WO2007041790A1

WO2007041790A1 - Salts of proton pump inhibitors and process for preparing same

Info

Publication number: WO2007041790A1
Application number: PCT/AU2006/001499
Authority: WO
Inventors: John Allen Hackett
Original assignee: Jon Pty Limited
Priority date: 2005-10-14
Filing date: 2006-10-11
Publication date: 2007-04-19

Abstract

Disclosed herein is a process for preparing magnesium and magnesium hydroxy salts of proton pump inhibitors (PPI) such as omeprazole, hydroxy omeprazole, s-omeprazole (esomeprazole), r-omeprazole, pantoprazole, lanzoprazole, leminoprazole, rabeprazole, tenatoprazole, mixtures thereof or respective isomers thereof. The process can be used to prepare magnesium salts of PPIs. In particular the process can also be used to prepare the magnesium hydroxy salts of PPIs which have the formula: (PPI-)x.Mg2+(OH-)2-x.(H2O)z wherein PPI is a proton pump inhibitor, x is 0.0001 to 1.9999, and z is 0 to 10, preferably 0 to 5. Compositions of the salts of the PPIs disclosed herein including pharmaceutical compositions are also disclosed. The magnesium and magnesium hydroxy salts of proton pump inhibitors disclosed herein can be used in the treatment of gastrointestinal disorders such as Ulcus ventriculi, Ulcus duodeni, gastritis, gastric ulcer, duodenal ulcer, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease or IBD.

Description

SALTS OF PROTON PUMP INHIBITORS AND PROCESS FOR PREPARING SAME

FIELD OF THE INVENTION

The present invention relates to a process for producing magnesium salts and magnesium hydroxy salts of Proton Pump Inhibitors (PPIs) particularly omeprazole, pantoprazole, leminoprazole, pariprazole, lanzoprazole, tenatoprazole, rabeprazole and respective isomers thereof, and compositions containing the prepared salts. The invention also relates in particular to magnesium hydroxy salts of PPIs and compositions thereof.

BACKGROUND OF THE INVENTION

PPIs are useful for gastrointestinal protection, inhibiting gastric acid secretion and have gastric mucosa protective activity in mammals including man. They may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases including, for example gastritis, gastric ulcer and duodenal ulcer.

Many PPIs are known, for example, rabeprazole, omeprazole, s-omeprazole (esomeprazole), r-omeprazole, lansoprazole, leminoprazole, pariprazole, tenatoprazole and pantoprazole.

Omeprazole is first described in EP 0005129. Certain salts of omeprazole are described in EP 0124495 and US 4,738,974.

Magnesium based salts of omeprazole and the other PPIs have proven to be very stable and is therefore, the most common commercial omeprazole salt used today.

USP 4,738,974 discloses the increased stability in storage of omeprazole alkali salts including the magnesium salt. The salts are prepared by reacting magnesium alcoholate with omeprazole in a non-aqueous solvent.

There are a number of other patents relating to methods of manufacturing magnesium salts of PPIs. EP 0124495 discloses the synthesis of magnesium omeprazole dihydrate, by making the sodium salt; adding a solution of magnesium chloride to obtain a precipitate; removing water, which is used as a solvent for the reaction, by centrifuging the precipitate; washing the precipitate with deionized water until no Cl ions are detectable, drying in air, grinding, and the drying under vacuum at 40°C for 24 h. Thus this process contains a number of steps in order to isolate the required salt

Moreover, because the resulting magnesium omeprazole dihydrate is crystalline, the rate of dissolution in intestinal fluid is relatively slow, unless the material is milled to a relatively fine particle size.

EP 0124495 also discloses the synthesis of magnesium omeprazole anhydrate by reacting magnesium with methanol to give a solution of magnesium methoxide in methanol. The solution is added to a solution of omeprazole in methanol, the quantity of omeprazole being one mole for each two moles of magnesium. The methanol is then evaporated to give a crystalline solid, which is magnesium omeprazole anhydrate. However, as the magnesium omeprazole precipitates from the solution upon evaporation of the methanol, residual methanol is trapped in the solid particles and cannot easily be removed by evaporation. Methanol is toxic and high levels are generally considered unacceptable in pharmaceutical ingredients and thus it is unlikely that this process would be useful for the preparation of an omeprazole salt that could be employed in a pharmaceutical composition.

In a subsequently filed application, CA2254572, the following comments are made in relation to the process of EPO 124495 :

"This procedure cannot be practised on a large scale because of the need to evaporate to dryness. It has been found that unacceptable and potentially dangerous amounts of methanol become trapped in this solid, making it pharmaceutically unacceptable."

Canadian patent 2166794 (WO 95/01977) describes what is said to be an improved form of magnesium omeprazole dihydrate, which has a higher degree of crystallinity and an improved process for the production of same. However, once again the process proposed is relatively complex in that it involves a number of steps.

