IES84623Y1 - A process for the preparation of an orally administered unit dose tablet - Google Patents
A process for the preparation of an orally administered unit dose tabletInfo
- Publication number
- IES84623Y1 IES84623Y1 IE2006/0277A IE20060277A IES84623Y1 IE S84623 Y1 IES84623 Y1 IE S84623Y1 IE 2006/0277 A IE2006/0277 A IE 2006/0277A IE 20060277 A IE20060277 A IE 20060277A IE S84623 Y1 IES84623 Y1 IE S84623Y1
- Authority
- IE
- Ireland
- Prior art keywords
- weight
- approximately
- carprofen
- ingredients
- microns
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 5
- IVUMCTKHWDRRMH-UHFFFAOYSA-N Carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims description 54
- 229960003184 carprofen Drugs 0.000 claims description 54
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- 239000002245 particle Substances 0.000 claims description 35
- 239000004615 ingredient Substances 0.000 claims description 27
- 235000019359 magnesium stearate Nutrition 0.000 claims description 22
- 239000004480 active ingredient Substances 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
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- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims description 14
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Description
A Process for the Preparation of an Orally
Administered Unit Dose Tablet
Field of the Invention
The present invention is directed to a process for preparing an orally
administered unit dose tablet comprising carprofen.
Background to the Invention
Carprofen (6-chloro-alpha-methyl-9H-carbazoleacetic acid 2-(6-chloro-
carabazolyl)-pronionic acid (C15-,H12C|NO2)) is a known non-steroidal anti-
inflammatory drug for veterinary use. Carprofen has analgesic and
antipyretic effects and may be used for the treatment of disorders in
muscles, joints and skeletons, including managing post-operative pain and
degenerative joint disease. Carprofen belongs to the group of propionic acid
derivatives and belongs to the non-steroidal anti-inflammatory drugs
(NSAID)-group of arylpropionic acids.
Carprofen is a white, crystalline compound, freely soluble in ethanol but
insoluble in water at 25 “C. Carprofen exists in two enantiomeric forms.
Differences in pharmacokinetics and pharmacodynamics between the two
enantiomers occur in animals and can also vary significantly among species.
Carprofen generally contains a racemic (50:50) mixture of the two
enantiomers, S(+) and R(-). Studies have shown that the S(+) enantiomer is
more active than the R(-) enantiomer.
Whilst the mechanism of action of carprofen is not completely clear, research
suggests that carprofen selectively inhibits cyclooxygenase 2 (COX-2) over
cyclooxygenase 1 (COX-1) in dogs. It is thought that the selective inhibition of
QQ4530
[)84623
COX-2 improves gastrointestinal tolerance.
Carprofen is generally rapidly absorbed and maximal serum concentrations
(20-30mg/ml) are reached within 2 hours from oral administration of 4mg/kg
bodyweight.
One of the problems associated with the large-scale manufacture of carprofen
formulations is to produce a fonnulation with little product variation, in terms of
hardness, disintegration and dissolution patterns, within each batch.
Thus, there is a need to develop an industrial |arge—scale process for the
preparation of carprofen which deals with these problems.
