Absorption Enhancers for Drug Administration

• US 20080299079A1
• Filed: 08/11/2008
• Published: 12/04/2008
• Est. Priority Date: 08/25/2004
• Status: Active Grant

• Current Assignee: Aegis Therapeutics, LLC
• Original Assignee: Aegis Therapeutics, LLC
• Inventors: Maggio, Edward T., Meezan, Elias, Pillion, Dennis J.
• Granted Patent: US 8,551,468 B2
• Time in Patent Office: Days
• US Class Current: 514/1.1
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants

Abstract

A composition including a surfactant and at least one alkyl glycoside and/or saccharide alkyl ester and a drug. The surfactant composition(s) when admixed with a drug is non-toxic and non-irritating, while stabilizing and increasing the bioavailability of the drug. The invention also provides compositions that enhance absorption of drugs via the oral, ocular, nasal, nasolacrimal, inhalation or pulmonary, oral cavity (sublingual or Buccal cell) or CSF delivery route of a patient, including but not limited to insulin, glucagon and exendin-4.

Claims

1. A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount of a peptide having a molecular weight of about 1-75 kD in a pharmaceutically acceptable carrier, with the proviso that the peptide is not insulin, calcitonin, and glucagon.

3. The method of claim 1 for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent such that the therapeutic agent persists in the cerebro-ventricular space for a time sufficient to ameliorate the disorder.

5. A method for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent as in claim 1 such that the therapeutic agent persists in the cerebroventricular space for a time sufficient to ameliorate the disorder.

7. A method for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent as in claim 3 such that the therapeutic agent persists in the cerebroventricular space for a time sufficient to ameliorate the disorder.

2. A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a therapeutically effective amount erythropoietin in a pharmaceutically acceptable carrier.

4. The method of claim 2 for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent such that the therapeutic agent persists in the cerebro-ventricular space for a time sufficient to ameliorate the disorder.

6. A method for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent as in claim 2 such that the therapeutic agent persists in the cerebroventricular space for a time sufficient to ameliorate the disorder.

8. A method for ameliorating neurological disorder which comprises intranasal administration to the cerebrospinal fluid (CSF) of a subject with the disorder of a therapeutically effective amount of a therapeutic agent as in claim 4 such that the therapeutic agent persists in the cerebroventricular space for a time sufficient to ameliorate the disorder.

9. A method of increasing absorption of a compound into the CSF of a subject comprising administering intranasally the compound and an absorption increasing amount of a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl joined by a linkage to a hyrdrophilic saccharide.

10. The method of claim 9, wherein the alkyl glycoside has a concentration in the range of about 0.01% to 1.0%.

11. The method of claim 9, wherein the alkyl has from 9 to 24 carbons.

12. The method of claim 9, wherein the alkyl has from 9 to 14 carbon atoms.

13. The method of claim 9, wherein the alkyl glycoside further has a hydrophile-lipophile balance number in the range of about 10 to 20.

14. The method of claim 9, wherein the compound is a protein or a peptide.

15. The method of claim 14, wherein the protein or peptide drug is selected from the group consisting of insulin and glucagon.

16. The method of claim 9, and further comprising administering a protease or peptidase inhibitor.

17. The method of claim 9, wherein the compound is administered in a format selected from the group consisting of a drop, a spray, an aerosol and a sustained-release format.

18. A method of controlling caloric intake by administering a composition comprising a therapeutic effective amount of exendin-4, or related GLP-1 peptide, with an effective amount of TDM alkyl saccharide.

19. A method of controlling blood glucose levels in a subject by administering to a subject a composition comprising a therapeutic effective amount of exendin-4, or related GLP-1 peptide, with an effective amount of alkyl saccharide.

20. A pharmaceutical composition comprising a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent wherein the mucosal delivery-enhancing agent is selected from:

(a) an aggregation inhibitory agent;

(b) a charge-modifying agent;

(c) a pH control agent;

(d) a degradative enzyme inhibitory agent;

(e) a mucolytic or mucus clearing agent;

(f) a ciliostatic agent;

(g) a membrane penetration-enhancing agent selected from;

(i) a surfactant;

(ii) a bile salt;

(ii) a phospholipid additive, mixed micelle, liposome, or carrier;

(iii) an alcohol;

(iv) an enamine;

(v) an NO donor compound;

(vi) a long-chain amphipathic molecule;

(vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

(ix) a glycerol ester of acetoacetic acid;

(x) a cyclodextrin or beta-cyclodextrin derivative;

(xi) a medium-chain fatty acid;

(xii) a chelating agent;

(xiii) an amino acid or salt thereof;

(xiv) an N-acetylamino acid or salt thereof;

(xv) an enzyme degradative to a selected membrane component;

(ix) an inhibitor of fatty acid synthesis;

(x) an inhibitor of cholesterol synthesis; and

(xi) any combination of the membrane penetration enhancing agents recited in (i)-(x);

(h) a modulatory agent of epithelial junction physiology;

(i) a vasodilator agent;

(j) a selective transport-enhancing agent; and

(k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, resulting in stabilization of the compound for enhanced nasal mucosal delivery, wherein the formulation of the compound with the intranasal delivery-enhancing agents provides for increased bioavailability of the compound in a blood plasma of a subject.

21. The pharmaceutical composition of claim 20, further comprising a plurality of intranasal delivery-enhancing agents.

22. The pharmaceutical composition of claim 20, wherein said mucosal delivery-enhancing agent(s) is/are selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, L-ascorbic acid, sodium metabisulfite, EDTA disodium, benzalkonium chloride, sodium hydroxide and mixtures thereof.

23. The pharmaceutical composition of claim 20, wherein the alkyl has from 10 to 16 carbon atoms.

24. A method of increasing absorption of a low molecular weight compound into the circulatory system of a subject comprising administering, via the ocular, nasal, nasolacrimal, inhalation, or CSF delivery route (a) the compound;

(b) an absorption increasing amount of a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl joined by a linkage to a hydrophilic saccharide; and

(c) a mucosal delivery-enhancing agent.

25. The method of claim 24, wherein the alkyl glycoside has a concentration in the range of about 0.01% to 1.0%.

26. The method of claim 24, wherein the alkyl has from 9 to 24 carbons.

27. The method of claim 24, wherein the alkyl has from 9 to 14 carbon atoms.

28. The method of claim 24, wherein the alkyl has from 10 to 16 carbon atoms.

29. The method of claim 24, wherein the saccharide is selected from the group consisting of maltose, sucrose and glucose.

30. The method of claim 24, wherein the alkyl glycoside further has a hydrophile-lipophile balance number in the range of about 10 to 20.

31. The method of claim 24, wherein the linkage is selected from the group consisting of a glycosidic linkage, a thioglycosidic linkage, an amide linkage, a ureide linkage and an ester linkage.

32. The method of claim 24, wherein the compound is a protein or a peptide.

33. The method of claim 24, wherein the method comprises a protease or peptidase inhibitor.

34. The method of claim 24, wherein the compound is administered in a format selected from the group consisting of a drop, a spray, an aerosol and a sustained-release format.

35. The method of claim 24, wherein the compound is selected from nicotine, interferon, PYY, GLP-1, synthetic exendin-4, parathyroid hormone, human growth hormone, or a small organic molecule.