Irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis

• US 20030105126A1
• Filed: 06/25/2002
• Published: 06/05/2003
• Est. Priority Date: 12/12/1995
• Status: Abandoned Application

• Current Assignee: Omeros Medical Systems, Inc.
• Original Assignee: Omeros Medical Systems, Inc.
• Inventors: Demopulos, Gregory A., Herz, Jeffrey M., Pierce, Pamela Anne
• Application Number:
  US10/180,815
• Publication Number:
  US 20030105126A1
• Time in Patent Office: Days
• US Class Current: 514/304
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• 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 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

A method and solution for perioperatively inhibiting a variety of pain, inflammation, spasm and restenosis processes resulting from cardiovascular or general surgical, therapeutic and diagnostic procedures. The solution preferably includes multiple pain and inflammation inhibitory agents, including at least one local anesthetic agent, and spasm inhibitory agents at dilute concentration in a physiologic carrier, such as saline or lactated Ringer'"'"'s solution. Specific preferred embodiments of the solution of the present invention for use in cardiovascular and general vascular procedures also include anti-restenosis agents.

Claims

1. A method of inhibiting pain and inflammation at a wound during a surgical procedure, comprising:

delivering to a wound during a surgical procedure a solution including a plurality of agents comprising at least one pain/inflammation inhibitory agent and at least one local anesthetic agent in a liquid carrier, the plurality of agents being selected to act on a plurality of differing molecular targets, wherein the solution is applied locally and perioperatively to the surgical site and the agents are collectively effective at inhibiting pain and inflammation at the wound during the procedure.

2. The method of claim 1, comprising continuously applying the solution to the wound.

3. The method of claim 2, comprising continuously irrigating the wound with the solution.

4. The method of claim 1, wherein the solution is applied by irrigation of the wound.

5. The method of claim 1, wherein the solution is locally applied to the wound in the absence of metabolic transformation.

6. The method of claim 1, wherein the perioperative application of the solution comprises intraprocedural application together with preprocedural or postprocedural application of the solution.

7. The method of claim 6, wherein the perioperative application of the solution comprises preprocedural, intraprocedural and postprocedural application of the solution.

8. The method of claim 6, wherein the solution is continuously applied to the wound.

9. The method of claim 1, wherein the at least one local anesthetic agent in the solution is selected from the group consisting of benzocaine, bupivacaine, chloroprocaine, cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, QX-314, RAC-109, HS-37 and the pharmacologically active enantiomers thereof.

10. The method of claim 1, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration in the range of about 125 to about 1,600,000 nanomolar.

11. The method of claim 1, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration in the range of about 225,000 to about 1,100,000 nanomolar.

12. The method of claim 1, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration of no greater than 750,000 nanomolar.

13. The method of claim 12, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration of no greater than 500,000 nanomolar.

14. The method of claim 9, wherein the at least one local anesthetic agent is lidocaine delivered locally at a concentration of about 500 to 1,600,000 nanomolar.

15. The method of claim 9, wherein the at least one local anesthetic agent is bupivacaine delivered locally at a concentration of about 125 to 400,000 nanomolar.

16. The method of claim 1, wherein each of the plurality of agents in the solution other than local anesthetic agents is delivered locally at a concentration of no greater than 100,000 nanomolar.

17. The method of claim 16, wherein each of the plurality of agents in the solution other than local anesthetic agents is delivered locally at a concentration of no greater than 10,000 nanomolar.

18. The method of claim 1, wherein each of the plurality of agents in the solution applied is included at a concentration that is sufficient to provide a predetermined level of pain/inflammation inhibitory effect at the wound when locally applied in the absence of metabolic transformation, and that is less than a concentration which would be required to provide the same predetermined level of inhibitory effect at the wound if applied in a manner which would entail metabolic transformation of the agents.

