WO2001021178A2 - Method of treating cognitive dysfunction syndrome in dogs and chewable tablet for dogs - Google Patents

Method of treating cognitive dysfunction syndrome in dogs and chewable tablet for dogs Download PDF

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Publication number
WO2001021178A2
WO2001021178A2 PCT/US2000/025771 US0025771W WO0121178A2 WO 2001021178 A2 WO2001021178 A2 WO 2001021178A2 US 0025771 W US0025771 W US 0025771W WO 0121178 A2 WO0121178 A2 WO 0121178A2
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WO
WIPO (PCT)
Prior art keywords
tablet
dogs
propentofyuine
chewable tablet
tablets
Prior art date
Application number
PCT/US2000/025771
Other languages
French (fr)
Other versions
WO2001021178A3 (en
Inventor
Elizabeth M. Abbott
Susan M. Cady
Original Assignee
Akzo Nobel, N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akzo Nobel, N.V. filed Critical Akzo Nobel, N.V.
Priority to AU75953/00A priority Critical patent/AU7595300A/en
Publication of WO2001021178A2 publication Critical patent/WO2001021178A2/en
Publication of WO2001021178A3 publication Critical patent/WO2001021178A3/en

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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to methods of treating cognitive dysfunction
  • the present invention also relates to a tablet containing
  • propentofyUine which may be used, for example, to treat cognitive dysfunction
  • CD cognitive dysfunction syndrome
  • CD is often referred to by veterinarians as “old dog syndrome” or, simply,
  • CD may manifest itself as one of several brain conditions including
  • the present invention relates to methods of treating cognitive dysfunction
  • the method includes administering to a dog identified as having
  • propentofyUine is
  • propentofyUine is
  • PropentofyUine is a xanthine derivative having the formula 3 -methyl- 1 -
  • PropentofyUine is a also selective inhibitor of adenosine transport and
  • the present invention also relates to a tablet which can be used, for example, to
  • the tablet comprises propentofyUine
  • the flavor enhancing ingredient is at least one sweetener and at least one flavoring agent.
  • the tablet may additionally contain one or more binders
  • propentofyUine is present in an amount effective to treat cognitive
  • Fig. 1 is a perspective view of a tablet suitable for use in the present invention
  • Fig. 2 is a view in elevation along the length of the tablet of Figure 1;
  • Fig. 3 is a view in elevation along the width of the tablet of Figure 1 ;
  • Fig. 4 is a plan view of the top of the tablet of Figure 1.
  • Fig. 5 is a graph demonstrating efficacy results of dogs provided with
  • Fig. 6 is a graph demonstrating efficacy results of dogs provided with
  • Fig. 7 is a graph demonstrating efficacy results of dogs provided with
  • Fig. 8 is a graph demonstrating efficacy results of dogs provided with
  • Fig. 9 is a graph demonstrating efficacy results of dogs provided with
  • Fig. 10 is a graph demonstrating efficacy results of dogs provided with
  • the present invention relates to methods of treating cognitive dysfunction
  • the method includes administering to a dog identified as having
  • CD cognitive dysfunction syndrome
  • propentofyUine is administered to an elderly dog
  • An “elderly dog,” as defined in the present invention, is a dog at least
  • propentofyUine is administered to the dog orally.
  • propentofyUine is administered while the dog has an
  • the dosage amount of propentofyUine in the method of the present invention is not limited
  • the dosage amount of propentofyUine is about 10 (i.e. 8-12) mg/kg
  • This amount may be administered in a single dosage
  • propentofyUine is about 1-10 mg/kg body weight of the dog, twice daily. More preferably in this embodiment, the dosage amount is about 5 (i.e., 3-7) mg/kg body
  • the present invention also relates to a tablet that may be used, for example, to
  • the tablet comprises propentofyUine
  • propentofyUine is present in the tablet in an amount
  • the amount of propentofyUine in the tablet is preferably from
  • Preferred dosages are about 50 mg to about 200 mg, but is not limited thereto. Preferred dosages are about
  • the tablets may be scored such that they
  • the flavor enhancing ingredient provides an aroma and flavor, such
  • the at least one flavor enhancing ingredient is at least one sweetener and at least one sweetener
  • the drug to sweetener to flavoring agent ratio is the drug to sweetener to flavoring agent ratio
  • the drug to sweetener to flavoring agent ratio is
  • Suitable sweeteners in accordance with the present invention include sugars (or
  • sugar derivatives such as sucrose, fructose, dextrose, glucose, maltose; liquid
  • sweeteners such as sorbitol, mannitol, maltitol, lactitol and xylitol; and artificial
  • sweeteners such as aspartame, saccharine, sucralose, cyclamates, acesulfame and acesulfame-K.
