GB2475701A

GB2475701A - An orally administered anthelmintic unit dose and process for the preparation thereof

Info

Publication number: GB2475701A
Application number: GB0920721A
Authority: GB
Inventors: Michael Hilary Burke
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-11-26
Filing date: 2009-11-26
Publication date: 2011-06-01
Anticipated expiration: 2029-11-26
Also published as: GB2475701B; GB0920721D0

Abstract

A method for the manufacture of an orally administered anthelmintic unit dose comprising praziquantel, pyrantel embonate and febantel, wherein not less than 50% of the praziquantel particles are below 10µm, not less than 97% of the praziquantel particles are below 50µm with the remaining below 75µm; approximately 95% of the pyrantel embonate particles are less than 5µm; and 99% of the febantel particles are less than 5µm. The method comprises the steps of (i) sifting the active ingredients, lactose monohydrate, half of the microcrystalline cellulose and half of the croscarmellose sodium to form sifted active ingredients; (ii) sifting the remaining microcrystalline cellulose and croscarmellose sodium, colloidal anhydrous silica and sodium lauryl sulphate to form a sifted lubricant mixture; (iii) mixing the sifted active ingredients in a granulator and adding water until a uniform wet mass of granulated material is formed; (iv) drying the wet granulated material to form dried granules; (v) mixing the dried granules with the sifted lubricant mixture (ii); (vi) sifting magnesium stearate and adding to the dried granules and sifted lubricant mixture to form lubricated granules and (vii) compressing the mixture into unit dose tablets. A flavouring agent may optionally be added.

Description

"AN ORALLY ADMINISTERED ANTHELMINTIC UNIT DOSE TABLET AND PROCESS FOR THE PREPARATION THEREOF"

Introduction

The present invention relates to an orally administered anthelmintic unit dose tablet comprising an effective amount of praziquantel, febantel and pyrantel embonate and a process for preparing the same.

Praziquantel ((2-cyclohexylcarbonyl) 1, 2, 3, 6, 7, -lib -hexahydro -4h -pyrazino [2, 1-a] isoquinolin -4 -one) is a known antiparasitic drug and belongs to the group isoquinolones. The mode of action of praziquantel is on the musculature of the parasites where it causes spastic paralysis. Praziquantel damages the normal function of the tegument. Glucose intake by the parasites is inhibited and the production of lactate is stimulated. The membrane of the parasites therefore becomes more sensitive to the action of proteolytic enzymes. This anthelmintic has excellent activity against all species of tapeworms and schistosomes.

Febantel is a starting material used to produce broad spectrum benzimidazole anthelmintics and their derivatives such as fenbendazole and oxfendazole. Febantel is N-[-[2,3-bis- (methoxycarbonyl)-guanido]-5-(phenylthio)-phenyl]-2-methoxyacetamide. With in the mammalian system, febantel undergoes ring closure, forming fenbendazole and oxfendazole. It is these chemical entities which exert the anthelmintic effect by inhibition of tubulin polymerisation. Formation of microtubules is thereby prevented, resulting in disruption of structures vital to the normal functioning of the helminth. Glucose uptake in particular is affected, leading to a depletion in cell ATP. The parasite dies upon exhaustion of its energy reserves, which occurs 2 to 3 days later.

Pyrantel embonate is highly effective against common hookworms (Ancylostoma caninum) and Ascarids. It is poorly soluble in water, higher efficacy on parasites at lower end of large intestine and is a cholinergic agonist and mimics the effects of excessive amounts of acetyl choline causing irreversible paralysis of worms.

It is well known that the efficacy of praziquantel can be enhanced by simultaneous administration with other anthelmintics such as fenbendazole (formed by febantel in the mammalian system) such as disclosed in UK Patent No. 2 252 730 for example. Additionally, US 5,036,069 discloses a composition comprising praziquantel, fenbendazole and pyrantel embonate. Many other compositions comprising known antiparasitics/antihelmintics are known as the advantage of these compositions is that they have broad spectrum anthelmintic properties compared to a single active ingredient alone.

However, the administration of multiple active ingredients in a single composition gives rise to several problems.

Firstly, the dissolution profiles of the active ingredients generally differ. Praziquantel is very slightly soluble in water whereas pyrantel and febantel are practically insoluble in water. In this case praziquantel and febantel are both absorbed into the bloodstream and pyrantel acts locally in the gut. Thus, it can be problematic to ensure all active ingredients when administered together as a single unit dose tablet have the desired dissolution profiles.

There is therefore a need for improved anthelmintic unit dose tablets comprising more than one active ingredient which allows quick and immediate release of the each active agent.

Secondly, palatability can also be a problem. For example, it has been recognised that praziquantel is an unpalatable compound and as with other unpalatable compounds there are problems in getting animals, particularly non-human animals to ingest it or any compositions comprising praziquantel. There are many solutions to this problem of unpalatable compounds.

