AU2006230974B2 - Benzimidazole formulation - Google Patents

Abstract

A dry manufacturing process for the production of a pharmaceutical formulation of a benzimidazole and an alkaline substance is described. A tablet is compressed directly from a dry powder or a dry particulate matter avoiding any liquid or excipient conventionally used as a wet binder. The manufacturing process has the advantage of being simple and cost efficient. At the same time an expensive drying step is superfluous. The resulting pharmaceutical formulation has a good stability and a good dissolution profile.

Description

WO 2006/105798 PCT/DK2006/000409 BENZIMIDAZOLE FORMULATION FIELD OF INVENTION The present invention relates to the field of pharmaceutical formulation science. In 5 particular, the present invention relates to pharmaceutical formulations comprising acid labile benzimidazoles. The invention provides cost-effective production methods providing stable formulations. BACKGROUND Due to the acid labile nature of the benzimidazoles it is necessary to protect the drug 10 substance from exposure to acids, especially in the presence of humidity. In the first stage, the benzimidazole has to be protected from acid attack during storage of the drug. In the prior art, this is provided by contacting the benzimidazole with an alkaline substance present in the pharmaceutical formulation. In the next stage the benzimidazole must be protected from acid attack in the stomach. The person skilled in the art will realise that this 15 can be achieved by applying an enteric coating. Itsis however acknowledged in the art that an enteric coating will introduce a stability problem in that commonly used enteric coatings are acidic by nature. This stability problem is described in EP 0244380 (Hassle). Applying a neutral subcoating for protection of the acid labile benzimidazole was suggested by EP 244 380 for solving the stability problem. 20 Wet granulation techniques are traditionally employed in such formulation approaches. EP 0244380 e.g. discloses use of conventional granulation process, wherein a wet binder is used as well as an aqueous granulation liquid. EP 0589981 e.g. discloses use of polyvinylpyrrolidone as a wet binder. 25 WO 05009410 (Dr. Reddy's) discloses an enteric coated benzimidazole formulation, wherein the tablets are arrived at via different combinations of wet mixing and dry mixing. Example 7 e.g. discloses dry mixing and compression of esomeprazole and magnesium oxide. 30 WO 9850019 (Sage) discloses an enteric coated formulation comprising omeprazole or lanzoprazole. In Example 2C, ten grams of omeprazole were mixed with pharmaceutical excipient lactose anhydrous USP/NF and then passed through a screen to obtain a homogenous granule size. In Example 4, it is stated that "The individual core granulation 35 was mixed with lactose and talc or magnesium stearate and compressed into tablets by known pharmaceutical techniques." No stability assays are disclosed with tablets according to Example 2C+4. WO 04075881 (Ranbaxy) discloses an enteric coated formulation comprising rabeprazole 40 and a low viscosity hydroxypropyicellulose optionally in combination with antioxidants produced by a method comprising dry granulation.

2 Several approaches of providing a stable pharmaceutical formulation of benzimidazoles are thus suggested in the art. The suggested manufacturing processes are however relatively laborious. There is thus a need in the art for simple and cost efficient manufacturing methods for producing benzimidazole formulations with good stability properties and good 5 dissolution profiles. There is furthermore a need in the art for obtaining such tablets in a relatively small size for efficient passage and drug delivery in the intestinal tract. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of 10 these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. SUMMARY OF INVENTION 15 The present invention preferably provides a stable and cost-efficient pharmaceutical formulation intended for oral administration and subsequent efficient delivery of the active benzimidazole in the intestinal tract, wherein said formulation has a good shelf life stability and release profile. 20 In particular, the present invention relates to a method for producing a pharmaceutical tablet formulation comprising a benzirnidazole as the biologically active component, wherein: - said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach, 25 - said benzimidazole is further stabilized by an alkaline substance in the tablet, - said method comprising dry granulating steps and dry compressing of tablets, wherein said formulation is further characterized by one or more of the following features: (i) the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry 30 compression steps, (ii) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (iii) the benzimidazole and the alkaline substance have been mixed and dry 35 granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 1:5, (v) the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, 40 (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal-value of 6 or more and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vii) the alkaline substance has a BET-area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, 2A (viii) the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight. The invention furthermore relates to a pharmaceutical tablet formulation comprising a 5 benzimidazole as the biologically active component, wherein: - said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach, WO 2006/105798 PCT/DK2006/000409 3 - said benzimidazole is further stabilized by an alkaline substance in the tablet, wherein said formulation is further characterized by one or more of the following features: (i) the alkaline substance raw material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g, 5 (ii) the alkaline substance raw material is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m2g, (iii) the benzimidazole and the alkaline substance raw material have been mixed and dry granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 10 - 1:5, (v) the alkaline substance raw material has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal value of 6 or more and a BET area of at least about I m 2 /g, 15 (vii) the alkaline substance raw material has a BET-area of at least about 1 m 2 /g, (viii) the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight. The manufacturing process involves only few production steps and the use of any liquid is 20 avoided rendering an expensive drying step superfluous, A liquid can, however, be applicable in the subsequent coating steps providing an enteric coat and optionally a subcoat. .

DETAILED DESCRIPTION OF THE INVENTION 25 In a first aspect, the present invention relates to a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein: - said formulation comprises an enteric coating for protection of the active component from acid attack in the stomach, - said benzimidazole is further stabilized by an alkaline substance in the tablet, 30 wherein said formulation is further characterized by one or more of the following features: (i) the alkaline substance raw material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g, (ii) the alkaline substance raw material is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g, 35 (iii) the benzimidazole and the alkaline substance raw material have been mixed and dry granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0,2 - 1:5, (v) the alkaline substance raw material has a pKa of at least about 10 and a BET 40 area of at least about 1 m 2 /g, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal value of 6 or more and a BET area of at least about 1 m/g, (vii) the alkaline substance raw material has a BET-area of at least about I m 2 /g, (viii) the tablet formulation further comprises a disintegrant in an amount of about 45 1-30% by weight.

4 In a second aspect, the present invention relates to a method for producing a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein: - said formulation comprises an enteric coating for protection of the active component 5 from acid attack in the stomach, - said benzimidazole is further stabilized by an alkaline substance in the tablet, - said method comprising dry granulating steps and dry compressing of tablets wherein said formulation is further characterized by one or more of the following features: (i) the alkaline substance is an alkali metal carbonate with high water solubility 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (ii) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, 15 (iii) the benzimidazole and the alkaline substance have been mixed and dry granulated together prior to dry compression, (iv) the weight ratio of benzimidazole and alkaline substance is from about 1:0.2 1:5, (v) the alkaline substance has a pKa of at least about 10 and a BET area of at least 20 about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vi) if the alkaline substance is polyvalent, said alkaline substance has a pKal-value of 6 or more and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, (vii) the alkaline substance has a BET-area of at least about 1 m 2 /g prior to any dry 25 granulation and/or dry compression steps, (viii) the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight. In another aspect, the invention provides a pharmaceutical tablet formulation comprising a 30 benzimidazole as the biologically active component, said formulation comprising an enteric coating for protection of the active component from acid attack in the stomach, said benzimidazole being further stabilized by an alkaline substance or a mixture of two or more different alkaline substances in the tablet, and the weight ratio of benzimidazole and alkaline substance is from about 1:02 -1.5, characterized in that the alkaline substance 35 raw material has a BET-area of at least about 1 m 2 /g, prior to any dry granulation and/or compression steps and the tablet formulation optionally further comprises a disintegrant in an amount of about 1-30% by weight. In yet another aspect, the invention provides a method for producing a pharmaceutical 40 tablet formulation comprising a benzimidazole as the biologically active component, wherein: - said formulation comprising an enteric coating for protection of the active component from acid attack in the stomach, - said benzimidazole is further stabilized by an alkaline substance or a mixture of two or 45 more different alkaline substances in the tablet, and the weight ratio of benzimidazole and alkaline substance is from about 1:02 -1.5, 4A - said method comprising dry granulating steps and dry compressing of tablets, wherein the benzimidazole and at least one of the alkaline substances have been mixed and dry granulated together prior to dry compression - said formulation is further characterized that the alkaline substance has a BET-area of at 5 least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, and the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight. In a preferred embodiment the benzimidazole is pantoprazole such as pantoprazole sodium 10 hydrate or pantoprazole sodium sesquihydrate. In other preferred embodiments the benzimidazole may be omeprazole or a salt and/or a hydrate thereof, lansoprazole or a salt and/or a hydrate thereof, esomeprazol or a salt and/or a hydrate thereof, aripiprazole or a salt and/or a hydrate thereof, rabeprazol or a salt and/or a hydrate thereof, or timoprazole or a salt and/or a hydrate thereof. 15 In another preferred embodiment, said formulation further comprises other pharmaceutically acceptable excipients such as fillers, dry binders, glidants and lubricants. In a particularly preferred embodiment, said formulation comprises crospovidone as a disintegrant in an amount of from about 5-20%, preferably 7,5-15%, most preferably 10 20 1 3 % by weight. In yet another embodiment, said formulation comprises a subcoat. In a particularly preferred embodiment however, said formulation does not comprise a subcoat. In the Examples it is shown that it is possible according to the present invention to obtain tablet 5 formulations with good stability properties and good dissolution profiles without the laborious steps of applying a subcoat. In yet another preferred embodiment, the alkaline substance is a salt of an organic or an 5 inorganic acid where the anion of the salt is carbonate (C0 3 2 ), hydrogenphosphate (HP0 4 2 ) or phosphate (PO 4 3 ). The alkaline substance may also be a salt of an organic or an inorganic acid where the kation is sodium (Na*), calcium (Ca2+) or magnesium (Mg 2 +). Preferably, the salt of the organic and/or inorganic acid according is sodiumcarbonate (Na 2