19. The method of claim 1, wherein the pain/inflammation inhibitory agents other than local anesthetic agents are selected from the group consisting of:

serotonin receptor antagonists;

serotonin receptor agonists;

histamine receptor antagonists;

bradykinin receptor antagonists;

kallikrein inhibitors;

tachykinin receptor antagonists including neurokinin₁ receptor subtype antagonists and neurokinin₂ receptor subtype antagonists;

calcitonin gene-related peptide receptor antagonists;

interleukin receptor antagonists;

phospholipase inhibitors including PLA₂ isoform inhibitors and PLC_γ

isoform inhibitors;

cyclooxygenase inhibitors;

lipooxygenase inhibitors;

prostanoid receptor antagonists including eicosanoid EP-1 receptor subtype antagonists and eicosanoid EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists;

leukotriene receptor antagonists including leukotriene B₄ receptor subtype antagonists and leukotriene D₄ receptor subtype antagonists;

opioid receptor agonists including μ

-opioid receptor subtype agonists, δ

-opioid receptor subtype agonists, and κ

-opioid receptor subtype agonists;

purinoceptor agonists and antagonists including P_2Y receptor agonists and P_2X receptor antagonists; and

ATP-sensitive potassium channel openers.

20. The method of claim 19, wherein the selected pain/inflammation inhibitory agents other than local anesthetic agents are delivered locally at a concentration of:

0.1 to 10,000 nanomolar for serotonin receptor antagonists;

0.1 to 2,000 nanomolar for serotonin receptor agonists;

0.01 to 1,000 nanomolar for histamine receptor antagonists;

0.1 to 10,000 nanomolar for bradykinin receptor antagonists;

0.1 to 1,000 nanomolar for kallikrein inhibitors;

0.1 to 10,000 nanomolar for neurokinin₁ receptor subtype antagonists;

1.0 to 10,000 nanomolar for neurokinin₂ receptor subtype antagonists;

1 to 1,000 nanomolar for calcitonin gene-related peptide receptor antagonists;

1 to 1,000 nanomolar for interleukin receptor antagonists;

100 to 100,000 nanomolar for PLA₂ isoform inhibitors;

100 to 200,000 nanomolar for cyclooxygenase inhibitors;

100 to 10,000 nanomolar for lipooxygenase inhibitors;

100 to 10,000 nanomolar for eicosanoid EP-1 receptor subtype antagonists;

100 to 10,000 nanomolar for leukotriene B₄ receptor subtype antagonists;

0.1 to 500 nanomolar for μ

-opioid receptor subtype agonists;

0.1 to 500 nanomolar for δ

-opioid receptor subtype agonists;

0.1 to 500 nanomolar for κ

-opioid receptor subtype agonists;

100 to 100,000 nanomolar for purinoceptor antagonists; and

0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers.

21. The method of claim 1, wherein the solution applied comprises:

a serotonin₂ receptor subtype antagonist included at a concentration of 50 to 500 nanomolar;

a serotonin₃ receptor subtype antagonist included at a concentration of 200 to 2,000 nanomolar;

a histamine₁ receptor subtype antagonist included at a concentration of 5 to 200 nanomolar;

a serotonin receptor agonist included at a concentration of 10 to 200 nanomolar;

a cyclooxygenase inhibitor included at a concentration of 500 to 5,000 nanomolar;

a neurokinin₁ receptor subtype antagonist included at a concentration of 10 to 500 nanomolar;

a neurokinin₂ receptor subtype antagonist included at a concentration of 10 to 500 nanomolar;

a purinoceptor antagonist included at a concentration of 10,000 to 100,000 nanomolar;

an ATP-sensitive potassium channel opener included at a concentration of 100 to 1,000 nanomolar;

a calcium channel antagonist included at a concentration of 100 to 5,000 nanomolar;

a bradykinin₁ receptor subtype antagonist included at a concentration of 10 to 200 nanomolar;

a bradykinin₂ receptor subtype antagonist included at a concentration of 50 to 500 nanomolar; and

a μ

-opioid receptor subtype agonist included at concentration of 10 to 200 nanomolar.

22. The method of claim 1, wherein the at least one local anesthetic agent is selected to act by inhibiting voltage-gated sodium channels.

23. The method of claim 1, wherein the at least one local anesthetic agent in the solution is selected from the group consisting of benzocaine, bupivacine, cocaine, etiodocaine, lidocaine, mepivacalne, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, QX-314, RAC-109, HS-37 and the pharmacologically active enantiomers thereof.

