WO2010132286A1

WO2010132286A1 - Orally administered tablet formulation of an antianxiolytic compound

Info

Publication number: WO2010132286A1
Application number: PCT/US2010/033976
Authority: WO
Inventors: Nahla Fattohi; Shobhan Shashikant Sabnis; Moses Columbus Lawrence
Original assignee: Wyeth Llc
Priority date: 2009-05-12
Filing date: 2010-05-07
Publication date: 2010-11-18

Abstract

The present invention relates to orally administered chewable tablets comprising N-methyl-N-[3-(3-methyl-1,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, which are useful in treating and preventing noise-phobia in companion animals.

Description

ORALLY ADMINISTERED TABLET FORMULATION OF AN ANTIANXIOLYTIC

COMPOUND

FIELD OF THE INVENTION The present invention relates to orally administered chewable tablets comprising an antianxiety compound, which is useful in treating and preventing noise-phobia in companion animals.

BACKGROUND OF THE INVENTION

Noise and thunderstorm phobias are among the most commonly recognized disorders associated with panic or phobic responses in companion animals such as dogs, cats or horses, particularly dogs. Thunderstorms, fireworks, gunfire, car backfire, etc. frequently induce undesirable nonspecific clinical symptoms in companion animals, particularly dogs, such as salivating, defecating, urinating, destroying, escaping, hiding trembling, vocalizing and the like. Known treatments for general anxiety behavior in companion animals generally involve either a long period of onset, i.e. 3-4 weeks, or if quick-acting, cause sedation and/or ataxia. However, most companion animal owners and veterinarians would prefer to treat their animals suffering from noise phobia with a method which does not promote sedation or ataxia and which is effective within an hour or two of administration.

The present application provides compositions for the treatment or prevention of anxiety and noise phobia in a companion animal, which exhibits favorable palatability properties.

SUMMARY OF THE INVENTION

The present invention provides a composition comprising N-methyl-N-[3-(3-methyl-1 ,2,4- triazolo-[4,3-b] pyridazin-6-yl)phenyl] acetamide, wherein the composition is in the form of a chewable tablet.

In another embodiment, the present invention provides a method for the treatment or prevention of anxiety in a companion animal which comprises orally administering to said animal a therapeutically effective amount of a composition comprising N-methyl-N-[3-(3-methyl-1 ,2,4- triazolo-[4,3-b]pyridazin-6-yl)phenyl] acetamide, wherein the composition is in the form of a chewable tablet.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION Owners of companion animals and veterinarians strive to find means to control noise phobia in their animals such as dogs, cats and horses, particularly dogs. Noise phobia behaviors may include hiding, scanning, urinating, defecating, panting, chewing, pacing, escaping, trembling, vocalizing and the like. Known therapies used for noise phobia include off-label therapies such as clomipramine, amitriptyline and buspirone which can take more than 3-4 weeks before an effect is apparent, or the use of benzodiazepines, acepromazine or antidepressants which act more quickly but often cause sedation and ataxia.

US Patent Publication No. 2006-0270677, incorporated herein by reference, describes N- methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b]pyridazin-6-yl) phenyl] acetamide for the therapeutic treatment and prevention of noise phobia in a companion animal. Surprisingly, by administering a chewable tablet, as described herein, uptake of the active is greatly improved for treatment of noise phobia.

A preferred aspect of the invention provides a composition comprising N-methyl-N-[3-(3- methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl)phenyl] acetamide, wherein the composition is in the form of a chewable tablet. In another embodiment, the chewable tablet comprises about 20% to about 60% w/w, about 30% to about 50%, about 35% to about 45% w/w or about 40% w/w wheat germ. In another embodiment, the chewable tablet comprises at least one of a sweetener, a tabletting agent, a lubricant and a flavorant. In another embodiment, the sweetener comprises at least one of sugar, corn syrup and sucrose. In another embodiment, the tabletting agent comprises at least one of dibasic calcium phosphate, lactose monohydrate and microcrystalline cellulose. In another embodiment, the flavorant comprises at least one of powdered pork liver, yeast flavor, preferably OPTIMIZER® Veggie-BASE 5OB, chicken liver flavor preferably OPTIMIZER® VARIANT I SPIKE, garlic and artificial butter flavor. In another embodiment, the sweetener comprises corn syrup and corn sugar. In another embodiment, the tabletting agent comprises dibasic calcium phosphate and lactose monohydrate. In another embodiment, the flavorant is pork liver.

In one embodiment, a palatant, tabletting agent, sweetener, flavorant, or lubricant may be used in combination with one or more other palatants, tabletting agents, sweeteners, flavorants, or lubricants, respectively. In another embodiment, the composition comprises N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo- [4,3-b]pyridazin-6-yl) phenyl] acetamide and: about 20% to about 50% w/w palatant; about 15% to about 55% w/w sweetener; about 0% to about 1 % w/w lubricant; about 5% to about 20% w/w tabletting agent; and about 15% to about 25% w/w flavorant.