  • the sweetener is at least one artificial sweetener. More
  • the at least one artificial sweetener is aspartame.
  • Suitable flavoring agents in accordance with the present invention include meat
  • a preferred flavoring agent is PC- 125, a meat flavoring available from Pharma
  • an antioxidant may be included in certain formulations, particularly those including oils.
  • the antioxidant protects oils such as soybean oil from
  • the tablet may also contain binders and/or lubricants to create a tablet of an
  • the tablet in one embodiment of the tablet according to the present invention, the tablet
  • binders further comprises one or more binders.
  • at least one of the binders is a
  • binders that are suitable for use in the
  • tablet of the present invention include microcrystalline cellulose, silicon dioxide,
  • tablet further comprises one or more lubricants.
  • lubricants that are suitable for use in the tablet of the present invention include stearic acid, magnesium
  • the chewable tablet is in the shape of a bone.
  • suitable chewable tablets in the shape of a bone are the bone-shaped tablets
  • Fig. 1 depicts an embodiment of a bone-shaped tablet suitable for use in the
  • Bone-shaped tablets such as the tablet illustrated in Fig. 1 ,
  • the present invention may have a length of from about 1 cm to about 3
  • Fig. 2 - 4 are different views of the bone-shaped tablet depicted in Fig.1.
  • tooling such as bone shape 0.5000" x 0.9610" tooling.
  • the study was a randomized double blind, placebo
  • the dosage form of the propentofyUine was 50 and 100 mg film coated tablets.
  • the 50 mg tablets were double scored, while the 100 mg tablets were single scored.
  • the dose rate was 5.0 mg propentofylline/kg body weight (bw) twice a day
  • the dose route was orally on an empty stomach (at least
  • the dosage for the placebo was the control equivalent of 50 (double scored)
  • the dose rate for the placebo was the control equivalent of 5.0 mg
  • test and control tablets were identical in size and appearance. The identity
  • test and control articles were not known to the referring DVMs, the behavior consultants and the dog owners. Both test and control tablets were supplied as film
  • CD cognitive dysfunction syndrome
  • disorientation (4 categories) spatial disorientation; staring into space; getting stuck in corners or under furniture; and aimless locomotion or pacing
  • activity level (3 categories) whether the dog exercised on lead; whether the dog exercised loose; and the level of the dog's initiative, for example, his interest in toys or bones and his demand for attention,
  • non-recognition (3 categories) whether the dog greets his owner on arrival; whether the dog greets other family members and familiar people on arrival; and whether the dog recognizes his owner's car
  • responsiveness (4 categories) responsiveness to owner initiated events such as food, exercise, and games; responsiveness to other animals; responsiveness to other familiar people; and responsiveness to outside stimuli such as the postman, telephone ringing and the door bell,
  • total anxiety (9 categories), including factors relating to separation anxiety, salivation, elimination in the house, destructiveness, and excessive vocalization; phobias, being afraid of noise, and the inability to cope with scheduled changes; and night-time problems, pacing, vocalization and destructive behavior.
  • the individual dog was the unit of observation and statistical analysis.
  • Table 2 Number of dogs showing signs of CD and the average score at enrollment.
  • Figure 5 demonstrates that the scores of dogs with regard to the first endpoint
  • Figure 8 demonstrates that the scores of dogs with regard to the first endpoint

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Zoology (AREA)
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  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Fodder In General (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Methods of treating cognitive dysfunction syndrome in dogs. The method includes identifying dogs that have cognitive dysfunction syndrome and administering to them propentofylline. The amount of propentofylline administered to the dogs is an effective amount to treat cognitive dysfunction syndrome. Also described are chewable tablets for dogs containing propentofylline and at least one flavor enhancing ingredient. The tablet may also contain binders, lubricants and/or antioxidants.

Description

Method of Treating Cognitive Dysfunction Syndrome in Dogs and Che able Tablet for Dogs
Field of the Invention
The present invention relates to methods of treating cognitive dysfunction
syndrome in dogs. The present invention also relates to a tablet containing
propentofyUine, which may be used, for example, to treat cognitive dysfunction
syndrome in dogs.
Background of the Invention
In dogs, cognitive dysfunction syndrome (CD) is the age-related aggregated
deterioration of cognitive abilities (such as spatial orientation, responding to humans,
learning, and memory) that cannot be completely attributed to motor or sensory
impairment or general medical conditions (such as neoplasia, infection or organ
failure). CD is often referred to by veterinarians as "old dog syndrome" or, simply,
"senility". CD may manifest itself as one of several brain conditions including
dementia, memory disturbance, disorientation, loss of prior house-training,
disturbances of sleep and wake cycles, altered social interactions and decreased
activity. (See Dodman NH and Schuster L. eds. Psychopharmacology of Animal
Behavior Disorders. Ames, IA: Iowa State University Press; 1998: 284; and The Brain
on the Wane, Veterinary Forum, July 1998.)
