Medicated device for warts, corns, calluses and nails

A plaster preparation comprising a synthetic rubber; a reinforcing agent based on silica or random styrene-butadiene, copolymer; a tackifier; salicylic acid or a pharmaceutically acceptable salt or ester thereof.

BACKGROUND
 Self-adhesive topical products based on salicylic acid containing plasters
 as the active ingredient are used widely in a number of corn removers,
 callus remover and wart remover medicated patches sold over-the-counter
 (OTC). Many of these products are commonly based on natural rubber.
 However, many individuals are allergic to natural rubbers and government
 regulatory agencies have responded by mandating that medical devices
 containing natural rubber must bear label warnings of possible allergic
 sensitization after mid-1998. Another problem with presently available
 com/callus/wart remover plasters is that they are subject to a phenomena
 known as "cold flow" in which during storage the plaster or polymeric
 component tends to ooze out or extrude beyond the edge of the medicated
 disk. Further, a number of presently available plasters may not have
 adequate tack properties for adhering to the site of application on the
 skin. Thus, it would be desirable to provide a salicylic acid containing
 plaster for treating and/or removing warts, corns and calluses that
 overcomes the above problems.
 SUMMARY OF THE INVENTION
 The present invention has the advantage of providing a corn/callus/wart
 remover medicated plaster, which utilizes polymeric materials other than
 natural rubber, which might cause undesirable allergic reactions in some
 individuals.
 Another advantage of the present invention is that it provides a medicated
 plaster disk which significantly reduces "creep" or "cold flow" from the
 disk upon standing, storage or use. Such creep or cold flow can cause the
 plaster component of the disk to migrate out from under the plaster
 substance and slide or smear onto both target non-target areas, such as
 the packaging, socks, foot or skin surface, hosiery, shoes and the like.
 Another advantage of the present invention is that it provides a medicated
 plaster, which has sufficient or improved tack or adhesive properties for
 adhering securely to the site of application on the skin surface.
 Another advantage of the present invention is that it provides a medicated
 plaster, which is efficacious and can release the active ingredient into
 the skin at a sufficient rate and/or quantity to treat or remove warts,
 corns and calluses.
 Another advantage of the present invention is that it provides a medicated
 plaster, which has adequate shelf-life stability with respect to the
 content of the active ingredient at the expiry date assigned to the
 product.
 Another advantage of the present invention is that it provided for a
 medicated product whose plaster component has improved and more uniform
 product consistency compared to previous devices.
 Another advantage of the present invention is that it provides a medicated
 device, which is simpler to manufacture, compared to devices, which
 utilize natural rubbers.
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention is directed to medicated plaster preparations
 comprising salicylic acid or a pharmaceutically acceptable salt or ester
 thereof. The present invention includes medicated plaster preparations
 comprising a synthetic rubber; a reinforcing agent based on silica or
 random styrene-butadiene, copolymer; a tackifier; salicylic acid or a
 pharmaceutically acceptable salt or ester thereof, and optionally other
 ingredients.
 The term "medicated plaster" refers to a combination of salicylic acid or a
 salt, ester or mixture intimately dispersed in a plaster preparation.
 The term "plaster" refers to any non-liquid vehicle, which can be applied
 to the skin or nail and which can hold the salicylic acid against the skin
 or nail surface. Suitable plaster vehicles include, but are not limited
 to, plasters or preformed films based upon rubbers, acrylics,
 polyvinylalkylethers, gels or impregnated microporous membranes.
 Alternatively, the plaster could be combined with or formed into shape of
 an artificial or fake nail to improve cosmetic appearance.
 Preferably, the plaster preparation is self-adhesive, i.e. self-adhering to
 the nail or skin, although any suitable means such as a bandage could be
 used to hold the plaster against the nail or skin surface.
