COMPOSITION ET PROCEDE DE PREVENTION ET DE TRAITEMENT DES REACTIONS RETARDEES D'HYPERSENSIBILITE CUTANEE

COMPOSITION AND PROCESS FOR PREVENTION AND TREATMENT OF CUTANEOUS DELAYED HYPERSENSITIVITY REACTIONS

Abrégé français

Ce procédé et cette composition pharmaceutique préviennent et traitent les réactions retardées (de type IV A) d'hypersensibilité cutanée. Cette composition comprend un composé à base de chromone, correspondant à la formule (I), ou un de ses sels, esters ou amides pharmacologiquement acceptables, dissous ou en dispersion dans un excipient pharmacologiquement acceptable. Selon le procédé, on administre localement une quantité préventive ou curative efficace de cette composition à l'endroit du corps d'une personne nécessitant un tel traitement, c'est-à-dire dans la zone vulnérable à une exposition à l'antigène, ou dans celle d'une réaction cutanée de type IV A.

Abrégé anglais

A process and pharmaceutical composition for prevention and treatment of
cutaneous delayed (Type IV A) hypersensitivity reactions in humans is
disclosed. The pharmaceutical composition comprises a chromone compound of
formula (I), or a pharmacologically acceptable salt, ester or amide thereof,
dissolved or dispersed in a pharmacologically acceptable carrier. In
accordance with the process, a preventively or therapeutically effective
amount of the composition is topically administered to the site of a human
patient regarding such treatment, i.e. the area susceptible to exposure to
antigen or the site of a cutaneous Type IV A reaction.

Revendications

- 27 -
Claim:
1. A process for treatment of cutaneous
delayed hypersensitivity reactions in humans comprising
topically administering to the reaction site of said
human a composition of a pharmacologically acceptable
carrier having dissolved or dispersed therein a
therapeutically effective amount of a substituted
chromone compound or a pharmacologically acceptable
salt, ester or amide thereof, said chromone compound
having a structure represented by the formula:
<IMG> I
wherein
(a) R1 R2 R3 R4, R5, and R6 can each be the
same, or different, and each R group is selected from
the group consisting of hydrogen, a halo group, a C1-C6
lower alkyl group, hydroxyl, C1-C6 lower alkoxy,
substituted C1-C6 lower alkoxy group, and a substituted
C1-C6 lower alkyl, where the substituent is selected
from the group consisting of a hydroxyl, a lower (C1-C6)
alkoxy group, a carboxy group, a halo group, a lower
alkenyl group, a benzyl group and nitro group;
(b) the X group can be a straight or
branched, saturated or unsaturated hydrocarbon chain
having between 3 and 10 carbon atom, whose hydrocarbon
chain can be interrupted by a substituent selected from
the group consisting of oxygen, a carbonyl group, a
carbocyclic or heterocyclic ring and can contain a

- 28 -
substituent selected from the group consisting of a halo
group, a hydroxyl group, and a C1-C6 lower alkoxy group.
2. The process of claim 1 wherein no more
than one of said R1, R2 and R3 and no more than one of
said R4, R5 and R6 is other than hydrogen wherein each
said R1-R6 is unsubstituted; and wherein X is a straight
or branched hydrocarbon chain that contains 3-7 carbon
atoms.
3. The process of claim 1 wherein each of
said R1, R2, R3, R4, R5, and R6 is hydrogen and said
carboxyl groups are present as alkali metal carboxylate
salts.
4. The process of claim 3 wherein X is
is a polymethylene chain substituted by one or more
hydroxyl groups.
5. The process of claim 1 wherein said
carrier contains a penetration enhancer to aid in
absorption by the skin of said substituted chromone
compound.
6. The process of claim 1 wherein said
administration is repeated a plurality of times.
7. A process for treatment of cutaneous
delayed hypersensitivity reactions in humans comprising
topically administering a therapeutically effective
amount of the compound, 1,3-bis(2-carboxychromon-5-
yloxy)-2-hydroxypropane, or a pharmacologically
acceptable salt, ester or amide thereof, dissolved or
dispersed in a pharmacologically acceptable carrier to
the reaction site of said human.
8. The process of claim 7 wherein said
compound is administered in an amount of about 40 to
about 1200 milligrams per day.

- 29 -
9. The process of claim 7 wherein said
administration is repeated a plurality of times.
10. The process of claim 7 wherein said
compound is administered in an amount of about 100 to
about 500 milligrams per day.
11. The process of claim 7 wherein said
carrier contains a penetration enhancer to aid in
absorption, by the skin, of said compound.
12. A pharmaceutical composition used for the
treatment of cutaneous delayed hypersensitivity
reactions comprising a therapeutically effective amount
the compound 1,3-bis-(2 carboxychromon-5-yloxy)-2-
hydroxypropane, or a pharmacologically acceptable salt,
ester or amide thereof as the active ingredient
dissolved or dispersed in a pharmacologically acceptable
carrier.
13. The composition of claim 12, wherein the
pharmacologically acceptable carrier is an oil-in-water
emulsion comprised of:
(a) a water phase;
(b) an oil phase; and
(c) emulsifier.
14. The composition claim 13 wherein the pH
value is of said oil-in-water emulsion is between about
3 and about 8.
15. The composition of claim 13 wherein said
oil phase comprises a wax, squalene, a C2-C4 acyl
polypropyleneglycol C12-C18 alkyl ether with 2-4 PPG
groups per molecule and silicone oil.
16. The composition of claim 15, wherein said
wax is a mixture of white wax and emulsifying wax.
17. The composition of claim 13 wherein said
emulsifier is emulsifying wax and a mixture of a C2-C4