The prevalence of cognitive dysfunction syndrome in elderly dogs is high. It
has been reported that as many as 32% of eleven year old dogs and 100% of sixteen year old dogs exhibit signs of cognitive dysfunction syndrome. (J. Am Vet MedAssoc
1997; 210: 1129-1134.)
There is thus a need for a method of treating cognitive dysfunction syndrome
in dogs.
Summary of the Invention
The present invention relates to methods of treating cognitive dysfunction
syndrome in dogs. The method includes administering to a dog identified as having
cognitive dysfunction syndrome a dosage amount of propentofyUine effective to treat
the cognitive dysfunction syndrome. In a preferred embodiment, propentofyUine is
administered to the dog orally. In another preferred embodiment, propentofyUine is
administered while the dog has a relatively empty stomach.
PropentofyUine (ppf) is a xanthine derivative having the formula 3 -methyl- 1 -
(5-oxohexyl)-7-propylxanthine.
The use of propentofyUine for the treatment of cognitive dysfunction syndrome
in dogs is believed to be advantageous because propentofyUine stimulates synthesis
and liberation of nerve growth factor and reduces ischemic damage to the brain.
PropentofyUine is a also selective inhibitor of adenosine transport and
phosphodiesterase.
The present invention also relates to a tablet which can be used, for example, to
treat cognitive dysfunction syndrome in dogs. The tablet comprises propentofyUine
and at least one flavor enhancing ingredient. In a preferred embodiment, the flavor enhancing ingredient is at least one sweetener and at least one flavoring agent. In
other preferred embodiments, the tablet may additionally contain one or more binders
and/or lubricants. In another preferred embodiment of the tablet according to the
present invention, propentofyUine is present in an amount effective to treat cognitive
dysfunction syndrome in dogs affected by cognitive dysfunction syndrome.
Brief Description of the Drawings
Fig. 1 is a perspective view of a tablet suitable for use in the present invention;
Fig. 2 is a view in elevation along the length of the tablet of Figure 1;
Fig. 3 is a view in elevation along the width of the tablet of Figure 1 ; and
Fig. 4 is a plan view of the top of the tablet of Figure 1.
Fig. 5 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo.
Fig. 6 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo.
Fig. 7 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo.
Fig. 8 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo.
Fig. 9 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo. Fig. 10 is a graph demonstrating efficacy results of dogs provided with
propentofyUine treatment than as opposed to dogs provided with a placebo.
Detailed Description
The present invention relates to methods of treating cognitive dysfunction
syndrome in dogs. The method includes administering to a dog identified as having
cognitive dysfunction syndrome (CD), a dosage amount of propentofyUine effective to
treat said cognitive dysfunction syndrome. In a preferred embodiment of the method
according to the present invention, propentofyUine is administered to an elderly dog
having CD. An "elderly dog," as defined in the present invention, is a dog at least
seven years old.
In a preferred embodiment, propentofyUine is administered to the dog orally.
In another preferred embodiment, propentofyUine is administered while the dog has an
empty stomach.
The dosage amount of propentofyUine in the method of the present invention is
preferably about 1 -20 mg/kg body weight of the dog per day, but is not limited thereto.
More preferably, the dosage amount of propentofyUine is about 10 (i.e. 8-12) mg/kg
body weight of the dog per day. This amount may be administered in a single dosage
unit or preferably in multiple dosage units, which accumulate to 1 -20 mg/kg body
weight per day. For example, in one embodiment the dosage amount of
propentofyUine is about 1-10 mg/kg body weight of the dog, twice daily. More preferably in this embodiment, the dosage amount is about 5 (i.e., 3-7) mg/kg body
weight of the dog, twice daily.
The present invention also relates to a tablet that may be used, for example, to
treat cognitive dysfunction syndrome in dogs. The tablet comprises propentofyUine
and at least one flavor enhancing ingredient. In a preferred embodiment of the tablet
according to the present invention, propentofyUine is present in the tablet in an amount
effective to treat cognitive dysfunction syndrome in dogs affected by cognitive
dysfunction syndrome. The amount of propentofyUine in the tablet is preferably from
about 50 mg to about 200 mg, but is not limited thereto. Preferred dosages are about
50 mg (i.e., 30-70 mg), about 100 mg (i.e., 80-120 mg), about 150 mg (i.e., 130-170
mg), and about 200 mg (i.e., 170-230 mg). The tablets may be scored such that they
can be broken in approximately half to administer a portion of the tablet.