In another embodiment, the preferred composition comprises N-methyl-N-[3-(3-methyl- 1 ,2,4-triazolo-[4,3-b]pyridazin-6-yl) phenyl] acetamide and: about 30% to about 50% w/w wheat germ; about 4% to about 8% w/w corn syrup; about 10% to about 15% w/w corn sugar; about 0% to about 1% magnesium stearate; about 3% to about 7% w/w dibasic calcium phosphate; about 4% to about 8% w/w lactose monohydrate; and about 15% to about 25% w/w powdered pork liver powder.

In another embodiment, the composition comprises about 1% to about 30% w/w, about 5% to about 20% w/w, or about 5% to about 15% w/w N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide. More particularly, the composition comprises about 10% N- methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide.

Another aspect of the invention provides a method for the treatment or prevention of anxiety in a companion animal which comprises orally administering to said animal a therapeutically effective amount of a composition comprising N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, wherein the composition is in the form of a chewable tablet. In another embodiment, the anxiety is associated with noise phobia. In another embodiment, the composition is as provided in any of the aforementioned embodiments. In another embodiment, the maximum plasma concentration of N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide is achieved in greater than 30 minutes following administration. In another embodiment, the animal is a dog. In another embodiment, the area under the plasma concentration curve (AUC) for N-methyl-

N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, more than 1 hour after administration, is 1.5 times greater than the AUC from 0 to 1 hour of administration. This embodiment is illustrated through the following mathematical formulae: defining AUC as follows: AUC = f ⁼ Cp • dt

then:

where Z = 1.5. The right-hand side integral of the above inequality may be also referred to as

and the left-hand side integral of the above inequality may be also referred to as

In another embodiment, the area under the plasma concentration curve (AUC) for N-methyl-N-[3-(3-methyl- 1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, more than 1 after administration, is two times greater than the AUC from 0 to 1 hour of administration. Accordingly, in the above formulae, Z = 2. In another embodiment, Z =1.1 , Z = 1.2, Z = 1.3, Z = 1.4, Z = 1.5, Z = 1.6, Z = 1.7, Z = 1.8, Z = 1.9, Z = 2.5 or Z = 3.

In a preferred embodiment, the tablet is well-tolerated and/or provides a favorable toxicity profile in the companion animal.

In another embodiment, the palatability of the composition is greater than 87%, 88%, 89%, 90%, 91 %, 92% or 93%.

In another embodiment, the therapeutically effective amount of N-methyl-N-[3-(3-methyl- 1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide is about 1.0 mg to about 100 mg per kg, about 3.0 mg to about 50 mg per kg, about 5.0 mg to about 40 mg per kg, about 10.0 mg to about 30 mg per kg of body weight, or most preferably 2.5 mg to about 25 mg per kg. For certain terms and abbreviations used in this specification, the following definitions are provided:

A "palatant" refers to an agent that enhances palatability through enhancement of flavor, taste, texture or other sensory perception. Examples of palatants include ground wheat, wheat flour, wheat mill run, wheat germ, brewer's yeast , barley, barley flower, rice, brown rice, corn, corn bran, soybean meal, dehydrated eggs, dried milk, dried whey, oatmeal, potatoes, peas, carrots, tallow, dried kelp, lamb fat, and molasses.

A "tabletting agent" refers to an inert component which may be compacted in a tabletting machine with no difficulty, and which may do so even when quantities of drugs and/or other formulation components are mixed with it. Examples of tabletting agents include lactose monohydrate, dibasic calcium phosphate, microcrystalline cellulose, sucrose, mannitol, crystalline sorbitol and microcrystalline chitosan. A "sweetener" refers to an agent that enhances the sweetness of a composition. Examples of sweeteners include sugars, such as sucrose, corn sugar, corn syrup, honey, sorbitol, mannitol, and artificial sweeteners such as aspartame, acesulfame K, and the like.

A "flavorant" refers to an agent that specifically enhances the flavor or scent of a composition. Examples of flavorants for canines include powdered pork liver, brewer's yeast, garlic, chicken liver flavor, OPTIMIZER® Veggie-BASE 5OB, OPTIMIZER® VARIANT I SPIKE, artificial butter flavor, bacon flavor, chicken liver powder, chicken flavor, turkey flavor, beef flavor, lamb flavor, carob, peanut butter, mint, cheese flavor, fish flavor, fruit flavor, vegetable flavor, or compounds found in meat, including: L-proline, L-cysteine, L-histidine, L-lysine, inosine 5'- triphosphate (ITP), inosine 5'-diphosphate (IDP) and/or adenosine 5'-triphosphate (ATP).

