WO2004062695A1

WO2004062695A1 - Orally deliverable pharmaceutical composition containing protein pump inhibitors

Info

Publication number: WO2004062695A1
Application number: PCT/AU2004/000013
Authority: WO
Inventors: John Allen Hackett
Original assignee: Nature Vet
Priority date: 2003-01-10
Filing date: 2004-01-09
Publication date: 2004-07-29
Also published as: AU2003900096A0

Abstract

Compositions comprising a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof, a multivalent alkali metal oxide (MAMO) in an amount sufficient to scavenge water and thicken the composition, a hydrophobic wetting agent, and a non-aqueous hydrophobic or hydrophilic liquid carrier in the form of an orally administrable paste are described. Also described are use of the orally administrable paste for the manufacture of a medicament for the treatment of gastric acid related diseases in humans and animals, and methods for the treatment of gastric acid related diseases in humans and animals.

Description

ORALLY DELIVERABLE PHARMACEUTICAL COMPOSITION CONTAINING

PROTEIN PUMP INHIBITORS

This invention provides an orally administrable pharmaceutical composition in the form of a paste containing a protein pump inhibitor as the active pharmaceutical ingredient and a multivalent alkali metal oxide (MAMO), use of the composition and methods of treating gastric diseases using same and use of a MAMO as a water scavenger in paste formulations with moisture sensitive active pharmaceutical ingredients. The composition enables highly efficient and effective delivery of acid labile protein pump inhibitors to animals and humans, such as: high performance sporting animals, for example, race horses and horses involved in competitive sport; husbandry animals such as cattle, sheep and pigs; companion animals such as cats and dogs; and administration to humans, particularly those who have difficulty in swallowing solid dosage forms such as tablets. Background of the Invention

Protein pump inhibitors (PPI) have been used extensively in the treatment of gastric acid related diseases in humans and animals. PPI are inhibitors of gastric acid secretion, inhibiting the 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. Gastric diseases, which may be treated with PPI include gastric and duodenal ulcers, and reflux disorders. Peptic 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 peptic ulcers, and horses involved in sporting pursuits. Gastro-duodenal ulcers are also problematic in other animals. These gastric disease are not simply uncomfortable to the sufferer but also dangerous as an untreated ulcer may burst leading to internal bleeding and may in some instances be fatal. PPIs are well known molecules whose preparation, chemistry and pharmaceutical properties are well understood. In the years 1999 and 2000, omeprazole was one of the largest selling drugs in the world. This reflects the outstanding activity of PPIs in the treatment of gastric acid related disease in humans and animals.

PPIs are known compounds in the art, and their chemical and pharmaceutical properties are very well described. A principal chemical property of PPIs are their high acid lability, that is, the PPIs are unstable in acidic solutions, and are hydrolysed to inactive species 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. Enterically coated formulations are time consuming to manufacture, require elaborate technology and equipment, and are consequently expensive to produce. Enterically coated formulations are also sensitive to moisture uptake which effects product storage and stability. The degree of protection offered by these various oral preparations however at best appears to be only 50% or 50% bioavailabihty, when compared with direct intravenous injections ofPPIs.

WO 94/25070 discloses oral compositions containing a protein pump inhibitor in the form of enterically coated dry particles mixed with a dried gelling agent. This mixture may then be made into a paste-like gel prior to administration. The composition requires enteric coating, and suffers from the disadvantages of enteric coating mentioned above. Additionally, moist gels as disclosed in WO94/25070 are not stable during long-term storage at room temperature and thus these formulations must be prepared at the time of administration, which is generally inconvenient. WO 96/01624 describes enteric coating of layered pellets comprising the active PPI substance. These enterically coated layered pellets are compressed into tablets. Preferably, the preparation of pellets containing the active substances is performed by spray layering the active substance onto seeds, such as sugar spheres, and thereafter applying the enteric coating layer, optionally after a separating layer has first been applied to separate the active substance from the finally applied enteric coating layer. The methods of production used and equipment necessary to produce this product are complicated, and formulations produced are consequently relatively expensive on a per unit basis.

WO 96/01622 discloses enterically coated formulations containing a core material comprising a magnesium salt of the PPI omeprazole coated with one or more enteric coating layers. The omeprazole has a high degree of crystallinity, and the enteric coating thickness is finely selected so as not to deleteriously retard the release of the omeprazole into aqueous solutions at pH values predominant in the small intestine. WO 96/24338 discloses oral pharmaceutical dosage forms comprising a core material that contains a PPI, preferably omeprazole, one or more alkaline reacting compounds and optionally one or more pharmaceutical acceptable excipients. The core material has a water soluble separating layer with an enterically coated layer thereupon. WO 00/27366 describes oral pharmaceutical formulations comprising omeprazole, where the formulation comprises a core material including omeprazole and an alkaline reacting compound in admixture with a pharmaceutically acceptable excipient, and a binding agent. A separating layer separates the core material from an enteric coating layer. A specific form of hydroxy propyl cellulose with a cloud point at 38°C is utilised as the separating layer.

