WO2019220420A1 - Non-aqueous patch with superior adhesion characteristics - Google Patents

Abstract

The present invention relates to non-aqueous tapes and patches containing lidocaine that have superior adhesive properties and to methods of administering these tapes and patches so that patients receive an effective amount of lidocaine without causing undue side effects. The present invention also relates to methods for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug where the tape maintains at least 90% adhesion to at least 90% of the patient population for a period of time of administration where the adhesion is determined by a standard test including but not limited to the FDA Adhesion Rating Scale or EMA Adhesion Rating Scale.

Description

NON- AQUEOUS PATCH WITH SUPERIOR ADHESION CHARACTERISTICS

Cross- Reference to Related Applications

This application claims priority to and benefit of United States provisional patent application no. 62/762,753 filed on May 18, 2018 entitled“Non-Aqueous Patch With Superior Adhesion Characteristics”, the entire contents of which is incorporated herein by reference in its entirety

Field of the Invention

The present invention relates to non-aqueous patches containing lidocaine that have superior adhesion properties.

Background of the Invention

Lidocaine is used for the purpose of local anesthesia or topical anesthesia. The usage form of lidocaine is an external preparation comprising lidocaine or a patch comprising lidocaine. Examples of external preparations include ointment, cream, jelly, spray, etc., which are used, for example, for topical anesthesia of the skin in the treatment of postherpetic neuralgia. Examples of patches include aqueous base patches (cataplasms) and non-aqueous patches (tapes).

An example of aqueous base patches is Lidoderm® which is mainly used for topical anesthesia of the skin in the treatment of postherpetic neuralgia, and is also used to relieve muscle pain. These patches, also referred to as topical systems, are typically drug-in-adhesive systems where the drug is compounded directly in the adhesive, and releases from the adhesive to the skin. Many aqueous-base patches have a thick adhesive layer because they contain moisture; therefore, aqueous base -patches are poorly compatible with the skin and thus are difficult to attach to the skin for long durations. Primarily, the thickness of the patch inhibits the product to complete adhere to contour-challenged areas of the body and/or do not allow stretching associated with body movements. Furthermore, the vaporization of moisture from the patch causes changes in adhesion and physical properties. Additionally, in order to make lidocaine permeate the skin, it is necessary to dissolve lidocaine, and moisture is thus required to dissolve lidocaine for these products.

Patent Japanese Patent No. 3159688 discloses a technique for alleviating postherpetic neuralgia, in which 5 to 30 wt.% of lidocaine is added as a local anesthetic. Japanese Unexamined Patent Publication No. 7-215850 discloses a technique relating to a percutaneous absorption tape for local anesthesia comprising 5 to 100 wt.% of lidocaine. Japanese Unexamined Patent Publication No. 9-315964 and Japanese Unexamined Patent Publication No. 2001-392501 disclose techniques relating to a patch comprising 0.5 to 5 wt % of lidocaine. These patent publications suggest using a small amount of lidocaine, and can be used for household use; however, even after the small amount of lidocaine is completely dissolved, the lidocaine cannot be stably released over a long period of time (e.g., 12 hours or more) and cannot permeate into the skin. Thus, there is a problem with the pain-relieving effect of the patches as described. WO 2009/060629 discloses a technique relating to a patch comprising 10 to 40 wt % of lidocaine. These non-aqueous patches have poor permeability to the skin because the lidocaine is not dissolved and is present in a crystalline state. In addition, the technique disclosed therein uses a high concentration of lidocaine. Lidocaine has an adverse effect on the heart. Prolonged use of a high concentration of lidocaine causes side effects, such as shock, rubor, and irritating sensation. External preparations comprising more than 5 wt % of lidocaine are designated as powerful drugs, and cannot be used as household (nonprescription) medicine. In addition, while lidocaine dissolve easily in organic solvents such as methanol, ethanol, diethyl ether, and the like, it is difficult to dissolve in water and thus lidocaine is not completely dissolved in aqueous patches. Moreover, aqueous based lidocaine containing preparations have poor adhesive properties and thus these patches fall off easily. There is a need to provide a tape or patch that delivers an effective amount of drug substance while staying adhered to a patient’s skin without inducing a significant degree of irritation to the skin of a patient.

Summary of the Invention

The present invention relates to non-aqueous tapes and patches containing drug substances that adhere to a patient’s skin and remain adhered to the skin for the duration of the treatment. The present invention relates to non-aqueous tapes and patches containing lidocaine that have superior adhesive properties and to methods of administering these tapes and patches so that patients receive an effective amount of lidocaine without causing undue side effects.

The present invention relates to methods for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug where the tape maintains at least 90% adhesion to at least 90% of the patient population for a period of time of administration where the adhesion is determined by a standard test including but not limited to the FDA Adhesion Rating Scale or EMA Adhesion Rating Scale.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing the lidocaine where the tape maintains greater than 90% adhesion to at least 90% of the patient population at the time the tape is adhered to the patients in the patient population.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing the lidocaine where the tape maintains at least 90% adhesion to at least 90% of the patient population at the time the tape is adhered to the patients in the patient population.

The present invention relates to methods for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time of at least 3 hours.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing lidocaine wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time of at least 6 hours.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing lidocaine wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time of at least 12 hours.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing lidocaine wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time of at least 24 hours.

The present invention relates to methods for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape adhesion to the patient population at the time of administration has a mean value of no more than 0.50 as measured by the FDA Adhesion Rating Scale.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing the lidocaine wherein the tape adhesion to the patient population at the time of administration has a mean value of no more than 0.50 as measured by the FDA Adhesion Rating Scale.

The present invention relates to methods for administering lidocaine to a patient population comprising adhering to the patient population a non-aqueous tape containing lidocaine wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time where the tape comprises 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin.

The present invention relates to methods for administering a drug to a patient comprising adhering to the patient a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape remains adhered to the patient for a period of at least 12 hours.

Brief Description of the Figures

Figure 1 represents the appearance of the product transparency.

Figure 2 represents the product area not adhered to the skin using a lift-off which is marked and the number of dots were counted over the lift-off area.

Detailed of the Invention

Lidoderm^® (lidocaine patch 5%) is an aqueous lidocaine patch which is comprised of an adhesive material containing 5% lidocaine, which is applied to a non-woven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner. The release liner is removed prior to application to the skin. The size of the patch is 10 cm x 14 cm. Each adhesive patch contains 700 mg of lidocaine (50 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: dihydroxyaluminum aminoacetate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea. Aqueous patches contain large amounts of lidocaine and have poor bioavailability and adhesive qualities.

The present invention relates to non-aqueous tapes and patches containing lidocaine and methods of administering these tapes and patches so that patients receive an effective amount of lidocaine without causing undue side effects. The present invention relates to non-aqueous tapes and patches that contain less lidocaine but are bioequivalent to aqueous lidocaine patches. The non-aqueous patches and tapes of the present invention have superior adhesion characteristics which enable the patches and tapes to adhere more securely to the skin over the full patch area for a longer period of time than aqueous based patches and tapes. The superior ability of the non-aqueous patches and tapes of the present invention to adhere to patient skin permits the patches and tapes to have lower lidocaine concentrations as compared to aqueous patches and tapes. The patches and tapes of the present invention provide effective relief to patients.

