AU778364B2 - Drinkable pharmaceutical solution - Google Patents

Description

WO 00/59468 PCT/FR00/00870 "Oral pharmaceutical suspension" The present invention relates to an oral pharmaceutical composition intended for facilitated oral administration.

The oral administration of solid forms such as tablets can prove difficult or even dangerous for children and the elderly, who prefer chewable tablets, tablets which dissolve in the mouth or in a spoon of water, granules, powders, solutions or suspensions.

The active ingredients incorporated into these types of formulations sometimes have a bitter taste which persists for a long time and which cannot be effectively masked by the addition of a sweetener or a flavoring. However, the taste and the aftertaste are important criteria for the acceptance of the medicament by the patient.

In the oral suspensions of bitter active ingredient already described in the prior art, the active ingredient is generally coated with a lipid substance, either directly or after incorporation into a core. The lipid substances used are for example a partially hydrogenated vegetable oil (EP 670 722), stearic acid and/or palmitic acid (FR 2 615 101), glyceryl tripalmitate (EP 664 701), or a mixture of glyceryl monostearate and beeswax in the proportions 9/1 (EP 769 948) In WO 91/16043, the granules containing the active ingredient are coated with a polymer membrane which is soluble at a pH greater than or equal to 5. The granules also contain 1 to 20% by weight of an acidic compound intended to reduce the dissolution of the membrane in the oral cavity.

2 Ibuprofen is an active ingredient with a bitter taste which has been the subject of numerous studies in order to formulate it in stable compositions in which its taste is masked.

A prior art solution consists in coating the ibuprofencontaining granules with a polymer intended to mask its bitter taste. This polymer is for example a phthalate (WO 91/16043), a vinyl acetal (JP 91/83922), a cellulose acetate phthalate (WO 95/05166) or a methacrylic acid copolymer (EP 524 180).

The disadvantage of these formulations consists in the properties of the polymer used. Indeed, all the prior art polymers used for masking the taste of ibuprofen causes the delayed release of the active ingredient, such that its dissolution profile is modified.

Another prior art solution consists in preparing an aqueous suspension of ibuprofen. This suspension contains either a lipid substance and a surfactant (WO 94/25006, US 5 110 606, WO 96/22762, WO 94/05260), or a suspending agent, such as a polysaccharide (JP 98/182 449), a mixture of cellulose and of xanthan gum (EP 556 057), a mixture of polyethylene glycol and of sodium carboxymethyl cellulose (US 5 602 182), a mixture of xanthan gum and of pregelatinized starch (EP 405 930), a mixture of xanthan gum, of microcrystalline cellulose and of carboxymethyl cellulose (EP 298 740) The subject of the present invention is an oral pharmaceutical suspension consisting of a liquid phase in which one or more solid active ingredients are dispersed, characterized in that the soluble fraction of said active ingredient(s) in the liquid phase is less than 10% by weight, preferably 5% by weight, more preferably still 1% by weight relative to the weight of the suspension.

004514011 -3- An aspect of the present invention therefore provides an oral pharmaceutical suspension consisting of a liquid phase in which one or more solid active ingredients are dispersed, containing a viscosity agent selected from carboxyvinyl copolymers, and the mass percentage of active ingredients released in the liquid phase is less than The active ingredient is in the form of crystals, preferably crystals of less than 500 microns in size, or formulated in granules or flexible spheroids.

The granules may be coated with a material intended either to allow the modified or prolonged release of the active ingredient(s) embedded in the centre of the granules, or to mask the taste of said active ingredient(s), or to avoid solubilizing the active ingredient(s) in the liquid phase of 15 the suspension.

The granules and spheroids have a final size of between oand 1000 microns, preferably between 200 and 600 microns.

They consist of an inert core having a size substantially between 100 and 350 microns and a spherical shape onto which S 20 the active ingredient(s) is (are)applied by means of a binder or by mere absorption if the active ingredients are *o in solution.

oeo The granules are for example obtained by coating the active *o• ingredient(s) onto a neutral support consisting of sugar and starch.

The coating may be carried out according to several techniques, such as dusting, spraying of a solution, the MELT technique, or any other conventional technology known to persons skilled in the art.

The neutral support coated with active ingredient is then optionally coated with a polymer film consisting of a single polymer or of a combination of several polymers or a 004514011 -3asuccession of different layers of polymer depending on the expected effect.

This step may be carried out using the various excipients and technologies well known to persons skilled in the art.

