AU2018101236A4 - Transdermal delivery of lidocaine prilocaine mixture from cataplasm matrix - Google Patents

Abstract

This invention relates to transdermal delivery system for lidocaine and prilocaine eutectic mixture from cataplasm matrix for the management of post herpetic neuralgia (PHN) including other sorts of pain. The formulation includes active ingredient, hydrophilic polymer matrix, humectants, and plasticizer, which provide desirable adhesive characteristics and effective transdermal therapeutic properties for 24 h or multiple days.

Description

Description

FIELD OF INVENTION

[0001] The present invention relates to pharmaceutical formulations, their preparation and use in treatment of disease. In particular, the present invention relates to transdermal system for lidocaine prilocaine eutectic mixture for the management of pain. More particularly this invention describes transdermal delivery of lidocaine prilocaine eutectic mixture from cataplasm matrix for the management of PHN including others sorts of pain.

BACKGROUND OF THE INVENTION

[0002] Surgical techniques can only be performed after the highly sensitive nerve endings in the skin are anesthetized. Anesthetic agents are pharmacologically active agents that block nerve impulses conduction in sensory and motor nerve fibers when applied in therapeutically effective amounts. Their action is reversible, their use being followed by the complete recovery in nerve function with no evidence of structural damage to nerve fibers or cells.

[0003] To be effective, a topical anesthetic should contain sufficient concentration of the active agent to produce an anesthetic effect, it should penetrate intact skin sufficiently to deliver a therapeutic dose, it should exhibit a rapid onset of anesthetic action and have a prolonged anesthetic effect. Potency of anesthetics in clinical situations depends on both their ability to reach the nerve fibers and their intrinsic blocking activities. Factors such as nerve penetration, vascular absorption, and local tissue binding are all of them determinants for anesthetic potency.

[0004] Local anesthetics are traditionally injected into the desired site with a syringe. Most formulations of local anesthetics are aqueous solutions designed for injection into tissue, around nerves, or into the epidural spaces. The use of syringe is disadvantageous because the needle itself causes pain on penetration, the volume of anesthetic dissolution can cause stretching at the site (also causing pain), and furthermore preservatives contained in the aqueous dissolution can cause stinging at the wound site. Pain relief is especially important in the area of pediatrics, where even minimal pain may result in an anxious and uncooperative patient.

[0005] Local anesthetics are traditionally injected into the desired site with a syringe. Most formulations of local anesthetics are aqueous solutions designed for injection into tissue, around nerves, or into the epidural spaces. The use of syringe is disadvantageous because the needle itself causes pain on penetration, the volume of anesthetic dissolution can cause stretching at the site (also causing pain), and furthermore preservatives contained in the aqueous dissolution can cause stinging at the wound site. Pain relief is especially important in the area of pediatrics, where even minimal pain may result in an anxious and uncooperative patient.

[0006] Transdermal delivery is advantageous over intravenous delivery because the former avoids risks associated with parenteral treatment and eliminates gastrointestinal adverse effects due to pharmaceutical active ingredients, preservatives, etc. However, the use of transdermal anesthetics (i.e. through the skin) is often problematic, fluid and gel compositions have often proven unsuccessful.

[0006] The amide type local anesthetic known as lidocaine has a melting point of 68-69 °C. and it is the most commonly used local anesthetic, especially in the form of aqueous dissolutions of its hydrochloride, which are administered intravenously or topically, as jelly, ointment or spray (U.S. Pat. No. 2,441,498). However, when lidocaine administered topically, these formulations are not effectively absorbed transdermally, but only through mucosal surfaces. In order to use lidocaine for the treatment of herpes zoster neuralgia and postherpetic neuralgia, it is administered in to the epidural cavity via a block needle in case of nerve block therapy. However, this method has several disadvantages. Such as this treatment requires monitoring the blood pressure, heart rate and systemic conditions, developing systemic side effects in the aged or patients with heart or liver disease, patients must go to hospital before every treatment.

[0007] US patent 5827529 describes external preparation for application to the skin containing lidocaine. But lidocaine applied alone has low permeability through skin and onset of action may be longer. Another means of treatment for transdermal absorption is the use of ointments. Although ointments can be applied to body surface easily, still it has several disadvantages. Such as difficult to apply exact amount of drug and hand, finger, clothes etc are stained quite often, solvent is evaporated from the preparation causing crystallization of drug, lidocaine is quickly metabolized, so the ointment should apply several times a day.