The non-aqueous tapes and patches of the present invention have a lower amount of lidocaine than comparable aqueous patches. The non-aqueous tapes and patches of the present invention may have lidocaine or its pharmaceutically acceptable salts in amount of from about 0.5 to about 7 wt%, or from about 0.5 to about 6 wt%, or from about 0.5 to about 5 wt%, or from about 0.5 to about 4 wt%, or from about 0.5 to about 3 wt%, or from about 0.5 to about 2.5 wt% or from about 0.5 to about 2 wt% or from about 0.5 to about 1.5 wt% or from about 0.5 to about 1 wt% or from about 1 to about 7 wt%, or from about 1 to about 6 wt%, or from about 1 to about 5 wt%, or from about 1 to about 4 wt%, or from about 1 to about 3 wt%, or from about 1 to about 2.5 wt% or from about 1 to about 2 wt% or from about 1 to about 1.5 wt% or from about 1.5 to about 7 wt%, or from about 1.5 to about 6 wt%, or from about 1.5 to about 5 wt%, or from about 1.5 to about 4 wt%, or from about 1.5 to about 3 wt%, or from about 1.5 to about 2.5 wt% or from about 1.5 to about 2 wt% or from about 0.5 to about 1.8 wt% or from about 1 to about 1.8 wt%or from about 1.8% to about 5.6%. The non-aqueous tapes and patches of the present invention may have lidocaine or its pharmaceutically acceptable salts in amount of 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%. 5.7%, 5.8%, 5.9% and 6.0%. The lidocaine and/or its pharmaceutically acceptable salts may be mixed in a plaster or adhesive, thereby producing a non- aqueous patch in which the lidocaine is completely dissolved, and which is effective to relieve various neuropathic pains and muscle pains over a long period of time. The amount of lidocaine and/or its reactant in the plaster is preferably 0.1 to 1 mg/cm².

The non-aqueous patch is required to have a low plaster wt. When the size of one patch is 14 x 10 cm, the plaster wt may be 0.84 to 2.8 g. Because the lidocaine content of the plaster may be 0.5 to 7 wt%, the amount of lidocaine per patch can be kept as 196 mg or less.

In order to make lidocaine present uniformly and stably in the plaster for effective use, the lidocaine content is set to be 0.5 to 7 wt%. The reason for this is that when the lidocaine content is less than 0.5 wt%, the effect of relieving various muscle pains is low, and the desired effectiveness cannot be achieved. In contrast, when the lidocaine content is more than 7 wt%, a large amount of dissolving agent is required to ensure the release of lidocaine. The adhesion of the patch is thereby reduced, and the physical properties of the patch cannot be maintained, failing to cause the patch to be sufficiently attached to the affected part. Another reason is that the lidocaine content is desired to be low.

According to the present invention, a small amount of lidocaine is efficiently dissolved, and thereby the lidocaine can be released stably and reliably over a long period of time. Particularly, the present invention is focused on a dissolving agent that can efficiently dissolve lidocaine over a long period of time, revealing that a dissolving agent composed of a mixture of an organic acid and a polyalcohol allows continuous and reliable dissolution of lidocaine.

Examples of organic acids include acetic acid, oleic acid, isostearic acid, etc. Examples of polyalcohols include 1, 3-butylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol, glycerin, etc.

The most effective proportion of dissolving agent and lidocaine is 0.5 to 5 wt% of dissolving agent relative to 1 wt% of lidocaine. In this proportion, lidocaine can be stably mixed in a dissolved state, increasing the release rate of the lidocaine to the skin, and causing the drug to effectively permeate into the muscle. Here, the reason for this proportion, i.e., 0.5 to 5 wt% of dissolving agent relative to 1 wt% of lidocaine, is as follows. When the amount of dissolving agent is less than 0.5 wt%, lidocaine cannot be stably dissolved and cannot therefore be favorably released. In contrast, when the amount of dissolving agent is more than 5 wt%, the adhesion of the patch decreases, and sufficient attaching power to the skin cannot be achieved.

Although general starting materials for non-aqueous patches can be used for the plaster, the patch can maintain moderate flexibility by using an elastomer as the base. As the elastomer usable as the base, for example, isoprene rubber, polyisobutylene, and styrene isoprene rubber are preferably used. The amount of elastomer is preferably 10 to 50 wt%, and more preferably 20 to 40 wt%, based on 100 wt% of the plaster.

Further, a tackifier resin for increasing adhesive power can be freely added. Usable examples thereof include rosin-based resin, synthetic petroleum resin, terpene resin, phenol resin, alicyclic petroleum resin, and other resins that are generally used in patches.

The non-aqueous tapes and patches of the present invention may have a tackifier resin in amount of from about 5% to about 70 wt%, or from about 5% to about 60 wt%, or from about 5% to about 50 wt%, or from about 5% to about 40 wt%, or from about 5% to about 30 wt%, or from about 5% to about 25 wt% or from about 5% to about 20 wt% or from about 5% to about 15 wt% or from about 5% to about 10 wt% or from about 10 to about 70 wt%, or from about 10 to about 60 wt%, or from about 10 to about 50 wt%, or from about 10 to about 40 wt%, or from about 10 to about 30 wt%, or from about 10 to about 25 wt% or from about 10 to about 20 wt % or from about 10 to about 15 wt % or from about 15 to about 70 wt %, or from about 15 to about 60 wt %, or from about 15 to about 50 wt%, or from about 15 to about 40 wt%, or from about 15 to about 30 wt%, or from about 15 to about 25 wt% or from about 15 to about 20 wt% or from about 20 to about 70 wt% or from about 20 to about 60 wt% or from about 20 to about 50 wt%, or from about 20 to about 40 wt%, or from about 20 to about 30 wt%,. The non-aqueous tapes and patches of the present invention may have a tackifier in amount of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, and 49%.

Polybutene or liquid paraffin may be added as a softener, and menthol, camphor, or the like may be added as a skin stimulant. Moreover, anhydrous silicic acid, zinc oxide, or other inorganic substances, zinc stearate, polyvinylpyrrolidone, or the like can be used as a regulator. Furthermore, antioxidants, UV absorbers, preservatives, sequestrants, and other additives that are designed to prevent the degradation of preparations may be used.

The plaster prepared by mixing these starting materials is held by a substrate comprising nonwoven fabric, woven fabric, knitted fabric, film, or a combination thereof, which can be generally used for patches. As a peeling film covering the plaster surface, a film moderately subjected to a mold release treatment is generally used. Since the drug may be adsorbed to the substrate or peeling film, polyester is generally used as their material; however, any materials can be used unless they cause problems.

The wt of the plaster is preferably in the range of 60 to 200 g/m², and more preferably 80 to 180 g/m². When the plaster wt is less than 60 g/m², it is necessary to increase the proportion of lidocaine to the entire plaster, in order to maintain the sufficient efficacy of lidocaine. In this case, however, lidocaine is not sufficiently dissolved and is crystallized; the crystallized lidocaine cannot be efficiently transferred to the skin. Additionally, it is difficult to control the adhesion of the patch, and the plaster is not flexible against the skin and fails to maintain moderate adhesion. In contrast, when the plaster wt is more than 200 g/m², the plaster is so heavy that plaster dripping easily occurs.

