Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-07-12
2001-05-29
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S422000, C424S426000
Reexamination Certificate
active
06238702
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to biocompatible controlled release formulations including formulations comprising surprisingly high loads of local anesthetic, for providing local anesthesia of sustained duration, as well as to methods for providing the same.
BACKGROUND OF THE INVENTION
While compounds utilized as general anesthetics reduce pain by producing a loss of consciousness, local anesthetics act via a loss of sensation in the localized area of administration in the body. The mechanism by which local anesthetics induce their effect, while not having been determined definitively, is generally thought to be based upon the ability to locally interfere with the initiation and transmission of a nerve impulse, e.g., interfering with the initiation and/or propagation of a depolarization wave in a localized area of nerve tissue. The actions of local anesthetics are general, and any tissue where nerve conduction, e.g., cell membrane depolarization occurs can be affected by these drugs. Thus, nervous tissue mediating both sensory and motor functions can be similarly affected by local anesthetics.
The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with the nervous tissues. Consequently, previous attempts to prolong the duration of local anesthesia have focused on. procedures or formulations that maintain localization of the drug at the nerve. For example, epinephrine is art known to briefly prolong the action of local anesthetics by inducing vasoconstriction adjacent to the site of injection. However, the duration of prolongation provided by epinephrine is on the order of about an hour, at best, in a highly vascularized tissue. This strategy is also severely limited by the risk of gangrene due to prolonged impairment of blood flow to local tissues.
The art has also attempted to prolong the duration of local anesthesia by providing more lipid-soluble compounds for use as long-acting anesthetics, i.e., local anesthetics that have a prolonged local anesthetic affect, but even these compounds provide a relatively limited duration of activity. For example, local anesthetics with a relatively short duration of action include, e.g., procaine with a duration of ranging from about 20-45 minutes, local anesthetics with an intermediate duration of action, e.g., lidocaine or mepivacaine, with a duration of action ranging from about 60-120 minutes and local anesthetics with a long duration of action, e.g., bupivacaine or etidocaine, with a duration ranging, under the most favorable circumstances, from about 400 to 450 minutes. However, this strategy for prolonging local anesthesia is limited by the possibility of local and systemic toxicity from excessive drug levels.
In fact, all local anesthetics are toxic, i.e., potentially toxic, and therefore it is of great importance that the choice of drug, concentration, rate and site of administration, as well as other factors, be considered in their use. On the other hand, as the preceding discussion makes clear, a local anesthetic must remain at the site long enough to allow sufficient time for the localized pain to subside.
Other pharmacological methods for prolonging local anesthesia have also been tried. European Patent Application No. 93922174.3 by Children's Medical, Center Corporation, discloses biodegradable synthetic polymers releasing local anesthetic over prolonged periods of time, as measured in vitro. Dexamethasone was included in the described formulation simply in order to avoid inflammation due to the polymer that was employed, however, the formulations described therein were of relatively low loading, e.g., microspheres with about 20% loading were exemplified, and it was taught by that publication that the duration of local anesthetic action was dependent upon the nature of the controlled release polymers described therein.
Other formulations directed to injectable microparticles and/or microcapsules, etc. are known. For example, U.S. Pat. No. 5,061,492 related to prolonged release microcapsules of a water-soluble drug in a biodegradable polymer matrix which is composed of a copolymer of glycolic acid and a lactic acid. The microcapsules are prepared as an injectable preparation in a pharmaceutically acceptable vehicle. The particles of water soluble drug are retained in a drug-retaining substance dispersed in a matrix of the lactic/glycolic acid copolymer in a ratio of 100/1 to 50/50 and an average molecular weight of 5,000-200,000. The injectable preparation is made by preparing a water-in-oil emulsion of aqueous layer of drug and drug retaining substance and an oil layer of the polymer, thickening and then water-drying. In addition, controlled release microparticles containing glucocorticoid agents are described, for example, by Tice et al. in U.S. Pat. No. 4,530,840.
In order to provide local anesthesia for extended periods, i.e., for more than about six hours, clinicians currently use local anesthetic agents administered through a catheter or syringe to a site where anesthesia is to be induced. Thus, prolonged local anesthesia, where the anesthesia is to be maintained over a period of greater than about 6 hours, has heretofore required that local anesthetic be administered either as a bolus or through an indwelling catheter connected to an infusion pump.
Thus, it has not heretofore been known to provide controlled release formulations with a relatively high loading of local anesthetic at a level that is substantially above 20% by weight, that is able to provide both a controlled release of local anesthetic and a substantially prolonged local anesthesia. It has also not heretofore been known to combine a formulation with a relatively high loading of a local anesthetic, e.g., substantially above 20% by weight, with a glucocorticosteroid agent in either immediate release or controlled release form, for providing prolonged local anesthesia that is achieved without a significant modification of the in vitro kinetics of local anesthetic release from the formulation.
OBJECTS OF THE INVENTION
It is therefore an object of the present invention to provide a controlled release dosage form for prolonged treatment of localized areas in humans and animals. More particularly, it is an object of the invention to provide formulations and methods for delivering a high load of local anesthetic in a biocompatible, controlled release form which provides a prolonged local anesthesia.
It is a further object of the present invention to provide a method for prolonging the effect of a local anesthetic agent at a desired site of treatment which is safe and effective, particularly for the control of post-operative pain.
It is a still further object to prolong the duration of the local anesthesia by administering a glucocorticosteroid agent (also referred to herein as glucocorticoid agents) in combination with a high loading of local anesthetic formulation or separately from the local anesthetic formulation, before, during or after the infiltration, injection or implantation of the compositions according to the invention.
SUMMARY OF THE INVENTION
In accordance with the above-mentioned objects and others, the invention is related to controlled release formulations for the prolonged administration of a high load, by weight percent, of a local anesthetic agent. In a preferred aspect, the high load controlled release local anesthetic is administered in combination with a glucocorticosteroid agent that is effective to prolong the duration of the local anesthetic effect, in vivo, for a time period greater than that possible by the use of the local anesthetic in controlled release form alone. Methods for the manufacture thereof are also disclosed. The controlled release formulation can be formed into slabs, pellets, microparticles, e.g., microspheres or microcapsules, spheroids and pastes suitable for insertion, implantation, injection, infiltration or topical application. Preferably, the formulation is in a form suitable for suspension in isotonic saline, physiological buffe
Berde Charles B.
Castillo Jenny
Curley Joanne
Langer Robert S.
Bennett Rachel M
Children's Medical Center Corp.
Davidson Davidson & Kappel LLC
Spear James M.
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