U.S. patent application number 12/401812 was filed with the patent office on 2009-10-01 for stabilized compositions of alkylating agents and methods of using same.
Invention is credited to Robert Alonso, Peter A. Crooks, Barry R. Walker.
Application Number | 20090247645 12/401812 |
Document ID | / |
Family ID | 41114573 |
Filed Date | 2009-10-01 |
United States Patent
Application |
20090247645 |
Kind Code |
A1 |
Alonso; Robert ; et
al. |
October 1, 2009 |
STABILIZED COMPOSITIONS OF ALKYLATING AGENTS AND METHODS OF USING
SAME
Abstract
A composition and method for treatment of cancer. The
composition for treating a skin disorder, comprising: an alkylating
agent such as, for example, a Nitrogen Mustard or an HX salt of the
Nitrogen Mustard, wherein the alkylating agent is in a non-aqueous
vehicle or carrier that does not include petrolatum or ethanol,
wherein the non-aqueous vehicle or carrier that does not include
petrolatum or ethanol does not include petrolatum or ethanol. The
method comprises topically applying the composition of the
alkylating agent to the affected skin, wherein the alkylating agent
is in a non-aqueous vehicle or carrier that does not include
petrolatum or ethanol, wherein the non-aqueous vehicle or carrier
does not include petrolatum or ethanol.
Inventors: |
Alonso; Robert; (Rye,
NH) ; Walker; Barry R.; (Bryn Mawr, PA) ;
Crooks; Peter A.; (Nicholasville, KY) |
Correspondence
Address: |
GFD PATENTS, LLC
P.O. BOX 752
CLIFTON PARK
NY
12065
US
|
Family ID: |
41114573 |
Appl. No.: |
12/401812 |
Filed: |
March 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61039840 |
Mar 27, 2008 |
|
|
|
Current U.S.
Class: |
514/672 ;
514/772 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 31/131 20130101; A61K 9/0014 20130101; A61K 9/06 20130101;
A61K 47/10 20130101 |
Class at
Publication: |
514/672 ;
514/772 |
International
Class: |
A61K 31/131 20060101
A61K031/131; A61K 47/10 20060101 A61K047/10 |
Claims
1. A dispersion, comprising: between about 0.001% and about 2.0% by
weight of an alkylating agent, or pharmaceutically acceptable
salts, polymorphs, or solvates thereof, and between about 15% and
about 60% by weight of a pharmaceutically acceptable excipient.
2. The dispersion of claim 1, wherein the pharmaceutically
acceptable excipient is 2-(2-ethoxyethoxy)ethanol.
3. The dispersion of claim 2, wherein the alkylating agent
MCHCl.
4. A method for treating a person with a skin disorder, comprising:
topically applying a dispersion to the affected skin, wherein the
dispersion comprises between about 0.001% and about 2.0% by weight
of an alkylating agent, or pharmaceutically acceptable salts,
polymorphs or solvates thereof, and between about 15% and about 60%
by weight of a pharmaceutically acceptable excipient.
5. The method for treating the person with the skin disorder of
claim 4, wherein the pharmaceutically acceptable excipient is
2-(2-ethoxyethoxy)ethanol.
6. The method for treating the person with the skin disorder of
claim 4, wherein the alkylating agent is MCHCl.
7. A method for stabilizing a volatile alkylating agent,
comprising: dispersing between about 0.001% and about 2.0% by
weight of an alkylating agent, or pharmaceutically acceptable
salts, polymorphs or solvates thereof and between about 15% and
about 60% by weight of a pharmaceutically acceptable excipient.
8. The method of claim 7, wherein the pharmaceutically acceptable
excipient is 2-(2-ethoxyethoxy)ethanol.
9. The method of claim 7, wherein the alkylating agent is
MCHCl.
10. A method for stabilizing a nitrogen mustard or pharmaceutically
acceptable HX salt of the nitrogen mustard, comprising: dispersing
the nitrogen mustard or pharmaceutically acceptable HX salt of the
nitrogen mustard in between about 0.001% and about 2.0% by weight
of an alkylating agent, or pharmaceutically acceptable salts,
polymorphs, or solvates thereof and between about 15% and about 60%
by weight of a pharmaceutically acceptable excipient.
11. The method of claim 10, wherein the pharmaceutically acceptable
excipient is 2-(2-ethoxyethoxy)ethanol.
12. The method of claim 10, wherein the alkylating agent may is
MCHCl.
13. A method of treating vitiligo, comprising: administering a
dispersion to a person in need thereof, wherein the dispersion
comprises between about 0.001% and about 2.0% by weight of an
alkylating agent, or pharmaceutically acceptable salts, polymorphs,
or solvates thereof and between about 15% and about 60% by weight
of a pharmaceutically acceptable excipient.
14. The method of claim 13, wherein the pharmaceutically acceptable
excipient is 2-(2-ethoxyethoxy)ethanol.
15. The method of claim 13, wherein the alkylating agent is
MCHCl.
16. A method of formulating a pharmaceutical product, a component
of which is an at least one hydrolytically unstable alkylating
agent(s), comprising: providing a formulation aid, wherein said
formulation aid is a pre-solvated or pre-dispersed form of the
alkylating agent; and dispersing the formulation aid into a
pharmaceutical formulation or other preparation, wherein the
formulation aid and the pharmaceutical formulation are
substantially homogeneous.
17. A composition for treating a skin disorder, comprising: a
Nitrogen Mustard or an HX salt of the Nitrogen Mustard, wherein the
Nitrogen Mustard or the HX salt of the Nitrogen Mustard is in a
non-aqueous vehicle or carrier, wherein the non-aqueous vehicle or
carrier comprises between about 15% and about 60% by weight of a
pharmaceutically acceptable excipient, wherein the Nitrogen Mustard
is represented by the following structures: ##STR00019## wherein
each R.sub.1, R.sub.2, R.sub.3 . . . R.sub.34 (R.sub.1-R.sub.34) is
independently selected from the group consisting of H, linear alkyl
group having 1-6 carbon atoms, a branched alkyl group having 2-12
carbon atoms, a cycloalkyl group having 3-17 carbon atoms, a
fluorinated linear alkyl group having 2-12 carbon atoms, a
fluorinated branched alkyl group having 2-12 carbon atoms, and a
fluorinated cycloalkyl group having 3-17 carbon atoms, aryl groups,
aralkyl groups, alkaryl groups, cycloalkyl groups, bicycloalkyl
groups, alkenyl groups, alkalkenyl groups, and alkenylalkyl groups,
alkynyl groups, alkalkynyl groups, alkynylalkyl groups,
trifluoropropyl groups, cyanopropyl groups, acryloyl groups,
arylacryloyl groups, acryloylaryl groups, alkylacyl groups,
arylacyl groups alkylenylacyl groups and alkynylacyl groups,
wherein n is 1, 2, . . . 3, wherein p is 0, 1, . . . 2, wherein
n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34 in the same
molecule may be linked to form a three- to eight-membered cyclic
group.
18. The composition of claim 17, wherein the pharmaceutically
acceptable excipient is 2-(2-ethoxyethoxy)ethanol.
19. The composition of claim 17, wherein the alkylating agent is
MCHCl
20. A method for treating a skin disorder, comprising:
administering to a person in need thereof a composition,
comprising: a Nitrogen Mustard or an HX salt of the Nitrogen
Mustard, wherein the Nitrogen Mustard or the HX salt of the
Nitrogen Mustard is in a non-aqueous vehicle or carrier, wherein
the non-aqueous vehicle or carrier comprises between about 15% and
about 60% by weight of a pharmaceutically acceptable excipient,
wherein the Nitrogen Mustard is represented by the following
structures: ##STR00020## wherein each R.sub.1, R.sub.2, R.sub.3 . .
. R.sub.34 (R.sub.1-R.sub.34) is independently selected from the
group consisting of H, linear alkyl group having 1-6 carbon atoms,
a branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group.
21. The method of claim 20, wherein the pharmaceutically acceptable
excipient is 2-(2-ethoxyethoxy)ethanol.
22. The method of claim 20, wherein the alkylating agent is MCHCl.
Description
[0001] The present patent application is a non-provisional
application claiming priority from provisional application with
Ser. No. 61/039,840 (filed Mar. 27, 2008 and titled "Stabilized
Compositions of Alkylating Agents and Methods of Using Same").
FIELD OF THE INVENTION
[0002] The present invention relates generally to compositions of
alkylating agents and method using the compositions for topical
treatment of skin disease, and more specifically to a stabilized
Nitrogen Mustard composition and method of use for topically
treating the skin disease.
BACKGROUND
[0003] Alkylating agents may be used in the pharmaceutical industry
as anticancer drugs. Therefore, there is a need for improved
alkylating agents.
SUMMARY OF THE INVENTION
[0004] A first aspect of the present invention provides a
dispersion, comprising: between about 0.001% and about 2.0% by
weight of an alkylating agent, or pharmaceutically acceptable
salts, polymorphs, or solvates thereof, and between about 15% and
about 60% by weight of a pharmaceutically acceptable excipient. The
pharmaceutically acceptable excipient may be
2-(2-ethoxyethoxy)ethanol. The alkylating agent may be MCHCl.
[0005] A second aspect of the present invention provides a method
for treating a person with a skin disorder, comprising: topically
applying a dispersion to the affected skin, wherein the dispersion
comprises between about 0.001% and about 2.0% by weight of an
alkylating agent, or pharmaceutically acceptable salts, polymorphs
or solvates thereof, and between about 15% and about 60% by weight
of a pharmaceutically acceptable excipient. The pharmaceutically
acceptable excipient may be 2-(2-ethoxyethoxy)ethanol. The
alkylating agent may be MCHCl.
[0006] A third aspect of the present invention provides a method
for stabilizing a volatile alkylating agent, comprising: dispersing
between about 0.001% and about 2.0% by weight of an alkylating
agent, or pharmaceutically acceptable salts, polymorphs or solvates
thereof and between about 15% and about 60% by weight of a
pharmaceutically acceptable excipient. The pharmaceutically
acceptable excipient may be 2-(2-ethoxyethoxy)ethanol. The
alkylating agent may be MCHCl.
[0007] A fourth aspect of the present invention provides a method
for stabilizing a nitrogen mustard or pharmaceutically acceptable
HX salt of the nitrogen mustard, comprising dispersing the nitrogen
mustard or pharmaceutically acceptable HX salt of the nitrogen
mustard in between about 0.001% and about 2.0% by weight of an
alkylating agent, or pharmaceutically acceptable salts, polymorphs,
or solvates thereof and between about 15% and about 60% by weight
of a pharmaceutically acceptable excipient. The pharmaceutically
acceptable excipient may be 2-(2-ethoxyethoxy)ethanol. The
alkylating agent may be MCHCl.
[0008] A fifth aspect of the present invention provides a method of
treating vitiligo, comprising administering a dispersion to a
person in need thereof, wherein the dispersion comprises between
about 0.001% and about 2.0% by weight of an alkylating agent, or
pharmaceutically acceptable salts, polymorphs, or solvates thereof
and between about 15% and about 60% by weight of a pharmaceutically
acceptable excipient. The pharmaceutically acceptable excipient may
be 2-(2-ethoxyethoxy)ethanol. The alkylating agent may be
MCHCl.
[0009] A sixth aspect of the present invention provides a method of
formulating a pharmaceutical product, a component of which is an at
least one hydrolytically unstable alkylating agent(s), comprising:
providing a formulation aid, wherein said formulation aid is a
pre-solvated or pre-dispersed form of the alkylating agent; and
dispersing the formulation aid into a pharmaceutical formulation or
other preparation, wherein the formulation aid and the
pharmaceutical formulation are substantially homogeneous.
[0010] An seventh aspect of the present invention provides a
composition for treating a skin disorder, comprising: a Nitrogen
Mustard or an HX salt of the Nitrogen Mustard, wherein the Nitrogen
Mustard or the HX salt of the Nitrogen Mustard is in a non-aqueous
vehicle or carrier, wherein the non-aqueous vehicle or carrier
comprises between about 15% and about 60% by weight of a
pharmaceutically acceptable excipient, wherein the Nitrogen Mustard
is represented by the following structures:
##STR00001##
[0011] wherein each R.sub.1, R.sub.2, R.sub.3 . . . R.sub.34
(R.sub.1-R.sub.34) is independently selected from the group
consisting of H, linear alkyl group having 1-6 carbon atoms, a
branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group. The pharmaceutically acceptable
excipient may be 2-(2-ethoxyethoxy)ethanol. The alkylating agent
may be MCHCl.