For example, the ingredients may be coated with a substantially inert compound so that the unpleasant taste of the pharmaceutical agent is disguised as disclosed in WO 01/35925.

Alternatively, the active agent is enclosed as a component in active cores, the active cores being covered by a coating at least to such an extent that the first active agent can no longer be sensorically perceived by the animal (German Patent Application No. DE 19941024).

The disadvantage of the above coated preparations, it that as the pharmaceutical agent in each case is encapsulated within an inert coating, a greater time span elapses before the pharmaceutical agent becomes effective. Upon ingestion of the product, the outer coating must be first disrupted before the pharmaceutical agent can be released. Thus, the dissolution profile can be negatively affected. Additionally in the above coated preparations, some animals are able to physically separate the coating from the pharmaceutical agent and only eat the sweet-tasting coating.

Thus, there is a further need for a palatable anthelmintic composition wherein the unpalatable pharmaceutical agent cannot be easily separated from the sweet tasting components, before ingesting.

Finally, there are many problems associated with large-scale manufacture of a drug including producing a formulation with little product variation, in terms of hardness, moisture content, friability, disintegration and dissolution patterns, within each batch. Thus, there is a need to develop an industrial large-scale process which deals with one or more of these problems.

Statements of Invention

According to a first aspect of the invention, there is provided a method for the manufacture of an anthelmintic orally administered unit dose tablet comprising the active ingredients praziquantel wherein not less than 50% of the praziquantel particles are below 10pm, not less than 97% of the praziquantel particles are below 5Opm with the remaining below 75pm; pyrantel embonate wherein approximately 95% of the pyrantel embonate particles are less than 5pm; and febantel wherein 99% of the febantel particles are less than 5pm; wherein the method comprises the steps of: i) a. sifting the active ingredients praziquantel, pyrantel embonate, febantel, and filler agent, part of the disintegrant and dissolution enhancer though a 20# screen to form sifted active ingredients; b. sifting the remaining disintegrant and dissolution enhancer, anti-adherent and a first lubricant though a 20# screen to form a sifted lubricant mixture; ii) mixing the sifted active ingredients in a granulator for 5 minutes at slow speed, adding purified water and mixing until a uniform wet mass of granulated material is formed; iii) drying the uniform wet mass of granulated material to form dried granules with a LOD moisture of less than approximately 4%, followed by sifting through a 12# mesh screen; iv) a lubrication step comprising mixing the dried granules with the sifted lubricant mixture in a blender or drum tumbler sifting the second lubricant, magnesium stearate, and adding to the dried granules and sifted lubricant mixture and mixing for approximately 5 minutes to form lubricated granules; v) compressing the lubricated granules to form orally administered unit dose tablets; and vi) packaging the tablets.

Detailed Description of the Invention

In the specification, the term "effective amount" refers to the amount of active ingredients which are required to destroy parasites.

In the specification, the term "by weight" refers to the weight of the final unit dose tablet.

In the specification, references to particle size correspond to the average particle size of the specific ingredient/component. This generally relates to the diameter of the particle in question.

As explained above, 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.

These manufacturing problems are exacerbated when more than one active ingredient is present in a unit dose tablet. In the present invention, three active ingredients, praziquantel, pyrantel and febantel, are incorporated into a single unit dose tablet. The advantage of using praziquantel, pyrantel and febantel in the composition is that as these pharmaceutical agents work by different modes of action they are more effective in the control of parasites. This leads to the further advantage that less of the composition is required in order to effectively control anthelmintic infestation in animals. However, as the orally administered unit dose tablet of the invention, comprises three active ingredients with different characteristics, the manufacture of a combination tablet present the large-scale manufacturer with additional problems to overcome.

Thus, the present invention is directed to providing an optimised process for the manufacture of a unit dose tablet with three active ingredients with uniform distribution of each of the active ingredients.

In general terms, the process and formulation according to the invention provides a robust, simple process for producing tablets of good hardness and quality attributes. Specifically, the process of the invention provides process for the manufacture of an orally administered unit dose tablet which has adequate hardness, good dissolution pattern and good uniformity when manufactured on a large-scale.

There are several aspects of this method which provide an advantage particularly on a large-scale.

Firstly, a binder is not used in this process. The use of binders, such as maize starch or povidone, results in extra processing steps. Thus, the choice of specific excipients in the unit dose table of the invention results in a streamlined and faster process which is advantageous when carrying out manufacture on a large scale.

Secondly, wet granulation is used. This advantageously provides for fast disintegrating tablets and results in a tablet with a fast dissolution rate of less than 5 minutes. This ensures the active ingredients are available to act quickly in the gut. We have note that the active ingredients are physically very sticky materials. This feature has been utilised in the method, wherein the active ingredients are moistened using water to form uniform granules with the appropriate particle size. This reduces the total processing time and improves the process output and yield.

Finally, that this method advantageously provides for an oral anthelmintic composition with an improved dissolution profile compared to other similar tablets. Specifically the unit dose tablet of the invention is a fast disintegrating tablet which provides a fast dissolution time in the initial five minutes. It is a combination of the specific excipients and method steps which result in the improved tablet of the invention.