Aqueous solvents or the MELT technique will preferably be used.

a i* a 4 Flexible spheroids are the subject of as yet unpublished applications FR 97 146 31 and FR 97 146 whose content is included by reference in the present application.

These spheroids consist of a core and/or of a layer coating said core containing at least one thermoplastic excipient, coated with a deformable flexible film based on a polymeric material whose glass transition temperature is less than 300C.

The thermoplastic excipient has a melting point of between 25 and 100°C; it is characterized by a pasty to semisolid consistency, at 20 0 C. It may be chosen, inter alia, from partially hydrogenated oils, beeswax and silicone waxes.

The polymeric material is preferably an acrylic, vinyl or cellulosic copolymer, to which a plasticizer is optionally added so that its percentage extension is greater than The oral pharmaceutical suspension according to the invention advantageously consists of a liquid phase which is aqueous or consists of a mixture of water with a cosolvent, for example an oil, propylene glycol, glycerin or a solution of sorbitol.

The active ingredient may be chosen, without limitation, from Ibuprofen, Secnidazole hydrate, Erythromycin and its derivatives, Paracetamol, Tinidazole and Codeine.

The oral pharmaceutical suspension according to the invention contains a viscosity agent, a filler and a preservative.

The viscosity agent is chosen from pharmaceutically 5 acceptable viscosity agents, for example xanthan gum, hydroxypropylmethyl cellulose, methyl cellulose, carageenan, carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone and carboxyvinyl copolymers.

The viscosity agent is advantageously a carboxyvinyl copolymer, such as Carbopol®. This viscosity agent has the advantage of being used in small quantities.

The viscosity agent represents 0.1 to 10%, preferably 0.1 to by weight relative to the weight of the suspension.

The filler represents 10 to 70%, preferably 30 to by weight relative to the weight of the suspension.

The preservative represents 0.05 to preferably 0.1 to by weight relative to the weight of the suspension.

The preservative is chosen from methyl hydroxybenzoates, propyl hydroxybenzoates, alkylparabens and sorbic acid.

The oral suspension according to the invention may contain, in addition, at least one agent chosen from an alkalinizing or acidifying agent, a flavoring, an antioxidant, a surfactant, a coloring, a stabilizer, a lubricant and a sweetener.

The sweetener is chosen, for example, from natural or synthetic sweeteners such as sorbitol, sucrose, xylitol, aspartame, saccharin sodium, sodium cyclamate and mixtures thereof.

The flavoring is chosen, for example, from products with mint, strawberry and banana flavor. It represents 0.1 to 3% by weight relative to the weight of the 6 suspension.

The coloring is, for example, a titanium dioxide or iron oxide pigment.

The lubricant is, for example, talc, aluminum oxide or silica.

The surfactant is, for example, chosen from sodium lauryl sulfate, polyethylene copolymers, nonionic polyoxypropylene copolymers and mixtures thereof.

The surfactant preferably represents 0.1 to 10% by weight relative to the weight of the suspension.

The suspension according to the invention is given to the patient in ready-to-use liquid form or in the form of a reconstitutable powder.

The reconstitutable powder is prepared by mixing the active ingredient in the form of crystals, granules or spheroids, and the suspending adjuvant. It may be granulated according to the various conventional granulation techniques well known to persons skilled in the art.

The powder is then distributed into unit bottles or sachets. The bottles are sufficiently large to allow the quantity of water necessary for the reconstitution to be added.

The following examples illustrate the present invention without limiting the scope thereof.

Example 1: Suspension of ibuprofen crystals A batch corresponding to 300 liters of suspension, that is 2 000 bottles of 150 ml, is prepared from the following formula 7 COMPONENTS

MANUFACTURING

FORMULA

Ibuprofen 6.00 kg Sucrose 115.50 kg Noncrystallizable sorbitol at 70% 18.30 kg Carbomers (Carbopol® 971 P) 0.51 kg Parabens (Nipasept® base) 0.35 kg Strawberry flavor 0.35 kg Cochineal Red A coloring 0.010 kg Sodium hydroxide (1N solution) 2.00 kg Purified water 208.30 kg Preparation No. 1 Water (127 kg) is introduced into the 200 1 tank at room temperature and then the Carbopol® 971P is dispersed in small quantities in the water.

The mixture is homogenized with a deflocculating turbine for 1 hour at 1 500 rpm and then for 4 hours at 800 rpm.

