WO1998009665A2

WO1998009665A2 - Iontophoretic method of using phenylephrine to improve the effect of local anesthetics

Info

Publication number: WO1998009665A2
Application number: PCT/US1997/015410
Authority: WO
Inventors: Philip G. Green; Wallace Ring
Original assignee: Becton Dickinson And Company
Priority date: 1996-09-04
Filing date: 1997-09-03
Publication date: 1998-03-12
Also published as: AU4175197A; WO1998009665A3

Abstract

An iontophoretic patch and method capable of increasing the duration or intensity of iontophoretically administered local anesthesia.

Description

I0NT0PH0RETIC METHOD OF USING PHENYLEPHRINE TO IMPROVE THE EFFECT OF LOCAL ANESTHETICS

BACKGROUND OF THE INVENTION

Field of the Invention

Local anesthetics are commonly administered by injection. However, in many instances, the use of an injection may not be desirable, for example, when dealing with small children.

Administration of local anesthetics using iontophoresis is known e.g. Petelenz, T., et a!., Int. J. Clin. Pharm. Ther. and Tox.. 22, 152-155, 1984. Using this method, a patch containing an appropriate quantity of the drug is applied to the skin. A small current enables the anesthetic to cross the dermal barrier and enter the bloodstream. Lidocaine is a specific example of a local anesthetic drug which can be delivered by iontophoresis.

Following dermal penetration, the drug is rapidly carried away by the bloodstream and therefore, the local anesthetic effect is short, regardless of the method of delivery. Accordingly, other agents have been included with local anesthetics to enhance or prolong the anesthetic effect.

For example, epinephrine is widely used as a vasoconstrictor to reduce local blood flow. Since the blood flow is reduced, the local anesthetic is removed from the application site less rapidly. Epinephrine is therefore used to potentiate the effect of intravenously administered anesthetics. Epinephrine has also been used to increase the intensity and duration of anaesthesia during iontophoresis of lidocaine. Bezzant, J.L. et ah, J. Am. Acad. Derm..12, 869-875 (1988).

However, use of epinephrine suffers from several drawbacks. First, epinephrine is unstable in aqueous solutions. Since iontophoretic patches are commonly aqueous based, this instability causes problems in the manufacture and storage of such patches. For example, commercially available epinephrine products contain anti-oxidants and are packaged under reduced oxygen head space. These additional ingredients and manufacturing precautions obviously increase the cost of epinephrine containing products. Further, due to its instability, the potency of the epinephrine is always subject to question.

A second problem with epinephrine arises from epinephrine's pharmacological activity. Epinephrine has potent cardiovascular effects. Such effects should be avoided or minimized where the objective of drug administration is limited to local anaesthesia.

Phenylephrine is structurally similar to epinephrine. It possesses similar, but weaker cardiovascular properties. Singh, P. et al., J. Pharm. Sci.. SI, 783-991 (1994). Phenylephrine is also more stable than epinephrine in aqueous solutions and in air. Phenylephrine is commercially available in several forms at varying concentrations.

Nasal drops, eye drops and injection are marketed under the tradename Neo-Synephrine. The injectable Neo-Synephrine may be used in conjunction with local anesthetics (Physicians Desk Reference, 1996, pp. 2324-25).

Since phenylephrine is less potent than epinephrine, it would be expected that higher-quantities of phenylephrine would have to be included in an iontophoretic patch to provide a similar pharmacological effect. However, since phenylephrine is smaller (molecular weight = 167) than anesthetics such as lidocaine (molecular weight = 234) it is likely that it will carry a higher percentage of current (i.e. have a higher current efficiency) than lidocaine. Thus, while it would be expected that increased amounts of phenylephrine, as compared to epinephrine, would be necessary to achieve a useful effect, it would also be expected that too high a concentration of phenylephrine would inhibit delivery of the active agent, i.e. the local anesthetic, by competing with it.

Phenylephrine and lidocaine have been administered to exposed rat dermis, i.e. after removal of the epidermis, in a study reported in Singh, P. et al., J. Pharm. Sci.. S3_, 783-791 (1994). The authors concluded that the concentrations of compounds, including lidocaine, in underlying tissues after dermal application are significantly increased in the presence of phenylephrine. Since the epidermis of the test animals were removed, this study neither considered transdermal delivery or iontophoretic delivery of lidocaine and phenylephrine. Having removed the epidermis, the authors did not need to evaluate the very high resistance of the upper layer of skin, which is an important consideration in iontophoretic delivery. Nor could the expected problem of the phenylephrine competing with the lidocaine, thus reducing the delivery of the lidocaine, be considered by this study, which involved direct application of the drugs to exposed dermis.