- 30 -
acyl polypropyleneglycol C12-C18 alkyl ether with 2-4 PPG
groups per molecule and a polyoxyethyleneglycol C14-C26
ether having an average of 8-12 groups per molecule
18. The composition of claim 17 wherein said
PPG molecule is PPG-2-myristyl ether propionate and said
PEG molecule is polyoxyethylene-10-oleyl ether.
19. The composition of claim 12, wherein the
pharmacologically acceptable carrier also includes a
penetration enhancer to aid in absorption by the skin of
said compound.
20. A process for prevention of cutaneous
delayed hypersensitivity reactions in humans comprising
topically administering to the area susceptible to
exposure to allergen of said human a composition of a
pharmacologically acceptable carrier having dissolved or
dispersed therein a therapeutically effective amount of
a substituted chromone compound or a pharmacologically
acceptable salt, ester or amide thereof, said chromone
compound having a structure represented by the formula:
<IMG> I
wherein
(a) R1, R2, R3, R4, R5, and R6 can each be the
same, or different, and each R group is selected from
the group consisting of hydrogen, a halo group, a C1-C6
lower alkyl group, hydroxyl, C1-C6 lower alkoxy,
substituted C1-C6 lower alkoxy group, and a substituted
C1-C6 lower alkyl, where the substituent is selected
from the group consisting of a hydroxyl, a lower (C1-C6)

- 31 -
alkoxy group, a carboxy group, a halo group, a lower
alkenyl group, a benzyl group and nitro group;
(b) the X group can be a straight or
branched, saturated or unsaturated hydrocarbon chain
having between 3 and 10 carbon atom, whose hydrocarbon
chain can be interrupted by a substituent selected from
the group consisting of oxygen, a carbonyl group, a
carbocyclic or heterocyclic ring and can contain a
substituent selected from the group consisting of a halo
group, a hydroxyl group, and a C1-C6 lower alkoxy group.
21. The process of claim 20 wherein no more
than one of said R1, R2 and R3 and no more than one of
said R4, R5 and R6 is other than hydrogen wherein each
said R1-R6 is unsubstituted; and wherein X is a straight
or branched hydrocarbon chain that contains 3-7 carbon
atoms.
22. The process of claim 20 wherein each of
said R1, R2, R3, R4, R5, and R6 is hydrogen and said
carboxyl groups are present as alkali metal carboxylate
salts.
23. The process of claim 22 wherein X is
is a polymethylene chain substituted by one or more
hydroxyl groups.
24. The process of claim 22 wherein said
administration is repeated a plurality of times.
25. The process of claim 20 wherein said
pharmacologically acceptable carrier includes a
penetration enhancer to aid in absorption of said
substituted chromone compound by the skin.
26. A process for prevention of cutaneous
delayed hypersensitivity reactions in humans comprising
topically administering a therapeutically effective
amount of the compound, 1,3-bis(2-carboxychromon-5-

- 32 -
yloxy)-2-hydroxypropane, or a pharmacologically
acceptable salt, ester or amide thereof, dissolved or
dispersed in a pharmacologically acceptable carrier to
the area of skin of said human susceptible to exposure
to antigen.
27. The process of claim 26 wherein said
compound is administered in an amount of about 40 to
about 1200 milligrams per day.
28. The process of claim 26 wherein said
administration is repeated a plurality of times.
29. The process of claim 26 wherein said
compound is administered in an amount of about 100 to
about 500 milligrams per day.
30. The process of claim 26 wherein said
pharmacologically acceptable carrier includes a
penetration enhancer to aid in absorption by the skin of
said compound.
31. A pharmaceutical composition used for the
prevention of delayed hypersensitivity reactions
comprising a therapeutically effective amount 1,3-bis-(2
carboxychromon-5-yloxy)-2- hydroxypropane, or a
pharmacologically acceptable salt, ester or amide
thereof as the active ingredient dissolved or dispersed
in a pharmacologically acceptable carrier.
32. The composition of claim 31, wherein the
pharmacologically acceptable carrier is an oil-in-water
emulsion comprised of:
(a) a water phase;
(b) an oil phase; and
(c) emulsifier.
33. The composition claim 32 wherein the pH
value is of said oil-in-water emulsion is between about
3 and about 8.

- 33 -
34. The composition of claim 32 wherein said
oil phase comprises a wax, squalene and silicone oil.
35. The composition of claim 34, wherein said
wax is a mixture of white wax and emulsifying wax.
36. The composition of claim 32 wherein said
emulsifier is a mixture of a C2-C4 acyl
polypropyleneglycol C12-C18 alkyl ether with 2-4 PPG
groups per molecule and a polyoxyethyleneglycol C14-C26
ether having an average of 8-12 groups per molecule
37. The composition of claim 36 wherein said
PPG molecule is PPG-2-myristyl ether propionate and said
PEG molecule is polyoxyethylene-10-oleyl ether.
38. The composition of claim 31, wherein the
pharmacologically acceptable carrier includes a
penetration enhancer to aid in absorption by the skin of
said compound.

Description

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COMPOSITION AND PROCESS FOR PR~v~NlION AND TREATMENT
OF CUTANEOUS DELAYED HYPERSENSITIVITY REACTIONS
Description
Technical Field
This invention relates to the prevention and
treatment of cutaneous delayed hypersensitivity
reactions such as those caused by exposure to poison ivy
and poison oak, and more particularly to a composition
and process for preventing and treating cutaneous
delayed hypersensitivity reactions that utilizes a
chromone compound of the general formula shown in
~ormula I, hereinafter, wherein Rl, R2, R3, R4, R5 and R6
i.e. Rl-R6 and X are defined hereinafter.
Backqround of Invention
A compound o~ ~ormula I, hereina~ter, and its
pharmacologically acceptable salts, esters and amides
has been used successfully in the prophylactic treatment
o~ asthma for many years. One particular compound,
commonly known as cromolyn, (~ormula II hereina~ter) is
routinely used as a prophylactic treatment for asthma,
rhinitis, conjunctivitis and intestinal mastocytosis.
These compounds do not alleviate the symptoms of asthma
once an attack has begun.
Cromolyn is not a bronchial or vaso dilator as
is usual for asthma treatments. Rather, cromolyn acts
to inhibit the release of inflammatory mediators such as
histamine ~rom several types of cells in the lungs.
Inhalation of a solution containing the disodium salt of
cromolyn, (cromolyn sodium), on a regular schedule by an
individual su~ering from asthma provides a prophylactic
treatment for bronchial asthma. The prophylactic
response increases with the length of use of the drug.