CO

3 ), or Calciumcarbonate (CaCO 3 ) trisodiumphosphate (NaPO4), 10 disodiumhydrogenphosphate (Na 2 HPO4), hydrazine or derivatives thereof, lysine or a derivative thereof, arginine or a derivative thereof, or histidine or a derivative thereof. In yet another preferred embodiment, dry granulation is provided by means of a roller compactor. 15 In a final preferred embodiment, the mixture has been subject to sieving prior to tablet compression with a sieve size (Roller compactor) of 1,25 mm or less. It is shown in the examples that relatively small and relatively homogenous particles result in a more accurate dosing of the active compound. Doze accuracy is of particular importance in 20 production of relatively small tablets. In a final aspect, the present invention relates to products produced by the methods disclosed herein. Definitions 25 Pharmaceutical tablet formulation: A pharmaceutical tablet formulation according to the present invention is equivalent to a solid dosis form. Druas: According to the present invention, the drug substance belongs to the group of 30 benzimidazoles or salts and/or hydrates thereof. The benzimidazole is preferably pantoprazole, omeprazole, lansoprazole, timoprazol, aripiprazole, rabeprazol or esomeprazole, as well as pharmaceutically acceptable salts, hydrates and mixtures thereof. Preferably, the benzimidazole is pantoprazole sodium sesquihydrate. Any pharmaceutically acceptable salt can be used. Examples of conventionally used salts are 35 sodium or potassium salts of the drug substance. A pharmaceutical formulation according to the present invention comprises about 1 to 500 mg drug pr. dose; such as 1 to 200 mg; or 1 to 100 mg. Preferably, the unit dose comprises 10-120 mg; 15-100 mg; 15-80 mg, 15-70 mg; 15-60 mg; 15-50 mg; 15-45 40 mg; such as 20, 30, or 40 mg of benzimidazole, preferably pantoprazole.

WO 2006/105798 PCT/DK2006/000409 6 Unit dose is a pharmaceutically formulated unit comprising the dosage of drug substance intended for administration. The dosage unit can be a tablet. Alkaline substance: 5 Due to the acid labile nature of the drug substance, the unit dose comprises an alkaline substance, or a mixture of two or more different alkaline substances, in the core to confer shelf life stability of the pharmaceutical formulation. The alkaline substance according to the present invention may be soluble in water or even 10 practically insoluble in water. E.g., I part of water soluble alkaline substance might be dissolved in about e.g. 100, 50, 30, or 10 parts of water or less. 1 part of alkaline substance with low water solubility may be dissolved in at least about 100, 300, 500, 1000, 10,000 or even more than 10,000 parts of water. This is in contrast to conventional production methods employing wet granulation wherein water soluble alkaline substances 15 are preferred. The rationale behind using water soluble alkaline substances in conventional methods is that water soluble alkaline substances are thought to generate a humid environment with an alkaline pH protecting the active drug substance during disintegration of the tablet in the gastric system. In the present invention it is surprisingly demonstrated in the Examples 6, 8 og 15 that alkaline substances such as calcium carbonate which are 20 practically insoluble in water (1 part in more than 10,000 parts of water according to handbook of Pharmaceutical Excipients, 5 th ed.) may result in stable formulations with good dissolution profiles. It however appears that alkaline substances with low water solubility should preferably have a relatively large BET area (about 1 m 2 /g or more). 25 Generally, alkaline earth metal salts (such as e.g. calcium carbonate, magnesium oxide, magnesium carbonate) tend to have low water solubility. On the other hand, alkali metal salts (such as e.g. sodium carbonate and potassium carbonate) tend to be more water soluble. 30 According to the prior art such as e.g. W005009410 (Dr. Reddy's), ratios between benzimidazole and alkaline substance of about 1:0.17 are disclosed (Examples 1 and 2). On basis of the existing knowledge in the art, the skilled man would thus not expect that it would be possible to use ratios of 1:0.2 and above and definitely not ratios of about 1:0.5 or 1:1 or more since increasing amounts of base would be expected to result in slow 35 dissolution profiles of the active compound. According to the present invention however, the weight ratio between the drug substance and the alkaline substance ranges between 1:0.2 to 1:10, preferably between 1:0.5 and 1:5, and most preferably between 1:1 to 1:5 while surprisingly still providing formulations with a combination of good shelf life stabilities and good dissolution profiles (examples 6, 8, and 15). The weight ratio between 40 the drug and the alkaline substance may thus be about 1:0.2, or 1:0.3, or 1:0,4, or 1:0.5, or 1:0.6, or 1: 0.7, or 1: 0.8, or 1:0.9 or 1:1, or 1:1.5, or 1:2, or 1:2.5, or 1:3, or 1:3.5, or 1:4, or 1:4.5, or 1:5, or 1:6, or 1:7, or 1:8, or 1:9, or 1:10. It is preferred that the pKa of the chosen alkaline material is at least 10. However, this 45 alone is not sufficient. If the alkaline material is polyvalent the pKal, (where pKaI is the WO 2006/105798 PCT/DK2006/000409 7 most acidic pKa value) should be above 6. As shown in ex. 6 the use of tricalcium phosphate which has a pKaI of 2.2 results in a poorer stability than if disodium carbonate (which has a pKaI of 6.4) is used. 5 Alkaline substance preferably having a pKa value of 6 or above. The alkaline substance will typically provide an alkaline pH in the range of 7-12, when being dissolved and/or dispersed in water at room temperature in an amount of about 10-100 mg/ml. Accordingly, the term alkaline substance includes the corresponding base of an organic or 10 an inorganic acid, such as provided In the form of a pharmaceutically acceptable salt of an organic or inorganic acid and/or a mixture thereof, and some amino acids. According to the present invention, it is understood that a pharmaceutical formulation may very well comprise more than one alkaline substance, if appropriate. 15 The alkaline substance raw material is understood to be the alkaline substance prior to any formulation processing steps. Examples of alkaline substances are listed in the following table.

WO 2006/105798 PCT/DK2006/000409 8 Table 1: Examples of alkaline substances Substance Examples Structure pKa* Salt of carbonic acid DiSodium carbonate Na 2

CO

3 10.3 (carbonate) and phosphoric acid Sodium hydrogen NaHCO 3 6.4 (phosphate). Soluble carbonate salts with pKa-values of 9 and above Trisodium phosphate Na 3

PO

4 12.4 Disodium hydrogen Na 2

HPO

4 7.2 phosphate Sodium dihydrogen NaH 2 P0 4 2.2 phosphate Salt of carbonic acid Calcium carbonate CaCO 3 10.3 (carbonate). Practically insoluble with pKa-value of 9 or above Amino acids with pKa 3 - Lysine C 6