A "lubricant" refers to an inert component which reduces the friction between the inner die wall of the tabletting machine and the tablet edge during tablet's ejection from the die cavity. Examples of lubricants include magnesium stearate and other metallic stearates, talcum, stearic acid, high melting waxes and corn starch. The term "chewable tablet" refers to a palatable composition that is chewed prior to ingestion.

The term "palatability" refers to voluntary (free choice) acceptance or ingestion of a pharmaceutical composition by companion animals, as measured by a standard palatability test, such as acceptance testing, preference testing or consumption testing (see A. G. Thombre, Oral delivery of medications to companion animals: palatability considerations, Adv. Drug DeNv. Rev., 56: 1399 - 1413 (2004), which is hereby incorporated by reference). Preferably the voluntary acceptance by a companion animal of a product being tested is ≥ 80%, and more preferably, about ≥ 90% as determined by the above tests.

As used in the specification and claims, the terms "about" and "approximately" designate that a value is within a statistically meaningful range. Such a range can be typically within 10%, more typically still within 5%, and even more typically within 2% of a given value or range. The allowable variation encompassed by the terms "about" and "approximately" depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

As used herein, the term "w/w" designates weight of component/weight of composition, and the term "mg/kg" designates milligrams per kilogram of body weight. The term "a.i." or "ai" designates active ingredient, and may be combined with other terms. For example "mg a.i./kg" designates milligrams of active ingredient per kilogram of body weight.

As used herein, the term "treating" or "treatment" of a condition, such as treatment of noise phobia includes inhibiting an existing condition or arresting its development; or ameliorating or causing regression of the condition. The term "preventing" or "prevention" of a condition, such as prevention of noise phobia, includes substantially blocking or inhibiting the onset or development of a condition before it starts.

"N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide" refers to a compound having the following structural formula:

and encompasses tautomers, salts and isotopes of the compound. The compound N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide and a method to prepare said compound is described in US 4,767,765, incorporated herein by reference. To manufacture the chewable tablet compositions of the present invention, the N-methyl-N-

[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide is wet granulated with palatant, tabletting agent, and sweetener. The dried granulation is then sized and mixed with flavorant, lubricant, sweetener and then compressed into tablets. Alternatively, N-methyl-N-[3-(3-methyl- 1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide is mixed with palatant, flavorants, tabletting agents, sweeteners and directly compressed into tablets. These compositions may then be further processed and packaged for distribution with other agents or packaging materials that will increase/maintain stability, dryness and/or shape during distribution.

The compositions of the invention may further comprise other agents known in the art, such as preservatives (e.g., methylparaben and propylparaben), colorants, antioxidants, UV-absorbing compounds, photostabilizers, viscosity modifying agents, antimicrobial agents, dyes, thickeners, vitamins, adherents, perfumes, deodorants, carriers, diluents, excipients or adjuvants. Generally, these agents are present in the composition in an amount up to about 2% on a weight to volume basis.

The therapeutically effective amount provided in the treatment of noise phobia may vary according to the specific condition(s) being treated, the size, age and response pattern of the companion animal, the severity of the disorder, the judgment of the attending veterinarian or the like. In general, effective amounts for daily oral administration of the chewable tablets provided herein may be about 0.01 to 1 ,000 mg/kg of active, preferably about 0.1 to 100 mg/kg of active or 0.5 to 50 mg/kg of active. Companion animals suitable for use in the method of invention include dogs, cats, horses, hamsters, guinea pigs, or any common domesticated pet, preferably dogs.

For a more clear understanding of the invention, the following examples are set forth herein below. These examples are merely illustrative and are not understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the examples set forth herein below and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

EXAMPLES Example 1 :

A mixture of the anxiolytic active ingredient, wheat germ, lactose, and dibasic calcium phosphate was added to a high shear granulator. Water was added and mixed well to wet the solids. Corn syrup (diluted to 60% solid), was added and mixed with chopper speed at 3000 rpm. The granulation was then dried in an oven at 65°C until moisture level is 3% or less. The dried mixture was then milled and then mixed with pork liver and corn sugar. The resulting mixture was lightly mixed with magnesium stearate, and resulting powder was then compressed into tablets using a conventional tablet press. The composition make-up is shown in Table 1.

Table 1

Example 2:

Artificial butter flavor liquid was first added to a small portion of sucrose for uniform distribution. The mixture is then added to a blend of the remaining solids listed in Table 2 and the resulting powder was then compressed into tablets using a conventional tablet press. Table 2

contains up to 0.5% magnesium stearate.

