CHEMICAL PERMEATION ENHANCERS ENHANCE NERVE BLOCKADE BY TOXINS

• US 20110237611A1
• Filed: 05/19/2009
• Published: 09/29/2011
• Est. Priority Date: 05/19/2008
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Original Assignee: Children's Medical Center Corporation Massachusett S, Massachusetts Institute of Technology
• Inventors: Sagie, Itay, Simons, Emmanuel J., Kohane, Daniel S.
• Granted Patent: US 8,658,699 B2
• Time in Patent Office: Days
• US Class Current: 514/267
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 23/02 Local anaesthetics

Abstract

Chemical permeation enhancers (CPEs) improve access of local anesthetics to the nerve, thereby improving their performance. Surfactants, representing three CPE sub-groups: anionic, cationic, and nonionic surfactants, were co-injected with tetrodotoxin (TTX) or bupivacaine at the sciatic nerve of Sprague-Dawley rats. All enhancers produced marked concentration-dependent improvements in the frequency and duration of block with TTX but not bupivacaine. An in vitro toxicity assay showed a wide range of CPE myotoxicity, but in vivo histological assessment showed no signs of muscle or nerve damage at concentrations of CPEs that produced a half-maximal increase in the duration of block of TTX. There was no systematic relationship between the enhancers'"'"' charge or hydrophobicity and their enhancement of block duration or potency. Thus, CPEs can provide marked prolongation of nerve blockade from TTX, without apparent local tissue toxicity, and therefore enhance the clinical applicability of TTX for prolonged-duration local anesthesia.

Claims

1. A method for enhancing nerve blockade without significant cytotoxicity comprising administering a site I sodium channel local anesthetic in combination with an effective amount of chemical permeation enhancer selected from the group consisting of surfactants, terpenes, amino amides, amino esters, azide-like compounds and alcohols, to increase blockade more than the additive effect of the local anesthetic or chemical permeation enhancer alone.

2. The method of claim 1 wherein the local anesthetic is selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and the gonyautoxins.

3. The method of claim 1 wherein the chemical penetration enhancer is selected from the group consisting of anionic, cationic, and nonionic surfactants.

4. The method of claim 1 further comprising administering a vasoconstrictor.

5. The method of claim 1 further comprising a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics.

6. The method of claim 1 comprising providing a kit comprising a vial having the local anesthetic therein and a second vial containing a diluent therein.

7. The method of claim 1 comprising administering the anesthetic as a bolus dosage unit.

8. The method of claim 1 comprising administering the anesthetic in a continuous or sustained release formulation.

9. The method of claim 1 comprising administering the anesthetic in a topical or aerosol formulation.

10. An anesthetic composition for enhancing nerve blockade without significant cytotoxicity comprising a site I sodium channel local anesthetic in combination with an effective amount of chemical permeation enhancer selected from the group consisting of surfactants, terpenes, amino amides, amino esters, azide-like compounds and alcohols, to increase blockade more than the additive effect of the local anesthetic or chemical permeation enhancer alone.

11. The composition of claim 10 wherein the local anesthetic is selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and the gonyautoxins.

12. The composition of claim 10 wherein the chemical penetration enhancer is selected from the group consisting of anionic, cationic, and nonionic surfactants

13. The composition of claim 10 further comprising a vasoconstrictor.

14. The composition of claim 10 further comprising a charged local anesthetic selected from the group consisting of amino-amide or ambo-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics.

15. The composition of claim 10 in a kit comprising a vial comprising the local anesthetic therein and a second vial comprising a diluent therein.

16. The composition of claim 10 comprising the anesthetic as a bolus dosage unit.

17. The composition of claim 10 comprising the anesthetic in a continuous or sustained release formulation.

18. The composition of claim 10 comprising the anesthetic in a topical or aerosol formulation.

19. A method for providing local anesthesia comprising providing an effective amount of a site I sodium channel blocker in combination with a local anesthetic selected from the group consisting of a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics.

20. The method of claim 19 wherein the local anesthetic is a lidocaine or lidocaine derivative.

23. The method of claim 19 wherein the site I sodium channel blocker is saxitoxin, decarbamoyl saxitoxin, or neosaxitoxin.

24. The method of claim 19 wherein the local anesthetic is an amino-amide or amino-ester local anesthetics or derivatives thereof.

25. The method of claim 19 wherein the site I sodium channel blocker is neosaxitoxin and the local anesthetic is bupivacaine.

26. The method of claim 19 wherein the pH of the composition is less than 5.5.

21. A composition for providing local anesthesia comprising an effective amount of a site I sodium channel blocker in combination with a local anesthetic selected from the group consisting of a charged local anesthetic selected from the group consisting of amino-amide or amino-ester local anesthetics or derivatives thereof, at least partly amphiphilic local anesthetics, local anesthetics that act not on the surface of the cell, and at least partly charged local anesthetics.

22. The composition of claim 21 wherein the local anesthetic is a lidocaine or lidocaine derivative.

27. The composition of claim 21 wherein the site I sodium channel blocker is saxitoxin, decarbamoyl saxitoxin, or neosaxitoxin.

28. The composition of claim 21 wherein the local anesthetic is an amino-amide or amino-ester local anesthetics or derivatives thereof.

29. The composition of claim 21 wherein the site I sodium channel blocker is neosaxitoxin and the local anesthetic is bupivacaine.

30. The composition of claim 21 wherein the pH of the composition is less than 5.5.