AU2005100669A4 - Enteric coated paste compositions and uses thereof - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR AN INNOVATION PATENT

ORIGINAL

Name of Applicant: Actual Inventors: Metelli Pty Ltd William Harold Bamford and James Steven Rowe Address for Service is: SHELSTON IP Margaret Street SYDNEY NSW 2000 CCN: 3710000352 Attorney Code: SW Telephone No: Facsimile No.

(02) 97771111 (02) 9241 4666 Invention Title: ENTERIC COATED PASTE COMPOSITIONS AND USES

THEREOF

Details of Associated Provisional Application No. 2004905152 (dated 09 September 2004) The following statement is a full description of this invention, including the best method of performing it known to us File: 43489AUP00 5006689321 .DOC/5845 -la- ENTERIC COATED PASTE COMPOSITIONS AND USES THEREOF Technical Field The present invention is concerned with an oral formulation containing an acid labile active component, suitable for administration to mammals. More specifically the compositions of the present invention incorporate a proton pump inhibitor comprised on or within enteric-coated pellets and formulated into a non-aqueous stable, ready-to-use, paste suitable for delivery to horses and other animals.

Introduction Acid labile pharmaceutically active agents intended for oral use are usually protected from acid degradation by an enteric coating applied to the dosage form. Such formulations may take the form of tablets, caplets, pellets and the like. However, in these forms they are not suitable for oral administration to animals. There are a number of paste-like formulations, particularly of proton pump inhibitors (PPIs), described in the literature.

Proton pump inhibitors (PPIs) have been used extensively in the treatment of gastric acid related diseases in humans and animals. PPIs are regulators of gastric acid secretion, inhibiting the activity of H+K+-ATPase, which is an enzyme involved in the last step of hydrogen ion production in the acid producing parietal cells of the stomach.

By interrupting the final step in acid secretion, PPIs prevent acid secretion regardless of stimuli. The principle strategy of ulcer therapy with PPIs is to administer treatment that will inhibit gastric acid secretion to maintain gastric acidity above pH 4, thereby rendering the gastric fluid non-aggressive to the squamous mucosal epithelium.

By maintaining gastric acidity at pH 4 or above, gastric ulcers in horses have been shown to spontaneously heal and not recur.

-2- Gastric ulcers are particularly common in horses, especially high performance horses such as racehorses, for which it has been estimated that as many as 80-90% suffer from gastric ulcers. Horses that are stabled and subjected to intermittent feed intake and for which there are long periods without the ingestion of feed are generally vulnerable to gastric ulcer disease. Gastro-duodenal ulcers are also problematic in other animals due to the aggressive action of highly acidic gastric fluid secreted in the stomach.

PPIs are well known molecules whose preparation, chemistry and pharmaceutical properties are well understood. A principal chemical property of PPIs is their high acid lability, ie. PPIs are unstable in acidic solutions, and are hydrolysed to inactive compounds on contact with an acidic environment, such as in the stomach. The consequence of this acute acid lability is that manufacturers of compositions containing PPIs have gone to great lengths to protect PPIs from acidic degradation in the stomach.

Oral formulations of PPIs have been enterically coated to try and protect them from acid degradation in the stomach and enable absorption from the duodenum.

WO 94/25070 discloses oral compositions containing a protein pump inhibitor in the form ofenterically coated dry pellets mixed with a dried gelling agent. This mixture may then be made into a paste-like gel prior to administration. Although this composition is enteric coated, thus protecting the acid labile proton pump inhibitor, the carrier used is an aqueous carrier and hence the formulation is inherently unstable for any period of time and must be kept in dry form until required to be mixed and administered. The moist gel is not stable during long term storage at room temperature and hence it cannot be manufactured and sold as a ready-to-use formulation. This makes the formulation inconvenient to use.

WO 96/31213 discloses pharmaceutical compositions for oral administration which comprises one or more PPI such as omeprazole, a hydrophobic oily liquid vehicle, -3a basifying agent, and a thickening agent. The basifying agent such as an amine base or potassium sorbate is used to provide a non-acidic environment for the acid-labile protein pump inhibitors. However, in the watery and acidic environment of the stomach the basifying agent may not be able to fully protect omeprazole from acidic inactivation.

