U.S. patent application number 14/257577 was filed with the patent office on 2015-01-22 for use of tellurium compounds for the treatment actinic keratosis.
This patent application is currently assigned to BioMAS Ltd.. The applicant listed for this patent is BioMAS Ltd.. Invention is credited to Michael ALBECK, Benjamin SREDNI.
Application Number | 20150023914 14/257577 |
Document ID | / |
Family ID | 37865380 |
Filed Date | 2015-01-22 |
United States Patent
Application |
20150023914 |
Kind Code |
A1 |
SREDNI; Benjamin ; et
al. |
January 22, 2015 |
USE OF TELLURIUM COMPOUNDS FOR THE TREATMENT ACTINIC KERATOSIS
Abstract
Methods for treating skin conditions such as basal cell
carcinoma and/or actinic keratosis are provided, which are effected
by administering a pharmaceutically effective amount of a
tellurium-containing compound. A pharmaceutical composition for
treatment of skin conditions such as basal cell carcinoma and/or
actinic keratosis is also provided.
Inventors: |
SREDNI; Benjamin; (Kfar
Saba, IL) ; ALBECK; Michael; (Ramat-Gan, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioMAS Ltd. |
Jerusalem |
|
IL |
|
|
Assignee: |
BioMAS Ltd.
Jerusalem
IL
|
Family ID: |
37865380 |
Appl. No.: |
14/257577 |
Filed: |
April 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12517222 |
Jun 2, 2009 |
8703753 |
|
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PCT/IL2006/001080 |
Sep 14, 2006 |
|
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14257577 |
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60716923 |
Sep 15, 2005 |
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Current U.S.
Class: |
424/85.4 ;
514/184; 514/185 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/555 20130101; A61K 31/395 20130101; A61P 17/12 20180101;
C07F 11/005 20130101; A61K 45/06 20130101 |
Class at
Publication: |
424/85.4 ;
514/185; 514/184 |
International
Class: |
C07F 11/00 20060101
C07F011/00; A61K 31/555 20060101 A61K031/555; A61K 45/06 20060101
A61K045/06 |
Claims
1-42. (canceled)
43. A method of treating basal cell carcinoma in a subject in need
thereof, the method comprising administering to the subject a
therapeutically effective amount of at least one
tellurium-containing compound, wherein said at least one
tellurium-containing compound is selected from the group consisting
of tellurium dioxide (TeO.sub.2), a complex of TeO.sub.2, a
compound having general Formula I: ##STR00015## a compound having
general Formula II: ##STR00016## a compound having general Formula
III: ##STR00017## and a compound having general Formula IV:
##STR00018## wherein: each of t, u and v is independently 0 or 1;
each of m and n is independently an integer from 0 to 3; each of j
and k is independently an integer from 0 to 4; Y is selected from
the group consisting of ammonium, phosphonium, potassium, sodium
and lithium; X is a halogen atom; and each of R.sub.1-R.sub.22 is
independently selected from the group consisting of hydrogen,
hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl,
alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl,
alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano,
N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl,
alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl,
sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate
and sulfoneamido.
44. The method of claim 43, wherein said tellurium-containing
compound is selected from the group consisting of a compound having
said general Formula I and a compound having said general Formula
II.
45. The method of claim 43, wherein t, u and v are each 0.
46. The method of claim 43, wherein each of R.sub.1, R.sub.8,
R.sub.9 and R.sub.10 is hydrogen.
47. The method of claim 43, wherein X is a halogen atom.
48. The method of claim 43, wherein X is chloro.
49. The method of claim 43, wherein Y is ammonium.
50. The method of claim 43, wherein said tellurium-containing
compound has said general Formula III.
51. The method of claim 43, wherein each of R.sub.11-R.sub.14 is
hydrogen.
52. The method of claim 43, wherein said tellurium-containing
compound has said general Formula IV.
53. The method of claim 43, wherein n and m are each 0.
54. The method of claim 43, wherein each of R.sub.15, R.sub.18,
R.sub.19 and R.sub.22 is hydrogen.
55. The method of claim 43, wherein said administering is effected
topically.
56. The method of claim 43, wherein said at least one
tellurium-containing compound forms a part of a pharmaceutical
composition, said pharmaceutical composition further comprising a
pharmaceutically acceptable carrier.
57. The method of claim 43, wherein a concentration of said at
least one tellurium-containing compound of formula I, II or III
ranges from about 0.01 weight percent to about 50 weight percents
of the total weight of said composition.
58. The method of claim 43, wherein a concentration of said at
least one tellurium-containing compound of formula IV ranges from
about 0.02 weight percent to about 85 weight percents of the total
weight of said composition.
59. The method of claim 43, wherein said at least one
tellurium-containing compound forms a part of a pharmaceutical
composition designed for topical application and is being in a form
selected from the group consisting of a cream, an ointment, a
paste, a gel, a lotion, a milk, a suspension, a solution, an
aerosol, a spray, a foam, a shampoo, a mousse, a serum, a swab, a
pledget, a pad, a tincture, a patch and a soap.
60. The method of claim 43, wherein said pharmaceutical composition
further comprises at least one additional active agent selected
from the group consisting of an antineoplastic agent, an
immunomodulator, an interferon and a non-steroidal
anti-inflammatory drug.
61. The method of claim 43, wherein said at least one tellurium
containing compound is ##STR00019## wherein X=Cl; t=u=v=0;
R.sub.1=R.sub.8=R.sub.9=R.sub.10=H; Y.sup.+=NH.sub.4.sup.+.
62. The method of claim 43, wherein said at least one tellurium
containing compound is ##STR00020## wherein m=n=0;
R.sub.15=R.sub.18=R.sub.19=R.sub.22=H.
Description
FIELD AND BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel therapeutic methods
and pharmaceutical compositions for treating skin conditions and,
more particularly, to compositions comprising and methods utilizing
tellurium-containing compounds for treatment of basal cell
carcinoma and/or actinic keratosis.
[0002] Basal cell carcinoma (BCC) is the most common form of skin
cancer, affecting to 800,000 Americans each year, and is, in fact,
the most common malignancy in humans. Such carcinomas occur most
frequently on the face, ears, neck, scalp, shoulders, and back. BCC
is usually slow growing and rarely metastasizes, but it can cause
significant local destruction and disfigurement if neglected or
treated inadequately.
[0003] Contributing factors to BCC include exposure to radiation,
such as X-ray exposure; arsenic exposure; immunosuppression; the
autosomal-recessive disease, Xeroderma pigmentosum; nevoid BCC
syndrome (basal cell nevus syndrome, Gorlin syndrome); Bazex
syndrome; and complications of burns, scars, vaccinations, or even
tattoos are contributing factors.
[0004] BCC is believed to arise from pluripotential cells within
the basal layer of the epidermis or follicular structures. These
cells form continuously during life and are capable of forming
hair, sebaceous glands, and apocrine glands. Tumors usually arise
from the epidermis and occasionally arise from the outer root
sheath of a hair follicle, specifically from hair follicle stem
cells residing just below the sebaceous gland duct.
[0005] The mechanism by which BCC develops is believed to include a
decrease in Langerhans cells, dendritic epidermal T cells, and
Thy1+ cells. Furthermore, systemic proliferation of suppressor T
cells and the release of immunosuppressive factors (eg, tumor
necrosis factor-a (TNF-.alpha.), interleukin-1-.beta. (IL-1),
prostaglandin (PG), interleukin 10 (IL-10) are believed to be
pathogenic to the development of BCC.
[0006] In a large proportion of BCC biopsy specimens, high IL-10
expression has been found. Immunohistochemical evaluation has
revealed that IL-10 is specifically localized in BCC tumor-bearing
lesions, but not in the normal epidermis or dermis [1, 2]. IL-10 is
not expressed in the tumor-infiltrating-lymphocytes (TIL) which
attempt to destroy the tumor. Moreover, it has been demonstrated
that this TIL population is inactivated by BCC-derived IL-10,
resulting in their inability to respond to the tumor. Inactivation
of IL-10 by anti-IL-10 neutralizing antibodies restores, in vitro,
the anti-BCC TIL recognition. These findings indicate that
BCC-derived IL-10 is, at least in part, responsible for
immunosuppression of the local immune response. In addition, it has
been found that IL-10 serves as a tumor growth factor, which
constitutively activates transcription factors needed for cellular
proliferation.
[0007] Treatment of BCC generally involves use of antineoplastic
agents, such as 5-fluorouracil, which interferes with DNA synthesis
by blocking methylation of deoxyuridylic acid and inhibiting
thymidylate synthetase and, subsequently, cell proliferation;
imiquimod, which is believed to increase tumor infiltration of
lymphocytes, dendritic cells, and macrophages; interferon .alpha.
2-.beta., which is believed to act via direct antiproliferative
effects against malignant cells and modulation of host immune
response.
[0008] Actinic keratosis is the most common skin growth. Actinic
keratoses are chiefly found on the face, the ears, the forearms,
and the dorsum of the hands. However, they may occur on other areas
such as the back, the chest, and the legs. They usually appear as
multiple discrete, flat or elevated, verrucous, keratotic lesions.
Lesions typically have an erythematous base covered by scale
(hyperkeratosis). They are usually 3-10 mm in diameter and
gradually enlarge into broader, more elevated lesions. Actinic
keratoses are pre-cancerous growths, which may develop into
squamous cell carcinomas if left untreated.
[0009] Actinic keratosis is believed to be associated with
decreased expression or activity of cytokine signal regulators.
Langerhans cells, situated in the epidermis layer of the skin, have
been found to have changed shape and altered function in actinic
keratosis. These cells are involved in presenting presentation of
antigens to T-cells. Damage to these cells results in an
immunosuppressive effect on the skin. Increased incidence of
actinic keratosis is found in patients having a weak or suppressed
immune system.
[0010] Actinic keratosis is most commonly treated with
5-fluorouracil. Other medications include diclofenac sodium and
imiquimod.
[0011] However, 5-fluorouracil may result in local erythema and
hypersensitivity Further common side effects of fluorouracil
include extreme fatigue; nausea; mouth sores and ulcer; diarrhea;
and temporary drop in bone marrow function, causing a drop in white
blood cell count, which increases the risk of severe infection,
anemia and drop in blood platelets. Occasional side effects include
hair thinning; brittle, chipped and ridged nails; sensitivity of
the skin to sunlight; rashes; watery eyes; and loss of
appetite.
[0012] Imiquimod is not indicated for treatment of tumors of the
head or neck, and is not suitable for treatment of tumors of more
than 2 cm in diameter. Side-effects of imiquimod include skin
infection and skin rash, back pain, burning or itching, changes in
skin color, diarrhea, headache, muscle aches, redness of the skin,
scabbing and crusting, skin peeling, skin that becomes hard or
thickened and swelling of the skin.
[0013] Common side-effects of interferon .alpha. 2-.beta. include
flu-like syndrome with fever, chills, tiredness, headache, muscle
and bone aches; decreased appetite, mild nausea, mild diarrhea,
seizures, irritability, poor mental concentration, and sleepiness.
Less common side effects include changes in taste and dry mouth,
dizziness, and abnormal results on kidney function blood tests.