H

14 0 2

N

2 pKa 2 : 8.9 Values of 9 or above pKa 3 : 10.3 Arginine C 6

H

14

N

4 0 2 pKa 2 : 9.1 pKa3: 13.2 pHz11.4 (100 g/L H20) Histidine C 6

H

9 0 2

N

3 pKa 3 : 9.0 pH~7.7 (10 g/L H20) * The pKa-values in this table are approximate values and refer to the pKa of the acid. Only relevant pKa values are included. 5 A suitable disintegration time means that the pharmaceutical formulation must comply with the standards set up in the European Pharmacopoeia. Those skilled in the art will appreciate that it is desirable for compressed tablets to disintegrate within 30 minutes, most desirable within 15 minutes upon contact with an aqueous solution, provided that the enteric coating is absent or bursted. Disintegration is preferably performed in a dissolution 10 apparatus such as the Ph.Eur. Basket method as disclosed in e.g. example 11. Furthermore, it should be understood that the alkaline substance should be provided in solid form, such as in the form of a powder, granulate or the like. 15 In connection with the present invention (example 16) it has been demonstrated that different alkaline substances may have different surface areas (BET areas) and that the same compound purchased under different trade names (e.g. calcium carbonate - "Sturcal L" and "Scoralite") may have different BET areas (see the SEM pictures in the figures). It is furthermore demonstrated that alkaline substances with relatively large BET areas (at least 20 about 0.5, 0.6, 0.7, 0.8, 0.9, preferably at least about 1.0, 1.1, 1.2, 1.3, 1.4, and most WO 2006/105798 PCT/DK2006/000409 9 preferably 1.5 m 2 /g or more) tend to result in tablets with improved stability properties while at the same time retaining good dissolution properties (example 15). A plausible explanation for this finding is that porous alkaline substances with relatively large BET areas used as a raw material tend to be crushed into fine particles upon mechanical 5 pressure such as e.g. dry granulation and/or dry compression. In contrast, substances with relatively small BET areas (such as e.g. calcium carbonate purchased under the trade name "Scoralite") tends to either not being affected by mechanical pressure andlor to be crushed into relatively large particles and/or to show a slightly improved distribution of the particles around the drug substance. It is thus preferred to use porous and/or polycrystallic 10 alkaline substances with relative large BET area having a tendency to be crushed into very fine particles upon mechanical pressure. Such alkaline substances in the form of very fine particles in the resulting tablet most likely provide a better "alkaline shield" against acid and humidity attacks of the active compound by providing a close physical contact between the drug and the protective alkaline substance. It is shown in Example 10 that a 15 particularly preferred way of providing a close physical contact and thus a stable tablet with good dissolution profiles is to include a step wherein the two substances are mixed and subsequently dry granulated together prior to compression into a tablet. Pharmaceutical excipients: It is shown in the Examples that it is possible to compress tablets with good stability and 20 dissolution profiles where the only pharmaceutical excipient, apart from the alkaline substance, is minute amounts of MgStearate (example 5). When manufacturing tablets according to the invention in larger scale, such as in production scale, it can however be advantageous to add at least one of the following ingredients: a olidant, a lubricant, a filler, a dry binder, a color, and a disintegrant to the formulation comprising alkaline 25 substance and a benzimidazole. Preferably, the only additional pharmaceutical excipient is a glidant or a lubricant, preferably along with at least one disintegrant, thus providing a simple and cost efficient production method. Examples of clidant and lubricants are stearic acid, metallic stearates, talc, colloidal silica, 30 sodium stearyl fumarate and alkyl sulphates. In the present invention, a dry binder such as e.g. sorbitol, isomalt, or mixtures thereof may be used. The dry binder provides the effect of binding a material and thereby providing a powder that can be compressed into a tablet. 35 A filler substance is any pharmaceutically acceptable substance that does not interact with the drug substance or with other excipients. Commonly used filler substances are: mannitol, Dextrins, maltodextrins (e.g. Lodex@ 5 and Lodex® 10), inositol, erythritol, isomalt, lactitol, maltitol, mannitol, xylitol, low-substituted hydroxypropylcellulose (e.g LH 40 11, LH 20, LH 21, LH 22, LH 30, LH 31, LH 32 available from Shin-Etsu Chemical Co.), starches or modified starches (e.g potato starch, maize starch, rice starch, pre-gelatinised starch), polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, agar (e.g. sodium alginate), , carboxyalkylcellulose, dextrates, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene WO 2006/105798 PCT/DK2006/000409 10 glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide, sodium carbonate, and sodium chloride. A wet binder is an excipient that in combination with water facilitates a powder to be 5 compressed into coherent bodies such as tablets or facilitates a powder to be granulated into a particulate matter. A wet binder must, at least to some extent, be soluble in water. Examples of wet binders are PVP (polyvinylpyrrolidone), HPMC (hydroxymethylpropylcellulose) or gelatine. If a wet binder is used according to the present invention, the wet binder will merely act as a filler and will not exhibit the binding 10 properties normally associated with such wet binders. It will therefore be understood that excipients conventionally regarded as wet binders might be used as mere fillers in the context of the present invention. A disintegrant is a pharmaceutically acceptable substance that improves the disintegration 15 of tablets without interacting with the drug substance or with any other excipients. The disintegrant has the capability of swelling upon contact with water, causing the tablet to swell/disintegrate and thus releasing the active compound. This effect is shown in the Examples (example 18), where dissolution profiles are improved upon addition of disintegrant in the tablet. Traditional wet granulated benzimidazole formulations normally 20 comprise large amounts of disintegrants (at least about 30%) since "wet" production steps cause a significant proportion of the disintegrant to swell and thus irreversibly reducing its swelling capacity. However, in connection with the present invention it has surprisingly been shown that it is possible to obtain a good dissolution profile using relatively small amounts of disintegrant thus enabling production of smaller tablets using more cost 25 efficient methods (disintegrants are often relatively expensive ingredients). Small tablets have the advantage of being easier to swallow, pack, store, transport, etc. Small tablets furthermore improve movement through the gastric system and are less dependent on the gastric emptying. This effect is probably achieved because dry granulation techniques do not result in unwanted preswelling of the disintegrant. It is furthermore shown that it is 30 possible to use water in connection with the subcoating and/or the enteric coating process without causing unwanted preswelling and/or disintegration of the tablets (example 12, figure 8). Examples of commonly used disintegrants are: Alginic acid - alginates, 35 carboxymethylcellulose calcium, carboxymethylcellulose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcel lu lose (HPMC), cellulose derivatives such as low-substituted hydroxypropylcellulose (e.g LH 11, LH 20, LH 21, LH 22, LH 30, LH 31, LH 32 available from Shin-Etsu Chemical Co.) and microcrystalline cellulose, polacrilin , potassium or sodium, polyacrylic acid, polycarbofil, polyethylene glycol, polyvinylacetate, 40 crosslinked polyvinylpyrrolidone (e.g. Polyvidon@ CL, Polyvidon@ CL-M, Kollidon@ CL, Polyplasdone@ XL, Polyplasdone@ XL-10); sodium carboxymethyl starch (e.g. Primogel@ and Explotab@), sodium croscarmellose (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol@), sodium starch glycolate, starches (e.g potato starch, maize starch, rice starch), and pre-gelatinised starch. 45 WO 2006/105798 PCT/DK2006/000409 11 The disintegrant may be present in the tablet in an amount of about 1-30%, preferably 3 25%, more preferably 5-20% and most preferably 10-15%, and even most preferably about 8-1 4 %. 5 Granulation and compression: Powders comprising either the drug in question, the alkaline substance, the pharmaceutical excipient(-s), or any combination thereof are subjected to a dry granulation process. The dry granulation process causes the powder to agglomerate into larger particles having a size suitable for further processing. Dry granulation can'thus be said to improve the 10 flowability of a mixture in order to be able to produce tablets that comply with the demand of mass variation or content uniformity set out in the European Pharmacopoeia. Formulations according to the invention may be produced using one or more mixing and dry granulations steps. The order and the number of the mixing and granulation steps do 15 not seem to be critical. However, it seems to be of importance that at least one of the alkaline substance and the drug has been subject to dry granulation before compression into tablets. Dry granulation of drug and alkaline substance together prior to tablet compression seem, surprisingly, to be a simple, inexpensive and efficient way of providing close physical contact between the alkaline substance and the drug and thus a tablet 20 formulation with good stability properties. Relatively large BET areas of the alkaline raw material do also have a beneficial effect on the stability properties. Dry granulation is carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous 25 solutions, solutions based on organic solutes, or mixtures thereof) in contrast to conventional wet granulation processes. Generally, the mechanical process requires compaction such as the one provided by roller compaction. An example of an alternative method for dry granulation is slugging. 30 Roller compaction is a process comprising highly intensive mechanical compacting of one or more substances. The powder is pressed, that is roller compacted, between 2 counter rotating rollers to make a solid sheet which is subsequently crushed in a sieve to form a particulate matter. In this particulate matter a close mechanical contact between the substance(-s) has been obtained. An example of equipment is Minipactor* or a Gerteis 35 3W-Polygran from Gerteis Maschinen + Processengineering AG. Tablet compression according to the present invention takes place without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof). In a typical embodiment the resulting core or tablet must 40 have a crushing strength in the range of 10 to 150 N; such as 15 to 125 N, preferably in the range of 20 to 100 N. A core is thus provided by compression of a powder or a particulate matter. Typically the core has a weight in the range of 75 mg to 2.5 g; such as 80 mg to 1 g; such as 80 mg to 45 500 mg; such as 100 mg to 300 mg. Preferably, the core is a tablet with a weight in the WO 2006/105798 PCT/DK2006/000409 12 range of 75 mg to 2.5 g; such as 80 mg to 1 g; such as 80 mg to 500 mg; such as 100 mg to 300 mg. In the present invention, the core is further coated with an enteric coat and optionally a subcoat to obtain the desired tablet formulation. 5 Tablets according to the present invention may be smaller than conventional tablets, i.e. having a diameter of about 7, preferably about 6 and most preferably about 5 mm or below. In contrast to tablets with a diameter of e.g. 7.5 mm or above, tablets having a smaller diameter will be able to move freely through the pylorus sphincter into the small intestine and thus be less dependent on the gastric emptying. 10 Subcoating: Any conventionally used water soluble film forming excipient can be used for subcoating such as a sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, 15 polyvinyl acetal diethylenaminoacetate, "Kollicoat IR" (polyvinyl alcohol - polyethylene grycol graft copolymer), etc. Water or any conventionally used organic solvent or a mixture thereof is suitable as a subcoating solvent. It is a general teaching within the field that the subcoat is critical to the stability of the 20 entire formulation. In Sage (WO 9850019) it is e.g. disclosed that the enteric coating and the drug must be separated by a subcoat in order to avoid acid degradation of the drug (page 8, lines 16-30). Even though absence of a subcoat may be suggested in various patent documents (e.g. as a non-enabling statement in WO 04075881 on page 3, line 21) the existing knowledge leads the skilled person to the conclusion that tablets produced 25 without subcoating have a poor drug stability. In contrast to the general teaching, the inventors of the present invention have surprisingly shown that is possible to produce tablets without subcoating having a drug stability compared with tablets with conventional subcoating (table 18 and figure 9). As the subcoating process is laborious and time consuming, a production process according to the present invention without laborious 30 subcoating steps is thus far more cost-efficient while still obtaining a product with the desired stability and dissolution properties, Enteric coating Any conventionally used enteric coating polymer can be used such as cellulose acetate 35 phthalate such as Aquacoat@ CPD (FMC) or C-A-P NF (Eastman Chemical), polyvinyl acetate phthalate such as Sureteric® (Colorcon), carboxymethylethylcellulose, co polymerized methacrylic acid/methacrylic acid methyl esters such as Eudragit@ L 30 D, or Eudragit@ L 12.5 or Eudragit@L 100 (Degussa - Rohm Pharma Polymers) or Kollicoat MAE 30 DP or Kollicoat 1ooP (BASF) or Acryl-Eze (Colorcon) or Eastacryl 30 D (Eastman 40 Chemical) etc. Preferred plasticizers include cetanol, triacetin, citric acid esters such as Citroflex@ (Pfizer), phthalic acid esters, dibutyl succinate, acetylated monoglyceride, acetyltributyl, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate, castor oil, WO 2006/105798 PCT/DK2006/000409 13 cetanol, chlorebutanol, colloidal silica dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethyl succinate, dimethylphthalate, dioctyl phthalate, glycerin, glyceroltributyrate, glyceroltriacetate, glyceryl behanate, glyceryl monostearate, 5 hydrogenated vegetable oil, lecithin, leucine, magnesium silicate, magnesium stearate, polyethylene glycol, propylene, glycol, polysorbate, silicone, stearic acid, talc, titanium dioxide, triacetin, tributyl citrate, triethyl citrate, zinc stearate, PEG (polyethylene glycol), etc. Methods for enteric coating are well known in the art such as described in e.g. (Stuart C. Porter in Remmington 2 1 st Ed. 2005, pp 929), hereby incorporated by reference. 10 Stability Preferably, at least 95% (w/w) of the declared content of drug substance remains in the tablet formulation according to the present invention after storage at 25Co/60 %RH (relative humidity) of a period of 2, 3, 4, or 5 years. Alternatively, the stability can be 15 determined after storage at other conditions according to appropriate ICH guidelines. Methods of assessing stability are described in the Examples. Brief description of drawings 20 Figure 1: Stability test of coated tablets containing Sodium Carbonate, Calcium Carbonate (Sturcal L), or Tri calcium phosphate. Test performed in open petri dishes at 700 and not more than (nmt) 10 % relative humidity. Example 6. Figure 2: Stability test of coated tablets containing Sodium Carbonate or Calcium 25 Carbonate (Sturcal L) in the mixing ratio's of 1:0.2 or 1:0.8. Test performed in open petri dishes at 70* and not more than (nmt) 10 % relative humidity. Example 8. Figure 3: Stability test of coated tablets containing Sodium Carbonate (Sturcal L) 1:0.8 based on different sequential order of mixing and roller compaction. Test performed in 30 open petri dishes at 700 and not more than (nmt) 10 %-relative humidity. Example 10. Figure 4: Particle size distribution using two different sieve sizes (1.25 mm and 1.0 mm) during roller compaction. Example 11. 35 Figure 5: Impact on dose variation of Roller compactor sieve size illustrated by tablet core dissolution. Example 11. Figure 6: Impact on dissolution of amount of subcoat, HPMC E15, applied. Example 12. 40 Figure 7: Impact on dissolution of type of subcoat, HPMC E 5 and HPMC E 15. Evaluated on subcoated tablets. Example 12. Figure 8: Impact on dissolution of type of subcoat, HPMC E 5 and HPMC E 15. Evaluated for enteric coated tablets. Example 12.

