# US 2010/0166804 A1 · Methods

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- Number: US 2010/0166804 A1
- Document ID: US20100166804A1
- Status: Published application
- Kind: A1
- Application number: 12/600,510
- Filed: 2008-05-23
- Published: 2010-07-01
- Earliest claimed: 2007-05-23
- Inventors: Dennis Penn
- Web page: https://patentgrep.com/patent/US20100166804A1

## CPC

- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to methods of prophylactically treating, reducing, delaying or controlling severe allergic reaction, e.g., to food and/or hymenoptera allergen, e.g. peanut allergen or bee venom allergen, in patients at risk of systemic anaphylaxis, e.g., patients receiving allergen desensitization therapy, through the use of a mast cell stabilizer, e.g., ketotifen and/or its metabolites or derivatives in free or pharmaceutically acceptable acid addition salts thereof. The invention further provides methods to desensitize a patient to one or more allergens comprising administering (i) one or more allergen to induce tolerance and (ii) one or more mast cell stabilizers in free or pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A method for prophylactically treating, controlling, delaying or reducing severe reaction to allergen or symptoms of mediator release during allergen desensitization in a patient at risk of systemic anaphylaxis if exposed to such allergen, comprising: administering to said patient an effective amount of ketotifen in free or pharmaceutically acceptable acid addition salt.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said acid addition salt is selected from the group consisting of hydrochloride, hydrobromide, hydrogen sulfate, phosphate, maleate, nitrate, besylate and fumarate.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said acid addition salt is the fumarate salt.

### Claim 4

A method for desensitizing a patient to an allergen comprising: administering to the patient one or more allergens and an effective amount of one or more mast cell stabilizers in free or pharmaceutically acceptable acid addition salt form to inhibit or prevent symptoms of mediator release.

### Claim 5 (depends on 4)

The method of claim 4, wherein the mast cell stabilizer is selected from the group consisting of cromolyn, cromoglycate, nedocromil, bepotastine, ebastine, epinastine, azelastine, lodoxamide tromethamine, lodoxamide trometamol, pemirolast, olopatadine, ketotifen, norketotifen, 10-OH-norketotifen, 9-OH-norketotifen, 9,10-di-OH-norketotifen and those having the general formula:
wherein:
a) -A-B— is a moiety having the formula:
i) —CO—CH2—
ii) —CH2—CO—
iii) —CH2—CH2—
iv) —CHOH—CH2—
v) —CHOH—CHOH—
vi) —CH2—CHOH—; or
vii) —CO—CO—; and
b) R is a hydroxyalkyl or a carboxyalkyloxyalkyl moiety;
wherein:
a) —Z— is —CH2—CH2— or —CH═CH—;
b) R1 is a H or C1-4alkyl; and
c) R2 is H or halogen.
or
wherein:
a) A is
b) n is 1 or 2;
when n is 1, X is H, halogen, CF3, alkyne, —S(O)n′, OR or NO2;
when n is 2, X is H or halogen;
c) n′ is 0, 1 or 2;
d) R is C1-5(un)branched alkyl;
e) Y is Z(C(R′)(R′))n″Z′ or
wherein:
i) n″ is 2-4;
ii) m is 0, 1, 2, 3;
iii) R′ is H or R;
iv) X′ is H, halogen, CF3, alkyne, —S(O)n′R, OR or NO2;
v) Z is NH or O;
vi) Z′ is N(R′)(R″) or
or R″ is
in free or pharmaceutically acceptable acid addition salt form.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the one or more allergens is peanut allergen.

### Claim 7 (depends on 4)

The method according to claim 4 in combination with a second method for prophylactically treating, controlling, delaying or reducing severe reaction to allergen in a patient at risk of systemic anaphylaxis if exposed to such allergen and for desensitizing a patient to an allergen, wherein the second method comprises: administering to the patient an effective amount of ketotifen in free or pharmaceutically acceptable acid addition salt.

### Claim 8

A method of allergen desensitization comprising: administering to a patient in need thereof: (i) increasing doses of allergen to induce tolerance, and
(ii) an amount of one or more mast cell stabilizers in free or pharmaceutically acceptable acid addition salt form effective to inhibit symptoms of mediator release;
or an amount of at least one antihistamine to inhibit symptoms of mediator release;
or an amount of a compound having dual antihistamine and mast cell stabilizing activities to inhibit symptoms of mediator release.

