubicin, Vinblastine, Vincristine, Vinorelbine, Zoledronate, or Zoledronic acid.

11. A method for treating a cancer in a patient comprising administering to said patient the composition according to claim 10.

12. The method according to claim 11, wherein the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin'"'"'s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia, wherein said micelle encapsulates a chemotherapeutic agent suitable for treating said cancer.

13. The composition according to claim 10, wherein the hydrophobic chemotherapeutic drug is Doxorubicin or Doxorubicin hydrochloride.

14. The composition according to claim 10, wherein the hydrophobic chemotherapeutic drug is Gemcitabine.

15. The composition according to claim 10, wherein the hydrophobic chemotherapeutic drug is Letrozole.

16. The composition according to claim 1, wherein the composition is formulated for parenteral administration to a patient.

17. The composition according to claim 16, wherein the composition is formulated for intravenous administration to a patient.

18. The composition according to claim 1, wherein the composition is formulated for oral administration to a patient.

19. The composition according to claim 18, wherein the composition is formulated for oral administration to a patient as a capsule, a tablet, an aqueous suspension or a solution.

20. The composition according to claim 1, wherein the micelle encapsulates a drug for treating Alzheimer'"'"'s disease, Parkinson'"'"'s disease, multiple sclerosis, asthma, schizophrenia, inflammation, an autoimmune disorder, cardiovascular disease, liver disease, a viral disorder, a blood disorder, or an immunodeficiency disorder.

21. The composition according to claim 20, wherein the micelle encapsulates a drug selected from Aricept®

, Excelon®

, L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, amantadine, beta interferon, Copaxone®

, mitoxantrone, a steroid, albuterol, Singulair®

, zyprexa, risperdal, seroquel, haloperidol, a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, sulfasalazine, cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, cyclophophamide, azathioprine, sulfasalazine, an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, a statin, cholestyramine, an anti-viral agent, an anti-leukemic agent, a growth factor, or gamma globulin.

22. The composition according to claim 18, wherein the micelle encapsulates a drug for treating Alzheimer'"'"'s disease, Parkinson'"'"'s disease, multiple sclerosis, asthma, schizophrenia, inflammation, an autoimmune disorder, cardiovascular disease, liver disease, a viral disorder, a blood disorder, or an immunodeficiency disorder.

23. The composition according to claim 22, wherein the micelle encapsulates a drug selected from Aricept®

, Excelon®

, L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, amantadine, beta interferon, Copaxone®

, mitoxantrone, a steroid, albuterol, Singulair®

, zyprexa, risperdal, seroquel, haloperidol, a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, sulfasalazine, cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, cyclophophamide, azathioprine, sulfasalazine, an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, a statin, cholestyramine, an anti-viral agent, an anti-leukemic agent, a growth factor, or gamma globulin.