Preferably the flavor enhancing ingredient provides an aroma and flavor, such
that dogs will eat the tablets. In a preferred embodiment of the tablet of the present
invention, the at least one flavor enhancing ingredient is at least one sweetener and at
least one flavoring agent. Preferably, the drug to sweetener to flavoring agent ratio is
1 : 0.5-1.5 : 3-7. More preferably, the drug to sweetener to flavoring agent ratio is
about 1 :1 :4.5 or 1 :1 :5.
Suitable sweeteners in accordance with the present invention include sugars (or
sugar derivatives) such as sucrose, fructose, dextrose, glucose, maltose; liquid
sweeteners, such as sorbitol, mannitol, maltitol, lactitol and xylitol; and artificial
sweeteners such as aspartame, saccharine, sucralose, cyclamates, acesulfame and acesulfame-K. Preferably, the sweetener is at least one artificial sweetener. More
preferably, the at least one artificial sweetener is aspartame.
Suitable flavoring agents in accordance with the present invention include meat
flavoring, whey, soybean oil, and other oils and flavor bases known to those skilled in
the art. A preferred flavoring agent is PC- 125, a meat flavoring available from Pharma
Chemie company of Syracuse, Nebraska.
In certain formulations, particularly those including oils, an antioxidant may
also be added to the tablet. The antioxidant protects oils such as soybean oil from
becoming rancid. An example of a suitable antioxidant for use in the present invention
is Tenox™ 8 available from Eastman Chemical Company.
The tablet may also contain binders and/or lubricants to create a tablet of an
appropriate taste, aroma, consistency and size for administration of the tablet to dogs.
Hence, in one embodiment of the tablet according to the present invention, the tablet
further comprises one or more binders. Preferably at least one of the binders is a
directly compressible binder. Examples of binders that are suitable for use in the
tablet of the present invention include microcrystalline cellulose, silicon dioxide,
compressible sugar, bicalcium phosphate, spray dried lactose, anhydrous lactose,
dicalcium phosphate dihydrate, direct compression starch, spray-crystallized
dextrose/maltose, calcium sulphate dihydrate, γ-sorbitol, tricalcium phosphate, lactose
monohydrate, modified rice starch and crystalline lactose.
In another embodiment of the tablet according to the present invention, the
tablet further comprises one or more lubricants. Examples of lubricants that are suitable for use in the tablet of the present invention include stearic acid, magnesium
stearate, talc, calcium stearate, zinc stearate, propylene glycol, and polyethylene
glycol.
In a preferred embodiment, the chewable tablet is in the shape of a bone. An
example of suitable chewable tablets in the shape of a bone are the bone-shaped tablets
shown in design patent application entitled "Bone Shaped Tablet," filed April 28,
1999, by Susan Mancini Cady and Robert C. Sterling, which is herein incoφorated by
reference. The bone-shaped tablets set forth in the design patent application are
demonstrated in Figures 1 - 4 herein.
Fig. 1 depicts an embodiment of a bone-shaped tablet suitable for use in the
present invention. Bone-shaped tablets such as the tablet illustrated in Fig. 1 ,
according to the present invention, may have a length of from about 1 cm to about 3
cm; a width of from about 0.5 cm to about 1.5 cm at its widest, and a height of from
about 0.5 cm to about 1.5 cm as shown.
Fig. 2 - 4 are different views of the bone-shaped tablet depicted in Fig.1.
The following examples provide a more specific description of the present
invention but are not limitative thereof.
EXAMPLE 1
Product:
PropentofyUine 50 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 65.000
Stearic Acid, NF 13.000
Magnesium Stearate, NF 6.500
Silicon Dioxide, NF 6.500
PC-125 225.000 Aspartame, NF 50.000
Compressible Sugar, NF 234.000 PropentofyUine 50.000
Total Tablet Weight 650.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using a tooling such
as bone shape 0.3150" x 0.6054" tooling.
Physical Tablet Characteristics: Average Tablet Weight 652.0 mg (10 tablets)
Average Tablet Hardness 24.7 Kilopods (Kp) (10 tablets)
Average Tablet Thickness 0.210 inches (10 tablets)
Average Tablet Friability 0.06 % (20 tablets, 100 rev)
Average Tablet Disintegration 9.8 min. (6 tablets, 37 C)
Tests providing the above physical tablet characteristics would be known to
those skilled in the art and are commonly performed with regard to making tablets. EXAMPLE 2
Product:
PropentofyUine 150 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 195.000
Stearic Acid, NF 39.000
Magnesium Stearate, NF 19.500
Silicon Dioxide, NF 19.500
PC-125 675.000
Aspartame, NF 150.000
Compressible Sugar, NF 702.000
PropentofyUine 150.000
Total Tablet Weight 50.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using a tooling such
as bone shape 0.4543" x 0.8731 " tooling.