It is therefore an object of this invention to enhance the effects of local anesthetics which are delivered transdermally, specifically by iontophoresis.

It is another object of this invention to reduce the manufacturing costs of iontophoretic patches containing a potentiating agent.

Another object of this invention is to deliver local anesthetics iontophoretically, without the possible adverse cardiovascular effects produced by epinephrine.

Yet another object of this invention is to provide increased local anaesthesia of longer duration than provided by local anesthetic alone. A further object is to obtain enhanced anaesthesia without adverse cardiovascular side effects.

SUMMARY OF THE INVENTION

The present invention is a transdermal, iontophoretic patch containing an effective amount of a local anesthetic and an effective amount of phenylephrine. A method of using such an iontophoretic patch is also an aspect of the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph showing the amount of anaesthesia obtained as a function of varying concentrations of phenylephrine hydrochloride at a constant 10% lidocaine hydrochloride concentration immediately after completing iontophoresis on human volunteers.

Fig. 2 is a graph showing the amount of anaesthesia as a function of phenylephrine hydrochloride concentration at a constant 10% lidocaine hydrochloride concentration twenty minutes after completing iontophoresis on human volunteers.

DETAILED DESCRIPTION OF THE INVENTION

The use of a combination of a local anesthetic in combination with phenylephrine is described. The two active agents are combined for administration from an iontophoretic patch. Anodes and cathodes are included in the iontophoretic patch as well as a means to supply current to the patch. A method of obtaining enhanced local anaesthesia using such a patch is also described.

The construction of the iontophoretic patch used is not critical in the present invention. In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are positioned to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged (i.e., a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e., an anion), then the cathode will be the active electrode and the anode will be the counter electrode.

Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.

It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis" and "iontophoretic" apply equally to electrically powered devices which deliver charged/ionic agents by iontophoresis as well as to electrically powered devices which deliver uncharged/nonionic agents by electroosmosis.

The iontophoretic delivery device of the present invention is preferably flexible enough to conform to contours of the body. While not limited to any particular size or shape, the device typically is about two or three inches long, about one and one-half inches wide, and has a thickness of approximately one-quarter of an inch. The combined skin-contacting areas of electrode assemblies can vary from less than 1 cm² to greater than 200 cm². The average device however, will have electrode assemblies with a combined skin-contacting area within the range of about 5 to 50 cm². As constructed, electrode assemblies are electrically isolated from each other until the device is applied to the human body, whereupon a circuit through the human tissue is completed between the electrode assemblies.

A matrix of reservoirs to hold the drug, or beneficial agent, and the "counter" ion is provided. A reservoir can be any material adapted to absorb and hold a sufficient quantity of liquid therein in order to permit transport of agent therethrough by iontophoresis. For example, gauzes made of cotton and other absorbent fabrics as well as pads and sponges, both natural and synthetic, may be used. Most preferably, the matrix of reservoirs is composed, at least in part, of a hydrophilic polymer material. Both natural and synthetic hydrophilic polymers may be used. Suitable hydrophilic polymers include polyvinylpyrrolidones, polyvinyl alcohol, polyethylene oxides such as Polyox® manufactured by Union Carbide Corp.; Carbopol® manufactured by BF Goodrich of Akron, Ohio; blends of polyoxyethylene or polyethylene glycols with polyacrylic acid such as Polyox® blended with Carbopol®, polyacrylamide, Klucel®, cross-linked dextran such as Sephadex (Pharmacia Fine Chemicals, AB, Uppsala, Sweden); Water

Lock® (Grain Processing Corp., Muscatine, Iowa) which is a starch-graft-poly(sodium acrylate-co-acrylamide)polymer; cellulose, derivatives such as hydroxyethyl cellulose, hydroxypropylmethylcellulose, low substituted hydroxypropylcellulose, and cross-linked Na-carboxymethylcellulose such as Ac-Di-Sol (FMC Corp., Philadelphia, Pa.); hydrogels such as polyhydroxyethyl methacrylate (National Patent Development Corp.); natural gums, chitosan, pectin, starch, guar gum, locust bean gum, and the like, along with blends thereof. Of these, polyvinylpyrrolidones are preferred.