[0012] An eighth aspect of the present invention provides a method
for treating a skin disorder, comprising: administering to a person
in need thereof a composition, comprising: a Nitrogen Mustard or an
HX salt of the Nitrogen Mustard, wherein the Nitrogen Mustard or
the HX salt of the Nitrogen Mustard is in a non-aqueous vehicle or
carrier, wherein the non-aqueous vehicle or carrier comprises
between about 15% and about 60% by weight of a pharmaceutically
acceptable excipient, wherein the Nitrogen Mustard is represented
by the following structures:
##STR00002##
[0013] wherein each R.sub.1, R.sub.2, R.sub.3 . . . R.sub.34
(R.sub.1-R.sub.34) is independently selected from the group
consisting of H, linear alkyl group having 1-6 carbon atoms, a
branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group. The pharmaceutically acceptable
excipient may be 2-(2-ethoxyethoxy)ethanol. The alkylating agent
may be MCHCl.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The features of the invention are set forth in the appended
claims. The invention itself, however, will be best understood by
reference to the following detailed description of an illustrative
embodiment when read in conjunction with the accompanying drawings,
wherein:
[0015] FIG. 1 illustrates a method for the use of compositions
having stabilized alkylating agents for treating skin disease, in
accordance with embodiments of the present invention;
[0016] FIGS. 2-4 illustrate a front cross-sectional view of an
apparatus having a first compartment, in accordance with
embodiments of the present invention;
[0017] FIG. 5 depicts a Log-linear plot of the stability of MCHCl
in 2-(2-ethoxyethoxy)ethanol (2-ethoxy-(2ethoxy)ethanol) at various
temperatures over time, in accordance with embodiments of the
present invention; and
[0018] FIG. 6 depicts rate of MCHCl decomposition vs pH, in
accordance with embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Alkylating agents, such as nitrogen mustard
(Mechlorethamine) may be used in the pharmaceutical industry as
anticancer drugs. For example, in theory, the aziridinium cation,
(Structure II), may undergo nucleophilic attack by an electron
donor,
##STR00003##
resulting in alkylating the nucleophile. For example, reaction with
the nucleophile guanine (G), structure III, shown in Reaction 2, at
position N-7 of the guanine (G) occurs to the greatest extent.
Other sites on guanine (G), and other DNA bases such as adenine
(A), cytosine (C) and thymine (T), and phosphate oxygens also can
be alkylated.
##STR00004##
[0020] Unfortunately, the electrophilicity of alkylating agents,
such as nitrogen mustards, causes them to be subject to
decomposition in the presence of natural nucleophiles in the
environment, such as water. There is a need for stabilizing
alkylating agents to protect them from nucleophilic attack by
nucleophiles in the environment.
[0021] Cutaneous T-cell lymphoma (CTCL) is a malignancy of the
T-helper (CD4+) cells of the immune system. CTCL, also known as
mycosis fungoides (MF), is a cancer of the white blood cells that
primarily affects the skin and only secondarily affects other
sites. This disease involves the uncontrolled proliferation of
T-lymphocytes known as T-helper cells, so named because of their
role in the immune response. T-helper cells are characterized by
the presence of a protein receptor on their surface called CD4.
Accordingly, T-helper cells are said to be CD4+.
[0022] The proliferation of T-helper cells results in the
penetration, or infiltration, of these abnormal cells into the
epidermal layer of the skin. The skin reacts with slightly scaling
lesions that itch, although the sites of greatest infiltration do
not necessarily correspond to the sites of the lesions. The lesions
are most often located on the trunk, but can be present on any part
of the body. In the most common course of the disease, the patchy
lesions progress to palpable plaques that are deeper red and have
more defined edges. As the disease worsens, skin tumors develop
that are often mushroom-shaped, hence the name mycosis fungoides.
Finally, the cancer progresses to extracutanous involvement, often
in the lymph nodes or the viscera.
[0023] CTCL is a rare disease, with an annual incidence of about
0.29 cases per 100,000 persons in the United States. It is about
half as common in Eastern Europe. However, this discrepancy may be
attributed to a differing physician awareness of the disease rather
than a true difference in occurrence. In the Unites States, there
are about 500-600 new cases a year and about 100-200 deaths. CTCL
is usually seen in older adults; the median age at diagnosis is
55-60 years. It strikes twice as many men as women. The average
life expectancy at diagnosis is 7-10 years, even without
treatment.
[0024] The most common side effect for treatments applied to the
skin is skin hypersensitivity to the drug. There is a need for
improved compositions and methods for skin diseases that avoid or
minimize skin hypersensitivity to the drug.
[0025] In an embodiment, patients having MF topically treated with
Nitrogen Mustard compounded into a polypropylene glycol (PPG,
molecular weight from about 300 to about 2500), propylene glycol
(PG,), polyethyleneglycol (PEG, molecular weight from about 100 to
about 1000) or ethylene glycol ointment or cream showed no evidence
of any systemic toxicities.
[0026] Table 1 below provides a summary of topical treatment of
patients having MF with nitrogen mustard in propylene glycol (PG),
including response rates and toxicities.
TABLE-US-00001 TABLE 1 Topical Nitrogen Mustard In Mycosis
Fungoides (MF): Summary Of Clinical Outcomes & Toxicities. %
HYPER- F/U SENSITIVITY % SYSTEMIC #PTS (YRS) VEHICLE DOSE % CR %
PCR REACTIONS TOXICITIES* 14 <1 PG 10 mg % 36% 42% 7% 0%
Topically Applied Once Daily *Systemic toxicities monitored by
serial History & Physicals and laboratory studies.
Abbreviations: PTS = patients studies; F/U = follow-up; CR =
complete response; PG = propylene glycol, PCR = partial response;
NR = not reported
Systemic Absorption
[0027] There is no evidence of any clinically significant systemic
absorption of topically applied Nitrogen Mustard. No systemic
toxicities from percutaneous absorption have been observed in
long-term topical Nitrogen Mustard use in MF.
[0028] Genetic toxicity--No genetic toxicity has been observed with
the use of topical Nitrogen Mustard application. This is best
documented in a study that demonstrated no effect on
sister-chromatid exchanges in the peripheral blood lymphocytes of
CTCL-MF patients assayed before and after topical Nitrogen Mustard
treatment.
[0029] Bone Marrow Suppression--No evidence of bone marrow
suppression (anemia, leukoopenia or thrombocytopenia) has reported
with long term use of topical Nitrogen Mustard, based on serial
monitoring of the complete blood count.
[0030] Heptatotoxicity--No evidence of hepatotoxicty has reported
with long term use of topical NM, based on serial monitoring of
peripheral blood liver function tests.
[0031] Nephrotoxicity--No evidence of nephrotoxicity has been
reported with long term use of topical Nitrogen Mustard, based on
serial monitoring of peripheral blood renal function tests.
Environmental Contamination
[0032] Minimal evidence of environmental contamination has been
demonstrated with topical Nitrogen Mustard use.
Cutaneous Side Effects
[0033] Hyperpigmentation--resulting from the direct melanogenic
effects of Nitrogen Mustard, has been reported in a large
percentage of treated patients. The hyperpigmentation is reversible
and decreases gradually in most patients, even if topical therapy
is continued.
[0034] Contact dermatitis--is a common complication of topical
Nitrogen Mustard application. An irritant contact dermatitis is
most common and can be seen in up to 25% of individuals using
topical Nitrogen Mustard ointment, particularly if used in
sensitive areas such as the face or skin folds. Allergic contact
dermatitis is also observed with topical Nitrogen Mustard use.
[0035] Immediate-type (urticarial) reactions--are rare.
[0036] Allergic contact dermatitis--from delayed-type
hypersensitivity (DTH) reactions is more common and appears to be
dose-dependent. Higher concentrations of aqueous preparations are
associated with a DTH frequency of 10-67%. Desensitization with
lower concentrations of Nitrogen Mustard has been successfully
employed in patients with DTH reactions to Nitrogen Mustard. The
use of a lower concentration ointment preparation dramatically
reduces the incidence of DTH reactions. Stanford University
reported 0% DTH reactions in patients using Nitrogen Mustard
ointment for the first time and an 8% frequency of DTH in patients
with a previous history of HN hypersensitivity, in their series
utilizing an Nitrogen Mustard ointment preparation.
Pediatric Use
[0037] Topical Nitrogen Mustard has been reported to be used in
children and adolescences (<18 years) without any significant
differences in toxicities than in adults.
Use in Pregnancy
[0038] Despite the lack of evidence of percutaneous absorption of
topical Nitrogen Mustard, the use of topical Nitrogen Mustard has
historically been avoided in pregnant and nursing women.
Cutaneous Carcinogenesis
[0039] There are no reports of a significantly increased incidence
of squamous cell carcinoma (SCC) of the skin with prolonged use of
topical Nitrogen Mustard. Several groups have reported an
approximately 10% (4%-14%) frequency of SCC in CTCL-MF patients
using topical Nitrogen Mustard and suggest a potential risk of
epidermal carcinogenesis. These retrospective studies, however, do
not account for confounding variables, such as CTCL-MF associated
risk for second malignancies, prior therapies (e.g. radiation
therapy to the skin), and do not have adequate control groups.
[0040] In normal DNA strand replication, a DNA strand having
deoxyribonucleosides, wherein each deoxyribonucleoside may include
a base adenine (A), thymine (T), cytosine (C) and guanine (G),
replicates by linking each deoxyribonucleoside on the strand with
another deoxyribonucleoside, wherein typical linking occurs between
adenine (A) and thymine (T), forming an A-T linkage and between
cytosine (C) and guanine (G), forming a C-G linkage between the
original DNA strand and its replicated DNA strand.
[0041] Nitrogen Mustard alkylating agents may act as anti-cancer
agents by impairing natural DNA strand replication of cancer cells,
allowing unnatural base-base linkages such as a guanine (G) base
linking to another guanine (G) base if the particular Nitrogen
Mustard alkylating agents are bifunctional alkylators. Hereinafter,
bifunctional alkylators are Nitrogen Mustards having at least two
2-chloroethyl side chains, e.g. bis-(2-chloroethyl)methyl amine,
such as structure I of Reaction 1, infra.
[0042] Reaction 1, infra, depicts a reversible reaction,
represented by forward reaction 1a and reverse reaction 1b in
Reaction 1, in which a Nitrogen Mustard alkylating agent having a
2-chloroethyl side chain, e.g., bis-(2-chloroethyl)methylamine,
represented by structure I, infra, may undergo an intramolecular
cyclization, resulting in formation of a highly reactive
ethyleniminium intermediate (aziridinium cation), represented by a
structure II, infra. A concentration of the aziridinium cation, II,
infra, may be in equilibrium with a concentration of the Nitrogen
Mustard, I, infra, wherein the equilibrium constant K.sub.eq(1a,1b)
may be represented by a ratio of a rate k.sub.1a, of the forward
reaction 1a, to a rate k.sub.1b, of the reverse reaction 1b.
##STR00005##
[0043] In structure I, a carbon atom bonded to chlorine may
initially have a partial positive charge, .delta.+, and a chlorine
atom may initially have a partial negative charge, .delta.-. In
Reaction I, an unshared pair of electrons of nitrogen may form a
covalent bond to the carbon having .delta.+, releasing the chlorine
atom as chloride, and forming structure II.
[0044] Structure II, supra, may undergo nucleophilic attack by an
electron donor, i.e., a nucleophile, resulting in alkylating the
nucleophile. Reaction with the nucleophile guanine (G), structure
III, shown in Reaction 2, supra, at position N-7 of the guanine (G)
occurs to the greatest extent. Other sites on guanine (G), and
other DNA bases such as adenine (A), cytosine (C) and thymine (T),
and phosphate oxygens also can be alkylated. Hereinafter, structure
III represents all stereoisomers and racemates of the
deoxyribonucleoside having any DNA base.
##STR00006##
[0045] Reaction 2 results in forming the alkylated
deoxyribonucleoside, structure IV. In Reaction 2 supra, position
N-7 of the guanine (G) base of the deoxyribonucleoside, represented
in structure III, may nucleophilically attack the aziridinium ring,
structure II, that may have been formed by the intramolecular
cyclization represented by Reaction 1, supra, resulting in
alkylating position N-7 of the guanine (G) base of structure III.
Hereinafter, structure IV represents all stereoisomers and
racemates of the deoxyribonucleoside having any DNA base.
[0046] Alkylating agents have four actions on nucleic acids. First
of all, the agent may cause crosslinking of DNA strands which
interferes with DNA and RNA synthesis. This is thought to be the
most important reason for the cytotoxic effect of alkylating
agents. Secondly, the agent may alter the "side chain groups" of
the nucleotide base ring which would lead to abnormal base pairing
and point mutations in the synthesized DNA and RNA chains. Thirdly,
the alkylating agent may split the base ring from the nucleotide
which again interrupts proper DNA and RNA synthesis. Finally, the
alkylating agent may break the ring structure of a nucleotide base
which would prevent base pairing during DNA and RNA synthesis.