The thickening agents used in the composition are insoluble or impractically insoluble in water, and in combination with the protein pump inhibitor and hydrophobic liquid vehicle forms a paste. The nature of the formulations has the disadvantage that the basifying agents would appear to be only partially protective and, therefore, relatively high levels of PPIs need to be used in the final composition, such as 4mg/kg bodyweight to try and allow for significant losses during passage through the stomach.

WO 00/50038 describes oral formulations which comprise omeprazole, two to four basifying agents, a thickening agent and hydrophobic oily liquid vehicle. The basifying agents according to the application are amine bases such as monoethanolamine, diethanolamine, triethanolamine, or salts of carboxylic acid such as sodium acetate, sodium citrate, potassium sorbate, sodium stearate. The total basifying agent is 2% maximum and all are highly water soluble. This application appears to be an improvement on WO 96/31213 employing a multiplicity of basifying agents in an attempt to counteract omeprazole inactivation in the acidic environment in the stomach.

Whilst the formulations are described as having an omeprazole content up to about w/w this is said to be "tolerated" suggesting this maximum content is not a practical one.

It would appear that the practical maximum of omeprazole content in these formulations is from about 30 to about 40% w/w.

As for WO 96/31213, the basifying agents in the compositions may not fully protect the omeprazole from inactivation in the watery acidic environment of the stomach and appears to be primarily present as a formulation stabiliser to improve -4formulation shelf life. The presence of omeprazole together with basifying agents which are water soluble have the potential to increase the hydrophilic nature of the omeprazole making it more likely to be partitioned out of the protective oily phase into the acidic aqueous environment of the stomach. This would lead to partial loss of the omeprazole due to degradation effectively reducing the bioavailability of the active omeprazole, and would explain the relatively high treatment dosage regimen for horses such as 4mg/kg bodyweight (BW) once daily when the literature describes a treatment dosage regimen of 1 mg/kg BW when given as enteric coated PPI.

The above described enterically coated formulations are also sensitive to moisture uptake which affects product storage and stability.

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

Summary of the Invention The paste formulations as described herein are stable, ready-to-use paste formulations which can include any acid labile active agent, and is suitable for use with acid labile proton pump inhibitors, within a plurality of enteric coated pellets, suitable for administering to animals such as horses, cattle, pigs and other domestic animals and pets and to human subjects who cannot easily swallow solid dosage forms.

The paste formulations of the present invention are stable during long term storage at room temperature as well as being able to protect the active agent from acid environments in which the formulation may find itself. Another advantage of the present formulations is enhanced bioavailability of acid labile active agents such as PPIs.

This enables administration of smaller amounts of active agents to achieve comparable therapeutic effects.

In a first aspect the present invention provides a stable composition of an acid labile active agent comprising, a. an inert particulate matrix, b. an acid labile active agent, c. enteric coating and d. a non-aqueous carrier in the form of a ready-to-use orally administrable paste.

The advantages achieved through use of the particular combination of excipients and carriers can be applied to any acid labile active agent. However, the preferred active agent is a proton pump inhibitor (PPI) such as for example Omeprazole. It will be understood however that other, or more than one, PPI can be used in the formulation.

Examples of other suitable PPIs are lansoprazole, pantoprazole, leminoprazole and related compounds.

Preferably the inert particulate matrix is chosen from the group comprising sugar spheres or any other inert matrix such as spheres comprising lactose, mannitol or nonpariel seeds.

The enteric coating can consist of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, shellac, methacrylic acid copolymer or any other enteric coat which will be readily known to those skilled in the art.

When highly acid labile active agents are used the enteric coating may be separated from the acid labile agent-coated matrix (the core) by a sub-coating layer which forms a protective barrier between the enteric coating and the acid labile agent.