Australian Patent Application No. 13541/00 describes oral pharmaceutical preparations containing omeprazole which are prepared by suspending omeprazole in a polyvinyl alcohol solution, spraying the solution onto a sugar seed to form microgranules, coating the microgranules with a binder, followed by application of an enteric coating. WO 96/31213 discloses pharmaceutical compositions for oral administration which comprises one or more PPI such as a omeprazole, a hydrophobic oily liquid vehicle, a basifymg 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 unpractically insoluble in water, and in combination with the protein pump inhibitor and hydrophobic liquid vehicle forms a paste. The water insoluble nature of the thickening agent may give rise to an unpleasant mouth feel of the composition. The nature of the formulations has the disadvantage that relatively low amounts of PPIs can be incorporated into the final composition, such as from 1 to 35% w/w.

WO 00/50038 describes oral formulations of omeprazole 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 60%w/w this is said to be "tolerated" suggesting this maxim 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 formulation 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 bioavailabihty of the active omeprazole. Additionally, such formulations may be costly to prepare. Whilst not wishing to be bound by theory, it is thought that the use of a multivalent alkali metal salt of a PPI or a PPI and a MAMO minimises any hydrophilic properties of the PPI and thus minimises the possibility of it partitioning out of the carrier such as an oily phase into the acidic aqueous environment in the stomach, which would result in degradation and possible destruction of some or all of the PPI before the therapeutic target can be reached. Minimising the PPI's hydrophilic properties renders it more compatible with the carrier such as an oily liquid carrier which is generally a substantial component of paste formulations, enabling a stabilised formulation to be prepared.

The inventor has also found that water in macro and micro (trace) quantities affects, that is facilitates, degradation kinetics of protein pump inhibitors in the composition. Additionally it has been found that the multivalent alkali metal oxides (MAMOs) will scavenge trace water from the preparation. The incorporation of alkali metal oxides as water scavengers removes free water from the preparations and promotes stability on storage. The MAMOs have also been found by the inventor to serve a rheology function by increasing the composition viscosity and assist in stabilising the composition in the form of a paste. This may obviate the need to employ additional excipients as thickening agents, which is advantageous as generally regulatory authorities, such as the FDA, require the number of components to be minimised for such compositions and reducing the number of components may also reduce the manufacturing costs. Summary of the Invention

The present invention in its various aspects relates to a pharmaceutical composition in the form of an orally administrable paste including a multivalent alkali metal salt of a protein pump inhibitor (PPI), or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof. hi accordance with a first aspect of this invention there is provided a composition comprising a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof, a multivalent alkali metal oxide (MAMO) in an amount sufficient to scavenge water and thicken the composition, a hydrophobic anionic wetting agent, and a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or non aqueous hydrophilic liquid carrier or mixture thereof, in the form of an orally administrable paste. Preferably the composition comprises: (a) from 1 to 70%, for example, 1 to 65% of a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a conesponding multivalent alkali metal salt thereof;

(b) from 5 to 70% of a multivalent alkali metal oxide (MAMO);

(c) from 0.1% to 20% , for example, 1 to 20% of a hydrophobic anionic wetting agent; and

(d) from 10 to 90%, for example, 30 to 90% of a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or a non aqueous hydrophilic liquid carrier.

In another aspect of the invention there is provide use of a composition comprising a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof, a multivalent alkali metal oxide (MAMO) in an amount sufficient to scavenge water and thicken the composition, a hydrophobic organic acid wetting agent and/or a hydrophobic multivalent alkali metal anionic organic acid wetting agent, and a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or a non aqueous hydrophilic liquid carrier, in the form of an orally administrable paste in the manufacture of a medicament for the treatment of gastric acid related diseases in humans and animals.

In another aspect of the invention there is provided use of a composition comprising: (a) from 1 to 70%, for example, 1 to 65% of a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof;

(b) from 5 to 70% of a multivalent alkali metal oxide (MAMO);

(c) from 0.1 to 20%, for example, 1 to 20% of a hydrophobic anionic wetting agent; and

(d) from 10 to 90%, for example, 30 to 90% of a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or non aqueous hydrophilic liquid carrier, in the manufacture of a medicament for the treatment of gastric acid related diseases in humans and animals. In another aspect of the invention there is provided a method for the treatment of gastric acid related diseases in humans and animals which comprises administering to a subject in need of such treatment an effective amount of a composition comprising multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a conesponding multivalent alkali metal salt thereof, a multivalent alkali metal oxide (MAMO) in an amount sufficient to scavenge water and thicken the composition, a hydrophobic anionic wetting agent, and a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or a non aqueous hydrophilic liquid carrier, in the form of an orally administrable paste. In another aspect of the invention there is provided a method for the treatment of gastric acid related diseases in humans and animals which comprises administering to a subject in need of such treatment an effective amount of a composition comprising: (a) from 1 to 70%, for example, 1 to 65% of a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof; (b) from 5 to 70% of a multivalent alkali metal oxide (MAMO);

