WO2001039774A1

WO2001039774A1 - Topical administration of ketotifen

Info

Publication number: WO2001039774A1
Application number: PCT/US2000/013587
Authority: WO
Inventors: Gerald Klein
Original assignee: Klein Pharmaceuticals
Priority date: 1999-12-01
Filing date: 2000-05-17
Publication date: 2001-06-07
Also published as: AU5139800A

Abstract

A method of treating has a step in which a pharmacological composition comprising Ketotifen is provided. In another step, a skin area of a patient is identified that is affected with itching, and the pharmacological composition is topically administered to the area of skin at a dosage effective to reduce the itching. Contemplated compositions may have various formulations and may further comprise pharmacologically active and/or inactive ingredients.

Description

TOPICAL ADMINISTRATION OF KETOTIFEN

This application claims me benefit of U.S provisional application number 60/168.323 filed on December 1, 1999. which is incorporated herein by reference m its entirety

Field of The Invention

The field of the invention is topical treatment of pruritus

Backeround of The Invention

Ketotifen (4.9-Dιhydro-4-( 1 -methyl-4-pιpeπdιnyhdene)- 10H-benzo[4,5]cyclohepta[ 1 ,2- b]thιophene-10-one; U.S. Pat. No 3,682,930 to Bourquin et al ) is a relatively selective non- competitive histamine antagonist for the HI receptor, and known to stabilize mast cells Among other properties, Ketotifen has been shown to inhibit the release of mediators from cells involved m hypersensitivity reactions, and to decrease chemotaxis and activation of eosinophiles. Due to its multifaceted biological properties, Ketotifen has found various applications where anti-asth- matic and anti-histamimc properties of a drug are desirable

For example, in one indication Ketotifen is administered as a prophylactic therapeutic agent to prevent asthma attacks Typically, the dosage of Ketotifen in the asthma prophylaxis is between l-4mg twice daily in form of a lmg tablet. To prolong the mean residence time of Ketotifen in plasma, an improved oral composition is descπbed in U.S.Pat. No 5,399,360 to Swrer et al , m which a tablet is prepared by granulating Ketotifen together with a hpophilic mateπal. The new oral composition contains preferably 2mg Ketotifen, and a single dose is sufficient to maintain a mean residence time exceeding 24hrs in plasma. Although the increased mean residence time of Ketotifen in plasma is almost doubled, some patients might still forget their medication and may therefore increase their πsk for an asthma attack.

To completely circumvent at least some of the problems associated with oral administra- tion, transdermal systemic administration of Ketotifen has been developed, and is descπbed m U.S.Pat No. 5,364,625 and 5,593,686 both to Kissel et al In the transdermal systemic administration, Ketotifen is admixed with a polycatiomc polymeπc compound and deposited m a thin film on a support. The support is then removably attached to the skm, e g. behind the ear. and a single dose of Ketotifen ranges between l-20mg in a patch of approximately lOcπr, which is changed every three days. In another indication, oral administration of Ketotifen is utilized m systemic treatment of pruπtus Treatment has been descπbed in vaπous cases, for example in neurodermatitis [Effecti- \eness of Ketotifen in the treatment of neurodermatitis m childhood, Kikindjamn, V , et al , Der- matol Monatsschr 1990, 176(12), 741-744] and chronic urticaπa [Treatment of chronic urtica- ria with Ketotifen Egan. T A and Ral s T M , Arch Dermatol 1997 133,147-149], both of which utilized a regimen of multiple oral doses of Ketotifen Although the oral administration successfully relieved at least some of the symptoms, the treatment was nevertheless limited to a systemic administration of Ketotifen in oral form

In a still further indication, Ketotifen is administered into the eye for temporary preven- tion of itching of the eye due to allergic conjunctivitis, and topical ophthalmic compositions and methods are descπbed in U S Pat No 5,441.958 to anni et al In a human con unctival allergen challenge study. Zatidor™ (a 0 025° ₀ Ketotifen-fumarate solution for ophthalmic use) was significantly more effective than a placebo in preventing ocular itching associated with allergic conjunctivitis In this study, the formulation of Ketotifen was adapted to a relatively dilute solu- tion and administered by dropping the solution in the affected eye, thereby limiting treatment to allergic conjunctivitis

In a yet further indication, U S Pat No 5,624,962 to Takeuchi et al , Ketotifen is included in an aqueous drug composition with reversible thermosetting gelation, and Takeuchi et al teach that the drug composition mav include Ketotifen as an antiallergic agent for ophthalmic use or as an antihistamimc for body cavitical use Similarly, in U S Pat No 5 322.685 to Naka- ga-Λa et al . the inventors descπbe a skin cream preparation for external use that contains an active ingredient to remedy a skin disease Nakagana et al teaches the active ingredient includes anti-mflammatory, anti-bacteπal and antiallergic agents, and lists as an example Ketotifen as antiallergic agent