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A chromone compound corresponding to ~ormula I
and its pharmacologically acceptable salts, esters and
amides has also been reported to be e~ective against
certain atopic skin disorders such as atopic eczema and
various other chronic skin conditions that involve skin
mast cells and/or an antibody-antigen reaction.
(Sullivan U.S. Patent Nos. 4,362,742 and 4,271,182).
Skin conditions o~ the type discussed in
Sullivan et. al. (atopic dermatoses) are systemic skin
diseases that do not result ~rom exposure to an external
allergen, but rather are believed to have internal
causative ~actors. Outbreaks o~ atopic skin lesions
generally occur periodically throughout li~e, o~ten
beginning in early in~ancy. These conditions are also
known or suspected to have hereditary causation or
predisposition.
One common and e~ective treatment of the
lesions associated with atopic dermatitis is the topical
application o~ corticosteroids. Oral corticosteroids
are also given in severe cases. However, oral as well
as topical steroids should be given with care since
there is often a rebound reaction when the treatment is
stopped.
Topical antihistamines are not e~ective.
However, the itching caused by the lesions may be
relieved by large doses o~ antihistamines (~or example
diphenhydramine 50mg orally b.i.d. or q.i.d. ~or
adults).
Treatment o~ the lesions associated with
atopic dermatitis with a chromone compound corresponding
to ~ormula I or its pharmacologically acceptable salts,
esters or amides has been shown to ~acilitate healing o~
-

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the lesion being treated. However treatment does not
actually cure the disease itself.
Chromone compounds have also been shown to be
e~fective against certain allergic conditions o~ the
eye.
However, chromone compounds are not
predictably or uni~ormly absorbed by all types o~
tissues and the e~ectiveness o~ these compounds against
other conditions o~ the skin or epidermis is not
predictable.
The exact mechanism of action o~ a chromone
compound is unknown. A chromone compound is believed to
possess no vasodilator, antihistaminic or anti-
in~lammatory activity. It is known that a chromone
compound, and particularly cromolyn, is poorly absorbed
by the lungs and by the gastrointestinal tract. Only
about 7-8 percent o~ a usual total dose is absorbed ~rom
the lung, and is then rapidly excreted, unchanged, in
the bile or urine. The remainder is expelled ~rom the
nose or, if swallowed, excreted by the alimentary tract.
Delayed hypersensitivity reactions, also
called Type IV A reactions, occur between twenty-~our
(24) to seventy-two (72) hours a~ter exposure to a
soluble antigen. One example o~ a cutaneous Type IV A
reaction is contact hypersensitivity such as occurs
after exposure to poison ivy, poison oak, sumac and
other "poisonous" plants o~ this ~amily.
These plants contain irritating oils that act
as antigens when applied to the skin. The main
constituent o~ the irritating oil oE poison ivy is
urushiol.
The pathology o~ Type IV A reactions in
general involves interaction o~ the antigen with

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sensitized, lymphokine-secreting T lymphocytes. A
mononuclear cell infiltrate containing lymphocytes,
monocytes macrophages and a variable number of basophils
is generated. The Type IV A reaction is mediated by
l~phokirles, such as inte~-feron-~r (I~N- y~, that activate
monocytes and macrophages causing them to secrete
enzymes and other mediators. Those secreted substances
can cause tissue injury.
The delay before a reaction is observed is
needed for the body to accumulate monocytes at the
reaction site.
The physical characteristics of contact
hypersensitivity or a cutaneous Type IV A reaction, are
rash and inflammation at the point of contact, reddening
of skin (erythema), mild to severe pruritus, and
vesiculation. In more severe cases the inflammation can
be considered and accompanied by bulla formation. As
the reaction progresses the vesicles and bulla rupture
with oozing and crusting. As the inflammation subsides,
scaling and some thickening of the skin are seen.
If left untreated, most symptoms caused by
cutaneous Type IV A hypersensitivity reactions gradually
subside and then go away entirely. The time required
varies considerably from individual to individual.
Simple erythema can disappear in a few days; however, in
severe cases an untreated reaction may persists 2-3
weeks or longer if scratching has caused secondary
infection.
During the time the reaction and symptoms
persists, the individual is uncomfortable, often
intensely uncomfortable. If untreated, the affected

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area is ~requently scratched or rubbed raw. This action
can result in secondary in~ection at the site and
scarring in some instances.
Topical treatment ~or Type IV A cutaneous
reaction include application of corticosteroid lotions
and bland compresses. As crusting and scaling occur
bland greases, such as petrolatum, cold cream and
hydrophilic ointments are help~ul.
Antihistamines are not e~fective topically or
orally as histamines are not generally present.
In severe cases oral steroids (prednisone 20-
40mg orally ~or 4-5 days) may be given.
These remedies have ~on~trated varying
degrees o~ e~ectiveness.
Currently, prevention o~ a Type IV A reactions
requires avoidance o~ the antigen.
Although cutaneous Type IV A reactions are not
generally li~e-threatening or dehabilitating, they do
cause discom~ort and at certain times o~ the year can
occur quite o~ten. It would there~ore be advantageous
to be able to prevent and e~fectively treat these types
o~ reactions with a simple topically applied remedy.
Disclosure o~ one such remedy is as ~ollows.
Brie~ Summarv oE Invention
A process ~or preventing and/or treating a
cutaneous Type IV A hypersensitivity reaction
(hereina~ter re~erred to as a Type IV A reaction or a
cutaneous Type IV A reaction) is disclosed herein. The
compounds utilized ~or prevention and ~or treatment are
a the same. The process ~or application o~ the compounds
is highly similar. -For both prevention and treatment a
- composition containing a compound o~ ~ormula I,