(c) from 0.1 to 20%) , for example, 1 to 20% of a hydrophobic anionic wetting agent; and

(d) from 10 to 90%, for example, 30 to 90% of a non aqueous liquid carrier such as a hydrophobic oily liquid carrier or a non aqueous hydrophilic liquid carrier. It is thought that the properties of the components, particularly the MAMO and the hydrophobic anionic wetting agent are appropriately matched and that this advantageously provides a more effective interaction of the components in the composition, resulting in a composition of suitable stability. Without wishing to be bound to theory, applicants believe that the paste composition according to various aspects of the invention forms a protective coating over the hydrophobic PPI/metal salt protecting it from acid degradation in the stomach. On passage to the alkaline environment the intestinal region, the PPI becomes biologically available and is rapidly absorbed into the bloodstream. PPI's such as omeprazole are accordingly protected from acid degradation in a cost effective and an efficient manner. Thus the present invention provides a composition: with increased stability on storage and, on administration to the patient, to the acids found in the stomach; which also allows a large percentage of the PPI to be incorporated into the formulation thereby allowing the volumes required to dispensed the desired dose to the animal or human to be reduced. Detailed Description of the Invention

The present invention provides an orally administrable PPI composition in the form of a stable paste using a carrier such as a hydrophobic oily liquid carrier or a non aqueous hydrophilic liquid carrier, suitable for direct paste administration or for filling into capsules for human or animal use.

The PPIs are strongly protected from acid inactivation in the stomach and are efficiently absorbed and delivered to the bloodstream according to the various aspects of the invention. Compositions are of high potency, in the sense that they contain relatively high amounts of PPIs which maybe effectively systemically delivered substantially free of inactivation in the acid environment of the stomach.

The orally administrable pastes according to the invention also have the characteristic of sticking to wet oral surfaces which makes it difficult to expel and particularly suitable for animal application. The invention covers all protein pump inhibitors such as omeprazole, pantoprazole, lansoprazole, lemonprazole and any other protein pump inhibitors (PPI) as well as their metal salts. The composition may contain two or more different PPIs. The preferred PPI inhibitor used in the various aspects of the present invention is the compound known as omeprazole. The structure and synthesis of the PPI's are disclosed in the following patents: Omeprazole is described in US Patent 4,255,432 and EP 5129 Pantoprazole is described in US Patent 4,758,579 and EP 166287 Lanzoprazole is described in US Patent 4,628,098 and EP 174726 Lemonprazole is described in GB 2163737. The PPIs and their metal salts are described by the following formulae

M^ in Mx is a multivalent metal ion present in the PPI metal salt, in R_a is

R and R are independently selected from hydrogen, lower alkyl, lower alkoxy and halogen R² is selected from hydrogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower fluoroalkoxy and

R >4 and R are independently selected from lower alkyl A is

R⁶ and R⁷ are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen.

wherein R is lower alkyl or lower alkoxy.

Lower when used in this specification in relation to alkyl or alkoxy refers to Cι-₆, for example, Cι-₃ such as methyl, ethyl or propyl and includes straight chain as well as branched moieties.

Preferably compositions according to the invention will have about between 30% and 50%w/w of the above identified PPIs and/or the corresponding multivalent alkali metal salts of magnesium, calcium or aluminium, particularly preferred is omeprazole and/or its magnesium salt. The metal salts of these PPI's used in this invention are multivalent to render the PPI more hydrophobic. Typical metal salts are based on calcium, magnesium, aluminium or other divalent metal.

