Note: Descriptions are shown in the official language in which they were submitted.
~ 3 ~ 8 ~
10692-6F/'T15
TREATMENT OF SKIN DISEASES AND TUMORS
~ his invention relates to the treatment of certain
skin conditions characterized by hyperactive mitochondria of
skin cells including those that are inflammatory,
hyperproliferative, hyperplastic or dy~plastic, with 5 to 19
carbon atom length aliphatic monocarboxylic acids and their
est~rs and amides, and 5 to 19 carbon atom length aliphatic
amines and their pharmaceutically acceptable salts,
including hydrohalides. This invention is a treatment
directed against inflammatory, hyperproliferative and
hyperplastic skin diseases and dysplastic skin growths
induced by viral infections and ultraviolet light, utilizing
medium and long chain monocarboxyllc acids and certain
analogs in topical therapeutic pharmaceutical formulations.
All of the compounds in this invention have in common
antimicrobial activity against a wide-range of human
pathoyens in the same bacterial, yeast, fungus, mycoplasma,
and enveloped virus assays. The aliphatic monocarboxylic
acids and their esters inhibit mltochondrial respiratory
enzymes and kill malignant tumor cells.
In particular, this invention is a treatment
directed against non-infectious in1ammatory skin diseases
in which microbes play a significant adjunctive
; pathophysiologic role. Several of these diseases alfio have
as30ciated hyperproliferative skin cells or hyperplastic
glandular cells. This invention is also a treatment for
~iral and ultraviolet radiation-induced hyperplastic or
~ dysplastic skin growths. In addition, this invention is a
; treatment for condition~ due to hyperplastic skin cells.
The present invention resides in the discovery that medium
and long chain aliphatic monocarboxylic acids and their
esters, amides, and~anhydrides, and medium and long chain
aliphatic amines and pharmaceutically acceptable salts
,~
~ ~31788~
thereof effectively treat acne, ro.sacea, psoriasis,
seborrheic dermatitis, diaper dermatitis. numular eczema,
atopic eczema, contact eczema, warts, molluscum contagiosum,
condylomatous carcinoma in situ, actinic (solar~ keratoses,
Bowen s disease, lentigo maligna, and melasma. These
compounds may function as primary or adjunctive therapeutlc
agents.
U.S. Patents Nos. 4,292,326 (Nazarro-Porro,
September 29, 1981) and 4,3a6,104 (Nazarro-Porro, May 31,
1983) and 4,713,394 (Thornfeldt, December 15, lg87) disclose
the use of certain dicarboxylic acids as therapeutic agents
for a variety of skin diseases. U.S. Patent No. 4,067,997
(Kabara, January 10, 1978) discloses the activity against
yeast, fungus, and bacteria of a synergistic combination of
a 12 carbon atom monocarboxylic acid glycerol ester and a
phenolic compound, used as a food preservative.
Acne vulgaris is a multifactorial disease
occurring in teenagers and young adults, with inflammatory
and noninflammatory comedos on the face and upper trunk.
The disease prere~uisite is sebaceous glands activated by
androgens. For some yet unknown reason hypercornification
in the gland duct occurs blocking normal mobility of skin
and follicle microorganisms. The restricted environment
stimuIates release of enzymes (lipases) by Propionobacterium
~cnes (an anaerobic corynebacterium), Staphylococcus
Epidermidis, and Pitrosporum Ovale (a yeast). Damage to the
gland structure and surrounding tissue by the lipases
results in inflammatory papules, pustules, and cysts. The
comedos are free of these microbes. In some, the disease is
only manifest as noninflammatory lesions but all patients
with inflammatory lesions have some comedos. Ma~or
treatments consist of oral and topical antibiotics and
retinoids; salicylic acid, sulfur, and benzoyl peroxide
topically, and oral antiandrogen birth control pills.
Psoriasis is a multifactorial disease with
epidermal hyperproliferation and epidermal and dermal
inflammation producing the lesions. Microbes play an
8~
etiologic role since at least 50% of the patients carry
Staphylococcus Aureus in the lesions. Be-ta hemolytic
streptococcus is known to cause guttate psoriasis. The
psoriasis lesions are sharply demarcated red with thick
white scale. They occur predominately on knees, elbows,
scalp, genitalia, and buttocks. ~urrent treatments consist
of topical corticosteroids, tar, anthralin. methotrexate,
azathioprine, etretinate, psoralens plus ultraviolet A
light, and tar plus ultraviolet B light.
Eczema is a descriptive term referring to poorly
demarcated pruritic, erythematous, scaley, blistered,
weeping, fissured or crusted lesions due to many causes.