Preparation No. 2 A 400 liter jacketed tank is heated to 800C and water kg) is introduced at 80 0 C. The temperature of the water is maintained between 75 0 C and 80 0 C during the preparation.

The three-blade AE 200 mm turbine is mounted on the RAYNERI DIRECT T 80 stirrer.

The stirring is started and maintained (200 rpm) throughout the preparation. The preservatives and the flavor are dispersed until they are completely dissolved.

The sucrose is added and allowed to dissolve completely (the clarity of the solution is checked), the liquid sorbitol is added and then the container is rinsed with water (6.3 kg).

The coloring is added and the stirring is continued until a clear solution is obtained.

8 The the jacket is cooled and the temperature of the solution is allowed to return to 35 0

C.

In the 400 1 tank, the preparation No. 1 is poured, with stirring (200 rpm), into the preparation No. 2.

The mixture is homogenized (300 rpm) for at least minutes.

A 1N NaOH solution is prepared.

A fraction of the 1N NaOH solution is gradually introduced, with stirring (300 to 500 rpm). The mixture is homogenized for 15 minutes.

The ibuprofen is introduced, with stirring (500 rpm), and the mixture is homogenized for 1 hour.

While maintaining the stirring, the remainder of the 1N NaOH solution is added and then the pH is checked. The pH is adjusted, if necessary, to 5.4 with the remainder of the 1N NaOH solution.

The mixture is homogenized for 2 hours (300 rpm).

The unit volume is adjusted (150 ml) and the bottles are filled. The stirring is maintained in the 400 liter tank and the buffer tank during the filling of the bottles.

Bottles are removed at the beginning, in the middle and at the end of the filling.

Results beginning middle end bottle 1 99 103 103.5 bottle 2 98.5 101.2 101.2 The content does not vary significantly during the filling.

The suspension remains homogeneous.

Tests of stability carried out under accelerated conditions (40 0 C and 75% relative humidity) 004514011 T 0 T 1 month T 3 months Content (mg/1) 19.0 20.4 19.6 release 0.35 0.25 0.24 Parabens (mg/ml) 1.17 1.15 1.09 Example 2: Suspension of ibuprofen crystals A batch corresponding to 10 000 bottles of 200 ml is prepared in the example below:

COMPONENTS

-i Ibuprofen crystals Sucrose Noncrystallizable sorbitol at 70% Carbopol® 971 P Nipagin Nipasol® Ethyl hydroxybenzoate Strawberry flavour Cochineal Red A colouring Sodium hydroxide Purified water 40.0 kg 770.666 kg 122 kg 3.446 kg 1.707 kg 0.253 kg 0.373 kg 2.333 kg 0.067 kg 0.533 kg 1355 kg ft o o* o Preparation 5 The ibuprofen suspension according the same procedure, adapting the material to the size of the batch. A 2 000 litre tank equipped with a jacket is used for the preparation, as well as a 500 litre tank for the preparation of the Carbomer dispersion.

Results Samples (1 to 12) are collected during the emptying of the 2 000 litre tank.

2 batches of suspension are prepared and the contents are the following: 1 2 3 4 58900 104 107.0 107.3 58901 106.5 106.9 105.2 102.9 004514011 The contents specifications.

are homogenous, contained in the Example 3: Suspension of ibuprofen crystals The procedure is carried out as in example 1.

The suspension is prepared according to the formula: following a Component Unit formula (w/w) 150 ml* Ibuprofen 3.000 g 1.71 Sucrose 57.800 g 32.93% Noncrystallizable sorbitol at 70% 9.150 g 5.21 Carbomers (Carbopol® 971 P) 0.260 g 0.15 Parabens (Nipasept base) 0.175 g 0.10 Strawberry flavour 0.175 g 0.10 Cochineal Red A colour 0.005 g 0.003 Sodium hydroxide 0.040 0.02 Purified water 104.895 g 59.78 The total parabens representing 0.1% of the suspension are a mixture of three para-hydroxybenzoate esters in the following proportions: 73% Methylparaben 16% Ethylparaben 11% Propylparaben This suspension is subjected to accelerated conditions (40 0 C and 75% relative humidity).

storage The results obtained are summarised in the following table.

T 0 T 6 months Content mg/l 16.8 20.1 released 0.51 0.21 11 T 6 months Total microorganisms: (CFU/ml) Yeasts molds CFU/ml Escherichia coli: (CFU/ml) <1 <1 Absence The suspension is stable for six months under these conditions.

