Polymeric micelles for drug delivery

• US 20060240092A1
• Filed: 04/03/2006
• Published: 10/26/2006
• Est. Priority Date: 04/01/2005
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin N., Breitenkamp, Rebecca
• Granted Patent: US 7,638,558 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• 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 micelle comprising a multiblock copolymer which comprises a polymeric hydrophilic block, a crosslinked poly(amino acid block), and a poly(amino acid block), characterized in that said micelle has an inner core, a crosslinked outer core, and a hydrophilic shell.

2. The micelle according to claim 1, wherein the multiblock copolymer is of formula II:

3. The micelle according to claim 2, wherein R³ is an optionally substituted aliphatic group.

4. The micelle according to claim 3, wherein R³ is an aliphatic group substituted with one or more of CN, N₃, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, N-methyl propiolamido, N-methyl-4-acetylenylanilino, N-methyl-4-acetylenylbenzoamido, bis-(4-ethynylbenzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, N-methyl-propargylamino, N-methyl-hex-5-ynyl-amino, N-methyl-pent-4-ynyl-amino, N-methyl-but-3-ynyl-amino, 2-hex-5-ynyldisulfanyl, 2-pent-4-ynyldisulfanyl, 2-but-3-ynyldisulfanyl, or 2-propargyldisulfanyl.

5. The micelle according to claim 2, wherein R³ is an optionally substituted aryl group.

6. The micelle according to claim 5, wherein R³ is phenyl or pyridyl substituted with one or more of CN, N₃, NO₂, —

CH₃, —

CH₂N₃, —

CH═

CH₂, —

C≡

CH, Br, I, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

7. The micelle according to claim 2, wherein R³ is a group suitable for Click chemistry.

8. The micelle according to claim 2, wherein Q is a valence bond.

9. The micelle according to claim 2, wherein Q is a bivalent, saturated C_1-12 alkylene chain, wherein 0-6 methylene units of Q are independently replaced by -Cy-, —

O—

, —

NH—

, —

S—

, —

OC(O)—

, —

C(O)O—

, or —

C(O)—

, wherein -Cy- is an optionally substituted 5-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfuer.

10. The micelle according to claim 2, wherein R^x a crosslinked natural or unnatural amino acid side-chain group selected from a a glutamic acid side-chain, an aspartic acid side-chain, a cystein side-chain, a serine side-chain, an aldehyde containing side-chain, a lysine side-chain, an arginine side-chain, or a histidine side-chain.

11. The micelle according to claim 2, wherein R^y is a hydrophobic amino acid side-chain selected from a suitably protected tyrosine side-chain, a suitably protected serine side-chain, a suitably protected threonine side-chain, a phenylalanine side-chain, an alanine side-chain, a valine side-chain, a leucine side-chain, a tryptophan side-chain, a proline side-chain, or a mixture thereof.

12. The micelle according to claim 2, wherein R^y is an ionic amino acid side chain group selected from a lysine side-chain, arginine side-chain, or a suitably protected lysine or arginine side-chain, an aspartic acid side chain, a glutamic acid side-chain, or a suitably protected aspartic acid or glutamic acid side-chain.

13. The micelle according to claim 2, wherein R^y comprises a mixture of hydrophobic and hydrophilic amino acid side-chain groups such that the overall poly(amino acid) block comprising R^y is hydrophobic.

14. The micelle according to claim 2, wherein R^2a is —

NHR⁴ or —

N(R⁴)₂, wherein each R⁴ is an optionally substituted aliphatic group.

15. The micelle according to claim 14, wherein R^2a is —

NHR⁴ or —

N(R⁴)₂, wherein each R⁴ is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-(tetrahydropyran-2-yloxy)ethyl, pyridin-2-yldisulfanylmethyl, methyldisulfanylmethyl, (4-acetylenylphenyl)methyl, 3-(methoxycarbonyl)-prop-2-ynyl, methoxycarbonylmethyl, 2-(N-methyl-N-(4-acetylenylphenyl)carbonylamino)-ethyl, 2-phthalimidoethyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-iodobenzyl, 4-propargyloxybenzyl, 2-nitrobenzyl, 4-(bis-4-acetylenylbenzyl)aminomethyl benzyl, 4-propargyloxy-benzyl, 4-dipropargylamino-benzyl, 4-(2-propargyloxy-ethyldisulfanyl)benzyl, 2-propargyloxy-ethyl, 2-propargyldisulfanyl-ethyl, 4-propargyloxy-butyl, 2-(N-methyl-N-propargylamino)ethyl, 2-(2-dipropargylaminoethoxy)-ethyl, vinyl, allyl, crotyl, 2-propenyl, but-3-enyl, —

CH₂CN, —

CH₂CH₂CN, —

CH₂CH(OCH₃)₂, 4-(bisbenzyloxymethyl)phenylmethyl, —

CC≡

CH, —

CH₂C≡

CH, —

CH₂C≡

CCH₃, or —

CH₂CH₂C≡

CH.

