IES83876Y1 - Palatable oral anthelmintic composition - Google Patents

Abstract

ABSTRACT A palatable oral anthelrnintic composition, comprising at least an effective amount of praziquantel and fenbendazole. The composition allows quick release of the pharmaceutical agents after ingesting and which cannot be separated from the palatable part of the composition before ingesting. The invention also relates to a process for preparing the composition and the use of the composition.

Description

"Palatable Oral Anthelmintic Composition" Introduction The present invention relates to a palatable oral anthelmintic composition comprising at least an effective amount of praziquantel and fenbendazole. The invention further relates to a process for preparing that composition. in the specification the term "effective amount" refers to the amount of praziquantel and fenbendazole which must be added to destroy parasites. In the specification the term "by weight" refers to the weight of the final composition.

Praziquantel ((2-cyclohexylcarbonyl) 1, 2, 3, 6, 7, - 11b - hexahydro — 4h - pyrazino [2, 1-a] isoquinolin — 4 — one) is a known antiparasitic drug. 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.

Fenbendazole (methyl 5(6) - phenylthio benzimidazole carbamate) works by a second mode of action by disrupting the formation of microtubules by binding tubulin in parasitic intestinal cells hence preventing the absorption of glucose. The parasites are thus gradually starved to death.

It is well known that the efficacy of praziquantel can be enhanced by simultaneous administration with other anthelmintics such as fenbendazole such as disclosed in UK Patent No. 2 252 730. Furthermore the combination of these compounds provides for a composition having broad spectrum anthelmintic properties. It has also been recognised that praziquantel is an unpalatable compound and as with other unpalatable compounds there are problems in getting animals to ingest it or any compositions comprising praziquantel.

Some solutions to the delivery of unpalatable compounds are disclosed in the prior art. PCT publication no. WO 01/35925 discloses a food product for the oral delivery of particles of a pharmaceutical agent to a non—human animal, wherein each of the particles is encapsulated within a substantially inert coating, so that the unpleasant taste ofthe pharmaceutical agent is disguised.

German Patent Application No. DE 19941024 discloses an active agent preparation for veterinary use wherein 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.

The disadvantage of the above 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. Additionally in the above preparations, some animals are able to physically separate the coating from the pharmaceutical agent and only eat the sweet-tasting coating.

There therefore a need for a palatable anthelmintic composition which allows quick release of the pharmaceutical agent. There is further a need for a palatable anthelmintic composition wherein the unpalatable pharmaceutical agent cannot be easily separated from the sweet tasting components, before ingesting.

Statements of invention According to the invention, there is provided a palatable oral anthelmintic composition comprising an effective amount of praziquantel and an effective amount of fenbendazole in combination with a sweet excipient in the range 12-88% by weight, a non—sweet carbohydrate in the range 7—21% by weight, a taste-masking polymer: in the range 2-20% by weight, a dissolution retarding agent in the range 2-20% by weight, a preservative in the range 0.054% by weight, a disintegrating agent in the range 2.55-25% by weight, an adhesive in the range 0.2-2.5% by weight, a sweetener in the range 0.05-2% by weight, a flavouring agent in the range 2—12% by weight, water in the range 0% to 25% by weight.

Preferably, praziquantel is in the range 0.5-1 .5% by weight.

Ideally praziquantel is in a granular form.

Preferably fenbendazole is in the range 18-22% by weight.

Ideally fenbendazole is in a granular form.

The advantage of using both praziquantel and fenbendazole 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.

The advantage of orally administering the composition is that, the administration can be carried out by an unskilled person. Other methods of administration such as intravenous administration usually require the skill and knowledge of a veterinary practitioner. This results in the administration being more a time consuming and expensive procedure.

In one embodiment of the invention the sweet excipient is selected from the group comprising castor sugar, dry castor sugar, aspartane, acesulphone potassium, dextrose, glucose, fructose, glycerol, lactitol, maltitol, maltose, saccharin, saccharin sodium, sodium cyclamate, sorbitol, xylltol.

In a further embodiment of the invention the non-sweet carbohydrate is selected from the group comprising maize starch, sodium starch, carboxymethyl starch, compressible starch, corn starch, white starch, double dressed starch, potato starch, pregelatinised starch, rice starch, sodium carboxymethyl starch, wheat starch, tapioca starch. in a still further embodiment of the invention the taste-masking polymer: co-polymer is selected from the group comprising ammonio methacrylate co-polymer, microcrystalline wax, poloxamer, polyethylene propylene glycol, polyoxyethylene polyoxypropylene, carrageenan, cellulose acetate, glyceryl monostearate, zein, white wax, yellow wax.

Further preferably the sweetener is selected from the group comprising saccharin sodium, aspartane, acesulphone potassium, dextrose, glucose, fructose, glycerol, lactitol, rnaltitol, maltose, saccharin, saccharin sodium, sodium cyclamate, sorbitol, xylitol.