The following table outlines the preferred composition of the oral anthelmintic composition of the invention.

Ingredients Suitable % by Preferred Preferred Preferred Ingredients (Ph weight range % Quantity Eur)

by weight mg/tablet

Active substance(s): Praziquantel 5-10% 7.69 50.00 Praziquantel Pyrantel Embonate 20-25% 22.15 144.00 Pyrantel Embonate Febantel 20-25% 23.08 150.00 Febantel Exci pients: Disintegrant 25-30% 30.00 195.00 Microcrystalline Cellulose Filler 10-15% 12.58 81.75 Lactose monohydrate Lubricant 1-5% 2.00 13.00 Sodium lauryl sulphate Lubricant 0.1-5% 1.00 6.50 Magnesium stearate Dissolution enhancer 0.1-5% 1.00 6.50 Croscarmellose sodium Anti-adherent 0.1-5% 0.50 3.25 Colloidal anhydrous silica Total 100% 650 mg

Table 1

An optional flavouring ingredient may also be added, at a level of 1 to 5% by weight based in the total composition. If such a flavouring agent is added, the amount of the disintegrant may be reduced accordingly. Such a flavouring agent may be a meat flavouring agent.

It will be understood that other disintegrants, fillers, lubricants, dissolution enhancers and anti-adherents commonly used in the pharmaceutical fields may be used instead of those outlined on

the above table.

The specific particle size of each of the active ingredients are important aspects of the invention.

Not less than 50% of the praziquantel particles are 10pm, not less than 97% are below SOpm with the remaining below 75pm. Preferably, praziquantel is in the range 5-10% by weight. Ideally praziquantel is in a micronised form.

Approximately 95% of the pyrantel particles are less than 5pm. Preferably, pyrantel embonate is in the range 20-25% by weight. Ideally, pyrantel embonate is in a micronised form.

Approximately, 99% of the febantel particles are less than 5pm. Preferably febantel is in the range 20-25% by weight. Ideally febantel is in a micronised form.

According to a preferred embodiment of the invention, the disintegrant is microcrystalline cellulose wherein 90% by weight or less have an average particle size of greater than 250 microns and 50% by weight or more have an average particle size in the range of approximately 140-210 microns and 10% by weight has an average particle size in the range of 35-80 microns. It will be understood that hydroxypropyl methylcellulose or other cellulose materials may also be used according to the invention.

According to another preferred embodiment of the invention, the filler is lactose monohydrate wherein approximately 90% by weight have an average particle size of less than 355 microns in diameter; in the range of 40% by weight has an average particle size of less than 150 microns by weight. Other fillers which may be used according to the invention include starches such as corn starch.

According to yet another preferred embodiment of the invention, the lubricant is sodium lauryl sulphate and magnesium stearate. 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 ingredients. The process of the present invention aims to minimise the contact time between the blended ingredients and the magnesium stearate. The recommended time for magnesium stearate mixing should not be more than five minutes to avoid the hydrophobic characteristics of magnesium stearate and to prevent it from laminating the drug particles and ultimately affecting the dissolution and the release rate.

According to still another preferred embodiment of the invention, the dissolution enhancer is croscarmellose sodium.

According to yet another preferred embodiment of the invention, the anti-adherent is colloidal anhydrous silica.

Ideally a 20# mesh (or 20# screen) is used to break down particles with an average particle size of greater than approximately 800 to 900 microns, preferably 850 microns. A 12# mesh (or 12#screen) is typically used to break down particles with an average particle size of greater than approximately 1400 microns. Typically, a Russell Sieve is used. The 12# mesh is equivalent to a 1.5mm Mesh sieve which is also used. It will be understood that the narrow particle size for these excipients ensures a low tablet weight variation and good uniformity of the drug.

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, foil strip packed in aluminium foil and extruded polythene 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, 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 a dose of 15mg/kg bodyweight febantel, 5 mg/kg pyrantel (equivalent to 14.4 mg/kg pyrantel embonate) and 5 mg/kg praziquantel per kg bodyweight. Preferably, the dose should be given as a single dose.

According to a preferred embodiment of the invention, there is provided a palatable oral anthelmintic composition. In this embodiment a flavouring agent, such as a meat flavouring, is added at a level of approximately 1 to 5% by weight based on the total composition/tablet. Any meat flavouring may be used, including pork flavouring. This embodiment overcomes the problems of palatability of praziquantel. Ideally, the flavouring agent is added just before the second lubricant, magnesium stearate is added.

In another embodiment of the invention the flavouring agent is a sweet excipient and is selected from the group comprising castor sugar, dry castor sugar, aspartame, acesulphone potassium, dextrose, glucose, fructose, glycerol, lactitol, maltitol, maltose, saccharin, saccharin sodium, sodium cyclamate, sorbitol, xylitol.