Despite vaπous indications where Ketotifen may be employed as an appropπate mast cell inhibitor, antiallergic or anti-histamimc therapeutic agent, it is generally not recognized that Ketotifen may be topically applied to the skin of a person to relieve or prevent localized or wide spread pruπtus

Summary of the Invention The present invention is directed to methods and compositions of topical treatment of pruπtus. in which m one step a pharmacological composition compπsmg Ketotifen is provided, and m a next step a skm area of a patient is identified that is affected with itching. Subsequently, the pharmacological composition is topically administered to the area of skm at a dosage effective to reduce the itching Ketotifen may be present in the pharmacological composition at less than 5%, preferably less than 1%, and more preferably less than 0.5%

In one aspect of the inventive subject matter, the pruntus is a symptom of an allergic or non-allergic condition and especially contemplated allergic conditions include insect bites and stings, hives, atopic-. and contact dermatitis, and eczema Contemplated non-allergic conditions include uremic dermatitis, neurodermatitis, dry skm, and sunburn.

In another aspect of the inventive subject matter, the pharmacological composition is a gel. a lotion, or a spray, but may also include a mousse, a cream, an ointment, and vaπous liquids. Depending on the formulation of the pharmacological composition, the topical application may include spaying, rubbing into the skm, and application under occlusion

Vaπous objects, features, aspects and advantages of the present invention ill become more apparent from the following detailed description of preferred embodiments of the mven- tion, along with the accompanying drawing.

Brief Description of The Drawings

Fig 1 is a flow diagram of a treatment method according to the inventive subject matter

Detailed Description

As used herein, the term "topically admimsteπng" refers to any form of application of a pharmacological composition that disposes the pharmacological composition on the surface of a patients skin. The term "skm^" as used herein is meant to include the dermis of the entire body surface, which may or may not include hair. In contrast, the surface of the eye is not considered the surface of a skm under the scope of this definition Furthermore, it should be noted that

"topical administration" as used herein is limited to a surface deposition of the pharmacological composition, and excludes any mechanism of transdermal systemic delivery

As also used herein, the term "pruπtus" refers to a cutaneous sensation that provokes a desire to rub or scratch the skin to obtain relief, and particularly refers to itching associated with and symptomatic of some other disease or abnormality For example, the itching sensation associated with dry skm, an insect bite, or symptomatic itching of a contact dermatitis is referred to as pruπtus under the scope of this definition. It should be especially noted, however, that the term "pruπtus" as used herein does not refer to a disease or condition itself whose predominant symptom is itching. For example, pruπtus does not refer to an allergic condition itself

In Figure 1, a method 100 has a first step 110 m which a pharmacological composition compπsmg Ketotifen is provided. In a next step 120. a skm area of a patient that is affected with itching is identified, and in a subsequent step 130 at least part of the pharmacological composition is topically administered to the area of skm at a dosage effective to reduce the ltchm *»s of the skm

In a preferred embodiment, the pharmacological composition compπsmg Ketotifen is a C₁₈- fatty acid based cream containing 2 wt% of Ketotifen, titanium dioxide as a coloπng agent, and bisphenol as antimicrobial agent The step of identifying the skm area of a patient that is affected with itching is performed by the patient by sensing and visually confirming the affected area, and the pharmacological composition is massaged into the affected area of skm at a dose of about 0 2g of the pharmacological composition per 10cm^: of affected skin, wherein the affected area compπses an insect bite

In alternative aspects of the inventive subject matter, the formulation of the pharmacological composition compπsing Ketotifen need not be limited to a C₁₈-fatty acid based cream containing 2% of Ketotifen, but may v ary considerably Vaπous alternative formulations are contemplated and include formulations in a gel. a mousse, an ointment, a cream, a lotion, a liquid, and a spray, and the ingredients and methods of preparation of appropπate formulations are w ell known to the art Tables 1 and 2 depict exemplary skm cream formulations compπsing Ketotifen for treating pruπtus

Ingredient Amount (in wt%)

Glycerol tπoleate 25%

Glvceπde oil 25%

Hydrogenated glyceπde oil 35%

Lecithin 5%

D-α-Tocopherol 3%

Sorbitol 5%

Ketotifen 2%

Table 1

Ingredient Amount (in wt%)