Statement of the Invention
According to a first aspect of the invention, there is provided a process for the
preparation of an orally administered unit dose tablet comprising the steps of ;
a. Providing carprofen comprising particles wherein at least 90%
by weight of the carprofen particles are less than 10 microns in
diameter and at least 97% by weight of the carprofen particles
are less than 50 microns in diameter;
b. Sieving lngredients (i) to (iv) in a ratio of approximately from
‘l:3:2.5:0.05 to 1:3.5:3.0:0.1 to obtain particles of approximately
800 to 900 microns in diameter
i. Carprofen from step (a) in the range of 10 to 15% by
weight;
ii. Lactose monohydrate wherein approximately 10 to 30%
by weight have an average particle size of less than 30
microns in diameter; in the range of 30 to 55% by
weight;
iii. Microcrystalline cellulose wherein 8% by weight or less
have an average particle size of greater than 250
microns and 45% by weight or more have an average
particle size of less than 75 microns; in the range of 25
to 45% by; and
iv. Colloidal silicon dioxide with a specific surface area of
from 175 to 225 m3 per gram; in the range of 0.1 to 5%
by weight;
. Placing the sieved ingredients from step (b) through a blender
and blending the ingredients to achieve uniform mixing of the
ingredients;
. Testing the blended ingredients from step (c) to ensure that
the desired uniform mixing of the ingredients has occurred;
. Sieving from approximately 0.1 to 5% by weight magnesium
stearate to obtain particles of approximately 800 to 900
microns in diameter
Placing the magnesium stearate obtained from step (e), in a
ratio of carprofen to magnesium stearate of from 120.01 to 0.1,
preferably 1:0.05, into the blender and blending to achieve
uniform mixing of the ingredients;
. Testing the blended ingredients from step (f) to ensure that the
desired uniform mixing of the ingredients has occurred;
h. Once the desired uniformity has been reached unloading the
blended material into double polythene lined drums;
i. Transferring the blended material into a hopper;
j. Loading the blended material into a rotary tablet compression
machine with upper and lower punches;
k. Setting the diameter of the upper and lower punches to a
specific diameter depending on the amount of active ingredient
in the tablet;
l. Forming unit dose tablets under direct compression to achieve
unit dose tablets with friability of less than 1% after 100
minutes and a disintegration time of less than 15 minutes;
m. Discharging the tablets from the tableting press into a chute;
n. Transferring the tablets via a hopper into containers and
packaging; or directly packaging the tablets obtained from step
(m) into blister packs or plastic containers.
Preferably, from approximately 10 to 15% by weight of Carprofen is used;
and/or from approximately 40 to 50% by weight of lactose monohydrate is
used; and/or from approximately 30 to 40% by weight of microcrystalline
cellulose is used; and/or from approximately 0.1 to 1% by weight of colloidal
silicon dioxide is used; and/or from approximately 0.1 to 1% of Magnesium
Stearate is used.
Detailed Description of the Invention
In the specification the term “by weight" refers to the weight of the final
composition.
The industrial large-scale manufacture of any drug presents the
pharmaceutical manufacturer with many issues to consider.
In the large—scale manufacture of a tablet, it is essential that the entire batch
being manufactured meets the various criteria set by regulatory legislation. in
particular, each tablet within a batch must confomi to the active ingredient
weight and there must be little or no product variation within a batch.
Product variation is usually attributed to segregation of the ingredients, in
particular the active ingredient, within a batch. This is an unpredictable or
random event because pockets of segregated material may end up at the
tableting press at irregular intervals. If product variation is found within a
batch, this could result in the batch not meeting the required standards and
the subsequent wastage of an entire batch. This is expensive and time-
consuming and something a pharmaceutical manufacturer will avoid.
The present invention is directed to solving these manufacturing problems
when making an orally administered unit dose carprofen tablet on a large-
scale.
In general terms, the process and fonnulation according to the invention
provides a robust, simple process for producing tablets of good hardness and
quality of attributes. Specifically, the process of the invention provides
process for the manufacture of an orally administered unit dose carprofen
tablet which has adequate hardness, good dissolution pattern and good
uniformity when manufactured on a large-scale.
According to one embodiment of the invention, a racemic mixture of carprofen
may be used according to the invention. Preferably, the racemic mixture
comprises the S(+) and R(-) enantiomers in a 50:50 ratio.
The carprofen used in the process of the present invention comprises active
ingredient particles wherein at least 97% by weight of the particles are less
than approximately 50 microns in diameter and at least approximately 90% by
weight of the particles are less than approximately 10 microns in diameter.
Preferably, approximately 97 to 100% by weight of the particles are less than
approximately 50 microns in diameter and from 90% to 100% by weight of the
particles are less than 10 microns in diameter.
The particle size of the carprofen is an essential requirement for this invention
and significantly improves the manufacture of a uniform tablet with the
required dissolution and disintegration parameters. Furthermore, the particle
size of the active ingredient carprofen provides for good bioavailability of the
active ingredient when administered to an animal.