The sub-coating layer may be comprised of any water soluble or dispersible agent or agents as long as it is capable of protecting the core from the enteric coating, should that be required. Other water soluble and/or dispersible sub-coats may consist ofpolyvinyl -6pyrrolidone, methylcellulose, hydroxymethylcellulose, polyethylene glycol, polyvinyl alcohol and the like. Other suitable sub-coats would be known to those skilled in the art.

The preferred non-aqueous carrier is liquid paraffin but other similar carriers, for example, saturated and unsaturated vegetable oils, mineral oils, synthetic and natural triglycerides and the like. In essence any non-aqueous carrier may be used which is acceptable from a toxicology viewpoint.

Other suitable vehicles include fats and oils such as paraffin oil, sesame oil, peanut oil and other pharmaceutical oils. Various esters of oils which are suitable for oral use are also within the scope of the invention such as ethyl oleate and various di and triglycerides which are esters of fatty acids and glycerol, for example glyceryl stearate, ethyl oleate and the like. Hydroxylic solvents such as glycerol, propylene glycol and polyetlylene glycol (PEG) are also suitable for use in the formulations of the present invention as are the higher alcohols and fats provided they exist in the liquid form. Any non-aqueous liquid material which is non-toxic when administered orally and will not damage the enteric coat of the beads can be used.

Excluded are non-aqueous liquids which will interfere with the enteric coat and compromise the gastric resistance of the coat or which will extract the active from the core through the coat. Examples of these include water free ethanol, isopropanol and other materials capable of penetrating the coat.

In a second aspect the present invention provides a method of treating a disorder or a disease in an animal comprising orally administering the composition according to the first aspect.

Preferably the disorder or disease to be treated is a gastrointestinal disorder and even more preferably it is gastric and/or duodenal ulcer and associated disorders. The

I

-7preferred animal is a horse but it will be understood that any animal requiring similar treatment can be treated with the compositions of the present invention.

Brief Description of the Figures Figure 1. Treatment Phase Drug Group. Mean lesion score in each location before and after two weeks' treatment with omeprazole 1.0mg/kg BW Q.D. There was a significant decrease (p 0.05) in severity and surface area of lesions in all three locations after two-weeks' treatment. The "After" scores in the FU for both variables were zero in all horses.

Figure 2. Mean lesion score in each location before and after two weeks' treatment with sham paste (placebo).

Figure 3. Maintenance Phase. Mean lesion score in each location before and after two weeks' maintenance treatment with omeprazole at 0.5mg/kg BW Q.D. The "Before" and "After" scores for all Drug treated horses were zero in every location. After two weeks' Maintenance Placebo, lesions recurred with a severity and area equal to that at the beginning of the first phase of the trial.

Description of the Preferred Embodiment The present invention provides a stable, ready-to-use oral paste formulation, particularly of proton pump inhibitors such as 2-[(2-pyridyl)methylsulphinyl] benzimidazole or a derivitive thereof (hereninafter sometimes referred to collectively as "benzimidazole compounds" which are useful as antiulcer agents. Examples of which are omeprazole, lansoprazole, pantoprazole, leminoprazole and related compounds However, it will be understood by those skilled in the art that the combination of excipients and carriers, including the final paste formulation, is suitable for use with any acid labile active agent intended for oral administration or otherwise exposed to an acid environment.

-8- More particularly the present invention provides compositions comprising one or more proton pump inhibitors and an inert particular matrix which is enteric coated following the application of the active agent, and finally formulated into a stable, readyto-use paste with a non aqueous carrier. The paste formulation can be advantageously used for oral administration of PPIs and other acid labile active agents to domestic animals and human patients for the treatment of various conditions and diseases in which the active agent is likely to come into contact with an acid environment.

PPIs are well known molecules whose preparation, chemistry and pharmaceutical properties are well understood.

The PPIs used in the present invention, merely as an example of acid labile active agents, are compounds of the general formula I: Ra--S---N

NH

wherein Ra is: R2 Q R3 CH2- N

CH

2 o R4N, R 5 or

H

3

CQ

R' and R 3 are independently selected from hydrogen, lower alkyl, lower alkoxy and halogen, R 2 is selected from hydrogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower fluoralkoxy and 0

N

R

4 and R 5 are independently selected from lower alkyl, A is Ror OCH 3 or

R

6 and R 7 are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen,

O

-C-Rg N wherein R 8 is lower alkyl or lower alkoxy.