The palatable oral anthelmintic composition of this embodiment of the invention overcomes the problem of praziquantel being an unpalatable compound which will prevent the animal ingesting the composition. -10-

The invention will be more clearly understood from the following description of the process according to the invention described with reference to the non-limiting Examples and Figures.

Figure 1 shows an outline of the process of Example 2.

Figure 2 shows a comparative dissolution profile of praziquantel in tablets made in accordance with Example 2 compared to Drontal Plus ® tablets.

Figure 3 shows a comparative dissolution profile of pyrantel in tablets made in accordance with Example 2 compared to Drontal Plus ® tablets.

Figure 4 shows a comparative dissolution profile of febantel in tablets made in accordance with Example 2 compared to Drontal Plus ® tablets.

Figure 1 shows an outline of the method steps for the manufacture of an anthelmintic orally administered unit dose tablet comprising the active ingredients praziquantel, pyrantel embonate and febantel.

All the equipment used in carrying out the process is well known equipment and accordingly

does not require any further description.

Referring to Figure 1, the first step is to carry out a potency adjustment calculation for each of the active ingredients and for microcrystalline. This is an optional step as Table 2 and 3 outline the percentage of each ingredient to be used in Example 2. However, if tablets of a potency different to that of Table 2 and 3 is desired, then this potency adjustment calculation should be carried out.

The active ingredients (as defined in Table 2) praziquantel, pyrantel embonate, febantel, and filler agent, part of the disintegrant and dissolution enhancer are sifted though a 20# screen to form sifted active ingredients and collected in a suitable container. This step breaks down particles greater than 800 to 900 microns. At this stage, ideally half of the disintegrant and dissolution enhancer are used. This aids the granulation process.

At the same time the remaining disintegrant and dissolution enhancer, anti-adherent and a first lubricant (as defined in Table 2) are also sifted though a 20# screen to form a sifted lubricant mixture and collected in a suitable container. This step breaks down particles greater than 800 to 900 microns.

The next step is to mix the sifted active ingredients in a granulator for 5 minutes at slow speed to form a uniform mix. Ideally, the granulator is set at a low speed of approximately 55 to 75rpm, preferably 65 rpm. Purified water is then added to the mixture and mixed until a uniform wet mass of granulated material is formed. In this case, for a batch size of 71.5kg, approximately 20 to 25 litres of water was added. The amount of water will depend on the total batch size and is the amount necessary to form a uniform wet mass of granulated material. Wet granulation speeds up the process particularly on a large-scale and provides for a tablet with a fast disintegration times of less than 5 minutes. In this step, the sifted active ingredients are wetted, dried and immediately sieved to obtain uniform granules. This takes advantage of the physical characteristics of the active ingredients which once mixed and wetted, bind together and form uniform granules. Accordingly, wet granulation also ensures the formation of good and uniform granules with a proper particle size.

After this, the uniform wet mass of granulated material is dried to form dried granules with a limit of moisture content (LOD) of approximately less than 4% (ideally 2 to 4%).

After drying, the dried granules are sifted into a blender or drum tumbler through a sieve number 12 (12# mesh/screen). This step breaks down particles greater than 1400 microns.

Any retained granules are then passed through a 1.5mm Mesh sieve (also equivalent to 1400 micrometers) and are also passed into the blender or drum tumbler.

This further step of sifting ensures that the correct particle size is retained in order to generate uniform size granules so that all the compression and physical parameters are controlled and tablets with good physical and chemical properties are obtained.

After this, a lubrication step is carried out. This step comprises mixing the dried granules with the sifted lubricant mixture in a blender or drum tumbler. Ideally, they are mixed in a drum tumbler. Then, the second lubricant, magnesium stearate, is sifted through sieve number 20 (i.e. 20# screen). This step breaks down particles greater than 800 to 900 microns.The sifted magnesium stearate is added to the dried granules and sifted lubricant mixture and mixed/blended in a drum blender for approximately 5, minutes to form lubricated granules.

-12 -The lubricated granules are then compressed to form orally administered unit dose tablets.

When compression is completed, samples are collected by QC (not shown) to carry out complete analysis of the product as per the finished product specification.

The unit does tablets are then packaged the tablets using conventional techniques.

Example I

Preferred manufacturing formula for orally administered unit dose tablets Raw Material per 650 mg Praziquantel 50 mg Pyrantel Embonate 144 mg Febantel 150 mg Disintegrant (e.g. Microcrystalline Cellulose) 195 mg Filler (e.g. Lactose Monohydrate) 81.75 mg Anti-adherent (e.g. Colloidal Anhydrous Silica) 3.25 mg Lubricant (e.g. Sodium Laurilsulfate) 13 mg Dissolution enhancer (e.g. Croscarmellose 6.50 mg Sodium) ________________________ Lubricant (e.g. Magnesium Stearate) 6.50 mg Total 650 mg

Table 2

Example 2

Manufacturing process for orally administered unit dose tablet Equipment All the equipment used in carrying out the process is well known equipment and accordingly

does not require any further description. -13-Sieve

Granulator Fluid Bed dryer Blender/Drum Tumbler Compression Machine Electronic Scales Polybags Protective clothing Materials Initially 650mg tablets were made with a batch size of 110,000 tablets (approx 71.5kg).