 The term "rubber" or "synthetic rubber" refers to any of a number of
 synthetic (i.e. man-made) high molecular weight homopolymers (e.g., weight
 average nuclear weight of 50,000 Daltons or higher) and/or random
 synthetic copolymers having unique properties of deformation (elongation
 or yield under stress). Thus, the present invention does not include the
 class of rubbers known as "natural rubbers" whose properties from batch to
 batch may be highly variable and whose use may give rise to allergic
 reactions in certain individuals. Preferably the synthetic rubber has a
 low glass transition temperature such as from -10.degree. C. to about
 -100.degree. C. Representative synthetic rubbers can include nitrile
 butadiene rubbers (NBR), polyisoprene rubbers, polybutadiene rubbers
 (PBD), and styrene-butadiene rubbers (SBR). Preferably the synthetic
 rubber is cis-1,4polyisoprene, commercially available, for example, as
 Natsyn 2200 or Natsyn 2205, available from the Goodyear Tire and Rubber
 Company, Akron, Ohio. The amount of synthetic rubber in the plaster
 formulation can range from about 15 to about 50% by weight of the plaster
 formulation, more preferably from about 20 to about 40% by weight, most
 preferably from about 25 to about 35% by weight.
 The plaster preparations can be reinforced with a suitable reinforcing
 agent such as silica-based compositions such as silica, zirconium silicate
 or silica aerogels. Preferably the reinforcing agent is a silica-based
 composition, including any of the following silicas: silazane treated
 silica, precipitated silica, fumed silica, mined silica or mixtures of any
 of the above, as well as various reinforcing silica fillers taught in U.S.
 Pat. No. 3,635,743. More preferably, the reinforcing filler is a
 precipitated amorphous silica (silicon dioxide), such as that found in the
 Hi Sil 2000 Series, available from PPG Industries, Chemical Division,
 Pittsburgh, Pa. The surface area of the silica-based reinforcing agent can
 range from about 80 to about 400 square meters/gram (m.sup.2 /g),
 preferably from about 200 to about 400 m.sup.2 /g. Where the reinforcing
 agent is silica-based, the amount of reinforcing agent in the plaster
 preparation can range from about 2 to about 20% by weight of the plaster
 preparation, more preferably from about 5 to about 15% by weight, most
 preferably from about 6 to about 12% by weight. Alternatively, the
 reinforcing agent can be a styrene-butadiene rubber or copolymer (SBR),
 preferably a random styrene-butadiene rubber such as Plioflex 1028 M85-017
 and Plioflex 1027 available from the Goodyear Tire and Rubber Company.
 Where the reinforcing agent is a styrene-butadiene rubber, the amounts of
 the reinforcing agent can range from about 5 to about 40% by weight of
 plaster preparation, preferably from about 10 to about 30% by weight of
 the plaster preparation, more preferably from about 12 to about 20% by
 weight.
 A tackifier is a substance, which enhances the tack or adhesive properties
 of the plaster preparation. Suitable tackifiers include rosin acid
 derivatives such as Pentalyn H from the Hercules Corporation, terpene
 based derivatives and synthetic C-5 tackifiers based on synthetic
 derivatives of petroleum stream fractions such as Escorez 2520 and Escorez
 1310 from the Exxon Corporation or synthetic polyterpene resins such as
 Wingtack 10 from the Goodyear Tire and Rubber Company. The amount of
 tackifier in the plaster preparation can range from about 2 to about 20%
 by weight of the plaster preparation, preferably from about 5 to about
 15%, more preferably from about 6 to about 12% by weight.
 Salicylic acid, salts or esters thereof can be employed as the active
 ingredient in the plaster preparation. Suitable salts include the sodium,
 potassium, calcium, lithium or magnesium salts thereof. Suitable esters
 include the C-1 to C-4 esters thereof, such as methyl salicylate. Other
 esters include salsalate (salicylsalicylic acid), the salicylate ester of
 salicylic acid. Most preferably the acid form is employed as the active
 ingredient. Salicylic acid is also known as 2-hydroxybenzoic acid. Also
 preferred is that Salicylic Acid Powder USP grade is employed. The amount
 of salicylic acid in the plaster preparation can range from about 12 to
 about 60% by weight of the plaster formulation, preferably from about 20
 to about 45% by weight, more preferably from about 36 to about 44% by
 weight. The salicylic acid can be admixed with mineral oil as a processing
 aid.