Diglyceryl monoisostearate 5%

Aluminum tπstearate 0.08%

Squalane 8%

Isopropyl myπstate 2%

MgS0 1%

Methylparaben 0.2%

Propylene glycol 3%

Ketotifen 2%

Puπfied water 78 72%

Table 2

Depending on the nature of the pruπtus and the overall size of the affected area the concentration of Ketotifen need not be restπcted to 2%. For example, where smaller areas are treated and the itching is relatively strong, higher concentrations of Ketotifen are contemplated, including concentrations of 2%-5%, more than 5%, more than 10%, and more than 25%. Where larger areas are affected, or the itching is less severe, lower concentrations than 2% are contemplated, including 1%. and concentrations of less than 1%. With respect to additives, contemplated additives are not limited to titanium dioxide as a coloπng agent, and a bisphenol as antimicrobial agent There are many coloπng agents and antimicrobial agents known in the art and it is contemplated that such known agents are appropπate for alternative formulations It should further be appreciated that vaπous ingredients other than coloπng agents and antimicrobial agents are contemplated For example, contemplated ingredients include inactive ingredients such as sorbitol. cety 1 alcohol isopropyl alcohol, myπstatε, glyceryl stearate. PEG-100 stearate. petrolatum, benzyl alcohol, zinc acetate, lactose, and puπfied water Other ingredients may exhibit cooling propemes, including volatile organic solvents, and volatile aromatic compounds. Still further contemplated ingredients may include pharmaco- logically active ingredients For example, pain relievers, wound healing promoters, or anti- scamng agents may be added

In other aspects of the invenm e subject matter, it is contemplated that the step of identifying the skin area of a patient that is affected ith itching need not be restπcted to the patient by sensing and visually confirming the affected area Identification may also include a person other than the patient, for example a physician, caregiver. or a family member It should further be appreciated that the step of identification may include methods other than sensing and visual confirmation, including staining or thermo scanning

With respect to applying the pharmacological composition to the affected are it is contemplated that vaπous methods other than massaging are also appropπate Alternative methods of topically applying are predominantly dependent on the formulation and area that is affected. Thus it is contemplated that appropπate formulations mav be sprayed, rubbed, poured onto the body surface, topically applied under occlusion, etc It should further be appreciated that contemplated compositions may be administered in vaπous amounts, depending on the size of the affected area, Ketotifen concentration in the composition and seventy of itching For example, while in some cases (e g , an insect bite) a single topical administration of about 0 2g per 10cm² may be sufficient, other situations (e g , contact dermatitis) may require more frequent administrations

It is still further contemplated that the affected area need not necessaπly compπse an insect bite, but may be affected in numerous aspects, including allergic and non-allergic itching For example allergic itching may include an insect sting, hives, atopic dermatitis, contact dermatitis, etc. Non-allergic itching may include neurodermatitis, uremic dermatitis, eczema, sunburn, and so forth It should be especially appreciated that the method of treating pruπtus according to the inventive subject matter presented herein need not be restπcted to treating pruπtus m a human subject, but may also be employed m treatment of pruπtus in an animal. Contemplated animals include vertebrates, and particularly contemplated vertebrates include pets and live stock such as horses, dogs. cats, birds, pigs, cows, etc

In yet another aspect of the inventive subject matter, appropπate amounts of Ketotifen may advantageously admixed with cosmetic preparations, including liquid and solid soaps, shampoos, conditioners, and anti-aging skm creams For example, where liquid or solid soaps are formulated without moistuπzing agents, or here a particular amount of moistuπzmg agent is not sufficient for a person having relatively dry skm. the user of such liquid or solid soap may expeπence localized or widespread itching of the skm due to excessive dryness In another example, scalp itch is known to have \ aπous causes and is a relatively common ailment for many people Despite the availability of vaπous anti-itch shampoos and tinctures, many of those preparations tend to be not entirely satisfactory Thus, it is contemplated that a shampoo and/or conditioner compπsmg appropπate quantities of Ketotifen may be employed to reduce or stop scalp itch Furthermore, cosmetic preparations, and especially preparations to restore dehydrated and/or wπnkled skin, may advantageously be supplemented with amounts of Ketotifen to reduce or stop pruπtus due to dehydrated and/or wπnkled skin

Therefore, it is contemplated that pharmacological compositions may include vaπous cosmetic preparations, and particularly contemplated cosmetic preparations are liquid and solid soaps, hair shampoo, hair conditioner, and cosmetic skm creams that reduce diyness and/or wπnkles of skin There are many cosmetic preparations know n in the art. and composition, consistency, and application purpose are not considered limiting to the inventive subject matter For example, a commercially available hair shampoo or conditioner may be admixed with a 50mg/ml Ketotifen stock solution to obtain a modified shampoo having a final Ketotifen concen- tration of 0.2% (by weight). In another example, w here relatively high concentrations of Ketotifen are desirable. Ketotifen in solid form may be admixed to the shampoo or conditioner to obtain a final concentration of 5% (by weight) Similarly, conv entional soaps may be admixed with appropπate amounts of Ketotifen With respect to the amounts of Ketotifen in the cosmetic preparation the same considerations as descπbed above apply