In the methods of the present invention the adhesion to the skin by the non-aqueous tape for an individual patient can be greater than 95%, or greater than 90%, or greater than 85%, or greater than 80%, or greater than 75%, or greater than 70% or greater than 65%. In the methods of the present invention the adhesion to the skin by the non-aqueous tape can be between about 60% to about 95%, or from about 60% to about 90%, or from about 60% to about 85%, or from about 60% to about 80%, or from about 60% to about 75%, or from about 60% to about 70%, or from about 60% to about 65%, or from about 65% to about 95%, or from about 65% to about 90%, or from about 65% to about 85%, or from about 65% to about 80%, or from about 65% to about 75%, or from about 65% to about 70% or from about 70% to about 95%, or from about 70% to about 90%, or from about 70% to about 85%, or from about 70% to about 80%, or from about 70% to about 75%, or from about 75% to about 95%, or from about 75% to about 90%, or from about 75% to about 85%, or from about 75% to about 80%, or from about 80% to about 95%, or from about 80% to about 90%, or from about 80% to about 85%, or from about 85% to about 95%, or from about 85% to about 90%, or from about 90% to about 95%.

In the methods of the present invention the adhesion of the tape to the patient skin can be determined by the Food and Drug Administration (FDA) Adhesion Rating Scale or the European Medicines Agency (EMA). In the FDA scale the adhesion to the skin is scored as follows: 0 - greater or equal to 90% adhered; 1 - greater or equal to 75% adhered but less than 90% adhered; 2 - greater or equal to 50% adhered but less than 75% adhered; 3 - greater than 0% adhered but less than 50% adhered; and 4 - 0% adhered. The EMA scale is a six point scale with the best adhesion scoring a 6 and the worse adhesion scoring a 0.

In the methods of the present invention the adhesion to the skin by the non-aqueous tape to a patient population can be assessed by the percentage of the population in which a certain percentage of adhesion is achieved. For example at the time of administration 90% or more of the patient population to which the tape is administered may have 90% or greater adhesion. Thus for any given tape administration timeframe at least 90% of the patient population may achieve 90% adhesion, or at least 85% of the patient population may achieve 90% adhesion, or at least 90% of the patient population may achieve 80% adhesion, or at least 90% of the patient population may achieve 75% adhesion, or at least 90% of the patient population may achieve 70% adhesion, or at least 90% of the patient population may achieve 65% adhesion, or at least 90% of the patient population may achieve 60% adhesion, or at least 90% of the patient population may achieve 55% adhesion, or at least 85% of the patient population may achieve 90% adhesion, or at least 85% of the patient population may achieve 85% adhesion, or at least 85% of the patient population may achieve 80% adhesion, or at least 85% of the patient population may achieve 75% adhesion, or at least 85% of the patient population may achieve 70% adhesion, or at least 85% of the patient population may achieve 65% adhesion, or at least 85% of the patient population may achieve 60% adhesion, or at least 85% of the patient population may achieve 55% adhesion, or at least 80% of the patient population may achieve 90% adhesion, or at least 80% of the patient population may achieve 85% adhesion, or at least 80% of the patient population may achieve 80% adhesion, or at least 80% of the patient population may achieve 75% adhesion, or at least 80% of the patient population may achieve 70% adhesion, or at least 80% of the patient population may achieve 65% adhesion, or at least 80% of the patient population may achieve 60% adhesion, or at least 80% of the patient population may achieve 55% adhesion, or at least 75% of the patient population may achieve 75% adhesion, or at least 80% of the patient population may achieve 85% adhesion, or at least 80% of the patient population may achieve 80% adhesion, or at least 75% of the patient population may achieve 75% adhesion, or at least 75% of the patient population may achieve 70% adhesion, or at least 75% of the patient population may achieve 65% adhesion, or at least 75% of the patient population may achieve 60% adhesion, or at least 75% of the patient population may achieve 55% adhesion, or at least 70% of the patient population may achieve 90% adhesion, or at least 70% of the patient population may achieve 85% adhesion, or at least 70% of the patient population may achieve 80% adhesion, or at least 70% of the patient population may achieve 75% adhesion, or at least 70% of the patient population may achieve 70% adhesion, or at least 70% of the patient population may achieve 65% adhesion, or at least 70% of the patient population may achieve 60% adhesion, or at least 70% of the patient population may achieve 55% adhesion, or at least 65% of the patient population may achieve 90% adhesion, or at least 65% of the patient population may achieve 85% adhesion, or at least 65% of the patient population may achieve 80% adhesion, or at least 65% of the patient population may achieve 75% adhesion, or at least 65% of the patient population may achieve 70% adhesion, or at least 65% of the patient population may achieve 65% adhesion, or at least 65% of the patient population may achieve 60% adhesion, or at least 65% of the patient population may achieve 55% adhesion, or at least 60% of the patient population may achieve 90% adhesion, or at least 60% of the patient population may achieve 85% adhesion, or at least 60% of the patient population may achieve 80% adhesion, or at least 60% of the patient population may achieve 75% adhesion, or at least 60% of the patient population may achieve 70% adhesion, or at least 60% of the patient population may achieve 65% adhesion, or at least 60% of the patient population may achieve 60% adhesion, or at least 60% of the patient population may achieve 55% adhesion, or at least 55% of the patient population may achieve 90% adhesion, or at least 55% of the patient population may achieve 85% adhesion, or at least 55% of the patient population may achieve 80% adhesion, or at least 55% of the patient population may achieve 75% adhesion, or at least 55% of the patient population may achieve 70% adhesion, or at least 55% of the patient population may achieve 65% adhesion, or at least 80% of the patient population may achieve 60% adhesion, or at least 55% of the patient population may achieve 55% adhesion.

Administration timeframes for the methods of the present invention can be from 0 time (which is the time the tape is adhered to the patient skin) or greater than 1 hour, or 2 hours, or 3 hours, or 4 hours, or 5 hours, or 6 hours, or 7 hours, or 8 hours, or 9 hours, or 10 hours, or 11 hours, or 12 hours, or 13 hours, or 14 hours, or 15 hours, or 16 hours, or 17 hours, or 18 hours, or 19 hours, or 20 hours, or 21 hours, or 22 hours, or 23 hours, or 24 hours or greater than 24 hours. Administration timeframes for the methods of the present invention can be from about 0 time (which is the time the tape is adhered to the patient skin) to about 24 hours or from 0 hours to about 24 hours or from 0 hours to about 18 hours or from 0 hours to 12 hours or from 0 hours to about 9 hours or from 0 hours to about 6 hours or from 0 hours to about 3 hours or from about lhour to about 24 hours or from 1 hour to about 18 hours or from about 1 hour to 12 hours or from about 1 hour to about 9 hours or from about 1 hour to about 6 hours or from about 1 hour to about 3 hours or from about 2 hours to about 24 hours or from about 2 hours to about 18 hours or from about 2 hours to 12 hours or from about 2 hours to about 9 hours or from about 2 hours to about 6 hours or from about 2 hours to about 3 hours or from about 3 hours to about 24 hours or from about 3 hours to about 18 hours or from about 3 hours to 12 hours or from about 3 hours to about 9 hours or from about 3 hours to about 6 hours or from about 6 hours to about 24 hours or from about 6 hours to about 18 hours or from about 6 hours to 12 hours or from about 6 hours to about 9 hours or from about 9 hours to about 24 hours or from about 9 hours to about 18 hours or from about 9 hours to 12 hours or from about 12 hours to about 24 hours or from about 12 hours to about 18 hours or from about 18 hours to about 24 hours.

The method of producing the non-aqueous patch of the present invention may be a general method that is conventionally used, such as a hot melt method or a solvent method.

