United States Patent (19)
`Tenta
`
`3,949,072
`11
`(45) *Apr. 6, 1976
`
`Notice:
`
`TOPCAL COMPOSITION FOR
`TREATMENT OF SEBORRHEIC
`KERATOSIS
`Inventor: Louis T. Tenta, 6007 N. Sheridan
`Road, Chicago, Ill. 60660
`The portion of the term of this
`patent subsequent to June 28, 1991,
`has been disclaimed.
`May 1, 1974
`Filed:
`Appl. No.: 465,740
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 123,380, March 1 1,
`1971, Pat. No. 3,821,370.
`
`U.S. C. ................ 424/145; 424/235; 424/343;
`424/DIG. 13
`int. Cl’.......................................... A61K 33/30
`Field of Search................... ... 424/145, 235, 343
`
`(54)
`
`76)
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`*
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`22
`21
`(63)
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`52
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`51
`58)
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`(56)
`
`References Cited
`UNITED STATES PATENTS
`5/967 Brunner et al............... 424/DIG. 3
`
`3,317,382
`
`3,821,370
`
`6/974 Tenta.................................. 424/343
`OTHER PUBLICATIONS
`Chemical Abstracts, Vol. 73 (1970), p. 85,963W.
`Gregory, "Uses & App. of Chem. & Related Materi
`als", (1939), pp. 16, 504, 551, 554, 648, Reinhold
`Pub. Co.
`
`Primary Examiner-V. D. Turner
`Attorney, Agent, or Firm-Hill, Gross, Simpson, Van
`Santen, Steadman, Chiara & Simpson
`
`ABSTRACT
`57
`An improved topical composition for application to
`skin effected by seborrheic keratosis so as to provide a
`superficial slough of the epidermis, the composition
`containing an inhibited phenol, preferably potassium
`phenolate, a salicylate, a zinc compound and resorci
`nol, the active ingredients being dissolved in a non
`aqueous solvent which includes a hydrophilic non
`toxic lower aliphatic alcohol, the amount of phenolate
`present being generally lower than the amount of phe
`nolate in comparable compositions.
`10 Claims, No Drawings
`
`AQUESTIVE EXHIBIT 1018 page 0001
`
`

`

`10
`
`15
`
`30
`
`45
`
`TOPCAL COMPOSITION FOR TREATMENT OF
`SEBORRHEIC KERATOSIS
`REFERENCE TO RELATED APPLICATION
`This application is a continuation-in-part of my co
`pending Ser. No. 123,380 filed Mar. 11, 1971 now U.S.
`Pat. No. 3,821,370.
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention is in the field of topical compositions
`for the treatment of seborrheic keratosis and includes
`as its essential ingredients, inhibited phenol, a salicyl
`ate, resorcinol, a zinc compound, and a non-aqueous
`solvent including a non-toxic lower aliphatic alcohol.
`2. Description of the Prior Art
`In my copending application, now U.S. Pat. No.
`3,821,370, I have described a topical composition for
`use in the treatment of various skin conditions, includ
`20
`ing seborrheic keratosis. In this patent, there was sug
`gested a composition containing 20 to 60 parts of an
`inhibited phenol calculated as potassium phenolate, 1
`part of a salicylate calculated as sodium salicylate, 5
`parts of resorcinol, and 4 parts of a zinc compound
`25
`calculated as zinc sulfate. The present invention pro
`vides a significant improvement over the type of com
`positions disclosed in the aforementioned patent by
`reducing the amount of inhibited phenol required to
`produce the same ameliorative effect.
`SUMMARY OF THE INVENTION
`The present invention relates to a topical composi
`tion for application to the skin to improve the external
`appearance that may be caused by certain skin disor
`35
`ders. In order to understand more clearly the action of
`my topical composition upon its application to the skin
`for the general purpose just stated, the following back
`ground information might be helpful.
`The skin is composed of two layers, a thin outer
`40
`layer, the epidermis, which is about 0.1 mm. in thick
`ness and a deeper, thicker layer, the dermis, of up to 2
`to 4 mm. in thickness, depending upon its location in
`the human body.
`a
`The epidermis is composed of cells arranged in lay
`ers, with the outermost layer cells thickened or, as it is
`sometimes known, keratinized or hornified. Pigment
`cells are present in the deepest layer as well as in the
`"parent' cells which give rise to generations of younger
`cells to replace those lost to attrition and to wear and
`tear.