 A processing aid or lubricant, such as mineral oil, may be used in the
 preparation of the plaster preparation. Mineral oil refers to an oil
 derived from a liquid petroleum derivative. Preferably, the mineral oil is
 USP grade, extra heavy. Also preferred is that the mineral oil has a
 viscosity in the range of about 360 to about 390 SUS. The amount of
 mineral oil in the plaster preparation can range from about 1 to about 10%
 by weight of the plaster preparation, preferably from about 2 to about 8%
 by weight, more preferably from about 4 to about 6% by weight.
 A pigment may optionally be employed in the plaster preparation to provide
 a darker coloration, such as a brown or reddish brown color, to the
 plaster preparation. Preferably the pigment can be an iron oxide pigment
 or a blend of iron oxides and talc, such as Umber Iron Oxide 19850,
 available from the Warner-Jenkinson Company, A Division of Wamer-Jenkinson
 Co., Inc., 107 Wade Street, P. O. Box 705, South Plainfield, N.J. 07080.
 The amount of the pigment employed in the plaster preparation can range
 from about 0% (i.e. none) to about 2% by weight of the plaster
 preparation, preferably from about 0.25 to about 1%, more preferably from
 about 0.4 to about 0.6% by weight.
 An antioxidant may optionally be employed in the plaster preparation to
 retard deterioration of the plaster formulation by oxidation. Suitable
 antioxidants include
 4-(4,6-bis(octylthio)-5-triazin-2-yl)amino)-2,6-di-tert-butylphenol, also
 known as Irganox 565, and 2-methyl4,6-bis((octylthio)methyl)phenol
 (expoxidized triglyceride), also known as Irganox 1520 LR, available from
 the Novartis Corporation, Summit, N.J. The amount of the antioxidant
 employed in the plaster preparation can range from about 0% (i.e. none) to
 about 1% by weight of the plaster preparation, more preferably from about
 0.05 to about 0.5% by weight.
 Optionally, other ingredients can be employed in the topical preparation to
 assist penetration of salicylic acid into the nail and/or skin. Such
 agents can include nail softeners and avulsers, such as urea, sulfhydryl
 agents and sulfur-based reducing agents such as sodium sulfide, nail
 penetration enhancers, and occluding agents and/or hydrophillic fillers to
 promote hydration of the nail and/or skin.
 Where the medicated device is intended to treat disorders or diseases of
 the nail (i.e. onychomycosis), other active ingredients can be added, such
 as antifungal agents including clotrimazole butenafine, SP terbinaFine,
 miconazole, etc. in amounts up to 20% by weight of the plaster. Also, nail
 softening agents can also be added to the plaster formulation, such as
 urea, acetyl cysteine, N-ethylmaleimide, sodium sulfide, thioglycolic
 acid, etc. in amounts up to 20% by weight of the plaster.
 The plaster preparations may be prepared as follows. A powdered blend of
 the active ingredient(s), the reinforcing agent and mineral oil is
 prepared in a high intensity powder mixer, ribbon blender or other
 appropriate mixer. The synthetic rubber is banded on a two-roll rubber
 mill and the antioxidant (if any) is added to the rolling bank of rubber
 in the nip between the rolls. The powdered blend is added to the rolling
 bank of rubber on the mill portion by portion; at the same time, the
 liquid tackifier is added portionwise to help incorporate the powdered
 blend into the rubber. As the above ingredients are mixing, the pigment is
 added to the rubber mix on the mill to form the raw plaster. The raw
 plaster is allowed to continue to mix on the mill with cutting and folding
 over plaster into the nip until it is uniformly mixed, as evaluated by
 consistency and appearance. The raw plaster is then cut on the bias across
 the roll and removed from the mill for subsequent processing such as
 calendering and/or die-cutting.