Rare side effects include decreased white cell count with increased
risk of infection, decreased platelet count with increased risk of
bleeding, vomiting, confusion, depression, chest pain, change in
blood pressure, partial hair loss, rash, dry throat, irritation at
the site of injection, congestive heart failure, impotence and
menstrual irregularities. Incidence of severe or fatal
gastrointestinal hemorrhage has been reported.
[0014] There is thus a widely recognized need for and it would be
highly advantageous to have novel treatments for BCC and actinic
keratosis, devoid of the above limitations.
[0015] Various tellurium compounds have been described in the art
as having immunomodulating properties. A particularly effective
family of tellurium-containing compounds is taught, for example, in
U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739,
whereby another effective family is taught, for example, in a
recently filed U.S. Provisional Patent Application No. 60/610,660,
which are all incorporated by reference as if fully set forth
herein. The immunomodulating properties of this family of
tellurium-containing compounds is described, for example, in U.S.
Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and 5,213,899, which are
all incorporated by reference as if fully set forth herein.
[0016] One of the most promising compounds described in these
patents is ammonium trichloro(dioxyethylene-O,O')tellurate, which
is also referred to herein and in the art as AS101. AS101, as a
representative example of the family of tellurium-containing
compound discussed hereinabove, exhibits antiviral (Nat. Immun.
Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses.
8(5):613-23, 1992), and tumoricidal activity (Nature
330(6144):173-6, 1987; J. Clin. Oncol. 13(9): 2342-53, 1995; J
Immunol. 161(7):3536-42, 1998.
[0017] It has been suggested that AS101, as well as other
tellurium-containing immunomodulators, stimulate the innate and
acquired arm of the immune response. For example, it has been shown
that AS101 is a potent activator of interferon (IFN) (IFN) in mice
(J. Natl. Cancer Inst. 88(18):1276-84, 1996) and humans (Nat.
Immun. Cell Growth Regul. 9(3):182-90, 1990; Immunology
70(4):473-7, 1990; J. Natl. Cancer Inst. 88(18):1276-84, 1996.)
[0018] It has also been demonstrated that AS101, as well as other
tellurium-containing immunomodulators, induce the secretion of a
spectrum of cytokines, such as IL-1.alpha., IL-6 and TNF-.alpha.,
and that macrophages are one main target for AS101 (Exp. Hematol.
23(13):1358-66, 1995) and it was found to inhibit IL-10 at the
m-RNA level, and this inhibition may cause an increase in IL-12
(Cell Immunol. 176(2):180-5, 1997); J. Natl. Cancer Inst.
88(18):1276-84, 1996).
[0019] Other publications describing the immunomodulation
properties of AS101 include, for example, "The immunomodulator
AS101 restores T(H1) type of response suppressed by Babesia
rodhaini in BALB/c mice". Cell Immunol 1998 February; "Predominance
of TH1 response in tumor-bearing mice and cancer patients treated
with AS101". J. Natl Cancer Inst 1996 September; "AS-101: a
modulator of in vitro T-cell proliferation". Anticancer Drugs 1993
June; "The immunomodulator AS101 administered orally as a
chemoprotective and radioprotective agent". Int J Immunopharmacol
1992 May; "Inhibition of the reverse transcriptase activity and
replication of human immunodeficiency virus type 1 by AS 101 in
vitro". AIDS Res Hum Retroviruses 1992 May; "Immunomodulatory
effects of AS101 on interleukin-2 production and T-lymphocyte
function of lymphocytes treated with psoralens and ultraviolet A".
Photodermatol Photoimmunol Photomed 1992 February; "Use and
mechanism of action of AS101 in protecting bone marrow colony
forming units-granulocyte-macrophage following purging with ASTA-Z
7557". Cancer Res 1991 Oct. 15; "The effect of the immunomodulator
agent AS101 on interleukin-2 production in systemic lupus
erythematosus (SLE) induced in mice by a pathogenic anti-DNA
antibody". Clin Exp Immunol 1990 March; "Toxicity study in rats of
a tellurium based immunomodulating drug, AS-101: a potential drug
for AIDS and cancer patients". Arch Toxicol 1989; "The biological
activity and immunotherapeutic properties of AS-101, a synthetic
organotellurium compound". Nat Immun Cell Growth Regul 1988; and "A
new immunomodulating compound (AS-101) with potential therapeutic
application". Nature 1987 November.
[0020] In addition to its immunomodulatory effect, AS101 is also
characterized by low toxicity. Toxicity tests have shown that LD50
values in rats following intravenous and intramuscular
administration of AS101 are 500-1000 folds higher than the
immunologically effective dose.
[0021] While the immunomodulating effect of tellurium-containing
compounds was studied with respect to various aspects thereof, the
use of tellurium compounds in the treatment of skin diseases such
as basal cell carcinoma and/or actinic keratosis has never been
suggested nor practiced hitherto.
SUMMARY OF THE INVENTION
[0022] The present invention successfully addresses the
shortcomings of the presently known methods of treating skin
conditions such as basal cell carcinoma and actinic keratosis by
providing methods and compositions comprising tellurium compounds,
which are devoid of the side effects of the commonly known
treatments for these conditions.
[0023] According to one aspect of the present invention there is
provided a method of treating a condition of the skin selected from
the group consisting of basal cell carcinoma and actinic keratosis
in a subject in need thereof, the method comprising administering
to a subject a therapeutically effective amount of at least one
tellurium-containing compound.
[0024] According to another aspect of the present invention there
is provided a method of treating basal cell carcinoma, the method
comprising administering to a subject a therapeutically effective
amount of at least one tellurium-containing compound.
[0025] According to yet another aspect of the present invention
there is provided a method of treating actinic keratosis, the
method comprising administering to the subject a therapeutically
effective amount of at least one tellurium-containing compound.
[0026] According to still an another aspect of the present
invention there is provided a use of a tellurium-containing
compound in the manufacture of a medicament, whereby the medicament
is for treating actinic keratosis and/or treating basal cell
carcinoma.
[0027] According to an additional aspect of the present invention
there is provided pharmaceutical composition identified for use in
the treatment of a condition of the skin selected from the group
consisting of basal cell carcinoma and actinic keratosis, the
composition comprising at least one tellurium-containing compound
and a pharmaceutically acceptable carrier.
[0028] According to further features in preferred embodiments of
the invention described below, the tellurium-containing compound of
the present invention is a compound comprising a tellurium dioxide
moiety and optionally and preferably is at least one of tellurium
dioxide (TeO.sub.2) per se, an organic complex of TeO.sub.2 (as
detailed hereinbelow), a compound having general Formula I:
##STR00001##
a compound having general Formula II:
##STR00002##
[0029] a compound having general Formula III:
##STR00003##
and a compound having general Formula IV:
##STR00004##
wherein:
[0030] each oft, u and v is independently 0 or 1;
[0031] each of m and n is independently an integer from 0 to 3;
[0032] each of j and k is independently an integer from 0 to 4;
[0033] Y is selected from the group consisting of ammonium,
phosphonium, potassium, sodium and lithium;
[0034] X is a halogen atom; and
[0035] each of R.sub.1-R.sub.22 is independently selected from the
group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy,
alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl,
carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido,
cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl,
alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl,
sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate
and sulfonamido.
[0036] Preferably, the tellurium-containing compound has general
Formula I or general Formula IV.
[0037] According to an embodiment in which the tellurium-containing
compound has general Formula I, preferably t, u and v are each 0.
More preferably, each of R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is
hydrogen; more preferably X is a halogen atom, most preferably the
halogen atom is chloro. More preferably, Y is ammonium. The
preferred compound according to this embodiment is referred to
hereinafter as AS101.
[0038] According to an alternative embodiment of this feature of
the present invention, the tellurium-containing compound has the
general Formula IV. Preferably, according to this embodiment, n and
m are each 0. More preferably, each of R.sub.15, R.sub.18, R.sub.19
and R.sub.22 is hydrogen. The preferred compound according to this
embodiment is referred to hereinafter as SAS.
[0039] According to still further features in the described
preferred embodiments of the methods of the present invention,
administering is effected systemically. Preferably, for systemic
administration, a therapeutically effective amount of a compound of
formula I, II or III ranges from about 0.1 mg/m.sup.2/day to about
10.0 mg/m.sup.2/day. Also preferably, a therapeutically effective
amount of a compound of formula IV ranges from about 0.17
mg/m.sup.2/day to about 17 mg/m.sup.2/day.
[0040] According to still further features in the described
preferred embodiments of the methods of the present invention,
administering is effected topically, preferably by applying a
therapeutically effective amount of a tellurium-containing compound
onto a treated skin area.
[0041] According to still further features in the described
preferred embodiments of the methods, uses or compositions of the
present invention, the tellurium-containing compound forms a part
of a pharmaceutical composition, further comprising a
pharmaceutically acceptable carrier. Preferably, a concentration of
tellurium-containing compound of formula I, II or III in the
carrier ranges from about 0.01 weight percent to about 50 weight
percents, more preferably from about 0.01 weight percent to about
20 weight percents, of the total weight of the composition. Also
preferably, a concentration of tellurium-containing compound of
formula IV in the carrier ranges from about 0.02 weight percent to
about 85 weight percents, more preferably from about 0.02 weight
percents to about 40 weight percents of the total weight of the
composition.
[0042] For topical administration, the pharmaceutical composition
is preferably in the form of a cream, an ointment, a paste, a gel,
a lotion, a milk, a suspension, a solution, an aerosol, a spray, a
foam, a shampoo, a mousse, a serum, a swab, a pledget, a pad, a
tincture, a patch or a soap.
[0043] Optionally, the pharmaceutical composition may further
comprise at least one additional active agent, including, but not
limited to, an antineoplastic agent, an immunomodulator, an
interferon and a non-steroidal anti-inflammatory drug (such as
oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304,
salicylates, aspirin, disalcid, benorylate, trilisate, safapryn,
solprin, diflunisal, fendosal, acetic acid derivatives, diclofenac,
fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,
tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,
oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic,
flufenamic, niflumic, tolfenamic acids, propionic acid derivatives,
ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen,
fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin,
pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,
tiaprofen, pyrazoles, phenylbutazone, oxyphenbutazone, feprazone,
azapropazone, trimethazone and derivatives, esters, salts and
mixtures thereof).
[0044] More preferably, the additional active agent is at least one
of fluorouracil, imiquimod, interferon-.alpha., and diclofenac.
[0045] According to still further features in the described
preferred embodiments of the methods, uses or compositions of the
present invention, the composition may optionally further comprise
at least one ingredient selected from the group consisting of a
humectant, a deodorant agent, an antiperspirant, a sun screening
agent, a sunless tanning agent, a pII adjusting agent, a chelating
agent, a preservative, an emulsifier, an occlusive agent, an
emollient, a thickener, a solubilizing agent, a penetration
enhancer, an anti-irritant, a colorant, a propellant and a
surfactant.
[0046] The pharmaceutical composition may be packaged in a
packaging material and identified in print, in or on the packaging
material, for use in treating a condition of the skin selected from
the group consisting of basal cell carcinoma and actinic
keratosis.
[0047] According to still further features in the described
preferred embodiments the carrier is selected such that: the
tellurium-containing compound, at a concentration of 10 weight
percents, is soluble, dispersible and/or suspendable therein; and
the formulation is chemically and physically stable upon storage at
room temperature for at least 30 days.
[0048] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. In
case of conflict, the patent specification, including definitions,
will control. In addition, the materials, methods, and examples are
illustrative only and not intended to be limiting.