Improved processes for the production of magnesium omeprazole crystalline dihydrate are also described in WO 97/41114. The degree of crystallinity of the product of example 1 is said to be 80%. Again, the processes disclosed are relatively complex.

In US 6,048,981 (Macel) a process is employed where omeprazole is dissolved in aqueous ammonia to which various inorganic magnesium salts are added to precipitate magnesium omeprazole. A disadvantage of this process is that the removal of the ammonia and inorganic by-product salts is required.

The US patent application 2002/0188008 by Kohl produces magnesium pantoprazole by reacting a water soluble salt of pantoprazole such as the sodium salt with an inorganic or organic magnesium salt in water or a polar solvent.

The US patent application 2003/0181487 by Kamiyama uses a sodium salt of the PPI lansoprazole to react with inorganic or organic magnesium salts to produce magnesium lansoprazole.

US 6,713,495 (Sherman) discloses a process for producing substantially amorphous magnesium omeprazole by reacting magnesium alkoxide with omeprazole dissolved in a lower alcohol to produce after drying a final product with a low level of alcohol.

US Patent Application 20060189590 (Kohl and Muller) discloses a process for producing Magnesium, Calcium and Zinc Hydroxy salts of PPI' s.

The magnesium product prepared according to the process of the invention can be described by the following formula:

(PPI )_y.(Mg²t)_x(OH-)_z. wherein

PPI is a proton pump inhibitor, x is the whole number 1 or 2; y is the whole number 1, 2 or 3 and z is the whole number 1, 2 or 3 such that y+z=2x,

which can be translated as,

(PPr)₂.(Mg²⁺)₂(OH-)₂, or (PPr)₃.(Mg²⁺)₂(OH-)_L

There is no provision in US Patent Application 20060189590 (Kohl and Muller) for a continuous spectrum of fractional Mg to PPI ratio salts and it is not clear if the products made in US Patent Application 20060189590 are crystalline or amorphous.

The processes used by Kohl and Muller typically use an aqueous solution of the sodium salt of the PPI and sodium hydroxide to which is added magnesium chloride solution. The product requires filtration and washing to remove the sodium chloride impurity before drying. Again, the process disclosed is complex.

BRIEF SUMMARY OF THE INVENTION

The present application discloses a new and simple aqueous process for producing magnesium salts of PPIs that uses no organic solvents or inorganic salts that require removal which avoids or mitigates the problems associated with the above prior art documents and surprisingly have identified certain new and useful magnesium hydroxy salts of PPIs such as omeprazole, pantoprazole, leminoprazole, pariprazole, lanzoprazole, tenatoprazole, rabeprazole and respective isomers thereof. These magnesium and magnesium hydroxy salts thereof have a low degree of crystallinity or are substantially amorphous (non-crystalline), depending on the reaction conditions employed. Accordingly, a first aspect of the invention provides a process for preparing a magnesium or magnesium hydroxy salt of a PPI comprising the steps of: a) reacting a PPI with magnesium hydroxide and/or magnesium oxide in an aqueous environment; and b) removal of water from the product of step a).

hi a second aspect the invention provides a process comprising the steps of: a) premixing powdered magnesium oxide or magnesium hydroxide and a

PPI; b) adding sufficient water to the product of step a) and forming a paste; and c) extruding the product of step b) to provide a granule or pellet.

A third aspect of the invention provides a magnesium or magnesium hydroxy salt of a PPI that is prepared by the process as defined in the first or second aspect of the invention.

A fourth aspect of the invention provides a magnesium hydroxy salt of a PPI having the formula:

(PPr)_x.Mg²⁺(OH-)_2-x.(H₂O)_z wherein:

PPI is a proton pump inhibitor, x is 0.0001 to 1.9999, z is 0 to 10 preferably 0 to 5, except salts of the formula: (PPr)L(Mg²⁺)I(OIr)₁, (PPr)₁. (Mg²⁺)₂(OH-)₃,

(PPD₂.(Mg²⁺)₂(OH-)₂, or (PPr)₃-(Mg²⁺MOITh.

A fifth aspect of the invention provides a composition comprising one or more salts as defined in the fourth aspect of the invention or obtained by the process defined in the first or second aspects of the invention together with one or more excipients or carriers. A sixth aspect of the invention provides a pharmaceutical composition comprising one or more pharmacologically compatible salts as defined in the fourth aspect of the invention or obtained by the process defined in the first or second aspects of the invention and one or more pharmaceutically acceptable auxiliaries.

A seventh aspect of the invention provides a method of treating gastrointestinal disorders, especially those described herein, in a human or animal by administering to a human or animal in need thereof a therapeutically effective amount of one or more pharmacologically compatible salts as defined in the fourth aspect of the invention or obtained by the process defined in the first or second aspects of the invention.

An eighth aspect of the invention provides a use of one or more salts as defined in the fourth aspect of the invention or obtained by the process defined in the first or second aspects of the invention for the manufacture of a medicament for the treatment of gastrointestinal disorders, especially those described herein.

A BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the brucite structure of amorphous magnesium hydroxide, wherein the large spheres represent hydroxyls and the small spheres represent magnesium.

Figure 2 shows the orientation of hydroxyls in relation to magnesium atoms in a single "unit" (part a), from which the brucite structure is made up, and how several of these units fit together (part b).

DETAILED DESCRIPTION OF THE INVENTION

The magnesium and magnesium hydroxy salts of PPIs can be made by direct reaction of amorphous magnesium hydroxide with the PPIs in an aqueous system. Amorphous magnesium oxide is produced by addition of magnesium oxide to water.

Despite the generally low relative solubility of both magnesium hydroxide and PPIs in water the reaction and ion exchange if given sufficient time is complete. The process allows for the preparation of magnesium salts of PPIs₅ and magnesium hydroxy salts of PPIs. Preferably the process is employed to provide magnesium hydroxy salts of PPIs.

In the context of this specification the magnesium hydroxy salts of PPIs are not considered to be the same a magnesium Hydroxy PPI salts since Hydroxy PPIs is a distinct class of PPIs₅ which themselves form salts with magnesium.

Advantageously the process according to the invention is simple, can be performed on a commercial scale, does not involve the use of organic solvents which can be environmentally damaging, require careful disposal and are often toxic and flammable.

The process also does not require removal of by product salts.

Furthermore, these advantages may lead to cost savings, which are clearly beneficial, especially when the process is performed on a commercial scale.

The magnesium hydroxy salts of PPIs according to the invention provide a viable alternative to the magnesium salts currently used. Furthermore, it seems that when the magnesium hydroxy salts of the PPI according to the invention are formulated as an oral dosage form, such as a tablet, the salt form improves formulation stability and shelf life and may provide some protection for the PPI from the acid environment of the stomach and therefore may assist in ensuring the PPI reaches its intended therapeutic target.

Magnesium hydroxide is usually classified as being amorphous and is characterized by a sheet like structure which in mineralogical terms is called a brucite structure an integral part of which are sheets of OH ions coordinated by magnesium ions. The brucite sheets (Fig 1) consist of two layers of hydroxyl ions in hexagonal closest packing with magnesium ions occupying the interstices. The radius ratio of magnesium to hydroxyl is such that 6-fold coordination of hydroxyl about magnesium has maximum stability. Hence, the hydroxyl ions may be regarded as occupying the apices of a regular octahedron (Fig. 2 a) with the magnesium ion at its centre. The brucite sheet may then be visualized as made up of these octahedral tipped over and placed together so that certain of the faces are coplanar (Fig 2 b).

Figure 1 reveals that the magnesium ions in the resulting sheet form a pattern of interlocking hexagonal rings such that the magnesium ion fall at the centre of each ring of six hydroxyl ions. Hydroxyl ions are shared between adjacent octahedral so that there are three magnesium ions for each octahedron of hydroxyl ions. The brucite sheets are widely spaced from each other and easily separated.

This sheet like structure seems to lend itself to ion exchange and ready adsorption of organic anionic molecules on the brucite sheets. Thus whilst not wishing to be bound by theory, it is thought that this special sheet like structure readily undergoes ion exchange with PPI under aqueous conditions to form a range of magnesium hydroxy salts of PPIs or coordination compounds. The reaction kinetics may be slower than some of the traditional published methods but the simplicity of the reaction compensates for this.

Magnesium hydroxide is practically insoluble in water but is sufficiently soluble to participate in an ion exchange process.

In the process of manufacturing the magnesium hydroxy salts of PPI according to the present invention, magnesium oxide is reacted with high purity water to form an amorphous magnesium hydroxide suspension in the water.

The amount of water used in the process can be varied to suit the processing equipment design and typically a paste may contain from about 5% to about 25% water and a suspension may contain from about 25% to about 99% water.

Thus in one aspect the process of the invention comprises the further step of reacting magnesium oxide in water to form the amorphous magnesium hydroxide suspension. This may require adequate mixing, which may take from 1 to 30 minutes up to 4 hours. The PPI is then added in quantities of 0.0001 to 1.9999 moles per mole of magnesium hydroxide or 0.1% to 96% by weight of PPI to magnesium hydroxide.

Generally the step of reacting the magnesium hydroxide with the PPI is performed for 1 to 8 hours and possibly up to 24 hours depending on a number of factors including processing equipment design, temperature, degree of agitation, water content and viscosity of the suspension or paste etc. The step of reacting the magnesium hydroxide with the PPI can be performed at a temperature in the range 0 to 100°C, preferably 0 to 3O⁰C, particularly 10 to 3O⁰C.

