Polymeric micelle compositions

Details Polymeric micelle compositions Polymeric micelle compositions

2000-06-29

2002-01-15

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S426000, C514S772300

Reexamination Certificate

active

06338859

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to compositions comprising polymeric micelles which are useful for delivery of therapeutic agents, including, but not limited to, anticancer drugs.
2. BACKGROUND OF THE INVENTION
A major obstacle associated with the use of chemotherapeutic agents is the lack of selectivity toward cancerous cells. This lack of selectivity has been linked to the toxic side effects of the use of such agents due to their delivery to both normal and abnormal cells. Lack of selectivity of drugs towards target cells is also a problem in the treatment of a variety of disorders in addition to cancer. Much research effort has focused on development of carriers for drugs that can selectively deliver the drug to target cells. For example, in order to improve the specific delivery of drugs with a low therapeutic index, several drug carriers such as liposomes, microparticles, nano-associates and drug-polymer conjugates have been studied.
Of the targeting devices studied liposomes (phospholipid vesicles) have attracted considerable attention. Their targeting efficacy is, however, limited by quick scavenging by reticuloendothelial (RE) cells of the liver and spleen, instability in the plasma, limited capability at extravasation due to size, technical problems with their production and susceptibility to oxidation. Solutions to individual problems have been found, but solutions to more than one problem have rarely been combined in a single composition. For example, if recognition by RE cells is reduced and stability improved, it is difficult to obtain stable liposomes having a diameter of less than 50 nm.
Polymeric micelles were first proposed as drug carriers by Bader, H. et al. in 1984. Angew. Makromol. Chem. 123/124 (1984) 457-485. Polymeric micelles have been the object of growing scientific attention, and have emerged as a potential carrier for drugs having poor water solubility because they can solubilize those drugs in their inner core and they offer attractive characteristics such as a generally small size (<100 nm) and a propensity to evade scavenging by the reticuloendothelial system (RES).
Micelles are often compared to naturally occurring carriers such as viruses or lipoproteins. All three of these carriers demonstrate a similar core-shell structure that allows for their contents to be protected during transportation to the target cell, whether it is DNA for viruses or water-insoluble drugs for lipoproteins and micelles.
Lipoproteins were proposed as a vehicle for the targeting of antitumor compounds to cancer cells because tumors express an enhanced need for low density lipoproteins. The efficiency of lipoproteins as carriers has been questioned, however, mainly because drug-incorporated lipoproteins would also be recognized by healthy cells and because they would have to compete with natural lipoproteins for receptor sites on tumors. Conversely, viral carriers are mainly used for the delivery of genetic material and may have optimal use in applications that do not require repeated application of the delivery vehicle, since they are likely to elicit an immune response.
Polymeric micelles seem to be one of the most advantageous carriers for the delivery of water-insoluble drugs. Polymeric micelles are characterized by a core-shell structure. Pharmaceutical research on polymeric micelles has been mainly focused on copolymers having an A-B diblock structure with A, the hydrophilic shell moieties and B the hydrophobic core polymers, respectively. Multiblock copolymers such as poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO) (A-B-A) can also self-organize into micelles, and have been described as potential drug carriers. Kabanov, A.V. et al., FEBS Lett. 258 (1989) 343-345. The hydrophobic core which generally consists of a biodegradable polymer such as a poly(&bgr;-benzyl-L-aspartate) (PBLA), poly (DL-lactic acid) (PDLLA) or poly (&egr;-caprolactone) (PCL), serves as a reservoir for an insoluble drug, protecting it from contact with the aqueous environment. The core may also consist of a water-soluble polymer, such as poly(aspartic acid) (P(Asp)), which is rendered hydrophobic by the chemical conjugation of a hydrophobic drug, or is formed through the association of two oppositely charged polyions (polyion complex micelles). Several studies describe the use of non- or poorly biodegradable polymers such as polystyrene (Pst) or poly(methyl methacrylate) (PMMA) as constituents of the inner core. See, e.g., Zhao, C. L. et al., Langmuir 6 (1990) 514-516; Zhang, L. et al., Science 268 (1995) 1728-1731 and Inoue, T. et al., J. Controlled Release 51 (1998) 221-229. In order to be considered as clinically relevant drug carriers, non-biodegradable polymers must be non-toxic and have a molecular weight sufficiently low to be excreted via the renal route. The hydrophobic inner core can also consist of a highly hydrophobic small chain such as an alkyl chain or a diacyllipid such as distearoyl phosphatidyl ethanolamine (DSPE). The hydrophobic chain can be either attached to one end of a polymer, or randomly distributed within the polymeric structure.
The shell is responsible for micelle stabilization and interactions with plasmatic proteins and cell membranes. It usually consists of chains of hydrophilic, non-biodegradable, biocompatible polymers such as PEO. The biodistribution of the carrier is mainly dictated by the nature of the hydrophilic shell. Other polymers such as poly(N-isopropylacrylamide (PNIPA) and poly(alkylacrylic acid) impart temperature or pH sensitivity to the micelles, and could eventually be used to confer bioadhesive properties. Micelles presenting functional groups at their surface for conjugation with a targeting moiety are also known. See, e.g., Scholz, C. et al., Macromolecules 28 (1995) 7295-7297.
Poly(N-vinyl-2-pyrrolidone) (PVP) is a well-known water-soluble, biocompatible, amphiphilic polymer with the highly polar lactam group surrounded by apolar methylene groups in the backbone and methine a group in the ring. PVP is conventionally used as a steric stabilizer for the synthesis of polystyrene latexes. See, e.g., Gabaston, L. I. et al., Macromolecules 31 (1998) 2883-2888; Rutt, J. S. et al., J. Polym. Sci.: Part A: Polym. Chem., 32 (1994) 2505-2515. PVP may be also used as a cryoprotectant and a lyoprotectant. See, e.g. Skaer, H. B. et al., J. Microsc. 110 (1977) 257-270; Townsend, M. W. et al., J. Parenter. Sci. Technol., 42 (1988) 190-199.
In comparison with PEG, PVP is remarkable for the diversity of interactions it shows towards non-ionic and ionic cosolutes. See, Molyneux, P., Proc. Int. Symp. Povidone (1983) 1-19. Binding takes place most markedly with molecules having long alkyl chains or aromatic moieties. Similarly to PEG, PVP can also increase the in vivo circulation time of colloidal carriers and peptides/proteins. See, e.g., Kamada, H. et al., Biochem. Biophys. Res. Commun. 257 (1999) 448-453; Torchilin, V. P., J. Microencapsulation 15 (1998) 1-19. Further it has also been shown that nanoparticles containing diblock copolymers of poly(D,L-lactic acid) and poly (ethylene glycol) (PEG) aggregate after freeze drying. See, De Jaeghere, F. et al., Pharm. Res. 16 (1999) 859-866. This problem was circumvented by the use of a lyoprotectant. This problem would be obviated by use of PVP since the PVP is itself a lyoprotectant.
N-vinyl pyrrolidone (VP) can be copolymerized with a wide variety of vinyl monomers. With electronegative monomers, it forms alternating copolymers, whereas with acrylates, it forms random copolymers. For instance, a graft copolymer composed of poly(L-lactide) (PLLA) and PVP Has been prepared. See, Eguiburu, J. L., et al., J. San Roman, Polymer 37 (1996) 3615-3622. In this study, a PLLA macromonomer was copolymerized with VP, but the formation of polymeric micelles was not assessed.
Until now, most studies dealing with the preparation of biodegradable polymeric micelles have been focused on the utilization of PEG for the formation of the hydrophilic shell. See, e.g., X. Zhan

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