Composition of 650 mq Tablet Ingredients Quantity Function Reference

mg/tablet

Active substance(s): Praziquantel 50.00 Active Ph. Eur Pyrantel Embonate 144.00 Active Ph. Eur Febantel 150.00 Active Ph. Eur Exci pients: Microcrystalline Cellulose 195.00 Disintegrant Ph. Eur. Lactose monohydrate 81.75 Filler Ph. Eur. Sodium lauryl sulphate 13.00 Lubricant Ph. Eur. Magnesium stearate 6.50 Lubricant Ph. Eur. Croscarmellose sodium 6.50 Dissolution enhancer Ph. Eur. Colloidal anhydrous silica 3.25 Anti-adherent Ph. Eur. Total 650 mg

Table 3

-14 -Method Step I -Optional Potency Adjustment Potency adlustment on Praziquantel, Pyrantel Embonate and Febantel Potency Adjustment: Praziquantel, Pyrantel embonate and Febantel Potency as is basis = X % Calculation of quantity required Y = Quantity Required (kqlq) x 100 Potency X Y = Amount of Praziquantel, Pyrantel Embonate and Febantel Required (Based on potency calculation).

Calculation of Actual Quantity of Microcrystalline Cellulose A (kg) = Theoretical amount of Praziquantel + Pyrantel Embonate + Febantel.

Theoretical quantity of Microcrystalline Cellulose = Z kg Actual Qty of Microcrystalline Cellulose = Z + (A -Y) kg Step 2 -Sifting of Ingredients as defined in Table 3 a. Praziquantel, Pyrantel Embonate, Febantel, lactose monohydrate, microcrystalline cellulose (approximately half portion) and croscarmellose sodium (half the batch portion) were sifted through 20# screen and collected in a suitable container.

b. Microcrystalline cellulose (remainder), Colloidal anhydrous silica, Croscarmellose sodium (half the batch portion) and Sodium Laurilsulfate were sifted through a 20# screen and collected in a suitable container.

Step 3 -Granulating of Active Ingredients The materials from step 2 (a) were mixed in a granulator for 5 minutes at slow speed. Purified water was added portion wise and mixed until a uniform wet mass was formed.

Step 4-Drying The uniform wet mass from step 3 was dried in fluid bed dryer for approximately 40 -60 minutes to attain LOD moisture of less than or equal to 4% (ideally 2 to 4%) to form dried granules. -15-

After drying, the dried granules were sifted into a drum through a sieve number 12 (approximate particle size 1400 micrometer). Any retained granules are then passed through a 1.5mm Mesh sieve (equivalent to 1400 micrometers) into the drum blender.

Step 5 -Mixing and lubrication: The sifted and dried granules from step 4 were mixed with the sifted materials from step 2 (b) in a drum blender to form a blended material.

Magnesium Stearate was sifted through a 20# screen and added to the blended material above and mixed in the drum blender for not more than approximately 5 minutes.

Step 6 -Compression a. The compression machine was tooled up with 13 mm flat bevelled edge punches, upper punch -Cross breaklines and lower punch -plain (Speed 20 -100,000 Tabs per hour).

b. The granules were loaded onto the compression machine and a start up sample was

prepared according to tablet specification.

c. Start up sample conditions: -

Parameter Specification

Tablet Shape Round Flat Bevelled Edge with cross brea kline Tablet Diameter 13.0 ± 0.2 mm Disintegration Less than 15 mm Friability Less than 1% after 100 revs Average weight 650mg +1-5% Hardness Not less than 60 N Step 7 -Finished Product Analysis When compression was completed, samples were collected by QC to carry out complete analysis of the product as per the finished product specification.

Test Specification Method

Appearance Yellow coloured, uncoated, circular, flat Visual bevelled tablet with cross breakline on one side and plain on the other. Diameter 13mm ± -16-0.3 mm Identification (UV The chromatography of the HPLC assay H.P.L.C.

detector): exhibits major peaks due to Praziquantel and Praziquantel & Febantel the retention times of which are Febantel comparable to those exhibited in the chromatogram of the standard.

Pyrantel Embonate The chromatography of the HPLC assay exhibits major peaks due to Pyrantel Embonate the retention times of which are comparable to those exhibited in the chromatogram of the standard.

Identification (PDA The chromatography of the HPLC assay H.P.L.C. using detector): exhibits major peaks due to Praziquantel and PDA detector.

(Performed on every Febantel the retention times of which are 12' batch) comparable to those exhibited in the Praziquantel & chromatogram of the standard.