16. The micelle according to claim 1, wherein said multiblock copolymer is selected from the following compounds of the formula:

17. The micelle according to claim 1, wherein said multiblock copolymer is selected from the following compounds of the formula:

18. The micelle according to claim 1, wherein said multiblock copolymer is selected from the compounds of the formula:

19. The micelle according to claim 1, wherein said multiblock copolymer is selected from the following compounds of the formula:

20. A crosslinked multiblock copolymer of formula III:

21. The copolymer of claim 20, wherein L is a metal crosslinked amino acid side-chain group, a hydrazone crosslinked amino acid side-chain group, an ester crosslinked amino acid side-chain group, an amide crosslinked side-chain group, an imine crosslinked side-chain group, or a disulfide crosslinked side-chain group.

22. The copolymer of claim 21, wherein L is a bivalent, saturated or unsaturated, straight or branched C_1-12 alkylene chain wherein 2 methylene units of L are independently replaced by —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

S—

, —

C(O)O—

, —

OC(O)—

, —

C(O)NHN—

, -═

NNHC(O)—

, -═

N—

, —

N═

-, -M-OC(O)—

, or —

C(O)O-M-.

23. The copolymer of claim 20, wherein R^2a is selected from:

24. A drug-loaded micelle comprising a multiblock copolymer which comprises a polymeric hydrophilic block, a crosslinked poly(amino acid block), and a poly(amino acid block), characterized in that said rhicelle has a drug-loaded inner core, a crosslinked outer core, and a hydrophilic shell.

25. The drug-loaded micelle according to claim 24, wherein the multiblock copolymer is of formula III:

26. The drug-loaded micelle according to claim 25, wherein L is a metal crosslinked amino acid side-chain group, a hydrazone crosslinked amino acid side-chain group, an ester crosslinked amino acid side-chain group, an amide crosslinked side-chain group, an imine crosslinked side-chain group, or a disulfide crosslinked side-chain group.

27. The drug-loaded micelle according to claim 25, wherein L is a bivalent, saturated or unsaturated, straight or branched C_1-12 alkylene chain wherein 2 methylene units of L are independently replaced by —

C(O)—

, —

C(O)NH—

, —

NHC(O)—

, —

S—

, —

C(O)O—

, —

OC(O)—

, —

C(O)NHN—

, -═

NNHC(O)—

, -═

N—

, —

N═

-, -M-OC(O)—

, or —

C(O)O-M-.

28. The drug-loaded micelle according to claim 24, wherein said micelle is a mixed micelle.

29. The drug-loaded micelle according to claim 25, wherein R¹ is conjugated to a group selected from primany labels, dyes, proteins, oliogopeptides, antibodies, monosaccarides, oligosaccharides, vitamins, or other small biomolecules.

30. The drug-loaded micelle according to claim 25, wherein the micelle encapsulates a hydrophobic drug.

31. The drug-loaded micelle according to claim 25, wherein the hydrophobic drug is selected from analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β

-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolyptics, lipid regulating agents, anti-anginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opiod analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.

32. The drug-loaded micelle according to claim 25, wherein the hydrophobic drug is selected from acetretin, albendazole, albuterol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriene, calcitriol, camptothecin, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac, dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donezepil, efavirenz, eprosartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, fuirazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, topiramate, topotecan, toremitfene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, pharmaceutically acceptable salts, isomers, and derivatives thereof, and mixtures thereof.

33. The drug-loaded micelle according to claim 25, wherein the hydrophobic drug is an antiproliferative or chemotherapeutic drug.

34. The drug-loaded micelle according to claim 33, wherein the antiproliferative or chemotherapeutic drug is 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 (neutral), 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.

35. The drug-loaded micelle according to claim 25, wherein the micelle encapsulates an ionic drug.

36. The drug-loaded micelle according to claim 25, wherein the micelle encapsulates a DNA plasmid, a short interfering RNA (siRNA), a micro RNA (miRNA), a short hairpin RNA (shRNA), an antisense RNA, or other RNA-based therapeutic, an oligopeptide, a peptide, a monoclonal antibody, a cytokine, or other protein therapeutic.

37. A method for treating a cancer in a patient comprising adminsitering to said patient a drug-loaded micelle according to claim 33.