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hereinafter, is topically administered. The area to
which the compound is applied and the amount of compound
applied can vary for a preventative application and a
therapeutic application of the composition, as explained
hereinafter.
A process for prevention of a cutaneous Type
IV A reaction utilizes topical application to the area
of skin susceptable to exposure to an antigen capable of
causing a Type IV A reaction (the area to be protected)
of a formulation containing a Type IV A reaction-
preventing amount of a chromone compound of formula I,
or a pharmacologically acceptable salt, ester or amide
thereof. The particularly preferred compound is
commonly referred to as cromolyn [1,3-bis(2-
carboxychromon-5-yloxy)-2-hydroxypropane] and is
represented in formula II, hereinafter.
It is found that a topical application of a
chromone compound of formula I can prevent the onset or
decrease the severity of a cutaneous Type IV A
hypersensitivity reaction.
A process for treatment of a cutaneous Type
IV A reaction utilizes topical administration of a
formulation containing a symptom-reducing amount of a
chromone compound of formula I, or a pharmacologically
acceptable salt, ester or amide thereof. The
particularly preferred compound is commonly referred to
as cromolyn [1,3-bis(2-carboxychromon-5-yloxy)-2-
hydroxypropane] and is represented in formula II,
hereinafter.
It is found that topical treatment with a
chromone compound of formula I reduces the inflammation
of the reaction site and lessens or eliminates the
pruritus associated with the reaction. This process of

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treatment result~ in early resolution of a Type IV A
reaction and the accompanying symptoms with no known
side effects.
A chromone compound utilized in the present
processes as the active agent for both prevention and
treatment and hereinafter referred to as the "active
agent" or "active ingredient", conforms to the structure
of formula I, below, and includes pharmacologically
acceptable salts, esters and amides thereof where Rl,
R2, R3, R4, R5 and R6; i. e. Rl-R6 and X are further
defined hereinafter.
~, O--X--O ,~
The molecule of formula I can be generally
described as two chromone molecules linked by an O-X-O
chain. In the above formula, and in all other formulas
shown herein, hydrogen atoms that are not needed to show
conformation about a particular bond are not shown.
Although Rl-R6 can vary as fully described
hereinafter, in general, it is preferred that no more
than one of Rl, R2 and R3 and no more than one of R4, R5
and R6 is other than hydrogen, and each is selected from
a hydrogen, a halogen atom, a Cl-C6 alkyl, hydroxy, Cl-C6
ulcus or substituted ulcus group, and X is as defined
hereinafter. More preferred compounds of formula I are
those in which each of Rl-R6 is hydrogen, and the

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carboxyl groups are present as alkali metal carboxylate
salts.
The X group is preferably a straight or
branched hydrocarbon chain containing 3 to 7 carbon
atoms. The chain can be interrupted by one or more
oxygen atoms. Even more preferably the chain is a
polyethylene chain substituted by one or more hydroxyl
groups, with a 2-hydroxy-trimethylene chain
(-CH2CHOHCH2-) being a particularly preferred chain.
Although the above describes more preferred X
groups, X can be one of a wide variety of groups as
fully set forth hereinafter.
The structure of a particularly preferred
compound of formula I is shown below as formula II, and
is commonly known as cromolyn:
o OCH2CH(OH)CH20
Ho2c~ ~C~2
The most preferred derivative o~ formula II
for use in the disclosed process is the disodium salt
thereof, hereinafter referred to as cromolyn sodium.
A contemplated process for prevention of a
cutaneous Type IV A reaction comprises the
administration to area of skin to be protected of a
composition that contains a pharmacologically acceptable
carrier having dissolved or dispersed therein a
preventively effective (reaction-prevent) amount of a
compound of formula I or a pharmacologically acceptable
salt, ester or amide thereof, as an active ingredient or
agent.

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g
That composition is topically applied to the
area to be protected. The composition can be applied 4
times a day as needed and then either be covered or
preferably left open to the air. Exemplary preventively
5 effective amounts, by weight, of the active ingredient
can range from about 0.5 to about 5.0 percent of the
total composition.
A contemplated process ~or treatment of
cutaneous Type IV A reaction comprises the
10 administration to a human with cutaneous Type IV A
hypersensitivity reaction of a composition that contains
a pharmacologically acceptable carrier having dissolved
or dispersed therein a therapeutically effective
(symptom-reducing) amount of a compound of formula I or
15 a pharmacologically acceptable salt, ester or amide
thereof, as an active ingredient or agent.
That composition is topically applied to the
area of the skin involved in the reaction. The
composition can be applied to the site several times a
20 day and then either be covered or preferably left open
to the air. Exemplary therapeutically e~ective
amounts, by weight, o~ the active ingredient can range
~rom about 0.5 to about 10 percent of the total
composition.
The present invention has several benefits and
advantages.
One benefit is that use of the described
process and composition can act to prevent the onset of
a cutaneous Type IV A hypersensitivity reaction, without
30 adverse side effects.
- Another bene~it is that use o~ the described
process and composition can also be used to reduce or
eliminate the inflammation and pruritus caused by a

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cutaneous Type IV A reaction without adverse side
e~ects.
A ~urther bene~it is that the reduction o~ the
physical symptoms o~ a cutaneous Type IV A reaction will
reduce or eliminate scratching or rubbing o~ the site
and thereby reduce or eliminate the possibility of
secondary in~ections and scarring.
One advantage o~ the described process is that
many cutaneous Type IV A hypersensitivity reactions can
be easily prevented by the application o~ the
composition prior to exposure to antigen.
Another advantage o~ the described process is
that it can also be used to lessen or eliminate the
symptoms o~ most cutaneous Type IV A reaction, caused by
a variety o~ antigens.
Further bene~its and advantages o~ the
invention will be apparent to those o~ skill in the art
~rom the description that follows.
Detailed DescriDtion o~ the Invention
The present invention contemplates a process
~or prevention and/or treatment o~ cutaneous Type IV A
hypersensitivity reaction. A contemplated process
utilizes a chromone compound corresponding to ~ormula I,
pre~erably the compound commonly known as cromolyn,
(formula II) and more pre~erably the disodium salt o~
cromolyn, as an active agent compound in a composition
that is topically administered.
For prevention o~ a cutaneous Type IV A
reaction, the composition is topically administered to
the area o~ skin believed to be susceptible to exposure
to antigens (i.e.,-the area to be protected). Once a
cutaneous Type IV A reaction has occurred, a composition

