WO1995016444A1

WO1995016444A1 - Composition and method for producing local anesthesia of the skin

Info

Publication number: WO1995016444A1
Application number: PCT/US1994/014520
Authority: WO
Inventors: Albert M. Kligman; Thomas J. Franz
Original assignee: Kligman Albert M; Franz Thomas J
Priority date: 1993-12-13
Filing date: 1994-12-13
Publication date: 1995-06-22
Also published as: AU1403195A

Abstract

Local anesthesia of human or animal skin may be achieved with a topical solution of about 10 to 30 percent (w/v) lidocaine base dissolved in dimethyl sulfoxide (DMSO) solution. Preferably, the DMSO vehicle is a 60 to 90 (v/v) solution of DMSO in a dermatologically-acceptable solvent, such as ethanol. With a dosage of about 0.5 to 5 mg/cm2 of skin to be anesthetized, acceptable anesthesia is achieved in about 15 to 30 minutes on human facial skin and in about 1 to 2 hours on skin of the trunk or extremities. The topical anesthetic is particularly useful in minor surgical procedures on the skin, such as treatment of vascular malformations, for example by pulsed dye laser treatment.

Description

COMPOSITION AND METHOD FOR PRODUCING LOCAL ANESTHESIA OF THE SKIN

Field of the Invention

The present invention is directed to a local anesthetic for topical application to the skin, particularly for use prior to performing minor surgical procedures on the skin.

Background Of The Invention A painless topical anesthetic would be greatly appreciated by both patients and physicians for any painful procedure, particularly in pediatrics. Many surgical procedures which are not so extensive or invasive as to require general anesthetic, but which are nevertheless painful, require a local anesthetic. Despite the fact that such procedures may only involve the treatment of the skin (epidermis and dermis) , most such anesthetics must be applied by intradermal injection in order to give adequate anesthesia.

Examples of common painful surgical procedures which are performed on the skin of children include removal of warts and molluscum contagiosum, vaccine injections, venipuncture for blood samples, etc. Treatment of capillary vascular malformations, such as port wine stains and hemangiomas, with pulsed dye laser is now becoming commonplace. Small lesions can be treated without anesthesia, but young children with involvement of large areas do not tolerate the procedure very well. Many children do not tolerate pain well, so that the length of a single treatment is often limited by pain. Since many of these lesions are large and may encompass half of the face or an entire limb, multiple visits become necessary to complete treatments of the entire site.

It would therefore be advantageous to have a rapidly acting topical anesthetic which would reduce the pain associated with pulsed dye laser therapy and other painful surgical procedures, particularly for children's skin, yet one which will wear off within a few hours and have no prolonged side effects . Other minor surgical procedures which would benefit from such an anesthetic would include excision of tumors, biopsies, etc. , in both children and adults.

Lidocaine in the form of lidocaine hydrochloride is widely used as a local anesthetic but must be injected intradermally to give satisfactory anesthesia. Lidocaine hydrochloride is a water soluble, polar salt which does not penetrate the skin when applied topically. As a result, lidocaine creams have been ineffective, and cannot be used in preparation for surgical procedures.

Some physicians make up topical anesthetic preparations (e.g., 30 percent (w/w) lidocaine in proprietary creams, such as Acid Mantle Cream available from Dorsey Laboratories of Lincoln, NE) in their offices to apply to children. However, the ability of these preparations to penetrate skin has not been assessed. Anesthetic patches using lidocaine in Acid Mantle Cream have also been used for cutaneous anesthesia. When we performed in vitro penetration studies, we found that only a small amount of the lidocaine mixed in Acid Mantle Cream was absorbed percutaneously. This is insufficient to create a satisfactory degree of anesthesia. There are many other "caine" type anesthetics on the market, but all have the same deficiency. They do not induce local anesthesia and cannot prevent the pain of even a local injection and certainly not the pain of an excision biopsy. Benzocaine creams can induce anesthesia of the mucus membranes, such as the mouth, but are completely ineffective when applied to the skin, such as the face, extremities and trunk. EMLA (Eutectic Mixture of Local Anesthetics) is a combination cream of 2.5 percent lidocaine and 2.5 percent prilocaine, which has been used for several years in Europe and has just recently become available in the United States from Astra Pharma Inc. of Mississauga, Ontario, Canada. While EMLA is becoming a well-known anesthetic for superficial pain reduction, it must be used under an impermeable film (occlusive dressing) generally for an hour or more. Actually, we have found that it delivers very little anesthetic drug , within two hours of application.