`The dermis contains blood vessels and nerves which
`provide nutrition and sensation, respectively. More
`over, there are lymphatic vessels present which might
`be thought of as conveying "tissue juices'. Addition
`55
`ally, the structures from which hairs grow (follicles)
`and glands which lubricate the skin are contained in the
`dermis. From these structures project small tubes or
`channels which penetrate the epidermis and open upon
`the surface of the skin in the form of hairs and/or pores.
`These structures of the dermis (vessels, nerves, follicles
`and glands) are surrounded by cells which are referred
`to as connective tissue cells. These cells may be consid
`ered as a support or superstructure for the overlying
`epidermis as well as supporting the vessels, nerves,
`follicles and glands within the dermis proper.
`Moreover, intertwined among these various cells and
`structures contained within the dermis are elastic
`
`3,949,072
`2
`threads or fibers which permit the skin to regain shape
`after stretching. Additionally, the connective tissue
`cells are involved in the repair of these tissues from
`injurious or noxious sources. The repaired area of the
`tissue is manifested as a scar.
`Many disorders may affect the skin. Some are a con
`sequence of a local effect (such as a laceration, or cut)
`while others may reflect underlying constitutional dis
`orders (such as the yellowing of skin that may occur in
`liver diseases).
`.
`:
`Of those disorders that might be considered as arising
`from disturbances that are local in nature, certain ones
`will now be selectively discussed. Various changes
`occur which may affect the structure of anatomy of the
`skin. These changes may be manifested as a thickening
`of the outermost (keratinized or hornified) layer of the
`epidermis, and the resulting formation of brown or
`beige-colored warty-like areas (seborrheic keratosis).
`A change in the pigmentation of the skin may occur
`which produces random areas of brownish or tan dis
`coloration. Moreover, unsightly scarring may occur as
`a consequence of acne eruptions or from superficial
`burns. A loss of the elastic fibers necessary for normal
`skin consistency may result from the stretch marks of
`obesity or pregnancy or from the effects of wasting
`scars.
`Additionally, certain types of "birth marks' (which
`usually result from abnormally formed and expanded
`blood vessels) affect the color of the skin. Aging alters
`the skin structure by causing a weakness of the elastic
`fibers which results in a relaxation of the skin and con
`sequent wrinkling. The objectionable external appear
`ance caused by these disorders may be minimized or
`corrected in a non-surgical fashion by the application
`of a composition, such as that disclosed herein, which is
`not harmful to one's health and which produces two
`fundamental and simultaneous reactions, one in the
`epidermis and another in the dermis.
`These reactions occur at the site of the basic disorder
`and produce two responses, the one response being
`that of a superficial slough of the epidermis; and the
`other response being a stimulation of the connective
`tissue cells in the dermis. These responses, in turn, are
`manifest by a peeling of the outermost skin layer and
`the consequent removal of surface irregularities, blem
`ishes and discolorations, and by a strengthening of the
`underlying dermis which results from an increase in the
`numbers of connective tissue cells which surround and
`support the hair follicles, glands and vessels. This pro
`duces a firmer and more consistent support for the
`skin, which is manifest by a minimizing of depressions,
`wrinkles and scars. Moreover, this same response may
`cause the obliteration or collapse of certain poorly
`formed blood vessels in the dermis and result in the
`disappearance or fading of certain types of birth marks.
`The composition of the present invention includes
`phenol in an inhibited form which is rendered active by
`exposure to the moisture in the air or the moisture from
`the skin. To accelerate this response, I include in the
`new composition a non-aqueous solvent which includes
`a hydrophilic lower aliphatic (2 to 4 carbon atoms)
`non-toxic alcohol. The alcohol apparently absorbs sig
`nificant amounts of moisture and initiates the reaction
`on the skin which is characterized by warmth and red
`ness, or blushing of the skin. This response is followed
`quickly in turn by a frosting of the skin and a sensation
`of tautness or tightening. These reactions occur within
`minutes after the application of the composition has
`
`50
`
`60
`
`65
`
`AQUESTIVE EXHIBIT 1018 page 0002
`
`

`

`21 % by weight
`F
`A
`
`46
`30
`
`FF
`
`F
`t
`
`14 % by weight
`2
`FP
`
`2
`51
`30
`
`7 % by weight
`2
`FF
`4
`A
`FF
`FF
`FF
`
`52
`34
`
`21 % by yeight
`
`l
`
`w
`
`Fr.
