GB2437054A

GB2437054A - Orally administered carprofen tablet

Info

Publication number: GB2437054A
Application number: GB0607276A
Authority: GB
Inventors: Michael Hilary Burke
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-04-11
Filing date: 2006-04-11
Publication date: 2007-10-17
Anticipated expiration: 2026-04-11
Also published as: GB0607276D0; GB2437054B

Abstract

A process for the preparation of an orally administered dose of a carprofen tablet is provided. The process comprises providing carprofen particles, sieving these particles with lactose monohydrate, microcrystalline cellulose, an colloidal silicon dioxide in a ratio of 1:3:2.5:0.05 to 1:3.5:3.0.1 in order to obtain particles of 800-900 microns in diameter, placing the sieved ingredients through a blender, adding sieved magnesium stearate in a ratio of carprofen to magnesium of 1:0.01 to 1:0.1, mixing, and then forming unit dose tablets. Orally administered unit doses of carprofen comprising the above ingredients are also provided. The tablets are preferably used to treat pain in animals, such as cats or dogs.

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 and to an orally administered unit dose tablet comprising carprofen.

10:* . :

Background to the Invention

Carprofen acid 2-(6-chloro-: carabazol-2-yI)-pronionic acid (C15H12C1N02)) 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(-i-) and R(-). Studies have shown that the 5(+) 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 COX-2 improves gastrointestinal tolerance.

Carprofen is generally rapidly absorbed and maximal serum concentrations (20-30mg/mI) 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 formulation with little product variation, in terms of S.....

io hardness, disintegration and dissolution patterns, within each batch.

Thus, there is a need to develop an industrial large-scale process for the preparation of carprofen which deals with these problems. :w *..S S...

Statement of the Invention * * * * S... * . S S. S

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 Ingredients (i) to (iv) in a ratio of approximately from 1:3:2.5:0.05 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 75 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; S...

S S'S.

c. Placing the sieved ingredients from step (b) through a blender S...

and blending the ingredients to achieve uniform mixing of the S...

ingredients; .. : d. Sieving from approximately 0.1 to 5% by weight magnesium stearate to obtain particles of approximately 800 to 900 microns in diameter e. Placing the magnesium stearate obtained from step (d), in a ratio of carprofen to magnesium stearate of from 1:0.01 to 0.1, preferably 1:0.05, into the blender and blending to achieve uniform mixing of the ingredients; f. Unloading the blended material into double polythene lined drums; g. Transferring the blended material into a hopper; h. Loading the blended material into a tableting press; I. 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; j. Discharging the tablets from the tableting press into a chute; and * * S.....

k. Transferring the tablets into containers and packaging; or * : directly packaging the tablets obtained from step (j).

Preferably, from approximately 10 to 15% by weight of Carprofen is used; and/or from approximately 40 to 50% by weight of lactose monohyd rate is used; and/or from approximately 30 to 40% by weight of microcrystalline cellulose is used; and/or from approximately 0.1 to I % by weight of colloidal.. : silicon dioxide is used; and/or from approximately 0.1 to 1% of Magnesium Stearate is used.

According to a second aspect of the invention, there is provided an orally administered unit dose tablet comprising; i. Carprofen 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 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 75 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; v. Magnesium stearate, in a ratio of carprofen to magnesium stearate of from 1:0.01 to 0.1, preferably. : 1:0.05, in the range of 0.1 to 5% by weight; S wherein ingredients (I) to (iv) are provided in a ratio of from approximately: 1:3:2.5:0.05 to approximately 1:3.5:3.0:0.07. * S *SSS

Detailed DescriDtion 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 conform 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. *

io In general terms, the process and formulation 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. *::::* * * * * S 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 I.....

io size. Ideally, a 20# mesh is used to result in particles of approximately 800 to 900 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. * * S ** *

The sieved ingredients are then mixed in a blender. Ideally, 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-lubncation 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 S.....

io 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. S... * a

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.

