CA2216363A1 - Composition and process for prevention and treatment of cutaneous delayed hypersensitivity reactions - Google Patents

Abstract

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.

Description

W O96131203 PCTrUS96103962 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.

W O96131203 PCTrUS96/03962 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~
-W O96t31203 PCT/ub~Gl~3962 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 W O 96/31203 PCT/U',.'~3962 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 W O96/31203 PCT~US96103962 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, W O96/31203 PCTrUS96/03962 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 CA 022l6363 l997-09-24 W O 96/31203 PCTrUS96/03962 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 W O96/31203 PCTrUS96103962 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.

W O96t31203 PCTrUS96103962 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 W O96/31203 PCTrUS96103962 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 W O96/31203 PCT/U~G/~3962 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.

~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 W O96/31203 PCTrUS96/03962 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 W O96/31203 PCTnUS96/03962 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)--CH2CH (OC2H5) -CH2-~ CH2--_CH2<~H2C

-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 W O96/31203 PCTrUS96/03962 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.

CA 022l6363 l997-09-24 W O96/31203 PCTrUS9''~ 2 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~

CA 022l6363 l997-09-24 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 W O96/31203 PCTrUS96/03962 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 CA 022l6363 l997-09-24 W O96t31203 PCTrUS96/03962 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 W O 96/31203 PCTrUS9G,'3~62 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-CA 022l6363 l997-09-24 W O 96/31203 PCTrUS9G~3~62 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.

W O 96/31203 PCTrUS96103962 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 W O96t31203 PCTrUS96/03962 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 W O96/31203 PCTrUS9G/~3962 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.

W O 96/31203 PCTrUS96/03962 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.

CA 022l6363 l997-09-24 W O96/31203 PCTrUS~ v2 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.

W O96/31203PCTnUS96/03962 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.

Claims (38)

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:

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 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.

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 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:

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 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-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.

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.