Atopic and numular are the most common types, afflicting any
age group. Usually the lesions occur on the face, neck, and
flexural surfaces. In most patients, there is heavy growth
of Staphylococcus Aureus from the lesions of atopic and
numular eczema. A purulent rapidly progressive variant,
infectious eczematoid, is due to a m.ixed infection of
Staphylococcus Aureus and Streptococcus Pyogenes or either
bacteria alone. Current therapy includes topical and
systemic corticosteroids, antipruritics, and antibiotics and
topical tar.
Warts and molluscum contagiosum are hyperpro-
liferative tumors due to epidermal cell invasion by the
Human Papilloma virus and a pox virus, respectively. Unlike
other skin virus infections that kill the invaded cells,
both these viruses produce hyperplastic~ hyperproliferative
keratinocytes. Both viruses most commonly infect ch.ildren.
The wart tumors have different morphology depending upon the
viral subtype and the thickness of the skin invaded.
Molluscum contagiosum are always pearly papules with a
central umbilication on an erythematous base. There are
currently 23 different chemical and physical destructive
treatments, most of which are painful, poorly effective, or
may produce systemic toxicity. Poor treatment efficacy in
both infections results primarily from the marked -tissue
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hyperplasla induced by the virus. The H.P.V. virus is a
proven cancer causing agent.
Seborrheic dermatitis is a histopathologically
eczematous dermatosis characterized by poorly demarcated
scaley erythematous patches with yel].owish greasy scales.
"Dandruff" is a mild form of this condition, localized to
the scalp. This disease may involve any one, severa~, or
all of the following sites: scalp, eyebrows, glabella,
paranasal and chin folds, ears and retroauricular sulci,
presternal interscapular regions, pubic regions, and
intergluteal folds. Pityrosporum ovale, a yeast, has been
shown to play a significant role in 75% of afflicted
patients. Present therapy includes corticosteroids, tar,
sulfur, and antibiotics, including antiyeast agents.
Actinic keratoses are superficial inflamma-tory
tumors arisi.ng on sun exposed and irradiated skin. These
tumors are the most common premalignant skin lesions. Each
tumor is erythematous to brown with variable scaling.
Current therapies include excisional and cryosurgery, and 5-
fluorouracil cream. The treatments hurt and often produce
cosmetically unacceptable pigmentary residua.
Bowen s disease is a superficial intraepidermal
tumor of keratinocytes most commonly caused by ultraviolet
irradiation. Approximately 5% metastasize. These tumors
frequently cover large areas of the skin. They often
develop from actinic keratosis. Current treatments consist
of excisional and cryosurgery and 5-fluorouracil cream.
Lentigo maligna is a tumor of premalignart
melanocytes in the epidermis, usually occurring on sun
exposed facial skin of elderly patients. Up to 30% progress
to invasive cancer. These tumors frequently cover large
surface areas. Usually treatment is surgery, although it is
claimed that azelaic acid is effective in some patients.
Melasma is a hyperipigmentation state of sunex-
posed skin resulting from excessive hormonal stimulation ofmelanocytes producing pigment granule hyperplasia. This
condition is usually activated by pregnancy or oral
~317~8~
contraceptives. but may persist years after removal of
this stimulus. The only current therapy is hydroquinone,
which not only i8 poorly effective but may produce
permanent depigmentation and raxely a paradoxical
hyperpigmentation.
The conditions described above are the most common
skin diseases and tumors, for which it has now been di -
covered that certain aliphatic amines effectively treat
when applied topically. In general, this invention
applies to the treatment of inflammatory and
hyperproliferative skin diseases in which bacteria play a
siqnificant supporting pathophysiologic role. It also
applies to treatment of tumors induced by viruses. This
invention further applies to treatment of premalignant
skin tumors, including Bowen'~ disease, lentigo maligna,
actinic keratoses.
Thi invention provides a pharmaceutical composition
for topical use containing a compound selected from the
group con~isting of monocarboxylic acids having 5 to 19
carbon atoms, esters thereof, and amide~ thereo~, and
monoaliphatic amines having 5 to 1~ carbon atoms and
pharmaceutically acceptable ~alts thereof, in association
with a pharmaceutically acceptable vehicle that makes
said composition suitable for topical application,
characterized in that said compound is in a concentration
of 1% to 35~ by weight with respect to the total
composition.
This invention also provides a pharmaceutical
composition for topical use containing from about 1% to
about 35% by weight of a compound selected from the group
; consisting of aliphatic amines having 9 to 18 carbon
atoms, and pharmaceutically acceptable salts thereof.