Febantel Pyrantel Embonate The chromatography of the HPLC assay exhibits major peaks due to Pyrantel Embonate the retention times of which are comparable to those exhibited in the chromatogram of the standard.

Average Weight: 650 mg/tab ± 5% As per Ph. Eur (617.5-682.5mg/tab) Friability: Less than 1% after 100 revs As per Ph. Eur Hardness: Not less than 60N As per Ph. Eur Moisture Not more than 5% As per Ph. Eur Dissolution: Praziquantel: NLT 75%(Q+5) dissolved in 45 mins (as per Ph. Eur) Pyrantel Embonate: NLT 75%(Q+5) dissolved in 45 mins (as per Ph. Eur) Febantel: NLT 75%(Q+5) dissolved in 45 mins (as per Ph. Eur) -17-Assay: Praziquantel: 50 mg ± 5% (Limits: 47.5 -52.5 mg/tab) H.P.L.C Pyrantel Embonate: 144mg ± 5% (Limits: 136.8-151.2 mg/tab) Febantel: 150 mg ± 5% (Limits: 142.5-157.5 mg/tab) Uniformity of Dosage The requirements are met if the acceptance As per Ph. Eur Unit value of the first 10 dosage units is less than or equal to Li (15.0). If the acceptance value is greater than Li, the next 20 dosage units are tested and acceptance value calculated.

The requirements are met if the final acceptance value of the 30 dosage units is less than or equal to Li (15.0) and no unit is over the deviation of L2 (25.0) from the calculated value of M in calculation of acceptance value.

Microbial Purity As per Ph. Eur As per Ph. Eur (Performed on every 6th batch) Step 8 -Packing The compressed tablets were packed in strip packs or blister packs.

Example 3

Comparative Testing -Dissolution Test Development Materials and Methods: The dissolution profile of the tablet made in accordance with Example 2 was compared to the commercially available Drontal Plus ® which comprises the following: Drontal Plus ® Active substances Praziquantel 50mg Pyrantel Embonate 144mg Febantel 150mg -18-Drontal Plus ® Excipients Maize Starch Lactose Microcrystalline Cellulose Povidone Magnesium Stearate Sodium Lauryl sulfate Colloidal An hydrous Silica 1% Sodium Laurilsulfate was chosen as the dissolution medium. Dissolution testing was performed at 100rpm.

DISSOLUTION METHOD PROTOCOL

Dissolution conditions: Apparatus: Paddles Speed: 100rpm Temperature: 37°C ± 0.5°C Volume: 900mls Run Time: 60mins Sample taken: 5mls Dissolution Medium: 1% Sodium Laurilsulfate was prepared by weighing lOg of Sodium Laurilsulfate into a 1 litre volumetric flask. Water was added and mixed until dissolved. Dilute to volume with water.

Chromatographic conditions: as per assays for Praziquantel, Febantel and Pyrantel E mbonate.

Preparation of Praziquantel and Febantel Stock Standard Solution: 28mg of Praziquantel standard and 83mg of Febantel standard were weighed into a 1 OOml volumetric flask and dissolved in Mobile Phase and diluted to volume with same.

Preparation of Praziquantel and Febantel Working Standard Solution: 1 OmIs of the stock standard solution was pipetted into a 1 OOml volumetric flask, 50m1 dissolution medium was added and diluted to volume with Mobile Phase. -19-

Preparation of Pyrantel Embonate Standard Solution: 80mg of Pyrantel Embonate standard was weighed into a 1 OOml volumetric flask and dissolved in Mobile Phase and diluted to volume with same. 5m1 was pipetted into a 25m1 volumetric flask and diluted to volume with Dissolution Medium.

Preparation of Pyrantel Embonate Working Standard Solution: 2mls of the stock standard solution was pipetted into a lOmI volumetric flask and diluted to volume with Mobile Phase.

Preparation of Test Solution.

The dissolution apparatus was set up having the spindles centred and their heights set.

A tablet was dropped into 900 mIs of dissolution medium previously equilibrated at 37°C and degassed. The paddles started rotating immediately. After 60 mins a 25 ml sample was removed and filtered using PTFE filter.

For Praziquantel and Febantel samples, 5mls to 10 mIs was dilutedwith Mobile Phase.

For Pyrantel sample, 2mls to lOmIs was diluted with Mobile Phase.