14 Figure 9: Stability of batches 13030634 and 31030634 (without the application of a sub coat) at 70 *C in open petri dishes. Example 14. Figure 10: Pantoprazole Sodium Sesquihydrate (SEM picture). 5 Figure 11: Calcium Carbonate (Sturcal L) (SEM picture). Figure 12: Calcum Carbonate (Scoralite) (SEM picture). 10 Figure 13: Sodium Carbonate (SEM picture). Figure 14: Sodium Carbonate (SEM picture). Figure 15: Pantoprazole Sodium Sesquihydrate and Calcium Carbonate (Sturcal L); 15 Mixing followed by slugging (SEM picture). Figure 16: Pantoprazole Sodium Sesquihydrate and Calcium Carbonate (Scoralite) Mixing followed by slugging (SEM picture). 20 Figure 17: Pantoprazole Sodium Sesquihydrate and Sodium Carbonate; Mixing followed by slugging (SEM picture). Figure 18: Pantoprazole Sodium Sesquihydrate and Sodium Carbonate Pre rollercompaction of Pantoprazole, mixing with sodium carbonate, and slugging (SEM 25 picture). Figure 19: Impact of disintegrant on tablet core dissolution. Example 18. It should be noted that, according to the present invention, embodiments and features 30 described in the context of one of the aspects of the present invention also apply to the other aspects of the invention. The following non-limiting examples are meant to illustrate the present invention. Throughout this specification the word "comprise", or variations such as "comprises" or comprising", will be understood to imply the inclusion of a stated element, integer or step, 35 or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. EXAMPLES Example 1 40 Dry manufacture of tablets containing pantoprazole or omeprazole. Dry granulation is followed by compressing the resulting particulate matter into tablets.

WO 2006/105798 PCT/DK2006/000409 15 Table 2 Raw Manufactured bathes, no. Materials 1 2 3 4 5 6 7 8 9 10 11 12 L a+b a+b 1 Pantoprazole 20,0 20.0 20.0 20.0 20.0 20.0 Na 1.5HO 1 Omeprazole 20.0 20.0 20.0 20.0 20.0 20.0 Na 2 CaCO 3 56.4 56.4 56.4 56.4 2 Na 3

PO

4 56.4 56.4 56.4 56.4 2 Na 2

CO

3 56.4 56.4 56.4 56.4 3 Sorbitol 17.6 17.6 17.6 17.6 17.6 17.6 3 Mannitol 17.6 17.6 17.6 17.6 17.6 17.6 4 MCC 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5 Mg-stearate 0.75 0.75 0.75 0.75 0.75 0.75 0 .75 0.75 0.75 0.75 *: Amounts in % w/w Table 3: List of ingredients 1 Pantoprazole sodium sesquihydrate 1 Omeprazole sodium 2 CaCO 3 Sturcal Le 2 Na 3

PO

4 trisodium phosphate 2 Na 2

CO

3 sodium carbonate 3 Sorbitol 3 Mannitol 4 MCC; Cellulose Microcrystalline type 1010 5 Mg-stearate; magnesium stearate 5 The drug substance 1) (having a mean particle size of about 7 pm) was mixed by hand with the alkaline substance 2) and with 3). 10 The resulting mixture of the ingredients 1) to 3) was subjected to roller compaction by use of the following set of parameters: Rpm: 2.0 Gab size 2.5 mm 15 Sieve size 1.25 mm Force 10 kN/cm The resulting particulate matter of the dry granulated ingredients 1) to 3) was admixed with 4) and 5). Thereafter, tablets were compressed of the mixture of ingredients 1) to 5) 20 using a Diaf TM 20 press and 7.5 mm standard concave punch design. Unless otherwise stated, a relatively low compression force was used. Crushing strength and time of disintegration of the obtained tablets were measured by use of a Schleuniger E2 hardness tester (n=10) and a Sotax DT 2 (n=6). Both tests were 25 performed according to the European Pharmacopoeia.