[0047] In normal DNA strand replication, a DNA strand consisting of
deoxyribonucleosides, wherein each deoxyribonucleoside may include
a base adenine (A), thymine (T), cytosine (C) and guanine (G),
replicates by linking each deoxyribonucleoside on the strand with
another deoxyribonucleoside, wherein typical linking occurs between
adenine (A) and thymine (T), forming an A-T linkage and between
cytosine (C) and guanine (G), forming a C-G linkage between the
original DNA strand and its replicated DNA strand.
[0048] Nitrogen Mustard alkylating agents may act as anti-cancer
agents by impairing normal DNA strand replication, allowing
abnormal base-base linkages such as a guanine (G) base linking to
another guanine (G) base if the particular Nitrogen Mustard
alkylating agents are bifunctional alkylators. Hereinafter,
bifunctional alkylators are Nitrogen Mustards having at least two
2-chloroethyl side chains, e.g. bis-(2-chloroethyl)methyl amine,
structure I, supra.
[0049] In Reaction 2, supra, one of the 2-chloroethyl side chains
of the deoxyribonucleoside represented by the structure IV has
alkylated the guanine (G) base of the structure III. In reversible
Reaction 3, infra, the remaining 2-chloroethyl side chain of the
deoxyribonucleoside of the structure IV has also undergone an
intramolecular cyclization, resulting in formation of
deoxyribonucleoside V, having the highly reactive aziridinium
ring.
##STR00007##
[0050] Reaction 4, infra, depicts the abnormal linking of the
deoxyribonucleoside V, having a guanine (G) base and the activated
aziridinium ring, with another deoxyribonucleoside III, also having
a guanine (G) base, forming an abnormal guanine-guanine (G-G) link
in the product, represented by the structure VI. Hereinafter,
structure VI represents all stereoisomers and racemates of the
product from coupling two molecules of the deoxyribonucleoside
represented by structure III at the N-7 position with the
bifunctional alkylating Nitrogen Mustard represented by the
structure II, supra.
##STR00008##
[0051] A highly unstable nature and extremely short duration of
action of the Nitrogen Mustards in the presence of water may result
because water may decompose the highly reactive ethyleniminium
intermediate (aziridinium cation), represented by the structure II,
in Reaction 1, supra, replacing the chlorine atom on the
2-chloroethyl side chains of the Nitrogen Mustard by an OH group.
The Nitrogen Mustards are said to be highly unstable and have an
extremely short duration of action because they may react with
water, resulting in replacement of one or both of the chlorine
atoms by a hydroxyl (OH) group. Replacement of the chlorine atoms
may block formation of the aziridinium cation and therefore may
prevent the Nitrogen Mustards from acting as alkylating agents of,
for example, the N-2 position of the guanine base of DNA. Reaction
5 illustrates competing equilibrium reactions, 1a and 1b and 5a and
5b. In Reactions 1a and 1b, a free form of the Nitrogen Mustard,
structure I, may be in equilibrium with the aziridium ion II, as
described for Reaction 1, supra. The equilibrium constant for
Reactions 1a and 1b has been described as K.sub.eq(1a,1b), supra.
In like manner, the equilibrium constant for Reactions 5a and 5b,
K.sub.eq(5a,5b) may be expressed as the ratio of the concentration
of the HX salt, IX, to the product of the concentration of the free
form of the Nitrogen Mustard, structure I and the concentration of
HX. Therefore, in an embodiment, there may be an equilibrium
concentration of aziridinium cation represented by the ratio of
K.sub.eq(1a,1b) to K.sub.eq(5a,5b), even when the Nitrogen Mustard
has been stabilized by converting the free base form of the
Nitrogen Mustard, as represented by structure I, infra, as
illustrated by Reaction 5, infra, to its HX salt, as represented by
the structure IX. Therefore, the N-2 position of the guanine base
of DNA, structure III in Reactions 2-4 may be alkylated by the HX
salt IX, as in Reaction 5, infra, because the concentration of the
aziridinium cation in Reaction 5, infra, may be a real positive
number, equal to K.sub.eq(1a,1b) to K.sub.eq(5a,5b). Hereinafter,
the free base form of the Nitrogen Mustard is any non-salt form of
the Nitrogen Mustard, wherein a lone pair of electrons on the
nitrogen atom may be available for forming the aziridinium ion, II,
as in Reaction 1, supra. In embodiments of the present invention,
the aziridinium cation, Structure II, supra, may undergo
nucleophilic attack by an electron donor, resulting in alkylating
the nucleophile. For example, reaction with the nucleophile guanine
(G), structure III, shown in Reaction 2, supra, at position N-7 of
the guanine (G) occurs to the greatest extent. Other sites on
guanine (G), and other DNA bases such as adenine (A), cytosine (C)
and thymine (T), and phosphate oxygens also can be alkylated.
[0052] The inventors disclose that oxygen of primary alcohols often
are nucleophiles and therefore may have a disadvantageous effect on
the use of the free base or the pharmaceutically acceptable HX salt
IX, as in reaction 5, infra, because the free base of the nitrogen
mustard or the pharmaceutically acceptable HX salt IX is consumed
in the undesirable side reaction in which the nucleophile is
alkylated by the free base of the nitrogen mustard or the
pharmaceutically acceptable HX salt IX, instead of being available
to act as an anti-cancer agent against T-Cell lymphoma, for
example, by impairing normal DNA strand replication. Hereinafter,
pharmaceutically acceptable HX salt IX, as in reaction 5, infra,
refers to salt forms that are pharmacologically acceptable and
substantially non-toxic to the subject being treated with the
compound of the invention. Therefore, secondary and tertiary
alcohols, amines, amino alcohols having from 1 to 20 carbon atoms
and polypropylene glycol (PPG, molecular weight from about 300 to
about 2500), propylene glycol (PG,), polyethyleneglycol (PEG,
molecular weight from about 100 to about 5000),
2-(2-ethoxyethoxy)ethanol, or ethylene glycol are preferred over
petrolatum, ethyl alcohol or water in formulations of the free base
of the nitrogen mustard or the pharmaceutically acceptable HX salt
IX, when a pharmaceutically acceptable inert ingredient, i.e., a
pharmaceutically acceptable excipient, may be needed to promote
solubilization of the free base of the nitrogen mustard or the
pharmaceutically acceptable HX salt IX in the non-aqueous vehicle
or carrier that does not include petrolatum or ethanol.
[0053] Ethyl alcohol is not used to dissolve the nitrogen mustard
or its HX salt because it is a nucleophile that degrades the
nitrogen mustard or its HX salt by promoting loss of chlorine.
Isopropyl, cetyl, stearyl, cetearyl, or lanolin alcohol are
preferred pharmaceutically acceptable excipients for dissolving or
taking up the nitrogen mustard or its HX salt. Alternatively, for
example, for topical formulations, pharmaceutically acceptable
excipients may comprise solvents, emollients, humectants,
preservatives, emulsifiers, and pH agents. Suitable solvents
include acetone, glycols, polyurethanes, and others known in the
art. Suitable emollients include mineral oil, propylene glycol
dicaprylate, lower fatty acid esters, lower alkyl ethers of
propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl
alcohol, stearic acid, wax, and others known in the art. Suitable
humectants include glycerin, sorbitol, and others known in the art.
Suitable emulsifiers include glyceryl monostearate, glyceryl
monoleate, stearic acid, polyoxyethylene cetyl ether,
polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether,
polyethylene glycol stearate, propylene glycol stearate, and others
known in the art. Suitable pH agents include hydrochloric acid,
phosphoric acid, diethanolamine, triethanolamine, sodium hydroxide,
monobasic sodium phosphate, dibasic sodium phosphate, and others
known in the art. Alternatively, pH agents include from about 1
percent by weight to about 15 percent by weight acetic acid, citric
acid, tartaric acid, fumaric acid, lactic, glycolic and other alpha
hydroxy acids, malic acid, carnitine, glutamic acid, aspartic acid
and others known in the art. Suitable preservatives include benzyl
alcohol, sodium benzoate, parabens, and others known in the
art.
[0054] The inventors report that polyethylene glycol (PEG),
ethylene glycol (EG), polypropylene glycol (PPG), propylene glycol
(PG) and the diethylene glycol monosubstituted ether, polypropylene
glycol (PPG, molecular weight from about 300 to about 2500),
propylene glycol (PG,), polyethyleneglycol (PEG, molecular weight
from about 100 to about 5000) or ethylene glycol are useful
pharmaceutically acceptable excipients. The polyethylene glycol
(PEG), ethylene glycol (EG), polypropylene glycol (PPG), propylene
glycol (PG) and the diethylene glycol monosubstituted ether that
may hydrogen bond to trace nucleophiles that may be contaminants in
the pharmaceutically acceptable excipients, thereby reducing the
nucleophilic strength of the trace nucleophiles. Therefore
diethylene glycol monosubstituted ether or silicones such as
dimethicone or cyclomethicone are useful as pharmaceutically
acceptable excipients to promote dissolution of the free base of
the nitrogen mustard or the HX salt IX, infra, in formulations of
the free base of the nitrogen mustard or the pharmaceutically
acceptable HX salt IX, infra.
[0055] In embodiments of the present invention, pharmaceutically
acceptable HX salts of the Nitrogen Mustard, structure IX, infra,
are more stable and of longer activity duration than their
respective free bases, as measured by an effective alkylating
activity of the pharmaceutically acceptable HX salts of the
Nitrogen Mustard, structure IX, infra, in the non-aqueous vehicle
or carrier that does not include petrolatum or ethanol, wherein an
effective alkylating activity of the pharmaceutically acceptable HX
salts in the non-aqueous vehicle or carrier that does not include
petrolatum or ethanol after three (3) years is equivalent to the
effective alkylating activity of the free base form of the
respective Nitrogen Mustards, structure I, after 3 months in the
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol. The non-aqueous vehicle or carrier that does not include
petrolatum or ethanol in formulations of the nitrogen mustard free
base or the pharmaceutically acceptable HX salts, structure IX,
infra, does not include any grade of white or yellow petrolatum
recognized in the art as suitable for human application. The
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol does not include material commercially available as Penreco
Snow White Pet USP in formulations of the nitrogen mustard free
base or the pharmaceutically acceptable HX salts, structure IX,
infra. The non-aqueous vehicle or carrier that does not include
petrolatum or ethanol does not include hydrocarbon mixtures
formulated with mineral oils in combination with paraffin waxes of
various melting points in formulations of the nitrogen mustard free
base or the pharmaceutically acceptable HX salts, structure IX,
infra. The non-aqueous vehicle or carrier that does not include
petrolatum or ethanol does not include a lipophilic emollient
selected from the group consisting of: petrolatum; esters of fatty
acids. Hereinafter, the effective alkylating activity of the
pharmaceutically acceptable HX salts, structure IX, infra, in the
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol is equivalent to the effective alkylating activity of the
free base form of the respective Nitrogen Mustards in the
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol when a weight percent of the pharmaceutically acceptable HX
salt, structure IX, infra, in the non-aqueous vehicle or carrier
that does not include petrolatum or ethanol is essentially equal to
the weight percent of the respective free base of the Nitrogen
Mustard, structure I in the non-aqueous vehicle or carrier that
does not include petrolatum or ethanol.
[0056] In embodiments of the present invention, use of the
pharmaceutically acceptable HX salt, structure IX, infra, of the
Nitrogen Mustard in the non-aqueous vehicle or carrier that does
not include petrolatum or ethanol may preserve the effective
alkylating activity by reducing its volatility compared to that of
the free base form, since pharmaceutically acceptable HX salts of
Nitrogen Mustards generally have lower vapor pressures than their
corresponding free base forms.
[0057] Reaction represented by arrow 5c, infra, illustrates
formation of the stabilized Nitrogen Mustard.HX compositions of the
present invention that have been stabilized by converting said free
form highly reactive Nitrogen Mustard alkylating agents to
pharmaceutically acceptable HX salts by reaction of the Nitrogen
Mustard with HX.
##STR00009##
[0058] In an embodiment, X.sup.- may advantageously be halide, such
as Cl.sup.-, Br.sup.-, I.sup.- or HSO.sub.4.sup.- or
NO.sub.3.sup.-, wherein HX may be respectively, HCl, HBr, HI, or
H.sub.2SO.sub.4, or HNO.sub.3.sup.-. Alternatively pharmaceutically
acceptable HX salts include conventional acid-addition salts or
base-addition salts formed from suitable non-toxic organic or
inorganic acids or inorganic bases. Exemplary acid-addition salts
include those derived from inorganic acids such as hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic
acid, phosphoric acid, and nitric acid, and those derived from
organic acids such as p-toluenesulfonic acid, methanesulfonic acid,
ethane-disulfonic acid, isethionic acid, oxalic acid,
p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric
acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid,
phenylacetic acid, propionic acid, glycolic acid, stearic acid,
lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid,
hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid,
and fumaric acid. Exemplary base-addition salts include those
derived from ammonium hydroxides (e.g., a quaternary ammonium
hydroxide such as tetramethylammonium hydroxide), those derived
from inorganic bases such as alkali or alkaline earth-metal (e.g.,
sodium, potassium, lithium, calcium, or magnesium) hydroxides, and
those derived from non-toxic organic bases such as basic amino
acids.
[0059] FIG. 1 depicts an embodiment of the present invention, a
method 1, for treating a person with a skin disorder, comprising: a
step 10, topically applying to the affected skin a Nitrogen Mustard
or a pharmaceutically acceptable HX salt of the Nitrogen Mustard,
wherein the Nitrogen Mustard or the pharmaceutically acceptable HX
salt of the Nitrogen Mustard is in a non-aqueous vehicle or carrier
that does not include petrolatum or ethanol, wherein the
non-aqueous vehicle or carrier does not include petrolatum or
ethanol, wherein the Nitrogen Mustard is represented by the
following structures:
##STR00010## [0060] wherein each R.sub.1, R.sub.2, R.sub.3 . . .
R.sub.34 (R.sub.1-R.sub.34) is independently selected from the
group consisting of H, linear alkyl group having 1-6 carbon atoms,
a branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group.
[0061] In an embodiment, the Nitrogen Mustard is advantageously
selected from the group consisting of
bis-(2-chloroethyl)ethylamine, bis-(2-chloroethyl)methylamine, and
tris-(2-chloroethyl)amine, and combinations thereof. Hereinafter,
structures VII, VIII, IX and X (XI-XIV) may represent all racemic
forms and stereoisomers wherein said compounds may be capable of
optical activity.
[0062] Alternatively, in an embodiment, the Nitrogen Mustard may be
advantageously derived from a Nitrogen Mustard prodrug represented
by the following structures:
##STR00011## [0063] wherein each R.sub.35, R.sub.36, R.sub.37 . . .
R.sub.78 (R.sub.35-R.sub.78) is independently selected from the
group consisting of H, linear alkyl group having 1-6 carbon atoms,
a branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, and wherein any two R.sub.1-R.sub.57 in the
same molecule may be linked to form a three- to eight-membered
cyclic group, [0064] wherein each X group is a linking group
selected from the group consisting of linear or branched alkylene
having 1 to 7 carbon atoms, cycloalkylene having 3 to 17 carbon
atoms, alkylcycloalkylene having 4 to 20 carbon atoms, a
cycloalkylalkylene having 4 to 20 carbon atoms, an arylene, having
4 to 30 carbon atoms, an alkylarylene, having 4 to 30 carbon atoms,
an arylalkylene, having 4 to 30 carbon atoms, and combinations
thereof, [0065] wherein each Ar group is a bifunctional aromatic
linking group wherein each Ar is selected from the group consisting
of arylene, substituted arylene and/or heteroarylene.
[0066] Compounds represented by structures XI, XII, . . . XIV
(XI-XIV) may be prodrug candidate forms of the Nitrogen Mustards,
because they can be metabolized in vivo to generate the active
Nitrogen Mustard. Hereinafter, a "prodrug" is a precursor
(forerunner) of the active Nitrogen Mustard. A prodrug may undergo
chemical conversion by metabolic processes to the parent drug, thus
becoming an active Nitrogen Mustard. Hereinafter, structures XI,
XII, . . . XIV (XI-XIV) may represent all racemic forms and
stereoisomers wherein said compounds may be capable of optical
activity.
[0067] For example, phosphatase and phosphamidase enzymes may
hydrolyze the P--N bond of structure XI, supra, e.g.,
cyclophosphamide, structure XIA, infra or ifosphamide, structure
XIB, infra, resulting in an intermediate aldophosphamide, which may
nonenzymatically break down to a bifunctional phosphoramide
mustard. In an embodiment, cyclophosphamide, structure XIA, supra
or ifosphamide, structure XIB, supra may be oxidatively activated
by cytochrome P-450
##STR00012##
[0068] In an embodiment, structure XII, supra, e.g., Chlorambucil,
structure XIIA, infra, may be a bifunctional alkylating agent of
the nitrogen mustard type.
##STR00013##
Structure XII may be cell cycle-phase nonspecific, although it also
may be cytotoxic to nonproliferating cells. Activity may occur as a
result of formation of an unstable ethylenimmonium ion, which
alkylates or binds with many intracellular molecular structures,
including nucleic acids. Its cytotoxic action may be primarily due
to cross-linking of strands of DNA, which inhibits nucleic acid
synthesis
[0069] In an embodiment structure, XIII, supra, e.g., Melphalan,
structure XIIIA, infra, may be a bifunctional alkylating agent of
the nitrogen mustard type.
##STR00014##
Like the nitrogen mustard prodrugs of structure XII, prodrugs of
structure XIII may be cell cycle-phase nonspecific, although they
also may be cytotoxic to nonproliferating cells.
[0070] In an embodiment, structure XIV, supra, e.g., uracil
mustard, structure XIVA, infra, may be a bifunctional alkylating
agent of the nitrogen mustard type.
##STR00015##
[0071] In an embodiment, the pharmaceutically acceptable HX salt of
the Nitrogen Mustard may be advantageously selected from the group
consisting of Nitrogen Mustard.HCl, Nitrogen
Mustard.H.sub.2SO.sub.4, Nitrogen Mustard.HNO.sub.3, Nitrogen
Mustard.H.sub.2SO.sub.4, Nitrogen Mustard HBr, Nitrogen Mustard.HI
and combinations thereof.
[0072] In an embodiment, an ingredient of the non-aqueous vehicle
or carrier that does not include petrolatum or ethanol may be
selected from the group consisting of polyethylene glycol (PEG) or
ethylene glycol (PEG), polypropylene glycol (PPG) or propylene
glycol (PG), diethylene glycol monomethyl ether (DGME),
HOCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OR.sub.79
(HO(CH.sub.2CH.sub.2O).sub.2R.sub.79), wherein R.sub.79 is selected
from the group consisting of a linear alkyl group having 1-6 carbon
atoms, a branched alkyl group having 2-12 carbon atoms, a
cycloalkyl group having 3-17 carbon atoms, a fluorinated linear
alkyl group having 2-12 carbon atoms, a fluorinated branched alkyl
group having 2-12 carbon atoms, and a fluorinated cycloalkyl group
having 3-17 carbon atoms, an aryl group, an aralkyl group, an
alkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl
group, an alkalkenyl group, an alkenylalkyl group, an alkynyl
group, an alkalkynyl group, an alkynylalkyl group, a
trifluoropropyl group, a cyanopropyl group, an acryloyl group, an
arylacryloyl group, an acryloylaryl group, an alkylacyl group, an
arylacyl group, an alkylenylacyl group and an alkynylacyl group,
and combinations thereof. In an embodiment, each ingredient of the
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol may be selected from the group consisting of Ethoxy
Diglycol Reagent, Hydroxypropylcellulose, Menthol Crystals USP,
Butylated Hydroxytoluene NF, Glycerin USP, Edetate Disodium USP,
Decyl Methyl Sulfoxide, Kris-Ester 236 and combinations
thereof.
[0073] In an embodiment, pharmaceutically acceptable HX salts of
the Nitrogen Mustard alkylating agents used in the treatment of
skin disorders may be more stable and have a longer duration of
activity because the pharmaceutically acceptable HX salts of the
Nitrogen Mustards may be more resistant to attack by water than the
respective free base form of the Nitrogen Mustard. In an
embodiment, the pharmaceutically acceptable HX salts of the
Nitrogen Mustard alkylating agents may be added to a non-aqueous
vehicle or carrier that may not include petrolatum. In an
embodiment, the use of pharmaceutically acceptable HX salts of the
Nitrogen Mustard alkylating agents and/or adding them to the
non-aqueous vehicle or carrier that may not include petrolatum may
result in greater stability and longer duration of action in the
treatment of skin disorders.
[0074] In an embodiment, the skin disorder is selected from the
group consisting of psoriasis, eczema, actinic keratosis, lupus,
sarcoidosis, alopecia, cutaneous T-Cell lymphoma, i.e., mycosis
fungoides, lymphoreticular neoplasia, pleural and peritoneal
effusions, cutaneous B-cell lymphoma, pseudolymphomas of the skin,
squamous cell carcinoma, basal cell carcinoma, bronchogenic
carcinoma, malignant melanoma, lymphosarcoma, chronic lymphocytic
leukemia, polycythemia vera, lymphomatoid papulosis,
Mucha-Habberman's disease (PLEVA), vitiligo, and combinations
thereof.
[0075] The rationale for the use of topical NM for the treatment of
vitiligo lies in the clinical and experimental observations that NM
produces cutaneous hyperpigmentation not associated with an
inflammatory response. It has long been observed that the treatment
of MF with topical NM produces hyperpigmantation. The same
phenomenon has been reported in NM treatment of psoriasis. Indeed,
the inventors disclose successful regimentation of vitiligo treated
with topical NM has been demonstrated. Supporting the direct effect
of NM on melanogenesis, the pigmentation of hairless mice in
response to topical NM. In humans, ultra structure studies
demonstrate topical NM increases melanosome numbers and
distribution without toxic effects to epidermal
microenvironment.
[0076] Methods of delivery, as in the step 10 of the method 1
comprise topical administration of the Nitrogen Mustard or Nitrogen
Mustard.HCl to humans and animals of sterile solutions or
suspensions, wherein the dosage contains suitable quantities of an
active ingredient. Topical solutions or suspensions are
incorporated in a slow release non-aqueous matrix for administering
transdermally. In an embodiment, a dosage for mammals may be from
about 0.0001 percent by weight to about 2.0 percent by weight of
the active ingredient in the non-aqueous and non-petrolatum matrix
per day. In another embodiment, the dosage for mammals may be from
about 0.015 percent by weight to about 0.04 percent by weight of
the active ingredient in the non-aqueous and non-petrolatum matrix
per day. In an embodiment, the dosage for mammals may be from about
0.015 to about 0.030 percent by weight of the active ingredient in
the non-aqueous and non-petrolatum matrix per day. Hereinafter,
topical administration means applying a drug to a localized area of
the body or to the surface of a body part.
[0077] In embodiments of the present invention, a method for
treating a person with a skin disorder, comprising: topically
applying the Nitrogen Mustard or Nitrogen Mustard HCl to the
affected skin. In an embodiment of the method, the non-aqueous
vehicle or carrier that does not include petrolatum or ethanol
ameliorates skin irritation resulting from the Nitrogen Mustard or
its HX salt, by providing an effective dose of the Nitrogen Mustard
or Nitrogen Mustard HCl. Hereinafter, "ameliorates" means to lessen
pain and reduce skin irritation, resulting in making an improvement
because skin irritation has been reduced. Hereinafter, an effective
dose of the Nitrogen Mustard or Nitrogen Mustard HCl may be
sufficient to treat the skin having one of the aforementioned
diseases without causing hypersensitivity, as disclosed in Table 1,
supra.
[0078] In embodiments of the present invention, a method for
stabilizing a volatile alkylating agent, comprising: providing a
non-aqueous flowable ointment or cream, wherein the non-aqueous
flowable ointment or cream does not include petrolatum or ethanol;
reconsitituting an HX salt of the volatile alkylating agent in
solvent that does not include ethanol; combining with mixing the
non-aqueous flowable ointment or cream and the HX salt of the
volatile alkylating agent. In an embodiment, in the method for
stabilizing the Nitrogen Mustard or Nitrogen Mustard HCl, the HX
salt of the Nitrogen Mustard is Nitrogen Mustard.HCl. In an
embodiment of the method for stabilizing the Nitrogen Mustard or
the Nitrogen Mustard.HCl, a duration of activity of the Nitrogen
Mustard or the HX salt of the Nitrogen Mustard is from about 3
months to about 3 years.
[0079] In an embodiment, in the method for stabilizing the Nitrogen
Mustard or the Nitrogen Mustard.HCl, the non-aqueous flowable
ointment or cream includes polypropylene glycol (PPG), propylene
glycol (PG) or polyethylene glycol (PEG) or ethylene glycol (EG).
In an embodiment, in the method for stabilizing the Nitrogen
Mustard or the Nitrogen Mustard.HCl, the non-aqueous flowable
ointment or cream consists essentially of Propylene Glycol, Ethoxy
Diglycol Reagent, Hydroxypropylcellulose, Menthol Crystals USP,
Butylated Hydroxytoluene NF, Glycerin USP, Edetate Disodium USP,
Decyl Methyl Sulfoxide, and Kris-Ester 236.
[0080] In an embodiment, in the method for stabilizing the Nitrogen
Mustard or the Nitrogen Mustard.HCl, the Nitrogen Mustard or its HX
salt is selected from the group consisting of
bis-(2-chloroethyl)ethylamine, bis-(2-chloroethyl)methylamine,
tris-(2-chloroethyl)amine, and combinations thereof.