Prechner, V.L. et al . , "Dermal Anesthesia By The _v 5 Topical Application of Tetracaine Base Dissolved in Dimethyl Sulfoxide, " Annals of the New York Academy of Science, 141:524-531 (1967), have reported the use of 33 percent tetracaine base in 100 percent DMSO to achieve dermal anesthesia. DMSO is known as a penetration enhancer. 10 However, a major disadvantage for neat DMSO is its whealing response, often surrounded by an erythematous flare.

Various other methods to increase percutaneous absorption of medicines have been used in the past. For example, iontophoresis, the electrical enhancement of ionic 15 transport, increases penetration of topical medications but requires special equipment and trained technicians. There is a need for a simple and convenient topical method of achieving anesthesia.

Therefore, it would be desirable to have an 20 effective local anesthetic which can be applied simply and painlessly without intradermal injection, by a non-invasive topical procedure, and which does not produce undesired side effects.

25 Brief Summary of the Invention

According to the present invention, the above objectives are achieved by a topical solution for local anesthesia of human or animal skin comprising about 10 to 30 percent (w/v) lidocaine base dissolved in a solution of 30 dimethyl sulfoxide (DMSO) . Preferably, the DMSO is diluted to a 60 to 90 percent (w/v) concentration in a dermatologically- acceptable solvent, such as ethanol. K The topical solution is applied in an amount effective to produce anesthesia limited to the area of the ,35 skin to which it is applied. The solution can be applied about M hour to 2 hours, preferably about 30 to 90 minutes, prior to a surgical procedure. Surgical procedures for which the topical anesthesia is particularly suitable include treatment of vascular malfunctions, such as by pulsed dye laser treatment. The topical solution is applied to the skin at a dosage equivalent to about 0.5 to 5 mg lidocaine base per cm² of skin being anesthetized. The amount of lidocaine absorbed, assuming complete absorption, is far less than that required to produce unwanted systemic effects.

Detailed Description of Preferred Embodiments

Lidocaine free base is a traditional local anesthetic and is commercially available, for example, from Sigma Chemical Company of St. Louis, MO. The free base is lipid soluble and for that reason has a greater likelihood of being absorbed topically. Nevertheless, even 25 percent (w/v) solutions of lidocaine base in various lipid solvents and enhancers have not achieved anesthesia sufficient for surgical interventions such as excision of tumors, biopsies, laser treatments, etc. Dimethyl sulfoxide is a known penetration enhancer which makes the horny barrier layer of the skin more permeable to external chemicals. DMSO is also available commercially, for example, from Sigma Chemical Company of St. Louis, MO. The permeation enhancement with DMSO occurs in less than 30 minutes. In fact, at concentrations of 90 to 100 percent

(v/v) DMSO, the skin becomes permeable to many substances in less than 10 minutes.

Neat DMSO is unacceptable because it produces intense itching and a tense wheal (hive) surrounded by a red flare. Even at 90 percent (v/v) concentrations DMSO causes a transient wheal which flattens in 10 to 15 minutes but may be considered undesirable by general practitioners. On the other hand, at concentrations of 70 to 80 (v/v) percent DMSO these responses are muted and short-lived, with no after-effects on the skin. Therefore, according to the present invention it is preferred to use as a vehicle for the lidocaine base a solution of DMSO in a, dermatologically-acceptable liquid solvent, preferably an alcoholic solvent such as ethanol. Concentrations of DMSO in this solvent preferably range from about 60 to 90 percent (v/v) , and most preferably about 70 to 80 percent (v/v), particularly when the solvent is ethanol. Lidocaine free base readily goes into solution in the above dilutions of DMSO and has been found to produce appreciable anesthesia at concentrations of about 10 to 30 percent (w/v) , more preferably about 15 to 30 percent (w/v) , and optimally about 25 percent (w/v) of the lidocaine base in the DMSO solution.

The topical solution may be applied to the skin in any convenient manner, such as by a glass rod, spatula, dropper, swab, or other known means. As with injectable lidocaine, the amount of topical lidocaine applied should be limited. Large areas, such as an entire limb, should not be freely painted with the topical solution, nor should it be used on infants, without considering systemic absorption.

Major toxic effects of lidocaine involve the heart and central nervous system (CNS) . Cardiac effects occur because of direct action on the heart causing heart block in patients with pre-existing bundle-branch disease. CNS effects can be seen when the serum lidocaine concentration is 5 mg/L or greater. Dizziness, drowsiness, perioral paresthesias, and tinnitus may be seen early, and more toxic effects include delirium, disorientation, convulsions and coma.