[0008] The amide type anesthetic known as prilocaine, is a local anesthetic agent, which takes the form of crystalline needles having a melting point of 37-38 °C. (GB 839.943-A). Its hydrochloride is crystallized from ethanol and isopropyl ether and it is readily soluble in water. Unfortunately, methemoglobinaemia and cyanosis appear to occur more frequently with prilocaine than with other local anesthetics. Methemoglobinaemia is a disease state of the erythrocyte consisting in the formation of oxidized iron compound in the heme protein of the erythrocyte. Symptoms usually occur when doses of prilocaine hydrochloride exceed about 8 mg per kg body-weight although the very young may be more susceptible. This fact severely limits the size of the area to be anesthetized.

[0009] Enhancement of drug absorption through the skin has been a challenge for researchers for many years. Research has been also focused on finding effective topical formulations of an anesthetic which provide a rapid onset and a long duration of anesthesia. When applied onto intact skin, currently available topically used anesthetic preparations are generally ineffective or only partially effective.

[0010] One approach to the prolongation of anesthesia involves the combination of topical anesthetics with a vasoconstrictor, but also involves considerable adverse side effects. Another approach involves the combination of several anesthetic agents and different topical excipients (cf. e.g. EP 43.738-A, WO 9633706-A). In fact, at present, the most successful commercially available preparation for dermal anesthesia is the lidocaine-prilocaine cream named EMLA (a registered trademark in some countries) of Astra Lakemedel AB, Sweden (cf. U.S. Pat. No. 4,562,060). In some clinical tests, EMLA cream has been found preferable to lidocaine or to ethylchoride. EMLA is an oil-in-water emulsion in which the organic phase is an eutectic mixture of lidocaine and prilocaine bases (2.5% and 2.5% by weight) in water which is thickened with carbomer (Carbopol.RTM.). A eutectic mixture has a melting point lower than the any of its ingredients. EMLA cream is applied as a thick layer under an occlusive or semi occlusive dressing for inducing a rapid absorption through the skin.

[0011] A major inconvenience of EMLA is that its onset time for anesthesia is relatively long, approximately one hour or more. This onset time is not very practical for several clinical procedures. For more invasive procedures such as split skin graft harvesting, EMLA has to be applied at least two hours prior to surgical operation. Such delay is a problem for both patients and for medical staff, particularly in the area of pediatrics. Dermal application of EMLA may cause a transient, local blanching followed by a transient, local redness or erythema. Another disadvantage of EMLA is that for deep penetrative effect it is necessary that the cream is applied under occlusive dressing.

[0012] There have been several attempts trying to improve EMLA cream. One example are topical anesthetic compositions which additionally include a vasodilator. A formulation including lidocaine base, prilocaine hydrochloride, dibucaine, a vasodilator and carrier is described in the patent application WO 01/54679-A. Another example is the topical anesthetic composition comprising an eutectic mixture of lidocaine and prilocaine in a lipophilic base described in the U.S. Pat. No. 5,993,836. It has been reported that this anesthetic formulation has significantly more rapid onset than similar transdermal anesthetics, such as EMLA cream.

[0013] Thus, it appears to be highly desirable to have a topical anesthetic composition, which provides a rapid and deep anesthesia, with a high concentration on skin. In particular, it would be desirable to have a topical anesthetic with the benefits of lidocaine and prilocaine, but free of the above-described limitations associated therewith.

[0014] Lidocaine is safe and is the most widely used local anesthetic agent. However, due to low permeability of lidocaine through the stratum comeum, the efficacy of lidocaine alone for topical anesthesia through intact skin has been extremely disappointing. A preparation that is safe, effective for newborn and adult is especially needed for the management of aforementioned conditions. Hence a preparation containing lidocaine but little or no prilocaine would therefore have significant advantages over EMLA and other formulation containing lidocaine prilocaine eutectic mixture, specially prilocaine in higher amount. Moreover most of the formulations are cream or ointment type, which is not convenient to use for extended period of type or require additional support, which ultimately cause a critical issue for patient compliance. Hence a transdermal cataplasm containing lidocaine prilocaine eutectic mixture would be a good alternative of existing system for the management of postherpetic neuralgia (PHN) including other sorts of pain for the extended period of time both adult and children of age more than 1 year.

[0015] The present invention is believed to offer improvements and advantages over prior topical formulation containing lidocaine alone or lidocaine prilocaine combination.

SUMMARY OF THE INVENTION

[0016] The invention provides transdermal lidocaine prilocaine delivery device and formulations that deliver lidocaine and prilocaine at a therapeutically effective level. The formulations have no significant irritation potential and contain sufficient drug to support 24 or more h delivery at a reasonable adhesive layer thickness.