The advantage of the sweet excipient is to provide a sweeter taste to the composition. Praziquantel has an unpalatable taste which makes it difficult to consume orally. it may appear obvious that addition of a sweet excipient would make the composition more palatable however, mere addition of a sweet excipient will not alone make the composition palatable as the sweet excipient alone cannot mask the unpalatable taste of the pharmaceutical agent.

The advantage of the taste-masking polymers is to also overcome the unpalatable taste of the praziquantel. The presence of the sweetener, in particular saccharin sodium works in combination with the sweet excipient and taste making polymer to improve the palatability of the composition.

Praziqua.nte| and fenbendazole are added in amorphous forms and are granulated durlng,.processing. When the composition is granulated the praziquantel and fenbendazole are combined so as to form intergranular spaces. The sweet excipient, sweetener and taste-making polymer fill up the intergranular and intragranular mass of the composition, thereby providing a sweeter taste to the composition.

The advantage of the composition is that the taste masking ingredients, i.e. taste masking polymer, sweetener and sweet excipient are added to the pharmaceutical agents in a mix, and are dispersed between the intergranular and intragranular spaces of pharmaceutical agents thereby allowing the pharmaceutical agents to act freely and quickly upon ingestion into the body of the recipient.

Additionally, as the unpalatable pharmaceutical agent is combined with the taste- masking polymer, sweetener and sweet excipient in an intergranular matrix, it would be practically impossible for the animal, to separate the unpalatable agent from the sweet components.

Furthermore, generally with coating of pharmaceutical agents, chemicals are required in the process. This composition obviates the need for these chemicals. Additionally when pharmaceutical agents are coated, this can lead to degradation of the active ingredients.

The advantage of using a non-sweet carbohydrate is to dilute the composition.

In one embodiment of the invention the dissolution retarding agent is selected from the group comprising ammonio methacrylate co-polymer, microcrystalline wax, poloxamer, polyethylene propylene glycol, polyoxyethylene polyoxypropylene, carrageenan, cellulose acetate, glyceryl monostearate, zein, white wax, yellow wax.

The advantage of the dissolution retarding agent is to control the release of the active pharmaceutical ingredients praziquantel and fenbendazole into the system of the recipient. Thus,lby adjusting the amount of dissolution retarding agent in the composition, it is possible to provide a composition with either immediate release or sustained release properties. When the amount of dissolution retarding agent added is of the order of 2% by weight of the composition, the composition is an immediate release c:omposition. When the amount of dissolution retarding agent added is of the order of 20% by weight of the composition, the composition is a sustained release composition.

In a further embodiment of the invention the preservative is selected from the group comprising sodium benzoate. benzoic acid, editic acid, phenolic acid, sorbic acid, benzyl alcohol, isopropyl alcohol, benzethonium chloride, bronopol, butyl paraben, ethyl paraben, propyl paraben, methyl paraben, sodium benzoate.

The advantage of the preservative is to prevent the deterioration of the composition.

Preferably the disintegrating agent is sodium starch glycollate.

Ideally the adhesive is collodial anhydrous silica.

The advantage of the disintegrating agent is to ensure quick break up of the composition inside the alimentary canal of the target animal. The advantage of the adhesive is to bond the components.

Preferably the flavouring agent is cocoa powder.

The advantage of the flavouring agent is to stimulate the olfactory senses of the targeted animals.

The invention further provides the use of the composition for treating parasitic infestation in animals.

The invention still further provides a process for preparing the composition comprising: adding amorphous praziquantel and amorphous fenbendazole in a dry mix with non-sweet carbohydrate, preparing a binder solution by mixing taste masking polymer, water and preservative, adding the binder solution to the dry mix to form a composition, granulating the composition, to provide a composition comprising granular praziquantel and granular fenbendazole, sizing the composition, _drying the composition, adding a sweet excipient, adding a dissolution retarding agent, adding a disintegrating agent, adding an adhesive, adding a sweetener, adding a flavouring agent, blending the components to the dried composition to form a granular —composition.

The rheological properties of the composition may also be controlled by adjusting the process parameters, such as dry mixing, wet mixing, slow granulation, fast granulation and drying.

Detailed pescflption of the Invention The invention will be more clearly understood from the following description of the process according to the invention described with reference to Figs. 1 and 2 of the drawings which outlines in flow diagram form the process of preparing the composition.

All the equipment used in carrying out the process is well known equipment and accordingly does not require any further description.

Referring to Fig. 1, in Step 1, 0.5%-1.5%, by weight praziquantel, 18-22% by weight fenbendazole and 7-21% by weight non-sweet carbohydrate are added to another mixer and mixed for 10 minutes until homogenous to form a dry mix.

A binder solution is prepared by adding 2-20% by weight taste masking polymer: co- polymer, 0-25% by weight water and 0.05—1% by weight preservative to another mixer, and mixing for 5 minutes in step 2. in step 3, the binder solution is added to the dry mix in the ratio 10:90 and mixed for 5 minutes to form a composition.

