Enhanced transdermal anesthesia of local anesthetic agents

Details Enhanced transdermal anesthesia of local anesthetic agents Enhanced transdermal anesthesia of local anesthetic agents

1999-07-19

2001-10-09

Williamson, Michael A. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S447000, C424S443000, C424S078050, C424S078070, C514S817000, C514S887000, C514S947000, C514S969000

Reexamination Certificate

active

06299902

ABSTRACT:

BACKGROUND OF THE INVENTION
The search continues for a safe and effective topical anesthetic preparation that can ease the pain during dermal procedures, such as venipuncture, intravenous cannulation, punch biopsy and other small incisions, vaccination, and circumcision. A preparation that is safe for use in newborns is especially needed, since circumcision remains a common medical procedure performed on newborns, and existing scientific evidence demonstrates potential medical benefits of newborn male circumcision. Unfortunately, circumcision of infants is typically performed without any pain-relief treatment even though the American Academy of Pediatrics recommends procedural analgesia (AAP Circumcision Policy Statement, March 1999, pp. 686-693) because safe and effective topical preparations are not currently available.
EMLA cream (Astra Pharmaceuticals, Inc., Westboro, Mass.), a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% in an emulsified topical cream (U.S. Pat. No. 4,562,060; U.S. Pat. No. 4,529,601), is the only topical anesthetic product currently marketed in many countries, including the United States, for use on intact skin. Because EMLA cream contains a relatively high concentration of local anesthetic in its oil phase, it exhibits improved efficacy on intact skin compared with other conventional local anesthetic formulations, which are effective only on mucous membranes.
Metabolites of prilocaine, however, are known to be responsible for methemoglobinemia, a serious condition characterized by the ferric form of hemoglobin with impaired oxygen-carrying capacity (B. Jakobson et al.,
Acta Anaesthesialogica Scandinavica
29: 453-455 (1985)). As a result, the use of EMLA in young children has been severely restricted. For example, in the United States, EMLA is currently contraindicated in infants under 3 months old (M. Buckley et al., Drugs 46:126-151 (1993)), and in infants up to 1 year of age who are also receiving methemoglobin-inducing agents (Physician's Desk Reference, 49
th
Ed., Medical Economics Data Production Company, Montvale, N.H. (1995)). In the United Kingdom, EMLA is not approved for use in children under 1 year of age (S. Russell et al.,
Drug Safety
16:279-287 (1997)). Also, the Drug Information Handbook, 4
th
Ed. (1996-1997), published by the American Pharmaceutical Association, states that EMLA cream should not be used in infants under the age of 1 month. Very young patients, and patients with glucose-6-phosphate deficiencies, show increased susceptibility to methemoglobinemia.
Lidocaine, on the other hand, is safe and is the most widely used local anesthetic agent. However, due to low permeability of lidocaine through the stratum corneum, the efficacy of lidocaine alone for topical anesthesia through intact skin has to date been extremely disappointing. Conventional lidocaine creams may be readily prepared by simply dissolving lidocaine in a suitable pharmaceutical oil and emulsified, but these creams can not effectively deliver lidocaine for transdermal anesthesia on intact skin. Efficacy can only be achieved when the concentration of lidocaine in the topical formulation is unacceptably high (e.g., greater than about 30% by weight), posing a risk of systemic toxicity. Limited by the intrinsic solubility of lidocaine in pharmaceutical oils, lidocaine concentration in the oil phase of conventional creams cannot reach the concentration that is necessary for effective transdermal delivery.
EMLA cream achieves higher concentrations of lidocaine in the oil phase compared to other creams by including prilocaine in the formulation, thereby facilitating the solid to oil phase transition of lidocaine. The resulting eutectic mixture has a lidocaine:prilocaine ratio that ranges from 20:80 to 58:42 (U.S. Pat. No. 4,562,060) and the commercially available product (EMLA) has a lidocaine:prilocaine ratio of 50:50. However, as noted above, prilocaine is known for causing methemoglobinemia in children.
A preparation containing lidocaine but little or no prilocaine would, therefore, have a significant clinical advantage over EMLA and would also expand the use of topical anesthetics in children and particularly in infants and newborns.
SUMMARY OF THE INVENTION
A novel composition is provided that can be readily formulated into a topical anesthetic preparation. Preferred embodiments of the anesthetic preparation of the invention are characterized by enhanced transdermal absorption and safe and effective transdermal anesthesia through intact skin. The composition has two liquid phases: an aqueous phase and an oil phase, wherein the oil phase has a relatively high concentration a local anesthetic agent, preferably lidocaine. An aqueous phase is a phase that comprises water. Preferably, both the aqueous phase and the oil phase are homogeneous. A “homogenous” aqueous phase or oil phase is a liquid phase in which none of the components is present in a solid state. The aqueous and oil phases of the composition of the invention are preferably homogenous phases at about 37° C.; more preferably, they are homogenous phases at about 25° C. It should nonetheless be understood that the invention also encompasses two phase liquid compositions that contain nonhomogenous aqueous and/or oil phases; that is, the presence of some solids in the aqueous phase or the oil phase, or both, is not necessarily excluded.
The concentration of the local anesthetic agent in the oil phase of the composition is preferably at least about 60%, by weight, of the weight of the oil phase; more preferably it is at least about 70% by weight, of the weight of the oil phase; even more preferably it is at least about 80%, by weight, of the weight of the oil phase; most preferably it is at least about 85%, by weight, of the weight of the oil phase of the composition.
A preferred two phase liquid composition of the invention contains:
(a) a local anesthetic agent, preferably at least about 1% of the total composition, by weight, more preferably at least about 3% of the total composition, by weight, and preferably less than about 20% of the total composition, by weight, more preferably less than about 10% of the total composition, by weight;
(b) a first melting point depressing agent, preferably in an amount of at least about {fraction (1/20)} of the weight of the local anesthetic agent, more preferably at least about {fraction (1/10)} of the weight of the local anesthetic agent; and preferably less than about ⅔ of the weight of the local anesthetic agent, more preferably less than about ¼ of the weight of the local anesthetic agent;
(c) a second melting point depressing agent, preferably at least about 1% of the total composition, by weight, more preferably at least about 5% of the total composition, by weight, most preferably at least about 10% of the total composition, by weight, and preferably less than about 30% of the total composition, by weight, more preferably less than about 20% of the total composition, by weight, most preferably less than about 15% of the total composition, by weight; and
(d) water to 100%.
The local anesthetic agent is typically a solid at ambient temperature. However, it is to be understood that the term “solid” is used broadly to include hygroscopic compounds and other solids that, under certain conditions, take a semisolid form. When the local anesthetic agent is a solid, melting of the solid yields an oil. The first melting point depressing agent is typically a solid or an oil at ambient temperature. When the first melting point depressing agent is a solid, melting of the solid yields an oil. Preferably, the local anesthetic agent and the first melting point depressing agent have melting points lower than about 200° C.; more preferably, they have melting points lower than about 160° C.; most preferably, they have melting points lower than about 120° C.
Methods for making the two phase liquid composition of the invention are also provided. Components of the composition are mixed together in amounts effective to form a two phase liquid composition co

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