24. A method of inhibiting pain and inflammation at a wound during a surgical procedure, comprising:

delivering to a wound during a surgical procedure a solution including a plurality of agents comprising at least one pain/inflammation inhibitory agent and at least one local anesthetic agent in a liquid carrier, the plurality of agents being selected to act on a plurality of differing molecular targets, wherein the solution is applied locally and perioperatively and in the absence of metabolic transformation to the wound and the agents are collectively effective at inhibiting pain and inflammation at the wound during the procedure.

25. A method of inhibiting pain and inflammation at a wound during a surgical procedure, comprising:

delivering to a wound during a surgical procedure a solution including a plurality of agents comprising at least one pain/inflammation inhibitory agent and at least one local anesthetic agent in a liquid carrier, the plurality of agents being selected to act on a plurality of differing molecular targets, wherein the solution is applied locally and perioperatively to the wound and wherein each agent is included at a concentration or dosage that is sufficient such that the agents collectively provide a level of inhibitory effect at the wound when delivered locally to the wound and that results in a plasma concentration that is less than a plasma concentration that would be required to achieve the same level of inhibitory effect at the wound when delivered systemically.

26. A solution for use in the inhibition of pain and inflammation at a wound during a surgical procedure, the solution including a plurality of agents comprising at least one pain and inflammation inhibitory agent and at least one local anesthetic agent in a liquid procedural irrigation carrier, the plurality of agents being selected to act on a plurality of differing molecular targets, wherein each agent in the solution is included at a concentration or dosage that is sufficient such that the agents collectively provide a substantially constant level of inhibitory effect at the wound during at least a substantial portion of the procedure and that results in a plasma concentration that is less than a plasma concentration that would be required to achieve the same level of inhibitory effect at the wound when delivered systemically.

27. The solution of claim 26, wherein the at least one local anesthetic agent in the solution is selected from the group consisting of benzocaine, bupivacaine, chloroprocaine, cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, QX-314, RAC-109, HS-37 and the pharmacologically active enantiomers thereof.

28. The solution of claim 26, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration in the range of about 125 to about 1,600,000 nanomolar.

29. The solution of claim 28, wherein the at least one local anesthetic agent in the solution is delivered locally at a concentration in the range of about 225,000 to about 1,100,000 nanomolar.

30. The solution of claim 26 which comprises at least one local anesthetic agent at a concentration of no greater than 750,000 nanomolar.

31. The solution of claim 30 which comprises at least one local anesthetic agent at a concentration of no greater than 500,000 nanomolar.

32. The solution of claim 27 which comprises lidocaine at a concentration of about 500 to 1,600,000 nanomolar.

33. The solution of claim 27 which comprises bupivacaine at a concentration of about 125 to 400,000 nanomolar.

34. The solution of claim 26, wherein each of the plurality of agents in the solution other than local anesthetic agents is included at a concentration of no greater than 100,000 nanomolar, adjusted for dilution in the absence of metabolic transformation, at an intended local delivery site.

35. The solution of claim 34, wherein each of the plurality of agents in the solution other than local anesthetic agents is included at a concentration of no greater than 10,000 nanomolar, adjusted for dilution, in the absence of metabolic transformation, at an intended local delivery site.

36. The solution of claim 26, wherein the at least one local anesthetic agent is included at a sub-anesthetic concentration.

37. The solution of claim 26, wherein the pain/inflammation inhibitory agents other than local anesthetic agents are selected from the group consisting of:

serotonin receptor antagonists;

serotonin receptor agonists;

histamine receptor antagonists;

bradykinin receptor antagonists;

kallikrein inhibitors;

tachykinin receptor antagonists including neurokinin₁ receptor subtype antagonists and neurokinin₂ receptor subtype antagonists;

calcitonin gene-related peptide receptor antagonists;

interleukin receptor antagonists;

phospholipase inhibitors including PLA₂ isoform inhibitors and PLC_γ

isoform inhibitors;

cyclooxygenase inhibitors;

lipooxygenase inhibitors;

prostanoid receptor antagonists including eicosanoid EP-1 receptor subtype antagonists and eicosanoid EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists;

leukotriene receptor antagonists including leukotriene B₄ receptor subtype antagonists and leukotriene D₄ receptor subtype antagonists;

opioid receptor agonists including μ

-opioid receptor subtype agonists, δ

-opioid receptor subtype agonists, and κ

-opioid receptor subtype agonists;

purinoceptor agonists and antagonists including P_2Y receptor agonists and P_2X receptor antagonists; and

ATP-sensitive potassium channel openers.