Physical Tablet
Characteristics: Average Tablet Weight 1956.0 mg
(10 tablets)
Average Tablet Hardness 28.7 Kp (10 tablets)
Average Tablet Thickness 0.327 inches (10 tablets) Average Tablet Friability 1.63 %
(20 tablets, 100 rev)
Average Tablet Disintegration 12.9 min. (6 tablets, 37 C)
EXAMPLE 3
Product:
PropentofyUine 200 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 260.000
Stearic Acid, NF 52.000
Magnesium Stearate, NF 26.000
Silicon Dioxide, NF 26.000
PC-125 900.000
Aspartame, NF 200.000
Compressible Sugar, NF 936.000
PropentofyUine 200.000
Total Tablet Weight 2600.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using tooling such as
bone shape 0.5000" x 0.9610" tooling. Physical Tablet Characteristics: Average Tablet Weight 2584.0 mg (10 tablets)
Average Tablet Hardness 18.7 Kp (10 tablets)
Average Tablet Thickness 0.386 inches (10 tablets)
Average Tablet Friability 1.98 % (20 tablets, 100 rev)
Average Tablet Disintegration 11.2 min. (6 tablets, 37 C)
EXAMPLE 4
Product:
PropentofyUine 45.45 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 65.000
Stearic Acid, NF 13.000
Magnesium Stearate, NF 6.500
Silicon Dioxide, NF 6.500
PC-125 227.250
Aspartame, NF 45.450
Compressible Sugar, NF 240.850
PropentofyUine 45.450
Total Tablet Weight 650.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend. 3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using a tooling such
as bone shape 0.3150" x 0.6054" tooling.
Physical Tablet Characteristics: Average Tablet Weight 655.0 mg (10 tablets)
Average Tablet Hardness 23.3 Kp (10 tablets)
Average Tablet Thickness 0.210 inches (10 tablets)
Average Tablet Friability 0.28 % (20 tablets, 100 rev)
Average Tablet Disintegration 10.7 min. (6 tablets, 37 C)
EXAMPLE 5
Product:
PropentofyUine 136.35 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 195.000
Stearic Acid, NF 39.000
Magnesium Stearate, NF - 19.500
Silicon Dioxide, NF 19.500
PC-125 681.750
Aspartame, NF 136.350
Compressible Sugar, NF 722.550
PropentofyUine 136.350
Total Tablet Weight 1950.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients. 2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using a tooling such
as bone shape 0.45430" x 0.8731" tooling.
Physical Tablet Characteristics: Average Tablet Weight 1932.0 mg
(10 tablets)
Average Tablet Hardness 17.9 Kp (10 tablets)
Average Tablet Thickness 0.333 inches (10 tablets)
Average Tablet Friability 1.76 % (20 tablets, 100 rev)
Average Tablet Disintegration 12.1 min. (6 tablets, 37 C)
EXAMPLE 6
Product:
PropentofyUine 181.8 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 260.000
Stearic Acid, NF 52.000
Magnesium Stearate, NF 26.000
Silicon Dioxide, NF 26.000
PC-125 909.000
Aspartame, NF 181.800
Compressible Sugar, NF 963.400
PropentofyUine 181.800 Total Tablet Weight 2600.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using for example a
tooling such as bone shape 0.5000" x 0.9610" tooling.
Physical Tablet
Characteristics: Average Tablet Weight 2678.0 mg
(10 tablets)
Average Tablet Hardness 30.8 Kp
(10 tablets)
Average Tablet Thickness 0.375 inches (10 tablets)
Average Tablet Friability 1.83 % (20 tablets, 100 rev)
Average Tablet Disintegration 11.8 min. (6 tablets, 37 C) -
EXAMPLE 7
Product:
PropentofyUine 50 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
PropentofyUine 50.000 Microcry. Cellulose, NF 200.000 Dicalcium Phosphate, USP 5.000 Stearic Acid, NF 20.000
Magnesium Stearate, NF 10.000
Silicon Dioxide, NF 10.000
PC-125 250.000
> Aspartame, NF 50.000
Compressible Sugar, NF 250.000
Whey, Spray Dried 150.000
Soybean Oil 4.950
Tenox 8 0.050
Total Tablet Weight 1000.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using V." standard
round concave tooling.
Physical Tablet
Characteristics: Average Tablet Weight 980.5 mg
(10 tablets)
Average Tablet Hardness" 14.2 Kp (10 tablets)
Average Tablet Thickness 0.276 inches
(10 tablets)
Average Tablet Friability 0.03 %
(20 tablets, 100 rev)
Average Tablet Disintegration 24.83 min.
