U.S. patent application number 09/459935 was filed with the patent office on 2002-09-12 for topical immunomodulating compositions for treatment of aids, hepatitis b&c, other infectious diseases, and cancer.
Invention is credited to KAPLAN, LEONARD L., LEVIS, WILLIAM R..
Application Number | 20020128326 09/459935 |
Document ID | / |
Family ID | 26809864 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128326 |
Kind Code |
A1 |
KAPLAN, LEONARD L. ; et
al. |
September 12, 2002 |
TOPICAL IMMUNOMODULATING COMPOSITIONS FOR TREATMENT OF AIDS,
HEPATITIS B&C, OTHER INFECTIOUS DISEASES, AND CANCER
Abstract
Topical drug compositions, containing contact sensitizing agents
as the active components of the subject patent compositions, can
provide a pharmacological action that induces a delayed
hypersensitization reaction resulting in stimulation of cell
mediated immunity when applied to the skin. The preferred
composition contains, but is not limited to, Diphenylcyclpropenone
as a preferred embodiment of the class of contact sensitizing drugs
applied to the skin in an optimally prepared pharmaceutical
formulation with controlled absorption properties to reach the
peripheral circulation resulting in increases in CD4+ helper T
cells of benefit to immunocompromised patients.
Inventors: |
KAPLAN, LEONARD L.; (EAST
BRUNSWICK, NJ) ; LEVIS, WILLIAM R.; (STATEN ISLAND,
NY) |
Correspondence
Address: |
LEONARD L KAPLAN PHD
ONE MINUTE MAN COURT
EAST BRUNSWICK
NJ
08816
|
Family ID: |
26809864 |
Appl. No.: |
09/459935 |
Filed: |
December 13, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60112363 |
Dec 15, 1998 |
|
|
|
Current U.S.
Class: |
514/763 ;
514/558; 514/560 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/015 20130101; A61K 31/47 20130101; A61K 47/26 20130101;
A61K 31/47 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 47/14 20130101; A61K 2300/00 20130101; A61K 31/015 20130101;
A61K 45/06 20130101; A61K 31/20 20130101; A61K 31/20 20130101 |
Class at
Publication: |
514/763 ;
514/558; 514/560 |
International
Class: |
A61K 031/47; A61K
031/20; A61K 031/015 |
Claims
What is claimed is:
1. Drug compositions consisting of human contact sensitizers
formulated in non-irritating, highly skin absorable non-ionic
vehicles consisting of non-volatile, non-ionic surfactants and
esters of isopropyl alcohol and saturated high molecular weight
fatty acids, principally myristic acid and palmitic acid, wherein
the subject compositions are effective in raising the CD4 helper
and CD8 killer T cell counts that results in reductions in viral
loads in humans with viral infections including AIDS, Hepatitis C
and responsive forms of Cancer.
2. Drug compositions containing the ingredients in claim 1 wherein
the composition of ingredients are applied to absorbent pads under
occlusive and semi-occlusive backings that serve as skin patch
applications for administration of the contact sensitizers to the
skin surface.
3. Drug compositions containing purified dinitrochlorobenzene in a
vehicle of polyethylene 20 sorbitan monolaurate and isopropyl
palmitate in w/v concentrations from 0.001% to 1.000% for
application to the skin.
4. Drug compositions containing purified diphenylcyclopropenone in
a vehicle of polyoxyethylene 20 sorbitan monooleate and isopropyl
myristate in w/v concentrations from 0.001% to 1.000% for
application to the skin.
5. Drug compositions containng purified diphenylcyclopropenone in a
vehicle of polyoxyethylene 20 sorbitan monooleate in w/v
concentrations from 0.001% to 1.000% for application to the
skin.
6. Drug compositions containing purified squaric acid dibutyl ester
in a vehicle of polyoxyethylene 20 sorbitan monopalmitate and
isopropyl myristate in w/v concentrations from 0.25% to 1.00% for
application to the skin.
7. A method of treating human viral infectious diseases including
AIDS and Hepatitis C with topical application of contact
sensitizers in non-volatile, non-toxic vehicles consisting of
non-ionic surfactants and esters of isopropyl alcohol and saturated
high molecular weight fatty acids, principally, but not limited to
myristic acid and palmitic acid.
8. A method of treating responsive forms of Cancer with topical
application of contact sensitizers in non-volatile, non-toxic
vehicles consisting of non-ionic surfactants and esters of
isopropyl alcohol and saturated high molecular weight fatty acids,
principally, but not limited to myristic acid and palmitic
acid.
9. The method of claim 7 wherein the contact sensitizers and
non-volatile, non-toxic vehicles are applied to absorbent pads
under occlusive and semi-occlusive backings that serve as skin
patch applications for administration of the contact sensitizers to
the skin surface.