However, recommended dosage ranges for the topical solutions of the present invention are about 0.5 to 5 mg/cm² of skin to be anethetized. At the maximum topical dose of 5 mg/cm², treatment of a 5 cm² lesion in a 10 kg child would yield a dose of only 2.5 mg/kg, assuming total absorption of lidocaine. Treatment of larger areas would be possible in larger childen, e.g. application of the maximum does of 5 mg/cm² to 20 cm² would give a topical dose of 100 mg lidocaine, equivalent to 4.0 mg/kg in a 25 kg child. Again this assumes the unlikely event of total absorption. Even if totally absorbed, this dosage of topical lidocaine is less than what is recommended for maximum intralesional use, i.e., 4.4 mg/kg (1993 Physicians Desk Reference) . Topical use is inherently safer than intralesional use in that not only is the full dose not absorbed when applied to the skin, but the rate at which it is absorbed systemically is much slower and results in much lower blood levels. No evidence of EKG anomalies or cardiac or CNS disturbances has been observed in our trials.

The topical anesthetic solutions of the present invention may be used in connection with a variety of surgical procedures, including, for example, excision of tumors, injections, biopsies, laser treatments, chemical peels, etc. In general, the topical solutions of the invention are satisfactory for most minor procedures where a local anesthetic is desired and a general anesthesia or conscious sedation is not acceptable. The topical anesthetics of the invention have been found to be particularly useful in connection with the treatment of capillary vascular malformations, such as by pulsed dye laser treatment.

The topical solution should be applied to the skin about M hour to 2 hours, and preferably about 30 to 90 minutes, prior to the intended surgical procedure, depending upon the area of skin to be treated. Thus, in the case of human facial skin, anesthesia is usually achieved within about 15 to 30 minutes, whereas satisfactory anesthesia of the skin of the trunk or extremities may require as much as 1 to 2 hours. The anesthesia lasts long enough to perform minor surgery, at least 10 minutes.

In general, the topical anesthetic solutions of the present invention are well tolerated and produce no side effects except transient mild erythema. The topical solutions are painless and simple to use, requiring no special equipment and no occlusive dressings. Since no injection is required, the solutions are particularly desirable for minor skin surgery on children who hate needles and often have a low threshold of pain.

The invention will now be described in more detail with reference to the following specific, non-limiting example.

Clinical Evaluation The efficacy of 25% (w/v) lidocaine in 70% DMSO/ethanol solution was evaluated in 14 patients, ages 6 years and older, who were undergoing SPTL-1 laser (Candela Corporation, Wayland, MA) treatment for vascular malformations. A wavelength of 585 nm, a pulse duration of 450 microseconds, and a circular spot size of 5 mm was used. Power densities ranged from 6.00 J/cm² to 6.75 J/cm² depending upon the depth of color of the lesion. The lesions were outlined with a ball-point pen prior to applying solution, so that we could tell where the vascular lesion stopped if wheals developed from the solution. The experimental formulation was applied by dropper directly to the involved area of skin and spread with a plastic spatula. No more than 6 drops were used in any one patient, and each drop was found to deliver approximately 0.05 ml, or 12.5 mg lidocaine. Each drop covered approximately 1 to 2 cm².

When used on the extremities, the application site was covered with plastic wrap to prevent the unintentional removal of the anesthetic by clothes or physical contact until treatment was begun. When application was made to the face, the site was not occluded. Treatment was initiated 20 to 30 minutes after face application, and 1.5 to 2 hours after extremity or trunk application. Just prior to treatment, the area was cleansed with alcohol and the patient connected to an electrocardiogram (EKG) monitor. EKG readings were taken prior to, during, and immediately after treatment, as a precautionary measure to monitor lidocaine toxicity. Initially, an untreated area adjacent to the application site (2 to 6 cm distant) was pulsed, once or twice, with the laser. The farthest distance within the lesion was chosen to obviate diffusion of lidocaine. Using this site as a control (most painful) , the patient was then asked to assess the percentage improvement in pain following pulsing with the same fluence and number of pulses to the treated site. This was done using a visual analog scale of 0 to 10, and confirmed with a verbal scale, where 0 represented no pain and 10 represented pain equivalent to the untreated site. After documentation of the results, treatment of the patient's lesion was completed.

Thirteen out of fourteen patients had some degree of anesthesia (see Table 1) measured on a visual analog scale, ranging from 10 to 100 percent (mean 51.4 percent) . The youngest patient, age 7, (Patient 1) who described no anesthesia (0%) showed demonstrable excitability after the testing dose, and refused to be calmed. Patient 7, age 13 years, was mildly mentally retarded, and became inconsolable after the first laser dose. Other patients were very cooperative. The two oldest patients (ages 55 and 50 years) both had a very high tolerance to pain and independently stated that perhaps this biased their interpretation of anesthesia.

