Chemical permeation enhancers enhance nerve blockade by toxins

• US 8,658,699 B2
• Filed: 05/19/2009
• Issued: 02/25/2014
• 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, Massachusetts Institute of Technology
• Inventors: Kohane, Daniel S., Sagie, Itay, Simons, Emmanuel J.
• Primary Examiner(s): Soroush, Layla
• Application Number:
  US12/993,759
• Publication Number:
  US 20110237611A1
• Time in Patent Office: 1,743 Days
• Field of Search: 514/626
• US Class Current: 514/626
• 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 comprising administering an effective amount of a site I sodium channel local anesthetic selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and gonyautoxins in combination with an effective amount of a chemical penetration enhancer selected from the group consisting of sodium octyl sulfate, sodium dodecyl sulfate, octyl-trimethyl-ammonium bromide, and dodecyl-trimethyl-ammonium bromide

to increase duration of sensory nerve blockade more than the additive effect of the local anesthetic and chemical permeation enhancer.

2. The method of claim 1 wherein the local anesthetic is neosaxitoxin.

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

4. 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 ceil, and at least partly charged local anesthetics.

5. 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.

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

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

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

23. The method of claim 1 wherein the effective amount of local anesthetic and effective amount of chemical penetration enhancer do not increase cytotoxicity.

9. An anesthetic composition for enhancing nerve blockade comprising an effective amount of a site I sodium channel local anesthetic selected from the group consisting of tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, neosaxitoxin, and gonyautoxins in combination with an effective amount of a chemical penetration enhancer selected from the group consisting of sodium octyl sulfate, sodium dodecyl sulfate, octyl-trimethyl-ammonium bromide, and dodecyl-trimethyl-ammonium bromide,

to increase duration of sensory blockade more than the additive effect of the local anesthetic and chemical permeation enhancer.

10. The composition of claim 9 wherein the local anesthetic is neosaxitoxin.

11. The composition of claim 9 further comprising a vasoconstrictor.

12. The composition of claim 9 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.

13. The composition of claim 9 in a kit comprising a vial comprising the local anesthetic therein and a second vial comprising a diluent therein.

14. The composition of claim 9 comprising the anesthetic as a bolus dosage unit.

15. The composition of claim 9 comprising the anesthetic in a continuous or sustained release formulation.

16. The composition of claim 9 comprising the anesthetic in a topical or aerosol formulation.

17. The composition of claim 9 comprising a site I sodium channel local anesthetic selected from the group consisting of tetrodotoxin (TTX) in a concentration of between 10 and 120 micromolar, saxitoxin (STX) in a concentration of between 5 and 60 micromolar, decarbamoyl saxitoxin in a concentration between 30 and 480 micromolar, and neosaxitoxin in a concentration between 3 and 40 micromolar.

18. The composition of claim 9 comprising chemical penetration enhancer is selected from the group consisting of sodium octyl sulfate in a concentration of between 10 and 100 mM, sodium dodecyl sulfate in a concentration between one and 40 mM, octyl-trimethyl-ammonium bromide in a concentration of between 20 and 120 mM, and dodecyl-trimethyl-ammonium bromide in a concentration of between 0.5 and 10 mM.

19. The composition of claim 17 comprising chemical penetration enhancer is selected from the group consisting of sodium octyl sulfate in a concentration of between 10 and 100 mM, sodium dodecyl sulfate in a concentration between one and 40 mM, octyl-trimethyl-ammonium bromide in a concentration of between 20 and 120 mM, and dodecyl-trimethyl-ammonium bromide in a concentration of between 0.5 and 10 mM.

20. The composition of claim 12 wherein the local anesthetics has Formula I or Formula II:

21. The composition of claim 20 wherein the local anesthetic is selected from the group consisting of QX-314 ((N-(2,6)dimethylphenylcarbamoylmethyl triethylammonium bromide);

QX-222 (2-((2,6-dimethylphenyl)amino)-N,N,N-trimethyl-2-oxoethanaminium);

QX-572 (N,N-bis(phenylcarbamoylmethyl)-dimethylammonium chloride), tonicaine, bupivacaine, charged tetracine derivatives, and charged derivatives of flecainide.

22. The composition of claim 9 wherein the effective amount of local anesthetic and effective amount of chemical penetration enhancer do not increase cytotoxicity.