38. The solution of claim 37, wherein the selected pain/inflammation inhibitory agents other than the local anesthetic agents are included at a concentration of:

0.1 to 10,000 nanomolar for serotonin receptor antagonists;

0.1 to 2,000 nanomolar for serotonin receptor agonists;

0.01 to 1,000 nanomolar for histamine receptor antagonists;

0.1 to 10,000 nanomolar for bradykinin receptor antagonists;

0.1 to 1,000 nanomolar for kallikrein inhibitors;

0.1 to 10,000 nanomolar for neurokinin₁ receptor subtype antagonists;

1.0 to 10,000 nanomolar for neurokinin₂ receptor subtype antagonists;

1 to 1,000 nanomolar for calcitonin gene-related peptide receptor antagonists;

1 to 1,000 nanomolar for interleukin receptor antagonists;

100 to 100,000 nanomolar for PLA₂ isoform inhibitors;

100 to 200,000 nanomolar for cyclooxygenase inhibitors;

100 to 10,000 nanomolar for lipooxygenase inhibitors;

100 to 10,000 nanomolar for eicosanoid EP-1 receptor subtype antagonists;

100 to 10,000 nanomolar for leukotriene B₄ receptor subtype antagonists;

0.1 to 500 nanomolar for μ

-opioid receptor subtype agonists;

0.1 to 500 nanomolar for δ

-opioid receptor subtype agonists;

0.1 to 500 nanomolar for κ

-opioid receptor subtype agonists;

100 to 100,000 nanomolar for purinoceptor antagonists; and

0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers.

39. The solution of claim 38, wherein the solution comprises:

a serotonin₂ receptor subtype antagonist included at a concentration of 50 to 500 nanomolar;

a serotonin₃ receptor subtype antagonist included at a concentration of 200 to 2,000 nanomolar;

a histamine₁ receptor subtype antagonist included at a concentration of 5 to 200 nanomolar;

a serotonin receptor agonist included at a concentration of 10 to 200 nanomolar;

a cyclooxygenase inhibitor included at a concentration of 500 to 5,000 nanomolar;

a neurokinin₁ receptor subtype antagonist included at a concentration of 10 to 500 nanomolar;

a neurokinin₂ receptor subtype antagonist included at a concentration of 10 to 500 nanomolar;

a purinoceptor antagonist included at a concentration of 10,000 to 100,000 nanomolar;

an ATP-sensitive potassium channel opener included at a concentration of 100 to 1,000 nanomolar;

a calcium channel antagonist included at a concentration of 100 to 5,000 nanomolar;

a bradykinin₁ receptor subtype antagonist included at a concentration of 10 to 200 nanomolar;

a bradykinin₂ receptor subtype antagonist included at a concentration of 50 to 500 nanomolar; and

a μ

-opioid receptor subtype agonist included at concentration of 10 to 200 nanomolar.

40. A solution for use in the inhibition of pain and inflammation at a wound during a surgical procedure, the solution including a plurality of agents comprising at least one pain and inflammation inhibitory agent and at least one local anesthetic agent in a liquid procedural irrigation carrier, the plurality of agents being selected to act on a plurality of differing molecular targets, the concentration of each agent within the solution being the concentration of that agent which is desired to be delivered locally by continuous irrigation of the wound during at least a substantial portion of the procedure in order to maintain a substantially constant level of inhibitory effect at the wound.

41. The solution of claim 40, wherein the at least one local anesthetic agent is included at a concentration of about 125 to about 1,600,000 nanomolar.

42. The solution of claim 40, wherein the at least one local anesthetic agent is included at a sub-anesthetic concentration.