Note: Descriptions are shown in the official language in which they were submitted.
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10692-8-2/T15
TREATMENT OF SKIN DISEASES
WITH ARTEMISININ AND DERIVATIVES
This invention relates to the topical and/or
systemic treatment of psoriasis, viral- or ultraviolet
radiation-induced skin diseases and skin tumors, and other
related conditions with a class of compounds having
sesquiterpene structures, including artemisinin,
dihydroartemislnin, and derivatives and analogs of these
compounds.
Psoriasis is a common skin disease characterized
by hyperactive keratinocytes whose metabolism is increased
nine-fold. The skin lesions generally are thick scales on
sharply demarcated red plaques. The involved and uninvolved
skin lesions have markedly elevated levels of the regulatory
25 ~ proteins putrescine and spermidine and suppressed local cell
mediated immunity. No current therapies, includin~
corticosteroids, retinoids, and immunosuppressive~agents are
effective in curing this disease, significantly decre~asing
the levels of these two polyamines, or~stimulating lesional~
cell mediated immunity. ~ ~ ~
The polyamines of concern in this invention are
generally low molecular weight, long chain, cationic
aliphatic compounds with multiple amine and/or imino groups.
These compounds are~widely distributed in nature.
Putrescine, spermidines and spermine are the major
poly~mlnes found in m
.
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2~03~L77
Ultraviolet radiation is invisible light that
induces a number of diseases, including polymorphous light
eruption, collagen vascular diseases, premalignant
keratoses, and primary skin cancer. Current therapies
include topical sunscreens~ immunosuppressive agents,
corticosteroids, and sur~ery or destruction of the
premalignant and malignant lesions.
Treatment of viral tumors/diseases (warts,
molluscum contagiosum) and hemorrhoids suffer from being
usually inefective but painful. Unlike most viral infec-
tionsl the wart virus produces hypertrophic viable cells and
suppresses skin cellular immunity against the virus.
Pemphigoid and pemphigus are autoimmune blistering
diseases whose incidence increases with age and are life
threatening. Unfortunately, a significant percentage of
deaths are due to massive doses of the therapeutic agents,
corticosteroids and immunosuppressives.
Artemisinin or Qinghaosu is a proven systemic
antimalarial agent purified from the herb Artemisia Annua.
Artemisinin is a sesquiterpene lactone with a peroxide
grouping that is water insoluble but is extremely safe.
There are single reports from China that artemisinin was 1)
virustatic against influenza virus in chick embryo, 2)
beneficial in a case of systemic lupus erythematosus, 3)
suppresses humoral immunity, 4) stimulates cell mediated
immunity, and 5) significantly decreases levels of all three
human polyamines, especialy putrescine and spermidine.
In an effort to improve water solubility and
decrease recurrences, scientists have developed
semisynthetic derivatives and synthetic analogs of
artemisinin. These compounds display the aforementioned
sought after characteristics with -the added benefit of
increased antimalarial activity. These compounds have never
been studied for therapeutic activlty in any primary skin
diseases or tumors and along with artemisinin have never
been used as a topical treatment for any disease.
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Treating primary skin disease and tumors with
topically applied dru~s improves safety, therapeutic
success, and is much more cost effective. All topical drugs
must penetrate the stratum corneum "barrier" to be
effective. Nearly all drugs do not penetrate so penetration
enhancers or vehicles have been developed to cross this
barrier. When combined with the active drug, a dramatic
improvement in therapeutic effectiveness occurs.
It has been discovered that compounds having
structures which contain sesquiterpene groups are effective
therapeutic agents useful in the treatment of a group of
skin conditions. Included among these skin conditions are
psoriasis; diseases and tumors induced by ultraviolet
radiation or of viral origin, including primary plemalignant
and malignant skin tumors; blisteriny skin diseases; and
hemorrhoids. Skin conditions induced by utraviolet
radiation include polymorphous light eruption, collagen
vascular disease, premalignant keratoses, Bowen's disease,
lentigo maligna, basal cell cancer, squamous cell cancer,
and malignant melanomas. Tumors and diseases of viral
origin include warts, molluscum contagiosum, orf and ecthyma
contagiosum.