Examples

Example 1

Lidocaine Patch Formulation

Table 1: Lidocaine Patch Formulation

Total amount of plaster 60-200 g/m²

Backing tape: non-woven cloth -(0.8 ± 0.2mm)

Release liner: polyethylene terephthalate-(65 - llO jd m)

The styrene -isoprene-styrene block copolymer, polyisobutylene, terpene resin, light anhydrous silicic acid, dibutylhydroxytoluene, and liquid paraffin were placed in a dissolution mixer and dissolved under heating at up to l65°C. A solution separately prepared by mixing the lidocaine, dipropylene glycol, and isostearic acid, followed by dissolution at 70°C, was added thereto along with additional paraffin, and the mixture was mixed under heating at up to l45°C until the mixture became homogeneous, thereby obtaining a plaster solution. The plaster solution was applied to a polyester film. A polyester fabric was pasted to the film and cooled. The resultant was then cut into a rectangle (about 14 cm x 10 cm). Example 2

Adhesion Performance

An open label, single-treatment, single -period, single-application, Adhesion Performance study was performed in healthy, adult, human subjects. Fifty-four volunteers aged 18 years and older with a body mass index (BMI) of 18.00 to 36.00 kg/m2 were selected according to the inclusion and exclusion criteria. They were assessed to be in healthy condition based on demographic data including sex, date of birth, height, weight, BMI, history of smoking, history of intake of abusive/recreational drugs, history of alcohol consumption, history of blood donation, history of participation in a drug research study, pre -study medical history including medications, allergies, health history, physical examination including vital signs (completed at screening or check-in), normal laboratory test results. A single Lidocaine Patch 36 mg (1.8%) (lidocaine patch 1.8%) of Test (T) product was applied over a predetermined fixed area on subject’s left side of the back or right side of the back (lower/mid back) according to randomization schedule (27 on the left and 27 on the right) and worn for the 12 hours in study period. The patch was applied to the lower/mid back, away from any significant fold or creases, at least 1 inch away from the spine. The patch was applied by pressing it firmly into place and holding with the palm of the hand for approximately 15 seconds. Additionally, to ensure the patch was in good contact with the application site, the entire patch and edges were gently pressed with the hand. The patch was then smoothed out after application to ensure no air bubbles were entrapped under the surface. No overlays, adhesive tapes, bandages or similar products were applied during the application period. The patch was removed at 12 hours (±5 minutes) after application and discarded as per clinic guidelines. Once the patch was removed, the application site was gently wiped with dry gauze. The adhesion to the skin was scored as follows: 0 - greater or equal to 90% adhered; 1 - greater or equal to 75% adhered but less than 90% adhered; 2 - greater or equal to 50% adhered but less than 75% adhered; 3 - greater than 0% adhered but less than 50% adhered; and 4 - 0% adhered.

Adhesion analysis included all patches from 54 subjects and no patches were removed early for unacceptable irritation or dropped out of the study before the end of the 12 -hour application. The primary endpoint of adhesion was the Cumulative Adhesion Score (CAS) during the 12- hour application period (i.e. the CAS for a specific subject was the sum of the adhesion scores recorded immediately after the patch has been applied (0 hour) +3, +6, +9, and +12 hours after application). Descriptive statistics (e.g. mean, standard deviation, median, minimum and maximum) on CAS was generated. Mean CAS (i.e. score obtained by dividing the CAS with total number of observations) was provided. Descriptive statistics (e.g. mean, standard deviation, median, minimum and maximum) on mean CAS was generated. In addition to mean scores, proportion of subjects with a meaningful degree of detachment (i.e. score > 3) was provided. Adhesion analysis for Lidocaine was performed using SAS® Release 9.4. The cumulative adhesion score and mean adhesion score of lidocaine patches are summarized in the following tables.

Table 1. Descriptive Statistics of Cumulative and Mean adhesion scores of Lidocaine (N= 54)

Table 2. Subjects with Meaningful Degree of Detachment (i.e. score >3)

*R -right side of back; L-left side of back

Safety results: All the subjects’ vital signs were within normal range or considered not clinically significant by an investigator. All the subjects were in normal healthy status at the time of Subject Well Being Questionnaire. No adverse events were reported during the entire duration of the study. Serious/significant adverse events: No serious adverse events were reported during the entire duration of the study. No deaths were reported during the entire duration of the study. Conclusion: Conclusion of adhesive performance: Considering the adhesion scores of the subjects at all assessment time points and the proportion of subjects with a meaningful degree of detachment (i.e. score >3), it was concluded that greater than 90% of subjects had >90% adhesion (Score -0). Irritation assessment on the skin of volunteers was performed and a mean of 0.52 at 30 minutes after patch removal was observed. The irritation level was reduced to 0.3 at 2 hours post removal. The study demonstrates overall benign dermal safety profile which is balanced with superior adhesion performance.

Example 3

Adhesion Performance Comparison

An open label, three-period, single-application, adhesion performance study of lidocaine patch l.8%(Example 1) compared to Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%) in healthy, adult, human subjects was conducted to evaluate the adhesion performance of the patches. Lidoderm® (lidocaine patch 5%) is an approved drug product in the United States (US) and is indicated for the relief of pain associated with post-herpetic neuralgia (PHN). Versatis® (lidocaine medicated plaster 5%) is an approved drug product in the European Union (EU) for the same indication.

Once the patch was removed from the envelope and liner removed, a visual check of any residue on the liner and envelope was performed. Patches were applied to the upper back, away from any significant fold or creases, at least l-inch away from the spine. The patches were applied over a predetermined fixed area on the subject’s left side or right side of the upper back according to randomization schedule and worn for the 12- hour study period. The lidocaine patch 1.8% was randomized to be applied on one side and the Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%) products were both applied contralaterally at the same anatomical location during their respective periods. The patches were applied by pressing the patch firmly into place and holding with the palm of the hand for approximately 15 seconds. Additionally, to ensure the patch was in good contact with the application site, the entire patch and edges was gently pressed with the hand. The patch was then smoothed out after application to ensure no air bubbles were entrapped under the surface. No overlays, adhesive tapes, bandages or similar products were applied during the application period. The patch was not intentionally held in place by subjects or clinical personnel. If any patch fell off during the study, the date and time were recorded in the source documentation. A new patch was not applied. If any patch detached before the full 12-hour application period or was removed due to unacceptable irritation, the subject remained in the clinical facility until such time as the Investigator considered it safe for the subject to be discharged from the study. Irritation was assessed at the time of detachment or removal and the rest of the schedule of assessments was followed. A visual check of any residue on the skin was performed.

Immediately after application (0 hour) and at 3, 6, 9 and 12 (before patch removal) hours after application with window period ±15 minutes the patch was checked for degree of adhesion by the trained scorer using the Food and Drug Administration (FDA) (#1) and European Medicines Agency (EMA) (#2) recommended rating scales. The patches were also evaluated for the presence of cold flow such as formation of a dark ring around the transdermal patch during use, patch movement, patch displacement and wrinkling. Semi-quantitative information was collected for each assessment using the following categorical scale: none, minor, moderate and major. The adhesion to the skin was scored as follows: 0 - greater or equal to 90% adhered; 1 - greater or equal to 75% adhered but less than 90% adhered; 2 - greater or equal to 50% adhered but less than 75% adhered; 3 - greater than 0% adhered but less than 50% adhered; and 4 - 0% adhered. Eighteen (18) subjects each with 3 patches were scored with the FDA’s 5-point system hourly post-patch through 12 hours. Nine (9) with Test and 9 with Reference (parallel design).