 In a more preferred embodiment, the plaster preparation containing
 salicylic acid and the plaster preparation is attached to a carrier or
 substrate to form a medicated plater roll or sheet. In the medicated
 sheet, the carrier can impart occlusive properties and dimensional
 strength to the plaster preparation. The carrier can also provide
 dimensional stability to the plaster preparation against disintegration
 and/or tearing by external forces, such as shear forces exerted on the
 plaster from normal handling or from rubbing of the skin or nail against
 the shoe, sock or stocking. The carrier can be selected from a wide range
 of materials, including those, which can promote occlusion and hydration
 of the skin and/or nail, such as (but not limited to) a resin-impregnated
 woven cloth or fabric, flexible polyvinyl chloride film or a flexible
 polyester film. The carrier can be attached to the plaster preparation by
 lamination techniques, by coextrusion or by bonding the carrier onto the
 plaster preparation using adhesives, so that the plaster preparation is
 adhered to at least one side of the carrier surface. The carrier also
 serves the function of directing the salicylic acid toward the site of
 application, thus minimizing its dissipation or dispersion into the shoe
 or hose materials. The medicated plaster can be formed into any shape
 suitable for administering the salicylic acid to the skin or nail. Such
 shapes include but are not limited to disks, squares, rectangles or
 nail-shaped.
 Texture Analyzer creep and Texture Analyzer tack can be measured using a
 suitable instrument or device such as the TA.XT2i Texture Analyzer of
 Texture Technologies Corporation, Scarsdale, N.Y., whose website is
 located at www.texturetechnologies.com. Texture Analyzer Creep is a
 measure of cold flow of the plaster preparation. The Texture Analyzer
 Creep can be in the range between about 0 mm and 15 mm, preferably less
 than 7 mm, more preferably less 10 than 4 mm. The Texture Analyzer Tack,
 Peak Force is a measure of the tack or adhesive properties of the plaster
 preparation. The Texture Analyzer Tack, Peak Force can be in the range
 between about 0 g to about 100 g, preferably greater than 30 g, more
 preferably greater than 40 g.
 The medicated plasters can be topically applied according to a regimen
 effective to remove warts, corns or calluses of the skin or to treat
 diseases of the nail. For warts, corns and calluses, the area with the
 affliction is washed and dried thoroughly. If needed, the medicated
 plaster is cut to fit over the wart, corn or callus. The medicated plaster
 is applied with the sticky or tacky side adhering to the skin. Typically,
 the medicated plaster is covered with an enclosed cushion or pad. After 48
 hours the medicated plaster can be removed and replaced with another
 medicated disk. Optionally, the skin may be soaked in warm water for five
 minutes or more prior to the treatment to assist in removal of the wart,
 corn or callus. Typically, the procedure can be repeated every 48 hours as
 needed for up to 14 days or until the wart, corn or callus is removed.
 For treatment of nail diseases, the medicated plaster can be applied to the
 nail daily or for intermittent intervals, such as for two to three times
 per week. The duration of treatment can vary greatly, depending upon the
 degree of severity of the infection, the part of the body where the nail
 is being treated, the age of the person, the thickness of the nail, the
 rate of nail growth and the like. Generally, the toenails of a younger
 person can be expected to receive treatments up to 6 months, whereas the
 toenails of an older person can be expected to receive treatment up to
 about one year. These periods reflect the time required for toenails to
 completely grow out of the toe. Treatment of fingernails can be expected
 to be faster, since fingernail growth is approximately twice as fast as
 toenail growth. Effectiveness of the treatment can be evaluated by the
 subsidence or disappearance of symptoms. Less severe cases where only part
 of the distal portion of the nail is infected can be expected to require
 less time for treatment. The medicated device can be topically applied to
 the entire surface of the nail structure, including the region of the
 cuticle proximal to the nail fold, which overlies the growth center of the
 nail known as the matrix.

EXAMPLE 1
 A synthetic rubber-based plaster preparation is prepared by blending the
 following ingredients:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 31.72
 Hi-Sil 233 silica reinforcer 8.50
 Escorez 2520 tackifier 11.40
 Salicylic acid 43.00
 Mineral Oil 4.78
 Umber Iron Oxide Pigment 0.50
 Irganox 565 Anti-oxidant 0.10
 Total 100.00
 Texture Analyzer Creep 3.1 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 49.1 g
 Using a web coating machine with lamination stations, the plaster
 preparation is coated onto a release liner to form a film (i.e. plaster)
 containing about 13 milligrams of salicylic acid per square centimeter.