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can be topically administered to the reaction site of
humans in need of such treatment; i.e., having a
cutaneous Type IV A hypersensitivity reaction.
A. Compounds
A chromone compound utilized in the present
invention is represented by formula I.
Q 4R 0
~X~ O--X--O ~D~CO2H
Each of Rl-R6 can be the same, or different.
Each R1-R6 can be a hydrogen; a halogen (halo) group or
moiety (i.e. chloride, bromide, iodide or fluoride); a
C1-C6 lower alkyl group (i.e. a methyl, ethyl, propyl,
isopropyl, butyl, tertiary-butyl, or hexyl group);
hydroxy; Cl-C6 lower alkoxy (i.e. a methoxy, ethoxy,
propoxy, isopropoxy, butoxy, tertiary-butoxy or hexyloxy
group); substituted Cl-C6 lower alkoxy group; or a
substituted C1-C6 lower alkyl, as are discussed below.
The substituted lower alkyl or alkoxy group
can be substituted with the following groups: hydroxyl;
lower (C1- C6 ) alkoxy; carboxy or halo such as chloro-
bromo- iodo- or fluoro-); C1- C6 lower alkenyl, e.g.
allyl or methyl-allyl; benzyl; and nitro. A substituent
group is not itself substituted. It is preferred that
each R1-R6 be unsubstituted.
In general, it is preferred that no more than
one of R1, R2 and R3 and no more than one of R4, Rs and R6
is other than hydrogen, and each is selected from a
hydrogen, a halogen atom, a C1-C6 alkyl, hydroxy, C1-C6
- alkoxy or substituted alkoxy group, and X is as defined
before. A pre~erred compound is symmetric with R1 being
- the same as R4, R3 being the same as R5 and R2 being the

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same as R6. More preferred compounds of formula I are
those in which each o~ Rl-R6 is hydrogen.
The bridging X group of formula I is a
saturated or unsaturated, substituted or unsubstituted,
straight or branched polymethylene chain having between
3 and 10 carbon atoms can be interrupted by one or more
carbocyclic rings or oxygen-containing heterocyclic
rings, (e.g. benzene, dioxan, tetrahydrofuran, or
dihydropyran rings), oxygen atoms or carbonyl groups.
The X group is preferably a straight or
branched hydrocarbon chain containing 3 to 7 carbon
atoms. The chain can be interrupted by one or more
oxygen atoms. Even more preferably, the chain is a
polymethylene chain substituted by one or more hydroxyl
groups, with a 2 -hydroxy-trimethylene chain
(-CH2CHOHCH2-) being a particularly preferred chain.
The structure of a particularly preferred compound of
formula I is shown below as formula II, and is commonly
known as cromolyn:
o OcH2cH(oH)cH2o 0
HO2C ~ ~ O - co2~
Although the above describes more preferred X
groups, X can be one of a wide variety of groups as set
~orth hereinafter.
The X group can be a straight or branched,
saturated or unsaturated hydrocarbon chain.
Additionally, X can be such a chain interrupted by one
or more oxygen atoms, carbonyl groups or carbocyclic or
heterocyclic rings and can be substituted by one or more
halogen atoms (e.g. chlorine, bromine, iodine or

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fluorine atoms), or hydroxy or C1-C6 lower alkoxy (e.g.
~ methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary-
butoxy, etc.) groups. Some specific examples of the X
group are groups of the following formulas:
-(CH2) 5-
-CH2-CH=CH-cH2-
-CH2CH2CH-(CH3)-
- CH2CH20CH2CH2 -
- CH2COCH2 -
--CH2 CH2
-CH2CH (OC2H5) -CH2-
~ CH2--
--CH2
CH20H
_CH2<~H2C
CH2CI
- CH2CHOHCH2 -
-CH2CHOHcH2OcH2cHoHcH2-
Different or corresponding positions on the
chromone molecules can be linked by the O-X-O chain,
although symmetrical linkages are preferred.
Pharmacologically acceptable salts of a
compound of formula I or formula II suitable for use in
- the disclosed process include for example, ammonium
salts, alkali metal salts (e.g. sodium, potassium and
- lithium), alkaline earth metal salts (e.g. magnesium and

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calcium), and salts with organic amines (e.g. mono-, di-
or tri-C1-C6-alkyl amines, piperidine, morpholine and
trialkanol Cl-C6-alkyl amine salts).
Pharmacologically acceptable esters include
simple C1-C6 alkyl esters (e.g. methyl, ethyl, propyl,
isopropyl, butyl, tertiary-butyl and hexyl esters).
Pharmacologically acceptable amides include simple
amides (~or example amides with ammonia and C1-C6 lower
alkylamines such as methylamine, ethylamine, and the
like whose alkyl portions are discussed be~ore) and more
complex amides with amino acids, e.g. glycine.
Speci~ic examples o~ compounds o~ formula I
and derivatives thereof are provided in U.S. Patent No.
4,362,742, whose disclosures are incorporated herein by
reference.
The most pre~erred derivative o~ ~ormula II
~or use in the disclosed process is the disodium salt
thereo~, hereina~ter re~erred to as cromolyn sodium.
The phrase "pharmacologically acceptable"
salts, esters and amides as used herein re~ers to non-
toxic salts, esters and amides o~ ~ormula I as discussed
above.
B. Compositions
A compound o~ ~ormula I or one o~ its
pharmacologically acceptable salts, esters or amides
dissolved or dispersed in a preventively or a
therapeutically e~ective amount in a pharmacologically
acceptable carrier constitutes a composition
(preparation) useful in a process o~ this invention.
The disodium salt o~ a compound o~ formula II, where
R1=R2=R3=R4=R5=R6=H, and X=-CH2CHOHCH2-, is pre~erred ~or
use in treatment.

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Although a compound o~ ~ormula I and its
pharmacologically salts, esters and amides can be
administered as a pure chemical, it is pre~erred that it
be administered as a pharmaceutical composition. In
either event, a contemplated compound is administered in
an amount suf~icient to provide a therapeutically
e~ective dose, for prevention or treatment, as is
discussed hereina~ter.
Accordingly, the present invention utilizes a
pharmaceutical composition comprising a therapeutlcally
e~ective dose of a compound o~ ~ormula I or a
pharmacologically acceptable salt, esters or amide
thereo~, hereina~ter referred to as the "active
ingredient" or "agent", dissolved or dispersed in a
pharmacologically acceptable carrier or diluent.
A preventively e~ective amount of a
contemplated chromone compound o~ formula I ~or use in
prevention of a cutaneous Type IV A reaction, typically
constitutes about 0.5 to about 10.0 weight percent o~ a
contemplated composition. More pre~erably, that amount
is about 2.0 to about 6.0 weight percent.
A therapeutically e~ective amount o~ a
contemplated chromone compound of ~ormula I ~or use in
treatment o~ a cutaneous Type IV A reaction typically
constitutes about 0.5 to about 10.0 weight percent o~ a
contemplated composition. More pre~erably, that amount
is about 2.0 to about 6.0 weight percent.
A pharmaceutical composition is prepared by
any o~ the process well known in the art o~ pharmacy all
o~ which involve bringing into association the active
- ingredient and the carrier therefore. For preventative
and therapeutic use, a compound utilized in the present
invention can be administered in the ~orm o~

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conventional pharmaceutical compositions. Such
compositions can be ~ormulated so as to be suitable for
topical administration of the active ingredient. In
these compositions, the agent is typically dissolved or
dispersed in a physiologically tolerable carrier or
diluent.
A carrier or diluent is a material useful ~or
administering the active compound and must be
"pharmacologically acceptable" in the sense of being
compatible with the other ingredients of the composition
and not deleterious to the recipient thereo~. Thus, as
used herein, the phrases "physiologically tolerable" and
"pharmacologically acceptable" are used interchangeably
and re~er to molecular entities and compositions that do
not produce an allergic or similar untoward reaction
when administered to a human.
The pharmacologically tolerable carrier can
take a wide variety o~ forms suitable for topical
administration, such as an ointment, water-miscible
ointment, cream, lotion, paste, gel or liniment. These
carriers can be aqueous, oily (oleaginous) or water-
miscible or water-dispersible. They can be oil-in-water
or water-in-oil based emulsions. A discussion o~ some
types o~ suitable carriers is present in U.S. Patent No.
4,362,742, whose disclosures are incorporated herein by
reference.
The pre~erred carrier composition for the
disclosed process is an oil-in-water emulsion in which
the active ingredient is present in the water phase.
The preferred oil-in-water emulsion is comprised o~ a
water phase containing the active ingredient. Water is
typically present at about 40 to about 80 weight percent

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and more preEerably at about 66 to about 72 weight
percent o~ the composition.
One or more water-miscible organic solvents
such as glycerine, propylene glycol can also be present
in the water phase. A sequestering agent such as
edetate disodium dihydrate (EDTA) can also be present,
as can a pH value-adjusting acid. Phosphoric acid is
also pre~erably used in the water phase in an amount
required to obtain the required necessary pH value.
The pH value can range between about 3.0 and
about 8Ø The more preferred pH value range is about
4.0 to about 7Ø The most preferred pH value is
5.5.
Compound names used herein are usually used
common names as well as those utilized in the
International Cosmetic Inqredient Dictionary, The
Cosmetic, Toiletry, and Fragrance Association,
Washington, D.C. (1993), and The U.S. Pharmaco~eia, The
National Formular~, [USP XXII; NF XVII] United States
Pharmacopeial Convention, Inc., Rockville, MD, 1990.
The oil phase is comprised o~ materials that
individually can be solids or liquids at room
temperature, e.g. about 20~C. These materials include
waxes such as white wax and emulsi~ying wax, squalene
and a silicone oil such as dimethicone. The oil phase
also contains a component o~ the emulsi~ying wax, a C2-
C4-acyl polypropyleneglycol (PPG) C12-Cl8 alkyl ether that
contains an average o~ about 2-4 PPG groups per
molecule. These materials impart an appropriate creamy
feel to the composition upon the skin and tend to ~orm
- an oleaginous layer over the treated area.
A C12-C18 alcohol or mixtures thereo~ is also
pre~erably present. Illustrative C12-C18 alcohols

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include lauryl, myristyl, cetyl, stearyl and oleyl
alcohols.
The emulsi~ier includes emulsi~ying wax and
pre~erably a mixture of two ingredients. The ~irst is a
C2-C4-acyl polypropyleneglycol (PPG) C12-Cl8 alkyl ether
that contains an average o~ about 2-4 PPG groups per
molecule. The second is a polyoxyethyleneglycol (PEG)
C1~-C26 ether having an average o~ about 8-12 PEG groups
per molecule.
The emulsi~ying wax and PEG compounds are
pre~erably present together at about 8-17 weight percent
o~ the total preparation, and in a weight ratio o~ about
15:1 to about 1:1, more pre~erably at about 10:1 to
about 8:1, and most pre~erably about 9:1 in the order
mentioned.
The ratio o~ the emulsi~ying wax and PEG
emulsi:Eier used is designed to provide a calculated HLB
number o~ about 8 to about 14, and more pre~erably about
10 to about 12. The total amount o~ emulsi~ier used is
typically a function of the total amount o~ oil phase
ingredients, with more total emulsi~ier being used with
a greater amount of oil phase ingredients, and less
total emulsi~ier with the lower amount o~ oil phase
ingredients, as is well known.
Emulsi:Eying wax has an average HLB value o~
about 11. A particularly pre~erred PPG-containing
emulsi~ier is PPG-2 myristyl ether propionate that has
an HLB value of 11. A particularly prei~erred PEG-
containing emulsifier is polyoxyethylene-10-oleyl ether
that has an HLB value o~ 12.4. The above HLB value
ranges are calculated based upon these two emulsi~iers.
PPG-2 myristyl ether propionate can be
replaced with one o~ the compounds encompassed by the