[0081] In one embodiment, the acceptable non-aqueous vehicle or
carrier that does not include petrolatum or ethanol for the purpose
of this invention may be flowable non-aqueous pharmaceutical
vehicle or carriers such as creams or ointments that do not contain
nucleophiles, e.g., water or ethanol, that may decompose the
Nitrogen Mustard or its HX salt, structure IX, as depicted in
Reaction 5, supra. In an embodiment, suitable pharmaceutically
acceptable carriers include Ethoxy Diglycol Reagent,
Hydroxypropylcellulose, Menthol Crystals USP, Butylated
Hydroxytoluene NF, Glycerin USP, Edetate Disodium USP, Decyl Methyl
Sulfoxide, Kris-Ester 236, Propylene glycol and Ethylene Glycol. In
an embodiment, the polypropylene glycol (PPG), propylene glycol
(PG), polyethylene glycol (PEG) or ethylene glycol (EG) may be from
about 15 to about 60 weight percent propylene glycol or ethylene
glycol. The non-aqueous vehicle or carrier that does not include
petrolatum or ethanol may also contain adjuvants such as
preserving, stabilizing, wetting, emulsifying agents and the like
together with the sensitizer of this invention.
[0082] In an embodiment of the present invention, the sensitizers
can also be used as adjunct therapy in combination with existing
therapies, such as hyperthermia, in the management cancer treatment
in patients having cancer.
Example 1
Preparation of a Topical Ointment from about 0.001 to about 2.0
Parts by Weight Bis-(2-chloroethyl)methylamine Hydrochloride,
Structure Ix, as Depicted in Reaction 5 Supra, Per 100 Parts by
Weight of a Pharmaceutically Acceptable Nitrogen Mustard
Hydrochloride in a Pharmaceutically Acceptable Vehicle or
Carrier
[0083] The topical ointment comprises a pharmaceutically acceptable
nitrogen mustard hydrochloride in a pharmaceutically acceptable
vehicle or carrier, wherein the pharmaceutically acceptable vehicle
or carrier does not include petrolatum or ethanol. The
components/composition are provided in Table 2 that follows.
TABLE-US-00002 TABLE 2 Unit/Batch Composition Amount per Ingredient
100 ml Per Batch.sup.a Percent PPG, PG, PEG or EG USP 15-60 ml
0.15-0.6 L 15-60% Ethoxy Diglycol Reagent 15-60 ml 0.15-0.6 L
15-60% Hydroxypropylcellulose 0.75 gm 0.0075 kg 0.75% NF 1500 CPS
Menthol Crystals USP 0.08 gm 0.0008 kg 0.08% Butylated
Hydroxytoluene 0.05 gm 0.0005 kg 0.05% NF (BHT) Glycerin USP 12.75
ml 0.1275 L 12.75% Edetate Disodium USP 0.05 gm 0.0005 kg 0.05%
Decyl Methyl Sulfoxide 0.125 gm 0.00125 kg 0.13% Kris-Ester 236
liquid 5 gm 0.05 kg 5.00% Alchohol Anydrous 100% SDA 3A 2.175 ml
0.02175 L 2.18% Bis-(2-chloroethyl)methyl- 0.001-2.0 gm gm
0.00001-0.02 kg .001-2.0% amine HCl.sup.b .sup.aSlight overages of
the drug substances may be used as required to offset losses during
manufacture. .sup.bAvailble from Merck & Co., West Point, PA
19486. indicates data missing or illegible when filed
Manufacturing
[0084] The topical ointment, e.g., having 0.001-2.0 percent by
weight Nitrogen Mustard as Bis-(2-chloroethyl)methylamine.HCl,
structure IX, as in Reaction 5, supra, may be manufactured
according to the following general procedure:
[0085] Preparation of the Ointment [0086] 1. All dry excipient
ingredients are assembled and weighed out according to the formula
in Table 2 and placed in an appropriate vessel. Hereinafter, an
excipient is an inert substance which is added to the free form of
the nitrogen mustard or its pharmaceutically acceptable HX salt to
provide bulk. Hereinafter, the dry excipient ingredients are
indicated as being added as solid weight, such as gram, i.e. gm.
[0087] 2. Particle sizes of the dry material are reduced to a
uniform size through tritration. [0088] 3. Polypropylene glycol
(PPG), propylene glycol (PG), polyethylene glycol (PEG) or ethylene
glycol (EG) from about 15 to about 60 percent by weight is then
added via the principle of geometric dilution to form a smooth
paste. Once a smooth paste is achieved, the propylene or ethylene
glycol continues to be added until a volume that retains a flow
like quality is obtained. [0089] 4. The entire contents are then
transferred to a large beaker. A spin bar is added and the beaker
is placed on a magnetic stirring plate and mixing is begun. [0090]
5. As the mixture continues to spin, glycerin is added. While the
mixture spins, the original vessel is washed with from about 15 to
about 60 percent by weight ethoxy digycol and the contents of the
vessel are added to the spinning mixture in the beaker. [0091] 6.
After the ethoxy diglycol is added, kris-ester is added to the
spinning mixture. This mixture then is spun for approximately one
to two hours. After the spinning is finished the mixture is covered
and left to sit over-night. [0092] 7. The next day the mixture is
mixed with a high shear mixer to a uniform consistency with minimal
to no air. Air and moisture may be removed during mixing by
applying a vacuum from about 0.01 to about 0.1 torr. The mixture is
then brought to ambient pressure by adding dry nitrogen.
[0093] Adding the Nitrogen Mustard [0094] 8. The appropriate
concentration and amount of Nitrogen mustard is reconstituted with
absolute alcohol (200 proof) then added to the appropriate amount
of non-aqueous vehicle or carrier, wherein the non-aqueous vehicle
or carrier does not include petrolatum or ethanol and mixed to a
uniform consistency via agitation for 60-90 seconds For example, in
an embodiment, a concentration in mg/ml of the pharmaceutically
acceptable Nitrogen Mustard.HCl in the non-aqueous vehicle or
carrier that does not include petrolatum or ethanol is
advantageously from about 1 mg of Nitrogen Mustard.HCl per 100 ml
of non-aqueous vehicle to about 2000 mg of Nitrogen Mustard.HCl per
100 ml of non-aqueous vehicle. In an embodiment, a concentration in
mg/ml of Nitrogen Mustard HCl in a non-aqueous vehicle or carrier
that does not include petrolatum or ethanol is advantageously from
about 10 mg of Nitrogen Mustard.HCl per 100 ml of non-aqueous
vehicle or carrier that does not include petrolatum or ethanol to
about 40 mg of Nitrogen Mustard.HCl per 100 ml of non-aqueous
vehicle or carrier that does not include petrolatum or ethanol. In
an embodiment, a concentration in mg/ml of Nitrogen Mustard.HCl
used in a non-aqueous vehicle or carrier that does not include
petrolatum or ethanol is advantageously from about 15 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol to about 30 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol. [0095] 9. This mixture
is then poured into a 50 ml flip top plastic cylinder and shipped
to the appropriate patient.
[0096] Clean-up
[0097] All vessels used in the process are placed in a Sodium
Thiosulfate-Sodium Bicarbonate aqueous bath. Contents are left in
the bath for 2 hours and then the washed. The bath is then
discarded by normal means. Note: Sodium Thiosulfate reacts with
nitrogen mustard to create an innocuous, safe mixture that can be
discarded by normal means.
Example 2
Preparation of a Topical Ointment from about 0.001 to about 2.0
Parts by Weight Bis-(2-chloroethyl)methylamine Hydrochloride,
Structure IX, as Depicted in Reaction 5 Supra, in a
Pharmaceutically Acceptable Nitrogen Mustard Hydrochloride in a
Pharmaceutically Acceptable Vehicle or Carrier Per 100 Parts by
Weight of the Topical Ointment
[0098] The drug product formulation comprises a pharmaceutically
acceptable nitrogen mustard hydrochloride in a pharmaceutically
acceptable vehicle or carrier in a topical ointment base. The
components/composition are provided in Table 3 that follows.
TABLE-US-00003 TABLE 3 Unit/Batch Composition Parts per 100 Parts
by Ingredient.sup.a Weight of a Topical Ointment Dimethicone,
Cyclomethicone, or 10-60 HO(CH.sub.2CH.sub.2O).sub.2R.sub.79)
Ethoxy Diglycol Reagent 10-16 Hydroxypropylcellulose NF 1500 CPS
0-5 Menthol Crystals USP 0-1 Butylated Hydroxytoluene NF (BHT) 0-1
Glycerin USP 1-2 Edetate Disodium USP 0-0.05 Decyl Methyl Sulfoxide
0-0.125 Kris-Ester 236 liquid 0-5 Anydrous Secondary or tertiary
Alcohol 1-20 Bis-(2-chloroethyl)methylamine HCl.sup.b 0.001-2.0
C.sub.nH.sub.(2n + 2)COOH, (n = 1-6) 0.01-15 .sup.a Slight overages
of the drug substances may be used as required to offset losses
during manufacture. .sup.bAvailble from Merck & Co., West
Point, PA 19486.
[0099] The acceptable non-aqueous vehicle or carrier that does not
include petrolatum or ethanol for the purpose of this invention
that is the flowable non-aqueous pharmaceutically acceptable
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol such as creams or ointments do not contain nucleophiles,
e.g., water or ethanol, that may decompose the free form of the
Nitrogen Mustard or its HX salt, structure IX, as depicted in
Reaction 5, supra, may be dimethyl polysiloxane fluid such as
dimethicone or cyclomethicone having essentially no moisture
content.
[0100] Hereinafter dimethicone means low viscosity silicones, low
viscosity, i.e. from about 1 cps. to about 1,000 cps at 25.degree.
C. polydimethylsiloxanes, Hexamethyldisiloxane, CAS# 107-46-0, pure
silicone 1cSt, volatile silicone, volatile silicones, volatile
polydimethylsiloxanes, low temperature silicones, skin care
silicone, skin care silicones, Octamethyltrisiloxane, CAS#
107-51-7, CAS107-51-7, Decamethyltetrasiloxane, (CAS# 141-62-8,
Dodecamethylpentasiloxane CAS# 141-63-9, trisiloxane, low viscosity
dimethicone, volatile dimethicone, cosmetic dimethicone fluid,
cosmetic base fluids, suntan lotion silicone, antiperspirant
silicone, hair care silicone, low surface tension silicone, and low
heat of vaporization silicone.
[0101] Hereinafter, cyclomethicone means cyclopentasiloxane,
volatile poydimethylcyclosiloxane, CAS 541-02-6, CAS# 541-02-6, low
surface tension silicone, volatile silicone, D5 silicone, Dow
Corning 245 fluid, DC 245 fluid, 245 silicone, skin cream silicone,
antiperspirant silicone, suntan lotion silicone, silicone for skin,
skincare silicone, bodycare silicone, bath oil silicone, GE 1202,
GE SF1202 cyclopentasiloxane, D5 Cyclopentasiloxane, and D5
Decamethylcyclo Pentasiloxane.
[0102] Generally, dimethicone and cyclomethicone are dimethyl
silicone oils with good emollience, strong moisturization and
humectant properties. Dimethicone and cyclomethicone have very low
moisture content, as water, i.e. <0.1% by weight because they
are methyl stopped instead of OH stopped polymers.
Manufacturing
[0103] The drug product, e.g., having 0.001-2.0 percent by weight
Nitrogen Mustard as Bis-(2-chloroethyl)methylamine.HCl, structure
IX, as in Reaction 5, supra, in Dimethicone or Cyclomethicone
Ointment may be manufactured according to the following general
procedure:
[0104] Preparation of the Dimethicone or Cyclomethicone Ointment
[0105] a) All dry excipient ingredients are assembled and weighed
out according to the formula in Table 3 and placed in an
appropriate vessel. [0106] b) Particle sizes of the dry material
are reduced to a uniform size through tritration. [0107] c)
Dimethicone or cyclomethicone from about 10 to about 60 percent by
weight is then added via the principle of geometric dilution to
form a smooth paste. Once a smooth paste is achieved, the
Dimethicone or cyclomethicone continues to be added until a volume
that retains a flow like quality is obtained. [0108] d) The entire
contents are then transferred to a large beaker. A spin bar is
added and the beaker is placed on a magnetic stirring plate and
mixing is begun. [0109] e) As the mixture continues to spin,
glycerin is added. While the mixture spins, the original vessel is
washed with from about 10 to about 16 percent by weight ethoxy
diglycol and the contents of the vessel are added to the spinning
mixture in the beaker. [0110] f) After the ethoxy diglycol is
added, from about 0.01-15 percent by weight of a pH modifier such
as citric acid, lactic acid or aliphatic acids having a formula
C.sub.nH.sub.(2n+2)COOH, (n=1-6) is added to the spinning mixture.