According to a general embodiment of the invention, the active ingredient
carprofen and the remaining excipients (including fillers, diluents, glidants,
anti—caking agents and disintegrants but excluding the lubricant) are sieved to
achieve a mixture of desired particulate size.
Preferably, a micronization sieve is used to achieve particles of the desired
size. Ideally, a 20# mesh is used to result in particles of approximately 800 to
microns, preferably 850 microns. Typically, a Russell Sieve is used.
According to a preferred embodiment of the invention, the lubricant is
magnesium stearate and the remaining excipients include colloidal silicon
dioxide, microcrystalline cellulose and lactose monohydrate.
The sieved ingredients are then mixed in a blender. ldeally, a double cone
blender or a drum tumbler may be used. The blender is generally set at 32
revolutions per minute (rpm) for pre and post lubrication steps.
Blending is carried out to achieve uniformity of the active ingredient in the
blend. This is generally when 90 to 110% of the active ingredient is blended
with a relative standard deviation (RSD) of 6% or less. Once uniformity has
been tested and the desired uniformity has been reached, blending is
stopped. Ideally, blending at this step occurs for 10 to 30 minutes, preferably
minutes. These steps are the pre-lubrication steps.
The lubricant, preferably magnesium stearate, is then sieved to achieve a
desired particulate size. Ideally, a 20# mesh is used to result in particles with
an average particle size of approximately 800 to 900 microns, preferably 850
microns. Typically, a Russell Sieve is used.
The sieved magnesium stearate is then added to the blended ingredients and
blended. This is the lubrication step.
Typically, blending is only needed for a short time, for example five to ten
minutes. This ensures that the magnesium stearate and active ingredient
Carprofen are in contact for the minimum time necessary. Blending is
stopped once uniformity of the ingredients in the mix has been achieved. This
is generally when 90 to 110% of the active ingredient is blended with a relative
standard deviation (RSD) of 6% or less.
Post lubrication, the blended mixture, which is also known as the tableting
powder, is transferred to containers. Suitable containers include polyethylene
lined drums. These drums are lined in order to ensure that contamination of
the mixture is avoided.
The tableting powder is then transferred to a hopper and loaded into the
punches of a tableting press. Ideally, a rotary tablet compression machine is
used.
The tableting press generally comprises upper and lower punches and is set
to specific diameter depending on the amount of active ingredient in the tablet.
The pressure applied in the tableting press depends on the tablet being
manufactured, for example tablets may be manufactured with 20mg, 50mg
and 100mg of active ingredient. The diameter of the punches is set
depending on the weight of the tablet to be compressed. Generally,
compression forces applied are in the range of 4 to 8 tonnes.
Typically, the diameter is set at 7.5mm, 10.5mm and 12.5mm FBE for 20mg,
50mg and 100mg tablets respectively.
it is desirable to obtain tablets with a friability of less than 1% after 100
revolutions and a disintegration time of less than 15 minutes with appropriate
hardness and thickness. For 20mg tablets, hardness of 25 to 100 newtons is
desirable. For 50mg tablets, hardness of 25 to 125 newtons is desirable. For
100mg tablets, hardness of 40 to 200 newtons is desirable
After the tablets are punched, they loaded into hoppers are discharged into
containers for storage or packaged directly.
Preferably, the containers used according to this invention are double lined
polyethylene containers. They are double lined in order to provide the
requisite contamination-free conditions.
All the excipients used in the unit dose tablets according to the invention are
Other
conventionally used in the field may also be contemplated here.
pharmaceutically acceptable excipients. excipients which are
In one embodiment of the invention, the filler is a lactose. Preferably, the
lactose is a free flowing highly compactable, granulated lactose monohydrate.
Lactose monohydrate may also function as a diluent. Other fillers which may
be used according to the invention include starches, including corn starch.
in another embodiment of the invention, the disintegrant is microcrystalline
cellulose. Microcrystalline cellulose may also act as a diluent. Hydroxypropyl
methylcellulose or other cellulose materials may also be used according to the
invention.