10:*.: 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 I...

pharmaceutically acceptable excipients. Other excipients which are *..* : conventionally used in the field may also be contemplated here.

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 monohyd rate and microcrystalline cellulose are of a specific particle size.

-10 -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 greater than 250 microns and 45% by weight or more have an average particle size of less than 75 microns. * *

I.....

io 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 TM 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.

-11 -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 1:0.05. ir

LV

In yet another embodiment of the invention, the lubricant is magnesium * : * S. 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 * * S 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 -12 -tablet or capsule/caplet.

Accord ing 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.

io 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. S.

The invention further provides an orally administered unit dose tablet as prepared by the process. --

S

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 (AerosilTM), lactose monohydrate and microcrystalline cellulose (AvicelTM) of an appropriate particulate size and -13 -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.

io 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. * a a

S

The tableting powder is compressed to achieve tablets of set characteristics and then transferred to a container and then immediately packaged.

-14 -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 S.....

Lactose Monohydrate 69.00 172.50 345.00 *.

Microcrystalline Cellulose PhEur (AviceITM 58.14 145.35 290.72 PHIO2 PhEur) _______ _______ ______ AerosilTM 200 Pharma Grade PhEurO.9% 1.28 3.20 6.40 *.SS (colloidal silicon dioxide) ________ _______ Magnesium Stearate PhEur 1.00 2.50 5.0 Total 149.42 373.56 747.12 Equipment Required: 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 Method: The following general method was used in the manufacture of the different

unit dose tablets.

Carprofen, AerosilTM, lactose monohydrate and microcrystalline cellulose were sifted through a 20# screen on a sieve and loaded into a double cone -15 -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. ..:. )

AL I *

Example 2: Stability and Tolerance Results for Carprofen Tablets

Example 2A:

Stability Protocol for Lonu Term and Accelerated Stability Testing The tablets made in Example I 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.

-16 -i) long-term stability studies at 25 C/60%RH.

Test Specification Initial 6 mths 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 1.4m 0.5m 0.8m Dissolution 80% 100.4% 103.2% 98.7% 92.8% Carprofen dissolved after ** ______________ 30 mins _________ _________ _________ _________ Active Assay 50 mg/tablet 49.75mg 48.34mg 50.50mg 49.19mg Carprofen 5% (47.5-52.5 ________________ mg/tablet) ___________ __________ __________ __________

S

S -* .

ii) accelerated stability studies at 40 C/75%RH.

Test Specification Initial 6 mths 12 mths 24 mths

off-white tablet

with a breakline on ______________ one side __________ _________ _________ _________ Condition of Packaging Conforms Conforms Conforms Conforms packaging intact _________ _________ _________ _________ Disintegration <15 mins 0.9m 1.lm 0.5m 0.5m Dissolution > 80% 100. 4% 96.6% 98.7% 97.8% Carprofen dissolved after _____________ 30 mins _________ _________ _________ _________ Active Assay 50 mg/tablet 49.75mg 48.11mg 50.50mg 48.00mg Carprofen 5% (47.5-52.5 _______________ mg/tablet) __________ __________ __________ __________ -17 -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 * .1.: 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 I Untreated negative control 2 2 mg/kg twice daily: Days 0 to 6 inclusive 2 mg/kg once daily: Days 7 to 13 inclusive 3 6 mg/kg twice daily: Days 0 to 6 inclusive 6 mg/kg once daily: Days 7 to 13 inclusive 4 Placebo tablets only In this study (Study No. CHCC1484), thirty two adult Foxhound x Bloodhound dogs equal mix of male and female, aged from I 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.