This mixture then is spun for approximately one to two hours. After
the spinning is finished the mixture is covered and left to sit
over-night. [0111] g) The next day the mixture is mixed with a high
shear mixer to a uniform consistency with minimal to no air. Air
and moisture may be removed during mixing by applying a vacuum from
about 0.01 to about 0.1 torr. The mixture is then brought to
ambient pressure by adding dry nitrogen.
Combining the Nitrogen Mustard and the Dimethicone or
Cyclomethicone Non-Aqueous Vehicle or Carrier that does not Include
Petrolatum or Ethanol of Step g) Supra
[0112] In one embodiment, a pharmaceutically acceptable nitrogen
mustard.HCl having an essentially completely uniform consistency
may be formed by agitating for 60-90 seconds using a high shear
mixer to mix 1) an appropriate amount of Nitrogen Mustard having
been be reconstituted with an secondary or tertiary alcohol such as
isopropyl alcohol, wherein ethanol has been rigorously excluded
from the secondary or tertiary alcohol such as isopropyl alcohol,
and 2) the appropriate amount of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol from step g), supra,
wherein the non-aqueous vehicle or carrier does not include
petrolatum or ethanol. For example, in an embodiment, a
concentration in mg/ml of the pharmaceutically acceptable Nitrogen
Mustard.HCl in the non-aqueous vehicle or carrier that does not
include petrolatum or ethanol is advantageously from about 1 mg of
Nitrogen Mustard HCl per 100 ml of non-aqueous vehicle to about
2000 mg of Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle.
In another embodiment, a concentration in mg/ml of the
pharmaceutically acceptable Nitrogen Mustard.HCl used in a
non-aqueous vehicle or carrier that does not include petrolatum or
ethanol is advantageously from about 10 mg of Nitrogen Mustard.HCl
per 100 ml of non-aqueous vehicle or carrier that does not include
petrolatum or ethanol to about 40 mg of Nitrogen Mustard.HCl per
100 ml of non-aqueous vehicle or carrier that does not include
petrolatum or ethanol. In another embodiment, a concentration in
mg/ml of the pharmaceutically acceptable Nitrogen Mustard.HCl used
in a non-aqueous vehicle or carrier that does not include
petrolatum or ethanol is advantageously from about 15 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol to about 30 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol. This mixture is then
poured into a 50 ml flip top plastic cylinder and shipped to the
appropriate patient.
[0113] The inventors disclose that lower volume containers having
from about 0.01 to about 0.2 ml, from about 0.1 to about 0.5 ml, or
from about 0.1 to about 1 ml may advantageously be used to provide
from 1 to 10 applications of the pharmaceutically acceptable
Nitrogen Mustard.HCl over a shorter period of use than the 50 ml
flip top plastic cylinders, so that lower amounts of nucleophiles
such as ambient water or other ambient nucleophiles such as
methanol or ethanol may be introduced into the lower volume
containers than when the flip top plastic cylinder is opened to the
ambient environment over a period of 100 to 1000 applications. The
inventors anticipate decreased decomposition of the free form
nitrogen mustard or its HX salt, structure IX, depicted in Reaction
5, supra, when the pharmaceutically acceptable nitrogen mustard is
contained in lower volume containers intended for from about 1 to
10 applications. In theory, the chlorides of the free form of the
nitrogen mustard or its HX salt may be displaced by nucleophilic
attack, such as by water or ethanol, resulting in substitution of
the Cl by an OH. Said decomposition of the free form of the
nitrogen mustard or its HX salt may be avoided by isolating the
nitrogen mustard from traces of water, ethanol or other
nucleophiles in the environment. An apparatus 20, as depicted in
FIG. 2, infra, depicts this smaller volume container.
[0114] FIG. 2 depicts a front cross-sectional view of the apparatus
20 for containing the pharmaceutically acceptable Nitrogen
Mustard.HCl in the non-aqueous vehicle or carrier that does not
include petrolatum or ethanol or the stabilized volatile alkylating
agent or HX salt of the stabilized volatile alkylating agent,
comprising: a compartment 25 enclosed by a wall 31. The wall 31
comprises an outer surface 28 and an inner surface 23, ends 24 and
21, and opening 30. The first compartment 25 may be charged with
the essentially completely uniform mixture of the pharmaceutically
acceptable nitrogen mustard.HCl, supra, through the opening 30. The
opening 30 may be closed with plug 22. The plug 22 may be made of
the same material as the wall 31, or a lower melting plastic or wax
material.
[0115] FIG. 3 depicts the apparatus 20, after forming heat seals 26
and 27 by heating the plug 22 and the ends 21 and 24 to their
melting points, wherein heating physically and mechanically couples
ends 21 and 24 to form mechanically strong heat seals 26 and
27.
[0116] FIG. 4 depicts the apparatus 20, after forming serrated
perforations 33 and 34 in the plug 22 using a crimping tool or
other appropriate device for forming serrated perforations 33 and
34. The serrated perforations 33 and 34 weaken the heat seals 21
and 24 so that they become mechanically less strong, resulting in a
tear line for removal of the plug 22 by the patient seeking to
apply the pharmaceutically acceptable nitrogen mustard.HCl to a
diseased area or area for treatment. In one embodiment, a person
wishing to apply the pharmaceutically acceptable nitrogen
mustard.HCl to the diseased area or area for treatment may remove
plug 22 from the wall 31 of the apparatus 20, restoring the opening
30 in the wall 31 so squeezing or applying pressure to the wall 31
reduces the volume of the apparatus 20, resulting in the
pharmaceutically acceptable nitrogen mustard.HCl flowing outward
through opening 30 to be applied to the diseased area or area for
treatment.
[0117] In one embodiment, a concentration of the pharmaceutically
acceptable Nitrogen Mustard.HCl in the non-aqueous vehicle or
carrier that does not include petrolatum or ethanol in the
compartment 25 is from about 1 mg of Nitrogen Mustard.HCl per 100
ml of non-aqueous vehicle to about 2000 mg of Nitrogen Mustard.HCl
per 100 ml of non-aqueous vehicle. In another embodiment, a
concentration of the pharmaceutically acceptable Nitrogen
Mustard.HCl in the non-aqueous vehicle or carrier that does not
include petrolatum or ethanol is from about mg of Nitrogen
Mustard.HCl per 100 ml of non-aqueous vehicle or carrier that does
not include petrolatum or ethanol to about 40 mg of Nitrogen
Mustard.HCl per 100 ml of non-aqueous vehicle or carrier that does
not include petrolatum or ethanol. In another embodiment, a
concentration of the pharmaceutically acceptable Nitrogen
Mustard.HCl in the non-aqueous vehicle or carrier that does not
include petrolatum or ethanol is advantageously from about 15 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol to about 30 mg of
Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier
that does not include petrolatum or ethanol. An orifice or opening
30 may be made by forming an opening in the outer wall 31, through
which opening 30 this mixture of the Nitrogen Mustard is then
provided by prescription of a physician for treatment of the
patient.
[0118] The outer wall 31 of apparatus 20 is impermeable to the
mixture of step g) or step 9), supra, and/or the reconstituted
nitrogen mustard solutions. The wall 31 may be made from
elastomeric materials including ethylene/propylene copolymers,
ethylene/ethylacrylate copolymers, ethylene/vinyl acetate
copolymers, silicone elastomers, medical-grade
polydimethylsiloxanes, neoprene rubber, polyisobutylene,
chlorinated polyethylene, polyvinyl chloride, vinylchloride-vinyl
acetate copolymer, polymethacrylate polymer (hydrogel),
polyvinylidene chloride, poly(ethylene terephthalate), butyl
rubber, epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer,
ethylenevinyloxyethanol copolymer; silicone copolymers,
polysiloxane-polycarbonate copolymers,
polysiloxane-polyethyleneoxide copolymers,
polysiloxane-polymethacrylate copolymers,
polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene
copolymers polysiloxane-ethylene copolymers,
polysiloxane-alkylenesilane copolymers, polysiloxaneethylenesilane
copolymers, cellulose polymers, methyl cellulose, ethyl cellulose,
hydroxypropyl methyl cellulose, cellulose esters, polycarbonates,
polyesters, polytetrafluoroethylene, starches, gelatins, natural
gums, synthetic gums, and combinations thereof.
[0119] Clean-up
[0120] All vessels used in the process are placed in a 5% w/v
sodium bicarbonate-sodium thiosulfate aqueous bath. Contents are
left in the bath for 2 hours and then the washed. The bath is then
discarded by normal means. Note: Sodium Thiosulfate reacts with
nitrogen mustard to create an innocuous, safe mixture that can be
discarded by normal means.
[0121] Batches of dispersions of nitrogen mustard were compounded
by a pharmacist and included the following components listed in
Table 4 (below):
TABLE-US-00004 TABLE 4 Nitrogen Mustard Dispersion Material Name
Manufacturer/Supplier Hydroxypropyl Cellulose, MXF Hercules
Incorporated (Wilmington, DE) Edetate Disodium Dihydrate, USP
Spectrum Chemicals (New Brunswick, NJ) Menthol, USP Spectrum
Chemicals Butylated Hydroxytoluene, USP Spectrum Chemicals
2-(2-ethoxyethoxy) ethanol Gattefosse (SAINT PRIEST,
(pharmaceutical grade) Cedex, France) Absolute alcohol, USP
Spectrum Chemicals Propylene Glycol, USP Spectrum Chemicals
Glycerin, USP Spectrum Chemicals Citric Acid, USP Spectrum
Chemicals Nitrogen Mustard + Sodium Merck & Co. (Whitehouse
Chloride (from the use of Mustargen .RTM.) Station, NJ)
[0122] A second formula comprised:
TABLE-US-00005 TABLE 5 Nitrogen Mustard Dispersion. Quality
Component Standard Function Mechlorethamine Hydrochloride USP
Active Pharmaceutical Ingredient Hydroxypropyl Cellulose NF
Thickening Agent Edetate Disodium, (Dihydrate) USP Chelating Agent
(DL) Menthol USP Cooling Agent Butylated Hydroxytoluene NF
Preservative Diethylene Glycol Monoethyl Ether NF Diluent
(2-(2-ethoxyethoxy) ethanol) Isopropyl Alcohol USP Wetting Agent
Propylene Glycol USP Solubilizer Glycerin USP Surfactant Lactic
Acid (Racemic) USP pH Adjuster Sodium Chloride USP Ion Releasing
Agent
Stability of Nitrogen Mustard (NM) Ointment Batches
[0123] Initial R&D batches of the NM ointment were produced to
assess the differences in alcohols used for diluting the NM.
Samples were tested at various temperature conditions (5, 25 and
40.degree. C.) and assessed for stability with use of an HPLC
assay.
[0124] Pilot batch 09-08-05 (.about.15% ethanol) yielded the
following results when tested for stability at 1, 2 and 3 weeks
post production (See Table #6).
TABLE-US-00006 TABLE 6 Label strength of pilot batch 09-08-05 over
time stored at various temperatures. Day of assessment Storage
Temperature Label Strength (%) 7 5.degree. C. 96.36 25.degree. C.
81.37 40.degree. C. 20.50 14 5.degree. C. 92.94 25.degree. C. 68.44
40.degree. C. 1.26 21 5.degree. C. 92.83 25.degree. C. 58.85
40.degree. C. -2.22
[0125] Pilot batch 10-05-05 (.about.15% isopropanol) yielded the
following results when tested for stability at 10, 15 and 20 days
post production (Table #7).
TABLE-US-00007 TABLE 7 Label strength of pilot batch 10-05-05 over
time stored at various temperatures. Label Day of assessment
Storage Temperature Strength (%) 10 5.degree. C. 99.54 25.degree.
C. 98.42 40.degree. C. 79.25 15 5.degree. C. 99.11 25.degree. C.
95.75 40.degree. C. 72.91 20 5.degree. C. 96.89 25.degree. C. 93.07
40.degree. C. 67.48
[0126] The inventors report that after 18 months of storage at
ambient temperature, i.e., between about 200 and about 25.degree.
C., there was +/-20% or less loss of the active Mechlorethamine
Hydrochloride based on the formulation in Table 5, supra.
[0127] The following data revealed that Ethanol caused significant
degradation of the NM, where isopropyl alcohol did not. The
formulation was changed to reflect these differences (See Table 5
(above).
pH Effects
[0128] In addition to the above work to optimize the solvent used
for solubilizing the NM, work was performed to assess the
stabilizing effects of pH on the NM degradation. The following
graph, FIG. 5 shows the time course of NM decomposition in
different solutions. FIG. 5 shows NM decomposes much faster in pH
7.0 buffer, its half-life in this solution is about 2 hours, and
FIG. 5 shows NM decomposes totally after 28 hours. FIG. 5 shows NM
decomposes faster in higher pH solutions and inorganic salts can
accelerate its decomposition too.
