Compositions for treatment with glucagon-like peptide, and methods of making and using the same - Patents

Compositions for treatment with glucagon-like peptide, and methods of making and using the same

Agent: Foley Hoag, LLP Patent Group, World Trade Center West - Boston, MA, US
Inventor: Elijah M. Bolotin
Class: 424450000 (USPTO)
#20050260259
11/24/05
SUMMARY OF INVENTION
[0012] In part, the present invention is directed to the use of metal bridges to connect a carrier and GLP-1. In certain instances, the subject compositions provide a means of achieving sustained release of the active agent after administration to a patient. In certain instances, the release may be designed to be other than sustained. As used herein, a "metal bridge" comprises the metal binding domain (MBD) of the carrier, the MBD of the active agent, and the metal that is chelated to both of them. It may be the case that the metal bridge may comprise more than a single metal ion (i.e., multiple metal ions) with bridging ligands, provided that the MBDs of the carrier and active agent are capable of being connected through the metal ions and bridging ligand. It may be in the case of GLP-1 that an MBD is not necessary.
[0013] In part, the present invention is directed to a drug delivery system involving a polymeric carrier to which a drug may associate via a metal ion. It has been observed that polymeric carriers bearing chelated metal ion can bind biologically active peptides and proteins in the absence or presence of plasma proteins. The subject compositions, and methods of making and using the same, may achieve a number of desirable results and features, one or more of which (if any) may be present in any particular embodiment of the present invention: 1) protecting peptides and proteins and other associated drugs from the interaction with other macromolecules and cells; 2) decreasing undesirable immunogenicity of the carrier or peptide/protein/drug; 3) prolonging biological half-life of peptides and proteins and drugs in vivo (e.g. for decreasing glomerular filtration in kidneys, decreasing kidney and liver uptake, decreasing macrophage uptake etc); 4) stabilizing peptides/proteins/drugs by complexation with metal ion and carrier. One potential advantage of the metal binding domain of the present invention is to afford labile binding with peptides and proteins and other drugs which are capable of forming coordination bonds with metal ions (e.g., Zn and Ni). In many instances, coordinate bonding affords reversible dissociation of the peptide or protein or drug from the polymeric carrier. It may be possible to affect the dissociation rate by modulating with competitive ligands for the metal ion, such as imidazole or nitrilotriacetic acid (NTA).
[0014] In certain embodiments, the present invention may not require the use of a MBD with GLP-1, in so much as certain carriers associate with GLP-1 in the absence of a MBD.
[0015] In certain embodiments, the present invention relates to a biocompatible composition comprising: (i) a carrier with a metal binding domain (MBD); (ii) a metal ion chelated to the MBD; and (iii) an active agent with a MBD chelated to the metal ion, wherein after administration of the composition to a patient, the active agent is released in a sustained manner. It is understood that not all of the active agents in a sample of the composition will necessarily be attached to the carrier through the metal ion, but that some portion of the active agent may be combined with the carrier. Likewise, it is understood that not all of the metal binding domains attached to the carrier will chelate a metal ion, and that not all of the metal ions bound to a metal binding domain will form a coordinate bond with an active agent.
[0016] In a further embodiment, the present invention relates to the composition described above wherein the carrier is one of the following: polymer, micelle, reverse micelle, liposome, emulsion, hydrogel, microparticle, nanoparticle, microsphere, colloid or solid surface. In a further embodiment, the carrier is a biocompatible polymer. In a further embodiment, the carrier is a polymer having a molecular weight ranging from about 100 to about 1,000,000 daltons. In a further embodiment, the carrier is a polymer having a molecular weight ranging from about 10,000 to about 250,000 daltons. In a further embodiment, the carrier comprises a poly amino acid. In a further embodiment, the carrier comprises poly-lysine.
[0017] In a further embodiment, the present invention relates to the above described composition wherein the carrier comprises protective side chains. In a further embodiment, the protective side chain comprises poly(ethylene glycol). In a further embodiment, the protective side chain comprises alkoxy poly(ethylene glycol). In a further embodiment, the protective side chain comprises methoxy poly(ethylene glycol) (MPEG).
[0018] In a further embodiment, the present invention relates to the above described composition wherein the metal binding domain comprises a nitrogen containing poly carboxylic acid. In a further embodiment, the metal binding domain comprises one or more of the following moieties: N-(hydroxy-ethyl)ethylenediaminetriacetic acid; nitrilotriacetic acid (NTA); ethylene-bis(oxyethylene-nitrilo)tetraacetic acid; 1,4,7,10-tetraazacyclodo-decane-N,N',N",N'"-tetraacetic acid; 1,4,7,10-tetraaza-cyclododecane-N,N',N"-triacetic acid; 1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7,10-tetraarocyclodec- ane; 1,4,7-triazacyclonane-N,N',N"-triacetic acid; 1,4,8,11-tetraazacyclot- etra-decane-N,N',N",N'"-tetraacetic acid; diethylenetriamine-pentaacetic acid (DTPA); ethylenedicysteine; bis(aminoethanethiol)carboxylic acid; triethylenetetraamine-hexaacetic acid; ethylenediamine-tetraacetic acid (EDTA); 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; or polypeptide. In a further embodiment, the polypeptide in the metal binding domain has the formula: (AxHy)p where A is any amino acid residue, H is histidine, x is an integer from 0-6; y is an integer from 1-6; and p is an integer from 1-6.
[0019] In a further embodiment, the present invention relates to the above described composition wherein the metal ion is a transition metal ion. In a further embodiment, the metal ion is one or more of the following: Zn.sup.2+, Ni.sup.2+, Co.sup.2+, Fe.sup.2+, Mn.sup.2+, or Cu.sup.2+.
[0020] In a further embodiment, the present invention relates to the above described composition wherein the active agent is one of the following: a diagnostic, targeting moiety, or therapeutic agent. In a further embodiment, the present invention relates to the above described composition wherein more than one type of active agent forms a coordinate bond with the metal binding domain of the polymeric carrier. In a further embodiment, the active agent is a therapeutic agent comprising a protein, peptide, peptidomimetic, deoxyribonucleic acid, ribonucleic acid, oligonucleotide, other nucleic acid, oligosaccharide, antibody or proteoglycan.
[0021] In a further embodiment, the present invention relates to the above described composition wherein the carrier comprises poly-L-lysine, the protective side chain comprises MPEG, the metal binding domain comprises NTA, the metal ion is Ni.sup.2+, and the active agent is GLP-1.
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