United States Patent:  6,046,187

Assignee:  Children's Medical Center Corporation (Boston, MA)

Filed:  September 16, 1996

The use of glucocorticosteroids in methods and formulations for prolonging and/or reactivating local anesthesia or local anesthesia previously induced by a local anesthetic agent, is disclosed.

SUMMARY OF THE INVENTION

In accordance with the above-mentioned objects and others, the invention is related to methods and compositions for reactivating and/or prolonging a local anesthetic effect, that has previously been induced by an implanted or injected local anesthetic formulation.

Accordingly, the present invention broadly provides methods for reactivating and/or prolonging an induced local anesthesia at a site in a patient in need thereof, comprising administering to the patient at a site at which local anesthesia was previously induced, a pharmaceutically acceptable composition that includes a glucocorticosteroid in an amount effective to reactivate and/or prolong the previously induced local anesthesia. The previous local anesthesia is induced by any art known local anesthetic or by a combination of any suitable art-known local anesthetic and any suitable art-known glucocorticosteroid.

The glucocorticosteroid for reactivating and/or prolonging a local anesthesia is administered by, e.g., systemic administration, e.g., orally or intravenously, or by implantation, infiltration, injection and/or infusion at or adjacent to the site requiring reactivated or prolonged anesthesia, and is administered, for example, before or after the local anesthesia has substantially worn off, to provide reactivation and/or prolongation of the effect. At least a portion of the glucocorticoid is administered, simply by way of example, at a time ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 1 to about 12 hours, from about 1 to about 6 hours, and from about 1 to about 4 hours, or from about 4 to about 72 hours and from about 4 to about 24 hours, after the time that the (e.g., first) local anesthetic was administered.

The previously administered local anesthetic is, for example, bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and salts thereof or any other pharmaceutically acceptable art-known local anesthetic or mixtures thereof The glucocorticosteroid is, e.g., dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and mometasone and pharmaceutically acceptable mixtures thereof and salts thereof or any other suitable art-known glucocorticosteroid, either naturally occurring or synthetic.

In the method according to the invention, at least a portion of the glucocorticosteroid may be administered systemically, e.g., orally or by systemic injection, but is preferably administered locally at the desired site in a patient. The locally administered glucocorticosteroid can be administered in immediate release form, in controlled release form or in both immediate release and controlled release form. The immediate release and/or controlled release forms are preferably prepared in a form suitable for injection, infusion and/or application in a pharmaceutically acceptable medium, e.g., as a solution, suspension or even, e.g., as a plurality of microspheres incorporating one or more agents, including a glucocorticosteroid. When controlled release microspheres are provided, at least a portion of the glucocorticosteroid is optionally in immediate release form in the injection medium.

The methods according to the present invention provide a local anesthesia prolonged by reactivation of a previously administered local anesthetic agent, the reactivation providing a local anesthesia having a duration ranging from, e.g., about 1.1 to about 14 fold, or more, of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. In a preferred embodiment, the methods, the prolongation ranges from about 6 to about 13 fold of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. The methods according to the invention are therefore capable of providing an initial period of local anesthetic induced anesthesia, that is either prolonged or that is reactivated to provide a local anesthesia with a duration ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 4 to about 8 hours and from about 1 to about 2 hours, measured from the time of administration of the reactivating composition.

Further, the invention also provides pharmaceutical formulations for providing a regional local anesthesia in a patient that, when administered to a local site in a patient, sequentially releases an effective amount of a pharmaceutically acceptable local anesthetic and then at a time after administration, releases an amount of a glucocorticosteroid effective to reactivate and/or prolong the local anesthesia. Such a pharmaceutical formulation according to the invention also includes an effective amount of a biocompatible, controlled release material effective to prolong the release of said local anesthetic from said formulation and effective to delay the release of the glucocorticosteroid for a desired time after administration. Simply by way of example, the glucocorticoid agent according to the invention can be released or administered at the desired site at any time, but preferably at least a portion that is effective to prolong and/or reactivate the desired local anesthesia is released or administered after the local anesthetic has been administered. At least a portion of the glucocorticoid is released from said formulation, simply by way of example, at a time ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 1 to about 6 hours, or from about 4 to about 24 hours and from about 1 to about 2 hours, measured from the time that the (e.g., first) local anesthetic was administered.

While any pharmaceutically acceptable controlled release material may be employed, the pharmaceutically acceptable controlled release materials preferably are prepared from a polymer such as, for example, polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins and/or polysaccharides.

A pharmaceutically acceptable local anesthetic is, for example, ropivacaine, bupivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof and others well known to the art. The local anesthetic is incorporated into the controlled release formula at a weight percent ranging from about 0.1 to about 90%

A pharmaceutically acceptable glucocorticosteroid includes, e.g., dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and/or mometasone and pharmaceutically acceptable mixtures salts thereof or any other suitable glucocorticosteroid known to the art. Preferably, dexamethasone is used.

The pharmaceutically acceptable formulation according to the invention provides a reactivated local anesthesia of a duration ranging from about 1.1 to about 14 fold, or more, of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. In a preferred embodiment, the methods, the prolongation ranges from about 6 to about 13 fold of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. The methods and formulations according to the invention are therefore capable of providing an initial period of local anesthetic induced anesthesia, followed by a second period of anesthesia, that is either prolonged or that is reactivated to provide a second period of local anesthesia.

Claim 1 of 60 Claims

1. A method for reactivating or prolonging local anesthesia at a site in a patient in need thereof, comprising

administering to a patient at a site at which local anesthesia is desired, a pharmaceutically acceptable composition comprising an effective amount of a local anesthetic, and thereafter

administering a glucocorticosteroid agent, in an amount effective to reactivate or prolong local anesthesia, said glucocorticosteroid agent being administered at a time ranging from about 1 to about 72 hours after said local anesthetic was administered.

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