(6 tablets, 37 C) EXAMPLE 8
Product:
PropentofyUine 100 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
PropentofyUine 100.000
Microcry. Cellulose, NF 400.000
Dicalcium Phosphate, USP 10.000
Stearic Acid, NF 40.000
Magnesium Stearate, NF 20.000
Silicon Dioxide, NF 20.000
Meat flavoring 500.000
Aspartame, NF 100.000
Compressible Sugar, NF 500.000
Whey, Spray Dried 300.000
Soybean Oil 9.000
Tenox 8 0.100
Total Tablet Weight 2000.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time.
4. Compress the product blend for example on a tablet press using 11/16" standard
round concave tooling.
Physical Tablet Characteristics: Average Tablet Weight 1981.2 mg (10 tablets) Average Tablet Hardness 14.6 Kp
(10 tablets)
Average Tablet Thickness 0.304 inches (10 tablets)
Average Tablet Friability 0.16 % (20 tablets, 100 rev)
Average Tablet Disintegration 26.5 min. (6 tablets, 37 C)
EXAMPLE 9
Product:
PropentofyUine 136.35 mg Chewable Tablets for Dogs
Product Formula: Ingredients mg/tablet
Microcry. Cellulose, NF 195.000
Stearic Acid, NF 39.000
Magnesium Stearate, NF 19.500
Silicon Dioxide, NF 19.500
PC-125 681.750
Aspartame, NF 136.350
Compressible Sugar, NF 722.550
PropentofyUine 136.350
Total Tablet Weight 1950.000 mg/tablet
Production Process:
1. Weigh out all of the ingredients.
2. Mix all of the ingredients together to produce a uniform mix using geometric
dilution techniques, starting with PropentofyUine and proceeding down in the
ingredient listing order. Mix in a mixer such as a Kitchen Aid™ mixer at a speed of 1
for 15 minutes to produce a uniform blend.
3. Screen all product through a 20 mesh screen, then bag shake the product for 5
minutes mix time. 4. Compress the product blend for example on a tablet press using a tooling such
as bone shape 0.4543" x 0.8731 " tooling.
Physical Tablet
Characteristics: Average Tablet Weight 1932.0 mg (10 tablets)
Average Tablet Hardness 17.9 Kp (10 tablets)
Average Tablet Thickness 0.333 inches (10 tablets)
Average Tablet Friability 1.76 %
(20 tablets, 100 rev)
Average Tablet Disintegration 12.1 min. (6 tablets, 37 C)
Efficacy Tests
A study was performed to evaluate the effects of propentofyUine, given orally
at a dose rate of 5.0 mg/kg twice daily, on behavior changes associated with cognitive
dysfunction in elderly dogs. The study was a randomized double blind, placebo
controlled clinical study in elderly dogs showing signs of canine cognitive dysfunction.
The study was conducted in accordance with the principles of both the
FDA/CVM Guidelines Guidance for Industry, Good Target Animal Study Practices:
Clinical Investigators and Monitors, May 1997 and the European Union Guidelines
Good Clinical Practice for the Conduct of Clinical Studies for Veterinary Medicinal
Products and in accordance with the protocol.
The dosage form of the propentofyUine was 50 and 100 mg film coated tablets.
The 50 mg tablets were double scored, while the 100 mg tablets were single scored.
The tablets used were selected from the following batches: Batch Strength
A 50 mg
B 50 mg
C lOO mg
D lOO mg
The dose rate was 5.0 mg propentofylline/kg body weight (bw) twice a day
given about 12 hours apart. The dose route was orally on an empty stomach (at least
one hour before feeding or at least 4 hours after feeding). The negative control material
(placebo) tablets did not contain the active ingredient propentofyUine but in all other
respects (e.g. composition and appearance) were identical to the test tablets.
The dosage for the placebo was the control equivalent of 50 (double scored)
and 100 (single scored) mg film coated tablets. The tablets used were selected from
the following batches:
Batch Strength
E 50 mg
F 50 mg
G 100 mg
H 100 mg
The dose rate for the placebo was the control equivalent of 5.0 mg
propentofylline/kg body weight (bw) given twice daily about 12 hours apart. The dose
route was orally on an empty stomach (at least one hour before feeding or at least 4
hours after feeding).
The test and control tablets were identical in size and appearance. The identity
of the test and control articles was not known to the referring DVMs, the behavior consultants and the dog owners. Both test and control tablets were supplied as film
coated 50 and 100 mg tablets.
The animals tested in the study were elderly (7 years or older) dogs showing
signs of cognitive dysfunction syndrome (CD). They comprised pure bred and
crossbred animals of both sexes, intact or neutered. Their liveweights ranged from 2.4
to 47.3 kg (avg. 17.9 kg). Pregnant and lactating female dogs were not included as
propentofyUine has not been evaluated in this category.