[0049] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0050] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0051] The term "comprising" means that other steps and ingredients
that do not affect the final result can be added. This term
encompasses the terms "consisting of" and "consisting essentially
of".
[0052] The phrase "consisting essentially of" means that the
composition or method may include additional ingredients and/or
steps, but only if the additional ingredients and/or steps do not
materially alter the basic and novel characteristics of the claimed
composition or method.
[0053] As used herein, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopeia or other generally
recognized pharmacopeia for use in animals, and more particularly
in humans. Herein, the phrases "physiologically suitable carrier"
and "pharmaceutically acceptable carrier" are interchangeably used
and refer to an approved carrier or a diluent that does not cause
significant irritation to an organism and does not abrogate the
biological activity and properties of the administered
conjugate.
[0054] As used herein, the singular form "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0055] Throughout this disclosure, various aspects of this
invention can be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0056] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0057] The present invention is of methods and compositions
comprising tellurium-containing compounds for treatment of skin
conditions such as basal cell carcinoma and actinic keratosis.
[0058] The principles and operation of the compositions and methods
according to the present invention may be better understood with
reference to the accompanying descriptions.
[0059] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not limited
in its application to the details set forth in the following
description or exemplified by the Examples. The invention is
capable of other embodiments or of being practiced or carried out
in various ways. Also, it is to be understood that the phraseology
and terminology employed herein is for the purpose of description
and should not be regarded as limiting.
[0060] The present invention successfully addresses the
shortcomings of the presently known methods of treating skin
conditions such as basal cell carcinoma and actinic keratosis by
providing methods and compositions comprising tellurium compounds,
which are devoid of the side effects of the commonly known
treatments for these conditions.
[0061] The present invention provides a method of treating a
condition of the skin such as basal cell carcinoma or actinic
keratosis. As mentioned in the Background section hereinabove, the
development of BCC and AK is believed to involve cytokine-mediated
changes in the immune system, resulting in decreased number or
activity of Langherhans cells. Immune-response modifiers have been
found to induce activation of Toll-like receptors, which leads to
production of cytokines and chemokines, such as INF-[alpha],
TNF-[alpha], IL-12, MCP-1, and MIP-1[alpha] [3, 4]. The chemokines
attract immune cells to the site of application, and the cytokines
cause activation of immune cells. Toll agonists have been found to
promote cytokine and chemokine release from dendritic cells that
reside in the dermis and the epidermis [3]. Activation of immune
cells and release of cytokines by these dendritic cells can rally
the immune system back into action, overcoming the reduced number
or activity of Langerhans cells [5].
[0062] While conceiving the present invention, it was envisioned
that since AS101 is a potent modulator of the immune response, and
is further characterized as a substantially non-toxic agent, this
tellurium-containing compound, as well as other tellurium compounds
of this family, could serve as potent therapeutic agents against
skin conditions such as BCC and AK, devoid of the disadvantages
associated with the presently known agents for treating these
conditions described hereinabove.
[0063] As used herein, the phrase "tellurium-containing compound"
encompasses any compound that includes one or more tellurium atoms
and exhibits immunomodulating properties.
[0064] The phrase "immunomodulating properties" includes any effect
of the compound on the immune response of a subject. Exemplary
immunomodulating properties can be manifested, for example, by an
effect on cytokines secretion, interleukins production, lymphocytes
function, and the like.
[0065] Preferably, the tellurium-containing compound includes at
least one tellurium dioxide moiety.
[0066] Thus, the compound can be, for example, an inorganic
tellurium-containing compound such as, for example, tellurium
dioxide (TeO.sub.2) per se.
[0067] The compound can alternatively be an organic
tellurium-containing compound which includes one or more tellurium
atoms and one or more organic moieties that are attached
thereto.
[0068] Representative examples of inorganic tellurium-containing
compounds that were shown to exert immunomodulating properties and
hence are particularly useful in the context of the present
invention include, for example, TeO.sub.2 per se. Also included are
compounds that form TeO.sub.2 in aqueous solutions, preferably in
the form of an organic complex such as, for example, a TeO.sub.2
complex with citric acid or ethylene glycol. A representative
example of the latter is the complex
TeO.sub.2.HOCH.sub.2CH.sub.2OH.NH.sub.4Cl.
[0069] Organic tellurium-containing compounds that were shown to
exert immunomodulating properties and hence are particularly useful
in the context of the present invention include, for example,
ammonium salts, or any other salts, of halogenated
tellurium-containing compounds having a bidentate cyclic moiety
attached to the tellurium atom. The bidentate cyclic moiety is
preferably a di-oxo moiety having two oxygen atoms attached to the
tellurium atom. Alternatively, the bidentate cyclic moiety can be a
di-thio moiety, in which two sulfur atoms are attached to the
tellurium atom.
[0070] Preferred compounds in this category are collectively
represented by the general Formula I:
##STR00005##
[0071] In the general Formula I above, each oft, u and v is
independently 0 or 1, such that the compound may include a
five-membered ring, a six-membered ring, or a seven-membered ring.
Preferably, each of t, u and v is 0, such that the compound
includes a five-membered ring.
[0072] X is a halogen atom, as described hereinabove, and is
preferably chloro.
[0073] Y is selected from the group consisting of ammonium,
phosphonium, potassium, sodium and lithium, and is preferably
ammonium.
[0074] each of R.sub.1-R.sub.10 is independently selected from the
group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy,
alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl,
carboxy, carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl,
amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl,
cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic,
sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate,
phosphonate and sulfoneamido.
[0075] As used herein, the term "alkyl" refers to a saturated
aliphatic hydrocarbon including straight chain and branched chain
groups. Preferably, the alkyl group has 1 to 20 carbon atoms.
Whenever a numerical range; e.g., "1-20", is stated herein, it
implies that the group, in this case the alkyl group, may contain 1
carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 20 carbon atoms. More preferably, the alkyl is a medium
size alkyl having 1 to 10 carbon atoms. Most preferably, unless
otherwise indicated, the alkyl is a lower alkyl having 1 to 5
carbon atoms. The alkyl group may be substituted or unsubstituted.
When substituted, the substituent group can be, for example,
hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,
thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,
cyano, nitro, sulfonamide, phosphonyl, phosphinyl, carbonyl,
thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate,
amido, sulfonamido, and amino, as these terms are defined
herein.
[0076] As used herein, the term "hydroxyalkyl" refers to an alkyl,
as this term is defined herein, substituted by a hydroxy group, as
defined herein, and includes, for example, hydroxymethyl,
hydroxyethyl, hydroxypropyl and hydroxy-n-butyl.
[0077] As used herein, the term "halogen", which is also referred
to herein interchangeably as "a halogen atom" or "halo", includes
chloro (Cl), bromo (Br), iodo (I) and fluoro (F).
[0078] The term "haloalkyl" refers to an alkyl, as this term is
defined herein, substituted by a halogen, as defined herein, and
includes, for example, chloromethyl, 2-iodoethyl, 4-bromo-n-butyl,
iodoethyl, 4-bromo-n-pentyl and the like.
[0079] The term "alkanoyloxy" refers to a carbonyl group, as define
herein and includes, for example, acetyl, propionyl, butanoyl and
the like.
[0080] The term "carboxyalkyl" refers to an alkyl, as this term is
defined herein, substituted by a carboxy group, as defined herein,
and includes, for example, carboxymethyl, carboxyethyl,
ethylenecarboxy and the like.
[0081] The term "alkylcarbonylalkyl" refers to an alkyl, as this
term is defined herein, substituted by a carbonyl group, as defined
herein, and includes, for example, methanoylmethyl, ethanoylethyl
and the like.
[0082] The term "amidoalkyl" refers to an alkyl, as this term is
defined herein, substituted by an amide group, as defined herein,
and includes, for example, --CH.sub.2CONH.sub.2;
--CH.sub.2CH.sub.2CONH.sub.2; --CH.sub.2CH.sub.2CH.sub.2CONH.sub.2
and the like.
[0083] The term "cyanoalkyl" refers to an alkyl, as this term is
defined herein, substituted by an cyano group, as defined herein,
and includes, for example, --CH.sub.2CN; --CH.sub.2CH.sub.2CN;
--CH.sub.2CH.sub.2CH.sub.2CN and the like.
[0084] The term "N-monoalkylamidoalkyl" refers to an alkyl, as this
term is defined herein, substituted by an amide group, as defined
herein, in which one of R' and R'' is an alkyl, and includes, for
example, --CH.sub.2CH.sub.2CONHCH.sub.3, and
--CH--.sub.2CONHCH.sub.2CH.sub.3.
[0085] The term N,N-dialkylamidoalkyl refers to an alkyl, as this
term is defined herein, substituted by an amide group, as defined
herein, in which both R' and R'' are alkyl, and includes, for
example, --CH.sub.2CON(CH.sub.3).sub.2;
CH.sub.2CH.sub.2CON(CH.sub.2--CH.sub.3).sub.2 and the like.
[0086] A "cycloalkyl" group refers to an all-carbon monocyclic or
fused ring (i.e., rings which share an adjacent pair of carbon
atoms) group wherein one of more of the rings does not have a
completely conjugated pi-electron system. Examples, without
limitation, of cycloalkyl groups are cyclopropane, cyclobutane,
cyclopentane, cyclopentene, cyclohexane, cyclohexadiene,
cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group
may be substituted or unsubstituted. When substituted, the
substituent group can be, for example, alkyl, hydroxyalkyl,
trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy,
thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro,
phosphonyl, phosphinyl, carbonyl, thiocarbonyl, carboxy,
thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and
amino, as these terms are defined herein.
[0087] An "alkenyl" group refers to an alkyl group which consists
of at least two carbon atoms and at least one carbon-carbon double
bond.
[0088] An "alkynyl" group refers to an alkyl group which consists
of at least two carbon atoms and at least one carbon-carbon triple
bond.
[0089] An "aryl" group refers to an all-carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
naphthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy,
aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl,
sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium,
carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate,
thiocarbamate, amido, sulfonamido, and amino, as these terms are
defined herein.
[0090] A "heteroaryl" group refers to a monocyclic or fused ring
(i.e., rings which share an adjacent pair of atoms) group having in
the ring(s) one or more atoms, such as, for example, nitrogen,
oxygen and sulfur and, in addition, having a completely conjugated
pi-electron system. Examples, without limitation, of heteroaryl
groups include pyrrole, furan, thiophene, imidazole, oxazole,
thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline
and purine. The heteroaryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy,
aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl,
sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium,
carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate,
thiocarbamate, amido, sulfonamido, and amino, as these terms are
defined herein.
[0091] A "heteroalicyclic" group refers to a monocyclic or fused
ring group having in the ring(s) one or more atoms such as
nitrogen, oxygen and sulfur. The rings may also have one or more
double bonds. However, the rings do not have a completely
conjugated pi-electron system. The heteroalicyclic may be
substituted or unsubstituted. When substituted, the substituted
group can be, for example, lone pair electrons, alkyl,
hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,
thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,
cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl,
thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate,
amido, sulfonamido, and amino, as these terms are defined herein.
Representative examples are piperidine, piperazine, tetrahydro
furane, tetrahydropyrane, morpholine and the like.
[0092] A "hydroxy" group refers to an --OH group.
[0093] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group, as defined herein.