10 Examples of proton pump inhibitors according to Formula I are:

OCH

3

CH

3 CH 3 0NOH N CH 2 -S NH~j Omeprazole

OCH

2

CF

3

CH

3 N CH 2 -S NHC Lansoprazole

OCH

3 QON

OCHF

2 N CH 2 -S N Pantoprazole o~ ON

CH

2 -S

N

CHNH

CH

CH

3

CH

3 Leminoprazole The preferred proton pump inhibitor is Omeprazole. This and other proton pump inhibitors are known compounds, as are methods for their preparation.

11 The non-aqueous carrier, colouring, sweetener and preservative are combined, mixed, heated gently and homogenised to a base paste of uniform consistency. The enteric-coated PPI pellets are then added to the base paste and mixed until uniformly dispersed. Methods for preparing pharmaceutical and veterinary formulations are well know and can be sourced from standard manuals such as for example The Theory and Practice of Industrial Pharmacy, Lachman et al. Lea Febiger, Philadelphia 3 rd Edition, incorporated herein by reference.

The present composition may include additional ingredients commonly used in the formulation of human and veterinary medicines. For example, flavoring agents such as caramel, carrot, apple, vanillin and sausage flavours; coloring agents such as iron oxide, zinc oxide, titanium dioxide, aluminium lakes; sweeteners such as sugar, sodium saccharin; preservatives such as parabens; antioxidants such as BHT, BHA and viscosity regulating agents such as white wax or synthetic waxes such as glyceryl tribehenate, glyceryl trimyristate, hydrogenated coco-glycerides can be added. Other suitable carriers and excipients will be know to those skilled in the art from standard manuals such as for example Bentley's Textbook of Pharmaceutics Ed. EA Rawlings Ballilliere Tindall, London 8 th Edition, incorporated herein by reference.

The amount of the proton pump inhibitor can vary from 0.5 to 20% w/w in the final composition, preferably from about 2 to 8% w/w. The non-aqueous carrier comprises approximately 50 to 90% of the final composition; preferably, it is about 60 to w/w depending on the amount of other excipients in the paste. The amount of enterically-coated particulate matrix (pellets) used in the formulation is preferably 50 to 200 g/mL final paste formulation.

-12- The incorporation of acid labile drug substance in this formulation results in an orally palatable and pharmaceutically stable, ready-to-use paste with enhanced stability and bioavailability characteristics.

In one embodiment the composition of the present invention are useful in the treatment of peptic ulcer and associated conditions in animals or humans. However, it can be used for any treatment involving an acid labile drug to be delivered orally for systemic activity in animals. The composition can also be used for the delivery of the acid labile drugs in humans with difficulty of swallowing solid dosage forms such as enteric coated tablets and capsules. The composition may be administered directly into the back of the mouth of an animal, such as a horse, in need of anti-ulcer therapy.

Preferably a paste dosing syringe is used to facilitate drug administration. The consistency of this paste is such that it can not easily drip out or be expelled once it is deposited on the dorsal part of the animal's tongue. Another advantage of this formulation is that individualized doses can be administered.

The amount of the composition to be administered may vary according to the particular animal species to be treated, the specific active ingredient in the composition, the severity of the disease, the physical condition of the afflicted animal, and other factors. A physician or veterinarian skilled in the art will be able to determine the proper dosage for the specific host under treatment. In general, a dose range of from about to 1.0 mg/kg BW may be used. Of course, higher doses may be used if desired.

The invention will now be illustrated in more detail by way of non-limiting examples.

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EXAMPLES

Example 1: Batch Formula For Omeprazole Pellets Batch Size: 54.00kg.

S.No. INGREDIENTS Quantity in kgs.