The compounds which are discovered to have these
properties, in accordance with t.his invention, include
artemisinin; dihydroartemisinin; carbonate, sulfonate,
ester, and ether derivatives of dihydroartemisinin, notably
artemether, artesunate and artesunate salts, and
dihydroartemisinin propyl carbonate~ as well as the bis-
ether artelinic acid. In the practice of the invention,
formulations of these compoun~s are administered 0ither
parenterally, orally, or topically. For topical
administration, the compounds are preferably formulated with
vehicles ~hich enhance the penetration of the formulAtions
through the stratum corneum. These toplcal formulations are
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particularly effective in the treatment of viral tumors and
diseases, blistering diseases and hemorrhoids.
In accordance with the invention, it has been
discovered that compounds within this class significantly
suppress all three major polyamines found in man,
especially putrescine and spermine.
The compounds applied in accordance with the
present invention are generally those whose molecular
formulas include a sesquiterpene structure, preferably a
sesquiterpene lactone with an attached peroxide. Within
this group, those which are particularly preferred are
artemisinin, dihydroartemisinin, semisynthetic derivatives
of dihydroartemisinin including propyl carbonate
dihydroartemisinin, artemether, artesunate, and other
ethers, esters, carbonates and sulfonates, and the synthetic
analog, artelinic acid. These compounds, when formulated
for systemic administration or formulatéd with vehicles for
topical application effectively treat psoriasis, collagen
vascular diseases, polymorphous light eruption, xeroderma
pigmentosa, premalignant actinic keratoses and Bowen s
diseases, and basal cell, squamous cell, and melanoma skin
cancers. These topical formulations also effectively treat
hemorrhoids, viral induced tumors lwarts) and diseases,
pemphigoid and pemphigus. The collagen vascular diseases
include lupus er~thematosus, mixed~connective tissue
diseases, and dermatomyositis.
The compounds used in the present invention
include those falllng withln the following generic formula: -
:
' '
,~' ,'
2~)~3~
5~ ` ~
H3C ~ "`o~ " ~ J (I)
0 / \~
1 ¦ H
O ~H
where R is either
--C-- --CH--
0 1H
(artemisinin) (dihydroartemisinin)
-CH-
or ll
O~R'
in which R' is as follows:
300 O
-C-O-alkyl, -C-O-aryl, (carbonates~
o O , o o O O
. -C-alkyl, -C-aryl, -C-alkylene-C-OH, -C-alkylene-C-O M~,
(esters)
alkyl, (ethers~
O O
-S-O-alkyl or -S-O-aryl . ~ (~sulfonates) ~
In the R' definition, the terms "alkyl" and "alkylene~"
preferably refer to lower alkyl or alkylene groups, notably
Cl-C6, with Cl-C4 most preferred. Straight-chain and
branched-chain groups are included, with straight-chain
groups preferred. The term "aryl" preferably re~ers to
phenyl and naphthyl, with phenyl the~most preferred. The
symbol M in Formula I is an alkali or alkaline earth ~etal,
preferably sodium or potassium, wlth sodium the most
2003~
preferred. The ester in which R is -C(0)-(CH2~2-CO2H is
known by the common names artesunic acid and artesunate, and
the ester in which R is -C(0)-~CH2)2-C02 Na~ is known as
sodium artesunate.
Also included is the bis-ether, artelinic acid,
having the formula:
CH3
15H3C ~ ~ ~0
~: O ~
I I ~H
0 ~ ~ H
~CH3
o (II)
~ ~ H3
I"H
~
CH3 ~ -
. .