Preferably the lactose monohydrate and microcrystalline cellulose are of a
specific particle size.
Ideally, the lactose monohydrate has between approximately 10 to 30% by
weight of particles with an average particle size of less than 75 microns in
diameter.
The microcrystalline cellulose preferably has a particle size wherein 8% by
weight or less have an average particle size of greaterthan 250 microns and
45% by weight or more have an average particle size of less than 75
microns.
The narrow particle size distribution for these excipients ensures a low tablet
weight variation and good uniformity of the drug.
In another embodiment of the invention, the glidant and anti~caking agent is
colloidal silicon dioxide. Colloidal silicon dioxide acts as a glidant to improve
flow characteristics of the tableting powder. Colloidal silicon dioxide may also
act as a disintegrant. The colloidal silicon dioxide used according to the
invention has a specific surface area of from 175 to 225 m3 per gram.
Suitable dispersing/disintegrant agents include colloidal silicon dioxide such as
that sold under Aerosil 200 T” and/or a non-ionic surfactant such as a
polyoxyethylene derivative of a sorbitan ester marketed as Polysorbate 20.
Other diluents and excipients having disintegrant, glidant and lubricant
properties used in the pharmaceutical field may be used in the process of this
invention.
The active ingredient carprofen may be present in the formulation at levels of
20mg, 50mg or 100mg. The ratio of carprofen to lactose monohydrate to
microcrystalline cellulose to colloidal silicon dioxide is from approximately
1:3:2.5:0.05 to approximately 1:3.5:3.0:0.07, preferably approximately
1:3.45:2.9:0.06.
According to a preferred embodiment of the invention, the tablet comprises
from approximately 10 to 15% by weight of Carprofen is used, from
approximately 30 to 55% by weight of lactose monohydrate, from
approximately 25 to 45% by weight of microcrystalline cellulose, from
approximately 0.1 to 5% by weight of colloidal silicon dioxide is used and
from approximately 0.1 to 5% of Magnesium Stearate.
Ideally, the ratio of active ingredient carprofen to magnesium stearate is
approximately 110.05.
In yet another embodiment of the invention, the lubricant is magnesium
stearate. Other lubricants which may be used in accordance with the
invention include magnesium stearate, stearic acid, talcum and bentonites. It
is essential in the process of the invention that the magnesium stearate is
added at the latest moment possible to ensure it has the least amount of time
in contact with the active ingredient. Magnesium stearate is hydrophobic and
affects the solubility and dissolution profile of the active ingredient carprofen.
The process of the present invention aims to minimise the Contact time
between the blended ingredients and the magnesium stearate.
The process of the present invention provides an advantage in terms of
manufacture of a carprofen tablet on an industrial scale. The process used
involves fewer manufacturing steps than conventional granulation techniques
that would normally be used in the manufacture of such orally administered
unit dose tablets.
According to one embodiment, the tablets made according to the present
invention are packaged immediately after production. They may be packaged
in blister packs made of hard temper aluminium foil or high density
polyethylene twist-off plastic containers with white polypropylene twist-off
caps. The orally administered unit does may be in the form of a chewable
tablet or capsule/caplet.
According to another embodiment of the invention, the tablets are delivered to
a container and stored in contamination-free conditions prior to packaging.
Preferably, carprofen tablets according to the invention are administered to
dogs and cats. However, they may also be administered to other animals such
as horses and sheep.
For oral use, the recommended dosage is an initial dose of 2 to 4mg/kg
bodyweight per day. Preferably, the dose should be split and administered on
two occasions in equal amounts. Alternatively, the dose may be given as a
single dose.
The invention further provides an orally administered unit dose tablet as
prepared by the process.
The invention further provides an orally administered unit dose tablet for use
in treating pain in animals.
The invention is not limited to the embodiments described above but may be
varied within the scope of the claims.
The invention will now be described by reference to the following non-limiting
examples and figures.
Figure 1 shows a flowchart for the manufacture of unit dose carprofen tablet.
