WO2010132286A1 - Préparation en comprimé administrée par voie orale d'un composé antianxiolytique - Google Patents

Préparation en comprimé administrée par voie orale d'un composé antianxiolytique Download PDF

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Publication number
WO2010132286A1
WO2010132286A1 PCT/US2010/033976 US2010033976W WO2010132286A1 WO 2010132286 A1 WO2010132286 A1 WO 2010132286A1 US 2010033976 W US2010033976 W US 2010033976W WO 2010132286 A1 WO2010132286 A1 WO 2010132286A1
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WO
WIPO (PCT)
Prior art keywords
composition
methyl
pyridazin
triazolo
acetamide
Prior art date
Application number
PCT/US2010/033976
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English (en)
Inventor
Nahla Fattohi
Shobhan Shashikant Sabnis
Moses Columbus Lawrence
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Wyeth Llc
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Publication date
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Publication of WO2010132286A1 publication Critical patent/WO2010132286A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • 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.
  • 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.
  • compositions for the treatment or prevention of anxiety and noise phobia in a companion animal which exhibits favorable palatability properties.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the chewable tablet comprises at least one of a sweetener, a tabletting agent, a lubricant and a flavorant.
  • the sweetener comprises at least one of sugar, corn syrup and sucrose.
  • the tabletting agent comprises at least one of dibasic calcium phosphate, lactose monohydrate and microcrystalline cellulose.
  • 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.
  • the sweetener comprises corn syrup and corn sugar.
  • the tabletting agent comprises dibasic calcium phosphate and lactose monohydrate.
  • the flavorant is pork liver.
  • 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.
  • 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.
  • 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.
  • 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.
  • the anxiety is associated with noise phobia.
  • the composition is as provided in any of the aforementioned embodiments.
  • 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.
  • the animal is a dog.
  • 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
  • the tablet is well-tolerated and/or provides a favorable toxicity profile in the companion animal.
  • the palatability of the composition is greater than 87%, 88%, 89%, 90%, 91 %, 92% or 93%.
  • 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.
  • a "palatant” refers to an agent that enhances palatability through enhancement of flavor, taste, texture or other sensory perception.
  • 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.
  • 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.
  • 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.
  • 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).
  • a standard palatability test such as acceptance testing, preference testing or consumption testing
  • 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.
  • w/w designates weight of component/weight of composition
  • mg/kg designates milligrams per kilogram of body weight
  • a.i.” or “ai” designates active ingredient, and may be combined with other terms.
  • mg a.i./kg designates milligrams of active ingredient per kilogram of body weight.
  • the term “treating” or “treatment” of a condition 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 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:
  • [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.
  • 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.
  • 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.
  • preservatives e.g., methylparaben and propylparaben
  • colorants e.g., methylparaben and propylparaben
  • antioxidants e.g., methylparaben and propylparaben
  • UV-absorbing compounds e.g., UV-absorbing compounds
  • photostabilizers e.g., ethylene glycol, glycerin, glycerin, glycerin, ethylene glycol, glycerin, glycerin, glycerin, ethylene glyco
  • 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.
  • 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.
  • 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.
  • magnesium stearate 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 4 0 C.
  • 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 ma ⁇ , and AU C (0 - ⁇ ) values for each of the formulations.
  • 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 ⁇ g/ml for the capsule and 5.9 ⁇ g/ml for the tablet.
  • 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 ⁇ g-hr/ml for the capsule and 1 1.43 ⁇ g-hr/ml for the tablet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des comprimés à mâcher destinés à l'administration par voie orale comprenant N-méthyl-N-[3-(3-méthyl-1,2,4-triazolo-[4,3-b] pyridazin-6-yl) phényl] acétamide, qui sont utiles dans le traitement et la prévention de la phobie du bruit chez les animaux de compagnie.
PCT/US2010/033976 2009-05-12 2010-05-07 Préparation en comprimé administrée par voie orale d'un composé antianxiolytique WO2010132286A1 (fr)

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US61/177,379 2009-05-12

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WO2010132286A1 true WO2010132286A1 (fr) 2010-11-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020015393A1 (fr) * 2018-07-19 2020-01-23 中山大学 Application d'un inhibiteur de la voie du signal lin28/let-7 dans la préparation d'un médicament pour réguler l'expression de pd-l1
US10543170B2 (en) 2012-12-19 2020-01-28 Bayer Animal Health Gmbh Tablets with improved acceptance and good storage stability

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767765A (en) * 1985-10-31 1988-08-30 American Cyanamid Company N-substituted-N-[3-(1,2,4-triazolo-[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas
EP0753296A2 (fr) * 1995-06-13 1997-01-15 American Home Products Corporation Compositions orales, contenant de l'S(+)-ibuprofène
US5824336A (en) * 1994-05-20 1998-10-20 Janssen Pharmaceutica, N.V. Chewable flubendazole tablets for companion animals
WO2004016252A1 (fr) * 2002-08-16 2004-02-26 Merial Limited Formulations veterinaires ne contenant pas de produits d'origine animale
US20040166157A1 (en) * 2002-03-05 2004-08-26 Pfizer Inc Palatable controlled-released formulations for companion animals
US20060270677A1 (en) * 2005-05-26 2006-11-30 Wyeth Method for the treatment of noise phobia in companion animals

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4767765A (en) * 1985-10-31 1988-08-30 American Cyanamid Company N-substituted-N-[3-(1,2,4-triazolo-[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas
US5824336A (en) * 1994-05-20 1998-10-20 Janssen Pharmaceutica, N.V. Chewable flubendazole tablets for companion animals
EP0753296A2 (fr) * 1995-06-13 1997-01-15 American Home Products Corporation Compositions orales, contenant de l'S(+)-ibuprofène
US20040166157A1 (en) * 2002-03-05 2004-08-26 Pfizer Inc Palatable controlled-released formulations for companion animals
WO2004016252A1 (fr) * 2002-08-16 2004-02-26 Merial Limited Formulations veterinaires ne contenant pas de produits d'origine animale
US20060270677A1 (en) * 2005-05-26 2006-11-30 Wyeth Method for the treatment of noise phobia in companion animals

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A. G. THOMBRE: "Oral delivery of medications to companion animals: palatability considerations", ADV. DRUG DELIV. REV., vol. 56, 2004, pages 1399 - 1413

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10543170B2 (en) 2012-12-19 2020-01-28 Bayer Animal Health Gmbh Tablets with improved acceptance and good storage stability
US11147764B2 (en) 2012-12-19 2021-10-19 ELANCO US, Inc. Tablets with improved acceptance and good storage stability
WO2020015393A1 (fr) * 2018-07-19 2020-01-23 中山大学 Application d'un inhibiteur de la voie du signal lin28/let-7 dans la préparation d'un médicament pour réguler l'expression de pd-l1

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