Tests of the efficacy of the preservatives A microbiological test is carried out according to the method described in the European Pharmacopeia 3rd ed.

The test for the suspension of crystals is carried out against a placebo suspension of the same composition but containing no preservative.

Ssuspension with preservatives Inoculum T 0 14 d 28 d CFU CFU RF CFU RF CFU RF Pseudo aeruginosa 3.30x10 6 <100 <10 Staph.

Aureus 1.26x10 7 1.85x10 4 <10 E. coli 7.90x106 <100 <10 Candida albicans 1.00x10 6 4.85x10 3 <10 Aspergillus nigers 4.65x10 6 5.45x10 5 7.10x10 3 2.8 4.65x10 3 Ph Eur. 3rd ed. Bacteria Molds Yeasts Conclusion complies complies complies complies 12 0suspension without preservative _______Inoculum T 0 14 d 28 d CFU CFU RF CFU RF CFU RF Pseudo aeruginosa 3.30OX10 5 3.85x1 0 5 <10 Staph.

Aureus 1.26X1 0 7 1.22X10' <10 Candida albicans l.00x10 6 1.02x1 0 5 1.00X10 3 3 4 .10XlO 4 1.4 Aspergillus nigers 4.65X1 0 6 5.10X10' 3.40x10 4 2.1 6.60x1 0 3 2.8 Ph Eur. 3rd ed. Bacteria Molds Yeasts Conclusion complies complies does not does not comply comply The test meets the criteria of the European Pharmacopeia 3rd ed. The total paraben concentration of 0.1% allows effective protection of the suspension.

Example 4: Suspension of ibuprof en granules containing mg/mi of ibuprof en Formula of the microgranules: Excipients Quantities 96 (w/W) Ibuprofen 1.19 9.2 Neutres 4.64 35.7 Eudragit E 100®@ 0.071 0.55 Eudragit NE30D 0 0.060 0.46 Colloidal silica 0.006 0.04 Talc 0.024 0.18 Alcohol 95% (solvent) 0.52 The microgranules are prepared by spraying successive 13 layers of active agents followed by a dispersion of coating which makes it possible to mask the bitterness of the active ingredient.

Syrup formula: Components Carbopol® 971 P Purified water Ibuprofen granules NaOH (IN) Sorbitol at 70% Crystal sucrose Nipasept® Strawberry flavor [lacuna] (w/w) 0.14 q.s. 100% 1.7 q.s. pH 3.4 30.8 0.1 0.1 3 The ibuprofen granules having a titer of 200 mg/g are added in order to obtain a suspension at 20 mg/ml of ibuprofen.

The syrup is prepared according to the preceding examples.

Example 5: Dry suspension of microgranules The microgranules are prepared as in example 4 2) Formula of the dry adjuvant mixture: Excipients Quantities (w/w) (g) Carbopol® 971P 46.0 2.62 Sucrose 1529 87.14 Sorbitol 153.0 8.72 Trisodium citrate 10.0 0.57 Cochineal Red 0.6 0.03 Strawberry flavor 11.0 0.63 Total parabens 5.0 0.29 Total dry mass 1745.6 100%

H

2 0 (wetting liquid) 120.0 14 The various dry components are mixed for 15 minutes in a cubic mixer.

The excipients are then granulated by adding purified water to the mixture, for a sufficient period. The granules are dried at 35 0 C for 3 hours, and then sized on a screen with a 1.25 mm mesh.

Final preparation: ibuprofen suspension: Microgranules (g) Dry adjuvant mixture (g) Quantity of water to be added (ml) Ibuprofen per bottle of 60 ml 6 7 QS 60 ml 1.2 g A quantity of sparklets and of granules is added in the proportion defined in the table above.

The suspension is prepared by adding water to the bottle.

On stirring vigorously, the granules are dispersed in the liquid phase. After standing for 1 to 2 minutes, the suspension is again stirred. The granules are then homogeneously distributed in the liquid phase and remain in suspension.