In order to conduct electrical current, the reservoirs must be sufficiently hydrated to allow ions to flow therethrough. In most cases the liquid used to hydrate the matrices of the reservoirs will be water, but other liquids including non-aqueous liquids, can also be used to "hydrate" (i.e., activate) the matrices of the reservoirs. In the typical case where the hydrating liquid is water, the matrices of the reservoirs will be at least partly composed of a hydrophilic material such as a hydrophilic polymer, a cellulose sponge or pad or other water retaining material. Most preferably, the matrices of the reservoirs will be at least partly composed of a hydrophilic polymer of the type described hereinbefore.

The beneficial agent or drug, in the case of the donor electrode reservoir and the electrolyte salt in the case of the counter electrode reservoir may be added to the reservoir matrix either at the time of manufacture of the device or at the time of use of the device. For example, when the drug or electrolyte is added to the reservoir matrix at the time of manufacture of the device, blending of the drug or electrolyte with the reservoir matrix components can be accomplished mechanically either by milling, extrusion, or hot-melt mixing. The resulting dry state reservoirs may then be prepared by solvent casting, extrusion or by melt-processing, for example. In addition to the drug and electrolyte, the reservoirs may also contain other conventional materials such as dyes, pigments, inert fillers, and other excipients.

On the other hand, the reservoirs may be manufactured with no drug or electrolyte. In such a case, the drug and electrolyte can be added to the reservoirs, by adding a solution of the drug and electrolyte to the appropriate reservoir matrix at the time of use.

Suitable local anesthetics which may be used in the present invention are known to those familiar with the use of local anesthetics and include lidocaine, ropivicaine, procaine, bupivicaine, etidocaine, prilocaine, and mepivicaine etc. Lidocaine is the most preferred for use in the present invention.

For example, lidocaine may be present in amounts of about 1% to about 15%, with about 10% being most preferred.

The amount of local anesthetic which should be included in the iontophoretic patch will vary with the characteristics of each local anesthetic, and can be readily determined by one of ordinary skill in the art.

To assess whether combining phenylephrine with a local anesthetic for iontophoretic delivery achieves any beneficial effect, specifically on the intensity and duration of dermal iontophoretic analgesia, the clinical experiments described below were conducted.

EXAMPLE: Iontophoretic anode patches 5cm² containing 10% lidocaine hydrochloride (LH) and amounts of phenylephrine hydrochloride varying from 0% to 1.0% were prepared.

Three adult subjects participated in the study.

Each volunteer was first tested according to the "von Frey" technique as described in Kummar, et al., Diah. Res. Clin. Prac. 1991, ϋ: 63-68, to determine the baseline level of pressure perception prior to receiving anesthetic. This technique relies on the use of a series of graded, pressure sensitive nylon filaments of increasing calibre that buckle at a reproducible stress, and can measure the patients' cutaneous pressure perception threshold.

Iontophoretic devices were prepared consisting of an anode and cathode pair with 10% LH and an amount of phenylephrine hydrochloride ranging from 0, .01, 0.1, 0.5 and 1.0%. A single patch pair with a known concentration of lidocaine and phenylephrine was applied to each subject's forearm. Only one set of patches (anode/cathode) with a given phenylephrine concentration was applied to a volunteer at a time. While each volunteer received the identical series of patches containing lidocaine and phenylephrine, the charge density used at a given phenylephrine concentration varied with each volunteer. Charge densities of 2.5., 3.4 and 4.2mA min/cm² were used.

In each experiment, iontophoresis was conducted for ten minutes. At a given concentration of phenylephrine, a different charge density was used for each volunteer.

An iontophoretic controller was used to provide a constant current and variable voltage source, as well as a data acquisition system for capturing current and voltage measurements during the iontophoretic procedure.

von Frey readings were taken immediately after patch removal and again twenty minutes after patch removal.

The results obtained were subjected to a least squares statistical analysis and plotted in FIGS. 1 and 2.

FIG. 1 shows the anesthetic readings on a scale of 0 to 2. The higher the number, the greater the anesthetic effect. A reading of "2" indicates complete anaesthesia. The FIG. 1 readings are based on a comparison of the initial von Frey reading (prior to iontophoresis) and the von Frey reading immediately after patch removal. FIG. 1 clearly shows that the iontophoretic patches including phenylephrine provide superior anesthetic effect than provided by lidocaine alone.

FIG. 2 compares the initial von Frey reading to the reading taken twenty minutes after the patch was removed. The X-axis on this graph ranges from -2 to 2, the negative numbers indicating an increase in pressure perception over the measurement at time zero (prior to iontophoresis). FIG. 2 shows that the duration of the anaesthesia for phenylephrine and lidocaine is superior to lidocaine alone, and this result is statistically significant for concentrations of phenylephrine of 0.01% and 0.5%.