[0017] The incorporation of the ingredients, such lidocaine prilocaine and/or humectants and plasticizer, of the formulations provides enhanced rheological properties suitable for transdermal delivery.

[0018] Further, the present invention identifies hydrophilic polymers that can dissolve drug and other ingredients to facilitate the required solubility and flux for transdermal delivery. Preferred hydrophilic polymer is at least one member selected from the group consisting of polyacrylic acid (PAA), polyvinyl alcohol and like this.

[0019] In one aspect, the present invention provides a system for transdermal delivery of lidocaine prilocaine from cataplasm matrix.

[0020] In another aspect, the present invention provides a transdermal lidocaine prilocaine delivery system with satisfactory adhesive properties for applying to a body surface.

[0021] In one aspect, lidocaine prilocaine according to this invention penetrates the skin at therapeutically effective rates without requiring additional permeation enhancers.

[0022] Another aspect of the invention is to provide a lidocaine prilocaine transdermal cataplasm that is effective in treating post herpetic neuralgia including other sorts of minor pain both infants (Greater than and equal to 1 year) and adult for periods of 12 to 24 h or more.

[0023] It is an aspect of this invention to provide a transdermal cataplasm that can deliver lidocaine prilocaine at a rate that attains a therapeutic level to treat PHN and other pains in a patient with a reasonable size cataplasm.

[0024] It is another aspect of the invention to provide a transdermal lidocaine prilocaine cataplasm that avoids or minimizes skin irritation.

[0025] In another aspect, the present invention provides a transdermal lidocaine prilocaine delivery system with using least amount of prilocaine, which will reduce the propensity of methemoglobinaemia in infants.

[0026] These and other features of the invention will be apparent to those skilled in the art from the following detailed description and appended claims when taken in conjunction with the examples and figures.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to the transdermal delivery of lidocaine prilocaine free base accompanying adequate amount of humectants and plasticizer. The present invention relates especially to lidocaine prilocaine that is delivered with the use of hydrophilic matrix and other ingredients therein can act as adhesive and maintain the transdermal delivery system on a body surface of an individual.

[0028] The present invention provides a cataplasm comprising polymer gel containing eutectic mixture of lidocaine prilocaine at various ratios, humectants, plasticizer and a backing layer wherein the adhesive gel is casted to prepare cataplasm.

[0029] The present invention describes the cataplasm a hydrophilic base materials comprising water soluble polymer, a polyhydric alcohol, ethanol and water is preferable in consideration of long term stability, releaseability and percutaneous absorption ability of drug and safety for the skin.

[0030] The basic embodiment of the present invention comprises a backing layer and a polymeric adhesive matrix layer which serves both as a depot for lidocaine prilocaine and a means of adhering the device to the skin. The backing layer defines the non-skin facing side of the patch in use. The functions of the backing layer are to provide an occlusive layer that prevents loss of the lidocaine and prilocaine and other ingredients, to the environment and to protect the cataplasm. The material chosen should exhibit minimal galantamine and enhancer permeability. The backing layer can be clear or translucent. Ideally, the backing material should be capable of forming a support onto which the lidocaine prilocaine containing mixture can be cast and to which it will bond securely.

[0031] Release liners are used to cover the surface of the adhesive gel layer during storage. The release liner can prevent evaporative loss of one or more components of the drug delivery system or matrix. The release liner is removed and discarded from the composition to expose the adhesive matrix, which will be applied to the patient's skin. Suitable release liners include those known in the art for use with hydrophilic polymeric adhesive gel composition. For example, the release liner can comprise a fluorosilicone coated polyester, silicone coated polyester or a UV cured, silicone-coated polyester. Preferred release liners include MEDIRELEASE.RTM. 2500, MEDIRELEASE.RTM. 2249 and MEDIRELEASE.RTM. 2226, each manufactured by Mylan Technologies, Inc., Clearsil.RTM. release liner UV5A manufactured by CP Films, Inc. or Scotchpak.TM. 1022, manufactured by 3M Pharmaceuticals/D.D.S. The release liner, however, can comprise other materials, including paper or paper-containing layers or laminates, various thermoplastics, polyester films, foil liners, and the like. Non-adhesive components can be included in the adhesive composition, including preservatives, antioxidants and chelating agents. Suitable examples of such compounds include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfate, a tocopherol, maleic acid, ethylene diamine tetraacetic acid (EDTA), cysteine hydrochloride, colloidal silicone dioxide and metal oxides (ZnO, TiO.sub.2, etc.).