[0094] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0095] A "thiohydroxy" group refers to a --SH group.
[0096] A "thioalkoxy" group refers to both an --S-alkyl group, and
an --S-cycloalkyl group, as defined herein.
[0097] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0098] A "carbonyl" group refers to a --C(.dbd.O)--R' group, where
R' is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl
(bonded through a ring carbon) or heteroalicyclic (bonded through a
ring carbon) as defined herein.
[0099] A "thiocarbonyl" group refers to a --C(.dbd.S)--R' group,
where R' is as defined herein for R'.
[0100] A "carboxy" group refers to a --C(.dbd.O)--O--R' or a
--O--C(.dbd.O)--R' group, where R' is as defined herein.
[0101] A "sulfinyl" group refers to an --S(.dbd.O)--R' group, where
R' is as defined herein.
[0102] A "sulfonyl" group refers to an --S(.dbd.O).sub.2--R' group,
where R' is as defined herein.
[0103] A "sulfate" group refers to a --O--S(.dbd.O).sub.2--OR'
group, where R' is as defined herein.
[0104] A "sulfonamido" group refers to a --S(.dbd.O).sub.2--NR'R''
group or a R'S(.dbd.O).sub.2--NR'', with R' is as defined herein
and R'' is as defined for R'.
[0105] A "carbamyl" or "carbamate" group refers to an
--OC(.dbd.O)--NR'R'' group or a R''OC(.dbd.O)--NR'-- group, where
R' and R'' are as defined herein.
[0106] A "thiocarbamyl" or "thiocarbamate" group refers to an
--OC(.dbd.S)--NR'R'' group or an R''OC(.dbd.S)NR'-- group, where R'
and R'' are as defined herein.
[0107] An "amino" group refers to an --NR'R'' group where R' and
R'' are as defined herein.
[0108] An "amido" group refers to a --C(.dbd.O)--NR'R'' group or a
R'C(.dbd.O)--NR'' group, where R' and R'' are as defined
herein.
[0109] A "nitro" group refers to an --NO.sub.2 group.
[0110] A "cyano" group refers to a --C.ident.N group.
[0111] The term "phosphonyl" describes a --O--P(.dbd.O)(OR')(OR'')
group, with R' and R'' as defined hereinabove.
[0112] The term "phosphinyl" describes a --PR'R'' group, with R'
and R'' as defined hereinabove.
[0113] As cited hereinabove, the compounds in this category are
salts of organic tellurium-containing compounds. The salts can be,
for example, ammonium salts, phosphonium salts and alkaline salts
such as potassium salts, sodium salts, lithium salts and the
like.
[0114] Hence, Y in Formula I above can be a phosphonium group, as
defined herein, an ammonium group, as defined herein, potassium
(K.sup.+), sodium (Na.sup.+) or lithium (Li.sup.+).
[0115] As used herein, the term "phosphonium" describes a
--P.sup.+R'R''R''' group, with R' and R'' as defined herein and
R''' is as defined for R'. The term "phosphonium", as used herein,
further refers to a --P.sup.+R.sub.6 group, wherein each of the six
R substituents is independently as defined herein for R, R'' and
R'''.
[0116] The term "ammonium" describes a --N.sup.+R'R''R''' group,
with R', R'' and R''' as defined herein.
[0117] More preferred compounds in this category include compounds
having the general Formula I described above, in which Y is
ammonium or phosphonium, t, u and v are each 0, and each of
R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is independently hydrogen or
alkyl. These compounds can be represented by the following
structure:
##STR00006##
[0118] wherein each of R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is
independently hydrogen or alkyl, whereas a preferred alkyl is
methyl, and X is halogen, preferably chloro.
[0119] The presently most preferred compound for use in the context
of the present invention has the following structure:
##STR00007##
[0120] This compound is ammonium
trichloro(dioxyethylene-O,O')tellurate, which is also referred to
herein and in the art as AS101.
[0121] Additional representative examples of organic
tellurium-containing compound that are suitable for use in the
context of the present invention include halogenated tellurium
having a bidentate cyclic moiety attached to the tellurium atom.
The bidentate cyclic moiety is preferably a di-oxo ligand having
two oxygen atoms attached to the tellurium atom. Alternatively, the
bidentate cyclic moiety can be a di-thio ligand, in which two
sulfur atoms are attached to the tellurium atom.
[0122] Preferred compounds in this category can be represented by
the general Formula II:
##STR00008##
wherein t, u, v, X and R.sub.1-R.sub.10 are as defined
hereinabove.
[0123] More preferred compounds are those in which t, u, and v are
each 0, and X is chloro, such as, but not limited to, the compound
having the following structure:
##STR00009##
[0124] The above compound is also known and referred to herein as
AS103.
[0125] The organic tellurium-containing compounds having Formulae I
and II can be readily prepared by reacting tetrahalotelluride such
as TeCl.sub.4 with a dihydroxy compound, as is described in detail
in U.S. Pat. Nos. 4,752,614, 4,761,490, 4,764,461 and 4,929,739,
which are incorporated by reference as if fully set forth
herein.
[0126] Additional representative examples of organic
tellurium-containing compounds that are suitable for use in the
context of the present invention include compounds in which two
bidentate cyclic moieties are attached to the tellurium atom.
Preferably, each of the cyclic moieties is a di-oxo moiety.
Alternatively, one or more of the cyclic moieties is a di-thio
moiety.
[0127] Preferred compounds in this category are collectively
represented by the general Formula III:
##STR00010##
[0128] In the general Formula III above, each of j and k is
independently an integer from 0 to 4, such that the compound may
include a five-membered ring, a six-membered ring, a seven-membered
ring, an eight-membered ring and/or a nine-membered ring.
Preferably, each of j and k is an integer from 0 to 2, such that
the compound includes a five-membered ring, a six-membered ring
and/or a seven-membered ring. More preferably, each of j and k is
0.
[0129] R.sub.1-R.sub.12 are as defined hereinabove for
R.sub.1-R.sub.10.
[0130] More preferred compounds in this category are those in which
j and k are each 0, and R.sub.3, R.sub.4, R.sub.9 and R.sub.10 are
each hydrogen, having the following structure:
##STR00011##
[0131] wherein each of R.sub.11-R.sub.14 is independently selected
from the group consisting of hydrogen, hydroxyalkyl, hydroxy,
thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen,
haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy,
carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl,
N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl,
cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine,
aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these
terms are defined herein.
[0132] The most preferred compound in this category is a compound
in which each of R.sub.11-R.sub.14 is hydrogen. This compound is
also known as AS102.
[0133] Additional representative examples of organic
tellurium-containing compounds that are suitable for use in the
context of the present invention include the recently disclosed
bis-tellurium compounds having general Formula IV:
##STR00012##
[0134] wherein each of R.sub.15-R.sub.22 is independently selected
from the group consisting of hydrogen, hydroxyalkyl, hydroxy,
thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen,
haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy,
carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl,
N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl,
cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine,
aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these
terms are defined herein; and
[0135] m and n are each an integer from 0 to 3.
[0136] Preferred compounds in this category are those in which m
and n are each 0.
[0137] The presently most preferred compound in this family is a
compound in which R.sub.15, R.sub.18, R.sub.19 and R.sub.22 are all
hydrogen, referred to hereinafter as SAS, and which has the
following structure:
##STR00013##
[0138] Compounds having the general Formula IV can be readily
prepared by reacting substantially equimolar amounts of a tellurium
tetralkoxide and a polycarboxylic acid. These materials are
combined in the presence of a water free organic solvent such as
dried ethanol, dimethyl sulfoxide, i-propanol and the like.
Generally the reaction may take place at ambient conditions but if
desired higher or lower temperatures and higher or lower pressures
may be utilized.
[0139] Exemplary tellurium tetraalkoxide compounds that are usable
in the preparation of the compounds having general Formula IV above
include, without limitation, tetramethoxide, tetraethoxide,
tetrapropoxide, tetraisopropoxide, tetrabutoxide, and
tetrapentoxide tellurium compounds.
[0140] Useful polycarboxylic acids include also polyhydroxy
polycarboxylic and hydroxy polycarboxylic acids. Exemplary
polycarboxylic acids that are usable in the preparation of the
compounds having general Formula IV above include, without
limitation, tartaric acid, glutaric acid, succinic acid, malonic
acid, gluconic acid and the like.
[0141] Additional organic tellurium-containing compounds that are
suitable for use in the context of the present invention include
those having the general Formula. V:
##STR00014##
[0142] wherein each of Ra, Rb, Rc and Rd is independently selected
from the group consisting of halogen alkyl, aryl, cycloalkyl,
alkoxy, aryloxy, thioalkoxy, thioaryloxy, carboxy, carbonyl,
thiocarboxy, thiocarbonyl, carbamyl, and thiocarbamyl, as these
terms are defined hereinabove, whereby at least one of Ra-Rd is not
halogen, namely, is selected from the group consisting of alkyl,
aryl, cycloalkyl, alkoxy, aryloxy, thioalkoxy, thioaryloxy,
carboxy, carbonyl, thiocarboxy, thiocarbonyl, carbamyl, and
thiocarbamyl.
[0143] Compounds in this category include those in which one of Ra,
Rb, Rc and Rd is halogen alkyl, aryl, cycloalkyl, alkoxy, aryloxy,
thioalkoxy, thioaryloxy, carboxy, carbonyl, thiocarboxy,
thiocarbonyl, carbamyl, or thiocarbamyl, whereby the others are
halogen atoms, e.g., chloro.
[0144] Other compounds in this category include those in which two
or three of Ra, Rb, Rc and Rd are as described above and the others
are halogens e.g., chloro.
[0145] Other compounds in this category include those in which each
of Ra, Rb, Rc and Rd is as described hereinabove.
[0146] The compounds described above can be administered or
otherwise utilized in this and other aspects of the present
invention, either as is or as a pharmaceutically acceptable salt
thereof.
[0147] The phrase "pharmaceutically acceptable salt" refers to a
charged species of the parent compound and its counter ion, which
is typically used to modify the solubility characteristics of the
parent compound and/or to reduce any significant irritation to an
organism by the parent compound, while not abrogating the
biological activity and properties of the administered
compound.
[0148] The compounds described above can be administered to a
subject afflicted by a skin condition such as BCC or AK by any of
various systemic routes.
[0149] Suitable routes of systemic administration may, for example,
include the inhalation, oral, buccal, rectal, transmucosal,
transdermal, intradermal, transnasal, intestinal and/or parenteral
routes; the intramuscular, subcutaneous and/or intramedullary
injection routes; the intrathecal, direct intraventricular,
intravenous, intraperitoneal, intranasal, and/or intraocular
injection routes; and/or the route of direct injection into a
tissue region of a subject of the present invention.
[0150] Optionally and preferably, the compounds described above can
be administered to a subject afflicted by a skin condition such as
BCC or AK by local routes, and more preferably, the compounds are
administered topically.
[0151] Topical application of the tellurium-containing compounds
described herein is preferably effected by applying a
therapeutically effective amount of a tellurium-containing compound
onto a treated skin area.
[0152] The treated area can be, for example, an area of the face,
ears, neck, scalp, shoulder, back, forearm, hand, chest or leg.
[0153] Herein, the phrase "treated area" encompasses the affected
area as well as the tissues surrounding the indicated area. The
topical application is effected on and around the clinical
manifestation.