[0129] In one embodiment, dispersions of pharmaceutically
acceptable alkylating agents are dispersed in a pharmaceutically
acceptable excipient, e.g., 2-(2-ethoxyethoxy)ethanol (diethylene
glycol monoethyl ether) (structure XX, infra). The term
"pharmaceutically acceptable" refers to those properties and/or
substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[0130] The dispersed pharmaceutically acceptable alkylating agents
in 2-(2-ethoxyethoxy)ethanol (diethylene glycol monoethyl ether)
(structure XX, infra) may be used in the preparation of dispersed
systems and other pharmaceutical formulations, and for the storage,
transport and dispensing of said dispersions in a stabilized form.
Hereinafter, "stabilized" is defined as dispersing the
pharmaceutically acceptable alkylating agent in a pharmaceutically
acceptable excipient so that the pharmaceutically acceptable
alkylating agent undergoes hydrolysis or nucleophilic attack from
natural nucleophiles such as water in the environment at a lower
rate, compared to the rate that the neat pharmaceutically
acceptable alkylating agent undergoes hydrolysis or nucleophilic
attack from natural nucleophiles such as water in the environment.
Structure XX. Structure of 2-(2-ethoxyethoxy)ethanol.
##STR00016##
[0131] The physical, stability, transport and storage
characteristics of the dispersions are significantly different than
those of the corresponding pharmaceutically acceptable alkylating
agents themselves. These useful characteristics facilitate
formulation and production operations and rapid achievement of
pharmaceutically acceptable alkylating agent homogeneity in
dispersed system products during their manufacture, while
simultaneously reducing the potential for airborne and workplace
contamination and personnel exposure to the pharmaceutically
acceptable alkylating agents.
[0132] The pharmaceutically acceptable alkylating agents remain
stable in the dispersions across a wide range of temperatures, both
in storage and when in use as formulation aids, without requiring
the use of antioxidants or other stabilizing agents. These
dispersions have utility in imparting desirable physical,
stability, transport, storage and dispensing properties otherwise
not achievable with the pharmaceutically acceptable alkylating
agents themselves.
[0133] Such dispersions have a number of uses and applications,
such as formulation aids and as concentrated sources of
pharmaceutically acceptable alkylating agents for dilution and
incorporation into a variety of dispersed systems and
pharmaceutical products.
[0134] The invention is directed to the preparation of a dispersion
of an alkylating agent or agents in 2-(2-ethoxyethoxy)ethanol by
forming a dispersion, such as a paste, a coarse dispersion, a
suspension, a colloid, a molecular dispersion, or a solution of an
alkylating agent using 2-(2-ethoxyethoxy)ethanol as the continuous
phase.
[0135] Such a dispersion may be prepared by mixing one or more
alkylating agents with 2-(2-ethoxyethoxy)ethanol. Said mixing may
be accomplished by various means, including flocculation, wetting,
levigation, trituration, stirring, blending, homogenizing,
sonication, injection, countercurrent exchange, impinging jet
mixing, expansion of a supercritical fluid, and milling.
Hereinafter, "levigation" is defined as the grinding to a powder of
a moist or hard substance, or the mixing of a solid or particulate
substance together with a solvating or wetting agent, thereby
intimately mixing or coating the solid or particulate with the
solvating or wetting agent.
[0136] The invention is also directed to the use of such a
dispersion as a formulation aid, and as a means of storing,
transporting and dispensing discrete quantities of an alkylating
agent for use in pharmaceutical formulations and other preparations
in the form of a dispersion in 2-(2-ethoxyethoxy)ethanol.
[0137] As a formulation aid, such a dispersion serves as a
pre-solvated, pre-dispersed form of an alkylating agent for ready
dispersion and homogeneous mixing into a pharmaceutical formulation
or other preparation, such as a solution, a suspension, an
ointment, a cream, a lotion, a plaster, a spray, a colloid and a
paste. Such a pre-dispersed form of an alkylating agent, already
de-gassed and solvated, facilitates homogeneous mixing into such
dosage forms while minimizing or eliminating clumping,
flocculation, agglomeration, sticking and caking of alkylating
agents.
[0138] Such a dispersion might be stored in any suitable container,
such as a jar, a bottle, a flask, a bag, a collapsible bag, a
bladder, a syringe, a collapsible tube and a drum. Said container
might also have an appropriate dispensing port, such as a mouth, a
spigot, a valve, a syringe port, and a pump. Said container might
also be pressurized, or be charged by or attached to an inert gas
source, such as dry nitrogen or helium, in order to further
maintain stability of the dispersion and replace the dispensed
volume of the dispersion with inert gas.
[0139] Mechlorethamine hydrochloride (hereinafter MCHCl) is an
alkylating nitrogen mustard employed systemically as a cytotoxic
agent for the treatment of cancer and other conditions. MCHCl is
also employed topically for the treatment of psoriasis and other
dermatological conditions.
[0140] MCHCl is an unstable compound, and rapidly degrades to
inactive products in the presence of base, water and many
pharmaceutical excipients, including alcohols such as ethanol and
isopropanol. As such, most MCHCl topical formulations currently
employed for the treatment of dermatological conditions are
composed of MCHCl dispersed in hydrophobic excipients, such as
petrolatum, mineral oil and other lipophilic substances. These
products tend to be stiff, have a high skin drag, and leave an
adhesive, greasy layer on the skin that may also stain clothing or
rub off on others, characteristics not generally acceptable to
patients.
[0141] Formulation of these products is generally accomplished by
mixing MCHCl powder directly into these viscous substances. Thus,
the homogeneous incorporation and distribution of the dry powder
into the oleaginous vehicle is complicated by clumping, sticking
and caking of the dry powder in the vehicle, thereby requiring
extensive mixing and homogenizing, as well as levigation and
wetting agents not necessarily desirable in the final product. In
addition, current formulation methods require repeated handling of
the highly poisonous MCHCl powder, which is easily swept up and
dispersed in the air, thereby posing a serious contamination risk
for both personnel and the manufacturing facility.
[0142] Alternative topical formulations employing less lipophilic
and amphipathic excipients have been explored. These excipients
include 2-(2-ethoxyethoxy)ethanol (FIG. 1), marketed under various
trade names, including 2-(2-ethoxyethoxy)ethanol and diethylene
glycol monoethyl ether. Although 2-(2-ethoxyethoxy)ethanol has
served as an effective vehicle for many drugs, it is a primary
alcohol, and many commercial forms of this excipient contain
significant amounts of water and other potentially nucleophilic and
solvolytic impurities, including the primary alcohols
2-methoxyethanol and 2-ethoxyethanol.
[0143] The inventors report, however, that MCHCl may be dispersed
in 2-(2-ethoxyethoxy)ethanol across a wide range of concentrations
while remaining stable for extended periods of time across a wide
temperature range, even though 2-(2ethoxyethoxy)ethanol is a
primary alcohol. MCHCl remains stable when dispersed in commercial
2-(2-ethoxyethoxy)ethanol containing 0.1% w/w or more of water,
which generally promotes solvolysis of this nitrogen mustard. The
inclusion of stabilizing agents, such lactic acid or sodium
chloride, has no significant effect on nitrogen mustard stability
in the dispersion, and is not necessary for preparing a stable
dispersion. Notably, MCHCl remains completely stable when dispersed
in 2-(2-ethoxyethoxy)ethanol for over three months at room
temperature. Significant degradation of MCHCl in the dispersion is
only noted at elevated temperatures. Indeed, less than ten percent
of the MCHCl in such a dispersion degraded after storage at
temperature as high as 80 degrees Celsius for an entire week.
[0144] That MCHCl remains stable in the presence of primary
alcohols and water, and without stabilizers, preservatives or
cooling, is particularly surprising, as it is known that MCHCl
readily undergoes rapid solvolysis and nucleophilic substitution
when in contact with many primary alcohols, water and mixtures
thereof. This unexpected result, wherein MCHCl, known to be readily
degraded in the presence of water and primary alcohols, and at
elevated temperatures, remained stable in a
2-(2-ethoxyethoxy)ethanol dispersion for long periods of time at
practical working temperatures, is neither obvious nor predictable,
and underscores the novelty and utility of such a dispersion and
its applications and uses. Indeed, since the pKa of
2-(2-ethoxyethoxy)ethanol and the alkoxy alcohol impurities in
2-(2-ethoxyethoxy)ethanol is lower than that of ethanol, they are
theoretically even more nucleophilic than ethanol. Nevertheless,
MCHCl, normally labile when exposed to such compounds, is quite
stable in this dispersion.
[0145] In one embodiment, dispersing an alkylating agent or agents
in 2-(2-ethoxyethoxy)ethanol may be a convenient means of storing,
handling and dispensing an alkylating agent in the form of said
dispersion, and as a formulation aid.
[0146] In one embodiment, providing a dispersion, where the type of
dispersion so prepared and used is versatile, depending upon its
contemplated use, and is selected from the group comprising a
paste, a coarse dispersion, a colloidal dispersion, a molecular
dispersion, a suspension, and a solution.
[0147] In one embodiment, providing a dispersion, wherein the
concentration of the alkylating agent or agents dispersed in
2-(2-ethoxyethoxy)ethanol is readily adjustable, depending upon the
amount of alkylating agent or agents desired, or the concentration
of dispersion desired, and ranges between about 0.01% w/w and about
50% w/w.
[0148] In one embodiment, the alkylating agent is selected from the
group comprising a nitrogen mustard, a sulfur mustard, Lewisite, an
alkyl sulfonate, an ethyleneimine, a nitrosourea, a triazene, an
imidazotetrazine, mechlorethamine, chlorambucil, cyclophosphamide,
4-hydroxycyclophosphamide, aldophosphamide, ifosfamide, melphalan,
bis-(2-chloroethyl)ethylamine, tris-(2-chloroethyl)ethylamine,
carmustine, fotemustine, lomustine, streptozocin, busulfan,
dacarbazine, procarbazine, temozolomide, treosulfan, uramustine,
hexamethylmelamine, thiotepa, tepa, and pharmaceutically acceptable
salts, solvates and polymorphs thereof, and mixtures thereof, and
the alkylating agent is provided in a dispersion of an alkylating
agent or agents dispersed in 2-(2-ethoxyethoxy)ethanol.
"Polymorphism" is defined in materials science is the ability of a
solid material such as the pharmaceutically acceptable salts or
solvates of MCHCl to exist in more than one form or crystal
structure.
[0149] In one embodiment, an alkylating agent or agents dispersed
in 2-(2-ethoxyethoxy)ethanol is provided for use as a formulation
aid, where said formulation aid is employed as a dispersion of a
pharmaceutically acceptable alkylating agent or mixture of
alkylating agents for subsequent dispersion and dilution into a
bulk pharmaceutical product during the formulation and manufacture
of said product.
[0150] In one embodiment, the dispersion of an alkylating agent or
agents serves as a means of storing, transporting and dispensing a
dispersion of a pharmaceutically acceptable alkylating agent while
maintaining the stability of the pharmaceutically acceptable
alkylating agent for a period of time and across a range of
temperatures. Said period of time ranges between about 1 day and
about 3 years, and said temperature range is between about minus 80
degrees Celsius and about plus 60 degrees Celsius.
[0151] The invention will now be discussed by way of certain
examples, which illustrate, but in no way limit, the invention.
Example 3
Preparation of a Representative Dispersion
[0152] Mechlorethamine HCl (MCHCl) is readily dispersed in
2-(2-ethoxyethoxy)ethanol by deposing dry MCHCl powder into a
suitable container, such as a flask, a vial or a bottle, adding
2-(2-ethoxy ethoxy)ethanol, and dispersing the MCHCl by mixing,
such as by stirring, sonicating or shaking.
[0153] Accordingly, a 0.5% w/w solution of MCHCl dissolved in
2-(2-ethoxyethoxy)ethanol is readily prepared by placing 25 mg of
MCHCl powder in a 25 mL glass vial, adding 4.975 grams of
2-(2-ethoxyethoxy)ethanol, and stirring gently for 1 hour.
[0154] Equilibrium solubility experiments revealed that the
solubility of MCHCl in 2-(2-ethoxyethoxy)ethanol is approximately
1.6% w/w.
Example 4
Stability of Mechlorethamine HCL Dissolved in
2-(2-Ethoxyethoxy)Ethanol at Various Temperatures
[0155] A 0.5% w/w solution of MCHCl dissolved in
2-(2-ethoxyethoxy)ethanol was prepared, and aliquot parts were
stored at various temperatures in glass vials sealed from the
atmosphere, and tested for stability over time.