Many times a patient could tell exactly where the anesthetic was placed, and started complaining of pain when laser treatment progressed outside the anesthetized area, even without visually observing the sites under treatment. This demonstrated that anesthesia occurred specifically within the application area with very little diffusion into surrounding areas by the lidocaine. Measurement of pain or anesthesia is difficult to assess and is highly subjective. Visual analog scales for measuring pain in adults have a higher sensitivity than the traditional simple descriptive verbal scale. We used both in our study, mainly to confirm that the patient understood the procedure and the scale. Because many of our patients were young, we also needed to verify their understanding of the scale.

Time to achieve anesthesia varied from relatively rapid onset (about 20 to 30 minutes) on the face, to longer onset (1 to 2 hours) on extremities and trunk. No patients complained of stinging or itching at the site of application of the anesthetic, and initial transient local redness, which was seen in all patients, normalized by the time of laser treatment. No EKG abnormalities were noted before, during, or after treatment. Cosmetic results were comparable to those patients or areas where no anesthesia was used.

In summary, 25 percent (w/v) lidocaine base mixed in 70 percent DMSO/ethanol is an effective and well tolerated topical anesthetic which can be applied in the office prior to procedures, such as the above use of the pulsed dye laser. This approach did not produce total anesthesia, but proved sufficient to complete a treatment with minimal discomfort as opposed to bringing the patient back multiple times for therapy. It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

TABLE 1: Patient demographics, treatment parameters and percent improvement of pain (anesthesia) in patients undergoing SPTL-1 laser treatment for vascular malformations.

Patient Aqe Area Treated Energy Used Percent Comment Number (yrs) (J/cm²) Improvement of Pain

Inconsolable after initial laser test dose

Inconsolable after initial laser test ose.

High pain threshold.

High pain threshold.

Claims

1. A topical composition for local anesthesia of human or animal skin comprising about 15 to 30 percent (w/v) lidocaine base dissolved in dimethyl sulfoxide (DMSO) solution.

2. A topical composition according to claim 1 wherein the lidocaine base is present in the DMSO solution in an amount of about 25 percent (w/v) .

3. A topical composition according to claim 1 wherein the DMSO solution comprises a dermatologically- acceptable solvent.

4. A topical composition according to claim 3 wherein said solvent is ethanol.

5. A topical composition according to claim 3 wherein the DMSO is present in the solvent in an amount of about 60 to 90 percent (v/v) .

6. A topical composition according to claim 5 wherein the DMSO is present in the solvent in an amount of about 70 to 80 percent (v/v) .

7. A topical composition according to claim 1 comprising about 25 percent (w/v) lidocaine base dissolved in a vehicle comprising about 70 to 80 percent (v/v) DMSO in ethanol.

8. A method of locally anesthetizing human or animal skin comprising topically applying to the skin a composition comprising about 10 to 30 percent (w/v) lidocaine base dissolved in dimethyl sulfoxide (DMSO) solution, the composition being applied in an amount effective to produce anesthesia of substantially only the skin to which the composition is applied.

9. A method according to claim 8 wherein the lidocaine base comprises about 25 percent (w/v) of the composition.

10. A method according to claim 8 wherein the DMSO is dissolved in a dermatologically-acceptable solvent.

11. A method according to claim 10 wherein said solvent is ethanol .

12. A method according to claim 10 wherein the DMSO is present in the solvent in an amount of about 60 to 90 percent (v/v) .

13. A method according to claim 12 wherein the DMSO is present in the solvent in an amount of about 70 to 80 percent (v/v) .

14. A method according to claim 8 wherein the composition comprises about 25 percent (w/v) lidocaine base dissolved in a vehicle comprising about 70 to 80 percent (v/v) DMSO in ethanol.

15. A method according to claim 8 wherein said composition is applied to human skin about M to 2 hours prior to a surgical procedure on the skin.

16. A method according to claim 15 wherein said surgical procedure comprises treatment of vascular malformations.

17. A method according to claim 16 wherein said surgical procedure is pulsed dye laser treatment.

18. A method according to claim 15 wherein said composition is applied to facial skin about 15 to 30 minutes prior to the surgical procedure.

19. A method according to claim 15 wherein said composition is applied to skin of the trunk or extremities about 1 to 2 hours prior to the surgical procedure.

20. A method according to claim 8 wherein the composition is applied to the skin at a dosage equivalent to about 0.5 to 5 mg lidocaine base per cm² of skin to be anesthetized.