As shown in Figure 1, the general method involved the steps of dispensing the
materials carprofen, colloidal silicon dioxide (Aerosilm), lactose monohydrate
and microcrystalline cellulose (Avicelm) of an appropriate particulate size and
set ratio.
These ingredients are then sieved and mixed in a blender. This is the pre-
lubrication step.
A set ratio of magnesium stearate to carprofen is sieved to the appropriate
particulate size before adding it to the blended mixture. A further mixing step
is undertaken. This is the post-lubrication step.
The resultant blended ingredients are optionally transferred to a container and
then transferred through a chute to a hopper.
The tableting press is filled with the blended ingredients from the hopper. The
tableting press comprises upper and lower presses and is set to a specific
diameter depending on the tablet being produced.
The tableting powder is compressed to achieve tablets of set characteristics
and then transferred to a container and then immediately packaged.
Example 1: Manufacturing Process
The following ingredients were used in order to make 3 different unit dose
tablets. All values are given in mg.
Ingredient 20mg 50mg 100mg
Tablet Tablet Tablet
Carprofen 20.00 50.00 100
Lactose Monohydrate 69.00 172.50 345.00
Microcrystalline Cellulose PhEur (Avicelm 58.14 145.35 290.72
PH102 PhEur)
Aerosi|T'“ 200 Pharma Grade PhEur 0.9% 1.28 3.20 6.40
(colloidal silicon dioxide)
Magnesium Stearate PhEur 1.00 2.50 5.0
Total 149.42 373.56 747.12
Eguigment Reguired:
Sieve with 20# screen mesh to obtain particles of approximately 800 to 900
microns in diameter.
Blender — Double cone blender or drum tumbler may be used.
Compression machine — Rotary Tablet Compression Machine
V Method:
The following general method was used in the manufacture of the different
unit dose tablets.
Carprofen, Aerosilm. lactose monohydrate and microcrystalline cellulose
were sifted through a 20# screen on a sieve and loaded into a double cone
_l5_
blender. The blender was typically set to 32RPM. The double cone blender
was run for 20 minutes. Magnesium stearate was then added through a 20#
screen on a sieve and placed in the double cone blender. The blender was
run for approximately 5 minutes and the blended material was unloaded into
double polythene lined drums to form a tablet in a compression machine. A
Rotary Tablet Compression Machine with 7.5mm, 10.5mm or 12.5 mm FBE
punches was used in the manufacture of 20mg, 50mg and 100mg tablets
respectively. Typical compression forces applied are in the range of 4 to 8
tonnes.
The tablets were then packed in white high density polyethylene twist-off
plastic containers with child-proof tamper evidence polypropylene white
twist-off closure or in blisters made up of PVC/PVdC with a 20 micron hard
temper aluminium foil.
Example 2: Stability and Tolerance Results for Carprofen Tablets
Example 2A:
Stabilig Protocol for Long Term and Accelerated Stability Testing
The tablets made in Example 1 were packaged in a HDPE Container with
Polypropylene Cap (Child resistant tamper evident closure) and were
subsequently tested for stability over set time periods and storage conditions.
The results for 50mg Carprofen tablets are as follows.
i) long—term stability studies at 25°C/60%RH.
_]_6_
Test Specification Initial 6mths 12 mths 24 mths
Appearance A plain round Conforms Conforms Conforms Conforms
flat bevelled
edge white to
off-white tablet
with a
breakline on
one side
Condition of Packaging Conforms Conforms Conforms Conforms
paclgging intact
Disintegation < 15 mins 0.9m 1.4m 0.5m 0.8m
Dissolution > 80% 100.4% 103.2% 98.7% 92.8%
Carprofen dissolved after
mins
Active Assay 50 mg/tablet : 49.75mg 48.34mg 50.50mg 49.19mg
Carprofen 5%
(47.5-52.5
mg/tablet)
ii) accelerated stability studies at 40°Cl75%RH.