Calculations: % Dissolved Praziquantel: Wt std(mq) x Mean Peak area Sample x 900 x 10 x 10 x 100 x Purity Label Claim x Mean Peak area Std x 100 x 5 x 100 % Dissolved Febantel: Wt std(mq) x Mean Peak area Sample x 900 x 10 x 10 x 100 x Purity Label Claim x Mean Peak area Std x 100 x 5 x 100 % Dissolved Pyrantel Embonate: Wt std(mq) x Mean Peak area Sample x 900 x 10 x 5 x 2 x 100 x Purity Label Claim x Mean Peak area Std x 100 x 2 x 25 x 10

Results and Conclusions

Comparative dissolution profiles for the tablets made in accordance with Example 2 and the commercially available Drontal® Plus tablets are shown in Figures 2 to 4 and the results are summarized in the following tables: % Release of Praziquantel, Pyrantel Embonate and Febantel (Limit: NLT 80 % dissolved in 60 mins) Prazitel Drontal Prazitel Drontal Prazitel Drontal Prazitel Plus Plus Plus Plus Plus Plus Plus 5mm 5mm 10mm 10mm 15mm I5mins 20mm Praziquantel 70.5% 37.0% 81.3% 94.8% 87.8% 99.7% 91.0% Febantel 69.1% 32.4% 76.2% 78.5% 80.4% 92.6% 82.7% Pyrantel 57.3% 17.2% 73.6% 62.0% 79.9% 85.3% 84.2% Embonate Drontal Prazitel Drontal Prazitel Drontal Prazitel Drontal Plus Plus Plus Plus Plus Plus Plus mm 30 mm 30 mins 45 mm 45 mins 60 mm 60 mins Praziquantel 99.3% 93.6% 98.2% 94.4% 96.6% 94.0% 95.4% Febantel 94.9% 84.2% 96.7% 86.1% 96.3% 87.3% 95.4% Pyrantel 91.9% 92.4% 98.9% 95.6% 102.0% 97.2% 100.3% Embonate We found that the dissolution profile of the tablets made in accordance with Example 2 was ahead of Drontal Plus® tablets during the first five minutes. This improved dissolution profile is an advantage as initial delivery of the active ingredients is faster than the Drontal Plus® tablets.

In the specification the terms "comprise, comprises, comprised and comprising" or any variation thereof and the terms "include, includes, included and including" or any variation thereof are considered to be totally interchangeable and they should all be afforded the widest possible interpretation and vice versa.

The invention is not limited to the embodiment hereinbefore described, but may be varied in both construction and detail. -21 -