WO 2006/105798 PCT/DK2006/000409 16 Table 4: Crushing strength and disintegration time Batch no. Crushing strength Disintegration time in water [N] [sec.] 1 39.5 291.0 2 39.5 151.0 3 41.3 520.0 4 39.9 457.8 5 41.1 496.5 6 42.1 523.0 7 32.4 281.8 8 30.9 477.5 9 36.0 300 10 38.0 284.7 11a 45.3 269.7 Low Comp. Force 11b 90.6 301.8 High Comp. Force 12a 40.7 256.8 Low Comp. Force 12b 61.7 271.2 High Comp. Force The results from table 4 show that tablets containing pantoprazole or omeprazole having a 5 satisfactory crushing strength and disintegration time can be manufactured from a dry manufacturing process based on a particulate matter provided by dry granulation resulting from roller compaction. Furthermore, batches 11a+b and 12 a+b illustrate that the crushing strength can be 10 increased without any significant influence on the disintegration time. This means that the tablets are of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters. Optionally a sub coat comprising a standard water-soluble film like HPMC (Hydroxypropyl methylcellulose) can be used to protect the enteric coat from the alkaline reacting core. 15 Example 2 Crushing strength and disintegration time resulting from compression of particulate matter based on roller compaction WO 2006/105798 PCT/DK2006/000409 17 Table 5 Raw Materials Manufactured batches, no. ________________13114 1 Pantoprazole sodium 21.3 21.3 sesquihydrate (Mean particle size around 7pm) 2 Na- 3

PO

4 trisodium phosphate 60.0 60.0 3 Sorbitol 18.7 3 Mannitol - 18.7 *: Amounts in % w/w 5 1) was mixed by hand with 2) and 3). The resulting mixture of the ingredients 1) to 3) was roller compacted by use of the following set of parameters: Rpm: 2.0 10 Gab size 2.5 mm Sieve size 1.25 mm Force 10 kN/cm The particulate matter resulting from roller compaction of the ingredients 1) to 3) was 15 compressed into tablets using a Diaf TM 20 press and 7.5 mm standard concave punch design. Crushing strength and time of disintegration of the obtained tablets were measured by use of a Schleuniger E2 hardness tester (n=10) and a Sotax DT 2 disintegrations tester (n=6). 20 Table 6: Crushing strength and disintegration time Batch no. Crushing strength [N] Disintegration time [sec.] 13 42.6 443.0 14 52.6 486.7 The results from table 6 show that tablets containing pantoprazole having a satisfactory crushing strength and disintegration time can be manufactured by compression of a particulate matter provided by a dry granulation process based on roller compacted 25 granulates, without the addition of further excipients (apart from a dry binder). Addition of magnesium stearate could, however, be advantageous in production scale. The tablets are thus of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters. Optionally a sub coat comprising a 30 standard water-soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core. Example 3 Crushing strength and disintegration time of tablets resulting from direct compression of mixtures of pantoprazole and compactable alkaline excipient WO 2006/105798 PCT/DK2006/000409 18 Table 7 Raw material D(v;0.5) 10060531 10060532 [pm] 1 Pantoprazole sodium 7 20.00 20.00 sesquihydrate 2 Trisodium phosphate, 203 79.26 71.34 coarse 2 Trisodium phosphate, 40 7.92 fine 3 Magnesium stearate 0.74 0.74 *: Amounts in % w/w The drug substance 1) and the ingredient 2) were mixed by hand followed by admixing of 5 3). The mixture of ingredients 1) to 3) was compressed into tablets using a Diaf TM 20 press and 7.5 mm standard concave punch design. Crushing strength and time of disintegration of the obtained tablets were measured by use of a Schleuniger E2 hardness tester (n=10) and a Sotax DT 2 disintegration tester (n=6). 10 Table 8: Crushing strength and disintegration time Batch no. Crushing strength [N] Disintegration time Mass variation [sec.] [ s.rel - 0/] 10060531 37.4 657 0.96 10060532 41.2 631 The results shown in table 8 show that tablets containing pantoprazole having a satisfactory crushing strength and disintegration time result from direct compression of the 15 compactable alkaline substance. The mass variation illustrates that the flowability of the mixture of ingredients 1) to 3) is acceptable. It is conceivable that the coarse alkaline substance functions both as a filler substance and an alkaline substance in this formulation. 20 The resulting tablets are of a quality that allows the application of a standard enteric coating using standard coating equipment and parameters. Optionally a sub coat comprising a standard water soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core. 25 Example 4 Manufacture of tablets having a diameter of 5 mm based on a particulate matter resulting from dry granulation in a roller compactor WO 2006/105798 PCT/DK2006/000409 19 Table 9 RawMaterials* 1 2 3 47 8 1 Pantoprazole 40 40 40 40 sodium 1.5H20 1 Omeprazole 40 40 40 40 sodium 2 Na 3 PO4 40 40 40 40 2 Na 2

CO

3 40 40 40 40 3 Sorbitol 18.25 18.25 18.25 18.25 3 Mannitol 18.25 18.25 18.25 18.25 4 Mg-stearate 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 Amounts in %w/w 5 Table 10: List of ingredients 1 Pantoprazole sodium sesquihydrate 1 Omeprazole sodium 2 Na 3

PO

4 trisodium phosphate 2 Na 2

CO

3 sodium carbonate 3 Sorbitol 3 Mannitol 4 Mg-stearate; magnesium stearate The drug substance 1) was mixed by hand with 2) and 3). The resulting mixture of the ingredients 1) to 3) was dry granulated by roller compaction by use of the following set of parameters: 10 Rpm: 2.0 Gab size 2.5 mm Sieve size 1.25 mm Force 10 kN/cm 15 The resulting particulate matter of the dry granulated ingredients 1) to 3) was admixed with 4). The resulting mixture of the ingredients 1) to 4) was compressed into tablets using a 5.0 mm standard concave punch design. The resulting tablets are of a quality that allows applying a standard enteric coat using standard coating equipment and parameters. 20 Optionally a sub coat consisting of a standard water soluble film like HPMC can be used to protect the enteric coat from the alkaline reacting core. Example 5: Dry manufacture of tablets containing pantoprazole and alkaline excipients followed by 25 application of a sub coat and an enteric coating.