Test Specification Initial Gmths 12 mths 24 mths
Appearance A plain round Conforms Conforms Conforms Conforms
flat bevelled
edge white to
off—white tablet
with a
breakline on
one side
Condition of Packaging Conforms Conforms Conforms Conforms
packaging intact
Disintegration < 15 mins 0.9m 1.1m 0.5m 0.5m
Dissolution > 80% 100.4% 96.6% 98.7% 97.8%
Carprofen dissolved after
mins
Active Assay 50 mg/tablet i 49.75mg 48.11mg 50.50mg 48.00mg
Carprofen 5%
(47.5-52.5
mg/tablet)
Example 2B: Tolerance Study and Results
A tolerance study was designed and performed to evaluate the safety of the oral
carprofen formulation when administered to dogs at the recommended and elevated
levels. In addition, the safety of the test formulation and the combination of the
excipients used were also assessed.
This tolerance study was performed using tablets containing 50mg carprofen.
The animal phase was conducted by Veterinary Health Research Pty Ltd in Australia
and was conducted to the VICH standard Good Clinical Practice (GL9), July 2001.
Serum biochemical analysis, haematology and white cell differential counts were
performed at the ldexx laboratories in East Brisbane, Australia and was performed to
OECD Good Laboratory Practice.
Target animals were allocated and treated according to the following outline:
Group Treatment
Untreated negative control
mg/kg twice daily: Days 0 to 6 inclusive
2 mg/kg once daily: Days 7 to 13 inclusive
mg/kg twice daily: Days 0 to 6 inclusive
6 mg/kg once daily: Days 7 to 13 inclusive
Placebo tablets only
In this study (Study No. CHCC1484), thirty two adult Foxhound x Bloodhound dogs
equal mix of male and female, aged from 1 to 5 years (average 4 years) and
weighing between 26.5 and 51.5 kg (average 36.3 kg), were used. All thirty—two
animals were assigned to one of four groups of eight animals each. Animals were
individually identified using uniquely numbered neck tags weighted, ranked (within
each sex), sequentially blocked into fours and randomly allocated from each block of
four (4) treatment groups each of eight (8) dogs.
Summary of the Trial
Group 1 Group 2 Group 3 Group 4
Treatment
Days 0-6 Untreated 2 mg/kg twice 6 mg/kg 3 Placebo
inclusive Negative daily. twice daily. tablets twice
Control daily
Days 7-13 Untreated 2 mgfkg once 6 mg/kg 3 Placebo
inclusive Negative daily. once daily: tablets twice
Control daily
Clinical
examinations Once on Day-1, 6, 13 and Day 20
Bloodlurine
samples
General Twice daily
observations
Body weights Once on Day-1, 6, 13 and Day 20
Faeces Once Daily
Scored
Feed Intake
Clinical Observations
An individual clinical
examination was performed per animal on all animals on Day-1, 6, 13 and Day 20.
All animals were observed each morning and afternoon.
The clinical examination was performed by a veterinary surgeon who was blinded to
the treatment groups and including observation of general demeanour, heart rate and
rhythm, respiratory rate and thoracic auscultation, hydration status, rectal
temperature (°C), faeces, menace reflex, papillary light reflex, capillary reflex time,
gait. co-ordination and equilibrium. Blood and urine samples were obtained on days-
1, 6, 13 and 20. No clinical abnormalities were observed in any of the thirty-two
animals at any point throughout the trial.
Biochemical and Haematological
The biochemical parameters detected in the blood samples for included serum
glucose, urea, creatinine, total protein, albumin, globulin, total bilirubin, alkaline
phosphatase. aspartate aminotransferase, creatine phosphokinase, cholesterol,
calcium, phosphate calcium-phosphate ratio, sodium, potassium, sodium-potassium
_ 19 _
ration, chloride, bicarbonate, and anion gap. The haematological parameters
examined were red blood cells, haemoglobin, haematocrit, mean corpuscular volume,
mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white
cell count and platelets. The white cell differential count includes concentrations of
neutrophils, lymphocytes, monocytes, eosinophils and basophils. Blood clotting
parameters evaluated were Prothrombin time, Activated Partial Thromboplastin Time,
Protthrombin time ratio and Activated Partial Prothrombin time ratio.