10. The method of claim 8 wherein the contact sensitizers and
non-volatile, non-toxic vehicles are applied to absorbent pads
under occlusive and semi-occlusive backing tha serve as skin patch
applications for administration of the contact sensitizers to the
skin surface.
Description
[0001] This final patent application filing is a continuation of
the Provisional Patent Application No. 60/112,363 dated Dec. 15,
1998
[0002] Ten (10) claims, No drawings.
BACKGROUND OF THE INVENTION
[0003] Contact sensitizers such as dinitrochlorobenzene (DNCB) have
been reported to raise CD4+ helper T cell counts and reduce viral
load in HIV positive patients (1,2). The DNCB was applied to the
skin in 10% concentration dissolved in the volatile solvent acetone
which resulted in unreliable and unpredictable contact
sensitization reactions. Biologically, increases in CD+ helper T
cell counts are accompanied by variable decreases in HIV retroviral
replication as measured by human immunovirus ribonucleic acid (RNA)
levels in dendritic cells that are the primary antigen presenting
cells of the human immune system. It is the dendritic cells and
microphages that are infected during the initial phases of human
immunovirus growth in AIDS patients. Optimally formulated contact
sensitizers when topically applied, can induce TH-1 type immunity
by releasing cytokines including Interleukin 2, valuable in
treating hepatitis B&C, and forms of cancer as well as AIDS. On
the other hand, the medical use of the preferred contact sensitizer
diphenylcyclopropenone has been limited primarily to the treatment
of alopecia areata as disclosed in referenced U.S. Pat. No.
4,985,464 wherein the volatile solvent acetone with unreliable
absorption properties was used as the formulation vehicle. Other
contact sensitizers referenced in the literature (3) are, but not
limited to, squaric acid dibutylester, urishiol, oxazolone,
dinitrofluorobenzene, and paraphenylenediamine. In all referenced
cases, the volatile solvent acetone with unreliable absorption
characteristics was used as the drug delivery system for the
contact sensitizers. Accordingly, there is a need for a more
reliable stabilized composition in which the contact sensitizers
are soluble and will be reliably and predictably absorbed through
the skin to reach the aforementioned dendritic cells of the
dermis.
SUMMARY OF THE INVENTION
[0004] This invention provides compositions for the topical
application of contact sensitizers in a unique topical
pharmaceutical emulsion drug delivery system to reliably penetrate
the epidermis of immunocompromised human patients in order to
stimulate the release of CD4+ helper T cells and induce TH-1 type
immunity by releasing cytokines including Interleukin 2, valuable
in treating AIDS, Hepatitis B&C, other viral infectious
diseases, and Cancer. The compositions contain controlled amounts
of diphenylcyclopropenone, dinitrochlorobenzene,
dinitrofluorobenzene, squaric acid dibutylester, urishiol,
oxazolone, paraphenylenediamine or other medically useful contact
sensitizers emulfified in a non-toxic drug delivery system formula
consisting of pharmaceutically acceptable non-volatile, non-ionic
surfactants and pharmaceutically acceptable emollients at optimized
levels wherein the contact sensitizer(s) are reliably absorbed
through the epidermis to reach the dendritic cells in the dermis
during the early stages of viral infections in immunocompromised
patients. A preferrd embodiment of the invention includes
diphenylcyclopropenone as the contact sensitizer uniquely
formulated in a microemulsified drug delivery sytem consisting of
the non-ionic surfactant polyoxyethylene 20 sorbitan momooleate and
the emollients isopropyl myristate and/or isopropyl palmitate.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The immodulating compositions of this invention treat viral
infections embodied by AIDS, Hepatitis B&C, other viral
infectious diseases and certain types of cancer wherein the the
patient's immune system is attacked by the disease. The active
ingredients in these compositions are those that are classified
pharmacologically as contact sensitizers such as
dinitrochlorobenzene, dinitrofluorobenzene, diphenylcyclopropenone,
oxazolone, paraphenylenediamine, squaric acid dibutylester,
urushiol and the like that are generally recognized as
pharmacologically active contact sensitizers. Topically applied,
contact sensitizers have been shown to raise the CD4+ helper T cell
counts and variably reduce viral load in HIV positive patients when
applied as a concentrated solutions in Acetone as the vehicle
(1,2,3).
[0006] Acetone is a volatile and highly inflammable organic liquid
with an LD/50 of 10.7 mg/Kg in rodents and may be classified as a
toxic material with repeated human use causing epidermal erythema,
dryness, headache, bronchial irritation, CNS effects including
fatigue and excitement and with chronic use narcosis. In addition,
due to its high vapor pressure and volatility, the contact
sensitizer/ Acetone solutions when applied to the skin can result
in variable, inconsistent and unreliable levels of contact
sensitizer absorption through the skin.