Elderly dogs that satisfied the medical entry criteria (clinical exam E,) and were
confirmed to be showing signs of cognitive dysfunction syndrome (CD) following an
assessment (Pre-Enrollment Senility Assessment) by a behavior specialist were
randomly allocated to treatment or control (placebo) group using a provided random
number schedule. The owners were provided with sufficient medication for their dog
for about four weeks together with instructions on how to fill in the daily treatment and
health records. The dogs were brought back to the clinic at approximately four and
eight weeks after the study started for further clinical examinations (E2 and E3,
respectively). Sufficient tablets to complete the eight-week study were dispensed at the
week 4 clinical exam.
Senility assessments were done telephonically with the owner and behavior
specialist 1 , 2, 4, 6 and 8 weeks after the dog started medication.
Each dog enrolled met the following criteria: evidence of the presence of CD
based on a knowledge of the dog's behavior history and on a specific senility behavior
assessment performed by a behavior consultant. To qualify, a dog had to have a total
score of at least 12 points based on the following behavior endpoints: disorientation,
training / learned behavior, non-recognition, and nighttime anxiety. Furthermore, the dog had to have been showing signs of CD for at least two months prior to enrollment.
Additionally, the dogs had to be a minimum of 7 years of age.
The dog must not have been suffering from any known concurrent debilitating
disease which could interfere with the assessment of response to treatment. The dog
must not have received or been receiving treatment with medications which could
cause polyuria, polydypsia or substantially affect behavior and hence interfere with
monitoring any response to therapy. Dogs with partial or complete deafness or
blindness could be included if the behavior consultant agreed that the behavior signs
shown by the dog were not caused or influenced by these conditions.
Dogs suffering from terminal diseases or with diseases which could interfere
with the behavior assessments were excluded unless, in the case of the latter, the dog
was stabilized on appropriate therapy for at least one month prior to enrollment. Daily
treatment with other behavior modifying drugs was not allowed from one month prior
to the start of the study and during the study.
For randomization, a computer generated random number schedule was
provided to each site. The referring DVMs who dispensed the test and control
materials, the behavior consultants who assessed the dogs and the owners of the dogs
remained "blind" as to which treatment each dog received.
A dosing chart giving dog liveweights (in kg. and lbs.) and numbers of tablets
of either or both concentration(s) required in the morning and evening for each
liveweight range was used.
The assessment of drug efficacy was based on changes in behavior scores at
weeks 4 and 8 post-treatment relative to the pre-treatment behavior score. The
behavior endpoints that were evaluated were as follows: a) disorientation (4 categories) spatial disorientation; staring into space; getting stuck in corners or under furniture; and aimless locomotion or pacing,
b) activity level (3 categories) whether the dog exercised on lead; whether the dog exercised loose; and the level of the dog's initiative, for example, his interest in toys or bones and his demand for attention,
c) non-recognition (3 categories) whether the dog greets his owner on arrival; whether the dog greets other family members and familiar people on arrival; and whether the dog recognizes his owner's car,
d) responsiveness (4 categories) responsiveness to owner initiated events such as food, exercise, and games; responsiveness to other animals; responsiveness to other familiar people; and responsiveness to outside stimuli such as the postman, telephone ringing and the door bell,
e) training / learned behavior (3 categories) house training with regard to urine elimination in the house; house training with regard to feces elimination in the house; and failing to respond to simple commands or tricks, and
f) total anxiety (9 categories), including factors relating to separation anxiety, salivation, elimination in the house, destructiveness, and excessive vocalization; phobias, being afraid of noise, and the inability to cope with scheduled changes; and night-time problems, pacing, vocalization and destructive behavior.
At the Pre-Enrollment Assessment, each dog was given a score for each
category within each behavior endpoint. The scores in most categories were assigned based on frequency, with the possible scores ranging from 0 (never) to 5 (always). The
maximum score for all categories within each endpoint, except the activity category,
was 5. For the activity category the possible scores ranged from 0 (very active) to 3
(very inactive). The higher the score, the more severely the dog was affected. Drug
efficacy was assessed by comparing post-treatment scores at Week 8 (W8) with the pre-
treatment scores.
In addition, changes in sleep patterns and appetite were recorded. The behavior
assessments were conducted telephonically between a veterinary behavior specialist
and the owner.
The individual dog was the unit of observation and statistical analysis. The
data analysis-statistical methods were as follows. The data were processed
electronically and statistical analysis was performed. The response variables of interest
were the behavior endpoints indicated above: disorientation, activity level, non-
recognition, responsiveness, training/learned behavior, and anxiety. The changes in the
scores for each categories within each of the behavior endpoints were statistically
analyzed using the Mantel Haenszel test. Regions and sites were used as stratification
variables in the analysis. The study was conducted in compliance with the protocol
and amendments to it.