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5A
This invention al90 provides the use of the
aforementioned pharmaceutical compositions to treat skin
~ubject to:
a) a noninfectious inflammatory disease in
which bacteria or yeasts play an adjunctive
role;
b) psoriasis, acne vulgaris~ seborrhoeic
dermatitis, atopic eczema and numular eczema;
or
c) warts and molluscum contagiosum.
This invention also provides a process for the
production of a pharmaceutical composition for use in the
treatment of skin disea es characterized by kin cells
with hyperactive mitochondria, including skin diseases
that are inflammatory, hyperproliferative, hyperplastic
or dysplastic, which comprise3 as~ociating a compound
selected from the group consisting of monocarboxylic
acids having S to 19 carbon atoms, esters thereof, and
amides thereof, and monoaliphatic amines having 5 to 19
carbon atoms and pharmaceutically acceptable salts
thereof, with a pharmaceutically acceptable vehicle that
make said compound suitable for topical application.
The monocarboxylic acids and aliphatic amines of the
present invention are those of 5 to l9 carbon atom
length, inclusive. The compounds include straight-chain
and branched-chain species, and saturated and unsaturated
species, including species with multiple unsaturation
sites. Preferred are straight-chain aliphatic acids and
amines, either saturated or unsaturated, of 9 to 18
carbon atom length. Examples include pelargonic, capric,
undecanoic, lauric, tridecanoic, m~ri~tic, myristoleic,
palmitic, palmitoleic, hexadecanoic, oleic, linoleic,
i. Q~.' `
~317~
B
linolenic, and octadecanoic acids. Thi~ invention also
extends to esters~ amides, and amines and their salts,
including hydrochlorides. The ester group includes
glycerides and polyglycerides such as monoglyceride F ~
triglycerides, hexaglycerides, and decaglycerides, and
esters formed from methanol, ethanol, propylene glycol,
polyethylene glycol, orethanol, and sorbitol, and
saccharides such as sucrose. Spec.ific examples include
l-monolaurin, 2-monolaurin, monocaprin, monomyristin,
monolinolein; triglyeerol caprylate, pelargonate,
caprate, and laurate; hexaglycerol
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caproate, caprylate, pelargonate, caprate and laurate;
decaglycerol butyrate, caprylate, pelargonate, caprate, and
laurate; sucrose caprylate, caprate, laurate, myristate,
palmitate, elaidate, oleate, and linoleate. Examples of
amide are capratoyl-N,N--dimethylamide, lauryl-N,N-
dimethylamide, myristoleyl-N,N-dimethylamide, and
palmitoleyl-N,N-dimethylamide. A preferred example is
lauryl-N,N-dimethylamide. Examples of amines salts are
capratylamine hydrochloride, laury]amine hydrochloride,
tridecanylamine hydrochloride, myristoleylamine
hydrochloride, palmitoleylamine hydrochloride, linoleylamine
hydrochloride, and linolenylamine hydrochloride. Preferred
amines are dodecylamines, particularly laurylamine and
laurylamine hydrochloride.
Th0 compounds are generally applied in derma-
tological formulations. These include any of the various
known mixtures and combinations which may be applied
topically and will permit even spreading of the active
ingredient over the affected area. Examples include creams,
lotions, solutions, ointments, and unguents.
The concentration of the active ingredient in -the
formulation, i.e., the monocarboxylic acid or aliphatic
amine or its analog or salt, is not critical and may vary
over a wide range. The concentration may indeed range as
high as the upper limit of dissolvability in any given for-
mulation. The concentration should be a therapeutically
effective concentration, however, and in most cases, best
results are achieved within a range of about 1% to about 35%
by weight, preferably from about 2.5% to about 17.5% by
weight.
The formulation may contain additional ingredients
on an optional basis, including both those which are
biologically active and those which are biologlcally
inactive. Keratolytic agents are particularly useful in
some cases as added active ingredients. Examples are
salicylic acid, sulfur and retinoid derivatives. Optional
concentrations will vary among keratolytlc agents.
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Salicylic acid, for example, is preferably used at about
0.5% to about 5.0% while sulfur is preferably used at about
2.0% to about 10.0%. Appropriate concentration ranges for
any particular Xeratolytic agent will be apparent to those
skilled in the art.
Stratum corneum penetration enhancing compounds
are usually included in dermatologic formulations to boost
efficacy. Examples include propylene glycol, sodium lauryl
sulfate, dimethylamide, N-methyl-2-pyrrolidone, and Azone*
~Nelson Research~ Irvine, California).
Examples of inactive ingredients are wetting
agents, surfactants, emollients, and solvents.