ACTIVE LAYERING 1 Sugar spheres(20/24# ASTM) 1H 17.300 2. Omeprazole IP 19.000 3. Hydroxypropyl Methylcellulose E-5 IP 3.570 4. Dioctyl sodium sulphosuccinate IP 0.196 Titanium dioxide IP 0.446 6. Talc IP 0.446 7. Purified water IP 60.000

SUBCOATING

8. Hydroxypropyl Methylcellulose E-5 IP 3.570 9. Dioctyl sodium suiphosuccinate IP 0.196 Titanium dioxide IP 0.446 11. Talc IP 0.448 12. Purified water IP 30.000 ENTERIC COATING 13. Hypromellose Phthalate HP 55S USPNF 5.350 14. Diethylphithalate IP 0.535 Cetyl alcohol IP 1.605 16. Talc IP 0.446 -14- 17. Titanium dioxide IP 0.446 18. Isopropyl alcohol IP 50.000 19. Acetone IP 50.000 The procedure for manufacture of omeprazole enteric-coated 30% involves the micronization of the omeprazole, layering on an inert particulate matrix of sugar spheres, sub-coating the layered matrix and finally applying an enteric-coating and drying to form PPI enteric coated pellets. The same procedure may be used in the preparation of enteric coated pellets comprising other acid labile active agents. Less acid labile active agents may not require the sub-coating layer.

Paste formulation: PHASE DESCRIPTION %W/W AMOUNT 1000kg batch A Paraffin Liquid Light 73.090 730.9kg A Zinc Oxide BP 1.000 10.0kg A Saccharin 0.100 A Methylparaben 0.100 A Propylparaben 0.100 A Vanilla Flavour UA70805 1.000 10.0kg B Aerosil 200 6.700 67.0kg C Omeprazole Pellets 17.910 179.1kg Preparation of the formulation: Step 1. Into the batch vessel combine the Parrafin liquid light BP, Zinc oxide BP, Sodium saccharin, Methyl hydroxybenzoate BP and Propyl hydroxybenzoate BP.

Step 2. Heat with mixing to 65-70 degrees Celsius. Homogenise to disperse the zinc oxide. In small increments, add Aerosil 200 slowly while homogenising. Homogenise thoroughly between additions ensuring all solids are dispersed. Continue mixing until the paste is smooth and of uniform consistency.

Step 3. Add Vanillin to the bulk. Mix until of uniform consistency.

Step 4. Add PPI enteric-coated pellets and mix until uniformly dispersed.

Step 5. Quality Check for appearance, colour, viscocity, specific gravity and external determination of active to Certificate of analysis.

Example 2: Dose confirmation study Clinical field trial A blinded dose confirmation clinical field trial was conducted using the final paste formulation as described in Example Ito ascertain the efficacy.

Objective: To confirm the efficacy of omeprazole at 1.Omg/kgBW administered daily as entericcoated pellets in an oral paste in the treatment of gastric ulcers in racehorses that remain in training, and to confirm that a daily maintenance dose 0.5mg/kgBW prevents the recurrence of gastric ulcers.

Dosageform: Paste in pre-loaded 30mL Dial-a-dose syringes, identical to the final paste formulation as described in Example 1.

Route of administration: Oral Subjects: Data was collected from 26 thoroughbred racehorses between two and six years of age housed in stables and in race training, including 14 geldings, 5 fillies, six mares and one -16colt. Only those horses with gastric lesions along both the greater curvature (GC) and lesser curvature (LC) of the squamous mucosa diagnosed by endoscopy were used in the study. The fundus (FU) was also visualized and scored for lesions. Horses that were raced during the trial period and therefore had treatment withheld were eliminated from the trial. Also eliminated were those horses that had regular training interrupted due to injury and those that were spelled or transferred to another stable.

Experimental design: Horses were allocated to two groups a Drug Group (17 horses) and a Placebo Group (seven horses). Three sites within the squamous mucosa (GC, LC and FU) were evaluated and graded with a simplified version of a scoring system developed by MacAllister, GC, Andrews, FM el al. (1997) Equine vet. J. 29 430-433, for severity and surface area of gastric ulceration prior to commencing treatment. A significant change in scores after two phases of treatment was the desired outcome a two-week treatment phase, followed by a two-week maintenance phase.