[0032] The lidocaine prilocaine cataplasm adhesive matrix layer comprises lidocaine prilocaine eutectic mixture at various ratios dispersed in an adhesive polymer matrix. As used herein, the term ‘dispersed’ refers to the distribution of lidocaine and prilocaine throughout the matrix. The drug may be dispersed in a dissolved and/or undissolved state, but is preferably dissolved. In preferred embodiments, the content of combined drug amount in the cataplasm matrix comprises about 0.5 wt % to 15 wt % of the weight of the adhesive gel; preferably about 0.5 wt% to 10 wt %; more preferable about 0.5 wt % to 7.5 wt %; more preferably about 0.5 wt % to 5 wt %.

[0033] The adhesive layer may be prepared as follows. First a solution of the adhesive polymer gel is prepared by dissolving hydrophilic polymer to water and ethanol. Another solution of a lidocaine and prilocaine is prepared and mixed until the drug is dissolved or evenly dispersed. The eutectic mixture of lidocaine and prilocaine is then added to the adhesive polymer gel and the mixture is homogeneously mixed. The adhesive is cast on the release liner coated with silicone. The casting is then left for drying at room temperature for 40 minutes. After air-drying, the adhesive matrix is laminated with a cloth type backing membrane.

[0034] The polymer used in a cataplasm type formulation can be selected from a variety of polymer available commercially and known to those in the art. For example, common polymers are those at least one member selected from the group consisting of polyacrylic acid (PAA), a salt of polyacrylic acid, methyl cellulose, methyl cellulose sodium, carboxymethlcellulose sodium, polyvinyl pyrrolidone, and polyvinyl alcohol (PVA). The selection of the polymer and polymer ratio is critical to realize a functioning cataplasm type transdermal delivery system. The drugs and other ingredients are loaded directly into the polymeric adhesive gel and so the adhesive must retain its functioning properties in the presence of these additives. These adhesive properties include sufficient tack for good instantaneous adhesion to the skin as well as maintenance of adhesion.

[0035] Water contained in the adhesive gel base increases the swelling of the skin homy layer and the permeability of the drug. The water content is preferably in a range of 10 to 70 %, more preferably 20 to 50%.

[0036] The support is preferably made of flexible material which is capable of fitting in the movement of human body and includes for example various non oven fabrics, woven fabrics, spandex, flannel, or a laminate of these materials with polyethylene film, polyethylene glycol, polyvinyl chloride film, polyurethane film and the like.

[0037] The thickness of the cataplasm matrix containing lidocaine prilocaine eutectic mixture effects permeation of the lidocaine and prilocaine from the cataplasm. The cataplasm matrix has thickness of about 40 μιη to about 500 pm, preferably about 50 pm to about 250 pm and more preferably about 80 pm to about 160 pm.

[0038] The transdermal cataplasm of present invention is capable of releasing the drug quantitatively. Cataplasm of present invention can be applied for a long period of time. In addition, the external preparation of the present invention has the following advantages. I) Cataplasm of the present invention applied externally and avoid first pass metabolism. II) Cataplasm of present invention is applied externally for extended period of time, and hence expected that the activity of drug is stable for extended period of time. In addition to this cataplasm of present invention can be applied less frequently and patient compliance can be improved. III) The patients suffering from postherpetic neuralgia sometimes feel pain even by the touch of wind and rubbing with cloths. In this case pain can be reduced by covering the surface of the skin by cataplasm type formulation. IV) Cataplasm of present invention contains very little amount of prilocaine and hence there is less chance of causing methemoglobinaemia and can be admi nistered regardless of patients age, health condition.

EXAMPLES

The following examples are offered by way of illustration and not by way of limitation.

[0033] Example 1

Adhesive gel comprising PAA, PVA, glycerin, propylene glycol, water and ethanol were prepared. At first required amount of PAA and PVA was dissolved in ethanol and water. To enhance the solubility of PAA and PVA, the mixture was kept 25 minutes at 80 °C. Then required amount of glycerin and PG was added to the mixture and stirred for 12 hours at 37 °C to get homogenous adhesive gel.

[0034] Example 2

At first eutectic mixture of lidocaine and prilocaine was prepared using the following procedure. Required amount of lidocaine and prilocaine were weighed together and heated to 32°C. In this temperature two compounds melted and formed homogenous oil. This eutectic mixture was added to adhesive gel and stirred for 2 h using a teflon-coated magnetic bar. The resulting drug-adhesive gel was coated onto the release liner. After casting the cataplasm matrix was kept in air-drying for 40 min. After air-drying, it was laminated with backing film.

