Soluble Hydrophobic Core Carrier Compositions for Delivery of Therapeutic Agents, Methods of Making and Using the Same

• US 20090176892A1
• Filed: 01/09/2008
• Published: 07/09/2009
• Est. Priority Date: 01/09/2008
• Status: Abandoned Application

• Current Assignee: Pharmain Corporation
• Original Assignee: Pharmain Corporation
• Inventors: Bolotin, Elijah M., Castillo, Gerardo M.
• Application Number:
  US11/971,482
• Publication Number:
  US 20090176892A1
• Time in Patent Office: Days
• US Class Current: 514/773
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 17/02 Peptides being immobilised on, or in, an organic carrier

Abstract

The present invention relates to a soluble hydrophobic-core carrier composition comprising (i) a linear polymeric backbone; (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone and (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone. In certain embodiments, the weight ratio of hydrophilic protective chains to hydrophobic moieties in the carrier is at least 15:1. In other embodiments, at least 90% of the residues of the polymeric backbone are coupled to a hydrophilic polymeric protective chain or a hydrophobic moiety. In other embodiments, the composition further comprises (iv) a hydrophobic load molecule dissociably linked to the hydrophobic moiety of the carrier.

Claims

1. A soluble hydrophobic-core carrier composition comprising:

(i) a linear polymeric backbone;

(ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; and

(iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone;

wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water.

2. The composition of claim 1 wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is at least 15:

1, at least 17;

1, at least 20;

1, at least 50;

1 or at least 100;

1.

3. The composition of claim 1 wherein at least 90% of the residues of the polymeric backbone are derivatized with either hydrophilic protective chains or hydrophobic moieties.

4. The composition of claim 1, wherein the protective side chains comprise polyethylene glycol, polypropylene glycol, a co-polymer of polyethylene glycol, a co-polymer of polypropylene glycol, polysaccharide, or alkoxy derivatives thereof.

5. The composition in claim 4, wherein the alkoxy derivative is methoxypolyethylene glycol, methoxypolypropylene glycol, a methoxylated co-polymer polyethylene glycol and polypropyleneglycol, or ethoxylated polysaccharide.

6. The composition of claim 1, wherein the linear polymeric backbone is selected from a group consisting of polylysine, polyaspartic acid, polyglutamic acid, polyserine, polythreonine, polycysteine, polyglycerol, natural saccharides, aminated polysaccharides, aminated oligosaccharides, polyamidoamine, polyacrylic acids, polyalcohols, sulfonated polysaccharides, sulfonated oligosaccharides, carboxylated polysaccharides, carboxylated oligosaccharides, aminocarboxylated polysaccharides, aminocarboxylated oligosaccharides, carboxymethylated polysaccharides, and carboxymethylated oligosaccharides.

7. The composition of claim 1 further comprising:

(iv) a load molecule dissociably linked to the hydrophobic moiety of the backbone.

8. The composition of claim 7, wherein the hydrophilic protective side chains comprise methoxypolyethylene glycol.

9. The composition of claim 8, wherein the polymeric backbone comprises polylysine.

10. The composition of claim 9, wherein the hydrophobic moieties comprise a fatty acid.

11. The composition of claim 10, wherein the load molecule is a therapeutic agent.

12. The composition of claim 11, wherein the therapeutic agent is a hydrophobic peptide, hydrophobic protein, or a hydrophobic drug.

13. The composition of claim 11, wherein the therapeutic agent is GLP-1.

14. The composition of claim 11, wherein the therapeutic agent is selected from GLP-2, leptin, islet amyloid polypeptide and vasoactive intestinal peptide.

15. The composition of claim 7, wherein the linear polymeric backbone is polylysine.

16. The composition of claim 7, wherein the hydrophobic moiety(ies) comprises a fatty acid selected from the range of 6-carbon fatty acids to 36-carbon fatty acids.

17. The composition of claim 7, wherein the hydrophobic moiety(ies) comprise a fatty acid with at least one double bond.

18. The composition of claim 7, wherein the hydrophobic moiety(ies) comprises a multi-fatty acid-containing moiety.

19. The composition of claim 7, wherein the hydrophobic moiety(ies) comprises an aromatic ring containing moiety.

20. The composition of claim 7, wherein the therapeutic agent is hydrophobic peptide, hydrophobic protein, and hydrophobic drugs.