The removal of the water is required to recover the solid magnesium hydroxy salt of the PPI. The resulting material is substantially amorphous (non-crystalline). In particular an aqueous amorphous magnesium hydroxide suspension can be reacted with the PPI to produce magnesium hydroxy salts of omeprazole, pantoprazole, leminoprazole, pariprazole, lanzoprazole, tenatoprazole, rabeprazole and respective isomers thereof.

The terms "proton pump inhibitor", "PPI", "benzimidazole", and "benzimidazole compound", have the same meaning and can be used interchangeably, in the context of this specification.

Suitable benzimidazole compounds that can be employed as PPI in processes or salts according to the present invention include those of Formula 1:

Formula 1 wherein R_a is:

R¹ and R³ 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

R⁴ and R⁵ 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 R⁸ is lower alkyl or lower alkoxy. Lower alkyl and lower alkoxy in the context of this specification means C_1-6 alkyl or alkoxy. Halogen includes fluoro, chloro, bromo and iodo.

Preferably the PPI employed in the present invention is rabeprazole, omeprazole, s- omeprazole (esomeprazole), r-omeprazole, lansoprazole, leminoprazole, pariprazole, pantoprazole, tenatoprazole or a mixture thereof, especially omeprazole, s-omeprazole (esomeprazole) or r-omeprazole.

The product obtained from performing the process according to the invention can be modified by varying the ratio, for example the molar ratio, of magnesium oxide or magnesium hydroxide to that of the chosen PPI, and by varying the PPI chosen.

Amorphous magnesium salts of PPI can be prepared by using a molar ratio of 1 to 2 of magnesium hydroxide to PPI.

The magnesium hydroxy salts of PPIs prepared according to the process of the invention can be described by the following formula:

(PPr)_x.Mg²⁺(OH-)_2-x.(H₂O)_z

wherein:

PPI is a proton pump inhibitor, x is 0.0001 to 1.9999, and z is 0 to 10, preferably 0 to 5,

with the exception of salts of the formula:

(PPr)₂.(Mg²⁺)₂(OH-)₂, or (PPr)₃-(Mg²⁺MOIT)₁. For the purposes of this specification omeprazole has been chosen as a typical example of the PPIs but is not limiting.

The term "omeprazole" as used in this specification designates the neutral form of the compound that is the form without a salt-forming cation present.

Thus the invention provides a salt of formula 2

Formula 2

wherein: x is 0.0001 to 1.9999, and

"Magnesium hydroxy salt of PPIs" especially in respect of omeprazole, for example as given by Formula 2 above also forms a preferred aspect of the invention.

The molecular weight of magnesium oxide is 40.30 and magnesium hydroxide 58.32 and the molecular weight of omeprazole is 345.42. Since magnesium is divalent, the amount of magnesium oxide or magnesium hydroxide required to convert 345.42 grams of omeprazole to a magnesium salt of omeprazole is 20.15 grams of magnesium oxide or

29.16 grams of magnesium hydroxide. This is the "Theoretical Magnesium Hydroxide

Requirement". Hence 58.34 grams of magnesium oxide or 84.42 grams of magnesium hydroxide is needed to convert 1000 grams of omeprazole to the magnesium salt of omeprazole. The omeprazole content of this magnesium salt of omeprazole is 96.6% on an anhydrate or dry basis as shown in Formula 3:

Formula 3

and 92.7% on a di-hydrate basis as shown in Formula 4:

Formula 4

Magnesium salts of PPIs particularly salts of omeprazole containing magnesium oxide or magnesium hydroxide in excess of their "Theoretical Magnesium Hydroxide Requirement" or having an omeprazole content less than 96.6% on an anhydrate basis, which is a lower omeprazole content than known magnesium salts of omeprazole are a preferred aspect of the invention. In the case of other PPIs with different molecular weights the % of the PPI in the corresponding magnesium salt according to the invention will be different. As another example Pantoprazole with a higher molecular weight than omeprazole of 432.4 will contain 97.3% Pantoprazole in the anhydrate magnesium salt. Accordingly, the PPI content in the corresponding magnesium salt according to the invention can be in the range of about 0.01% to about 98% by weight.

Although the discussion below refers to magnesium and magnesium hydroxy salts of the commonly available PPI, omeprazole, as non-limiting examples, it is to be understood that the discussion also pertains to PPIs other than omeprazole. Typically a range of magnesium hydroxy salts of omeprazole containing from less than 96.6% say 96.5% down to very low therapeutic levels of less than 1% can be produced.

Daily dosage of the magnesium and magnesium hydroxy salts of the PPIs according to the invention can vary from about 0.1 to about 100 mg/kg of body weight based on the PPI and the type of formulation desired. Lower dosages are contemplated for parenteral treatment. Typically for human and animal therapeutic doses of 1 to 4 mg of omeprazole per Kg of body weight depending upon formulation style, bioavailability and medical condition requirements is employed. A formulation might typically incorporate magnesium hydroxy salts of omeprazole containing from 2% to 96.5 % omeprazole.

Where % terms are expressed these are on a weight-weight basis.

