United States Patent:   6,093,391

Assignee:  Supratek Pharma, Inc. (Montreal, CA)

Filed:  February 27, 1998

Compositions of peptides and block copolymers and methods of treatment using the same. The compositions enhance the activity of peptide-based and related biological agents, and reduce adverse side effects.

SUMMARY OF THE INVENTION

It has now been found that the activity of peptide-based and related biological agents can be enhanced, and adverse side effects reduced, by the administration of such peptides in conjunction with a block copolymer.

In one embodiment, the invention provides a pharmaceutical composition comprising:

(a) a biological agent;

(b) a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which have molecular weight contributions between about 30 and about 500, wherein at least about 80% of the linkages joining the repeating units for each of the polymeric segments comprise an ether linkage; and

(c) a targeting moiety coupled to a lipophilic moiety comprising a hydrocarbon having from about 3 to about 41 carbon atoms, more preferably a hydrocarbon having from about 5 to about 25 carbon atoms, and more preferably, a hydrocarbon having from about 9 to about 17 carbon atoms.

The invention thus relates to pharmaceutical compositions comprising a biological agent and a poly(oxyethylene)-poly(oxypropylene) block copolymer. Preferred compositions include those wherein the poly(oxypropylene) [i.e., hydrophobe] portion of said block copolymer comprises at least 50% by weight of the block copolymer. Also preferred are compositions wherein the hydrophobe molecular weight of the block copolymer is at least about 900, and more preferably at least about 1700. Especially preferred are compositions wherein the hydrophobe molecular weight of the polyether block copolymer is at least about 2000 and the hydrophobe weight percentage is at least about 20%. The invention also relates to methods of treatment using the same.

Also preferred are compositions wherein the block copolymers have a critical micellar concentration ("CMC") of about 0.5% wt/vol or less at 37^oC. in an isotonic aqueous solution.

Additionally preferred are compositions wherein the biological agent is a peptide, or derivative thereof. This includes oligopeptides, polypeptide, proteins, enzymes, hormones, or cytokines.

In yet another preferred embodiment, the polyether block copolymer is selected from the group consisting of polymers of formulas:

A--B--A', A--B, B--A--B', or L(R')(R²) (R³) (R⁴)

(I) (II) (III) (IV)

wherein A and A' are A-type linear polymeric segments, B and B' are B-type linear polymeric segments, and R¹, R², R³ and R⁴ are either block copolymers of formulas (I), (II) or (III) or hydrogen and L is a linking group, with the proviso that no more than two of R¹, R², R³ or R⁴ are hydrogen.

In a preferred embodiment, the composition is adapted to include micelles composed of the block copolymer or to form micelles composed of the block copolymers during the course of administration or subsequent thereto. Preferably, at least about 0.1% of the biological agent is incorporated in the micelles, more preferably, at least about 1% of the biological agent, yet more preferably, at least about 5% of the biological agent.

In a preferred embodiment, the hydrophobe percentage of the copolymer of the composition is at least about 50% more preferably, at least about 60%, yet more preferably 70%.

In another preferred embodiment, the hydrophobe weight of the copolymer is at least about 900, more preferably, at least about 1700, yet more preferably at least about 2000, still more preferably at least about 2300.

In further preferred embodiments, the hydrophobe weight is at least about 2000 and the hydrophobe percentage is at least about 20%, preferably 35%; or the hydrophobe weight is at least about 2300 and the hydrophobe percentage is at least about 20%, preferably 35%.

In yet another preferred embodiment, the copolymer or copolymers of the composition have a critical micellar concentration ("CMC") of no more than about 0.5% wt/vol at 37^oC. in an isotonic aqueous solution, preferably, no more than about 0.05% wt/vol., more preferably, no more than about 0.01% wt/vol., yet more preferably, no more than about 0.003% wt/vol.