[0156] The results of these stability studies are presented in
Tables 8 and 9, infra. Table 8 reveals that the inclusion of the
stabilizing agents sodium chloride, lactic acid or both do not
affect MCHCl stability in 2-(2-ethoxyethoxy)ethanol. Thus, simple
dispersions of MCHCl in 2-(2-ethoxyethoxy)ethanol are stable
without need of additional excipients and stabilizers, and would
serve as useful formulation aids.
[0157] Table 9 reveals that, even at elevated temperatures, MCHCl
remains stable in 2-(2-ethoxyethoxy)ethanol for significant periods
of time, even at temperatures as high as 80 degrees Celsius for 1
week. This further underscores the utility and versatility of the
unexpected observation that these simple dispersions of MCHCl in
2-(2-ethoxyethoxy)ethanol are stable and versatile formulation aids
while facilitating the storage, transport and dispensing of such
alkylating agents in dispersion.
TABLE-US-00008 TABLE 8 Stability of mechlorethamine HCl dissolved
in neat 2-(2-ethoxyethoxy) ethanol and in 2-(2-ethoxyethoxy)
ethanol containing the stabilizing agents sodium chloride, lactic
acid or both, stored at room temperature for three weeks.
Percentage undegraded nitrogen mustard (MCHCl) Remaining in samples
stored at ~25.degree. C. (mean .+-. SD) 0.5% 0.5% MCHCl in 2- 0.5%
MCHCl 0.5% MCHCl in MCHCl in 2- (2- in 2-(2- 2-(2-ethoxy- Time (2-
ethoxyethoxy) ethoxyethoxy) ethoxy)ethanol + Sample in
ethoxyethoxy) ethanol + ethanol + NaCl + Number Weeks ethanol NaCl
Lactic Acid Lactic Acid 1 Zero 102.31 .+-. 0.71 100.43 .+-. 0.29
98.40 .+-. 1.58 102.61 .+-. 0.53 2 One 97.31 .+-. 0.38 99.05 .+-.
0.24 103.68 .+-. 0.14 101.11 .+-. 0.15 3 Two 102.94 .+-. 1.21 99.39
.+-. 0.52 103.57 .+-. 0.19 104.72 .+-. 0.07 4 Three 97.43 .+-. 0.06
97.38 .+-. 0.04 95.25 .+-. 0.11 103.96 .+-. 0.41 5 Four 103 .+-.
2.65 100.79 .+-. 0.37 100.55 .+-. 0.10 101.33 .+-. 0.10 6 Five
99.59 .+-. 0.05 97.23 .+-. 0.31 99.98 .+-. 0.06 104.65 .+-. 0.27 7
Six 100.03 .+-. 0.87 97.11 .+-. 2.56 97.08 .+-. 1.87 100.75 .+-.
5.38 8 Seven 100.15 .+-. 5.56 96.19 .+-. 2.75 96.74 .+-. 1.58 99.07
.+-. 3.98 9 Eight 98.68 .+-. 5.04 92.18 .+-. 1.45 95.49 .+-. 3.46
96.09 .+-. 3.65
TABLE-US-00009 TABLE 9 Stability of MCHCl dispersed in
2-(2-ethoxyethoxy) ethanol at elevated temperatures over time.
Percentage undegraded MCHCl Remaining in samples stored at elevated
temperature (mean .+-. SD) MCHCl in 2-(2-ethoxy- MCHCl in
2-(2-ethoxy- Sample ethoxy) ethanol at 60.degree. C. ethoxy)
ethanol at 80.degree. C. Number (Percentage .+-. SD) (Percentage
.+-. SD) Time in Days 1 Zero 100.76 .+-. 0.91 103.13 .+-. 0.86 2
One 99.63 .+-. 3.66 97.20 .+-. 6.38 3 Two 98.79 .+-. 2.03 95.85
.+-. 3.45 4 Three 96.90 .+-. 4.9 92.98 .+-. 1.32 Time in Weeks 5
One 92.04 .+-. 4.06 90.66 .+-. 4.80 6 Two 78.99 .+-. 0.99 75.73
.+-. 2.96 7 Three 73.44 .+-. 4.91 65.36 .+-. 5.51 8 Four 67.99 .+-.
3.96 58.94 .+-. 4.96
[0158] FIG. 6 depicts a Log-linear plot of the stability of MCHCl
in 2-(2-ethoxyethoxy)ethanol 2-(2-ethoxyethoxy)ethanol at various
temperatures over time.
[0159] In one embodiment, a dispersion, comprising: at least one
alkylating agent(s) dispersed in a solvent consisting essentially
of 2-(2-ethoxyethoxy)ethanol.
[0160] In one embodiment, the dispersion is selected from the group
consisting of a paste, a coarse dispersion, a colloidal dispersion,
a molecular dispersion, a suspension, and a solution.
[0161] In one embodiment, a concentration of the at least one
alkylating agent(s) dispersed in the 2-(2-ethoxyethoxy)ethanol
ranges from about 0.01% w/w to about 50% w/w.
[0162] In one embodiment, the alkylating agent or agents are
selected from the group consisting of a nitrogen mustard, a sulfur
mustard, Lewisite, an alkyl sulfonate, an ethyleneimine, a
nitrosourea, a triazene, an imidazotetrazine, mechlorethamine,
chlorambucil, cyclophosphamide, 4-hydroxycyclophosphamide,
aldophosphamide, ifosfamide, melphalan, bis-(2-chloroethyl)
ethylamine, tris-(2-chloroethyl)ethylamine, carmustine,
fotemustine, lomustine, streptozocin, busulfan, dacarbazine,
procarbazine, temozolomide, treosulfan, uramustine,
hexamethylmelamine, thiotepa, tepa, and pharmaceutically acceptable
salts, solvates, polymorphs, thereof, and combinations thereof.
[0163] In one embodiment, the dispersion of a pharmaceutically
acceptable alkylating agent or agents for subsequent dispersion and
dilution is dispersed and diluted into a bulk pharmaceutical
product during the formulation and manufacture of the latter.
[0164] In one embodiment, the dispersion functions as a means of
storing and transporting a dispersion of an at least one
pharmaceutically acceptable alkylating agent(s) in liquid form
while maintaining the stability of the at least one
pharmaceutically acceptable alkylating agent(s) for a period of
time and across a range of temperatures.
[0165] In one embodiment the period of time the dispersion of the
at least one pharmaceutically acceptable alkylating agent(s) in
liquid form is stable ranges between about 1 day and about 3
years.
[0166] In one embodiment, the temperature range the dispersion of
the at least one pharmaceutically acceptable alkylating agent(s) in
liquid form is stable ranges between about minus 80 degrees Celsius
and about plus 60 degrees Celsius.
[0167] In one embodiment, a method of stabilizing at least one
alkylating agent(s), comprising: dispersing the at least one
alkylating agent(s) in a solvent consisting essentially of
2-(2-ethoxyethoxy)ethanol.
[0168] In one embodiment, a method of formulating a pharmaceutical
product, a component of which is an at least one hydrolytically
unstable alkylating agent(s), comprising: providing a formulation
aid, wherein said formulation aid is a pre-solvated or
pre-dispersed form of the alkylating agent; and dispersing the
formulation aid into a pharmaceutical formulation or other
preparation, wherein the formulation aid and the pharmaceutical
formulation are substantially homogeneous.
[0169] In one embodiment, a dispersion, comprising: between about
0.001% and about 2.0% by weight of an alkylating agent, or
pharmaceutically acceptable salts or solvates thereof, and between
about 15% and about 60% by weight of a pharmaceutically acceptable
excipient. The pharmaceutically acceptable excipient may be
2-(2-ethoxyethoxy)ethanol. The alkylating agent may be MCHCl.
[0170] In one embodiment, a method for treating a person with a
skin disorder, comprising: topically applying a dispersion to the
affected skin, wherein the dispersion comprises between about
0.001% and about 2.0% by weight of an alkylating agent, or
pharmaceutically acceptable salts or solvates thereof, and between
about 15% and about 60% by weight of a pharmaceutically acceptable
excipient. The pharmaceutically acceptable excipient may be
2-(2-ethoxyethoxy)ethanol. The alkylating agent may be MCHCl.
[0171] In one embodiment, a method for stabilizing a volatile
alkylating agent, comprising: dispersing between about 0.001% and
about 2.0% by weight of an alkylating agent, or pharmaceutically
acceptable salts or solvates thereof and between about 15% and
about 60% by weight of a pharmaceutically acceptable excipient. The
pharmaceutically acceptable excipient may be
2-(2-ethoxyethoxy)ethanol. The alkylating agent may be MCHCl.
[0172] In one embodiment, a method for stabilizing a nitrogen
mustard or pharmaceutically acceptable HX salt of the nitrogen
mustard, comprising dispersing the nitrogen mustard or
pharmaceutically acceptable HX salt of the nitrogen mustard in
between about 0.001% and about 2.0% by weight of an alkylating
agent, or pharmaceutically acceptable salts or solvates thereof and
between about 15% and about 60% by weight of a pharmaceutically
acceptable excipient. The pharmaceutically acceptable excipient may
be 2-(2-ethoxyethoxy)ethanol. The alkylating agent may be
MCHCl.
[0173] In one embodiment, a method of treating vitiligo, comprising
administering a dispersion to a person in need thereof, wherein the
dispersion comprises between about 0.001% and about 2.0% by weight
of an alkylating agent, or pharmaceutically acceptable salts or
solvates thereof and between about 15% and about 60% by weight of a
pharmaceutically acceptable excipient. The pharmaceutically
acceptable excipient may be 2-(2-ethoxyethoxy)ethanol. The
alkylating agent may be MCHCl.
[0174] In one embodiment, a method of formulating a pharmaceutical
product, a component of which is an at least one hydrolytically
unstable alkylating agent(s), comprising: providing a formulation
aid, wherein said formulation aid is a pre-solvated or
pre-dispersed form of the alkylating agent; and dispersing the
formulation aid into a pharmaceutical formulation or other
preparation, wherein the formulation aid and the pharmaceutical
formulation are substantially homogeneous.
[0175] In one embodiment, a composition for treating a skin
disorder, comprising: a Nitrogen Mustard or an HX salt of the
Nitrogen Mustard, wherein the Nitrogen Mustard or the HX salt of
the Nitrogen Mustard is in a non-aqueous vehicle or carrier,
wherein the non-aqueous vehicle or carrier comprises between about
15% and about 60% by weight of a pharmaceutically acceptable
excipient, wherein the Nitrogen Mustard is represented by the
following structures:
##STR00017##
[0176] wherein each R.sub.1, R.sub.2, R.sub.3 . . . R.sub.34
(R.sub.1-R.sub.34) is independently selected from the group
consisting of H, linear alkyl group having 1-6 carbon atoms, a
branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group. The pharmaceutically acceptable
excipient may be 2-(2-ethoxyethoxy)ethanol. The alkylating agent
may be MCHCl.
[0177] In one embodiment, a method for treating a skin disorder,
comprising: administering to a person in need thereof a
composition, comprising: a Nitrogen Mustard or an HX salt of the
Nitrogen Mustard, wherein the Nitrogen Mustard or the HX salt of
the Nitrogen Mustard is in a non-aqueous vehicle or carrier,
wherein the non-aqueous vehicle or carrier comprises between about
15% and about 60% by weight of a pharmaceutically acceptable
excipient, wherein the Nitrogen Mustard is represented by the
following structures:
##STR00018##
[0178] wherein each R.sub.1, R.sub.2, R.sub.3 . . . R.sub.34
(R.sub.1-R.sub.34) is independently selected from the group
consisting of H, linear alkyl group having 1-6 carbon atoms, a
branched alkyl group having 2-12 carbon atoms, a cycloalkyl group
having 3-17 carbon atoms, a fluorinated linear alkyl group having
2-12 carbon atoms, a fluorinated branched alkyl group having 2-12
carbon atoms, and a fluorinated cycloalkyl group having 3-17 carbon
atoms, aryl groups, aralkyl groups, alkaryl groups, cycloalkyl
groups, bicycloalkyl groups, alkenyl groups, alkalkenyl groups, and
alkenylalkyl groups, alkynyl groups, alkalkynyl groups,
alkynylalkyl groups, trifluoropropyl groups, cyanopropyl groups,
acryloyl groups, arylacryloyl groups, acryloylaryl groups,
alkylacyl groups, arylacyl groups alkylenylacyl groups and
alkynylacyl groups, wherein n is 1, 2, . . . 3, wherein p is 0, 1,
. . . 2, wherein n+p.ltoreq.3, and wherein any two R.sub.1-R.sub.34
in the same molecule may be linked to form a three- to
eight-membered cyclic group. The pharmaceutically acceptable
excipient may be 2-(2-ethoxyethoxy)ethanol. The alkylating agent
may be MCHCl.
[0179] The foregoing description of the embodiments of this
invention has been presented for purposes of illustration and
description. It is not intended to be exhaustive or to limit the
invention to the precise form disclosed, and obviously, many
modifications and variations are possible.
* * * * *