Increasing the ratio of magnesium hydroxide to omeprazole in the salt products of the invention will provide a greater protective effect on the omeprazole during storage and during transit through an acidic in vivo environment, particularly of the stomach.

The magnesium salts or magnesium hydroxy salts of omeprazole produced by this process can be dried by filtration, flash-evaporation, conventional oven, a fluid bed drier, or under vacuum to remove the water.

The drying processes can be controlled to produce a magnesium hydroxy salt of omeprazole which will be anhydrous. However, anhydrous magnesium hydroxy salt of the omeprazole are hygroscopic and will readily absorb water from air until they reach an equilibrium water content of about 1% to 8%, depending on the ratio of magnesium hydroxide to omeprazole in the magnesium hydroxy salt of omeprazole and the relative humidity of the air. This is not problematic, as it does not adversely affect stability.

Alternatively the water could be removed by spray drying the mixture. However, this can increase the processing costs.

The magnesium hydroxy salts of omeprazole are best characterized by assaying their omeprazole content which is readily measured by conventional High Performance Liquid Chromatographic methods.

The degree of crystallinity of the magnesium salts of omeprazole has been used to describe the products in various patents but is not relevant for the magnesium hydroxy salts of omeprazole of the invention which are mostly amorphous.

The amorphous nature and degree of crystallinity of the obtained products can be measured with powder X-ray diffraction (XRD), by methods well known to those in the relevant art. A thin layer of the triturated sample is smeared onto a cut silicon single crystal zero background holder which is rotated during the measurement. Cu K. alpha, radiation and constant or automatic antiscatter and divergence slits are used to obtain a diffractogram with 2.theta. from 1 or 2.degree. to at least 35. degree. The degree of crystallinity is calculated with the formula degree of:

crystallinity= 100+C/(A+C) where: C=the area from the peaks in the diffractogram ("the crystalline area"), and A=the area between the peaks and the background ("the amorphous area").

Area calculations are performed for 2.theta. between 4-33. degree. The lowest intensity value found in this interval is chosen as the constant background and subtracted from the area A. When constant slits are used, the increased background at low angles due to the influence from the primary beam is also subtracted from the area A. The degree of crystallinity of salts of the invention particularly the magnesium hydroxy salts of omeprazole is under 67%.

The degree of crystallinity will preferably be under 75%, less than 60%, preferably less than 50%, more preferably less than 40% such as less than 30%, even more preferably less than 25%, particularly less than 20%, especially less than 10% and particularly substantially amorphous.

The salts of PPIs such as omeprazole of the present invention can be administered orally, parenterally or percutaneously. Such compositions comprising one or more salts of PPIs of the present invention include, for example, tablets, aqueous or non-aqueous pastes such as oil based pastes for oral administration, capsules, powders, granules, suppositories, plasters (for example as TTS), emulsions, suspensions and solutions. The composition can be an immediate, controlled, delayed or sustained release formulation. The auxiliaries, excipients or carriers suitable for the desired compositions are known to the person skilled in the art. In addition to gums, sugars, starch, enteric coating agents, solvents, gel formers, suppository bases, tabletting auxiliaries and other carriers for active compounds, it is possible to use, for example, anti-oxidants, dispersants, emulsifiers, antifoams, flavour-masking agents, preservatives, solubilizers, colorants or, in particular, permeation promoters or complex formers (for example cyclodextrins) or mixtures thereof. Tablets can be multilayerd and will preferably have one or more enteric coats to protect the salts of omeprazole according to the invention from the effects of gastric acid. The salts of the PPIs according to the invention can also be formulated into tablets or water dispersible powders without enteric coating using an in vivo stabiliser such as Zipper Technology as disclosed in co-pending Australian patent application No. 2005906409. The pharmaceutical preparations may also comprise one or more pharmacologically active compounds selected from the group consisting of tranquilizers (for example from the group of the benzodiazepines), spasmolytic drugs (e.g. bletamiverine or camylofine), anticholinergic drugs (e.g. oxyphencyclimine or phencarbamide), local anaesthetics (e.g. tetracaine or procaine), optionally also enzymes, vitamins or amino acids, antacids cimetidine, ranitidine, P-CAB inhibitors, gastrin antagonists, NSAIDs or antibacterial substances for controlling Helicobacter pylori. Magnesium hydroxy salts of omeprazole with a higher ratio of magnesium hydroxide to omeprazole will have a higher buffering capacity increasing the protection of the omeprazole in formulations.

Alternatively the salts of the present invention may be formulated as a paste for administration to subjects who have difficulty swallowing tablets such as horses.

The salts of PPIs according to the invention are suitable for use in human and veterinary medicine for the treatment or prevention of gastrointestinal disorders including gastric acid related disorders and gastrointestinal inflammatory diseases including, for example gastritis, gastric ulcer, duodenal ulcer, Ulcus ventriculi, Ulcus duodeni, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease or IBD. The gastrointestinal disorders may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, medicaments (for example certain antiphlogistics, NSAIDS and antirheumatic drugs), chemicals (for example ethanol), gastric acid or stress. The salts of PPIs according to the invention can also be used to treat a human or animal exhibiting slow metabolisation.