WO 2006/105798 PCT/DK2006/000409 20 Table 11: Composition of tablet core % w/w: Batch no. 07030631 10030631 13030634 13030636 "33C" "34C" "35C" "36C" Granulate by roller compaction Pantoprazole, 1W H 2 0 13.3 11.7 14.1 12.9 Sodium carbonate 13.3 55.2 Calcium carbonate - 54.9 (Sturcal L) TriCalciumPhosphate 60.6 Pantoprazole:alkaline excipient 1:1 1:4.7 1:3.9 1:4.7 Mannitol - 13.5 - 14.9 Crospovidone 0.4 1.1 1.1 1.2 Tablet core excipients DiCafos A 62.7 8.5 19.2 Crospovidone 9.7 9.7 10.0 9.8 Mg Stearate 0.5 0.4 0.5 0.5 Table 12: Composition of sub coat [% w/w]: Raw materials Coating liquid Dry film composition composition Hypromellose 15 5 55,6% Propylenglycol 1 11,1% Talc 3 33,3% Water, purified 91 % Plasticizer of polymer 20,0% 5 Table 13: Composition of enteric coat [% w/w]:: Raw materials Coating liquid Dry film composition composition Methacryl acid-acryl 41,76 62,49 Copolymer disp. 30% Triethylcitrate 1,25 6,24 Talc 6,27 31,28 Water, purified 50,92 % Plasticizer of Polymer 10,0 WO 2006/105798 PCT/DK2006/000409 21 Table 17: Approximately amount of film dry matter applied [% w/wJ: Coat 07030631 10030631 13030634 13030636 "33C" "34C" "35C" "36C" Theoretical applied 9,7 10,3 10,9 9,0 amount of sub coat [mg polymer/cm') Theoretical applied 5,5 5,4 5,3 + 2 5,7 amount of enteric coat [mg polymer/cmJ Pantoprazole was mixed with the alkaline excipient in a tumble mixer together with 5 Crosspovidone and mannitol followed by roller compaction as described in example 1. The remaining tablet core excipients were admixed and tablets were compressed by use of a Korsch PH106 tablet press and 6 mm concave punches aiming at a mean weight of 160 mg and a crushing strength of 50 N. Thereafter the tablet cores were coated with the sub coat followed by the enteric coat by use of a lab-scale Combi Coata. The obtained coated 10 tablets were used for stability testing as described in example 6. Example 6 (stability testing) A stability testing program with batches obtained in example 5 was performed. The 15 batches were stored at accelerated stability testing conditions (open petri dishes at 70*C and not more than 10% relative humidity for three months). Such conditions probably correspond to shelf life stability testing of at least two years. The analytical method is as follows: 10 tablets are transferred to a 200 ml volumetric 20 flask. 150 ml mobile phase (the initial composition) is added and sample is shaken for 90 minutes. After the solutions pH-values have been adjusted to 8.0, mobile phase is added to the mark. The sample solution is filtered through 0.45 pm filter and analysed by reverse phase HPLC in order to quantify the amount of Pantoprazole as well as degradation products thereof. The amount is given in % of total area, see table 19. Furthermore, in 25 figure 1 is shown the amount of pantoprazole as a function of time. Table 18: HPLC method parameters Mobile phase ammonium phosphate buffer: methanol:acetonitril Time % Buffer % Methanol /b Acetonitril 0 min 65 10 25 Gradient profile 25 min 30 10 60 30 min 30 10 60 31 min 65 10 25 Flow 1,0 mi/m Column Waters Spherisorb, 250X4,6 mm, 5 pm particle size WO 2006/105798 PCT/DK2006/000409 22 Column temperature 30*C Auto sampler temperature 4 *C Detection UV-290 nm Injection volume 10 p1 Run time 40 min. Pantoprazole 10,7 min Approx. Retention time Impurity B 6,6 min Impurity A 13,4 min Table 19: Results of stability study Batch 07030631 10030631 13030634 13030636 1"33C" '34C" "35C" "36C" Pantoprazole:sodium carbonate 1:1 1:3,9 Pantoprazole:calcium carbonate 1:4,7 Pantoprazole:calcium phosphate 1:4,7 Pantoprazole:DiCafos A 1:4,7 1:0,7 1:1,4 . 25/60 C month 99,7 99,7 99,7 99,2 o C 70/10 OP month 97,4 96,6 97,3 93,9 N 2! ( 70/10 OP 2 months 96,4 95,5 96,1 91,9 70/10 OP 3 months 94,9 94,3 94,6 89,3 r- 40/75 3 months 99,4 99,4 99,5 97,2 25/60 C month 0,18 0,15 0,20 0,56 0 -M 70/10 OP month 2,2 3,2 2,3 6,0 8 70/10 OP 2 months 3,3 4,0 3,6 7,6 70/10 OP 3 months 4,3 4,8 4,4 9,3 40/75 3 months 0,5 0,5 0,5 2,6 70/10 OP: 70 *C / 10 % RH in Open petri dishes 5 25/60: 25 *C/ 60% RH in closed containers 40/75: 40 *C / 75% RH in closed containers According to table 19 and figure 1, use of Ca 5 (P0 4

)

3 OH as alkaline substance result in a relatively larger degree of pantoprazole degradation compared with use of Na 2

CO

3 , CaCO 3 , 10 and DiCafos A as alkaline excipients. The stability data for the stressed stability testing conditions (70 0 C open Petri dishes, 70/10 OP) probably corresponds to a shelf life of at least two years. Example 7: 15 Dry manufacture of tablets containing pantoprazole and Sodium carbonate or calcium carbonate and a disintegrant followed by application of a sub coat and an enteric coating.

WO 2006/105798 PCT/DK2006/000409 23 Table 20: Composition of tablet core % w/w: 01050633 3F-C 05050632 29050636 29050640 2F-C 7F-C 8F-C Granulate by roller compaction Pantoprazole, 1% H 2 0 14'.1 14.1 14.1 14.1 Sodium carbonate 2.82 11.3 Calcium carbonate (Sturcal L) 2.82 11.3 Pantoprazole:alkaline excipient 1:0.2 1:0.8 1:0.2 1:0,8 Tablet core excipients DiCafos A 69.6 61.1 69.6 61.1 Crosspovidone 13.0 13 13.0 13 Mg Stearate 0.5 0.5 0.5 0.5 Based on the tablet core compositions listed above coated tablets were manufactured as 5 described in example 5 with the following exception: The pantoprazole was pre-rollercompacted prior to mixing with the alkaline excipient by use of the following parameters Rpm: 2.0 10 Gap size: 1.0 mm Sieve size: 1.25 mm Force: 4 kN/cm The pre-roller compaction leads to formation of pantoprazole granules. 15 The obtained coated tablets were used for stability testing with the purpose of investigating the impact of lower amounts of alkaline material than used in example 5 and the use of pre-rollercompaction of the pantoprazole. The stability testing is disclosed in example 8. 20 Example B: stability testing A stability program, including batches obtained in example 7 was performed. The batches were stored in open petri dishes at 70 0 C and not more than 10 % RH for up to six weeks. 25 The analytical method is as described in example 6 WO 2006/105798 PCT/DK2006/000409 24 Table 21: Result of stability study 01050633 05050632 29050636 29050640 batch 3F-C 2F-C 7F-C 8F-C Pantoprazole:sodium carbonate 1:0.8 1:0.2 Pantoprazole:calcium carbonate 1:0.2 1:0.8 Pantoprazole:DiCafos A 1:5 1:4,3 1:5 1:4,3 25/60 C 2 weeks 99,7 99,8 99,8 99,1 Pantoprazole in % area 70/10 OP 2weeks 98,3 97,9 98,3 98,1 70/10 OP weeks 97,5 97,2 Degradation 25/60 C 2 weeks 0,20 0,15 0,10 0,52 products in 70/10 OP 2weeks 1,2 1,6 1,4 1,2 % area 70/10 OP weeks 2,0 2,4 It appears in table 21 and figure 2 that use of sodium carbonate and calcium carbonate as 5 alkaline excipient at the mixing ratios of 1:0.2 and 1:0.8 result in nearly identical and acceptable degradation ratios when tested at 700C and not more than 10 % RH for up to six weeks. It is surprising that the solubility of the alkaline material apparently does not affect stability of the benzimidazole composition (calcium carbonate is poorly soluble in water). 10 Example 9: Dry manufacture of tablets containing pantoprazole and alkaline excipients focusing on order of mixing and roller compaction followed by application of a sub coat and an enteric coating. 15 Table 22: Composition of tablet core % w/w: Granulate by roller compaction Pantoprazole, 1V1/ H20 14.1 Sodium carbonate 11.3 Pantoprazole:alkaline excipient 1:0.8 Tablet core excipients DiCafos A 61.1 Crospovidone 13 Mg Stearate 0.5 The composition shown in table 22 was mixed and roller compacted in different sequential order as shown in table 23 20 WO 2006/105798 PCT/DK2006/000409 25 Table 23: Sequential order of mixing and roller compaction: Batch no. 1 2 3 4 (Of coated Mixing with Pre-roller Mixing with Roller tablets) alkaline compaction alkaline compaction excipient (solely excipient pantoprazole) 01050633 3F-C Not used X X X 05050635 X Not used Not used - X 05050638 12F-C Not used X X Not used Mixing and roller compaction were carried out as described in example 5. 5 The remaining tablet core excipients (Dicafos A, Crosspovidone and Mg-stearate) were admixed and tablets were compressed and coated in accordance with example 5. The batches 01050633 and 05050638 were used for stability testing in example 10 and 05050635 was used for comparison with batches of example 16 with the purpose of 10 evaluating excipient homogeneity of granules. Example 10: stability testing A stability program, including batches mentioned in example 9 was performed. The 15 batches were stored in open petri dishes at 70*C for 2 weeks. The analytical method is as described in example 6 Table 24: Results of stability testing: 01050633 3F-C 05050638 12F-C batch Pantoprazole:sodium carbonate 1:0.8 1:0.8 Pantoprazole:DiCafos A 1:5 1:4,3 Pre rollercompacting, Pre mixing, rollercompacting, - rollercompacting mixing 25/60 C 2 weeks 99,7 99,5 .n topra 70/10 OP 2weeks 98,3 97,2 in % area 70/10 OP 6weeks 97,5 Degradation 25/60 C 2 weeks 0,20 0,33 products in 70/10 OP 2weeks 1,2 2,9 % area 70/10 OP 6weeks 2,0 20 WO 2006/105798 PCT/DK2006/000409 26 It appears in table 24 and figure 3 that panoprazole degradation is relatively small when pantoprazole is pre-roller compacted, mixed with the alkaline excipient and then roller compacted again. The pantoprazole degradation is relatively high when pantoprazole is pre-roller compacted and mixed with the alkaline excipient without including a step of 5 roller compacting pantoprazole and alkaline substance together. The impact on stability is seen already after two weeks. Example 11: Dry manufacture of tablets containing pantoprazole and alkaline excipients. Roller 10 compaction has been carried out using two different sieve sizes. Tableting was followed by application of a sub coat and an enteric coating. Table 25: Composition of tablet core % w/w: Granulate by roller compaction Pantoprazole, 1h H 2 0 14.1 Sodium carbonate 2.82 Pantoprazole:alkaline excipient 1:0.2 Tablet core excipients DiCafos A 69.6 Crospovidone 13.0 Mg Stearate 0.5 15 Based on the tablet core compositions listed above coated tablets were manufactured as described in example 5 with the following exception: The pantoprazole was pre-rollercompacted prior to mixing with the alkaline excipient by use of the following parameters 20 Rpm: 2.0 Gap size: 1.0 mm Sieve size: 1.25 mm (used for batch 29050641) or 1.0 mm (used for batch 29050645) Force: 4 kN/cm 25 The pre-roller compacted pantoprazole and the sodium carbonate were mixed by use of a tumble-mixer and roller compacted using the following parameters: Rpm: 2.0 30 Gap size: 2.5 mm Sieve size: 1.25 mm (used for batch 29050641) or 1.0 mm (used for batch 29050645) Force: 10 kN/cm The remaining tablet core excipients were admixed and tablets were compressed and 35 coated in accordance with example 5.

