Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1997-11-14
2001-09-25
Seidel, Richard K. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
Reexamination Certificate
active
06295469
ABSTRACT:
TECHNICAL FIELD
The present invention relates to non-invasive, electrically-assisted delivery of lidocaine through a body surface such as intact skin.
BACKGROUND ART
Anesthetics are drugs which produce anesthesia, a condition characterized by the inability to appreciate sensation. Two types of anesthesia are generally recognized: local anesthesia and general anesthesia. In local anesthesia, the anesthesia is confined to a portion of the body, whereas in general anesthesia, the anesthesia extends to the entire body.
Local anesthetics reversibly block impulse conduction in peripheral nervous tissue, thereby producing a transient loss of sensation in a circumscribed area of the body without causing a general loss of consciousness. This action can be used to block pain sensation to a specific area of the body. Hence, local anesthetics are used to prevent pain in surgical procedures, dental manipulations, injury and disease.
Lidocaine is a local anesthetic which may be applied topically, for example, to mucous tissues. However, its effectiveness as a topical anesthetic is limited by its low adsorption rate (via passive diffusion) through the skin; the salts of lidocaine do not diffuse through intact skin to any appreciable degree, whereas the base forms of lidocaine diffuse through intact skin only to a limited degree.
The hydrochloride salt form of lidocaine (lidocaine HCl) is also widely used as a local anesthetic and is normally administered via injection. However, systemic absorption of lidocaine can lead to adverse side effects such as drowsiness, confusion, nausea, seizures and coma. These side effects are aggravated by the vasodilating effect of lidocaine, which increases the rate of its absorption into the systemic blood circulation.
Systemic absorption can be reduced by the addition of a vasoconstrictor. For example, the presence of epinephrine helps retard adsorption of lidocaine, thereby reducing its systemic toxicity. Epinephrine has other desirable effects as well. For example, it may be desirable to increase the duration of the drug's local anesthetic effect. The duration of action of lidocaine, as with any local anesthetic, is proportional to the time during which it is in actual contact with nerve tissues. The vasoconstrictive effect of epinephrine maintains localization of lidocaine at the nerve thereby prolonging the drug's anesthetic effect, increasing the duration of action of lidocaine, as well as increasing its efficiency by decreasing the volume of solution required to achieve an anesthetic effect. In addition to reducing the systemic absorption of lidocaine, epinephrine acts to reduce bleeding at the site of the (i.e., subsequent) surgical procedure.
However, epinephrine is difficult to work with as it is rapidly degraded in the presence of oxygen (U.S. Pat. No. 5,334,138). Moreover, the addition of epinephrine to hydrochloric solutions of lidocaine reduces the storage stability of the anesthetic solution (WO 91111182).
In addition to problems associated with the side effects of lidocaine, local injection of the drug can be painful, particularly in sensitive areas of the body such as the face.
Although iontophoresis has been used as a painless and effective method to deliver lidocaine into the skin (Comeau et al., Arch Otolaryngol 98:114-120 (1973)), as with administration by injection, removal of lidocaine by the vasculature and subsequent systemic adsorption can result in toxic side effects. Although the use of vasoconstrictors to reduce adsorption of iontophoretically delivered drugs has been suggested, instability of epinephrine remains problematic (U.S. Pat. No. 5,334,138).
Thus, a need exists for stabilized formulations of lidocaine as well as non-invasive, convenient means of administering lidocaine which result in increased localized anesthetic effect of the drug.
DISCLOSURE OF THE INVENTION
The present invention relates to the electrically assisted transport of lidocaine and epinephrine. Specifically, the invention provides compositions for the electrically assisted delivery of lidocaine and epinephrine. Preferably, the compositions comprise about 1-10% lidocaine and about 0.01-0.2% epinephrine. In a preferred embodiment, both lidocaine and epinephrine are positively charged. Preferably, the compositions comprise lidocaine HCl and epinephrine bitartrate.
The compositions preferably further comprise one or more anti-oxidants, metal chelators or other agents, which deter microbial growth and enhance the stability of the epinephrine. Preferably, the antioxidant is sodium metabisulfite. Preferably, the metal chelator is edetate bisodium dihydrate.
The present invention further provides an electrotransport delivery device for delivering one or more agents, preferably a local anesthetic, and preferably lidocaine, by electrotransport through a body surface such as skin. The device comprises a pair of electrode assemblies, at least one of the assemblies comprising the agent to be delivered, and a source of electrical power adapted to be electrically connected to the pair of electrode assemblies. The device comprises a circuit means connecting the pair of electrode assemblies and the source of electrical power, the circuit means comprising an activation circuit and a current generating circuit. The activation circuit, which comprises a body surface resistance detection circuit and a current pulsing circuit, is electrically connected to the power source. The activation circuit is responsive to the completion of a circuit between the electrode assemblies, wherein upon completion of the circuit, the resistance detection circuit detects the resistance between the electrode assemblies (i.e., the electrical resistance of the body surface). Where the resistance is equal to or greater than a pre-determined threshold value, a pulsed voltage is delivered across the electrode assemblies which is effective to reduce the resistance of the body surface to a value less than the threshold value. Where the resistance is less than the threshold value, whether initially or as a result of being lowered by delivery of pulsed voltage, the activation circuit activates the current generating circuit. The generating circuit is electrically connected to the activation circuit for generating current for delivering the agents and is selectively activatable by the activating circuit. The activation circuit draws substantially no power consumption when the circuit between the electrodes assemblies is open, while the current generating circuit draws substantially no power consumption when not activated.
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Grubstein, et al.: “Stabilization of Epinephrine in a Local Anesthetic Injectable Solution Using Reduced Levels of Sodium Metabisulfite and EDTA”, Drug Development and Industrial Pharmacy, vol. 18 (14), pp. 1549-1566, (1992), XP002056303.
Comeau, Maurice et al., Arch Otolarynol./vol. 93,
Chin Ivan W.
Gyory J. Richard
Linkwitz Andreas
Thompson Ronald V.
Urbanski Paul J.
ALZA Corporation
Bates Owen
Hayes Michael J
Miller D. Byron
Seidel Richard K.
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