Table 3 Summary of Adhesion Assessment of Lidocaine Patch 1.8% by Time Points, Frequency Counts, (N=44)

Table 4 Summary of Adhesion Assessment of Lidoderm by Time Points, Frequency Counts, (N=44)

Table 5 Summary of Adhesion Assessment of Versatis by Time Points, Frequency Counts, (N=44)

A greater percentage of subjects had a FDA adhesion score of 0 (> 90% adhered, essentially no lift off the skin) at each time point during the 12-hour adhesion assessment period for lidocaine patch 1.8% versus Lidoderm^® (lidocaine patch 5%) and lidocaine patch 1.8% versus Versatis^® (lidocaine medicated plaster 5%). The mean (90% Cl) adhesion scores for lidocaine patch 1.8%, Lidoderm® (lidocaine patch 5%), and Versatis® (lidocaine medicated plaster 5%) were determined using the FDA adhesion scale for each time point. At the 0-hour time point, the mean (90% Cl) for lidocaine patch 1.8% was 0.003 (-0.040, 0.047), Lidoderm® (lidocaine patch 5%) was 0.049 (0.006, 0.093), and Versatis® (lidocaine medicated plaster 5%) was 0.047 (0.091). There was no significant difference between the 90% Cl of the test vs. reference product at the 0-hour time point (p = 0.2141 for lidocaine patch 1.8% vs. Lidoderm^®; p = 0.2350 for lidocaine patch 1.8% vs. Versatis^® ). With the exception of the 0-hour time point, all analyses showed superior adhesion of lidocaine patch 1.8% compared to either Lidoderm® (lidocaine patch 5%) or Versatis^® (lidocaine medicated plaster 5%). No lidocaine patch 1.8% patches completely detached during this study; 2 patches for both Lidoderm^® (lidocaine patch 5%), and Versatis^® (lidocaine medicated plaster 5%) completely detached.

Table 6 Summary of Mean Adhesion Assessments, Analysis of Variance FDA Scale #1 Per Population

Protocol

A significantly higher number of subjects had an FDA adhesion score of 0 (at least 90% adherence) at 12 hours post-application time point for lidocaine patch 1.8% (33 subjects, 75.0%) than Lidoderm® (lidocaine patch 5%) (6 subjects, 13.6%) or Versatis® (lidocaine medicated plaster 5%) (7 subjects, 15.9%). At the 12-hour post-application time point, the adhesion of lidocaine patch 1.8% was superior to the adhesion of Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%). A significantly lower number of subjects had an FDA adhesion score >2 at any time point for lidocaine patch 1.8% (1 subject, 2.3%) than Lidoderm® (lidocaine patch 5%) (9 subjects, 20.5%) or Versatis® (lidocaine medicated plaster 5%) (7 subjects, 15.9%).

A greater percentage of subjects had an EMA adhesion score of 6 (more than 95% of patch area adheres) at each time point during the 12-hour adhesion assessment period for lidocaine patch 1.8% versus Lidoderm® (lidocaine patch 5%) and versus Versatis® (lidocaine medicated plaster 5%). The mean (90% Cl) adhesion scores for lidocaine patch 1.8%, Lidoderm® (lidocaine patch 5%), and Versatis® (lidocaine medicated plaster 5%) were determined using the EMA adhesion scale for each time point. At the 0-hour time point, the mean (90% Cl) for lidocaine patch 1.8% was 5.992 (5.856, 6.129), Lidoderm® (lidocaine patch 5%) was 5.700 (5.564, 5.836), and Versatis® (lidocaine medicated plaster 5%) was 5.710 (5.573, 5.846). There was a significant difference between the 90% Cl of the test vs. reference product at the 0-hour time point (p = 0.0133 for lidocaine patch 1.8% vs. Lidoderm®; p = 0.0167 for lidocaine patch 1.8% vs. Versatis®). All analyses showed superior adhesion of lidocaine patch 1.8% compared to either Lidoderm® (lidocaine patch 5%) or Versatis® (lidocaine medicated plaster 5%). The LSM (95% Cl) for lidocaine patch 1.8% was 5.351 (5.080, 5.621), 3.210 (2.783, 3.638) for Lidoderm® (lidocaine patch 5%), and 3.523 (3.118, 3.928) for Versatis® (lidocaine medicated plaster 5%). The LSM was significantly different between lidocaine patch 1.8% and Lidoderm® (lidocaine patch 5%) (p=0.l072). A significantly higher number of subjects had an EMA adhesion score of 5 or greater (at least 90% adherence) at 12 hours post-application time point for lidocaine patch 1.8% (33 subjects, 75.0%) than Lidoderm® (lidocaine patch 5%) (6 subjects, 13.6%, p< 0.0001) or Versatis® (lidocaine medicated plaster 5%) (7 subjects, 15.9%, p=0.00l3). At the 12- hour post-application time point, the adhesion of lidocaine patch 1.8% was superior to the adhesion of Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%). No lidocaine patch 1.8% patches completely detached during this study; 2 patches for both Lidoderm® (lidocaine patch 5%), and Versatis® (lidocaine medicated plaster 5%) completely detached.

Table 7 - Summary of Adhesion Assessments by Time Point Percent Adhesion (N = 44)

Example 4

Adhesion Performance Comparison for Exercise and Elevated Temperatures The objectives of this study were to evaluate the pharmacokinetic and adhesion performance of Lidocaine Patch 36 mg/Patch (1.8% x 3 patches), in fasting with physical exercise, heat and normal conditions. This study was an open label, randomized, three-treatment, three-sequence, three-period, cross over, pharmacokinetic and adhesion performance study of lidocaine patch 1.8% (3 patches) in fasting, healthy, adult, human subjects, during physical exercise, exposed to heat, and under normal conditions. Three treatment periods were as follows: Treatment A: physical exercise condition, subjects were instructed to perform 30 minutes on an exercise bike achieving heart rate of 108 beats/minute (with continuous heart monitoring during exercise). Exercise was done immediately after patch application and at 2.50, 5.50 and 8.50, hour post-patch application with a window period of ±10 minutes. Treatment B: with heating condition, a heating pad adjusted to medium setting was applied for 20 minutes immediately after patch application and at 8.50 hours post-patch application. A blanket/towel was placed between the patches and heating pad to reduce the chance of skin burning. Treatment C: normal ambient conditions. Blood samples were taken from each subject in each of the treatment periods to evaluate pharmacokinetics profile of the lidocaine patch 1.8% under different conditions. A total of 16 venous blood samples pre-dose and post-dose were collected over a 48-hour time period. Each subject was evaluated for adhesion scores and standard dermal irritation scales during each of the study periods. For both studies adhesion was calculated as the Cumulative Adhesion Score (CAS) during the l2-hour application period. Descriptive statistics (e.g. mean, standard deviation, median, minimum and maximum) on CAS was generated. In addition to mean scores, proportion of subjects with a meaningful degree of detachment was provided. Table 8 - Summary of PK Parameters

*T_max median and range is disclosed

Table 9 - Summary of Adhesion Performance of 1.8% Patch with Physical Exercise, Heat and Normal Conditions

Table 10 - Subjects with Meaningful Degree of Detachment (i.e. score >3)