The PPI's are not considered to be particularly hydrophobic due to the numerous polar water avid groups on the molecule. As a consequence when a hydrophobic oily liquid carrier is employed an oil layer coating the PPI crystals will not necessarily be bound strongly enough to prevent preferential wetting of the PPI crystals by a water phase when the preparation comes in contact with water following administration to an animal. This being the case, the oil layer cannot fully protect the PPI from aqueous acid degradation. In this invention the problem has been overcome by use of a hydrophobic multivalent alkali metal salt of a protein pump inhibitor in concert with the other components of the composition. In one embodiment the surface chemistry of the crystalline PPI is converted to the corresponding multivalent alkali metal salt. Alternatively, the PPI may be completely converted to the multivalent alkali metal salt. The multivalent metal salts of the PPIs have a more hydrophobic character which, when coupled with the multivalent alkali metal hydrophobic organic acid wetting agent which adsorb to the PPIs, ensures that the PPI has a very hydrophobic surface not susceptible to aqueous wetting and degradation by the acidic aqueous environment in an animals stomach. A wetting agent including a multivalent alkali metal hydrophobic and/or hydrophilic wetting agent may also be employed where the carrier is a non aqueous hydrophilic liquid carrier. The corresponding multivalent alkali metal salts are produced by reaction of the PPI's with the corresponding multivalent alkali metal oxide which is an ion exchange process that occurs above pH 10 as the weak acidic PPI sulfinyl group is ionised. The PPI multivalent alkali metal salt can be prepared either under aqueous or non aqueous conditions. Typically the PPI can be quickly solubilised with sodium hydroxide in water adjusting the pH to 10.0-10.5 then adding an aqueous solution of an alkali metal salt such as the metal chloride or sulphate at room temperature. The PPI alkali salt then precipitates out as the water insoluble salt which can be recovered and dried, for subsequent addition to the preparation.

A preferred alternative is to prepare a suspension of PPI crystals and a multivalent alkali metal oxide in a non-aqueous liquid carrier containing an oil or non aqueous hydrophilic liquid and a soluble multivalent alkali metal organic acid salt. The, oil or hydrophilic liquid carrier, soluble multivalent alkali metal organic salt is the ion exchanger which enables transport of multivalent alkali metal ions between the PPI crystal surfaces and the suspended multivalent alkali metal oxide. The reaction is carried out at ambient temperatures 10 to 50°C.

Some PPI multivalent alkali metal salts, such as magnesium omeprazole, are available commercially. For the purposes of this invention where there is a solid suspension of PPI in a carrier, base it is not necessary to have 100% conversion of the PPI to the corresponding multivalent alkali metal salt. The surface layer of the crystalline PPI may be converted to the corresponding multivalent alkali metal salt to create a more hydrophobic crystal surface. There will be a slow kinetic diffusion of metal ions during normal storage of the preparation. This diffusion process is aided by the presence of the carrier soluble hydrophobic anionic wetting agent or other wetting agent which enables ion exchange between the insoluble multivalent alkali metal oxide and the PPI suspended solids. The amount of the PPI's and/or multivalent alkali metal salts of PPIs in the present invention is not critical and can be modified to fit a suitable dosage volume for particular animals. Paste preparations for equine use would typically contain up to about 40%w/w PPI (referring to PPI content whether in multivalent alkali metal salt form or not) based on a 5g dose but could range up to about 70% w/w.

Pharmaceutically acceptable multivalent alkali metal oxides (MAMO) which act as combined water scavengers, composition stabilising agents and thickening agents include magnesium oxide, calcium oxide and aluminium oxide. The preferred MAMO is magnesium oxide.

Optimising the physical surface area of the MAMO aids chemical diffusion kinetics and physical thickening requirements for the preparation. A fine physical particle size and narrow particle size distribution of the MAMO is preferred. In the case of magnesium oxide the preferred form is a grade of light or extra light magnesium oxide as opposed to dense magnesium oxide. Lighter grades have a finer particle size distribution and have a higher surface area to provide faster kinetics for its critical functions in the composition. A suitable particle size range is from 1 to 25 micron with an average particle size of 5 micron. Similarly finer grades of other MAMOs such as calcium oxide and aluminium oxide are beneficial in the preparation.

The amount of MAMO is from about 5% to about 70%w/w and preferably 10% to 20%w/w, which provides excellent results. Two or more MAMOs may be used. Preferably the hydrophobic anionic wetting agent is a multivalent alkali metal salt of an organic acid, such as a C₆-C₄₀ fatty acid (for example stearic acid, palmitic acid, oleic acid, or mixed vegetable oil acids), rosin acids (for example abietic acid), aromatic acids (for example tannic acid), and anionic FD&C dye acids. Preferably the multivalent alkali metal is selected from magnesium, calcium and aluminium. The hydrophobic anionic wetting agents are pharmaceutically acceptable. A pharmaceutically acceptable hydrophobic alkali metal anionic organic acid wetting agent may be added to the composition separately, or may be formed in situ by addition of an organic acid, such as a fatty acid, to the carrier base. Subsequent reaction with the suspended MAMO gives rise to the multivalent alkali metal anionic organic acid wetting agent in the composition. A particularly prefened hydrophobic multivalent alkali metal anionic organic acid wetting agent is magnesium stearate .

The hydrophobic anionic wetting agent is present in an amount from 0.1% to about 20%, such as 0.1% to 10%w/w, and preferably from about 1% to 5% w/w. Two or more hydrophobic anionic wetting agents may be used. The hydrophobic wetting agent should be soluble in the carrier. It has been found by the inventor that this property aids in metal ion exchange with the PPI, facilitating metal ion exchange between the PPI and MAMO in suspension, and secondly renders the PPI crystalline form fully hydrophobic. In this aspect of the invention the PPI crystals rendered more hydrophobic when the paste is exposed to water during passage through the digestive tract.

Hydrophobic oily liquid carrier may be any pharmaceutical acceptable biodegradable oil, that is insoluble or practically insoluble in water. Two or more biodegradable oils may be used. Examples include: (i) a vegetable oil; and

(ii) triglycerides of medium chain fatty acids or propylene glycol diesters of medium (C₅-C₂₀) chain fatty acids.

Examples of pharmaceutically acceptable vegetable oils include vegetable oils such as, but not limited to, canola, sunflower, palm oil, palm kernel oil, coconut oil, almond oil, cotton seed oil, olive oil, peanut oil, safflower oil, sesame oil, soya bean oil.

The preferred vegetable oils are mono unsaturated such as canola oil.

Medium chain fatty acids are those having chain lengths of from eight to eighteen carbons; preferably the fatty acids are saturated or mono unsaturated fatty acids. Other suitable oil carriers are triglycerides and propylene glycol diesters such as capric/caprylic triglycerides and propylene glycol caprate/caprylate (also refened to as propylene glycol octanoate dodecanoate). Capric triglyceride or caprylic triglyceride or a mixture thereof, are commercially available, for example, the product name MIGLYOL®

840 (Huls America Inc., New Jersey, United States). Other fatty acid esters suitable as carriers could include ethyl oleate, isopropyl, myristate, isopropyl palmitate, myristyl alcohol, lecithin, octyldodecanol and squalene. Alternatively sorbitan mono, di and tri fatty acid esters or glycerol mono, di and tri fatty acid esters or hydrophobic Surfactant with a HLB of less than 9 may be employed.

The more prefened hydrophobic oily liquid vehicles comprises canola oil and propylene glycol caprate/caprylate (such as Miglyol® 840) either alone or mixtures of both. The hydrophobic vehicle is preferably present at approximately 30% to 90% w/w, depending on the amount of other excipients in the paste.

Non aqueous hydrophilic liquid carriers include: glycols, polyglycols, alcohols, alcohol alkoxylates, polyethoxylates, polypropoxylates, hydrophilic surfactants with HLB of 9 or greater, fatty acid esters and ethers of glycols, polyglycols, polyalcoxides, polyoxyethylene sorbitan fatty acid esters, such as Tween 20, 40, 60 and 80 which are commercially available; polyoxyethylene fatty acid esters, such as Renex 20 G-2127; and polyoxyethylene alcohol ethers, such as Renex 30,31.

The composition of the present invention may include additional ingredients commonly used in the formulation of human and veterinary medicines. For example, fragrances and flavouring agents such as caramel, carrot, apple, cinnamon, vanilla and the like; colouring agents such as approved F&C dyestuffs, natural colouring such as beta carotene and natural vegetable oil colouring components; natural sweeteners such as sugar, molasses solids, artificial sweeteners such as saccharins, cyclamates; preservatives such as parabens; antioxidants such as BHT, BHA; viscosity and rheology agents such as natural or synthetic waxes can be added. Magnesium stearate may also be useful in controlling moisture ingression into the formulation. If desired additional thickening agents, such as, Aerosil and silicon dioxide may be employed in the compositions of the invention.

The composition of the present invention may be prepared by firstly dispersing the PPI powder or the PPI/multivalent alkali metal salt form in the hydrophobic or hydrophilic liquid carrier containing all the other excipients and half the multivalent alkali metal oxide (MAMO) powder. This avoids any unnecessary air entrainment on stirring. Once all the PPI has been thoroughly wetted and dispersed the remainder of the MAMO may be added with gentle mixing to minimise any further air entrainment. The resulting preparation is a stable solid suspension paste which can be filled into tubes, syringes, capsules or other dosage administration forms. The paste can be easily prepared with simple mixing equipment, is easy and cost effective to produce and does not involve advanced technical knowledge or complicated equipment.

The PPI paste preparations of the present invention have improved properties over previously described PPI paste formulations. The present preparations have better chemical and physical stability profiles on storage, and provide better administration characteristics as well as higher drug bioavailabihty. The paste can be either administered as a direct oral paste or be incorporated into traditional capsules.

The composition of the present invention is useful in the treatment of peptic ulcer diseases in humans or animals. It can be used to deliver PPIs orally for systemic activity in animals. The composition can also be used for the delivery of PPIs as a paste in humans with difficulty in swallowing solid dosage forms such as enterically coated tablets and capsules. The composition is also particularly suitable for incorporation into traditional capsules which is a more cost effective approach compared with enteric coated tablets. The composition may be administered directly into 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 the paste for horses is such that it is sticky and readily adheres to wet oral surfaces which makes it difficult to be expelled or drip out once it is deposited on the dorsal part of the animal's tongue. Individualised doses can be administered with this syringe technique. The amount of composition to be administered may vary according to the particular animal species to be treated, severity of the disease, physical condition of the afflicted animal, weight of the animal, and other factors. A physician or veterinarian skilled in the art of ulcer treatment may readily determine the proper dosage for the specific host under treatment. In general a dose range from about 0.2mg/kg to about 20 mg/kg may be used. Literature PPI dose rates vary from 0.2 to 0.4 mg/kg for human intravenous and/or enteric capsule administration, and 4.0 mg/kg for paste administration.

The compositions according to the invention are stable and can be stored for extended periods without water absorption or other degradative effects. The compositions of the present inventions are used for the treatment of gastric acid related diseases in humans and animals which include the treatment of peptic and duodenal ulcers, treatment of gastric reflux, treatment of the symptoms of hiatus hernia and the like. The composition may be administered to humans and animals such as: high performance sporting animals, for example, race horses and horses involved in competitive sport; husbandry animals such as cattle, sheep and pigs; companion animals such as cats and dogs; and administration to humans, particularly those who have difficulty in swallowing solid dosage forms such as tablets.

According to the invention, acid labile PPI can be delivered orally for systemic activity. The use of paste compositions is particularly advantageous in administering drugs orally to animals. The composition may be administered directly into the mouth of an animal, such as a horse, for example, in need of anti-ulcer therapy, using, for example, a dosage syringe to facilitate administration. The special sticky coherence to wet oral surfaces and consistency of the paste composition is such that it remains in the mouth of the animal and is not easily expelled once placed in the dorsal part of the mouth, such as on dorsal part of the tongue. The composition of the invention, from a veterinary perspective, finds particular application in horses.

The components of the composition of the invention described herein interact to provide a stable, sticky and thick paste which on administration to an animal protects the PPI from acid degradation in the stomach and provides effect and rapid systemic administration of the PPI. The high content of PPI in the compositions enables low volumes to be administered to animals and humans which is desirable from many perspectives including handling, dosage, storage and transport perspectives. The present invention also extends to the use of one or more MAMO in a paste formulation of a pharmaceutically active ingredient for improving stability and/or scavenging water and/or reducing the hydrophilic nature of the pharmaceutically active component and/or improving the bioavailabilty of the pharmaceutically active ingredient.

Furthermore the invention also included the use of one or more MAMO and a hydrophobic anionic wetting agent for preparing a paste formulation of a pharmaceutically active ingredient with improved stability.

The present invention will now be described by reference to the following non-limiting examples.

These examples produce a sticky type paste, which adheres well to wet oral surfaces and is particularly suitable for horses.

The following examples are provided to more fully illustrate the invention, and shall not be construed as limiting the scope of the invention in any manner.

Example 1

Preparation of PPI multivalent alkali metal oxide salts PPI multivalent alkali metal salts are prepared either under aqueous or non-aqueous conditions, this example PPIs, particularly omeprazole, lanzoprazole, pantoprazole and lemonprazole were rapidly solubilised with sodium hydroxide in water, adjusting the pH to

10-10.5. An aqueous solution of the desired alkali metal salt, such as the metal chloride or sulphate, is then added at room temperature. The PPI salt then precipitated out of water as the insoluble salt which is recovered, dried and then used in formulation.

Alternatively, a suspension of PPI crystals and a multivalent metal oxide in a non-aqueous media containing an oil soluble multivalent alkali metal organic salt is prepared. The oil soluble multivalent alkali metal salt acts as an ion exchanger which enables transport of multivalent alkali metal ions between the PPI surface crystals and the suspended multivalent alkali metal oxide. The ion exchange process is carried out at ambient temperatures from 10 to 50°C.

Example 2

Preparation of composition

18.5g of omeprazole and/or magnesium omeprazole powder 8 g of magnesium oxide lg of magnesium stearate

20g of canola oil ( hydrophobic carrier )

The components are added together and mixed and rapidly form a thick paste. Example 3

Preparation of composition

This example was prepared as Example 2 but replacing 20g of canola oil with 20g of

Tween 80 (hydrophilic carrier). Example 4

Preparation of composition

This example was prepared as Example 2 but replacing lg of magnesium stearate with lg of stearic acid.

Example 5 Preparation of composition

This example was prepared as Example 4 but replacing 20g of canola oil with 20g of

Tween 80 (hydrophilic carrier).

Example 6

Preparation of composition 18.5 g of lanzoprazole and/or magnesium lanzoprazole powder

8g of magnesium oxide-hydroxide powder lg of magnesium stearate

20g of canola oil ( hydrophobic carrier )

The components are added together and mixed and rapidly form a thick paste. Example 7

Preparation of composition

This example was prepared as Example 6 but replacing lg of magnesium stearate with lg of stearic acid.

Example 8 Preparation of composition

This example was prepared as Example 6 but replacing 20g of canola oil with 20g of

Tween 80 (hydrophilic carrier).

Example 9

Preparation of composition This example was prepared as Example 8 but replacing lg of magnesium stearate with lg of stearic acid.

Example 10

Preparation of composition 18.5 g of pantoprazole and/or magnesium pantoprazole powder

8g of magnesium oxide lg of magnesium stearate

20g of canola oil (hydrophobic carrier) The components are added together and mixed and rapidly form a thick paste.

Example 11

Preparation of composition

This example was prepared as Example 10 but replacing lg of magnesium stearate with lg of stearic acid. Example 12

Preparation of composition

This example was prepared as Example 10 but replacing 20g of canola oil with 20g of

Tween 80 (hydrophilic carrier).

Example 13 Preparation of composition

This example was prepared as Example 12 but replacing lg of magnesium stearate with lg of stearic acid.

Example 14

Preparation of composition 18.5g of lemonprazole and/or magnesium lemonprazole powder

8g of magnesium oxide lg of magnesium stearate

20g of canola oil (hydrophobic carrier )

The components are added together and mixed and rapidly form a thick paste. Example 15

Preparation of composition

This example was prepared as Example 14 but replacing lg of magnesium stearate with lg of stearic acid.

Example 16 Preparation of composition

This example was prepared as Example 14 but replacing 20g of canola oil with 20g of

Tween 80 (hydrophilic carrier).

Example 17 Preparation of composition

This example was prepared as Example 16 but replacing lg of magnesium stearate with lg of stearic acid.

Example 18 The composition of Example 1 was orally administered by syringe into the mouth of a group of 40 horses. Administration was once per day of 6g of the paste over a six week period. Control animals were dosed with a composition which was similar to Example 1, except that it did not include omeprazole.

All the treated animals showed much better appetite than control animals which did not receive the composition according to Example 1, consistent with treatment of ulceration .

Gastroscopy analysis of selected animals within the group treated with the composition of

Example 1 showed no ulceration or healing stomach ulceration, which contrasted with the ulceration observed in control animals. At the conclusion of the six week trial period, ulcers had healed, as demonstrated by visual analysis of the stomach by gastroscopy. Example 19

Horse Formulation Evaluation Trials.

Based on the knowledge that proton pump inhibitors reduce acid secretion and raise stomach fluid base pH levels a rapid screening technique was developed to compare formulations. The acid build up in a horse's stomach during periods of fasting and water withdrawal was measured. Reproducible baseline measurements were established and excellent formulation comparative data generated.

Typical results are as follows :-

Stomach Fluid pH levels

*No Treatment

Paste "A" -Hydrophobic carrier Paste "C" -Hydrophilic carrier All paste samples raised the base pH from from a 6 hour low of pH 2 to pH 4 to 5 which represents a 99% reduction in acid generation over that period .

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as an acknowledgment or any form of suggestion that that prior art fonns part of the common general knowledge in Australia.

Claims

1. A composition comprising a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a conesponding multivalent alkali metal salt thereof, a multivalent alkali metal oxide (MAMO) in an amount sufficient to scavenge water and thicken the composition, a hydrophobic anionic wetting agent, and a non aqueous hydrophobic or hydrophilic , in the form of an orally administrable paste.

2. A composition according to claim 1 which comprises: (a) from 1 to 70% of a multivalent alkali metal salt of a protein pump inhibitor (PPI) or a combination of a protein pump inhibitor and a corresponding multivalent alkali metal salt thereof;

(b) from 5 to 70% of a multivalent alkali metal oxide (MAMO);

(c) from O.P/o to 20% of a hydrophobic anionic wetting agent; and (d) from 10% to 90% of a non aqueous hydrophobic or hydrophilic liquid carrier.

3. A composition according to claim 1 wherein the protein pump inhibitors (PPIs) are selected from omeprazole, pantoprazole, lansoprazole and lemonprazoe.

4. A composition according to claim 3 wherein the protein pump inhibitor is omeprazole.

5. A composition according to claim 4 wherein the protein pump inhibitor is present wholly or partly as the multivalent alkali metal salt of the protein pump inhibitor.

6. A composition according to claim 5 wherein the protein pump inhibitor is present wholly or partly as the magnesium, calcium or aluminium salt.

7. A composition according to claim 5 wherein the protein pump inhibitor is present wholly or partly as the magnesium salt of the protein pump inhibitor.

8. A composition according to claim 1 wherein the protein pump inhibitor and/or protein pump inhibitor magnesium, calcium, or aluminium salts are present as hydrophobic solid suspensions.

9. A composition according to claim 7 wherein the protein pump inhibitor and/or protein pump inhibitor magnesium salt is present as a hydrophobic solid suspension.