[0035] Example 3

In the present invention, PVA was chosen as a hydrophilic component and PAA was chosen to increase the adhesive property in the cataplasm matrix. Proportions of PVA and PAA could affect the film properties, adhesive force and permeation of incorporated drug molecule(s). As shown in the Fig. 1, permeation of lidocaine and prilocaine proportionally increased when the ratio of PVA and PAA changed from 1:1 to 7:1. Permeation of both lidocaine and prilocaine was proportional to amount of PVA and inversely proportional to the amount of PAA in the combination matrix. To broaden the scope of present studies were also done with various grades of PVA. Fig. 2 shows the permeation profile of lidocaine and prilocaine from cataplasm containing various grades of PVA. Permeation profile was almost similar regardless of various grades of PVA. However, the viscosity increases with the increase of molecular weight.

[0036] Example 4

The effect of PG and glycerin was studied on the in vitro permeation as well as film properties of cataplasm matrix. Permeation study was carried out to check the effect of PG and glycerin on in vitro permeation of lidocaine and prilocaine alone and their combination. Fig. 3A and 3B shows the permeation profile of lidocaine and prilocaine. Both PG and glycerin enhanced the flux of lidocaine and prilocaine significantly.

[0037] Example 5

Permeation study was conducted with various ratios of lidocaine to prilocaine. Table 1 shows the cumulative individual flux of lidocaine prilocaine, their combined flux and potency ratio at 24 h. The permeation of drug was dependent on its ratio in the applied eutectic mixture. Increasing the proportion of an individual agent in the eutectic mixture increased its flux. The overall flux of lidocaine from the cataplasm matrix was higher than that of prilocaine.

Table 1. Flux of lidocaine and prilocaine at various ratios from the cataplasm containing at 2.66 % w/w combined drug load with respect to adhesive gel weight at 160 pm matrix thickness. Values are expressed as mean ± standard deviation. (n=3)

ARatio= lidocaine: prilocaine #Combined flux = lidocaine permeated + prilocaine permeated *Ratio of potency = Combined flux/theoretical amount of combined drug [0038] Example 6

Permeation study was conducted to justify the usefulness of eutectic mixture of lidocaine and prilocaine through the hairless mouse skin. Fig. 4 clearly shows that there is significant increment of lidocaine and prilocaine flux from eutectic mixture in comparison to the either compound alone. The increment is much more pronounced in case of lidocaine when compared with prilocaine.

[0039] Example 7

The thickness of the matrix is one of the important variables in the development of cataplasm. When the concentration of drug and other additives is same, a thicker cataplasm matrix, which serves as a drug reservoir, is able to deliver higher amount of drug to skin over relatively longer application time. It is because; the amount of drug in cataplasm is affected by the thickness of the cataplasm matrix. By increasing the thickness up to 225 pm, the cumulative amount of lidocaine and prilocaine that permeated through skin for 24 h was increased. Fig. 5 a and 5b shows the permeation profile of lidocaine and prilocaine at various matrix thicknesses, respectively. Permeation increased with the increased matrix thickness and permeation was highest at the thickness of 225 pm. Multiple day delivery is desirable for the long-term management of the disease to improve patient compliance. In order to check the permeation profile for an extended period of time, the permeation study was prolonged up to 48 h. Based on the consistent delivery of lidocaine and prilocaine for a period of 48 h, it may be inferred that the cataplasm could be designed for multiple day delivery to achieve a higher degree of patient compliance [0040] Example 8

To rationalize drug design and evaluation of dosage forms, the stability of the active component must be established for the acceptance or rejection of the of the dosage form. The stability studies of the formulated cataplasm patches were carried out at RT and accelerated condition i.e. 40 °C / 75 % RH for a period of 3 months. Results of physical and chemical stability tests are given in Table 2. Drug content in patch was determined by extraction with methanol. Briefly, a patch sample of 4 cm2 was put into bottle containing 50 ml methanol, sonicated for 60 mins and stirred with teflon coated magnetic bar for 3 h. The solution was filtered (Whatman® membrane, pore size 0.45pm; NJ, USA) and analyzed by HPLC. No change in morphology of the patches was observed by visual observation. These results indicated that the drugs remained stable in the cataplasm matrix for the study period of 3 months.