For the two-week treatment phase, omeprazole paste was administered orally to the Drug Group IOmL once-a-day (1.0mg/kg BW Sham paste blinded to the investigators was administered to the Placebo Group. After the two-week treatment phase lesions were again scored using endoscopy.

Horses in the Drug Group were then divided further into two groups: a Maintenance Drug Group and a Maintenance Placebo Group. Omeprazole paste was administered to the Maintenance Drug Group orally 5mL once-a-day (0.5mg/kg BW Sham paste blinded to the investigators was administered to the Placebo Group.

After two weeks lesions were again scored.

-17- Scoring gastric lesions Gastroendoscopy was performed on horses at time zero, two-week and fourweek time points. All horses were starved between the night feed and endoscopy on the afternoon of the following day. Prior to examination, each horse was sedated with detomidine HCI (12gg/kg IV) and a 3-metre fibreoptic gastroscope was used to visualize the GC, LC and FU in the stomach. Lesions were graded using the following scales.

The severity of lesions was graded on a scale of 0 to 3 as follows: 0 normal/intact epithelium.

1 superficial erosion of the epithelial layer.

2 partial erosion of the mucosa and areas of hyperkeratosis.

3 all mucosa was eroded with areas of haemorrhaging and hyperkeratosis.

The surface area of lesions was graded on a scale of 0 to 4 as follows: 250 No area affected 1 0-10% area affected 2 10-25% area affected 3 25-50% area affected 4 >50% area affected 4 >50% area affected -18- Statistical analysis The variable of interest was the change in the score for severity and for surface area for each horse before and after the two-week treatment phase and then after the two-week maintenance phase.

Multivariate analysis of variance (MANOVA) was carried out to test group differences (F-test) for severity and surface area using Package SPSS 10.1. Differences in score were tested between groups and within groups, before and after treatment.

Adjusting the Type 1 error rate for multiple t-tests on the same animals within groups, we used a =0.05/3 0.0167 in assessing significance.

1O Results The MANOVA revealed no significant differences between groups at the start of treatment and a significant 0.05) group effect after the two-week treatment phase.

The "Before" scores for both variables, severity and surface area, were significantly (P< 0.05) higher in the GC and LC and lower in the FU.

Univariate F-tests revealed a significant 0.05) decrease in severity and surface area of ulceration in all three locations (GC, LC and FU) in horses treated in the Drug Group during the treatment phase. Ulcers healed completely in 14 of the 19 horses or 74 percent of horses in the Drug Group and the severity of ulcers in the remaining five horses reduced to a score of one (1 superficial erosion). In this group, all ulceration in the FU healed completely.

Table 1. Mean change in score and standard error for each variable at each location after the treatment phase.

-19- Mean Site in change in std. P stomach Variable Treatment score error value GC Sev 1.0mglkg -1.95 0.44 0.05 SA 1.0mglkg -2.11 0.36 0.05 LC Sev 1.0mglkg -2.11 0.45 0.05 SA 1.0mglkg -2.21 0.44 0.05 FU Sev 1.0mglkg -0.63 0.46 0.05 SA 1.0mg/kg -0.68 0.51 0.05 GC Sev Placebo 0.71 0.45 0.05 SA Placebo 0.14 0.35 0.05 LC Sev Placebo 0.43 0.49 0.05 SA Placebo 0.43 0.49 0.05 FU Sev Placebo 0.29 0.45 0.05 SA Placebo 0.14 0.35 0.05 For the horses on placebo during the treatment phase, the average severity score increased significantly 0.05) in the GC and in other areas there was no significant change from "Before" scores.

Of the 19 horses that completed the two-week treatment phase, seven horses completed the two-week maintenance phase. For the balance of horses, treatment was interrupted due to racing, injury or transfer away from stables. Stomach ulcers were completely healed in all seven horses at the start of the maintenance phase.

All horses in the Maintenance Drug Group remained free from ulcers in all three locations of the stomach (GC, LC and FU) during the two-week maintenance phase. In the Maintenance Placebo Group, ulcers recurred in all three horses with a severity and surface area of ulceration equal to that before treatment.