 The film is laminated onto a carrier and prepared as rollstock. The
 rollstock is diecut into medicated disks of varying diameters depending on
 the application (e.g. corn, callus, or wart removal) and with a thickness
 of about 19 mm.
 EXAMPLE 2
 A medicated plaster is prepared essentially in accordance with the
 procedure of Example 1, except that the following synthetic rubber-based
 plaster preparation is used:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 35.99
 Hi-Sil 233 silica reinforcer 0.00
 Escorez 2520 tackifier 16.02
 Salicylic acid 42.74
 Mineral Oil 4.75
 Umber Iron Oxide Pigment 0.50
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 6.08 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 73.8 g
 EXAMPLE 3
 A medicated disk device is prepared essentially in accordance with the
 procedure of Example 1, except that the following synthetic rubber-based
 plaster preparation is used:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 36.00
 Hi-Sil 233 silica reinforcer 10.27
 Escorez 2520 tackifier 5.74
 Salicylic acid 42.74
 Mineral Oil 4.75
 Umber Iron Oxide Pigment 0.50
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 1.41 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 69.7 g
 EXAMPLE 4
 A medicated disk device is prepared essentially in accordance with the
 procedure of Example 1, except that the following synthetic rubber-based
 plaster preparation is used:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 25.73
 Hi-Sil 233 silica reinforcer 10.29
 Escorez 2520 tackifier 15.99
 Salicylic acid 42.75
 Mineral Oil 4.75
 Umber Iron Oxide Pigment 0.50
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 2.85 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 64.8 g
 EXAMPLE 5
 A medicated disk device is prepared essentially in accordance with the
 procedure of Example 1, except that a random styrene-butadiene
 rubber-based reinforcing agent is used in place of the silica-based
 reinforcing agent:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 28.46
 Random Styrene-butadiene rubber 18.07
 Escorez 2520 tackifier 5.21
 Salicylic acid 42.94
 Mineral Oil 4.77
 Umber Iron Oxide Pigment 0.55
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 3.22 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 16.4 g
 EXAMPLE 6
 A medicated disk device is prepared essentially in accordance with the
 procedure of Example 1, except that a styrene-butadiene rubber-based
 reinforcing agent is used in place of the silica-based reinforcing agent:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 15.50
 Random Styrene-butadiene rubber 18.12
 Escorez 2520 tackifier 18.06
 Salicylic acid 43.04
 Mineral Oil 4.78
 Umber Iron Oxide Pigment 0.50
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 6.77 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 36.5 g
 EXAMPLE 7
 A medicated disk device is prepared essentially in accordance with the
 procedure of Example 1, except that a styrene-butadiene rubber-based
 reinforcing agent is used in place of the silica-based reinforcing agent:

Ingredient Amount in Plaster Preparation (%)
 Natsyn 2205 synthetic rubber 28.48
 Random Styrene-butadiene rubber 5.19
 Escorez 2520 tackifier 18.17
 Salicylic acid 42.91
 Mineral Oil 4.77
 Umber Iron Oxide Pigment 0.49
 Irganox 565 Anti-oxidant 0.00
 Total 100.00
 Texture Analyzer Creep 7.25 mm@23.degree. C./50% RH
 Texture Analyzer Tack, Peak Force 70.4 g
 EXAMPLE 8
 The amount of salicylic acid released can be measured on medicated plaster
 disks by placing disks into vials with distilled water, placing the vials
 in a temperature-controlled shaker bath (32 degrees C.), and analyzing
 aliquots from the vials for salicylic acid by liquid chromatographic
 techniques at selected time points. The amounts of "reinforcing agent" (eg
 precipitated silica) and tackifier in the plaster formulation, in addition
 to controlling the balance of "cold flow" and "tack" (as described in the
 above Examples), can also be used to control the salicylic acid release
 characteristics. The following Table illustrates the effects of varying
 tackifier and "reinforcer" level: