Complexing agents for compositions containing inclusion complexes
View Patent ↗The invention provides a composition containing particulate composite of a polymer and a therapeutic agent. The composition also contains a complexing agent. The polymer interacts with the complexing agent in a host-guest or a guest-host interaction to form an inclusion complex. A therapeutic composition of the invention may be used to deliver the therapeutic agent and to treat various disorders. Both the polymer of the particulate composite and the complexing agent may be used to introduce functionality into the therapeutic composition. The invention also relates to a method of preparing a composition. The method combines a therapeutic agent, a polymer having host or guest functionality, and a complexing agent having guest or host functionality to form the therapeutic composition. The complexing agent forms an inclusion complex with the polymer. The invention also relates to a method of delivering a therapeutic agent. According to the method, a therapeutically effective amount of a therapeutic composition of the invention is administered to a mammal (e.g. person or animal) in recognized need of the therapeutic. Also disclosed are compounds having the formula:
1. A method of preparing a composition comprising a therapeutic agent and an inclusion complex of a cyclodextrin-containing polymer and a complexing agent of the formula:
wherein
Host/Guest is a guest moiety;
J is —NH—, —C(═O)NH—(CH 2 ) d —, —NH—C(═O)—(CH 2 ) d —, —CH 2 SS—, —C(═O)O—(CH 2 ) e —O—P(═O)(O—(CH 2 ) e —Y)O—,
a peptide or polypeptide residue, or —NH—(C═O)—CH(R 1 )—NH—(C═O)—CH(R 1 )—NH—;
Y is an additional host-guest functionality;
R 1 is —(CH 2 )—CO 2 H, an ester or salt thereof; or —(CH 2 ) a —CONH 2 ;
PEG is —O(CH 2 CH 2 O) z —, where z varies from 2 to 500;
L is —NH—, —NH—(C═O)—(CH 2 ) e —(C═O)—CH 2 —, —S(═O) 2 —HC═CH—, —SS—, —C(═O)O—, or a carbohydrate residue;
a is 0 or 1;
b is 0 or 1;
d ranges from 0 to 6;
e ranges from 1 to 6;
m is 1;
n ranges from 1 to 6;
q is 1;
w ranges from 1 to 5;
y is 1; and
x is 1,
said method comprising: combining the cyclodextrin-containing polymer, the complexing agent and the therapeutic agent, thereby forming the composition.
2. The method of claim 1 , wherein the complexing agent has the formula:
wherein J is a peptide or polypeptide residue.
3. The method of claim 1 , wherein the host/guest is selected from adamantyl, naphthyl, cholesterol, and mixtures thereof.
4. The method of claim 1 , wherein the therapeutic agent is selected from antibiotics, steroids, polynucleotides, small molecule pharmaceuticals, viruses, plasmids, peptides, peptide fragments, chelating agents, natural products, biologically active macromolecules, proteins, enzymes, and mixtures thereof.
5. The method of claim 4 , wherein the therapeutic agent is a polynucleotide.
6. The method of claim 1 , wherein at least one Functional Group includes a therapeutic agent, a ligand, a nuclear localization signal, an endosomal release peptide, an endosomal release polymer, or a membrane permeabilization agent.
7. The method of claim 6 , wherein at least one Functional Group includes a therapeutic agent.
8. The method of claim 7 , wherein the therapeutic agent is selected from antibiotics, steroids, polynucleotides, small molecule pharmaceuticals, viruses, plasmids, peptides, peptide fragments, chelating agents, natural products, biologically active macromolecules, proteins, enzymes, and mixtures thereof.
9. The method of claim 6 , wherein at least one Functional Group includes a ligand.
10. The method of claim 9 , wherein the ligand is selected from vitamins, proteins, monoclonal antibodies, monosaccharides, peptides, and polysaccharides.
11. The method of claim 10 , wherein the ligand is a protein.
12. The method of claim 11 , wherein the protein is transferrin.
13. The method of claim 1 , wherein a is 1.
14. The method of claim 1 , wherein at least one Functional Group includes at least one polymer portion.
15. The method of claim 1 , wherein the cyclodextrin-containing polymer and the complexing agent are in lyophilized form.
16. A method of treating a patient comprising administering to the patient a therapeutically effective amount of a composition comprising a therapeutic agent and an inclusion complex of a cyclodextrin-containing polymer and a complexing agent of the formula:
wherein
Host/Guest is a guest moiety;
J is —NH—, —C(═O)NH—(CH 2 ) d —, —NH—C(═O)—(CH 2 ) d —, —CH 2 SS—, —C(═O)O—(CH 2 ) e —O—P(═O)(O—(CH 2 ) e —Y)O—,
a peptide or polypeptide residue, or —NH—(C═O)—CH(R 1 )—NH—(C═O)—CH(R 1 )—NH—;
Y is an additional host-guest functionality;
R 1 is —(CH 2 )—CO 2 H, an ester or salt thereof; or —(CH 2 ) a —CONH 2 ;
PEG is —O(CH 2 CH 2 O) z —, where z varies from 2 to 500;
L is —NH—, —NH—(C═O)—(CH 2 ) e —(C═O)—CH 2 —, —S(═O) 2 —HC═CH—, —SS—, —C(═O)O—, or a carbohydrate residue;
a is 0 or 1;
b is 0 or 1;
d ranges from 0 to 6;
e ranges from 1 to 6;
m is 1;
n ranges from 1 to 6;
q is 1;
w ranges from 1 to 5;
y is 1; and
x is 1.
17. The method of claim 16 , wherein the complexing agent has the formula:
wherein J is a peptide or polypeptide residue.
18. The method of claim 16 , wherein the host/guest is selected from adamantyl, naphthyl, cholesterol, and mixtures thereof.
19. The method of claim 16 , wherein the therapeutic agent is selected from antibiotics, steroids, polynucleotides, small molecule pharmaceuticals, viruses, plasmids, peptides, peptide fragments, chelating agents, natural products, biologically active macromolecules, proteins, enzymes, and mixtures thereof.
20. The method of claim 19 , wherein the therapeutic agent is a polynucleotide.
21. The method of claim 16 , wherein at least one Functional Group includes a therapeutic agent, a ligand, a nuclear localization signal, an endosomal release peptide, an endosomal release polymer, or a membrane permeabilization agent.
22. The method of claim 21 , wherein at least one Functional Group includes a therapeutic agent.
23. The method of claim 22 , wherein the therapeutic agent is selected from antibiotics, steroids, polynucleotides, small molecule pharmaceuticals, viruses, plasmids, peptides, peptide fragments, chelating agents, natural products, biologically active macromolecules, proteins, enzymes, and mixtures thereof.
24. The method of claim 21 , wherein at least one Functional Group includes a ligand.
25. The method of claim 24 , wherein the ligand is selected from vitamins, proteins, monoclonal antibodies, monosaccharides, peptides, and polysaccharides.
26. The method of claim 25 , wherein the ligand is a protein.
27. The method of claim 26 , wherein the protein is transferrin.
28. The method of claim 16 , wherein a is 1.
29. The method of claim 16 , wherein at least one Functional Group includes at least one polymer portion.
30. The method of claim 16 , wherein the patient is suffering from cystic fibrosis, Gaucher's disease, muscular dystrophy, AIDS, cancer, a cardiovascular condition or a neurological condition.
31. The method of claim 16 , comprising administering the composition via oral administration, inhalation, topical application, parenteral administration, intravenous administration, intranasal administration, intraocular administration, intracranial injection, intraperitoneal injection or pulmonary administration.