Table 2. Summary of chemical and physical stability of final formulations at various stability conditions. (n=3)

[0041] Example 9

Permeation study was conducted to compare the present invention with a commercial cataplasm containing lidocaine only. The amount of lidocaine permeated from both formulations was similar (Table 3). It is noteworthy that the matrix thickness and amount of drug per cm in commercial cataplasm was almost 4 times higher than present invention.

Table 3. Comparative study between present invention and commercial preparation

THE DRAWINGS

Figure 1- Effect of various ratios of PVA and PAA on the permeation of lidocaine and prilocaine with 2.66 % w/w combined drug load at the ratio of 3:1 from cataplasm matrix. Values are expressed as mean ± standard deviation. (n=3) Figure 2- Effect of molecular weights of PVA on the permeation of lidocaine and prilocaine with 2.66 % w/w combined drug load at the ratio of 3:1 from cataplasm matrix. Values are expressed as mean ± standard deviation. (n=3) Figure 3- Effect of PG and glycerin on the permeation of lidocaine and prilocaine with 2.66 % w/w drug load at the ratio of 3:1 from cataplasm matrix. Keys: (A) Lidocaine; (B) Prilocaine. Values are expressed as mean ± standard deviation. (n=3)

Figure 4- Effect of eutectic mixture on the permeation of lidocaine and prilocaine with 2.66 % w/w combined drug load at the ratio of 3:1 from cataplasm matrix. Values are expressed as mean ± standard deviation. (n=3)

Figure 5- Effect of matrix thickness on the permeation of lidocaine and prilocaine with 2.66 % w/w combined drug load at the ratio of 3:1 from cataplasm matrix. Keys: (A) Lidocaine; (B) Prilocaine. Values are expressed as mean ± standard deviation. (n=3)

Claims (13)

1. CLAIMS What is claimed is:

   1. A cataplasm comprising a base on a support and the said base comprising drug, a polyhydric alcohol, water soluble polymer, ethanol and water.
2. 2. The cataplasm according to claim 1, wherein the said drug is lidocaine prilocaine mixture.
3. 3. The cataplasm according to claim 1, wherein the said drug is lidocaine prilocaine eutectic mixture.
4. 4. The cataplasm formulation of claim 1, wherein the said drug is present at various ratios ranging lidocaine to prilocaine ratios of 5:1 to 1:2.
5. 5. The cataplasm formulation of claim 1, wherein combined lidocaine and prilocaine is present in an amount of from 0.5 wt % to 10 wt %, preferably in an amount of from 0.5 wt % to 7.5 wt % and more preferably in an amount of from 0.5 wt % to 5 wt % of the weight of adhesive polymer gel.
6. 6. The cataplasm formulation of claim 1 wherein said hydrophilic polymer is at least one member selected from the group consisting of polyacrylic acid, salt of polyacrylic acid, methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone (PAA) and polyvinyl alcohol.
7. 7. The cataplasm formulation of claim 1, wherein said hydrophilic polymer is present in an amount of from 3 w/w % to 10 w/w %, preferably in an amount of from 3 w/w % to 7.5 w/w % and more preferably in an amount of from 3 w/w % to 5 w/w % of the weight of adhesive polymer gel. of the weight of adhesive polymer gel.
8. 8. The cataplasm fonnulation of claim 1, wherein said polyhydric alcohol at least selected from the group consisting of polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerol, diglycerol and sorbitol.
9. 9. The cataplasm fonnulation of claim 1, wherein said polyhydric alcohol is present in an amount of from 5 v/w % to 20 v/w % and more preferably in an amount of from 5 v/w % to 10 v/w % preferably in an amount of from 5 v/w % to 15 v/w % of the weight of adhesive polymer gel.
10. 10. The cataplasm fonnulation of claim 1, wherein said method is capable to 2 2 deliver 12 pg/cnr/h lidocaine and 4 pg/cirr/h prilocaine, preferably deliver 2 2 15 pg/cnr/h lidocaine and 4.5 pg/cnr/h prilocaine and more preferably 18 2 2 pg/cnr/h lidocaine and 5 pg/cnr/h prilocaine.
11. 11. The method of claim 1, wherein said method is a method of treating PHN in eluding other sorts of pain.
12. 12. The method of claim 1, wherein the method provides for a level of lidocaine prilocaine in the individual that is effective to PHN.
13. 13. The method of claim 1, wherein the method provides a substantially constant level of lidocaine prilocaine in the individual over an extended period of time, which is suitable for multiple days delivery.