Stereocomplex polymeric carriers for drug delivery

Details Stereocomplex polymeric carriers for drug delivery Stereocomplex polymeric carriers for drug delivery

1999-01-14

2002-04-02

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S422000, C424S468000, C424S484000, C424S486000, C514S944000, C514S969000

Reexamination Certificate

active

06365173

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a carrier formed of stereocomplexes of polymers for delivery of bioactive or bioreactive molecules.
CROSS REFERENCE TO RELATED APPLICATION
Priority is claimed to Israeli patent application Serial No. 122933, filed on Jan. 14, 1998.
BACKGROUND OF THE INVENTION
Much research has focused on the development of materials which are biocompatible and degrade chemically or enzymatically in vivo to inert or normal metabolites of the body. The preferred material degrades completely in vivo so there is no need to remove the device at the end of treatment. Direct implantation of a drug loaded device is particularly useful for drugs that undergo first pass metabolism. Linear polyesters of lactide and glycolide have been used for more than three decades for a variety of medical applications, including delivery of drugs. Handbook of Biodegradable Polymers, A. Domb, J. Kost and D. Wiseman, Harwood and Brooks (1997). Extensive research has been devoted to the use of these polymers as carriers for controlled drug delivery of a wide range of bioactive agents for human and animal use. Injectable formulations containing microspheres of lactide/glycolide polymers have received the most attention in recent years.
Polymer characteristics are affected by the monomer types and composition, the polymer architecture, and the molecular weight. The crystallinity of the polymer, an important factor in polymer biodegradation, varies with the stereoregularity of the polymer. For example, racemic D,L poly(lactide) or poly(glycolide) is less crystalline than the D or L homopolymers. Poly(lactide) (PLA) and its copolymers having less than 50% glycolic acid content are soluble in common solvents such as chlorinated hydrocarbons, tetrahydrofuran, and ethyl acetate while poly(glycolide) (PGA) is insoluble in common solvents but is soluble in hexafluoroisopropanol.
PLA has wide applications in medicine because of its biocompatibility and degradability to nontoxic products. Micelles and particles of the AB block copolymer poly(lactide)-b-poly(ethyleneglycol) (PLA-b-PEG) have received attention for use in intravenous injectable delivery systems for extended and target drug release. Gref, R. et al., Protein Delivery-Physical Systems, L. M. Sanders and H. Hendren, Eds, Plenum Press, (1997); and Gref, R. et al., Advanced Drug Delivery Reviews, 16: 215-233 (1995). Similarly, U.S. Pat. No. 5,578,325 to Domb et al. teaches multiblock copolymers comprising a multifunctional compound covalently linked with one or more hydrophilic polymers and one or more hydrophobic bioerodible polymers and including at least three polymer blocks. A PEG-coating on a microparticle or other polymeric device prevents the adsorption of plasma proteins and fast elimination by the reticulo endothelial system (RES). Possible applications for this kind of pharmaceutical depot devices are the delivery of drugs with short half-lives, transport of contrast agents, chemotherapy, and gene therapy.
AB-block copolymers of poly(styrene)-b-poly(acrylic acid) (PS-b-PAA) produce vesicle type particles which can be isolated from solution. Zhang, L. et al., Science (1995) 268, 1728. The vesicles have diameters up to 1 micron, which is much larger than that of a single micelle. This is explained by the irreversible formation of the vesicles by the fusion of micelles. However, once the micelles are associated, the high Tg of poly(styrene) (PS) freezes the structure since the PS-blocks are no longer in equilibrium with the solvent and the structure is still stable after removing the solvent. Vesicular architecture of block copolymers would appear to offer future opportunities for pharmaceutical drug devices. Nevertheless, PS and PAA cannot be used as biodegradable carriers because they are stable and do not degrade in biological mediums.
There is still a great need for a safe and effective delivery systems for labile and/or large molecules such as bioactive peptides, proteins, plasmid genes and antisense molecules, to be delivered to specific targets (tissue, cells or nucleus). Present methods are ineffective and result in poor transfection yield and toxicity when the carrier is a polycation. The major problems in the delivery of peptide and proteins are due to their instability and fast release from the polymer matrix.
It would be advantageous to have better polymeric carriers for macromolecules such as peptides, proteins, and nucleic acids.
It is therefore an object of the present invention to provide novel polymer-bioactive compositions and formulations having desirable properties for controlled and/or sustained drug delivery.
It is a further object of the present invention to provide materials which can be formulated into nano- and micro-structures for use as carriers for controlled drug delivery.
It is still another object of the present invention to provide methods for use of these compositions in the selective and extended release administration of bioactive small molecules and macromolecules such as peptides, proteins, and polynucleotides (antisense and genes).
SUMMARY OF THE INVENTION
A polymeric carrier for delivery of bioactive or bioreactive molecules is provided, including a stereocomplex of one or more biocompatible polymers and having incorporated on or within the complex the molecules to be delivered. In a preferred embodiment, the biocompatible stereoselective polymers are linear or branched D-PLA homo- and block-polymers, linear or branched L-PLA homo- and block-polymers, copolymers thereof, or mixtures thereof, in stereocomplexed form. In one preferred embodiment the polymeric carrier is complexed with a complementary stereospecific bioactive molecule. In other embodiments, the bioactive, or bioreactive (for example, for use in diagnostic applications), is bound to the complex by ionic, hydrogen, or other non-covalent binding reactions not involving stereocomplexation, or is physically entrapped within the complex, either at the time of complex formation or when the polymeric material is formulated into particles, tablets, or other form for pharmaceutical application. Exemplary bioactive molecules include peptides, proteins, nucleotides, oligonucleotides, sugars, carbohydrates, and other synthetic or natural organic molecules, as well as stereoselective drugs of a molecular weight of 300 Dalton or higher.
Examples demonstrate preparation of stereocomplexes, as well as their use for controlled and/or sustained release.
DETAILED DESCRIPTION OF THE INVENTION
Stereocomplexation of macromolecules to biodegradable polymers is a new approach in the delivery of macromolecules. The interaction at the molecular level between the polymer carrier and the bioactive macromolecule provides stability, which allows for extended release and for easy access to the target cell or tissue with minimal toxicity.
The formation of stereocomplexes between enantiomorphic PLAs and blends has previously been investigated by Cramer, K. et al., Polymer Bulletin 35:457-464 (1995); Brizzolara, D. et al., J. Computer-Aided Meter. Design, 3:341-350 (1996); and Brizzolara, D. et al., Macromolecules, 29:191 (1996). Stereocomplexes including a racemic packing of enantiomorphic poly(L-lactide) [L-PLA] and poly(D-Lactide) [L-PLA] have a melting point 60° C. higher than chiral crystals with the packing of isomorphic PLA's. As a consequence of the different packing, the chiral and racemic single crystals exhibit different morphologies. The stereocomplex forms lamella triangular or rounded hedrite type crystals instead of lozenge shaped crystals.
In contrast, as described herein in the examples, PLA-b-PEG aggregates to supra molecular assemblies like flat or tubular rods of hundreds of nanometers wide and a few microns long. Powder-diffraction patterns indicate that the crystallization of both blocks are the driving force for the formation of the mesoscopic suprastructures. The crystallized blocks are not in equilibrium with the solvent for very long, which explains the stability of the structures after remov

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