The invention will be further understood from the following examples, which are intended to be illustrative and not limiting of the invention.

EXAMPLES

EXAMPLE 1 Magnesium Hydroxy Salt of Omeprazole containing 91% Omeprazole.

64.7 gms of pharmaceutical grade light magnesium oxide is added to 130 mis of pharmaceutical quality water, stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

Add to the suspension of magnesium hydroxide 1000 grams of omeprazole stir thoroughly to make a thick paste. This may require a high shear mixer to mix well. To make a thinner paste or suspension which can be mixed with a low shear mixer, increase the water addition from 13OmIs to 150OmIs.

Allow the mixture to react and ion exchange for 2 to 8 hours or longer. Reaction temperatures can be 0 to 100°C with the preferable temperature in the 10 to 30°C range.

After reaction is complete the product is dried at ambient temperature.

Yield of magnesium hydroxy salt of omeprazole is 1094 grams containing 1000 gms of omeprazole or 91.4% omeprazole.

The product can then be ground, milled, micronised or otherwise comminuted to an appropriate particle size to suit formulation requirements.

EXAMPLE 2

Magnesium Hydroxy Salt of Omeprazole containing 88.7% Omeprazole. 87.5 gms of pharmaceutical grade light magnesium oxide is added to 180 mis of pharmaceutical quality water stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

Add to the suspension of magnesium hydroxide 1000 grams of omeprazole stir thoroughly to make a thick paste. This may require a high shear mixer to mix well.

To make a thinner paste or suspension which can be mixed with a low shear mixer, increase the water addition from 180mls to 1500mls.

After reaction is complete the product is dried at ambient temperature. Yield of magnesium hydroxy salt of omeprazole is 1127 gms containing 1000 gms of omeprazole or 88.7% omeprazole.

EXAMPLE 3

Magnesium Hydroxy Salt of Omeprazole containing 85.5% Omeprazole. 116.7 gms of pharmaceutical grade light magnesium oxide is added to 250 mis of pharmaceutical quality water, stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

To make a thinner paste or suspension which can be mixed with a low shear mixer, increase the water addition from 25OmIs to 160OmIs.

After reaction is complete the product is dried at ambient temperature.

Yield of magnesium hydroxy salt of omeprazole is 1169 gms containing 1000 gms of omeprazole or 85.5% omeprazole.

EXAMPLE 4

Magnesium Hydroxy Salt of Omeprazole containing 54.2% Omeprazole. 583.4 gms of pharmaceutical grade light magnesium oxide is added to 1200 mis of pharmaceutical quality water stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

To make a thinner paste or suspension which can be mixed with a low shear mixer, increase the water addition from 120OmIs to 200OmIs.

Allow the mixture to react and ion exchange for 2 to 8 hours or longer. Reaction temperatures can be 0 to 100⁰C with the preferable temperature in the 10 to 30°C range.

After reaction is complete the product is dried at ambient temperature.

Yield of magnesium hydroxy salt of omeprazole is 1844 gms containing 1000 gms of omeprazole or 54.2% omeprazole.

EXAMPLE 5

Magnesium Hydroxy Salt of Omeprazole containing 37.2% Omeprazole. 1166.8 gms of pharmaceutical grade light magnesium oxide is added to 2400 mis of pharmaceutical quality water, stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

1000 grams of omeprazole is added to the suspension which is stirred thoroughly and allowed to react and ion exchange for 2 to 8 hours or longer. The reaction temperature is in the range of 10 to 30°C.

After reaction is complete the product is dried at ambient temperature. Yield of magnesium hydroxy salt of omeprazole is 2688 gms containing 1000 gms of omeprazole or 37.2% omeprazole.

EXAMPLE 6

Magnesium Hydroxy Salt of Omeprazole containing 19.1% Omeprazole. 2917 gms of pharmaceutical grade light magnesium oxide is added to 6000 mis of pharmaceutical quality water, stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide.

1000 grams of omeprazole is added to the suspension which is stirred thoroughly and allowed to react and ion exchange for 2 to 8 hours or longer. The reaction temperature is in the range 10 to 30°C.

After reaction is complete the product is dried at ambient temperature.

Yield of magnesium hydroxy salt of omeprazole is 5221 gms containing 1000 gms of omeprazole or 19.1% omeprazole.

EXAMPLE 7

Magnesium Hydroxy Salt of Omeprazole containing 10.6% Omeprazole.