Example 6: Suspension of ibuprofen microgranules COMPONENTS UNIT FORMULA 150 ml bottles gram Ibuprofen microgranules 15 Carbopol® 971 P 0.2 0.11 Sucrose 59.2 33.75 Sorbitol 6.6 3.75 Total parabens 0.06 0.1 Strawberry flavor 0.2 0.1 Coloring <0.01 <0.01 NaOHlM qs pH 5.5 qs pH Purified water qs qs 004514011 Tests of stability carried out under accelerated conditions 0 C and 75% relative humidity) TO0 T Ti month T 3 months Content (mg/i) 103.3 98.1 108.2 released 0.52 0.63 0.70 TO0 Ti1month T 3months Total microorganisms <1 <1 <1 Yeast molds <1 <1 <1 Escherichia coli Absence ND Absence Example 7: Suspension of secnidazole microgranules 1) Formula of the microgranules: Excipients Quantities Percentage by mass (96.) Secnidazole hydrate 3 20.99 Neutres 2.751 19.25 PVP K30@ 0.215 1.50 PEG 4000 0.041 0.29 Eudragit NE3OD® 0.258 1.81 Talc 0.062 0.43 Silica 0.018 0.12 Paraffin 0.634 4.43 Talc 0.317 2.22 Alcohol 95% (solvent) 3.019 Mass of microgranules 7.295 The microgranules are prepared as in example 1.

16 2) Formula of the adjuvant mixture: Carbopol 971 P® 0.184 1.28 Icing sugar 6.1 42.67 Neosorb P100T® 0.61 4.27 Trisodium citrate 0.034 0.28 Cochineal Red 0.002 0.02 Strawberry flavor 0.044 0.31 Nipasept® 0.02 0.14

H

2 0 (wetting liquid) 0.48 Mass of microgranules 7.000 Total dry mass 14.295 100% Final preparation: secnidazole suspension Mass of microgranules (g) Mass of the adjuvant mixture (g) Quantity of water to be added (ml) Mass of Secnidazole per bottle of 60 ml 7 14.295 QS 60 ml 1.5 g Example 8: Suspension of erythromycin microgranules 1) Formula of the microgranules: Excipients Quantities Percentage by mass Erythromycin 1.500 11.48 Neutres 3.200 24.49 PVP K30® 0.058 0.44 Fine crystal sucrose 0.187 1.44 Eudragit L30D® 0.300 2.30 Triethyl citrate 0.030 4.04 Gelucire® 0.528 2.02 Talc 0.264 Solvent QS Mass of microgranules 6.067 The microgranules are prepared as in example 1.

17 2) Formula of the adjuvant mixture: Carbopol 971 P® Icing sugar Neosorb P100T® Trisodium citrate Cochineal Red Strawberry flavor Nipasept

H

2 0 (wetting liquid) Mass of microgranules Total dry mass 0.184 6.100 0.610 0.04 0.002 0.044 0.02 0.48 7.000 13.067 1.40 46.68 4.67 0.31 0.02 0.34 0.15 100% Example 9: Suspension of erythromycin microgranules 1) Formula of the microgranules Raw materials Formula in Neutres 23.77 Erythromycin 23.55 Coating by dusting Eudragit L30D® 2.16 Triethyl citrate 0.22 Eudragit L30D® 4.97 Triethyl citrate 0.50 1st protective coating Talc 0.75 Precirol® 2.24 2nd hydrophobic coating Talc 1.12 Eudragit L30D® 32.59 Triethyl citrate 3.26 3rd protective coating Talc 4.89 18 2) Formula of the suspension containing a dose of 125 mg/5 ml Raw materials Formula in Erythromycin microgranules 10.5 Avicel RC 591® 3.4 Purified water (qs) 52.6 Sucrose at 60% 26.2 Liquid sorbitol at 70% 5.6 Nipasept® 0.1 Strawberry flavor 0.1 Citric acid 0.1 Thick glycerin 1.4 Example 10: Suspension of Tinidazole microgranules 1) Formula of the tinidazole granules Raw materials Formula in Neutres 6.02 Tinidazole 40.14 Coating PVP K 30® 3.21 Triethyl citrate 0.32 Eudragit L30D® 4.97 Triethyl citrate 0.50 Protective coating Talc 0.75 Precirol 2.24 Hydrophobic coating Talc 1.12 Eudragit L30D® 32.59 Triethyl citrate 3.26 Coating Talc 4.89 004514011 -19- 2) Formula of the suspension containing a dose of 50 mq/ml Raw materials Formula in Tinidazole microgranules 10.68 Carbomer 971 P® 0.13 Crystal sucrose 29.99 Liquid sorbitol at 70% 4.73 Nipasept® 0.10 Strawberry flavour 0.10 Sodium hydroxide (pellets) 0.45 Purified water 53.82 Reference to any prior art in the specification is not, and 5 should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction.