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-- 19 --
designation C2-C4 acyl-PPG(2-4) C12-C18 ether. Exemplary
materials include PPG-3 lauryl ether butyrate and PPG-4
stearyl ether acetate, and the like. Similarly, PEG-10-
oleyl ether (oleth-10; PEG compound) can be replaced
5 with another PEG (7-12) C14-C20 alkyl ether such as PEG-
12-cetyl ether (ceteth-12), PEG-7-stearyl ether
(steareth-7), PEG-11-cetyl/stearyl ether (ceteareth-11),
and the like.
It is noted that substitution in the PPG
compound and PEG compound are considered together as
these two compounds are present in the carrier in a
combined total of 8-12 percent weight to weight with a
weight to weight PPG-containing emulsifier to PEG-
containing emulsifier ratio in the range of about
4:1-1:1, preferably about 10:1-8:1, most preferably of
9:1. This ratio results in the desired HLB number.
A contemplated preparation typically has a
viscosity of a cream or ointment. Exemplary viscosities
are thus about 20,000 to about 100,000 cps at 25~C, and
more preferably about 50,000 to about 70,000 cps.
One and preferably more than one preservative
is also preferably present in a commercial preparation.
Exemplary preservatives include methylparaben,
propylparaben and imidurea.
The following table provides a preferred range
of weight to weight percentages for each particularly
preferred ingredient present in a particularly preferred
oil-in-water emulsion preparation for commercial use.
Inqredient ~W/W Ranqes
Cromolyn sodium 0.5-10
Emulsifying wax, N.F. 8-17 total, in
Polyoxy-lOOOleyl Ether, N.F. a ratio of
PPG-2 Myristyl Ether Propionate 8:1-10:1 for the
wax:PEG and a 4:1-

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- 20 -
1:1 ratio for
PPG:PE~
Inqredient ~W/W Ranqes
Squalene, U.S.P. 2-10
White Wax, N.F. 0.5-5
Dimethicone, N.F. 0.5-5
Cetyl Alcohol, N,F. 1-10
Propylparaben, N.F. 0.05-0.2
Puri~ied Water, U.S.P. q.s.
Glycerin, U.S.P. 1-5
Edetate Disodium Dihydrate, U.S.P. 0.01-1.0
Propylene Glycol, U.S.P. 1- 5
Methylparaben, N.F. 0.1-0.4
Imidurea, N.F. 0.1-0.3
Phosphoric Acid, N.F. q.s.
Changes in the specific, particularly
pre~erred, ingredients listed are contemplated. Thus
one o~ ordinary skill in the art can substitute similar
ingredients ~or those discussed above without
substantially altering the e~ectiveness of the carrier
and the ~inal composition. The viscosity o~ carrier can
be changed so long as it rem;3; n.C suitable ~or topical
application.
In addition, i~ a certain ingredient is
changed resulting in di~erent hydrophilic/lipophilic
balance (HLB), this can be compensated for, using known
techniques, by changing another ingredient.
Speci~ic examples o~ the acceptable
alterations in the particularly preferred given
ingredients are set ~orth below. Speci~ic combinations
o~ changes that result in acceptable compositions are
easily determined by known procedures because
"acceptability" arises mostly ~rom emulsion
characteristics rather than ~rom a major change in drug
availability.

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Dimethicone is a mixture o~ fully methylated
linear siloxane polymers end-blocked with
trimethylsiloxy units. These materials are commercially
available ~rom several suppliers at varying viscosities
ranging from about 0.65 to about centistokes 2,500,000,
(cSt), with lower molecular weight polymers exhibiting
the lower viscosities up to about a weight o~ about
30,000 and viscosity o~ about 1000 cSt, at which polymer
chain entanglement occurs, resulting in a leveling in
properties.
A pre~erred dimethicone utilized herein has a
viscosity o~ about 100 to about 300 cSt, and more
pre~erably about 150 to about 250 cSt. [1 cSt = 1 cps.]
Cetyl alcohol can be substituted by Cl2-Cl8
alkyl such as lauryl, myristyl, and stearyl alcohols.
Methylparaben and propylparaben can be substituted by
Cl-Cs alkyl paraben, or other suitable preservatives.
Any pharmacologically suitable acid can be
used in place o~ phosphoric acid to adjust the pH o~ the
composition.
Other compounds that can be used in place o~
squalene include acetylated lanolin. Substitutions ~or
imidurea include DMDM Hydantoin. Emulsi~ying wax can be
replaced with cetyl alcohol: steareth-20 whereas
stearamidopropyldimethyl amine can be used in place o~
white wax.
It should also be understood that in addition
to the a~orementioned carrier ingredients and
substitutions, a pharmaceutical ~ormulation described
herein can include, as appropriate, one or more
- additional carrier ingredients such as bu~ers, binders,
sur~ace active agents, additional thickeners and
preservatives (including antioxidants), lubricants, and