[0154] The term "therapeutically effective amount" or
"pharmaceutically effective amount" denotes that dose of an active
ingredient or a composition comprising the active ingredient that
will provide the therapeutic effect for which the active ingredient
is indicated. Pharmaceutical compositions suitable for use in
context of the present invention include compositions wherein the
active ingredients are contained in an amount effective to achieve
the intended purpose. More specifically, a therapeutically
effective amount means an amount of active ingredients effective to
prevent, alleviate or ameliorate symptoms of disease or prolong the
survival of the subject being treated.
[0155] Determination of a therapeutically effective amount is well
within the capability of those skilled in the art.
[0156] When administering systemically, a therapeutically effective
amount of the tellurium-containing compounds described herein may
range, for example, from about 0.01 mg/m.sup.2/day to about 20.0
mg/m.sup.2/day and thus can be for example, 0.01 mg/m.sup.2/day,
0.02 mg/m.sup.2/day, 0.03 mg/m.sup.2/day, 0.04 mg/m.sup.2/day, 0.05
mg/m.sup.2/day, 0.1 mg/m.sup.2/day, 1 mg/m.sup.2/day, 2
mg/m.sup.2/day, 3 mg/m.sup.2/day, 4 mg/m.sup.2/day, 5
mg/m.sup.2/day, 10 mg/m.sup.2/day, and up to 20 mg/m.sup.2/day.
Preferably, for systemic administration, a therapeutically
effective amount of a compound of formula I, II or III ranges from
about 0.1 mg/m.sup.2/day to about 20 mg/m.sup.2/day. Also
preferably, a therapeutically effective amount of a compound of
formula IV for systemic administration ranges from about 0.017
mg/m.sup.2/day to about 17 mg/m.sup.2/day.
[0157] Preferably, when administered parenterally, the
therapeutically effective amount is 0.1 mg/m.sup.2/day and higher
and thus can be, for example, 0.2 mg/m.sup.2/day, 0.3
mg/m.sup.2/day, 0.4 mg/m.sup.2/day, 0.5 mg/m.sup.2/day, 0.6
mg/m.sup.2/day, 0.7 mg/m.sup.2/day, 0.8 mg/m.sup.2/day, 0.9
mg/m.sup.2/day, 1.0 mg/m.sup.2/day, 2.0 mg/m.sup.2/day, 3.0
mg/m.sup.2/day, 4.0 mg/m.sup.2/day, 5.0 mg/m.sup.2/day, and up to
20.0 mg/m.sup.2/day.
[0158] When administered orally in humans, a daily dose typically
ranges between 0.1 mg and 200 mg, more preferably between 1 mg and
100 mg and more preferably between 1 mg and 10 mg. The total daily
dose may be administered as a single dosage, or may be divided into
a number of separate doses, such as, for example 5 mg twice daily,
2.5 mg twice daily.
[0159] As used herein, the term "about" refers to .+-.10%.
[0160] For any preparation used in the methods of the invention,
the therapeutically effective amount or dose can be estimated
initially from in vitro assays. For example, a dose can be
formulated in animal models and such information can be used to
more accurately determine useful doses in humans.
[0161] Toxicity and therapeutic efficacy of the active ingredients
described herein can be determined by standard pharmaceutical
procedures in vitro, in cell cultures or experimental animals. The
data obtained from these in vitro and cell culture assays and
animal studies can be used in formulating a range of dosage for use
in human. The dosage may vary depending upon the dosage form
employed and the route of administration utilized. The exact
formulation, route of administration and dosage can be chosen by
the individual physician in view of the patient's condition. [See
e.g., Fingl, et al., (1975) "The Pharmacological Basis of
Therapeutics", Ch. 1 p.1].
[0162] Depending on the severity and responsiveness of the
condition to be treated, dosing can be of a single or a plurality
of administrations, with course of treatment lasting from several
days to several weeks or until cure is effected or diminution of
the disease state is achieved.
[0163] The method according to this aspect of the present invention
can further comprise, in addition to administering the
tellurium-containing compounds described above, co-administration
of an additional active agent. The co-administration can be
effected prior to, concomitant with or subsequent to the
administration of the tellurium-containing compound. The additional
active agent is used for providing an additive beneficial effect in
terms of the ailment being treated, conditions associated with the
ailment being treated or other parameters such as psychological
effects and prophylactic effects.
[0164] Hence, exemplary additional active agents according to this
embodiment of present invention include, without limitation, one or
more, or any combination of an antibiotic agent, an antimicrobial
agent, an anti-acne agent, an antibacterial agent, an antifungal
agent, an antiviral agent, a steroidal anti-inflammatory agent, a
non-steroidal anti-inflammatory agent, an anesthetic agent, an
antipruriginous agent, an antiprotozoal agent, a suitable
anti-oxidant, an antineoplastic agent, an immunomodulator, an
interferon, an antidepressant, an anti histamine, a vitamin, a
hormone and an anti-dandruff agent.
[0165] Suitable anti-acne agents for use in this context of the
present invention include, without limitation, keratolytics such as
salicylic acid, sulfur, glycolic, pyruvic acid, resorcinol, and
N-acetylcysteine and retinoids such as retinoic acid and its
derivatives (e.g., cis and trans, esters).
[0166] Suitable antibiotics for use in this context of the present
invention include, without limitation, benzoyl peroxide, octopirox,
erythromycin, zinc, tetracyclin, triclosan, azelaic acid and its
derivatives, phenoxy ethanol and phenoxy proponol, ethylacetate,
clindamycin and meclocycline; sebostats such as flavinoids; alpha
and beta hydroxy acids; and bile salts such as scymnol sulfate and
its derivatives, deoxycholate and cholate.
[0167] Representative examples of non-steroidal anti-inflammatory
agents that are usable in this context of the present invention
include, without limitation, oxicams, such as piroxicam, isoxicam,
tenoxicam, sudoxicam, and CP-14,304; salicylates, such as aspirin,
disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and
fendosal; acetic acid derivatives, such as diclofenac, fenclofenac,
indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,
zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
felbinac, and ketorolac; fenamates, such as mefenamic,
meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic
acid derivatives, such as ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles,
such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone,
and trimethazone. Mixtures of these non-steroidal anti-inflammatory
agents may also be employed, as well as the dermatologically
acceptable salts and esters of these agents. For example,
etofenamate, a flufenamic acid derivative, is particularly useful
for topical application.
[0168] Representative examples of steroidal anti-inflammatory drugs
include, without limitation, corticosteroids such as
hydrocortisone, hydroxyltriameinolone, alpha-methyl dexamethasone,
dexamethasone-phosphate, beclomethasone dipropionates, clobetasol
valerate, desonide, desoxymethasone, desoxycorticosterone acetate,
dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone
valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,
flumethasone pivalate, fluosinolone acetonide, fluocinonide,
flucortine butylesters, fluocortolone, fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxane, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenolone, fludrocortisone, difluorosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and the balance of its esters, chloroprednisone,
chloroprednisone acetate, clocortelone, clescinolone, dichlorisone,
diflurprednate, flucloronide, flunisolide, fluoromethalone,
fluperolone, fluprednisolone, hydrocortisone valerate,
hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,
paramethasone, prednisolone, prednisone, beclomethasone
dipropionate, triamcinolone, and mixtures thereof.
[0169] Suitable antipruritic agents include, without limitation,
pharmaceutically acceptable salts of methdilazine and
trimeprazine.
[0170] Non-limiting examples of anesthetic drugs that are suitable
for use in context of the present invention include
pharmaceutically acceptable salts of lidocaine, bupivacaine,
chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,
dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine and
phenol.
[0171] Suitable antimicrobial agents, including antibacterial,
antifungal, antiprotozoal and antiviral agents, for use in context
of the present invention include, without limitation, beta-lactam
drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline,
erythromycin, amikacin, triclosan, doxycyclinc, capreomycin,
chlorhexidine, chlortetracycline, oxytetracycline, clindamycin,
ethambutol, metronidazole, pentamidine, gentamicin, kanamycin,
lineomycin, methacycline, methenamine, minocycline, neomycin,
netilmicin, streptomycin, tobramycin, and miconazole. Also included
are tetracycline hydrochloride, farnesol, erythromycin estolate,
erythromycin stearate (salt), amikacin sulfate, doxycycline
hydrochloride, chlorhexidine gluconate, chlorhexidine
hydrochloride, chlortetracycline hydrochloride, oxytetracycline
hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride,
metronidazole hydrochloride, pentamidine hydrochloride, gentamicin
sulfate, kanamycin sulfate, lineomycin hydrochloride, methacycline
hydrochloride, methenamine hippurate, methenamine mandelate,
minocycline hydrochloride, neomycin sulfate, netilmicin sulfate,
paromomycin sulfate, streptomycin sulfate, tobramycin sulfate,
miconazole hydrochloride, amanfadine hydrochloride, amanfadine
sulfate, triclosan, octopirox, parachlorometa xylenol, nystatin,
tolnaftate and clotrimazole and mixtures thereof.
[0172] Non-limiting examples of anti-oxidants that are usable in
the context of the present invention include ascorbic acid (vitamin
C) and its salts, ascorbyl esters of fatty acids, ascorbic acid
derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl
phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol
sorbate, tocopherol acetate, other esters of tocopherol, butylated
hydroxy benzoic acids and their salts,
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
(commercially available under the trade name Trolox.RTM.), gallic
acid and its alkyl esters, especially propyl gallate, uric acid and
its salts and alkyl esters, sorbic acid and its salts, lipoic acid,
amines (e.g., N,N-diethylhydroxylamine, amino-guanidine),
sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid
and its salts, lycine pidolate, arginine pilolate,
nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine,
methionine, proline, superoxide dismutase, silymarin, tea extracts,
grape skin/seed extracts, melanin, and rosemary extracts.
[0173] Non-limiting examples of antineoplastic agents usable in
context of the present invention include daunorubicin, doxorubicin,
idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone,
etoposide, teniposide, vinblastine, vincristine, mitomycin C, 5-FU,
paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,
irinotecan, gemcitabine cyclosporin, verapamil, valspodor,
probenecid, MK571, GF120918, LY335979, biricodar, terfenadine,
quinidine, pervilleine A and XR9576.
[0174] Non-limiting examples of antidepressants usable in context
of the present invention include norepinephrine-reuptake inhibitors
("NRIs"), selective-serotonin-reuptake inhibitors (SSRIs),
monoamine-oxidase inhibitors (MAOIs),
serotonin-and-noradrenaline-reuptake inhibitors ("SNFIs),
corticotropin-releasing factor (CRF) antagonists,
.alpha.-adrenoreceptor antagonists, NK1-receptor antagonists,
5-HT.sub.1A-receptor agonist, antagonists, and partial agonists and
atypical antidepressants, as well as norepinephrine-reuptake
inhibitors such as, but are not limited to amitriptyline,
desmethylamitriptyline, clomipramine, doxepin, imipramine,
imipramine-oxide, trimipramine; adinazolam, amiltriptylinoxide,
amoxapine, desipramine, maprotiline, nortriptyline, protriptyline,
amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine,
dothiepin, fluacizine, iprindole, lofepramine, melitracen,
metapramine, norclolipramine, noxiptilin, opipramol, perlapine,
pizotyline, propizepine, quinupramine, reboxetine, tiancptinc, and
serotonin-reuptake inhibitors such as, but are not limited to,
binedaline, m-chloropiperzine, citalopram, duloxetine, etoperidone,
femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine,
milnacipran, nefazodone, oxaflazone, paroxetine, prolintane,
ritanserin, sertraline, tandospirone, venlafaxine and
zimeldine.