The composition is then granulated by slow granulation for 3 minutes in step 4, and granulated by fast granulation for 2 minutes in step 5.

In step 6, the composition is sized into particles of 4500 microns.

Referring now to Fig. 2 the sized particles are dried in a fluid bed drier at 60°C for 15 minutes in Step 7.

In step 8, the particles are further sized into particles of 1500 microns. The sized particles are mixed with 12-88% by weight the sweet excipient, 2-20% by weight dissolution retarding agent, 2.55-25% by weight disintegrating agent, 0.2-2.5% by weight adhesive, 0.05-2% by weight sweetener and 2-12% by weight flavouring agent in a double cone blender for 25 minutes in step 9.

The final composition is in a granular form.

Table 1: Final Anthelmintic Composition Component Amount (%) Praziquantel 1% Fenbendazole 20% Castor Sugar 52.25% Maize Starch 14.9% Ammonio Methacrylate 2% Sodium Benzoate 0.1% Sodium Starch Glycollate 4% Collodial Anhydrous Silica 0.5% Saccharin Sodium 0.25% Cocoa Powder 5% Example 1: Analysis of Anthelmintic Composition The composition was prepared according to the above process, having the quantities as outlined in table 1.

The composition was sampled from the top, middle and bottom of each batch, in order to determine the uniformity of each batch.

The following assays were carried out on each sample: Praziquantel Assay — HPLC Fenbendazole Assay — HPLC Appearance of powder —Visual Presence of impurities - related substances Praziquantel — HPLC — related substances Fenbendazole — HPLC Physical Parameters - granule flow — funnel test for flow measurement - Bulk density — density measurement - Tapped density — density measurement - Moisture ~ moisture analyser.

The results are tabulated in Tables 2, 3 and 4.

Table 2: Homogeneity Results Sample Point Praziquantel Fenbendazole Appearance Assay Assay Top 0.958% w/w 19.140% w/w Conform Middle " 1.008% w/w 20.070°/0 w/w Conform Bottom 0.958% w/w 19.078% w/w Conform Specification: Assay: 1% w/w Praziquantel (5% limit) Range: 0.95 — 1.05% w/w Assay: 20% w/w Fenbendazole (5% limit) Range: 19 — 21% w/w Appearance: A cream coloured granular powder.

Table 3: Presence of Impurities Sample Point Related Substances Related Substances Praziquantel Fenbendazole Composite Impurity A: 0.051% Impurity A: 0.00273% lmpurity B: 0.0713% Impurity B: 0.0168% Total: 0.321% Total: 0.1502% Table 4: Physical Parameters Physical Parameters Top Middle Bottom Granule flow (g/s) 27.41 g/s 26.33 g/s 23.78 g/s Bulk density (g/ml) 0.846 g/ml 0.862 g/ml 0.944 g/ml Tapped density (g/ml) 0.891 g/ml 0.909 g/ml 0.984 g/ml Moisture % (KF) 2.856% 3.162% 2.734% Specification: Uniform distribution of results for the physical parameters at the end of process blending.

The above results indicate that the resultant granular powder is homogenous throughout the batch.

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.

Claims (4)

1. A palatable oral anthelmintic composition comprising an effective amount of praziquantel and an effective amount of fenbendazole in combination with a sweet excipient in the range 12-88% by weight, a non—sweet carbohydrate in the range 7-21 % by weight, a taste—masking polymer: in the range 2-20% by weight, a dissolution retarding agent in the range 2-20% by weight, a preservative in the range 0.05-1% by weight, a disintegrating agent in the range 2.55—25% by weight, an adhesive in the range 0.2-2.5% by weight, a sweetener in the range 0.05-2% by weight, a flavouring agent in the range 2-12% by weight, water in the range 0% to 25% by weight.

2. .A composition as claimed in claimed in claim 1 comprising praziquantel in the range 0.5-1 .5% by weight, and comprising fenbendazole in the range 18-22% by weight, and wherein the praziquantel and the fenbendazole are in a granular form.

3. Use of the composition as claimed in any preceding claim for the manufacture of a medicament for treating parasitic infestation in animals.

4. A process for preparing the composition as claimed in any preceding claim 13 comprising: adding amorphous praziquantel and amorphous fenbendazole in a dry mix with non-sweet carbohydrate, preparing a binder solution by mixing taste masking polymer, water and preservative, adding the binder solution to the dry mix to form a composition, granuiating the composition, to provide a composition comprising granular praziquantel and granular fenbendazole, sizing the composition, drying the composition, adding a sweet excipient, adding a dissolution retarding agent, adding a disintegrating agent, adding an adhesive, adding a sweetener, adding a flavouring agent, blending the components to the dried composition to form a granular composition. A composition substantially as described herein with reference to and as illustrated in the accompanying drawings.