5834 gms of pharmaceutical grade light magnesium oxide is added to 12,000 mis of pharmaceutical quality water, stirred and reacted for 1 to 4 hours to produce a suspension or paste of amorphous magnesium hydroxide. 1000 grams of omeprazole is added to the suspension which is stirred thoroughly and allowed to react and ion exchange for 2 to 8 hours or longer. The reaction temperature is in the range of 10 to 3O⁰C.

After reaction is complete the product is dried at ambient temperature.

Yield of magnesium hydroxy salt of omeprazole is 9443 gms containing 1000 gms of omeprazole or 10.6% omeprazole.

EXAMPLE 8 Reaction Bv Extrusion 1 kg of light magnesium oxide powder and 500 gms of omeprazole were premixed. 500 mis to 1 litre of water is added to the premix. The resultant material is then reacted by extrusion on a self cleaning twin screw Reactor-Extruder to produce a granular or pelletised product. Reactor retention times should be adjustable to ensure the reaction is complete before the final die extrusion stage.

The moist granules or pellets are then dried. The product of this Example is suitable for direct therapeutic use or it can be processed further for incorporation into other types of formulations.

EXAMPLE 9

Magnesium Hydroxy Salt of Omeprazole Tablet

The following ingredients were mixed together in the proportions shown:

Magnesium Hydroxy Salt of Omeprazole minus 200 mesh (particle size) Containing 10% Omeprazole 200 mg Anhydrous lactose 141 mg

Croscarmellose sodium 6.0 mg

Magnesium stearate 3.0 mg Total: 350 mg.

The mixture was compressed into tablets having a weight of 350 mg per tablet, so that each tablet contained 200 mg of magnesium hydroxy salt of omeprazole containing 10% omeprazole, which is equivalent to a label claim of about 20 mg of omeprazole.

The tablet can be coated as follows:

A sub-coating comprising hydroxypropyl methylcellulose dissolved in water is applied to the tablets by spray-application in a side-vented coating pan.

An enteric coating is then applied over the sub-coating by spray-application of methacrylic acid copolymer aqueous dispersion, with triethyl citrate dissolved therein as plasticizer.

EXAMPLE 10 Magnesium Hydroxy Salt of Omeprazole Paste

The following ingredients are mixed together in the proportions shown:

Magnesium Hydroxy Salt of Omeprazole minus 200 mesh (particle size) Containing 50% Omeprazole 500 gms

Olive Oil or MCT Oil 420 gms Aerosil 200 80 gms

Total: 1000 gms.

This mix contains 250 mg of omeprazole per gm of paste.

Take 500 gms of magnesium hydroxy salt of omeprazole containing 50% omeprazole, which is equivalent to about 250 gms of omeprazole add to 420 gms of oil then add 80 gms of Aerosil to form a paste.

The paste may be administered to animals directly or incorporated into a capsule for human application. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and 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 in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification individually or collectively, and any and all combinations of any two or more of said steps or features.

Claims

The claims defining the invention are as follows:

1. A process for preparing a magnesium or magnesium hydroxy salt of a PPI comprising the steps of: a) reacting a PPI with magnesium hydroxide and/or magnesium oxide in an aqueous environment; and b) removal of water from the product of step a).

2. A process of claim 1 where the PPI is omeprazole, hydroxy omeprazole, s-omeprazole (esomeprazole), r-omeprazole, pantoprazole, lanzoprazole, leminoprazole, rabeprazole, tenatoprazole, mixtures thereof, or respective isomers thereof.

3. A process according to claim 2 wherein the PPI is omeprazole, s-omeprazole (esomeprazole), or a mixture thereof.

4. A process according to claim 2 wherein the PPI is pantoprazole, s-pantoprazole, r- pantoprazole or a mixture thereof.

5. A process according to claim 2 wherein the PPI is rabeprazole, s-rabeprazole, r- rabeprazole, or a mixture thereof.

6. A process according to claim 2 wherein the PPI is lansoprazole, s-lansoprazole, r- lansoprazole or a mixture thereof.

7. A process according to any one of claims 1 to 6 where the PPI is added to an aqueous suspension, paste or slurry of amorphous magnesium hydroxide.

8. A process according to claim 7 where the aqueous suspension, paste or slurry of the magnesium hydroxide is stirred or mixed prior to adding the PPI.

9. A process according to claim 8 where the mixing or stirring is performed for about 1 minute to 4 hours.

10. A process according to any one of claims 1 to 9 wherein the reaction of the PPI with magnesium hydroxide is performed from 1 to 24 hours.

11. A process according to claim 10 wherein the reaction of the PPI with magnesium hydroxide is performed up to 8 hours.

12. A process according to any one of claims 1 to 11 wherein the water is removed by filtration, flash-evaporation, evaporation, conventional oven, spray drying, use of a fluid bed drier and/or drying under vacuum to recover the salt of the PPI.

13. A process according to any one of claims 1 to 6 wherein the PPI and magnesium hydroxide and/or magnesium oxide are premixed before the addition of water.

14. A process according to claim 13, wherein the water is added with further mixing and if necessary the mixture is extruded to provide a product.