Claims

CLAIMS1. A method for the manufacture of an anthelmintic orally administered unit dose tablet comprising the active ingredients praziquantel wherein not less than 50% of the praziquantel particles are below 1 Opm, not less than 97% of the praziquantel particles are below 5Opm with the remaining below 75pm; pyrantel embonate wherein approximately 95% of the pyrantel embonate particles are less than 5pm; and febantel wherein 99% of the febantel particles are less than 5pm; wherein the method comprises the steps of: i) a. sifting the active ingredients praziquantel, pyrantel embonate, febantel, and filler agent, part of the disintegrant and dissolution enhancer though a 20# screen to form sifted active ingredients; b. sifting the remaining disintegrant and dissolution enhancer, anti-adherent and a first lubricant though a 20# screen to form a sifted lubricant mixture; ii) mixing the sifted active ingredients in a granulator for 5 minutes at slow speed, adding purified water and mixing until a uniform wet mass of granulated material is formed; iii) drying the uniform wet mass of granulated material to form dried granules with a LOD moisture of less than approximately 4%, followed by sifting through a 12# mesh screen; iv) a lubrication step comprising mixing the dried granules with the sifted lubricant mixture in a blender or drum tumbler sifting the second lubricant, magnesium stearate, and adding to the dried granules and sifted lubricant mixture and mixing for approximately 5 minutes to form lubricated granules; v) compressing the lubricated granules to form orally administered unit dose tablets; and vi) packaging the tablets.
2. The process according to claim 1 wherein the orally administered unit dose tablet comprises from 5-10% by weight praziquantel; -22 -from 20-25% by weight pyrantel embonate; from 20-25% by weight febantel; from 25-30% by weight disintegrant; from 10-15% by weight filler; from 1-5% by weight a first lubricant; from 0.1-5% by weight of the second lubricant magnesium stearate; from 0.1-5% by weight dissolution enhancer; and from 0.1-5% by weight anti-adherent.
3. The method according to claim 1 or claim 2 wherein a flavouring agent is added to prior to the addition of the second lubricant magnesium stearate in step (iv).
4. The method according to claim 3 comprising from 1 to 5% by weight of the flavouring agent.
5. The method according to claim 3 or claim 4 wherein the flavouring agent is a meat flavouring agent, such as pork flavour.
6. The process according to any of the preceding claims comprising an optional initial potency calculation to determine the amount of each active ingredient to be used.
7. The process according to any of the preceding claims comprising quality control steps throughout the process.
8. The process according to any of the preceding claims wherein the granulated material is dried in a fluid bed dryer for approximately 40 to 60 minutes in step (iii).
9. The process according to any of the preceding claims wherein the disintegrant is microcrystalline cellulose wherein 90% by weight or less of the microcrystalline particles have an average particle size of greater than 250 microns, 50% by weight or more have an average particle size in the range of approximately 140-210 microns and 10% by weight have an average particle size in the range of 35-80 microns 10. The process according to any of the preceding claims wherein the filler is lactose monohydrate wherein approximately 90% by weight of the lactose monohydrate particles have an average particle size of less than 355 microns in diameter and in the range of 40% by weight have an average particle size of less than 150 microns by weight.11. The process according to any of the preceding claims wherein the first lubricant is sodium lauryl sulphate and the second lubricant is magnesium stearate.12. The process according to any of the preceding claims wherein the dissolution enhancer is croscarmellose sodium.13. The process according to any of the preceding claims wherein the anti-adherent is colloidal anhydrous silica.14. An orally administrable unit dose tablet comprising from 5-10% by weight praziquantel wherein not less than 50% of the praziquantel particles are less than 10pm, not less than 97% of the praziquantel particles are below 5Opm; with the remaining praziquantel particles below 75pm; from 20-25% by weight pyrantel embonate wherein approximately 95% of the pyrantel particles are less than 5pm; from 20-25% by weight febantel wherein 99% of the febantel particles are less than 5pm; from 25-30% by weight disintegrant; from 10-15% by weight filler; from 1-5% by weight a first lubricant; from 0.1-5% by weight of a second lubricant magnesium stearate; from 0.1-5% by weight dissolution enhancer; and from 0.1-5% by weight anti-adherent; with a friability of less than 1% after 100 revs and a disintegration of less than 15 minutes.15. An orally administrable unit dose tablet according to claim 14 further comprising from 1 to 5% by weight of the flavouring agent.16. An orally administrable unit dose tablet and process for manufacture thereof as hereinbefore described with reference to the accompanying Figures and Examples.AMENDMENTS TO THE CLAIMS HAVE BEEN MADE AS FOLLOWSCLAIMS 24 1. A method for the manufacture of an anthelmintic orally administered unit dose tablet comprising the active ingredients praziquantel wherein not less than 50% of the praziquantel particles are below 10pm, not less than 97% of the praziquantel particles are below 5Opm with the remaining below 75pm; pyrantel embonate wherein 95% of the pyrantel embonate particles are less than 5pm; and febantel wherein 99% of the febantel particles are less than 5pm; wherein the method comprises the steps of: i) a. sifting the active ingredients praziquantel, pyrantel embonate, febantel, and filler agent, half part of the disintegrant and dissolution enhancer though a 20# screen to form sifted active ingredients; b. sifting the remaining disintegrant and dissolution enhancer, anti-adherent and a first lubricant though a 20# screen to form a sifted lubricant mixture; ii) mixing the sifted active ingredients in a granulator for 5 minutes, adding purified water CO and mixing until a uniform wet mass of granulated material is formed; O iii) drying the uniform wet mass of granulated material to form dried granules with a LOD moisture of less than 4%, followed by sifting through a 12# mesh screen; iv) a lubrication step comprising mixing the dried granules with the sifted lubricant mixture in a blender or drum tumbler sifting a second lubricant magnesium stearate and adding to the dried granules and sifted lubricant mixture and mixing for 5 minutes to form lubricated granules; v) compressing the lubricated granules to form orally administered unit dose tablets; and vi) packaging the tablets.2. The process according to claim 1 wherein the orally administered unit dose tablet comprises from 5-10% by weight praziquantel; from 20-25% by weight pyrantel embonate; from 20-25% by weight febantel; from 25-30% by weight disintegrant; from 10-15% by weight filler; from 1-5% by weight a first lubricant; from 0.1-5% by weight of the second lubricant magnesium stearate; from 0.1-5% by weight dissolution enhancer; and from 0.1-5% by weight anti-adherent.3. The method according to claim 1 or claim 2 wherein a flavouring agent is added to prior to the addition of the second lubricant magnesium stearate in step (iv).4. The method according to claim 3 comprising from 1 to 5% by weight of the flavouring agent.5. The method according to claim 3 or claim 4 wherein the flavouring agent is a meat flavouring agent.Q 6. The process according to claim 5 wherein the flavouring agent is pork flavour.CO 7. The process according to any of the preceding claims wherein the granulated material is Q 20 dried in a fluid bed dryer for 40 to 60 minutes in step (iii).8. The process according to any of the preceding claims wherein the disintegrant is microcrystalline cellulose wherein 90% by weight or less of the microcrystalline particles have an average particle size of greater than 250 microns, 50% by weight or more have an average particle size in the range of 140-210 microns and 10% by weight have an average particle size in the range of 35-80 microns 9. The process according to any of the preceding claims wherein the filler is lactose monohydrate wherein 90% by weight of the lactose monohydrate particles have an average particle size of less than 355 microns in diameter and in the range of 40% by weight have an average particle size of less than 150 microns by weight.
10. The process according to any of the preceding claims wherein the first lubricant is sodium lauryl sulphate.
11. The process according to any of the preceding claims wherein the dissolution enhancer is croscarmellose sodium.
12. The process according to any of the preceding claims wherein the anti-adherent is colloidal anhydrous silica.
13. A process for the manufacture of an orally administrable unit dose tablet as hereinbefore described with reference to the accompanying Figures and Examples. Co