WO 2006/105798 PCT/DK2006/000409 27 Evaluation of the impact of the sieve size was based on sieve analysis and dissolution testing. Dissolution was carried out by use of the following method: Table 26: Dissolution method. USP/Ph.Eur Dissolution apparatus 1 Spindle Basket Rotation 150 rpm Temperature 37 0 Ci 0,5 0 C Filter Whatman GF/F (0.7 pm) Dissolution medium O - 120 minutes 600 ml 0.1 N HCI After 120 minutes the dissolution medium 200 ml 0.20 M Na 3

PO

4 added to the is changed to pH 6.8 vessel (method A, USP) Detection, UV 288 nm Sampling time The absorbance is measured by each 10 minutes at 288 nm 5 From figure 4 it can be seen that the use of a sieve size of 1.0 mm results in a relatively narrow particle size distribution compared to sieve size 1.25. The narrow size distribution results in a better dose variation of pantoprazole as can be seen form figure 5. 10 Example 12: Dry manufacture of tablets containing pantoprazole and alkaline excipients followed by application of different types and amounts of sub coat. 15 Table 27: Composition of tablet core % w/w: Granulate by roller compaction Pantoprazole, 1% H 2 0 14,1 Sodium carbonate 55,2 Pantoprazole:a alkaline excipient 1:3,9 Crospovidone 1,1 Tablet core excipients DiCafos A 19,2 Crospovidone 10,0 Mg Stearate 0,5 Tablet cores according to the above mentioned composition were manufactured as described in example 5. Sub coat was applied as laid out in example 5 with the exception of variation in applied amount and type of polymer as shown in table 28: WO 2006/105798 PCT/DK2006/000409 28 Table 28: Amount (approximately) and type of sub coat applied: Batch no. HPMC type Theoretical amount of HPMC (mg/cm 2 ] 13030634 E15 10.9 (1/1 amount) 31030633 (C) E15 5.3 (h/ amount) 21040634 E5 9.9 (1/1 amount) 31030631 Enteric coat was applied as described in example 5. 5 Evaluation of the impact of amount and type of sub coat was based following dissolution results obtained obtained in example 1L, However, tablets only coated with a sub coat were analysed solely in a dissolution medium with pH 6.8. 10 Figures 6, 7 and 8 disclose the impact of type of sub coat on the dissolution rate form both sub coated tablets and sub + enteric coated tablets. A HPMC E5 based sub coat results in a relatively quick dissolution rate. Example 13: 15 Dry manufacture of tablets containing pantoprazole and alkaline excipients followed by application of an enteric coating. Tablet cores of batch 13030634 and 31030634 were manufactured as described in example 12. The tablet cores of batch 13030634 were enteric coated as described in 20 example 5. Batch 31030634 was produced with an enteric coating but without the application of a sub coat. The enteric coated tablets were used for stability testing in example 14. Example 14: stability testing 25 A stability program, including batches mentioned in example 13 was performed. The batches were stored in open petri dishes at 70 0 C for respectively 2 and 3 months. The analytical method is as described in example 6 30 WO 2006/105798 PCT/DK2006/000409 29 Table 29: Results of stability testing Batch 13030634 31030634 Without sub coat 25/60 C 1 month 99'7 99,7 Pantoprazole 70/10 OP in % of area I month 9 70/10 OP 2 months 96,1 97,4 25/60 C 1 month 0,20 0,22 Degradation products. 70/10 OP in % of area I month 2,3 1,7 70/10 OP 2 months 3,6 2,2 70/10 OP: 70 *C / 10 % RH in Open petri dishes 25/60: 25 *C / 60% RH in closed containers 5 It appears from table 29 and figure 9 that the stability (70 *C / 10 % RH in Open petri dishes and 25 *C / 60% RH in closed containers) of sub-coated tablets is fully comparable with tablets which has not been sub-coated. Example 15: 10 Impact of type and amount of alkaline excipient on degradation of pantoprazole in a stress test by the addition of a weakly acidic component (ibuprofen) Table 30: Composition of mixtures [gram] Raw materials Amounts in gram Sodium carbonate 4 16 20 25 Calcium carbonate 4 16 20 25 (Sturcal L) Ibuprofen 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0,8 Pantoprazole 1/2 H 2 0 20 20 10 5 20 20 10 5 Pantoprazole:alkaline 1:0.2 1:0.8 1:2 1:5 1:0.2 1:0.8 1:2 1:5 excipient 15 Table 31: Composition of mixtures [gram] Raw materials Amounts in gram Calcium carbonate 4 16 20 25 (Scoralite) Tri calcium phosphate 4 16 20 25 Ibuprofen 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Pantoprazole 11/2 H20 20 20 10 5 20 20 10 5 Pantoprazole:alkaline 1:0.2 1:0.8 1:2 1:5 1:0.2 1:0.8 1:2 1:5 excipient WO 2006/105798 PCT/DK2006/000409 30 Mixtures were made by grinding the raw materials in a steel bowl and subsequently placing the mixture in petri dishes in sealed alu-bags for two weeks at ambient conditions. 5 The evaluation of this stability test is shown in table 32 (pantoprazole degradation products are coloured). Discoloration is evaluated based on a scale ranging from 1 - 10 where "1" indicates no discoloration and "10" indicates a severe discoloration. Table 32. Discoloration scale of powder mixtures of table 30 and 31: Alkaline material Mixing ratio Mixing ratio Mixing ratio Mixing ratio 1:0.2 1:0.8 1:2 1:5 Sodium carbonate 9 8 4 1 Calcium carbonate 10 8 4 1 (Sturcal L) Calcium carbonate 10 10 7 7 (Scoralite) Tri calcium 9 6 - 1 phosphate 10 The results in table 32 are discussed in example 16. Example 16: Characterisation of alkaline materials. 15 Alkaline materials: * Calcium carbonate, Sturcal L * Calcium carbonate, Scoralite * Sodium carbonate anhydrate 20 Alkaline substance raw material particle sizes have. been measured by laser light scattering (Malvern) and BET area has been measured by use of a Micromeritics Gemini 2375 at relative target pressures (P/PO) of 0.1 and 0.2 and 0.3. Samples have been dried for minimum 12 hours at 40 0 C prior to the measurements. 25 Table 33: BET-areas Raw materials BET-area [m 2 /g] Particle size D(v 0,5) [pm] Calcium carbonate, Sturcal L 3.0 9 Calcium carbonate, Scoralite 0.2-0.5 29 Sodium carbonate anhydrate 2.1 99 The SEM pictures (figures 10-18) illustrate considerable differences in size and morphology on the alkaline raw materials. It should be noted that even though Sodium carbonate 30 anhydrate has a larger particle size than the Calcium carbonate (Scoralite), sodium carbonate anhydrate has the largest BET area. This difference is further illustrated in example 17 by use of Scanning Electron Microscope pictures. The impact of the BET area and particle size on stability was illustrated in example 15.