[0175] Exemplary anti-dandruff ingredients usable in context of the
present invention include, without limitation, zinc pyrithione,
shale oil and derivatives thereof such as sulfonated shale oil,
selenium sulfide, sulfur; salicylic acid, coal tar,
povidone-iodine, imidazoles such as ketoconazole, dichlorophenyl
imidazolodioxalan, clotrimazole, itraconazole, miconazole,
climbazole, tioconazole, sulconazole, butoconazole, fluconazole,
miconazolenitrite and any possible stereo isomers and derivatives
thereof such as anthralin, piroctone olamine (Octopirox), selenium
sulfide, and ciclopirox olamine, and mixtures thereof.
[0176] Non-limiting examples of vitamins usable in context of the
present invention include vitamin A and its analogs and
derivatives: retinol, retinal, retinyl palmitate, retinoic acid,
tretinoin, iso-tretinoin (known collectively as retinoids), vitamin
E (tocopherol and its derivatives), vitamin C (L-ascorbic acid and
its esters and other derivatives), vitamin B.sub.3 (niacinamide and
its derivatives), alpha hydroxy acids (such as glycolic acid,
lactic acid, tartaric acid, malic acid, citric acid, etc.) and beta
hydroxy acids (such as salicylic acid and the like).
[0177] Non-limiting examples of dermatological active ingredients
usable in context of the present invention include jojoba oil and
aromatic oils such as methyl salicylate, wintergreen, peppermint
oil, bay oil, eucalyptus oil and citrus oils, as well as ammonium
phenolsulfonate, bismuth subgallate, zinc phenolsulfonate and zinc
salicylate. Non-limiting examples of antifungal agents include
miconazole, clotrimazole, butoconazole, fenticonasole, tioconazole,
terconazole, sulconazole, fluconazole, haloprogin, ketonazole,
ketoconazole, oxinazole, econazole, itraconazole, terbinafine,
nystatin and griseofulvin.
[0178] Non-limiting examples of antihistamines usable in context of
the present invention include chlorpheniramine, brompheniramine,
dexchlorpheniramine, tripolidine, clemastine, diphenhydramine,
promethazine, piperazines, piperidines, astemizole, loratadine and
terfenadine.
[0179] Suitable hormones for use in the context of the present
invention include, for example, androgenic compounds and progestin
compounds.
[0180] Representative examples of androgenic compounds include,
without limitation, methyltestosterone, androsterone, androsterone
acetate, androsterone propionate, androsterone benzoate,
androsteronediol, androsteronediol-3-acetate,
androsteronediol-17-acetate, androsteronediol 3-17-diacetate,
androsteronediol-17-benzoate, androsteronedione, androstenedione,
androstenediol, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, dromostanolone, dromostanolone
propionate, ethylestrenol, fluoxymesterone, nandrolone
phenpropionate, nandrolone decanoate, nandrolone furylpropionate,
nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, androsteronediol-3-acetate-1-7-benzoate,
oxandrolone, oxymetholone, stanozolol, testosterone, testosterone
decanoate, 4-dihydrotestosterone, 5.alpha.-dihydrotestosterone,
testolactone, 17.alpha.-methyl-19-nortestosterone and
pharmaceutically acceptable esters and salts thereof, and
combinations of any of the foregoing.
[0181] Representative examples of progestin compounds include,
without limitation, desogestrel, dydrogesterone, ethynodiol
diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone
acetate, hydroxyprogesterone caproate, norethindrone, norethindrone
acetate, norethynodrel, allylestrenol, 19-nortestosterone,
lynoestrenol, quingestanol acetate, medrogestone, norgestrienone,
dimethisterone, ethisterone, cyproterone acetate, chlormadinone
acetate, megestrol acetate, norgestimate, norgestrel, desogrestrel,
trimegestone, gestodene, nomegestrol acetate, progesterone,
5.alpha.-pregnan-3.beta.,20.alpha.-diol sulfate,
5.alpha.-pregnan-3.beta.,20.beta.-diol sulfate,
5.alpha.-pregnan-3.beta.-ol-20-one,
16,5.alpha.-pregnen-3.beta.-ol-20-one,
4-pregnen-20.beta.-ol-3-one-20-sulfate, acetoxypregnenolone,
anagestone acetate, cyproterone, dihydrogesterone, flurogestone
acetate, gestadene, hydroxyprogesterone acetate,
hydroxymethylprogesterone, hydroxymethyl progesterone acetate,
3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone
and mixtures thereof.
[0182] More preferably, the additional active agent is at least one
of fluorouracil, imiquimod, interferon-.alpha., and diclofenac.
[0183] In addition to the above, the treatment of skin condition
such as BCC or AK according to the present invention may be
combined with other treatment methods known in the art (i.e.,
combination therapy). Thus, the method according to this aspect of
the present invention may further involve additional treatment by
any of the methods described above for treating BCC or AK, as well
as similar skin conditions. The tellurium-containing compounds
described above can thus be, for example, co-administered
(simultaneously or separately) with additional agents for treating
BCC or AK, such as 5-fluoruracil, imiquimod, and the like.
[0184] In any of the different embodiments of the method of the
present invention, the tellurium-containing compounds described
herein can be provided to a subject either per se, or as part of a
pharmaceutical composition where it is mixed with a
pharmaceutically acceptable carrier.
[0185] Hence, according to another aspect of the present invention
there is provided a pharmaceutical composition, which comprises a
tellurium-containing compound as described herein and a
pharmaceutically acceptable carrier.
[0186] Preferably, a concentration of tellurium-containing compound
of formula I, II or III in the carrier ranges from about 0.01
weight percent to about 50 weight percents, more preferably from
about 0.1 weight percents to about 20 weight percents, of the total
weight of the composition. Also preferably, a concentration of
tellurium-containing compound of formula IV in the carrier ranges
from about 0.02 weight percent to about 85 weight percents, more
preferably from about 0.2 weight percents to about 40 weight
percents of the total weight of the composition.
[0187] As used herein a "pharmaceutical composition" refers to a
preparation of one or more of the active ingredients described
herein with other chemical components such as physiologically
suitable carriers and excipients. The purpose of a pharmaceutical
composition is to facilitate administration of a compound to the
subject treated.
[0188] Hereinafter, the phrases "physiologically acceptable
carrier" and "pharmaceutically acceptable carrier" which may be
interchangeably used refer to a carrier or a diluent that does not
cause significant irritation to the subject and does not abrogate
the biological activity and properties of the administered
compound. As used herein, the term "carrier" refers to a diluent,
adjuvant, excipient, or vehicle with which the therapeutic is
administered.
[0189] Herein the term "excipient" refers to an inert substance
added to a pharmaceutical composition to further facilitate
administration of an active ingredient. Examples, without
limitation, of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils and polyethylene glycols.
[0190] Techniques for formulation and administration of drugs may
be found in "Remington's Pharmaceutical Sciences," Mack Publishing
Co., Easton, Pa., latest edition, which is incorporated herein by
reference.
[0191] Pharmaceutical compositions of the present invention may be
manufactured by processes well known in the art, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0192] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in conventional manner using
one or more physiologically acceptable carriers comprising
excipients and auxiliaries, which facilitate processing of the
active ingredients into preparations which, can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0193] For injection, the active ingredients of the invention may
be formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hank's solution, Ringer's solution, or
physiological salt buffer.
[0194] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0195] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions,
and the like, for oral ingestion by a patient. Pharmacological
preparations for oral use can be made using a solid excipient,
optionally grinding the resulting mixture, and processing the
mixture of granules, after adding suitable auxiliaries if desired,
to obtain tablets or dragee cores. Suitable excipients are, in
particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations such as, for example,
maize starch, wheat starch, rice starch, potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
sodium carbomethylcellulose; and/or physiologically acceptable
polymers such as polyvinylpyrrolidone (PVP). If desired,
disintegrating agents may be added, such as cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0196] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, titanium dioxide, lacquer
solutions and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0197] Pharmaceutical compositions, which can be used orally,
include push-fit capsules made of gelatin as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules may contain the active ingredients
in admixture with filler such as lactose, binders such as starches,
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active ingredients may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for the chosen route of
administration.
[0198] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0199] For administration by nasal inhalation, the active
ingredients for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
from a pressurized pack or a nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichloro-tetrafluoroethane or carbon dioxide. In the case of a
pressurized aerosol, the dosage unit may be determined by providing
a valve to deliver a metered amount. Capsules and cartridges of,
e.g., gelatin for use in a dispenser may be formulated containing a
powder mix of the compound and a suitable powder base such as
lactose or starch.
[0200] The preparations described herein may be formulated for
parenteral administration, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multidose containers with
optionally, an added preservative. The compositions may be
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0201] Pharmaceutical compositions for parenteral administration
include aqueous solutions of the active preparation in
water-soluble form. Additionally, suspensions of the active
ingredients may be prepared as appropriate oily or water based
injection suspensions. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acids
esters such as ethyl oleate, triglycerides or liposomes. Aqueous
injection suspensions may contain substances, which increase the
viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol or dextran. Optionally, the suspension may also
contain suitable stabilizers or agents which increase the
solubility of the active ingredients to allow for the preparation
of highly concentrated solutions.
[0202] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile,
pyrogen-free water based solution, before use.
[0203] The preparation of the present invention may also be
formulated in rectal compositions such as suppositories or
retention enemas, using, e.g., conventional suppository bases such
as cocoa butter or other glycerides.
[0204] The amount of a composition to be administered will, of
course, be dependent on the subject being treated, the severity of
the affliction, the manner of administration, the judgment of the
prescribing physician, etc.
[0205] Compositions including the preparation of the present
invention formulated in a compatible pharmaceutical carrier may
also be prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition.
[0206] Compositions of the present invention may, if desired, be
presented in a pack or dispenser device, such as an FDA approved
kit, which may contain one or more unit dosage forms containing the
active ingredient. The pack may, for example, comprise glass,
plastic foil, such as a blister pack. The pack or dispenser device
may be accompanied by instructions for administration. The pack or
dispenser may also be accommodated by a notice associated with the
container in a form prescribed by a governmental agency regulating
the manufacture, use or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the
compositions or human or veterinary administration. Such notice,
for example, may be of labeling approved by the U.S. Food and Drug
Administration for prescription drugs or of an approved product
insert.
[0207] Hence, in a preferred embodiment of the present invention,
the pharmaceutical composition is formulated in a form suitable for
topical application on the treated area.
[0208] By selecting the appropriate carrier and optionally other
ingredients that can be included in the composition, as is detailed
hereinbelow, the compositions of the present invention may be
formulated into any form typically employed for topical
application. Hence, the compositions of the present invention can
be, for example, in a form of a cream, an ointment, a paste, a gel,
a lotion, a milk, a suspension, an aerosol, a spray, a foam, a
shampoo, a hair conditioner, a serum, a swab, a pledget, a pad, a
patch and a soap.