Comparing treatment A (physical exercise) vs treatment C (normal conditions) the mean values of the primary PK parameters, Cmax, AUC0— >t and AUC0— »¥,were lower during treatment A (physical exercise) than during treatment C (normal conditions), by 7%, 11% and 10% respectively. The 90% Confidence Intervals for treatment A versus treatment C ratios of ln-transformed PK parameter all fell within the range of 79.65 to 112.73, suggesting the effects of physical exercise on the rate and extent of Lidocaine 36 mg (1.8%) absorption was not significant. The median T_max was 9.0 h for treatment A (physical exercise) and 11.5 h for treatment C (normal conditions). The half-life observed was similar for treatment A (5.602 h) and treatment C (5.230 h). Comparing treatment B (heating) versus treatment C (normal conditions) the mean values of the primary PK parameters, Cmax, AUC0— >t and AUC0— >¥, were higher during treatment B (heating) than during treatment C (normal conditions) by 64%, 16% and 15% respectively. The 90% Confidence Interval for treatment A versus treatment B ratio of ln-transformed Cmax (123.71 to 173.66) fell outside the 80-125% limits, suggesting that heating resulted in a significant increase in Lidocaine 36 mg (1.8%) absorption resulting in a higher C_max than under normal conditions. The corresponding ranges for AUC _l®i (95.34 to 122.40) and AUC0— >¥, (95.46 to 121.79) were within the 80-125% range, suggesting that the effect of heating on these parameters was not significant. The effects of heating were mainly evident at the 9-hour time point (immediately following 20 minutes of heating starting at 8.5 h), with little difference observed between the three treatments at other time points at which Lidocaine 36 mg (1.8%) concentrations were measured. Lidocaine 36 mg (1.8%) concentrations at 9 h were 171.8 ± 96.3 ng/mL after heating, compared to 88.5 ± 25.4 for treatment A and 92.9 ± 39.7 ng/mL for treatment C. Thus, the effects of heating on Lidocaine 36 mg (1.8%) absorption appeared to be immediate and reversible. Given the timing of heat application used in this study, heating increased the C_max via an immediate effect on the 9-hour time point, with little overall effect on the AUC. The median T_max was 9.0 h for treatment B (heating) and 11.5 h for treatment C (normal conditions). The half-life observed was similar for treatment B (5.390 h) and treatment C (5.230 h). The observed intra-subject coefficient variation (ISCV) for C_max was found to be 24.4%, indicating a higher variability in exposure during treatment B (heating). The overall coefficient variation obtained from descriptive statistics for treatment B (heating) was found to be twice in comparison with that of treatment C (normal conditions) and treatment A (physical exercise).

The effects of heat and exercise on PK profile and patch adhesion, no patches completely detached during the study, none were removed early for unacceptable irritation, and no subjects dropped out of the study before the end of the l2-hour application during any of the treatment periods.

Exercise appeared to have an effect on adhesion, but was not deleterious. While the percentage of patients with adhesion scores of 0 decreased initially, these scores rose by the end of the 12-hour dosing period, reflecting our observation that the patch appeared to re-adhere in some subjects. Adhesion scores during heating were minimally affected during first 6 hours; all subjects had an adhesion score of 0 (essentially no lift of the skin) while at 9 hours (83%) and at 12 hours (75%), respectively the adhesion score of 0. All subjects had an adhesion scores of 0 during normal conditions at all time points throughout the 12- hour dosing interval.

Heat had an effect on Cmax, but the drug returned to normal levels after removal of heat and there was no effect on AUC. Heat did not appear to have a deleterious effect on patch performance which may have presented as either a complete (lidocaine) dose dump (immediate and rapid rise Cmax) or reduced drug delivery due to changes in the adhesion system, resulting in a much lower AUC. There was no significant effect on PK observed with exercise when compared to subjects under normal conditions.

Example 5

Adhesion Comparison to Generic Lidocaine Patch 5%

The study was a label, randomized, two-treatment, two-period, single -dose study evaluating the product adhesion in healthy, adult, human subjects using ZTlido^® 1.8% topical system (TS) by Scilex Pharmaceuticals Inc. and a generic Lidocaine Patch 5%. Healthy, adult, human subjects 18 years of age and older with a Body Mass Index (BMI) ranging between 18.0 to 30.0 kg/m², inclusive, were selected according to the inclusion and exclusion criteria. Subjects screened within 28 days prior to the scheduled dosing day of period-I and who were found to fulfill the inclusion and exclusion criteria were enrolled in this study. This study was initiated with twenty-four (01-24) healthy, adult, human subjects and all subjects completed the study. All subjects checked into the clinical facility on Day -1 prior to dosing. Check-in occurred at least 10 hours prior to patch application for period-I. On study Day 1, a single ZTlido^® 1.8% TS of Test product 1 (Tl) or Lidocaine Patch 5% of Test product 2 (T2) was applied on a predetermined area on the upper back and worn for 12 hours each period according to the randomization schedule. A washout period of 12 hours was maintained between period-I dose removal and period-II new application.

Immediately after patch application 0 hour (+ 15 minute window period) and at 3, 6, 9 and 12 hours post-application with a window period of ± 15 minutes, the product was evaluated for degree of adhesion (‘lift-off score) by a trained scorer (evaluator) using the dot matrix method and reported as percent adhesion.

Adhesion assessments were performed within 10 minutes after notification of self-detachment. For products that completely detached, a score of 0% was carried forward in the adhesion analysis for all remaining observations in the application period.

Procedure of Patch Assessment using Dot Matrix and Score Collection

The clear acetate transparency recording has dots on it to record the area not adhered and, therefore, the amount of lift-off. To measure the lift-off, a dot-matrix transparency demarcated with the exact size of the product was gently laid over the top of the product (careful to not press the product into the skin) and areas of adhesion were outlined. The dots excluded from the adhered area were counted to identify exact amount of lift-off.

Figure 1 represents the appearance of the product transparency. Lift-off was marked and the number of dots were counted over the lift-off area, which represents the product area not adhered to the skin (Figure 2) Adhesion was assessed immediately after application and at 3, 6, 9 and 12 hours post-application with a window period of ± 15 minutes. Pictures were taken for every product at each assessment time. Both the product adhesion scores (i.e., adhered and lift-off) were recorded at each assessment time.

Subjects were admitted to the study unit approximately 10 hours prior to application of randomized ZTlido^® 1.8% TS X 1 of Test-l (Tl) or Lidocaine Patch 5% X 1 of Test-2 (T2) on a predetermined area on the upper back, and the product was worn for 12 hours each period according to the randomization schedule by study personnel. Subjects received the Test product 1 (Tl) once and Test product 2 (T2) once with the following treatment sequence as per the randomization schedule. Subjects had product application Test product 1 (Tl) once and Test product 2 (T2) at approximately the same time on a predetermined area on upper back and wore it for 12 hours in each period according to the randomization schedule.

Prior to product system application:

Flair at the application site may have been clipped (not shaved) by the clinical staff prior to product application, if needed. The site of application must have been of non-broken skin and was evaluated for presence of any skin conditions (e.g., cuts, scars, scratches, abrasions, moles, uneven skin texture, etc.). In addition, the site of application was not recently shaved, did not have excessive hair, was not covered with tattoos or similar embodiments, and avoided clothing lines or areas where the adhesion of the product may have been compromised by rubbing. Approximately one hour before product application, the application site was gently cleansed with water only and allowed to air dry. No soaps or any cleansing agents were used to clean the application site.

Before application of the product, the approximate location of the application site was outlined. The product was not cut or damaged in any way before or during the application process. The product was applied immediately after being removed from its outer package (pouch)/sachet and removal of the protective liner.