Preferably, the copolymers of the composition conform to Formula (V), which is set forth in the text below. Particularly preferred among these copolymers are those having hydrophobe weights between about 1500 and about 2000, preferably between about 1710 and about 1780, and hydrophobe percentages between about 85% and about 95%, preferably between about 88% and about 92%. Also particularly preferred among these copolymers are those having hydrophobe weights between about 3000 and about 3500, preferably between about 3200 and about 3300, and hydrophobe percentages between about 15% and about 25%, preferably between about 18% and about 22%. Additionally particularly preferred among these polymers are that having hydrophobe weights between about 3500 and about 4000, preferably between about 3700 and about 3800, and hydrophobe percentages between about 25% and about 35%, preferably between about 28% and about 32%.

In a preferred embodiment, the biological agent of the composition is an agent that affects the function of the brain or treats or prevents a disease of the brain.

In a second embodiment, the invention provides a pharmaceutical composition comprising a biological agent solubilized in polymeric micelles having associated therewith a targeting moiety coupled to a lipophilic moiety comprising hydrocarbon having from about 3 to about 41 carbon atoms, more preferably a hydrocarbon having from about 5 to about 25 carbon atoms, yet more preferably, a hydrocarbon having from about 9 to about 17 carbon atoms.

In another embodiment, the invention provides a method of targeting a biological agent to a pre-selected tissue. The method comprises administering the composition described above, wherein the targeting moiety is selected to target the tissue, to an animal having the pre-selected tissue.

In yet another embodiment, the invention provides a method of treating a microbial disease or a tumor of the brain by administering a composition comprising:

(a) a chemotherapeutic agent; and

(b) a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about 0.4 or less and have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which contribute an average Hansch-Leo fragmental constant of about -0.4 or more and have molecular weight contributions between about 30 and about 500, wherein at least about 80% of the linkages joining the repeating units for each of the polymeric segments comprise an ether linkage. In a preferred embodiment, the composition used in this embodiment will include a targeting molecule.

In yet another embodiment, the present invention relates to a composition comprising a poly(oxyethylene)-poly(oxypropylene) block copolymer and a protein, peptide, or derivative thereof covalently modified with a hydrophobe. The preferred block copolymers are of the formula: 

in which x, y, z, i, and j have values from about 2 to about 400, and wherein for each R¹, R² pair, one is hydrogen and the other is a methyl group.

In another preferred embodiment, the block copolymer is of the formula: 

wherein for each R¹, R² pair, one is hydrogen and the other is a methyl group. Preferred are those block copolymers wherein the ethylene(oxide) content of said block copolymer is less than 50%.

The invention also relates to a composition comprising a protein, peptide, or derivative thereof, and a POE-POP block copolymer of the formula: 

in which x, y, and z have values from about 2 to about 400.

In yet another preferred embodiment, the invention relates to compositions comprising at least one block copolymer with an ethylene(oxide) content of 50% or less, and at least one block copolymer with ethylene(oxide) content of 50% or more.

Preferred hydrophobes include lipids, and fatty acid residues.

Preferred protein, peptide, or derivatives are those with a molecular weight of at least about 1,000 Daltons, more preferably at least about 5,000 Daltons, even more preferably at least about 10,000 Daltons.

Preferred proteins, peptides, or derivatives thereof include immunomodulators, cytokines, hormones, enzymes, tissue plasminogen activators, clotting factors, colony stimulating factors, neuropeptides (or derivative thereof), recombinant soluble receptors, monoclonal antibodies, and erythropoetins.

Preferred hormones include human growth hormone.

The invention also relates to methods of treatment comprising administering to a patient the above poly(oxyethylene)-poly(oxypropylene) block copolymers and a protein, peptide or derivative thereof, covalently modified with a hydrophobe.

Claim 1 of 27 Claims

1. A composition comprising a mixture of poly(oxyethylene)-poly(oxypropylene) (POE-POP) block copolymers and a protein, peptide or derivative thereof wherein the mixture comprises at least one block copolymer with ethylene(oxide) content of 50% or less, and at least one block copolymer with ethylene(oxide) content of 50% or more.

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