[0209] Ointments are semisolid preparations, typically based on
petrolatum or petroleum derivatives. The specific ointment base to
be used is one that provides for optimum delivery for the active
agent chosen for a given formulation, and, preferably, provides for
other desired characteristics as well (e.g., emolliency). As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed., Easton,
Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may
be grouped in four classes: oleaginous bases; emulsifiable bases;
emulsion bases; and water-soluble bases. Oleaginous ointment bases
include, for example, vegetable oils, fats obtained from animals,
and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment bases, also known as absorbent ointment bases, contain
little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred
water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight.
[0210] Lotions are preparations that are to be applied to the skin
surface without friction. Lotions are typically liquid or
semiliquid preparations in which solid particles, including the
active agent, are present in a water or alcohol base. Lotions are
typically preferred for treating large body areas, due to the ease
of applying a more fluid composition. Lotions are typically
suspensions of solids, and oftentimes comprise a liquid oily
emulsion of the oil-in-water type. It is generally necessary that
the insoluble matter in a lotion be finely divided. Lotions
typically contain suspending agents to produce better dispersions
as well as compounds useful for localizing and holding the active
agent in contact with the skin, such as methylcellulose, sodium
carboxymethyl-cellulose, and the like.
[0211] Creams are viscous liquids or semisolid emulsions, either
oil-in-water or water-in-oil. Cream bases are typically
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase, also called the "internal" phase, is
generally comprised of petrolatum and/or a fatty alcohol such as
cetyl or stearyl alcohol. The aqueous phase typically, although not
necessarily, exceeds the oil phase in volume, and generally
contains a humectant. The emulsifier in a cream formulation is
generally a nonionic, anionic, cationic or amphoteric surfactant.
Reference may be made to Remington: The Science and Practice of
Pharmacy, supra, for further information.
[0212] Pastes are semisolid dosage forms in which the bioactive
agent is suspended in a suitable base. Depending on the nature of
the base, pastes are divided between fatty pastes or those made
from a single-phase aqueous gels. The base in a fatty paste is
generally petrolatum, hydrophilic petrolatum and the like. The
pastes made from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base. Additional reference
may be made to Remington: The Science and Practice of Pharmacy, for
further information.
[0213] Gel formulations are semisolid, suspension-type systems.
Single-phase gels contain organic macromolecules distributed
substantially uniformly throughout the carrier liquid, which is
typically aqueous, but also, preferably, contain an alcohol and,
optionally, an oil. Preferred organic macromolecules, i.e., gelling
agents, are crosslinked acrylic acid polymers such as the family of
carbomer polymers, e.g., carboxypolyalkylenes that may be obtained
commercially under the trademark Carbopol.TM.. Other types of
preferred polymers in this context are hydrophilic polymers such as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers
and polyvinylalcohol; cellulosic polymers such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums
such as tragacanth and xanthan gum; sodium alginate; and gelatin.
In order to prepare a uniform gel, dispersing agents such as
alcohol or glycerin can be added, or the gelling agent can be
dispersed by trituration, mechanical mixing or stirring, or
combinations thereof.
[0214] Sprays generally provide the active agent in an aqueous
and/or alcoholic solution which can be misted onto the skin for
delivery. Such sprays include those formulated to provide for
concentration of the active agent solution at the site of
administration following delivery, e.g., the spray solution can be
primarily composed of alcohol or other like volatile liquid in
which the active agent can be dissolved. Upon delivery to the skin,
the carrier evaporates, leaving concentrated active agent at the
site of administration.
[0215] Foam compositions are typically formulated in a single or
multiple phase liquid form and housed in a suitable container,
optionally together with a propellant which facilitates the
expulsion of the composition from the container, thus transforming
it into a foam upon application. Other foam forming techniques
include, for example the "Bag-in-a-can" formulation technique.
Compositions thus formulated typically contain a low-boiling
hydrocarbon, e.g., isopropane. Application and agitation of such a
composition at the body temperature cause the isopropane to
vaporize and generate the foam, in a manner similar to a
pressurized aerosol foaming system. Foams can be water-based or
hydroalcoholic, but are typically formulated with high alcohol
content which, upon application to the skin of a user, quickly
evaporates, driving the active ingredient through the upper skin
layers to the site of treatment.
[0216] Skin patches typically comprise a backing, to which a
reservoir containing the active agent is attached. The reservoir
can be, for example, a pad in which the active agent or composition
is dispersed or soaked, or a liquid reservoir. patches typically
further include a frontal water permeable adhesive, which adheres
and secures the device to the treated region. Silicone rubbers with
self-adhesiveness can alternatively be used. In both cases, a
protective permeable layer can be used to protect the adhesive side
of the patch prior to its use. Skin patches may further comprise a
removable cover, which serves for protecting it upon storage.
[0217] Examples of pharmaceutically acceptable carriers that are
suitable for pharmaceutical compositions for topical applications
include carrier materials that are well-known for use in the
cosmetic and medical arts as bases for e.g., emulsions, creams,
aqueous solutions, oils, ointments, pastes, gels, lotions, milks,
foams, suspensions, aerosols and the like, depending on the final
form of the composition.
[0218] Representative examples of suitable carriers according to
the present invention therefore include, without limitation, water,
liquid alcohols, liquid glycols, liquid polyalkylene glycols,
liquid esters, liquid amides, liquid protein hydrolysates, liquid
alkylated protein hydrolysates, liquid lanolin and lanolin
derivatives, and like materials commonly employed in cosmetic and
medicinal compositions.
[0219] Other suitable carriers according to the present invention
include, without limitation, alcohols, such as, for example,
monohydric and polyhydric alcohols, e.g., ethanol, isopropanol,
glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene
glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such
as diethyl or dipropyl ether; polyethylene glycols and
methoxypolyoxyethylenes (carbowaxes having molecular weight ranging
from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene
sorbitols, stearoyl diacetin, and the like.
[0220] When the pharmaceutical composition according to the present
invention is formulated for topical application, the concentration
of the tellurium-containing compound of formula I, II or III
preferably ranges from about 0.01 weight percent and about 50
weight percents, and the concentration of the tellurium-containing
compound of formula IV preferably ranges from about 0.02 to about
85 weight percents, of the total weight of the composition.
[0221] Thus, depending on the condition being treated and the
composition form, the concentration of the tellurium-containing
compound can be, for example, 0.01 weight percent, 0.05 weight
percent, 0.1 weight percent, 0.5 weight percent, 1 weight percent,
2 weight percents, 3 weight percents, 4 weight percents or 5 weight
percents. Higher concentrations can also be used and thus can be,
for example, 5 weight percents, 6 weight percents, 7 weight
percents, 8 weight percents, 9 weight percents or 10 weight
percents and up to 20 weight percents, 25 weight percents, 30
weight percents, 40 weight percents, 50 weight percents, 60 weight
percents, 70 weight percents, 80 weight percents, and can be up to
85 weight percents of the total weight of the composition.
[0222] A formulation of a tellurium-containing compound, which is
particularly useful for topical application of the active compound,
and more particularly, for obtaining stable compositions that
comprise relatively high concentration of a tellurium-containing
compound, has been recently designed by the present assignee. This
formulation is described in detail in a U.S. Provisional Patent
Application filed Sep. 11, 2006, having Attorney's Docket No. 31695
and entitled "Topical Formulations of tellurium-containing
compounds", to the present assignee, which is incorporated by
reference as if fully set forth herein. This formulation is based
on a carrier selected such that: the tellurium-containing compound,
at a concentration of 10 weight percents, is soluble, dispersible
and/or suspendable therein; and the formulation is chemically and
physically stable upon storage at room temperature for at least 30
days.
[0223] Hence, in preferred embodiments of the present invention,
any of the pharmaceutical compositions described herein comprises a
carrier as described in the above-mentioned U.S. Provisional Patent
Application filed Sep. 11, 2006, having Attorney's Docket No.
31695.
[0224] Each of the pharmaceutical compositions described herein may
further comprise, according to an embodiment of the present
invention an additional active agent, as described hereinabove.
[0225] Each of the pharmaceutical compositions described herein can
optionally further comprise a variety of components that are
suitable for providing the compositions with additional usage
benefits. Such conventional optional components are well known to
those skilled in the art and are referred to herein as
"ingredients". Some non-limiting representative examples of these
ingredients include humectants, deodorants, antiperspirants, sun
screening agents, sunless tanning agents, hair conditioning agents,
pH adjusting agents, chelating agents, preservatives, emulsifiers,
occlusive agents, emollients, thickeners, solubilizing agents,
penetration enhancers, anti-irritants, colorants, propellants (and
surfactants.
[0226] Thus, for example, the compositions of the present invention
can comprise humectants or moisturizing agents. Representative
examples of humectants that are usable in this context of the
present invention include, without limitation, guanidine, glycolic
acid and glycolate salts (e.g. ammonium slat and quaternary alkyl
ammonium salt), aloe vera in any of its variety of forms (e.g.,
aloe vera gel), allantoin, urazole, polyhydroxy alcohols such as
sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol,
hexylene glycol and the like, polyethylene glycols, sugars and
starches, sugar and starch derivatives (e.g., alkoxylated glucose),
hyaluronic acid, lactamide monoethanolamine, acetamide
monoethanolamine and any combination thereof.
[0227] The compositions of the present invention can further
comprise a pH adjusting agent. The addition of a pH-adjusting agent
is particularly preferred when the compositions are applied
topically on the skin. The pH of these treated areas is typically
lower than 6.0. Hence, it is preferable for the compositions of the
present invention to have a pH value of between about 4 and about
7, preferably between about 4 and about 6, so as to avoid
irritations to the skin or induction of imbalance of the bacteria
population if the genital areas. Suitable pH adjusting agents
include, for example, one or more of adipic acids, glycines, citric
acids, calcium hydroxides, magnesium aluminometasilicates, buffers
or any combinations thereof.
[0228] Representative examples of deodorant agents that are usable
in the context of the present invention include, without
limitation, quaternary ammonium compounds such as
cetyl-trimethylammonium bromide, cetyl pyridinium chloride,
benzethonium chloride, diisobutyl phenoxy ethoxy ethyl dimethyl
benzyl ammonium chloride, sodium N-lauryl sarcosine, sodium
N-palmlthyl sarcosine, lauroyl sarcosine, N-myristoyl glycine,
potassium N-lauryl sarcosine, stearyl, trimethyl ammonium chloride,
sodium aluminum chlorohydroxy lactate, tricetylmethyl ammonium
chloride, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, diaminoalkyl
amides such as L-lysine hexadecyl amide, heavy metal salts of
citrate, salicylate, and piroctose, especially zinc salts, and
acids thereof, heavy metal salts of pyrithione, especially zinc
pyrithione and zinc phenolsulfate. Other deodorant agents include,
without limitation, odor absorbing materials such as carbonate and
bicarbonate salts, e.g. as the alkali metal carbonates and
bicarbonates, ammonium and tetraalkylammonium carbonates and
bicarbonates, especially the sodium and potassium salts, or any
combination of the above.
[0229] Antiperspirant agents can be incorporated in the
compositions of the present invention either in a solubilized or a
particulate form and include, for example, aluminum or zirconium
astringent salts or complexes.
