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WO2019220420A1 - Timbre non aqueux aux caractéristiques d'adhérence supérieures - Google Patents

Timbre non aqueux aux caractéristiques d'adhérence supérieures Download PDF

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Publication number
WO2019220420A1
WO2019220420A1 PCT/IB2019/054155 IB2019054155W WO2019220420A1 WO 2019220420 A1 WO2019220420 A1 WO 2019220420A1 IB 2019054155 W IB2019054155 W IB 2019054155W WO 2019220420 A1 WO2019220420 A1 WO 2019220420A1
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WO
WIPO (PCT)
Prior art keywords
adhesion
lidocaine
patient population
hours
patch
Prior art date
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Ceased
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PCT/IB2019/054155
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English (en)
Inventor
William PEDRANTI
Emileigh GRUBER
Kip VOUGHT
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Individual
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Individual
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Publication of WO2019220420A1 publication Critical patent/WO2019220420A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to non-aqueous patches containing lidocaine that have superior adhesion properties.
  • 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.
  • 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.
  • patches include aqueous base patches (cataplasms) and non-aqueous patches (tapes).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PET polyethylene terephthalate
  • 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 2 wt
  • 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%.
  • 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/cm 2 .
  • the non-aqueous patch is required to have a low plaster wt.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • organic acids include acetic acid, oleic acid, isostearic acid, etc.
  • 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.
  • 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.
  • the reason for this proportion i.e., 0.5 to 5 wt% of dissolving agent relative to 1 wt% of lidocaine, is as follows.
  • the amount of dissolving agent is less than 0.5 wt%, lidocaine cannot be stably dissolved and cannot therefore be favorably released.
  • 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.
  • the patch can maintain moderate flexibility by using an elastomer as the base.
  • an elastomer 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.
  • 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
  • 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.
  • anhydrous silicic acid, zinc oxide, or other inorganic substances, zinc stearate, polyvinylpyrrolidone, or the like can be used as a regulator.
  • 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.
  • 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/m 2 , and more preferably 80 to 180 g/m 2 .
  • the plaster wt is less than 60 g/m 2 , 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/m 2 , the plaster is so heavy that plaster dripping easily occurs.
  • 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%.
  • 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 75% to about 90%
  • 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).
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • 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.
  • 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.
  • 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 the
  • 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 24 hours or from about 3 hours to about 24 hours or from about 3 hours to about 24 hours or from about 3 hours to about 24 hours or from about 3 hours to about 24 hours or from about 3
  • 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.
  • 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.
  • 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).
  • 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.
  • 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
  • Mean CAS i.e. score obtained by dividing the CAS with total number of observations
  • Descriptive statistics e.g. mean, standard deviation, median, minimum and maximum
  • lidocaine patch l.8% 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.
  • 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.
  • 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.
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • 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).
  • 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.
  • lidocaine patch 1.8% compared to either Lidoderm® (lidocaine patch 5%) or Versatis ® (lidocaine medicated plaster 5%).
  • lidocaine patch 1.8% 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%).
  • the adhesion of lidocaine patch 1.8% was superior to the adhesion of Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%).
  • lidocaine patch 5% Lidoderm® (lidocaine patch 5%) (9 subjects, 20.5%) or Versatis® (lidocaine medicated plaster 5%) (7 subjects, 15.9%).
  • 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.
  • 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 adhesion of lidocaine patch 1.8% was superior to the adhesion of Lidoderm® (lidocaine patch 5%) and Versatis® (lidocaine medicated plaster 5%).
  • 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.
  • 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%.
  • 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.
  • 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.
  • the clear acetate transparency recording has dots on it to record the area not adhered and, therefore, the amount of 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.
  • 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.).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the primary endpoint of this study for evaluating adhesion of the two test products 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.
  • Time to a percent adhesion score > X compared between two test products (Tl and T2).
  • 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)
  • 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 ZTlidoTM 1.8% TS are superior to that of a generic Lidocaine Patch 5%.
  • 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 1 ⁇ 4 (9 mg) patch of Lidocaine 1.8%, and 1 ⁇ 4 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 1 ⁇ 4 patch (9 mg) Lidocaine Patch 1.8%, and 1 ⁇ 4 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.
  • 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.
  • the challenge phase as both cohorts had completed a 21 -day induction phase, descriptive
  • 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.
  • 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.
  • 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.
  • a dog is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc.
  • qualifying terms that indicate singularity include “a single”, “one,” “alone”, “only one,” “not more than one”, etc.
  • 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.

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Abstract

La présente invention concerne des adhésifs et des timbres non aqueux contenant de la lidocaïne, qui ont des caractéristiques d'adhérence supérieures, et des méthodes d'administration de ces adhésifs et timbres de sorte que les patients reçoivent une quantité efficace de lidocaine sans entraîner d'effets secondaires excessifs. La présente invention concerne également des méthodes d'administration d'un médicament à une population de patients, comprenant l'application à une population de patients d'un adhésif non-aqueux contenant le médicament, l'adhésif maintenant au moins 90% d'adhésion à au moins 90% de la population de patients pendant une période d'administration, l'adhésion étant déterminée par un test standard mais n'étant pas limité au classement d'adhésion FDA ou au classement d'adhésion EMA.
PCT/IB2019/054155 2018-05-18 2019-05-20 Timbre non aqueux aux caractéristiques d'adhérence supérieures Ceased WO2019220420A1 (fr)

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US10765640B2 (en) 2011-09-27 2020-09-08 Itochu Chemical Frontier Corporation Non-aqueous patch
US10765749B2 (en) 2011-05-10 2020-09-08 Itochu Chemical Frontier Corporation Non-aqueous patch
US11278623B2 (en) 2011-05-10 2022-03-22 Itochu Chemical Frontier Corporation Non-aqueous patch
US11786455B2 (en) 2011-05-10 2023-10-17 Itochu Chemical Frontier Corporation Non-aqueous patch

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10765749B2 (en) 2011-05-10 2020-09-08 Itochu Chemical Frontier Corporation Non-aqueous patch
US11278623B2 (en) 2011-05-10 2022-03-22 Itochu Chemical Frontier Corporation Non-aqueous patch
US11786455B2 (en) 2011-05-10 2023-10-17 Itochu Chemical Frontier Corporation Non-aqueous patch
US10765640B2 (en) 2011-09-27 2020-09-08 Itochu Chemical Frontier Corporation Non-aqueous patch
US11793766B2 (en) 2011-09-27 2023-10-24 ITOCHU CHEMICAL FRONTIER Corporation; Non-aqueous patch for the relief of pain

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