In relation to the haematological and biochemical parameters, and with the exception
of serum glucose levels, no deviations from the reference values were noted in any of
the treatment groups. The serum glucose levels in all treatment groups were
consistently reported below and outside the reference range throughout the study.
This effect is attributed to the transport of samples to the analytical laboratory.
Urine Analysis
Urine parameters examined include glucose, bilirubin, ketones, haemoglobin, pH,
protein, urobilinogen, RBC/HPF and WCC/HPF. Urine samples were obtained on
day-1 and day 20. No significant changes to urine parameters were noted at either
time of analysis.
Additional Observations
Individual body weights, feed consumption and faecal consistency were recorded.
No abnormal results were observed throughout the duration of the study.
Conclusion of Tolerance Study
No abnormalities in the parameters examined were observed and no indicates of
toxicity were detected in any of the twenty-six biochemical, nineteen haematological,
four clotting, nineteen urinary or fourteen clinical parameters monitored. No changes
attributable to intolerance or toxicity due to the product were detected in any of the
animals. Therefore, the tolerance of Carprofen when administered at the anticipated
label dose rate and at elevated dose is confirmed.
Claims (3)
1:3:2.5:0.05 to 1:3.5:3.0:O.1 to obtain particles of approximately 800 to 900 microns in diameter Carprofen from step (a) in the range of 10 to 15% by weight; Lactose monohydrate wherein approximately 10 to 30% by weight have an average particle size of less than 75 microns in diameter; in the range of 30 to 55% by weight; Microcrystalline cellulose wherein 8% by weight or less have an average particle size of greater than 250 microns and 45% by weight or more have an average particle size of less than 75 microns; in the range of 25 to 45°/o by; and Colloidal silicon dioxide with a specific surface area of from 175 to 225 m3 per gram; in the range of 0.1 to 5% by weight; c. Placing the sieved ingredients from step (b) through a blender and blending the ingredients to achieve uniform mixing of the ingredients; . Testing the blended ingredients from step (c) to ensure that the desired uniform mixing of the ingredients has occurred; . Sieving from approximately 0.1 to 5% by weight magnesium stearate to obtain particles of approximately 800 to 900 microns in diameter Placing the magnesium stearate obtained from step (e), in a ratio of carprofen to magnesium stearate of from 110.01 to 0.1, preferably 1:0.05, into the blender and blending to achieve uniform mixing of the ingredients; . Testing the blended ingredients from step (f) to ensure that the desired uniform mixing of the ingredients has occurred; . Once the desired uniformity has been reached unloading the blended material into double polythene lined drums; Transferring the blended material into a hopper; Loading the blended material into a rotary tablet compression machine with upper and lower punches; . Setting the diameter of the upper and lower punches to a specific diameter depending on the amount of active ingredient in the tablet; Forming unit dose tablets under direct compression to achieve unit dose tablets with friability of less than 1% after 100 minutes and a disintegration time of less than 15 minutes; m. Discharging the tablets from the tableting press into a chute; and n. Transferring the tablets via a hopper into containers and packaging; or directly packaging the tablets obtained from step (m) into blister packs or plastic containers.
2. The process according to claim 1 wherein from approximately 10 to 15% by weight of Carprofen is used; and/or '. from approximately 40 to 50% by weight of lactose monohydrate is used; and/or iii. from approximately 30 to 40% by weight of microcrystalline cellulose is used; and/or iv. from approximately 0.1 to 1% by weight of colloidal silicon dioxide is used; and/or v. from approximately 0.1 to 1% of Magnesium Stearate is used.
3. An orally administered unit dose tablet prepared by the process according to claim 1 or 2. An orally administered unit dose tablet as claimed in claim 3 for use in treating pain in animals. A process for preparing an orally administered unit dose tablet substantially as described herein with reference to the examples and figure.
Publications (1)
Publication Number | Publication Date |
---|---|
IES84623Y1 true IES84623Y1 (en) | 2007-06-27 |
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