15. A process according to any one of the claims 1 to 14 wherein the amount of water used to prepare a paste is from about 5% to about 25% and the amount of water used to prepare a suspension is from about 25% to about 99%.

16. A process according to any one of claims 1 to 15 wherein the product of the process is sieved, milled or ground to a powder or granules.

17. A process according to any one of claims 1 to 16 wherein during the process formulation excipients are incorporated.

18. A process according to claim 17 wherein the formulation excipients are selected from gums, sugars, starch, enteric coating agents or a mixture thereof.

19. A process according to any one of claims 1 to 18 where the PPI content of the product of the process is in the range of about 0.01% to about 98% by weight.

20. A process according to any one of claims 1 to 19 wherein the crystallinity of the product of the process is less than 75%;

21. A process according to claim 20 wherein the crystallinity is less than 60%.

22. A process according to claim 20 wherein the crystallinity is less than 50%.

23. A process according to claim 20 wherein the crystallinity is less than 40%.

24. A process according to claim 20 wherein the crystallinity is less than 30%.

25. A process according to claim 20 wherein the crystallinity is less than 20%.

26. A process according to claim 20 wherein the crystallinity is less than 10%.

27. A salt of a PPI obtainable by the process as defined in any one of claims 1 to 26.

28. A magnesium hydroxy salt of a PPI having the formula:

(PPr)_x.Mg²⁺(OH-)_2-χ.(H₂O)_z wherein:

PPI is a proton pump inhibitor, x is 0.0001 to 1.9999, z is 0 to 10, except salts of the formula: (PPI-)i.(Mg²⁺)i(OH-)i, (PPr)₁-(Mg²⁺MOIT)₃,

(PPr)₂-(Mg²⁺HOHT)₂₅ or (PPr)₃. (Mg²⁺MOIT)₁.

29. A salt according to claim 28 wherein z is 0 to 5.

30. A salt according to claims 28 or 29, wherein the PPI is selected from the group consisting of omeprazole, s-omeprazole (esomeprazole), r-omeprazole, lansoprazole, leminoprazole, pantoprazole, rabeprazole, tenatoprazole, hydroxy- omeprazole, mixtures thereof and respective isomers thereof.

31. A salt according to claim 30, wherein the PPI is omeprazole, esomeprazole or a mixture thereof.

32. A salt according to any one of claims 28 to 31 wherein the crystallinity is less than 60%.

33. A salt according to claim 32 wherein the crystallinity is less than 50%.

34. A salt according to claim 32 wherein the crystallinity is less than 40%.

35. A salt according to claim 32 wherein the crystallinity is less than 30%.

36. A salt according to claim 32 wherein the crystallinity is less than 20%.

37. A salt according to claim 32 wherein the crystallinity is less than 10%.

38. A salt according to any one of claims 28 to 31 which is substantially amorphous.

39. A salt according to any one of claims 28 to 38 which is ground, milled, micronised or otherwise comminuted.

40. A composition comprising one or more salts as defined in any one of claims 28 to 39 or obtained by the process as defined in any one of claims 1 to 26, together with one or more excipients or carriers.

41. A composition according to claim 40 in the form of a solid dosage.

42. A composition according to claim 41 wherein the solid dosage is a tablet, capsule or powder.

43. A composition according to claim 42 wherein the tablet is multilayered.

44. A composition according to claim 43 wherein the tablet has an enteric coating.

45. A composition according to claim 40 wherein the composition is in the form of granules.

46. A composition according to claim 40 or 45 wherein the composition is in the form of an aqueous or non-aqueous paste.

47. A composition according to claim 40 wherein the composition is in the form of a liquid suspension.

48. A composition according to any one of claims 40 to 47 wherein the composition is a controlled release formulation.

49. A composition according to any one of claims 40 to 48 wherein the PPI is omeprazole or esomeprazole.

50. A composition according to any one of claims 40 to 48 wherein the PPI is pantoprazole or an isomer of pantoprazole.

51. A composition according to any one of claims 40 to 48 wherein the PPI is lansoprazole or an isomer of lansoprazole.

52. A composition according to any one of claims 40 to 48 wherein the PPI is rabeprazole or an isomer of rabeprazole.

53. A pharmaceutical composition comprising one or more pharmacologically compatible salts as defined in any one of claims 28-39 or obtained by the process as defined in any one of claims 1 to 26 and one or more pharmaceutically acceptable auxiliaries.

54. A method of treating gastrointestinal disorders in a human or animal comprising administering to the human or animal in need thereof a therapeutically effective amount of one or more pharmacologically compatible salts as defined in any one of claims 28-39 or obtained by the process as defined in any one of claims 1 to 26.

55. Use of one or more salts as defined in any one of claims 28 to 39 or obtained by the process as defined in any one of claims 1 to 26 for the manufacture of a medicament for the treatment of gastrointestinal disorders.