`
`4.
`
`% by weight
`
`F.
`
`l
`41
`41
`
`FP
`
`y
`
`% by weight
`
`:
`
`EXAMPLE 2
`
`Potassium phenate
`Resorcino
`Anhydrous zinc sulfate
`Sodium salicylate
`Benzyl alcohol
`Ethanol
`
`EXAMPLE 3
`
`Potassium phenate
`Resorcinol
`Zinc salicylate
`Zinc oxide
`Benzyl alcohol
`Ethanol
`
`EXAMPLE 4
`
`Potassium phenate
`Resorcinol
`Anhydrous zinc sulfate
`Sodium salicylate
`Propylene glycol
`Ethanol
`
`EXAMPLE 5
`
`Potassium phenate
`Resorcinol
`Anhydrous zinc sulfate
`Sodium salicylate
`Propylene glycol
`Ethanol
`
`EXAMPLE 6
`
`Potassium phenate
`Resorcinol
`Zinc salicylate
`Zinc oxide
`Propylene glycol
`Ethanol
`
`Potassium phenate
`Resorcinol
`Anhydrous zinc sulfate
`Sodium salicylate
`Benzyl alcohol
`Ethanol
`
`3,949,072
`3
`4
`been applied. Over the next three to five days, the skin
`The non-aqueous solutions or gels of the present
`takes on the character of an onion skin, somewhat rusty
`invention are more stable, uniform and clinically active
`or violaceous in color, following which a flaking or
`at lower concentrations of the active ingredients than
`peeling occurs which exposes from beneath a clearer,
`similar compositions of the past.
`Representative examples of solutions produced ac
`cleaner, smoother appearing surface.
`The inhibited phenol of the present invention may be
`cording to the present invention are given below:
`either potassium phenate, sodium phenate or ammo
`EXAMPLE 1.
`nium phenate. These phenates can be produced by
`neutralizing 90% phenol with the corresponding alkali
`metal or ammonium hydroxide. The product is then
`recovered by crystallization with ether.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`The topical composition of the present invention
`includes, as its active ingredients, from 5 to 25 parts by
`weight of an inhibited phenol, calculated as potassium
`phenate, 2 to 2 parts of a salicylate calculated as so
`dium salicylate, 1 to 5 parts of resorcinol, 1 to 4 parts
`of a zinc compound calculated as zinc sulfate, and a
`non-aqueous solvent system including a hydrophilic
`non-toxic lower aliphatic alcohol (2 to 4 carbon atoms)
`in an amount sufficient to bring the total to 100 parts
`by weight. As previously noted, the inhibited phenol
`25
`may be potassium phenate, sodium phenate or ammo
`nium phenate. A particularly preferred concentration
`of the phenate is from 10 to 20 parts by weight and,
`even more preferred is a concentration of about 18 to
`19 parts by weight calculated as potassium phenate. In
`this connection, potassium phenate contains approxi
`mately 70% by weight of equivalent phenol.
`The salicylate may be sodium salicylate or zinc sali
`cylate. The use of zinc in any available form, such as
`zinc oxide, zinc sulfate, or other zinc compounds, in
`35
`cluding zinc salicylate is believed to enhance and aug
`ment the subepithelial changes without necessitating
`any increase in the resorcinol and/or phenol concentra
`tions to such a level that irreparable chemical destruc
`tion of the epithelium and subepithelial structures may
`40
`OCC.
`The compositions of the present invention can be
`used as solutions because of their stability, their rela
`The solutions of Examples 1 to 6 can be made into
`tive non-volatility, and the absence of precipitation of
`stable gels to the addition of suitable gelling agents
`the active ingredients. The solvent system employed in
`such as cellulosic derivatives. Hydroxyethylcellose is
`45
`the present invention includes a hydrophilic, nontoxic
`particularly preferred but other binders such as car
`aliphatic alcohol. It is not practical to use a 95% alco
`boxymethyl cellulose can also be employed. Each of
`hol solution so I prefer to use solvent systems which
`the solutions of Examples 1 to 6 can be made into a
`include other non-toxic solvents which, when com
`stable gel by the addition of about 5 to 15% by weight
`bined with the alcohol, provide a solution with greater
`50
`of the cellulose derivative.