Example 3: PK Studies: In Phase 1 , Group 1 with 3 Beagle dogs/group, was treated orally with a gelatin capsule containing 180 mg active ingredient (N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3- b]pyridazin-6-yl)phenyl]acetamide) and Group 2 with 3 Beagle dogs/group was treated orally with the palatable tablet, as described in Table 1 , containing 180 mg active ingredient. In Phase 2, two weeks after Phase 1 began, Group 1 was treated orally with the palatable tablet containing active ingredient and Group 2 was treated orally with a gelatin capsule containing active ingredient. The dose range for each dog was approximately 12-16 mg/kg BW active ingredient. Capsules or tablets were administered in the back of the mouth so as to be reliably and completely swallowed by the dogs.

Blood (minimum of 4 ml per sample) was drawn from the jugular vein at the following time points after administration of the experimental compounds: -30 to 0 minutes (pretreatment), 0.25 hour, 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours. The blood was collected into labeled vacutainer tubes containing heparin in sufficient amounts to prevent clotting and held on ice until further processing. Blood plasma was separated from cellular material by centrifugation at approximately 1 ,000 x g (minimum) for 20 minutes at 4⁰C. The plasma fractions were transferred individually to plastic vials and held frozen until shipment on dry ice to a laboratory, where they were analyzed for their concentrations of N-methyl-N-[3-(3-methyl-1 ,2,4- triazolo-[4,3-b] pyridazin-6-yl) phenyl]acetamide. The resulting concentrations were normalized to a dose of 15 mg/kg BW. Table 3 summarizes the calculated mean T_max, C_maχ, and AU C₍₀-τ) values for each of the formulations.

Table 3

The average T_max was 0.54 hours for the capsule and 1.25 hours for the tablet. The average peak plasma concentration was 9.24 μg/ml for the capsule and 5.9 μg/ml for the tablet. At 2 hours post-tablet administration, the concentration of active was approximately 40% higher than the concentration of active 2-hours post-capsule administration. The average AUC(o_-T) was 13.07 μg-hr/ml for the capsule and 1 1.43 μg-hr/ml for the tablet.

Claims

1. A composition comprising N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, wherein the composition is in the form of a chewable tablet.

2. The composition of claim 1 , wherein the chewable tablet comprises about 30% to about 50% w/w wheat germ.

3. The composition of claim 1 or claim 2, wherein the chewable tablet comprises at least one of a sweetener, a tabletting agent, a lubricant and a flavorant.

4. The composition of claim 3, wherein the sweetener comprises at least one of sugar, corn syrup and sucrose.

5. The composition of claim 3, wherein the tabletting agent comprises at least one of dibasic calcium phosphate, lactose monohydrate and microcrystalline cellulose.

6. The composition of claim 3, wherein the flavorant comprises at least one of powdered pork liver, chicken liver flavor, yeast flavor, garlic and artificial butter flavor.

7. The composition of claim 3, wherein the sweetener comprises corn syrup and corn sugar.

8. The composition of claim 3, wherein the tabletting agent comprises dibasic calcium phosphate and lactose monohydrate.

9. The composition of claim 3, wherein the flavorant is powdered pork liver.

10. The composition of claim 1 , comprising: about 30% to about 50% w/w palatant; about 15% to about 55% w/w sweetener; about 0% to about 1 % w/w lubricant; about 5% to about 20% w/w tabletting agent; and about 15% to about 25% w/w flavorant.

11. The composition of claim 1 , comprising: about 30% to about 50% w/w wheat germ; about 4% to about 8% w/w corn syrup; about 10% to about 15% w/w corn sugar; about 0% to about 1% magnesium stearate; about 3% to about 7% w/w dibasic calcium phosphate; about 4% to about 8% w/w lactose monohydrate; and about 15% to about 25% w/w powdered pork liver.

12. The composition of any one of the previous claims, comprising about 5% to about 20% w/w N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide.

13. The composition of claim 12, comprising about 10% N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo- [4,3-b] pyridazin-6-yl) phenyl] acetamide.

14. A method for the treatment or prevention of anxiety in a companion animal which comprises orally administering to said animal a therapeutically effective amount of a composition comprising N-methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide, wherein the composition is in the form of a chewable tablet.

15. The method of claim 14, wherein the anxiety is associated with noise phobia.

16. The method of claim 14, wherein the composition is provided in any one of claims 1-13.

17. The method of any one of claims 14-16, wherein the palatability of the composition is greater than 90%.

18. The method of any one of claims 14-17, wherein the therapeutically effective amount of N- methyl-N-[3-(3-methyl-1 ,2,4-triazolo-[4,3-b] pyridazin-6-yl) phenyl] acetamide is about 2.5 mg to about 25 mg per kg of body weight.

19. The method of any one of claims 14-18, wherein the animal is a dog.