The product was applied by pressing it firmly into place and holding with the palm of the hand for approximately 15 seconds. Additionally, to ensure the product was in good contact with the application site, the entire product and edges were gently pressed with the hand. The product was then smoothed out after application to ensure no air bubbles were entrapped under the surface.

As the study objective is to compare the adhesive performance, under no circumstances were any overlays, adhesive tape, bandages or similar products applied during the application period. Subjects were discouraged from sitting for extended periods of time with the product pressed against the backs of chairs. Subjects were not allowed to lay in beds or recliners during the administration period. No product reinforcement was permitted during the study. If the product detached during the study, the date and time of detachment was recorded in the source documentation. A new product was not applied.

If the product completely detached within the 12-hour period of application in period-I, the subject continued in period-II of the study. In either period, if the product completely detached, the subject remained in the clinical facility such time as the Investigator considered it safe for the subject to be discharged from the study. For product that completely detached before the full l2-hour application period, a percentage of 0% adhesion was carried forward for all remaining observations in the application period.

The product was removed at approximately 12 hours (+15 minutes window period) after application. Once the product was removed, the application site was gently wiped with dry gauze.

After product application, release liners were stored in Ziploc bags at room temperature. The bags were marked with subject number, study period, treatment (Test 1 or Test 2), and date/time of application.

After removal, the products were folded in half with the adhesive sides facing each other. They were placed into the same Ziploc bags as the release liner and stored at room temperature.

Any remaining adhesive left on the back of the subjects was removed using dry cotton gauze. The cotton gauze, with any remaining adhesive, was placed into the same Ziploc bags as the used product. After completion of period-II, the used product was stored and not destroyed without written confirmation by Scilex Pharmaceuticals Inc. This includes systems worn by subjects. Immediately after product application 0 hour (+ 15 minute window period) and at 3, 6, 9 and 12 hours post-application with a window period of ± 15 minutes, the product was evaluated for degree of adhesion (Tift-ofP score) by a trained scorer (evaluator) using the dot matrix method and reported as percent adhesion. Adhesion assessments were performed within 10 minutes after notification of self-detachment. For products completely detached, a score of 0% was carried forward in the adhesion analysis for all remaining observations in the application period.

Twenty-four (24) subjects completed both periods of the study and were included in the adhesion analysis. All‘lift-off scores were collected using dot matrix method and reported as percent adhesion. The percent adhesion score was used for descriptive analyses as well as summarized in table format.

The primary endpoint of this study for evaluating adhesion of the two test products (Tl and T2) is the mean percent adhesion score derived for each of the two test products (Tl and T2) from individual adhesion scores at each assessment time point averaged across all the equally spaced time points (except baseline or timeO). Descriptive statistics (e.g., mean, standard deviation, median, minimum and maximum) were generated from the mean percent adhesion score.

Mean percent adhesion score was analyzed using Analysis of Variance (ANOVA). PROC GLM was used with sequence, period, and treatment as fixed effect terms and subject (sequence) as a random effect term. The SAS estimate statement was used to obtain an estimate of the Tl to T2 difference and the 90% confidence interval on the difference. If the lower limit of the confidence interval (i.e., the lower 95% confidence bound) is greater than zero, then the adhesion for Tl will be considered to be superior to that for T2.

In addition to mean present scores, the following secondary endpoints for evaluation of percent adhesion (descriptive statistics only) to assess the potential treatment group difference in clinically meaningful extreme values or events are:

Proportion of subjects with a percent adhesion score > X at any time point, compared between two test products (Tl and T2). Proportion of subjects with a Tl mean percent adhesion score greater than the corresponding T2 percent adhesion score by X or more, compared to the proportion of subjects with a T2 mean percent adhesion score greater than the corresponding Tl percent adhesion score by X or more. Time to a percent adhesion score > X compared between two test products (Tl and T2). Here“X” will be 10, 30, 50 and 90.

The proportion of subjects with percent adhesion scores < X at any time point was presented as counts and percentages. The proportion of subjects with a Tl mean percent adhesion score greater than the corresponding T2 mean percent adhesion score by X or more and the proportion of subjects with an T2 mean percent adhesion score greater than the corresponding Tl mean percent adhesion score by X or more was presented as counts and percentages. The time to a percent adhesion score < X was presented as a total number, and the percentages of event number, mean time, median time, and 95% confidence interval (Cl) of median will be tabulated. Meier cumulative incidence were plotted to capture time to percent adhesion score < X. Statistical comparison of the percent adhesion score of the two formulations was carried out using General Linear Model (PROC GLM) of SAS®, release version 9.3. Table 11 - Percent Adhesion Scores by Treatment (PPPA)

Table 12 - Proportion of Subjects with Percent Adhesion Scores <X at Any Timepoint between Treatment (PPPA)

Table 13 - Proportion of Subjects with T1 Mean Percent Adhesion Scores Greater Than T2 by X or More, compared to proportion of Subjects with T2 Mean percent Adhesion Score Greater Than T1 by X or More

Table 14 - Time to Percent Adhesion Score <X Between Treatment (PPPA)

Table 15 - Summary of Mean Adhesion Scores

Table 16 - Summary of Percent Adhesion Score Assessment by Time Point

The lower limit of the 95% confidence interval (lower 97.5% confidence bound) for the difference in Test 1 minus Test 2 least-squares means of the mean percent adhesion scores was greater than zero. The adhesive properties of the ZTlido™ 1.8% TS are superior to that of a generic Lidocaine Patch 5%.

Example 6

Irritation and Sensitization Study

A multi-center, randomized, evaluator-blinded, within-subject comparison study utilizing sensitization (repeat insult patch test [RIPT]) and an adhesion performance study design. The study population was divided into 2 cohorts:

Cohort 1 (adhesion and irritation/sensitization), enrolled approximately 40 subjects. Subjects received Lidocaine Patch 1.8% (36 mg), and its comparator Lidocaine Patch 5% (Lidoderm®) 700 mg; was applied for one 48 hour period to evaluate adhesion performance. In addition, each subject received ¼ (9 mg) patch of Lidocaine 1.8%, and ¼ patch (175 mg) of its comparator Lidocaine Patch 5% (Lidoderm®) every 48 - 72 hours over a 21 -day induction phase. Separate patches were worn for approximately 48-72 hours for a total of 9 patch applications.

Cohort 2 (irritation/sensitization), enrolled approximately 200 subjects. Subjects received ¼ patch (9 mg) Lidocaine Patch 1.8%, and ¼ patch (175 mg) of its comparator Lidocaine Patch 5% (Lidoderm®) every 48 - 72 hours over a 21 -day induction phase. Separate patches were worn for approximately 48-72 hours for a total of 9 patch applications.

Both Cohorts 1 and 2 entered into the rest period of the study (no patching) for 10-17 days and then proceeded to the challenge phase. In the challenge phase, subjects received Lidocaine Patch 1.8% and its comparator Lidocaine Patch 5% (Lidoderm®) for a single 48-hour application. The total duration of the study, after screening, was 37-44 days for each subject, unless rechallenge was required. If required, the rechallenge phase was conducted approximately 6-8 weeks post treatment, and was to be identical in treatment and duration to the original challenge procedure with patch application to a naive skin site. 248 subjects were enrolled to obtain 200 evaluable subjects who completed the challenge phase. Of these, 41 subjects were enrolled in Cohort 1 to obtain 37 evaluable subjects who completed one 48 hour application for adhesion and who completed RIPT (sensitization applications 3 times a week during the induction phase). 207 subjects were enrolled in Cohort 2 to obtain 181 evaluable subjects who completed RIPT (sensitization applications 3 times a week during the induction phase).