10. A composition according to claim 1 wherein the hydrophobic anionic wetting agent is a multivalent alkali metal salt of a fatty acid, aromatic acid or organic acid.

11. A composition according to claim 10 wherein the hydrophobic anionic wetting agent is the multivalent alkali metal salt of a C₆ to C₄₀ fatty acid.

12. A composition according to claim 10 wherein the hydrophobic anionic wetting agent is the multivalent alkali metal salt of an oleic acid, palmitic acid or stearic acid.

13. A composition according to claim 10 wherein the hydrophobic anionic wetting agent is the magnesium, calcium or aluminium salt of a C₆ to C₄₀ fatty acid.

14. A composition according to claim 12 wherein the hydrophobic anionic wetting agent is the magnesium, calcium, aluminium salts of an oleic acid, palmitic acid or stearic acid.

15. A composition according to claim 14 wherein the hydrophobic anionic wetting agent is the magnesium salt of an oleic acid, palmitic acid or stearic acid.

16. A composition according to claim 15 wherein the hydrophobic anionic wetting agent is the magnesium salt of stearic acid.

17. A composition according to any one of claims 1 to 16 wherein the non aqueous liquid carrier is hydrophobic.

18. A composition according to claim 17 wherein said hydrophobic liquid carrier comprises a vegetable oil, triglyceride of a medium chain fatty acid, propylene glycol diesters of fatty acids, or hydrophobic surfactants with HLB of less than 9 or mixtures thereof.

19. A composition according to claim 18 wherein said hydrophobic liquid carrier comprises a vegetable oil, triglyceride of a medium chain fatty acid, propylene glycol diesters of fatty acids or mixtures thereof.

20. A composition according to claim 19 wherein said hydrophobic liquid carrier comprises canola oil.

21. A composition according to any one of claims 17 to 20, which further comprises at least one non-ionic and/or ionic surfactant.

22. A composition according to any one of claims 1 to 16 wherein the non aqueous liquid carrier is hydrophilic.

23. A composition according to claim 22 wherein the hydrophilic liquid carrier comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 9.

24. A composition according to claim 23 wherein said hydrophilic liquid carrier comprises Tween 80.

25. A composition of claim 24, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

26. A composition according to claim 24 wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.

27. A composition according to claim 25 or claim 26, wherein the non-ionic hydrophilic surfactant comprises a reaction product of a polyol and a monoglyceride, diglyceride, triglyceride, or a mixture thereof.

28. A composition according to claim 27, wherein the non-ionic hydrophilic surfactant comprises a transesterification product of a polyol and a monoglyceride, diglyceride, triglyceride, or a mixture thereof.

29. A composition according to claim 28 wherein the polyol in is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.

30. A composition according to claim 24, wherein the non-ionic hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate,

PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG- 25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG- 25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether,

POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Renex 20, Renex 31 , Renex 35, Renex 36, Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 65, Tween 80, Tween 81, Tween 85, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-

100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.

31. A composition according to claim 24 wherein the non-ionic hydrophilic surfactant is lauroyl macrogol-32 glyceride.

32. A composition acconding to claim 24 wherein the non-ionic hydrophilic surfactant is stearoyl macrogol glyceride.

33. A composition according to claim 24, wherein the non-ionic hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.

34. A composition according to claim 24, wherein the non-ionic hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-

1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.

35. A composition according to claim 33, wherein the non-ionic hydrophilic surfactant is tocopheryl PEG- 1000 succinate.

36. A composition according to any one of claims 22 to 35, wherein the hydrophilic liquid carrier comprises at least one ionic surfactant.

37. A composition according to any one of claims 1 to 36 wherein the amount of protein pump inhibitor and or the conesponding multivalent alkali metal salt is about 30% to 50% w/w.

38. A composition according to claim 11 wherein the amount of the multivalent alkali metal salt of a fatty acid is 2% to 10%w/w.

39. A composition according to any one of claims 1 to 38 wherein the multivalent alkali metal oxide is magnesium oxide, calcium oxide or aluminium oxide.

40. A composition according to claim 40 wherein the multivalent alkali metal oxide is magnesium oxide.

41. A composition according to claim 39 or 40 wherein the amount of the multivalent alkali metal oxide is from 5%-20% w/w.

42. A composition according to any one of claims 1 to 41 wherein the amount of non-aqueous hydrophobic or hydrophilic liquid is 50% to 80%w/w.

43. A composition according to any one of claims 1 to 42 which adheres to wet oral surfaces.

44. Use of a composition according to any of claims 1 to 43 in the manufacture of medicament for the treatment of gastric acid related diseases in humans and animals.

45. A method for the treatment of gastric acid related diseases in humans and animals which comprises administering to a subject in need of such treatment an effective amount of a composition according to any of claims 1 to 43.