Seventy five (75) dogs fulfilled the entry criteria. The majority of the dogs
showed several behavioral changes associated with CD (Table 2). Table 1 : Number of dogs showing signs of CD and the average score at enrollment.
Figure imgf000025_0002
Table 2: Dropouts/Adverse Drug Events
Figure imgf000025_0003
Owners requested euthanasii
Figure imgf000025_0001
Table 3 : Response to Drug Therapy - Group mean behavior scores at Week and Week8 in propentofyUine treated and placebo treated dogs.
Figure imgf000026_0001
Although differences in overall behavior scores between treated and control
dogs were not significant at the four week date, (there appears to have been a placebo
effect, which persisted for about four weeks and small group sizes were the most likely
reason for a failure to show significant differences between treatment and control), as
shown in Table 3 by the eight week date there were positive trends in favor of the drug
in at least one category within each behavior endpoint. As shown in Table 3 and
Figures 5-10, by week eight in at least several categories, the dogs who were provided
with propentofyUine achieved reduced scores from their scores at the beginning of the
test, and additionally achieved scores that were better than the scores achieved by dogs
provided with the placebo.
Figure 5 demonstrates that the scores of dogs with regard to the first endpoint
of the disorientation category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo.
Figure 6 demonstrates that the scores of dogs with regard to the third endpoint
of the activity category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo. Figure 7 demonstrates that the scores of dogs with regard to the first endpoint
of the non-recognition category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo.
Figure 8 demonstrates that the scores of dogs with regard to the first endpoint
of the responsiveness category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo.
Figure 9 demonstrates that the scores of dogs with regard to the fourth endpoint
of the responsiveness category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo.
Figure 10 demonstrates that the scores of dogs with regard to the second
endpoint of the training category were more improved for dogs provided with the
propentofyUine treatment than for dogs provided with the placebo.
Although the present invention has been described with respect to several
exemplary embodiments, there are many other variations of the above-described
embodiments which will be apparent to those skilled in the art, even where elements
have not explicitly been designated as exemplary. It is understood that these
modifications are within the teaching of the present invention, which is to be limited
only by the claims appended hereto.

Claims

We claim:
1. A method of treating cognitive dysfunction syndrome in dogs comprising
administering to a dog identified as having cognitive dysfunction syndrome a dosage
amount of propentofyUine effective to treat said cognitive dysfunction syndrome.
2. The method of claim 1, wherein said dog is elderly.
3. The method of claim 1, wherein said propentofyUine is administered orally.
4. The method of claim 3, wherein said propentofyUine is administered while the
dog has an empty stomach.
5. The method of claim 1 , wherein said dosage amount is about 1-20 mg/kg body
weight per day.
6. The method of claim 5, wherein said dosage amount is about 10 mg/kg body
weight per day.
7. The method of claim 1 , wherein said dosage amount is about 1-10 mg/kg body
weight of said dog twice daily
8. The method of claim 7, wherein said dosage amount is about 5 mg/kg body
weight of said dog twice daily.
9. A chewable tablet for dogs comprising:
propentofyUine and at least one flavor enhancing ingredient.
10. The chewable tablet of claim 9, wherein said at least one flavor enhancing
ingredient comprises a sweetener and an additional flavoring agent.
1 1. The chewable tablet of claim 10, wherein said sweetener is aspartame.
12. The chewable tablet of claim 10, wherein the drug to sweetener to flavoring
agent ratio is 1 : 0.5-1.5 : 3-7.
13. The chewable tablet of claim 10, wherein the drug to sweetener to flavoring
agent ratio is about 1 : 1 : 4.5.
14. The chewable tablet of claim 10, wherein the drug to sweetener to flavoring
agent ratio is about 1 : 1 : 5.
15. The chewable tablet of claim 9, further comprising at least one binder.
16. The chewable tablet of claim 9, further comprising at least one lubricant.
17. The chewable tablet of claim 9, wherein said propentofyUine is present in said
tablet in an amount effective to treat cognitive dysfunction syndrome in dogs affected
by cognitive dysfunction syndrome.
18. The chewable tablet of claim 9, wherein the amount of propentofyUine ranges
from about 50 mg to about 200 mg.
19. The chewable tablet of claim 9, wherein the amount of propentofyUine is about
50 mg.
20. The chewable tablet of claim 9, wherein the amount of propentofyUine is about
lOO mg.
21. The chewable tablet of claim 9, wherein the amount of propentofyUine is about
150 mg.
22. The chewable tablet of claim 9, wherein the amount of propentofyUine is about
200 mg.
23. The chewable tablet of claim 9, wherein the tablet is in the shape of a bone.
PCT/US2000/025771 1999-09-22 2000-09-21 Method of treating cognitive dysfunction syndrome in dogs and chewable tablet for dogs WO2001021178A2 (en)

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