The concentrations of the sesquiterpene structure
compounds~1n the formulations to be~applied in~the practice
of the present invention are not critical and may vary
widely. In most appllcations, however,;~best r~esults will be
obtained using formulations containing the compounds at
levels of from about 0.01% to about 35% by weight,
preferably from about 0.5% to about 15%. The amount of the
compound actually administered ~or treatment will be a
therapeutically effective amountj which term is used herein
to denote the amount needed to produce a substantial
,
clinical improvement. ~ptimal amounts will vary with the
method of administration, and will generally be in
accordance with the amounts of conventional medicaments
administered in the same or a similar ~orm. Topical
application, for instance, is typically done from once to
three time~ a day.
The topical formulations may further include one or
more of the wide variety of agents known to be e~fective
as skin penetration enhancers. Examples of these are 2-
pyrrolidone, N-methyl-2-pyrrolidone, dimethylacetamide,
dimethylformamide, propylene glycol, alcohol, dimethyl
sulfoxide~ and ~æone. Additional agents may further be
included to make the formulation cosmetically acceptable.
Examples of these are ~ats, waxes, oils, dyes, fragrance,
preservatives, stabilizers, and surface active agents.
Keratolytic agents such as those known in the art may
also be included. Examples are salicylic acid, sulfur,
transretinoic acid and later generations of retinoids.
The amounts of each of these various types of additive
will be readily apparent to those skilled in the art
optimal amounts being the same as in other, known
formulations designed for the same type of
administration. Stratum corneum penetration enhancers.
for example, will typically be included at levels within
the range of about 0.1% to ahout 30% by weight,
preferably from about 1% to about 15%.
The following examples are offered for purposes of
illustration, and are intended neither to define nor
limit the invention in any manner.
EXAMPLE 1
Three patients with plaque psoriasis were treated
with an ointment containing artemisinin at 1% by weight
in a four-week, three-leg, open-paired comparison patch
study~ Trunkal or proximal extremity p oriatic plaques
1.5 to 3 centimeters in diameter that had been stable for
at least four weeks were treated.
The test consisted of applyin~ three different
formulations to separate test areas on each of three
patients. The formulations were a~ follows:
(a) 1% artemisinin ointment without added
penetration enhancers;
(b) Aristocort A 0.1% cream, a Class IV
corticosteroid; and
(c) Diprolene ointment, a Clas~ I corticosteroid.
Formulations (a) and (b) were applied twice daily
and occluded with an elastic cloth bandage. The third
was applied twice daily without occlusion. The lesions
were examined weekly.
One patient experienced 100% clearing of all three
test areas, while his untreated plaque~ improved by 50%,
probably indicating some spontaneous remission. ~he
three treated areas~ however, cleared faster and more
completely than the untreated areas, indioating that the
formulations did have a therapeutic effect.
On the second patient, the plaque treated with ;
formulation (a) improved by 75%. This plaque displayed 2+
erythema, but had no scale and was ~lat. By contrast,
the plaque treated with formulation (b) improved by only
25%, while the plaque treated with formulation (c)
remained unchanged.
::
On the third patient, the plaque treated with
formulation (a~ improved by 50% with 1~ violaceous
erythema, but with à 1+ elevated and 1~ scaley peripheral
rim. The plaque treated with formulation ~b) improved by
only 25%, while the plaque treated with formulation (c)
was 100% clear except for 1+ post inflammatory
hyperpigmentation.
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The conclusion from these tests is that occluded
artemisinin is superior to an occluded mid-potency
topical corticosteroid, and comparable to a megapotent
topical corticosteroid.
~XAMPLE 2
Three patents, each with one to three external
haemorrhoids that did not improve upon treatment with
either Anusol H~ or Preparation H~, two commercially
available haemorrhoids treatment products, were treated
with an ointment containing 1% artemisinin by weight
(without the inclusion of penetration-enhancing
additives), by topical administration applied four times
daily. All patients experienced relief of the itching,
tenderness and swelling symptoms after four to six days
of the treatment.
The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those
skilled in the art that further variations in the
formulations and uses of the compounds beyond those
described herein may be made without departing;from the
spirit or scope of the invention.
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