The source data was the individual patch test scores recorded following visual evaluation of the induction and challenge sites. The test scores were a combination of a numerical and letter score, which was transformed to numerical equivalents for statistical analyses. During the challenge phase as both cohorts had completed a 21 -day induction phase, descriptive

statistics (frequency of scores) were provided for the combined scores after the inductions, and for each post-challenge time point. The Investigator’s determination of sensitization was summarized. No statistical analysis of these data was performed.

For Cohort 1, the adhesion evaluation of the active test product and comparator product demonstrated that the upper bound of the one-sided 95% Cl of the mean adhesion score for the test product minus 1.25 times the mean adhesion score for the comparator product was to be less than or equal to 0. There was no sensitization to Lidocaine Patch 1.8% or Lidocaine Patch 5% during this study. The mean cumulative irritation was greater at the Lidocaine Patch 1.8% Patch site than at the Lidocaine Patch 5% site. The mean score for Lidocaine Patch 1.8% site was 0.37 and Lidocaine Patch 5% site was 0.04. Lidocaine Patch 1.8% was statistically significantly more irritating than the Lidocaine Patch 5% site (<0.000l). Forty- one subjects were included in the adhesion performance analysis. The Lidocaine Patch 1.8% group showed better adhesion performance than the Lidocaine Patch 5% group. Lidocaine Patch 1.8% group had 6 subjects with a score of 4 (patch completely detached from the skin), Lidocaine Patch 5% group had 10 subjects with a score of 4. Lidocaine Patch 1.8% group had 1 subject with a score of 3 (more than half the patch lifted off of the skin without falling off), Lidocaine Patch 5% group had 11 subjects with a score of 3. Lidocaine Patch 1.8% group had 4 subjects with a score of 2 (less than half of the patch lifted off of the skin), Lidocaine Patch 5% group had 6 subjects with a score of 2. Lidocaine Patch 1.8% group had 10 subjects with a score of 1 (some edges only lifted off of the skin), Lidocaine Patch 5% group had 7 subjects with a score of 1. Lidocaine Patch 1.8% group had 20 subjects with a score of 0 (patch did not lift off of the skin), Lidocaine Patch 5% group had 7 subjects with a score of 0.

Table 17 - Scoring of Dermal Response

Table 18 - Summary of Irritation Score

In response to treatment group Fidocaine Patch 1.8% at Challenge; a reaction of definite erythema, readily visible; or minimal edema; or minimal papular response (a score of 2) was observed in 1 subject at the 30 minute visit. A reaction of minimal erythema; barely perceptible (a score of 1) was observed in 18, 13, 5, and 1 subjects respectively, at the 30 minute, 24 hour, 48 hour, and 72 hour visits. No evidence of irritation (a score of 0) was observed in 199, 205, 213, and 217 subjects respectively, at the 30 minute, 24 hour, 48 hour, and 72 hour visits.

In response to treatment group Fidocaine Patch 5% at Challenge; a reaction of minimal erythema; barely perceptible (a score of 1) was observed in 5, 3, 2, and 1 subjects respectively, at the 30 minute, 24 hour, 48 hour, and 72 hour visits. No evidence of irritation (a score of 0) was observed in 213, 215, 216 and 217 subjects respectively, at the 30 minute, 24 hour, 48 hour, and 72 hour visits.

Within this disclosure, any indication that a feature is optional is intended provide adequate support (e.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and/or function)" "excluding," "not including", "not", "cannot," or any combination and/or variation of such language.

Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and/or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Non-limiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Further advantages of the present immunological compositions and adjuvants of the present invention can be achieved by those skilled in the art based upon the embodiments described herein and are thus specifically within the scope of the present invention.

Claims

Claims

1. A method for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape maintains at least 90% adhesion to at least 90% of the patient population for a period of time of administration.

2. The method of claim 1 wherein the determination of at least 90% adhesion is made by the FDA Adhesion Rating Scale.

3. The method of claim 2 wherein at least 90% of the patient population has a score of 0 as determined by the FDA Adhesion Rating Scale

4. The method of claim 1 wherein the determination of at least 90% adhesion is made by the EMA Adhesion Rating Scale.

5. The method of claim 4 wherein at least 90% of the patient population has a score of 6 as determined by the EMA Adhesion Rating Scale and as percent adhesion.

6. The method of claim of claim 1 wherein the period of time of administration is at least 0 hours.

7. The method of claim of claim 1 wherein the period of time of administration is at least 3 hours.

8. The method of claim of claim 1 wherein the period of time of administration is at least 6 hours.

9. The method of claim of claim 1 wherein the period of time of administration is at least 9 hours.

10. The method of claim of claim 1 wherein the period of time of administration is at least 12 hours.

11. The method of claim 6 wherein the drug is lidocaine.

12. The method of claim 10 wherein the lidocaine in the tape is present at 1.8%.

13. The method of claim 12 wherein the tape comprises 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin.

14. A method for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape maintains at least 75% adhesion to at least 90% of the patient population for a period of time of administration.

15. A method for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape maintains from at least 70% to 90% adhesion to at least 90% of the patient population for a period of time of at least 3 hours.

16. A method for administering a drug to a patient population comprising adhering to the patient population a non-aqueous tape containing the drug wherein the tape adhesion to the patient population at the time of administration has a mean of no more than 0.50 as measured by the FDA Adhesion Rating Scale.

17. The method of claim 16 wherein the mean is no more than 0.40

18. The method of claim 16 wherein the mean is no more than 0.30

19. A method for administering a drug to a patient comprising adhering to the patient a non-aqueous tape containing the drug wherein the tape remains adhered to the patient for a period of time of at least 3 hours.

20. The method of claim of claim 19 wherein the period of time is at least 6 hours.

21. The method of claim of claim 19 wherein the period of time is at least 9 hours.

22. The method of claim of claim 19 wherein the period of time is at least 12 hours.

23. The method of claim 19 wherein the drug is lidocaine.

24. The method of claim 19 wherein the lidocaine in the tape is present at 1.8%.

25. The method of claim 24 wherein the tape comprises 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin

26. A method for administering a drug to a patient population comprising adhering to the patients in the population a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape maintains at least 90% adhesion to at least 90% of the patient population at the time of adhesion.

27. A method for administering a drug to a patient population comprising adhering to the patients in the population a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape maintains at least 90% adhesion to at least 85% of the patient population at at least 3 hours after the time of adhesion.

28. A method for administering a drug to a patient population comprising adhering to the patients in the population a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape maintains at least 90% adhesion to at least 75% of the patient population at at least 6 hours after the time of adhesion.

29. A method for administering a drug to a patient population comprising adhering to the patients in the population a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape maintains at least 90% adhesion to at least 70% of the patient population at at least 9 hours after the time of adhesion

30. A method for administering a drug to a patient population comprising adhering to the patients in the population a non-aqueous tape comprising 1.8% lidocaine, 5 to 15 wt. % polyisobutylene, 0.1 to 0.5 wt. % dibutylhydroxytoluene, 10 to 20 wt. % styrene-isoprene-styrene block copolymer, 10 to 30 wt. % terpene resin wherein the tape maintains at least 90% adhesion to at least 70% of the patient population at at least 12 hours after the time of adhesion