Pulmonary delivery for bioconjugation

• US 6,706,892 B1
• Filed: 09/06/2000
• Issued: 03/16/2004
• Est. Priority Date: 09/07/1999
• Status: Expired due to Fees

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem, Inc. (Colabor Group, Inc.)
• Inventors: Ezrin, Alan M., Fleser, Angelica, Robitaille, Martin, Bridon, Dominique P., Milner, Peter G.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/656,121
• Time in Patent Office: 1,287 Days
• Field of Search: 544/274, 544/372, 544/269, 546/93, 546/208, 548/520, 548/548, 514/254.02, 514/290, 514/422, 514/423, 514/265, 514/326, 514/776, 424/45-46, 424/489, 424/78.17, 424/78.37
• US Class Current: 548/548
• CPC Class Codes: A61K 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/06 Antiarrhythmics

Abstract

Methods of and compositions for pulmonary delivery of therapeutic agents which are capable of forming covalent bonds with a site of interest or which have formed a covalent bond with a pulmonary solution protein are disclosed. Therapeutic agents useful in the invention include wound healing agents, antibiotics, anti-inflammatories, anti-oxidants, anti-proliferatives, immunosupressants, anti-infective and anti-cancer agents.

Claims

1. A pharmaceutical composition comprising a compound selected from the group consisting of:

a) 2-[2-[4-[(4-chlorophenyl)phenylmethyl[-1-piperazinyl]ethoxy]-maleimido-ethylacetamide;

b) 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine;

c) N-(2-maleimidoethyl)-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide;

d) N-[2-maleimidoethyl-ε

-(3,4,5-trimethoxybenzamido)-caproic amide;

e) Maleimidoethyl-1-theobromineacetamide;

f) N-(2-maleimidoethyl)-2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionamide;

g) N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine;

h) 4-[N-phenyl-3-maleimidopropionamido]-1-(2-phenylethyl)piperidine; and

i) N-(2-maleimidoethyl-3,5-3′

,5′

tetraiodothyroninamide.

2. The composition of claim 1, wherein the compound is N-(2-maleimidoethyl)-3,5-3′

,5′

tetraiodothyroninamide.

4. An aerosol composition for delivery of a compound as claimed in claim 1 to the pulmonary system of a host comprising an aerosolized aqueous solution containing the compound which reacts with thiol groups on pulmonary or blood components to form a stable covalent bond.

7. A composition as claimed in claim 4 wherein the blood component is serum albumin.

3. A compound selected from the group consisting of:

a) 2-[2-[4-[(4-chlorophenyl)phenylmethyl[-1-piperazinyl]ethoxy]-maleimido-ethylacetamide;

b) 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine;

c) N-(2-maleimidoethyl)-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide;

d) N-[2-maleimidoethyl-ε

-(3,4,5-trimethoxybenzamido)-caproic amide;

e) Maleimidoethyl-1-theobromineacetamide;

f) N-(2-maleimidoethyl)-2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionamide;

g) N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylamine;

h) 4-[N-phenyl-3-maleimidopropionamido]-1-(2-phenylethyl)piperidine; and

i) N-(2-maleimidoethyl)-3,5-3′

,5′

tetraiodothyroninamide.

5. The aerosol composition as claimed in claim 3 further comprising a pharmaceutically acceptable carrier.

6. A particulate formulation for delivery of a compound as claimed in claim 3 to the pulmonary system of a host comprising a dispersable dry powder containing the compound which reacts with thiol groups on pulmonary components to form a stable covalent bond.

8. A composition for treating excess histamine formed in body tissues, comprising a compound as claimed in claim 3 which is selected from the group consisting of 2-[2-[4-[(4-chlorophenyl)phenylmethyl[-1-piperazinyl]ethoxy]-maleimido-ethylacetamide and 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine, or mixtures thereof.

9. A composition for treating hypertension comprising a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide.

10. A composition for treating arrhythmia comprising a compound as claimed in claim 3 which is N-[2-maleimidoethyl-ε

-(3,4,5-trimethoxybenzamido)-caproic amide.

11. A bronchodilating composition comprising a compound as claimed in claim 3 which is maleimidoethyl-1-theobromineacetamide.

12. A composition for treating inflammation comprising a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionamide.

13. A composition for treating depression comprising a compound as claimed in claim 3 which is N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylamine.

14. A composition for alleviating pain comprising a compound as claimed in claim 3 which is 4-[N-phenyl-3-maleimidopropionamido]-1-(2-phenylethyl)piperidine.

15. A composition for treating anemia comprising a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-3,5-3′

,5′

tetraiodothyroninamide.

16. A method for treating excess histamine formed in body tissues, comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is selected from the group consisting of 2-[2-[4-[(4-chlorophenyl)phenylmethyl[-1-piperazinyl]ethoxy]-maleimido-ethylacetamide and 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine, or mixtures thereof.

17. A method for treating hypertension comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide.

18. A method for treating arrhythmia comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is N-[2-maleimidoethyl-ε

-(3,4,5-trimethoxybenzamido)-caproic amide.

19. A method for providing a bronchodilation effect comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is maleimidoethyl-1-theobromineacetamide.

20. A method for treating inflammation comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionamide.

21. A method for treating depression comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylamine.

22. A method for alleviating pain comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is 4-[N-phenyl-3-maleimidopropionamido]-1-(2-phenylethyl)piperidine.

23. A method for treating anemia comprising administering to a patient an effective amount of a compound as claimed in claim 3 which is N-(2-maleimidoethyl)-3,5-3′

,5′

tetraiodothyroninamide.

24. A conjugate comprising a compound as claimed in claim 3 covalently bonded to a pulmonary or blood component.

25. A conjugate as claimed in claim 24 wherein the blood component is serum albumin.

26. The compound of claim 3, wherein the compound is 2-[2-[4-[(4-chlorophenyl)phenylmethyl[-1-piperazinyl]ethoxy]-maleimido-ethylacetamide.

27. The compound of claim 3, wherein the compound is 11-(N-maleimidopropionyl-4-piperidylidene)-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine.

28. The compound of claim 3, wherein the compound is N-(2-maleimidoethyl)-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinylamide.

29. The compound of claim 3, wherein the compound is N-[2-maleimidoethyl-ε

-(3,4,5-trimethoxybenzamido)-caproic amide.

30. The compound of claim 3, wherein the compound is maleimidoethyl-1-theobromineacetamide.

31. The compound of claim 3, wherein the compound is N-(2-maleimidoethyl)-2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionamide.

32. The compound of claim 3, wherein the compound is N-maleimidopropionyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylmine.

33. The compound of claim 3, wherein the compound is 4-[N-phenyl-3-maleimidopropionamido]-1-(2-phenylethyl)piperidine.

34. The compound of claim 3, wherein the compound is N-(2-maleimidoethyl)-3,5-3,5′

tetraiodothyroninamide.