-18 -

Summary of the Trial

__________ Group I 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 mg/kg once 6 mg/kg 3 Placebo inclusive Negative daily. once daily: tablets twice ______________ Control _____________ ____________ daily Clinical examinations Once on Day-i, 6, 13 and Day 20 Blood/urine samples ______________________________________________ General Twice daily observations ___________________________________________________ Body weights Once on Day-I, 6, 13 and Day 20 Faeces Once Daily *-Scored ) Feed Intake __________________________________________ 1.: * Clinical Observations All animals were observed each morning and afternoon. An individual clinical examination was performed per animal on all animals on Day-i, 6, 13 and Day 20.

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, coordination and equilibrium. Blood and urine samples were obtained on days1, 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, Protthrombintime 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 S...

the treatment groups. The serum glucose levels in all treatment groups were

S

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-i 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

-20 -Claims: A process for the preparation of an orally administered

unit dose carprofen 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 Ingredients (i) to (iv) in a ratio of approximately from 1:3:2.5:0.05 to 1:3.5:3.0:0.1 to obtain particles of approximately * 800 to 900 microns in diameter S** is i. Carprofen from step (a) in the range of 10 to 15% by weight; S..

ii. Lactose monohydrate wherein approximately 10 to 30% S. by weight have an average particle size of less than 75 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; -21 -c. Placing the sieved ingredients from step (b) through a blender and blending the ingredients to achieve uniform mixing of the ingredients; d. Sieving from approximately 0.1 to 5% by weight magnesium stearate to obtain particles of approximately 800 to 900 microns in diameter e. Placing the magnesium stearate obtained from step (d), in a ratio of carprofen to magnesium stearate of from 1:0.01 to 0.1, preferably 1:0.05, into the blender and blending to achieve uniform mixing of the ingredients; *. . . f. Unloading the blended material into double polythene lined is drums; * g. Transferring the blended material into a hopper; h. Loading the blended material into a tableting press; i. 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; 25. Discharging the tablets from the tableting press into a chute; and k. Transferring the tablets into containers and packaging; or directly packaging the tablets obtained from step (j).

-22 -
2. The process according to claim I wherein i. from approximately 10 to 15% by weight of Carprofen is used; and/or ii. 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. The process according to claim 1 or claim 2 wherein a 20 mesh..*. S.

sieve is used in steps (b) and (d). *s..

S ***S

4. The process according to any of claims 1 to 3 wherein the unit dose tablet comprises 20mg of the active ingredient Carprofen.

5. The process according to claim 1 or 2 wherein the unit dose tablet comprises 50mg of the active ingredient Carprofen.

6. The process according to claim 1 or 2 wherein the unit dose tablet comprises 100mg of the active ingredient Carprofen.

7. The process according to any of the preceding claims wherein the blender is set at approximately 30 to 40 rpm and is run for approximately fifteen to thirty minutes in step (c) and approximately five to ten minutes in step (e).

8. The process according to any of the preceding claims wherein the -23 -tablets are packaged in high density polyethylene containers or blister packs made of hard temper aluminium foil.

9. An orally administered unit dose carprofen tablet comprising: I. Carprofen 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 in the range of 10 to 15% byweight; ii. 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; iii. Microcrystalline cellulose wherein 8% by weight or less *.S 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; v. Magnesium stearate, in a ratio of carprofen to magnesium stearate of from 1:0.01 to 0.1, preferably 1:0.05, in the range of 0.1 to 5% by weight; wherein ingredients (i) to (iv) are provided in a ratio of from approximately 1:3:2.5:0.05 to approximately 1:3.5:3.0:0.07.

10. An orally administered unit dose tablet according to claim 9 or prepared by the process according to any of claims I to 8 for use - 24 -in treating pain in animals, preferably dogs or cats.

11. A process for preparing an orally administered unit dose tablet substantially as described herein with reference to the examples and figure.

12. An orally administered unit dose tablet substantially as described herein with reference to the examples and figure.

13. An orally administered unit dose tablet substantially as described herein with reference to the examples and figure for use in treating pain in animals. . . S. * *S*S * *SSS' *S*. S * *S