Local anesthetic formulations

Details Local anesthetic formulations Local anesthetic formulations

1998-05-15

2001-12-04

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

Reexamination Certificate

active

06326020

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to formulations or methods that provide prolonged local anesthesia with an enhanced margin of safety based on the combination of site 1 sodium channel blockers, and agents such as vasoconstrictors, local anesthetics, vanilloid receptor agonists and/or corticosteroids, lipophilic or amphiphilic solvents, and microparticulate formulations thereof.
BACKGROUND OF THE INVENTION
Currently used amino ester and amino amide local anesthetics have limited duration of action, too short to relieve most postoperative pain, and low potency, requiring millimolar concentrations for effectiveness. These compounds only produce local anesthesia lasting for short periods and therefore require repeated administration or catheter infusions if clinical effect is desired for periods of longer than 4 to 6 hours. The commonly used local anesthetics of the amino-amide and amino-ester classes are of relatively low potency, in that they are administered in the mg/kg range in vivo, and they have blocking concentrations in isolated nerve ranging from 10 mM to 1 mM. There is also the risk of systemic toxicity, evidenced by seizures and cardiac arrythmias, the risk of local nerve toxicity, meaning that high concentrations of current-day local anesthetics can damage nerves and muscles, which is a significant clinical problem with spinal anesthesia with lidocaine. There is also a lack of modality-selectivity, resulting in numbness and low blood pressure along with pain relief.
It has been a long standing goal to obtain local anesthetic formulations enhancing or prolonging nerve blockade with minimal side effects. A number of naturally occurring toxins have much greater intrinsic potency, with concentrations of as low as 10
−7
to 10
−8
M being effective to block conduction of nerve impulses. However, tetrodotoxin systemic toxicity, like that of other local anesthetics, can result in diaphragmatic paralysis leading to respiratory arrest and death. Hypotension, presumably due to smooth muscle relaxation and/or vasomotor nerve blockade, is also a prominent feature. Tetrodotoxin is safer than conventional local anesthetics in a hospital setting with the availability of respiratory support, in that cardiotoxicity is relatively minimal, and tetrodotoxin does not cause seizures. Clinically, the toxic syndrome is similar to curare poisoning.
The site 1 toxins by themselves have too much uptake into the systemic circulation and too little local action to be effective. In the mid-1970s, Adams et al. reported that toxins such as tetrodotoxin and saxitoxin could be combined with local anesthetics to prolong local anesthesia. See U.S. Pat. Nos. 3,966,934, 3,957,996, 4,001,413, 4,029,794, 4,029,793, and 4,022,899 to Adams, et al. Better results were obtained with inclusion of epinephrine. This technology was never developed clinically, however. Published data did not clearly demonstrate nociceptive block, measured as loss of pain sensation. Blockade was simply defined as loss of motor function in the injected limb. The possibility that systemic toxicity was the cause of the observed nerve blocks was also not assessed. The addition of a vasoconstrictor to slow systemic absorption was shown to reduce toxicity and decrease mortality, but neither effect was quantified. Subsequent studies have confirmed that the observations by Adams, et al. were in fact due largely to systemic TTX toxicity (generalized weakness and numbness, and perhaps low blood pressure), not due to local nerve blockade, as they thought.
Other attempts to prolong nerve blockade have involved the use of polymeric formulations providing controlled release of local anesthetics, alone or in combination with a glucocorticoid. For example, U.S. Pat. No. 5,618,563 to Berde and Linger describes biodegradable polymer matrices for sustained release of local anesthetic agents. Dexamethasone was included to avoid inflammation due to the polymer, and was found to increase substantially the period of nerve blockade so that relief could be obtained for periods as long as a few days. There are many disadvantages, however, to the use of the polymeric microparticles, including difficulties in obtaining good suspensions for injection, the need to use a large gauge needle for delivery, polymer residual, and potential risk of infection.
It is therefore an object of this invention to provide improved long acting local anesthetic formulations to provide more prolonged nerve blockade, which is safe, efficacious, and easy to administer.
It is another object of this invention to provide formulations providing modality specific nerve blockade.
SUMMARY OF THE INVENTION
Combinations of naturally occurring site 1 sodium channel blockers, such as tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, and neosaxitoxin (referred to jointly herein as “toxins”), with other agents, have been developed to give long duration block with improved features, including safety and specificity.
In one embodiment, duration of block is greatly prolonged by combining a toxin with a local anesthetic, vasoconstrictor, glucocorticoid, and/or adrenergic drugs, both alpha agonists (epinephrine, phenylephrine), beta-blockers (propranalol), and mixed central-peripheral alpha-2 agonists (clonidine), or other agents.
Modality specific nerve block can be obtained using combinations of toxin with vanilloids.
In another embodiment, the duration of nerve block from toxin can be greatly enhanced by the inclusion of amphiphilic or lipophilic solvents.
In still another embodiment, the effectiveness of these compositions is enhanced by microencapsulation within polymeric carriers, preferably biodegradable synthetic polymeric carriers. As demonstrated by the examples, providing these formulations as microparticulate compositions yields even longer lasting local anesthesia than that obtained with toxin or local anesthesia in solution.


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