[0230] Representative examples of sun screening agents usable in
context of the present invention include, without limitation,
p-aminobenzoic acid, salts and derivatives thereof (ethyl,
isobutyl, glyceryl esters; p-dimethylaminobenzoic acid);
anthranilates (i.e., o-amino-benzoates; methyl, menthyl, phenyl,
benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters);
salicylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and
di-pro-pyleneglycol esters); cinnamic acid derivatives (menthyl and
benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);
dihydroxycinnamic acid derivatives (umbelliferone,
methylumbelliferone, methylaceto-umbelliferone);
trihydroxy-cinnamic acid derivatives (esculetin, methylesculetin,
daphnetin, and the glucosides, esculin and daphnin); hydrocarbons
(diphenylbutadiene, stilbene); dibenzalacetone and
benzalacetophenone; naphtholsulfonates (sodium salts of
2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);
di-hydroxynaphthoic acid and its salts; o- and
p-hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy,
7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenyl
benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);
quinine salts (bisulfate, sulfate, chloride, oleate, and tamale);
quinoline derivatives (8-hydroxyquinoline salts,
2-phenylquinoline); hydroxy- or methoxy-substituted benzophenones;
uric and violuric acids; tannic acid and its derivatives (e.g.,
hexaethylether); (butyl carbotol) (6-propyl piperonyl)ether;
hydroquinone; benzophenones (oxybenzene, sulisobenzone,
dioxybenzone, benzoresorcinol, 2,2',4,4'-tetrahydroxybenzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone;
4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane;
etocrylene; octocrylene; [3-(4'-methylbenzylidene bornan-2-one) and
4-isopropyl-di-benzoylmethane, and any combination thereof.
[0231] Representative examples of sunless tanning agents usable in
context of the present invention include, without limitation,
dihydroxyacetone, glyceraldehyde, indoles and their derivatives.
The sunless tanning agents can be used in combination with the
sunscreen agents.
[0232] The chelating agents are optionally added to the
compositions of the present invention so as to enhance the
preservative or preservative system. Preferred chelating agents are
mild agents, such as, for example, ethylenediaminetetraacetic acid
(EDTA), EDTA derivatives, or any combination thereof.
[0233] Suitable preservatives that can be used in the context of
the present composition include, without limitation, one or more
alkanols, disodium EDTA (ethylenediamine tetraacetate), EDTA salts,
EDTA fatty acid conjugates, isothiazolinone, parabens such as
methylparaben and propylparaben, propylene glycols, sorbates, urea
derivatives such as diazolindinyl urea, or any combinations
thereof.
[0234] Suitable emulsifiers that can be used in the context of the
present invention include, for example, one or more sorbitans,
alkoxylated fatty alcohols, alkylpolyglycosides, soaps, alkyl
sulfates, monoalkyl and dialkyl phosphates, alkyl sulphonates, acyl
isothionates, or any combinations thereof.
[0235] Suitable occlusive agents that can be used in the context of
the present invention include, for example, petrolatum, mineral
oil, beeswax, silicone oil, lanolin and oil-soluble lanolin
derivatives, saturated and unsaturated fatty alcohols such as
behenyl alcohol, hydrocarbons such as squalane, and various animal
and vegetable oils such as almond oil, peanut oil, wheat germ oil,
linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts,
pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach
pit oil, poppyseed oil, pine oil, castor oil, soybean oil, avocado
oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape
seed oil and sunflower seed oil.
[0236] Suitable emollients, that can be used in the context of the
present invention include, for example, dodecane, squalane,
cholesterol, isohexadecane, isononyl isononanoate, PPG Ethers,
petrolatum, lanolin, safflower oil, castor oil, coconut oil,
cottonseed oil, palm kernel oil, palm oil, peanut oil, soybean oil,
polyol carboxylic acid esters, derivatives thereof and mixtures
thereof.
[0237] Suitable thickeners that can be used in the context of the
present invention include, for example, non-ionic water-soluble
polymers such as hydroxyethylcellulose (commercially available
under the Trademark Natrosol.RTM. 250 or 350), cationic
water-soluble polymers such as Polyquat 37 (commercially available
under the Trademark Synthalen.RTM. CN), fatty alcohols, fatty acids
and their alkali salts and mixtures thereof.
[0238] Representative examples of solubilizing agents that are
usable in this context of the present invention include, without
limitation, complex-forming solubilizers such as citric acid,
ethylenediamine-tetraacetate, sodium meta-phosphate, succinic acid,
urea, cyclodextrin, polyvinylpyrrolidone,
diethylammonium-ortho-benzoate, and micelle-forming solubilizers
such as TWEENS and spans, e.g., TWEEN 80. Other solubilizers that
are usable for the compositions of the present invention are, for
example, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
n-alkyl ethers, n-alkyl amine n-oxides, poloxamers, organic
solvents, phospholipids and cyclo dextrines.
[0239] Suitable penetration enhancers usable in context of the
present invention include, but are not limited to,
dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin,
urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide
(C.sub.10 MSO), polyethylene glycol monolaurate (PEGML), propylene
glycol (PG), propylene glycol monolaurate (PGML), glycerol
monolaurate (GML), lecithin, the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Whitby Research Incorporated, Richmond, Va.),
alcohols, and the like. The permeation enhancer may also be a
vegetable oil. Such oils include, for example, safflower oil,
cottonseed oil and corn oil.
[0240] Suitable anti-irritants that can be used in the context of
the present invention include, for example, steroidal and non
steroidal anti-inflammatory agents or other materials such as aloe
vera, chamomile, alpha-bisabolol, cola nitida extract, green tea
extract, tea tree oil, licoric extract, allantoin, caffeine or
other xanthines, glycyrrhizic acid and its derivatives.
[0241] The compositions of the present invention may be packed or
presented in any convenient way. For example, they may be packed in
a tube, a bottle, or a pressurized container, using techniques well
known to those skilled in the art and as set forth in reference
works such as Remington's Pharmaceutical Science 15.sup.th) Ed. It
is preferred that the packaging is done in such a way so as to
minimize contact of the unused compositions with the environment,
in order to minimize contamination of the compositions before and
after the container is opened.
[0242] The compositions are preferably identified in print, in or
on the packaging material, for use in the treatment of a skin
condition such as BCC or AK, as described hereinabove.
[0243] Additional objects, advantages, and novel features of the
present invention will become apparent to one ordinarily skilled in
the art upon examination of the following examples, which are not
intended to be limiting. Additionally, each of the various
embodiments and aspects of the present invention as delineated
hereinabove and as claimed in the claims section below finds
experimental support in the following examples.
EXAMPLES
[0244] Reference is now made to the following examples, which
together with the above descriptions, illustrate the invention in a
non limiting fashion.
Example 1
Assessment of the Effect of Tellurium Compounds on Basal Cell
Carcinoma
[0245] The in vivo effects of the compounds of the invention can be
assayed through various animal models known to those of ordinary
skill in the art. Generally such assays involve the injection of a
carcinoma cell line, of mouse or preferably, human, origin, into a
cohort of mice.
[0246] In most experiments, two groups of experimental mice are
studied: a first, control, group which receives only the cell line
but no tellurium compound, and a second, test, group which receives
the tellurium compound. This second group is divided into several
subgroups each of which receives a different dose of the compound,
preferably between 10 .mu.g and 100 .mu.g per day for 10-20 days.
On these days, the control group will be administered control doses
containing only vehicle with no active agent.
[0247] The tellurium compounds may be administered at the time of
inoculation of the malignant cells, shortly thereafter or following
initiation of the disease. Similarly, any additional therapeutic
agent may be administered after the inoculation, but before the
full development of the tumor mass. In these ways, the effects of
agents on different stages of malignant growth and metastasis can
be tested.
[0248] For assessment of the effect of tellurium compounds on basal
cell carcinoma, human basal cell carcinoma cells are administered
either subcutaneously or submucosally into mice. Primary tumor
growth, survival time, resistance to tumor challenge, cellular
infiltrates characteristic of such tumors, and extent of tumor
angiogenesis are all parameters of interest which can be evaluated.
After 21 days, tumor growth is generally established and the
effects of the test agent after this point can be compared to
vehicle-alone.
Example 2
Assessment of the Effect of Tellurium Compounds on Actinic
Keratosis
[0249] Female, 6-7 weeks old, hairless albino mice (skh-1) are
used.
[0250] Mice are divided into three groups containing 5-14 mice per
group. A first group is treated with a composition comprising
AS101. A second group is treated with a composition comprising SAS.
Each treatment consists of a single topical application of the
composition over a 2 cm.sup.2 area on the dorsal surface. Each
composition comprises the tellurium compound and a pharmaceutically
acceptable carrier. A third group of mice, serving as control, is
treated with the carrier alone.
[0251] After 15 min. following application, the mice are irradiated
with x-rays. Exposure of mice is repeated three times a week for a
total of 20 weeks. The skin thickness of mice, and papillary skin
lesions greater than 1 mm in diameter are measured and recorded
twice every week and the average of the two measurements used in
the calculations. At the end of the study, 5-19 lesions from each
group are randomly biopsied, and fixed in 10% buffered formalin.
Formalin-fixed specimens are embedded in paraffin blocks, sectioned
at 4 .mu.m thickness, and stained in haematoxylin-eosin.
Example 3
Assessment of the Treatment by Tellurium Compounds of BCC and/or
AK-Human Studies
[0252] Double-blind, randomized studies are carried out on patients
with histologically confirmed, visible multiple actinic keratoses
and/or basal cell carcinoma. A topical composition comprising AS101
(4 percents) or SAS (7-8 percents) is applied to affected areas
once daily, three times per week, and washed off the next day,
after around 10 hours of exposure. Treatment is continued for 6
weeks. The effect on patients receiving AS101 is evaluated and
compared to that seen in patients receiving placebo.
[0253] For evaluation of the effect on actinic keratosis, clearance
of AK lesions is clinically and histologically assessed. Efficacy
is assessed by lesion number scores and lesion total thickness
scores, as determined prior to commencement of treatment and again
at 6 week post-treatment. The reduction of keratoses from baseline
is calculated.
[0254] For evaluation of the effect on basal cell carcinoma, a
blood sample is taken prior to treatment, and the skin lesion is
examined, measured, and photographed. Two punch skin biopsies are
taken from the area of the carcinoma prior to treatment. One sample
is examined to confirm the diagnosis of basal cell carcinoma; the
other sample undergoes histological testing. A second punch biopsy
and fine needle aspiration is taken at the conclusion of the
treatment period and subjected to histological analysis. The entire
lesion is then surgically removed and examined for skin cancer
cells.
[0255] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0256] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims. All
publications, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention.
REFERENCES CITED BY NUMERALS
Other References are Cited within the Text
[0257] 1. Soehnge, H; et al. Frontiers in Bioscience 2: 538-551,
1997. [0258] 2. Freedberg, I. M., et al, eds. Fitzpatrick's
Dermatology in General Medicine. Vol 1, 2. 5th ed. New York, N.Y.:
McGraw-Hill; 1999. [0259] 3. Fisher, M. S., et al. Proc. Natl.
Acad. Sci. 74:1688-1692, 1977. [0260] 4. Kadowaki, N., et al. J.
Exp. Med. 194:863-870, 2001. [0261] 5. Gibson, S. J., et al. J.
Interferon Cytokine Res. 15:537-545, 1995. [0262] 6. Suzuki, H., et
al. J. Invest Dermatol. 114:135-141, 2000.
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