During the study, dermal reactions were measured immediately after removing the patch, one hour after removing the patch and 24 hours after patch removal. The dermal reactions were measured using an evaluation described in Draize, J. Pharm. Exper. Thera.. 1944, S2, 377-390. This evaluation of erythema and edema uses a scale of 0 to 8. According to this well known technique, substances producing a primary irritation index of 2 or less are only mildly irritating whereas those with indices from 2-5 are moderate irritants and those above 6 are considered severe irritants (Id. at pp. 383- 384).

Additionally, as mentioned above, the degree and duration of analgesia were assessed by the "von-Frey" technique as described in Kummar, et al. Diab. Res. Clin. Prac, 1991, 12.: 63-68. These measurements were made 1) before the patches were applied, 2) immediately after the patches were removed; and 3) 20 minutes following patch removal.

The measurement made were: 1) the difference between the initial von Frey reading and the von Frey reading immediately after the patch was removed (Delta Initial to O); and 2) the difference between the initial reading and 20 minutes post patch removal

(Delta Initial to 20). Using the Draize scale, dermal observations seen after initial patch removal under the anode showed vasoconsfriction or mild erythema which increased to slight to mild erythema (Draize 1-2 in 21 of 24 sites) after one hour. After 24 hours the dermal effects under the anode patch decreased to Draize erythema scores of 0-1. Under the cathode at initial patch removal these was Draize erythema scores of 1 and 2, seen on all subjects.

This erythema was nearly resolved at 1 hour with Draize scores of 0 to 1. After 24 hours cathode erythema was not seen on any of the subjects (Draize = 0).

Edema was not observed at anode and cathode sites of treatment and placebo patches.

Therefore, the device and method of the present invention appear to have no lasting adverse effects on the skin of healthy volunteers.

Analgesia

With regard to the effect of iontophoretic delivery of lidocaine and phenylephrine, the main findings were as follows:

Delta initial to 0 (Figure 1) ~ Immediately following patch removal, all iontophoretic patches containing lidocaine, produced statistically superior analgesia to placebo. Patches containing lidocaine and phenylephrine produced higher mean analgesia than lidocaine alone.

Delta initial to 20 (Figure 2) ~ 20 minutes following patch removal, all iontophoretic patches containing lidocaine and phenylephrine, provided long lasting analgesia. Analgesia from patches containing lidocaine alone was not statistically different from placebo.

Therefore, the combination of phenylephrine with lidocaine provides enhanced anaesthesia for prolonged periods at surprisingly low doses.

Claims

WHAT IS CLAIMED:

1. An iontophoretic patch comprising an effective amount of a local anesthetic and an amount of phenylephrine effective to increase the intensity or duration of the local anesthetic.

2. An iontophoretic patch according to claim 1 wherein the local anesthetic is selected from the group consisting of lidocaine, procaine, bupivicaine, ropivicaine, mepivicaine, etidocaine and prilocaine.

3. An iontophoretic patch according to claim 2 wherein the local anesthetic is lidocaine.

4. An iontophoretic patch according to claim 3 wherein the lidocaine is present in an amount of about 1% to about 15%.

5. An iontophoretic patch according to claim 3 containing about 10% lidocaine.

6. An iontophoretic patch according to claim 1 -5, wherein the phenylephrine is present in the amount of about 0.01 to about 1.0%.

7. An iontophoretic patch containing 10% lidocaine and 1.0% phenylephrine.

8. An iontophoretic patch according to claim 1 further comprising a controller to maintain a constant current.

9. A method of increasing the duration or intensity of iontophoretically administered local anaesthesia comprising: a) combining an effective amount of local anesthetic and phenylephrine in an iontophoretic patch; b) applying the iontophoretic patch to a skin surface on or near a site where local anaesthesia is desired; and c) supplying current to the patch to iontophoretically deliver local anesthetic and phenylephrine through the skin.

10. A method for increasing the duration or intensity of a local anesthetic comprising: a) applying an iontophoretic patch containing a local anesthetic and phenylephrine to a skin surface at or near a site where local anaesthesia is desired; and b) applying current to the patch.

11. The method according to claims 8 or 9 where the current is supplied at a charge density of from 2.5 to 4.2 mAmin/cm².

12. The method according to claims 8 or 9 where the local anesthetic is lidocaine.