`viscosity and less volatility than would be characteristic
`The non-aqueous solutions or gels of the present
`of an alcohol solution. Specifically, I prefer to use a
`invention are more stable, uniform and clinically active
`solvent system containing about 61.5% weight benzyl
`at lower concentrations of the active ingredients than
`alcohol and 38.5% ethanol. Another satisfactory sys
`in previous systems. Consequently, the lower resultant
`tem contains 50% by weight propylene glycol and 50%
`concentration of potassium phenate permits the appli
`55
`by weight ethanol.
`cation of these compositions in either solution or gel
`In addition to their use as true solutions, the composi
`form in proportions that cover a larger area of skin. For
`tions of the present invention can be employed in gel
`example, a solution containing 1 gram of potassium
`form. Any non-toxic gel forming agent can be used for
`phenate in the improved formulation of the present
`this purpose, and hydroxyethylcellulose is particularly
`invention can be used to treat approximately 200
`preferred. A sufficient amount of the gelling agent is
`square centimeters of skin.
`added to the solution of active ingredients until a gel of
`It should be evident that various modifications can be
`the desired viscosity is obtained. The amount of gelling
`made to the described embodiments without departing
`agent will depend upon the concentration of the active
`from the scope of the present invention.
`materials, particularly the phenates, as well as viscosity
`I claim as my invention:
`65
`requirements, mixing speeds, pressure conditions, tem
`1. A topical composition for application to skin af
`perature, anerobic environment, and other physical
`fected by seborrheic keratosis to provide a superficial
`slough of the epidermis, said composition comprising
`characteristics.
`
`5
`
`10
`
`5
`
`30
`
`60
`
`AQUESTIVE EXHIBIT 1018 page 0003
`
`

`

`3,949,072
`S
`6
`from 5 to 25 parts by weight of an inhibited phenol
`5. The topical composition of claim 1 which also
`calculated as potassium phenate and selected from the
`contains sufficient amount of a gel forming agent se
`group consisting of potassium, sodium and ammonium
`lected from the group consisting of hydroxyethylcellu
`salts of phenol; one-half to two parts of a salicylate
`lose and carboxymethylcellulose, to form a stable gel.
`calculated as sodium salicylate and selected from the
`6. The composition of claim 5 in which the gel form
`group consisting of sodium and zinc salicylate; 1 to 5
`ing agent is hydroxyethylcellulose.
`parts of resorcinol; and 1 to 4 parts of a zinc compound
`7. The composition of claim 1 in which the concen
`calculated as zinc sulfate selected from the group con
`tration of the inhibited phenol is in the range from 10 to
`sisting of zinc salicylate, zinc oxide, and zinc sulfate,
`20 parts by weight.
`the aforementioned inhibited phenol, salicylate, and
`8. The composition of claim 1 in which said salt is
`Zinc compound being dissolved in a non-aqueous sol
`potassium phenate and said phenate constitutes from 5
`vent containing a hydrophilic non-toxic lower aliphatic
`to 25% by weight of the composition.
`alochol in an amount sufficient to bring the total to 100
`9. The composition of claim 8 in which said phenate
`parts by weight said non-aqueous solvent being suffi
`constitutes from 10 to 20% by weight of the composi
`cient to increase the viscosity and to reduce the volatil
`tion.
`ity of the resultant composition.
`10. A method for treating an effected skin area to
`2. The topical composition of claim 1 in which said
`minimize the objectionable appearance of seborrheic
`lower aliphatic alcohol is ethanol.
`keratosis thereon which comprises applying to the af.
`3. The topical composition of claim 1 in which said
`fected skin area the composition of claim 1, said com
`solvent consists of a mixture of benzyl alcohol and
`position being applied to the skin in an amount equiva
`ethanol.
`lent to one gram of potassium phenate per 200 square
`4. The topical composition of claim 1 in which said
`Solvent consists of a mixture of propylene glycol and
`centimeters of skin area.
`ethanol.
`ck
`k
`
`5
`
`O
`
`15
`
`20
`
`25
`
`:k
`
`k
`
`:
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`AQUESTIVE EXHIBIT 1018 page 0004
`
`