WO 2006/105798 PCT/DK2006/000409 31 The discoloration shown in table 32 demonstrates the impact of BET area (see example 16, table 33) and mixing ratio on pantoprazole stability. A high BET area favours good stability results. It appears from example 16 that a relatively small particle size may not suffice to 5 ensure a satisfactory stability. Relatively big particles can be useful, provided that their porosity leads to a sufficiently high BET area. Furthermore, it is illustrated that a high amount of alkaline material is preferred. However, the discoloration test cannot reveal smaller amount of degradation product as 10 can be seen by comparison of the addition of tri calcium phosphate in example 6. This means that tri calcium phosphate is not as efficient as e.g. sodium carbonate and calcium carbonate (Sturcal L). Example 17 15 Impact of type and amount of alkaline excipient on homogeneity of a mixture with pantoprazole with alkaline materials. Composition of powder mixtures 20 * Pantoprazole, 1/2 H20 : Calcium carbonate (Sturcal L), 1:0.8 * Pantoprazole, 1% H20 Calcium carbonate (Scoralite), 1:0.8 * Pantoprazole, 12 H20 (pre-roller compacted) : sodium carbonate, 1:0.8 25 Pantoprazole, 1/ H20 : Calcium carbonate (Sturcal L) and Pantoprazole, 1/2 H20 : Calcium carbonate (Scoralite) batches have been mixed in a lab. scale high shear mixer for 1 minute. The Pantoprazole, 11/. H20 (pre-roller compacted) batch was manufactured as described in example 7 prior to mixing with sodium carbonate. The mixing was done as described above. 30 All the mixtures were slugged on a single punch tableting machine using 11.3 mm flat faced punches. The slugs were evaluated for mixture homogeneity by use of scanning electronic microscopy (SEM). For reference, SEM pictures of the individual raw materials were obtained. 35 The SEM pictures are shown in the figures 10 - 18. Figure 11 and 12 disclose a considerable difference between Calcium carbonate (Sturcal L) and Calcium carbonate (Scoralite). SEM appearances of Sturcal L and Scoralite are in full accordance with the BET areas measured in example 16. 40 Figure 13 is a magnification of the particles shown in figure 14. The magnification showing the porosity of the particles clearly supports the finding of a high BET area of Sodium Carbonate is illustrated. 45 Figures 15 and 16 show that the use of Calcium carbonate (Sturcal L) leads to a much more homogeneous mixture than Calcium carbonate (Scoralite). The impact on stability of this difference was illustrated in example 15. Figure 17 shows that the sodium carbonate WO 2006/105798 PCT/DK2006/000409 32 particles are crushed during manufacturing. The physical structure of Sturcal L results in an improved distribution of the particles during mechanical pressure. An acceptable stability is obtained as illustrated in examples 15 and 6, 8 and 10. 5 Figure 18 illustrates the effect of pre-roller compacting pantoprazole prior to mixing with alkaline substance. Slugging (or roller compaction) of the mixture results in "coating" of the surface of the relative large pantoprazole granules with calcium carbonate particles (Sturcal L). This "coating" also leads to an acceptable stability as shown in example 6 and 8. The need for using roller compaction to apply this coat is indicated in example 9, which 10 was based on the use of sodium carbonate. Example 18. Impact of disintegrant on dissolution rate. 15 Table 34: Composition of tablet core % w/w: Pantoprazole, 112 H 2 0 14.1 14.1 Calcium carbonate (Sturcal L) 11.3 11.3 Pantoprazole:alkaline 1:0.8 1:0,8 excipient DiCafos A 74.1 61.1 Crospovidone' - 13 Mg Stearate 0.5 0.5 Based on the tablet core compositions listed above tablets were manufactured as described in example 7 with the following exception that no coat has been applied. 20 The cores were tested with respect to dissolution rate as described in example 11 with the exception that tablet cores were analysed solely in a dissolution medium with pH 6.8. The results shown in figure 19 illustrate the advantages of the incorporation a disintegrant as the presence of a disintegrant in the formulation significantly increases the dissolution rate. 25

Claims (24)

1. A pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, said formulation comprising an enteric coating for protection of the active component from acid attack in the stomach, said benzimidazole being further stabilized by an alkaline substance or a mixture of two or more different alkaline substances in the tablet, and the weight ratio of benzimidazole and alkaline substance is from about 1:02 -1.5, characterized in that the alkaline substance raw material has a BET-area of at least about 1 m 2 /g, prior to any dry granulation and/or compression steps and the tablet formulation optionally further comprises a disintegrant in an amount of about 1-30% by weight.

2. A pharmaceutical tablet formulation according to claim 1, wherein the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps

3. A pharmaceutical tablet formulation according to claim 1, wherein the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps

4. A pharmaceutical tablet formulation according to claim 1, wherein the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps

5. A method for producing a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component, wherein: - said formulation comprising an enteric coating for protection of the active component from acid attack in the stomach, - said benzimidazole is further stabilized by an alkaline substance or a mixture of two or more different alkaline substances in the tablet, and the weight ratio of benzimidazole and alkaline substance is from about 1:02 -1.5, - said method comprising dry granulating steps and dry compressing of tablets, wherein the benzimidazole and at least one of the alkaline substances have been mixed and dry granulated together prior to dry compression - said formulation is further characterized that the alkaline substance has a BET-area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps, and the tablet formulation further comprises a disintegrant in an amount of about 1-30% by weight.

6. A method according to claim 5, wherein the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps 34

7. A method according to claim 5, wherein the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps

8. A method according to claim 5, wherein the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m 2 /g prior to any dry granulation and/or dry compression steps

9. A method according to claim 5-8, wherein the benzimidazole is pantoprazole.

10. A method according to claim 9, wherein the pantoprazole is pantoprazole sodium hydrate or pantoprazole sodium sesquihydrate.

11. A method according to any one of claims 5-10, wherein said formulation further comprises pharmaceutically acceptable excipients.

12. A method according to any one of claims 5-11, wherein said formulation comprises crospovidone in an amount of from about 5-15% by weight.

13. A method according to any one of claims 5-12, wherein said formulation further comprises a subcoat.

14. A method according to any one of claims 5-13, wherein said formulation is lacking a subcoat.

15. A method according to any one of claims 5-14, wherein the alkaline substance is a salt of an organic or an inorganic acid and the anion of the salt is carbonate (C0 3 2 ), hydrogenphosphate (HP0 4 2 ) or phosphate (P0 4 3 ).

16. A method according to any one of claims 5-15, wherein the alkaline substance is a salt of an organic or an inorganic acid and the cation is sodium (Na*), calcium (Ca 2 +) or magnesium (Mg 2 +).

17. A method according to claim 15 or 16, wherein the salt of the organic and/or inorganic acid according is sodiumcarbonate (Na 2 CO 3 ), trisodiumphosphate (Na 3 PO4), disodiumhydrogenphosphate (Na 2 HPO4), hydrazine or derivatives thereof, lysine or a derivative thereof, arginine or a derivative thereof, or histidine or a derivative thereof.

18. A method according to any one of claims 5-8 and 11-17, wherein the benzimidazole is omeprazole or a salt and/or a hydrate thereof, lansoprazole or a salt and/or a hydrate thereof, esomeprazol or a salt and/or a hydrate thereof, aripiprazole or 35 a salt and/or a hydrate thereof, rabeprazol or a salt and/or a hydrate thereof, timoprazole or a salt and/or a hydrate thereof.

19. A method according to any one of claims 5-18, wherein the tablet has a weight in the range of 75 mg to 2.5 g.

20. A method according to any one of claims 5-19, wherein the dry granulation is provided by means of a roller compactor.

21. A method according to any one of claims 5-20, wherein the mixture has been subject to sieving prior to tablet compression with a sieve size of 1,25 mm or less.

22. A product produced by a method according to any one of claims 5-21.

23. A pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component as hereinbefore described with reference to any one of the Examples, excluding comparative Examples.

24. A method for producing a pharmaceutical tablet formulation comprising a benzimidazole as the biologically active component as hereinbefore described with reference to any one of the Examples, excluding comparative Examples.