Neosaxitoxin combination formulations for prolonged local anesthesia

• US 10,314,833 B2
• Filed: 03/17/2014
• Issued: 06/11/2019
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Berde, Charles, Kohane, Daniel S.
• Primary Examiner(s): Lundgren, Jeffrey S
• Assistant Examiner(s): Lee, William Y
• Application Number:
  US14/216,252
• Publication Number:
  US 20140288103A1
• Time in Patent Office: 1,912 Days
• Field of Search: None
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• 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 31/52 Purines, e.g. adenine
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Since each of the site I sodium channel blockers have a unique activity and cannot be used to extrapolate the same effective dosage for another site I sodium channel blocker, studies were conducted to identify dosages of neosaxitoxin (“NeoSTX”) and bupivacaine, alone or in combination with epinephrine, to provide two to three days of pain relief in humans. Bupivacaine-NeoSTX combinations produce more reliable blockade and longer duration blockade compared to NeoSTX alone. The three-way combination of NeoSTX-bupivacaine-epinephrine produces more prolonged local anesthesia than the two-way combination of NeoSTX-bupivacaine. Addition of epinephrine to this NeoSTX-bupivacaine combination dramatically prolongs the duration of complete blockade to a mechanical stimulus. These results led to development of specific combination dosage formulations.

Claims

1. A dosage unit for treatment or prevention of pain in an awake human consisting of

(a) an effective amount of between 5 and 40 mcg of neosaxitoxin in a volume between about 5 ml and about 120 ml, inclusive, and a concentration between 0.1 and 1 mcg neosaxitoxin/ml;

(b) a local anesthetic selected from the group consisting of bupivacaine, levobupivacaine and ropivacaine; and

(c) optionally one or more excipients.

2. The dosage unit of claim 1 in an effective amount for Cesarean delivery, open hysterectomy, esophago-gastrectomy, nephrectomy, or large abdominal cancer surgeries.

3. The dosage unit of claim 1 in an effective amount for wound infiltration for total hip replacement or total knee replacement.

4. The dosage unit of claim 1 for medium volume use of 15 to 50 ml comprising

Bupivacaine in a concentration range of 1.25-3 mg/ml, giving a systemic dose in adults of no more than 150 mg or no more than 2 mg/kg in children, and

Neosaxitoxin in a concentration range from 0.2-1 mcg/ml.

5. The dosage unit of claim 4 in an effective amount for peripheral nerve blocks.

6. The dosage unit of claim 4 in an effective amount for infiltration of a wound.

7. The dosage unit of claim 4 in an effective amount for shoulder, hand or arm surgery, infiltration or ilio-inguinal/ilio-hypogastric blocks for inguinal hernia repair, penile block for hypospadias repair, femoral block for total knee replacement or anterior cruciate ligament repair, intercostal nerve blocks for open chest surgery, or femoral and sciatic nerve blocks for leg amputation or foot and ankle surgery.

8. The dosage unit of claim 4 in an effective amount for nerve blocks for hip or knee joint for joint replacement surgery.

9. The dosage unit of claim 1 for medium volume uses, in effective amounts to provide anesthesia for surgery for periods of between 3 and 12 hours, analgesia after surgery for at least 24 hours, and recovery from motor block to permit some strength in limb movement within 24 to 48 hours after administration.

10. The dosage unit of claim 1 for low volume, long duration use comprising

Bupivacaine in a concentration of 2.5-5 mg/ml, wherein 5-15 ml dosing gives a systemic bupivacaine dose in adults of no more than 75 mg.

11. The dosage unit of claim 10 in an effective amount to provide lumbar sympathetic blockade for complex regional pain syndrome/reflex sympathetic dystrophy or vascular insufficiency of the leg or for celiac plexus blockade for pancreatitis or cancer of the pancreas.

12. The dosage unit of claim 10 in an effective amount to provide sciatic nerve blockade of prolonged duration where rapid motor recovery is not an issue, as for a lower leg amputation.

13. The dosage unit of claim 1 in an amount effective for peripheral nerve blocks and plexus blocks with motor effects on arms and legs, allowing recovery from motor block within 24 to 48 hours after administration.

14. A method for treatment or prevention of pain comprising administering an effective amount of the dosage unit of claim 1 to a human in need thereof.

15. The method of claim 14 wherein the human is an adult.

16. The method of claim 14 wherein the human is a child.

17. The method of claim 14 wherein the human is awake.