[0007] In order for the topically applied contact sensitizers to be
optimally safe and effective in raising the CD4+ helper T cell
counts and reduce viral loads, we found unexpectedly that the
topical compositions of this invention consisting of medically
accepted contact sensitizers microemulsified in drug delivery
vehicles of non-volatile, non-toxic combinations of non-ionic
surfactants and cosmetically acceptable emollient esters of
fatty-esters embodied by isopropyl myristate and isopropyl
palmitate result in consisitent and reliable absorption of the
contact sensitizers through the epidermis to the dendritic cells of
the dermis as demonstrated by increases in CD4+ helper T cell
counts and reductions in serum viral loads in AIDS patients.
[0008] The drug compositions of this invention accordingly may
contain non-ionic surfactants of the following classes:
[0009] Polyoxyethylene (POE) sorbitan fatty acid esters identified
generically as POE 20 sorbitan monolaurate, POE 4 sorbitan
monolaurate, POE 20 sorbitan monopalmitate, POE 20 sorbitan
monostearate, POE 20 sorbitan monooleate, POE 5 sorbitan
monooleate, POE 20 sorbitan trioleate and the like that are oily
liquids with low vapor pressure properties and therefore
non-volatile and non-irritating to the skin and have the property
of emulsifying immiscible combinations of the active ingredient
contact sensitizers and the emollient co-solvents embodied by the
following alcoholic esters of myristic and palmitic fatty
acids:
[0010] Isopropyl myristate consisting of esters of isopropyl
alcohol and saturated high molecular weight fatty acids,
principally myristic acid; and Isopropyl palmitate consisting of
esters of isopropyl alcohol and saturated high molecular weight
fatty acids, pricipally palmitic acid, and other like alcohol
esters of saturated high molecular weight fatty acids that are
mobile oily liquids at room temperature and are miscibly emulsified
with the polyoxyethylene sorbitan fatty acid esters embodied in
this invention to provide non-toxic, non-volatile topical drug
delivery vehicles for the contact sensitizers of this
invention.
[0011] The drug compositions of this invention are best
administered to the skin under an occlusive or semi-occlusive patch
to permit localized absorption of the contact sensitizer contained
in optimized pharmaceutical vehicles as described in the following
examples:
1 (1) Dinitrochlorobenzene 0.001% Polyoxyethylene 20 sorbitan
monolaureate 50.000 Isopropyl palmitate 49.999 Apply 0.1 ml to 1.0
ml to an absorbent pad bonded to a polyvinyl chloride backing with
adhesive to be applied to the skin surface (2)
Diphenylcyclopropenone 0.001% Polyoxyethylene 20 sorbitan
monooleate 50.000 Isopropyl myristate 49.999 Apply 0.1 ml to 1.0 ml
to a cellulosic pad bonded to a cotton backing with adhesive to be
applied to the skin surface (3) Squaric Acid Dibutylester 0.005%
Polyoxyethylene 20 sorb. monopalmitate 85.995% Isopropyl myristate
14.000% Apply 0.25 ml to 1.00 ml to a non-woven textile pad bonded
to an occlusive backing with adhesive to be applied to the skin
surface (4) Diphenyylcyclopropenone 0.400% Polyoxyethylene 20
sorbitan monoleate 99.600% Apply 0.05 ml to 0.5 ml to an absorbent
pad bonded to a to a suitable occlusive or semi-occlusive backing
with adhesive to be appled to the skin surface (5) Squaric Acid
Dibutylester 0.010% Polyoxyethylene 4 sorbitan monolaurate 99.990%
Apply 0.1 ml to 1.0 ml to cotton pad bonded to a suitable backing
with adhesive for controlled absorption when applied to the
skin.
[0012] These composition examples are cited to demonstrate, but not
to limit, various concentrations of active contact sensitizers in
non-volatile vehicles applied to the skin by means of various
absorbent pads under occlusive or semi-occlusive backings serving
as patch applications for administration of the sensitizers to the
skin surface.
[0013] Other examples of contact sensitizers applicable to
formulation in the unique non-volatile, non-irritating, skin
absorble vehicle compositions are as follows:
[0014] Oxazolone
[0015] Fluoroscine isothiocyanate
[0016] Dinitrofluorobenzene
[0017] Beryllium
[0018] Nickel Chloride
[0019] Trinitrochlorobenzene
[0020] Urishiol
[0021] Paraphenylenediamine
[0022] and the like.
[0023] As examples of the HIV viral load reducing effects of the
subject compositions, two patients were sensitized with 0.400%
diphenylcyclopropenone in a vehicle consisting of equal parts of
polyoxysorbitan 20 monooleate and isopropyl myristate and
subsequently rechallenged with 0.100% diphenylcyclopropenone in the
same vehicle two weeks, four weeks and eight weeks later. HIV-1 RNA
copies per 1.0 ml plasma are shown in Table (1):
2TABLE (1) HIV-1 RNA Copies/1.0 ml Plasma Patient #1 Baseline 400
Copies Two Weeks 118 Four Weeks 60 Eight Weeks 79 Patient #2
Baseline 440 Eight Weeks 351
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