As used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are 10 not intended to exclude other additives, components, integers or steps.

Claims (18)

1. An oral pharmaceutical suspension consisting of a liquid phase in which one or more solid active ingredients are dispersed, containing a viscosity agent selected from carboxyvinyl copolymers, and the mass percentage of active ingredients released in the liquid phase is less than

2. An oral pharmaceutical suspension according to claim 1, wherein the mass percentage of active ingredients released in the liquid phase is less than

3. An oral pharmaceutical suspension according to claim 1 or claim 2, wherein the mass percentage of active ag** S" 15 ingredients released in the liquid phase is less than 1%.

4. An oral pharmaceutical suspension according to any one B of claims 1 to 3, wherein the active ingredient(s) is (are) in the form of crystals or formulated in granules or OB e •iBO 20 flexible spheroids. OOBO

5. An oral pharmaceutical suspension according to claim 4, B gOwherein the granules are coated with a material intended to oo i mask the taste of the active ingredient(s) or to allow the modified or prolonged release of the active ingredient(s)

6. An oral pharmaceutical suspension according to claim 4, wherein the size of the crystals is less than 500 microns. 004514011 -21

7. An oral pharmaceutical suspension according to claim 4, wherein the size of the granules or of the spheroids is between 50 and 1 000 microns.

8. An oral pharmaceutical suspension according to any one of the preceding claims, wherein the liquid phase is aqueous or consists of a mixture of water and of a cosolvent.

9. An oral pharmaceutical suspension according to claim 8, wherein the cosolvent is an oil, propylene glycol, glycerin or a solution of sorbitol. An oral pharmaceutical suspension according to any one of the preceding claims, wherein the active ingredient is 15 chosen from Ibuprofen, Secnidazole, Hydrate, Erythromycin and its derivatives, Paracetamol, Tinidazole and Codeine.

11. An oral pharmaceutical suspension according to any one of the preceding claims, further containing a viscosity 20 agent, a filler and a preservative. e*e 12. An oral pharmaceutical suspension according to claim S* 11, wherein the viscosity agent is chosen from xanthan gum, hydroxypropylmethyl cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone and carboxyvinyl copolymers.

13. An oral pharmaceutical suspension according to claim 11 or claim 12, wherein the mass percentage of the viscosity agent is 0.1 to 004514011 -22-

14. An oral pharmaceutical suspension according to claim 13 wherein the mass percentage of the viscosity agent is 0.1 to

15. An oral pharmaceutical suspension according to any one of claims 11 to 14, wherein the mass percentage of the filler is 10 to

16. An oral pharmaceutical suspension according to claim 15, wherein the mass percentage of the filler is 30 to

17. An oral pharmaceutical suspension according to any one of claims 11 to 16, wherein the mass percentage of the o Spreservative is 0.05 to 3%. 9 S18. An oral pharmaceutical suspension according to claim 17, wherein the mass percentage of the preservative is 0.1 to 1%. 20 19. An oral pharmaceutical suspension according to any one oof claims 11 to 18, wherein the preservative is chosen from a*o methyl hydroxybenzoates, propyl hydroxbenzoates, 9.. 9 9 alkylparabens and sorbic acid. *999

20. An oral pharmaceutical suspension according to any one of claims 11 to 19, further comprising at least one agent selected from the group consisting of an alkalinising or acidifying agent, a flavouring, an antioxidant, a surfactant, a colouring, a stabiliser, a lubricant an a sweetener, the sweetener being chosen from natural or synthetic sweeteners, the mass percentage of flavouring is 0.1 to 3%, 004514011 -23- the colouring being a titanium dioxide or iron oxide pigment, the surfactant being chosen from sodium lauryl sulfate, polyethylene copolymers, non-ionic polyoxypropylene copolymers and mixtures thereof, and the mass percentage of the surfactant being 0.1 to

21. An oral pharmaceutical suspension according to claim wherein the sweetener is selected from the group consisting of sorbitol, sucrose, xylitol, aspartame, saccharin, sodium, sodium cyclamate and mixtures thereof.

22. An oral pharmaceutical suspension substantially as herein described with reference to'any one of the examples. 0 *5 0 0J 0 0 S V 5500 00 0 S o 04 5C 0 *000 Laboratories des Produits Ethiques Ethypharm By its Registered Patent Attorneys Freehills Carter Smith Beadle 6 September 2004