Thus, specific embodiments and applications of treating pruπtus by topical administration of Ketotifen have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already descπbed are possible without departing from the inventive concepts herein. The mventiv e subject matter, therefore, is not to be restπcted except in the spiπt of the disclosure. Moreover, in interpreting both the specification and the contemplated claims, all terms should be inteφreted in the broadest possible manner consistent with the context. In particular, the terms ""compπses" and "compπsing" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Claims

What is claimed is

1 A. method of treating pruπtus, compπsing

providing a pharmacological composition compπsing Ketotifen

identifying a skin area of a patient that is affected with itching, and

topically administeπng the pharmacological composition to the area of skm at a dosage effective to reduce the itching

2 The method of claim 1 w herein the pruπtus is a symptom of an allergic condition

3 The method of claim 2 wherein the allergic condition is selected from the group consisting of an insect bite, an insect sting, hives, atopic dermatitis, and contact dermatitis

4 The method of claim 1 wherein the pruπtus is a symptom of a condition selected from the group consisting of a sunburn, a neurodermatitis, an uremic dermatitis, and an eczema

5 The method of claim 1 w herein the pharmacological composition is selected from the group consisting of a gel. a mousse, an ointment, a cream, and a lotion

6 The method of claim 5 wherein the step of topically administeπng compπses manually spreading the composition on the skm area

7 The method of claim 1 wherein the pharmacological composition is a liquid

8 The method of claim 7 w herein the step of topically administeπng compπses spraying

9 The method of claim 5 or 7 wherein the step of topically administeπng compπses applying the pharmacological composition under occlusion

10 The method of claim 1 wherein the pharmacological composition compπses less than 0 5% (w/w) Ketotifen

11. The method of claim 1 wherein the pharmacological composition comprises less than 1% (w/w) Ketotifen.

12. The method of claim 1 wherein the pharmacological composition compπses less than 5% (w/w) Ketotifen.

13. The method of claim 1 wherein the pharmacological composition further compπses active ingredients.

14. The method of claim 13 wherein the active ingredient compπses an analgesic.

15 The method of claim 13 herein the active ingredient compπses an antibacteπai agent.

16 The method of claim 15 w herein the antibacteπai agent is an antibiotic.

17. The method of claim 1 wherein the pharmacological composition further comprises inactive ingredients.

18. The method of claim 15 wherein the inactive ingredients are selected from the group consisting of sorbitol, cetyl alcoholjsopropyl alcohol, myπstate, glyceryl stearate, PEG- 100 stearate, petrolatum, benzyl alcohol, titanium dioxide, zinc acetate, lactose, and purified water.

19. The method of claim 1 wherein the patient is an animal.

20. The method of claim 19 wherein the animal is selected from the group consisting of a horse, a dog, a cat. a bird, a pig, and a cow.

21. The method of claim 1 wherein the pharmacological composition further compπses a cosmetic preparation.

22. The method of claim 21 wherein the cosmetic preparation is selected from the group consisting of a hair shampoo, a hair conditioner, a liquid soap, a solid soap, a skin cream that reduces dryness of the skin, and a skin cream that reduces wπnkles of the skin. AMENDED CLAIMS

[received by the International Bureau on 25 September 2000 (25.09.00), original claim 1 amended, remaining claims unchanged (1 page)] What is claimed is.

1 A method of providing symptomatic relief of itching, compπsing' providing a pharmacological composition compπsing Ketotifen, identifying a skm area of a patient that is affected with symptomatic itching, and topically administeπng the pharmacological composition to the area of skm at a dosage effective to reduce the symptomatic itching.

2. The method of claim 1 wherein the pruπtus is a symptom of an allergic condition.

3. The method of claim 2 wherein the allergic condition is selected from the group consisting of an insect bite, an insect stmg, hives, atopic dermatitis, and contact dermatitis

5 The method of claim 1 wherein the pharmacological composition is selected from the group consisting of a gel, a mousse, an ointment, a cream, and a lotion

7 The method of claim 1 wherein the pharmacological composition is a liquid

8 The method of claim 7 wherein the step of topically administeπng compπses spraying.

10 The method of claim 1 wherein the pharmacological composition compπses less than 0.5% (w/w) Ketotifen

11. The method of claim 1 wherein the pharmacological composition compπses less than 1 % (w/w) Ketotifen.