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the like. It is also contemplated that a penetration
enhancer can be included to permit the active ingredient
to penetrate the skin more e~ectively. One
contemplated penetration enhancer is 2-n-nonyl-1,3-
dioxolane, known as SEPA (So~t Enhancer for PercutaneousAbsorption). SEPA can be used at about two weight
percent (2 wt~) to about twenty weight percent (20 wt~).
Fragrances and/or odor masking compounds can also be
added.
C. Process
As noted earlier, a process ~or prevention
and/or treating cutaneous Type IV A hypersensitivity
reactions is contemplated here.
Broadly, a chromone compound whose structure
corresponds to that o~ ~ormula I, or a pharmacologically
acceptable salt, ester or amide thereo~, as active
ingredient, dissolved or dispersed in a
pharmacologically acceptable carrier is topically
administered (applied) to a human.
I~ the purpose o~ application is prevention of
a Type IV A reaction the composition is applied to those
areas o~ the skin likely to be exposed to an antigen.
The compound is present in the composition in an amount
su~icient to provide a preventively e~ective amount (a
reaction preventing amount) o~ active ingredient
compound over the period o~ administration. This amount
ranges between about 0.02g and about 0.04g to about 0.2g
per treatment.
A composition is administrated by topically
applying the composition to an area to be protected.
The area can then be covered, but is pre~erably le~t
open to the air. This treatment can be repeated as
necessary to maintain an e~ective amount o~ the

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- 23 -
compound on the area to be protected. Typically
application is repeated every 6-8 hours until danger of
exposure is removed.
Efficacy of a contemplated process for
prevention can be assessed by visual inspection for any
reaction sites after known exposure to an antigen.
When the purpose of application is treatment
of a Type IV A reaction site, a compound whose structure
corresponds to that of formula I, or a pharmacologically
acceptable salt, ester or amide thereof, as active
ingredient, dissolved or dispersed in a
pharmacologically acceptable carrier is topically
administered (applied) to a cutaneous Type IV A reaction
site of a human patient. The compound is present in the
composition in an amount sufficient to provide a
therapeutically effective amount (a symptom-reducing
amount) of active ingredient compound over the period of
administration. This amount ranges between about 0. 02g
and about 0.4g per treatment, and more preferably about
0. 05g to about O.lg per treatment.
The composition is administered by topically
applying the composition to an area affected by the
reaction. The site can then be covered, but is again
preferably left open to the air. This treatment can be
repeated a plurality of times such as several times per
day for 7 days, or until the reaction and the symptoms
associated with it disappear.
The duration of a particular treatment can
vary depending upon the size, type and severity of the
reaction. Typical administration lasts about 3 days.
- ~m; n; stration is very easily carried out on
an out-patient basis.

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Efficacy of a contemplated process for
treatment of a reaction site can be assessed by visual
inspection of the reaction site and by assessment of the
severity of the pruritus by the patient. The
inflammation and irritation caused by the reaction
typically begins to noticeably decrease after 15-30
minutes. Treatment is then continued as necessary until
the reaction has subsided.
Example I: ExemPlary Topical Pre~aration
A topical preparation for prevention and
treatment of a cutaneous Type IV A hypersensitivity
reaction was prepared using the ingredients shown below
for the preparation of 60 kilograms of a 4 percent
Cromolyn Sodium Cream:
Inqredient ~W/W
Cromolyn sodium 4.00
Emulsifying wax, N.F. 9.00
PPG-2 Myristyl Ether Propionate 2.50
Polyoxy-10-Oleyl Ether, N.F. 1.00
Squalene, U.S.P. 4.00
White Wax, N.F. 2.00
Dimethicone, N.F. 1.00
Cetyl Alcohol, N.F. 3.00
Propylparaben, N.F. 0.10
Puri~ied Water, U.S.P. 68.80
Glycerin, U.S.P. 2.50
Edetate Disodium Dihydrate, U.S.P. 0.10
Propylene Glycol, U.S.P. 1.50
Methylparaben, N.F. 0.20
Imidurea, N.F. 0.30
Phosphoric Acid, N.F. q.s
pH value 5.5
Viscosity (25~c) 60,000cps
The cream is prepared by the following
procedure. Percentage of total weight is given in
parenthesis.

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- 25 -
Step 1. Charge the main mixing kettle with
25.68K of purified water (42.80~) and heat to 75-800C.
Add 1.50K of glycerin (2.50~), 60g of disodium EDTA
U.S.P. (0.10~) and 900g of propylene glycol (1.50~)
individually while mixing at 30 rpm. Add 120g o~
methylparaben N.F. (0.20~) and mix for 5 minutes at 30
rpm to disperse. Reduce speed to 20 rpm and mix for 1/2
hour.
Step 2. In a separate container, heat 5.4OK
of emulsifying wax N.F. (9.00~), 1.50K of PPG-2 myristyl
ether propionate (2.50~), 600g polyoxy-10 oleyl ether
N.F. (1.00~), 2.40K squalene U.S.P. (4.00~), 1.20K white
wax (2.00~), 600g dimethicone N.F. (1.00~), 1.80K cetyl
alcohol (3.00%) and 60g propylparaben N.F. (0.10~) to
75-80~C. Mix at 1700 rpm for 5 minutes.
Step 3. At 75-80~C, add Step #2 to Step #l
with mixing at 40 rpm. Mix at 40 rpm speed for 1/2
hour.
Step 4. Cool evenly to 35-40~C over a 60
minute period with mixer at 20 rpm.
Step 5. Premix 600g o~ purified water U.S.P.
(1.00~) and 180g of imidurea N.F. (0.30~) in a separate
container at 250 rpm on the Dayton Gearmixer. Mix
manually for 15 minutes. This premix phase should be
totally clear before addition to the batch.
Step 6. Add the mixture from step #5 to that
at Step #4 and mix well for 10 minutes at lOrpm.
Step 7. In a separate container premix
15.00K of purified water (25.00~) and 2.40K of cromolyn
sodium U.S.P. (4.00~) using the Lightnin' mixer at 1750
- rpm ~or 20 minutes and check for uniformity.
Step 8. Add the contents of step #7 to the
batch and mix for 1/2 hour at 20 rpm.

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- 26 -
Step 9. Adjust pH to 5.5 with phosphoric
acid N.F. i~ necessary.
Two sets o~ samples ~rom the top, middle and
bottom of the kettle are removed and submitted ~or
cromolyn sodium, methylparaben and propylparaben
analysis and other physical tests.
The ~oregoing description is intended as
illustratve and is not to be taken as limiting. Still
other variations within the spirit and scope o~ this
invention are possible and will readily present
themselves to those skilled in the art.

Dessin représentatif