### Claim 9

A method of allergen desensitization comprising administering to a patient in need thereof (i) increasing doses of allergen to induce tolerance and (ii) an amount of at least one antihistamine to inhibit symptoms of mediator release.

### Claim 10 (depends on 8)

The method of claim 8, wherein said antihistamine is ketotifen in free or pharmaceutically acceptable salt form.

### Claim 11

A method of allergen desensitization comprising administering to a patient in need thereof (i) increasing doses of allergen to induce tolerance and (ii) an amount of one or more mast cell stabilizer in free or pharmaceutically acceptable acid addition salt form effective to inhibit symptoms of mediator release.

### Claim 12

A method of allergen desensitization comprising administering to a patient in need thereof (i) increasing doses of allergen to induce tolerance and (ii) an amount of a compound having dual antihistamine and mast cell stabilizing activities to inhibit symptoms of mediator release.

### Claim 13 (depends on 8)

The method of claim 8, wherein said compound is ketotifen in free or pharmaceutically acceptable salt form.

### Claim 14 (depends on 8)

The method of claim 8, wherein the method comprises: the step of administering to the patient in need thereof: (i) the increasing doses of allergen to induce tolerance and (ii) the amount of one or more mast cell stabilizers in free or pharmaceutically acceptable acid addition salt form effective to inhibit symptoms of mediator release, wherein said doses of allergen to induce tolerance are higher than would be administered to the patient in the absence of co-administration of a mast cell stabilizer.

### Claim 15 (depends on 14)

The method of claim 14, wherein said mast cell stabilizer is ketotifen.

### Claim 16 (depends on 1)

The method of claim 1, wherein the allergen is a food allergen.

### Claim 17 (depends on 4)

The method of claim 4, wherein the one or more allergens is food, hymenoptera, tree or plant allergen.

### Claim 18 (depends on 8)

The method of claim 8, wherein the method comprises: the step of administering to the patient in need thereof:
(i) the increasing doses of allergen to induce tolerance, and
(ii) the amount of the compound having dual antihistamine and mast cell stabilizing activities to inhibit symptoms of mediator release, wherein said doses of allergen to induce tolerance are higher than would be administered to the patient in the absence of co-administration of the compound.

### Claim 19 (depends on 7)

The method according to claim 7, wherein the acid addition salt is selected from the group consisting of hydrochloride, hydrobromide, hydrogen sulfate, phosphate, maleate, nitrate, besylate and fumarate.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the acid addition salt is the fumarate salt.

### Claim 21 (depends on 7)

The method according to claim 7, wherein the mast cell stabilizer is selected from the group consisting of: cromolyn, cromoglycate, nedocromil, bepotastine, ebastine, epinastine, azelastine, lodoxamide tromethamine, lodoxamide trometamol, pemirolast, olopatadine, ketotifen, norketotifen, 10-H-norketotifen, 9-OH-norketotifen, 9,10-di-OH-norketotifen and those having the general formula:
wherein:
a) A-B— is a moiety having the formula:
i) —CO—CH2—
ii) —CH2—CO—
iii) —CH2—CH2—
iv) —CHOH—CH2—
v) —CHOH—CHOH—
vi) —CH2—CHOH—; or
vii) —CO—CO—; and
b) R is a hydroxyalkyl or a carboxyalkyloxyalkyl moiety;
wherein:
a) —Z— is —CH2—CH2— or —CH═CH—;
b) R1 is a H or C1-4alkyl; and
c) R2 is H or halogen.
or
wherein:
a) A is
b) n is 1 or 2;
when n is 1, X is H, halogen, CF3, alkyne, —S(O)n′R, OR or NO2;
when n is 2, X is H or halogen;
c) n′ is 0, 1 or 2;
d) R is C1-5(un)branched alkyl;
e) Y is Z(C(R′)(R′))n″Z′ or
wherein:
i) n″ is 2-4;
ii) m is 0, 1, 2, 3;
iii) R′ is H or R;
iv) X′ is H, halogen, CF3, alkyne, —S(O)n′, OR or NO2;
v) Z is NH or O;
vi) Z′ is N(R′)(R″) or
or R″ is
in free or pharmaceutically acceptable acid addition salt form.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the allergen is peanut allergen.