21. The composition of claim 7, wherein the therapeutic agent is selected from GLP-1, GLP-2, leptin, islet amyloid polypeptide and vasoactive intestinal peptide.

22. The composition of claim 7, further comprising a targeting molecule covalently linked to the protective side chains.

23. The composition of claim 22, wherein the targeting molecule is selected from a group consisting of an antibody, fragment of an antibody, chimeric antibody, lectins, receptor ligands, proteins, enzymes, peptides, saccharides, quasi substrates of enzymes, cell-surface-binding compounds, and extracellular-matrix-binding compounds.

24. The composition of claim 7, further comprising a second set of protective chain covalently linked to the hydrophobic moiety.

25. A pharmaceutical composition comprising a composition selected from compositions in claims 7-24, wherein the load molecule is a therapeutic agent.

26. A method of making a composition comprising:

(a) dissolving a polymeric backbone containing residues comprising free amino groups in an aqueous buffer of pH 7-8 to obtain solution A;

(b) activating a carboxyl group or alkyl carboxyl group of a protective chain by mixing it with a carbodiimide reagent in acidic buffer between pH 3-7 to obtain solution B; and

(c) adding solution B to solution A resulting in a solution C containing the polymeric backbone with covalently linked protective chains, wherein the pH of solution C is 7 or above.

27. A method of making a composition, comprising:

(a) dissolving in non-aqueous solvent with a tertiary amine, a component comprising a polymeric backbone covalently linked to protective chains, wherein the polymeric backbone comprises residues comprising free amino groups, thereby obtaining solution E;

(b) dissolving in a non-aqueous solvent hydrophobic molecules containing free carboxyl groups and activating the carboxyl groups by adding carbodiimide reagent to obtain solution F; and

(c) adding solution F to solution E to obtain solution G to form covalent linkage between the activated carboxyl groups and the free amine groups;

wherein solution E is added to solution G until at least 90% of the residues are linked to protective chains or hydrophobic groups.

28. A method of making a composition, comprising:

(a) dissolving in partially-aqueous solvent at pH of 7 to 9 a component comprising a polymeric backbone covalently linked to protective chains, wherein the polymeric backbone comprises residues comprising free amino groups, thereby obtaining solution E,

(b) dissolving in partially-aqueous solvent with pH of 3 to 7, hydrophobic molecules containing free carboxyl groups and activating the carboxyl groups by adding carbodiimide reagent resulting in solution F,

(c) adding solution F to solution E while maintaining the pH of the mixture between 7-8 to obtain solution G, to form covalent linkage between the activated carboxyl groups and the free amine groups;

wherein solution E is added to solution G until at least 90% of the residues are linked to protective chains or hydrophobic groups.

29. A method of loading a composition, comprising:

(a) dissolving in aqueous or partially-aqueous solvent A soluble hydrophobic-core carrier composition comprising;

(i) a linear polymeric backbone;

(ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons; and

(iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone;

wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water, thereby obtaining solution A.

(b) dissolving the load molecule in aqueous or partially-aqueous solvent to obtain solution B,

(c) mixing solution A with solution B to obtain solution C, incubating solution C for 30 minutes or longer followed by lyophilization or solvent evaporation to obtain a loaded carrier ready to be dissolved into appropriate solvent.

30. A method of administering a therapeutic molecule to a subject comprising:

administering to the subject a composition comprising;

(i) a linear polymeric backbone;

(ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons;

(iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone;

(iv) a therapeutic molecule dissociably linked to the hydrophobic moiety of the backbone;

wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water.

31. The method of claim 30 wherein the composition is administered subcutaneously or intramuscularly.

32. A pharmaceutical composition comprising:

(a) a composition comprising;

(i) a linear polymeric backbone;

(ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone, wherein each protective side chain has a molecular weight between about 400 and about 20,000 Daltons;

(iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone;

(iv) a therapeutic molecule dissociably linked to the hydrophobic moiety of the backbone;

wherein the weight ratio of the hydrophilic polymeric protective side chains and the hydrophobic moieties is selected so that the composition is soluble in water; and

(b) a pharmaceutically acceptable carrier;

wherein the composition is in unit dose form.