The lower mean lesion scores in the fundus reflected a lower incidence with only 10 of the 26 trial horses with ulcers in this location at the commencement of the trial.

The mean healing response was therefore also less marked, yet ulcers in this location healed completely in all affected horses during the treatment phase.

Trainers reported a dramatic improvement in clinical signs within days of commencing treatment gauged by improved appetite and more settled temperament despite an increase in training intensity.

Oral dosing once daily with a pre-filled Dial-a-Dose® syringe marked at increments was considered by trainers to be convenient and manageable. Each syringe provided three 10mL treatment doses or six 5mL maintenance doses. The paste was administered by placing the nozzle to the back of the horse's mouth.

Conclusion The results of this study confirm that the omeprazole paste formulation, administered daily for 14 days at a dose rate of 1.0mg/kg BW is effective for treatment of gastric ulcers in racehorses that remain in training. Continuation of treatment with a daily maintenance dose of 5mL omeprazole paste (0.5mg/kg BW) effectively prevents recurrence of gastric ulcers.

Observations: No adverse reactions were reported.

Some horses appear to tolerate the discomfort of gastric ulcers better than others, and not all horses show clinical signs of the disease. Many horses showed a dramatic improvement in mood, appetite and appearance within days.

Example 3: Confirmatory field studies Use of the omeprazole paste has been confirmed under field conditions and the findings are summarized as follows: No. of target species: 95 horses in training No. of doses 10mL: 1330 doses No. of doses 5mL: 2980 doses administered after 14 days x -21 Adverse effects: Nil.

Summary: All changes in attitude, condition and wellbeing of horses were positive.

Although the present invention has been described with reference to specific examples and embodiments it will be understood that alternatives and variants in keeping with the spirit of the invention as described are also within the scope of the invention.

Claims (12)

1. Stable composition of an acid labile active agent comprising, a. an inert particulate matrix, b. an acid labile active agent, c. enteric coating and d. a non-aqueous carrier in the form of a ready-to-use orally administrable paste.

2. A composition according to claim 1 wherein the active agent is a proton pump inhibitor.

3. A composition according to claim 2 wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, pantoprazole and leminoprazole.

4. A composition of claim 2 wherein the proton pump inhibitor is omeprazole.

5. A composition according to any one of claims 1 to 4 wherein the inert particulate matrix is comprised of sugar spheres or non-pariel seeds.

6. A composition according to any one of claims 1 to 4 wherein the inert particulate matrix is comprised of sugar spheres wherein the spheres comprise lactose or mannitol.

7. A composition according to any one of claims 1 to 6 wherein the enteric coating is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, shellac and methacrylic acid copolymer.

8. A composition according to any one of claims 1 to 6 further comprising a sub- coating layer between the enteric coating and the acid labile agent-coated inert particulate matrix (core). -23-

9. A composition according to claim 8 wherein the sub-coating layer is comprised of a water soluble or dispersible agent or agents capable of protecting the core from the enteric coating. A composition according to claim 9 wherein the water soluble or dispersible sub- coating layer is selected from the group consisting ofpolyvinyl pyrrolidone, methylcellulose, hydroxymethylcellulose, polyethylene glycol and polyvinyl alcohol.

11. A composition according to any one of claims 1 to 10 wherein the non-aqueous carrier is selected from the group consisting of liquid paraffin, saturated and unsaturated vegetable oils, mineral oils, synthetic and natural di- and triglycerides, esters of oils, glycerol, propylene glycol, polyetlylene glycol and higher alcohols and fats. 1l2. Method of treating a disorder or a disease in an animal comprising orally administering a composition according to any one of claims 1 to 11.

13. A method according to claim 12, wherein the disorder or disease to be treated is a gastrointestinal disorder.

14. A method according to claim 12, wherein the gastrointestinal disorder is gastric and/or duodenal ulcer. A method according to any one of claims 12 to 14 wherein the animal is a horse.. DATED this 19 th day of August 2005 Shelston IP Attorneys for: Metelli Pty Ltd