The term "therapeutically effective amount" is
used herein in terms of the amount of dermatological
formulation to be applied in any particular case to denote
any amount which will cause a substantial improvement in a
disease condition (such as a subsidence of a lesion, for
example) when applied to the affected area repeatedly over a
period of time. The amount will vary with the condition
being treated, the stage of advancement of the condition,
and the type and concentration of formulation applied.
Appropriate amounts in any given instance will be readily
apparent to those skilled in the art or capable of
determination by routine experimentation.
The term "pharmaceutically acceptable salts" is
used herein to denote salts of the amines which are
biologically compatible and otherwise suitable for admin-
istration to human subjects, and which deliver the thera-
peutic activity of the amine to the subject in substantially
the same degree as if the amine itself were administered.
The compositions are generally applied in topical
manner to the affected area, i.e., ]ocalized application to
the skin region where the inflammation or hyperproliferation
abnormality or tumor is manifest.
The following examples are offered for purposes of
illustration, and are intended neither to define nor limit
the invention in any manner.
* Trade-mark
~17~
Examples 1 through 4 illustrate the preparation of
topical formulations in accordance with the present
invention.
EXAMP~E 1
; A therapeutic ointment was prepared by dissolving
17.5 grams of l-monolaurin (obtained from Lauricidin, Inc.,
Okemos, Michigan) in 10 mL of commercial isopropyl alcohol
heated to 50C. Commercial propylene glycol ~7 mL) was the
incorporated into the solution and the resulting mixture was
cooled overnight at 24C. The mixt~re was then worked into
100 g of Aquaphor*~4-chloro-5-sulfamoyl-2 ,6 -
salicyloxylidide, obtained from Beiersdorf, Inc., Norwalk
Connecticut) on a pill tile.
The resulting ointment is hereinafter referred to
as Formula A.
EXAMPLE 2
A therapeutic ointment was prepared in a manner
identical to that described in Example l, except that 9 g of
l-monolaurin, 5 mL of isopropyl alcohol and l mL of
propylene glycol were used.
The resulting ointment is hereinafter referred to
as Formula B.
EXAMPLE 3
A therapeutic formulation was prepared by
dissolving 17.5 g of l-monolaurin ln 52 mL of isopropyl
alcohol mixed with 24 mL of propylene glycol and heated to
50C.
The resulting formula-tion is hereinafter referred
to a~ Formula C.
EXAMPLE 4
A therapeutic formulation was prepared in a manner
identical to that described in Example 3, except that 24 g
* Trade-mark
of 1-monolaurin~ 52 mL of isopropyl alcohol and 24 mL of
propylene glycol were used.
The resulting formulation is hereinafter referred
to as Formula D.
Examples 5 through 10 illustrate the therapeutic
effects of these formulations.
EXAMP~E 5
Eleven patients with grade I-III acne vulgaris
were treated twice daily with Formula C for 6 weeks. All
these patients had failed to completely clear using all
standard topical and therapeutic agents. Several had also
failed using isotretinoin. With Formula C, however, seven
of the patient~ cleared completely, two cleared more than
50% of their lesions, and two experienced mi].d worsening of
their disease.
EXAMPLE 6
Six patients with re~ractory pla~ue type psoriasis
vulgaris were treated for four weeks twice daily with
Formula A. These patients had failed to respond to all
other topical and oral psoriasis treatments. As a result of
the administration of Formula A, one patlent completely
cleared all skin lesions and the other five each experienced
at least 75% clearing.
EXAMPLE 7
Three patients with refractory facial seborrheic
dermatitis were treated twice daily with Formula B for two
weeks. These patients had previously failed to respond to
topical corticosteroids, antifungals and antibiotics. As a
result of the use of Formula ~, all three ~ained complete
resolution of the skin rash during the treatment period, and
one of the three cleared in only three days.
lo 1~7~8~
EXAMPLE 8
Three patients with refr~ctory atopic dermatitis
were treated with Formula A twice daily for six weeks.
These patients had previously failed to respond to topical
corticosteroids, tars, oral and topical antibiotics, and
antihistamines. As a result of the use of Formula A, all
three patients cleared completely during the treatment
period.
EXAMPLE 9
Two patients with refractory condyloma acuminata
were treated with Formula D twice daily for six weeks. One
completely cleared after two weeks of treatment; the other
cleared after five weeks of treatment
EXAMPLE 10
Five patients wlth persistent melasma that had
failed to be resolved by hydroquinone were treated for si~
weeks, twice daily, with Formula C. As a result, two of the
five completely resolved, two others improved by 75%, and
the remaining one by 50%.
The foregoing description is offered primarily for
purposes of illustration. It will be readily apparent to
those skilled in the art and numerous variations in both the
formulations and their method of use, not mentioned above,
may be made without departing from the spirit and scope of
the invention.
