PHARMACEUTICAL COMPOSITION COMPRISING GRANULAR PANTOPRAZOLE

Field of the invention

The present invention relates to pharmaceutical compositions which comprise granular pantoprazole as active ingredient and a method for the preparation or granular pantoprozole .

Background of the invention

Pantoprazole (5- (difluoromethoxy) -2 { (3, 4-di-methoxy-2- pyridinyl) -methyl] -sulphinyl } -H-benz-imidazole) is a proton pump inhibitor belonging to the group of benzimidazoles . This compound inhibits gastric acid formation and thereby it is very efficient for the treatment of gastric and duodenum ulcers, gastro-oesophageal reflux and the like. It inhibits gastric acid secretion by inhibiting H ⁺ -K ⁺ ATPase (proton-pump) activity. Pantoprazole and physiologically acceptable salts thereof are known from EP 0 166 287 and Kohl et al . , The Journal of Medicinal Chemistry; 1992, 35, No. 6, 1049-1057.

Pantoprazole is known to be sensitive to heat and unstable in an acidic environment as well as in the presence of moisture and organic solvents. Thus, pharmaceutical compositions comprising this drug, as well as processes for the manufacture thereof, must be designed to protect the drug from moisture and acidic conditions . Due to the rapid drug degradation that occurs in acidic gastric fluids, such formulations usually comprise an enteric coating.

The stability problems associated with benzimidazole compounds are well known in the art, which teaches various measures for preparing stable formulations containing benzimidazole

compounds. The most common approach is the use of an alkaline core, a separating layer and an enteric coating. By use of an alkaline substance within the core benzimidazole compounds can be protected against acid degradation.

EP 0 244 380 discloses pharmaceutical preparations containing acid labile compounds. The preparations consist of a core containing either the active ingredient together with an alkaline reacting compound or an alkaline salt of the active ingredient, one or more water-soluble sub-coating layers which may also contain an alkaline component and an enteric coating layer.

According to WO 92/22284 certain ingredients such as lactose, microcrystalline cellulose and hydroxypropyl cellulose being present in the compositions of EP 0 244 380 accelerate the decomposition of the pantoprazole . It is said that more stable formulations could be obtained by using polyvinylpyrrolidone and/or hydroxypropyl-methyl cellulose as binder and mannitol as an optional inert filler in the tablet core.

WO 2005/051348, on the other hand, discloses that hygroscopic polymeric binders such as polyvinylpyrrolidone impair the release of the active ingredient after storage due to absorbed humidity. It was found that by using appropriately chosen excipients compatible with the active ingredient the use of a polymeric binder can be avoided. This document teaches the use of tablet cores containing pantoprazole as active ingredient, spray-dried or granulated mannitol having an average particle size between 100 μm and 500 μm, an alkalizing substance, a disintegrant and a lubricant. The active ingredient can be granulated with an aqueous solution of mannitol in order to improve its flowability. It is known that drying of granulates based on sugar alcohols is difficult and time consuming and requires a high energy input. Furthermore, prolonged drying

times are disadvantageous in view of the heat sensitivity of pantoprazole .

Description of the Invention

It is the object of the present invention to provide tablets comprising pantoprazole as the active ingredient which are stable and which can be prepared by a direct compression process. It is a further object of the present invention to provide a process for granulating pantoprazole which does not require excessive heating.

It was found by the present inventors that this object can be achieved by using pantoprazole in the form of particles having an average particle size of 60 to 250 μm, preferably 100 to 250 μm, more preferably 125 to 250 μm, even more preferably 125 to 230 μm and most preferably 140 to 200 μm. If pantoprazole having average particle size in the range 60 to 250 μm is mixed with other ingredients such as alkalizing substances, fillers and disintegrants, the mixture can easily be formed into tablet cores by direct compression thereof without the addition of water. Pantoprazole which is commercially available may have an average particle size of as little as 25 μm.

This finding is surprising since pantoprazole exhibits inappropriate physical properties for direct compression. Furthermore, the tablet cores usually contain 20 to 50 % by weight, preferably 25 to 30 % by weight of pantoprazole. Due to the relatively high amount of the active ingredient the addition of other excipients which are better suited for direct compression is limited. If the size of the tablet cores exceeds a certain weight the disintegration of the tablets within the small intestine would be delayed and the pharmacological effect of the active ingredient would be diminished.

The term "average particle size" as used herein refers to the volume mean diameter of particles . The volume mean diameter can be determined by laser light scattering using e.g. a Malvern- Mastersizer Apparatus MS 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The size distribution is determined from the light scattering data using the theory of light scattering developed by Gustav Mie.

In addition to pantoprazole, the pantoprazole particles may contain further additives but it is preferred that they essentially and more preferably completely consists of pantoprazole or pharmaceutically acceptable a salt thereof.

The compositions according to the invention contain as active ingredient pantoprazole, preferably in the form of a pharmaceutically acceptable salt thereof such as the sodium salt of pantoprazole, more preferably the sesquihydrate of the sodium salt of pantoprazole.

The compositions preferably have the form of a tablet comprising

(a) a core comprising the active ingredient, an alkalizing substance, a filler and a disintegrant; (b) an optional water-soluble separating layer or subcoating; and

(c) an enteric coating.

An additional water-soluble protecting layer may be applied to the enteric coating layer.

The tablets according to the invention contain as the alkalizing agent preferably an alkali or earth alkali hydroxide, an alkali or earth alkali carbonate, an alkali or earth alkali hydrogen carbonate, an alkali phosphate, such as sodium phosphate, a

glucosamine or a mixture of two or more of these compounds, preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, or a mixture of two or more of these components, more preferably sodium carbonate.

As filler the tablets preferably contain lactose or a sugar alcohol, such as mannitol, sorbitol, maltitol, erythrol, or a mixture of two or more of these components . The most preferred fillers are mannitol and sorbitol and mixtures thereof. It is preferred that the filler has an average particle size of 30 to 500 μm, more preferably an average particle size of 250 to 500 μm. Mannitol is known for its non-hygroscopicity while sorbitol which is an isomer of mannitol is hygroscopic. Mixtures of mannitol and sorbitol proved to be particularly suitable as a filler. This finding is surprising since hygroscopic additives are said to impair the release of pantoprazole after storage. Tablets prepared according to the present invention did not show a significant degrease in the dissolution of the active ingredient after storage even if sorbitol was used as the only filler. It is preferred to use mixtures comprising 1 part by weight of mannitol and 1 to 5 parts by weight of sorbitol, more preferably 2 to 4 parts by weight of sorbitol and most preferably 2.8 to 3.8 parts by weight of sorbitol.

Preferred disintegrants are crospovidone, sodium starch glycolate, cross-linked carboxylic methylcelluloses, such as croscarmelose, sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, or a mixture of two or more of these components. Crospovidone is the most preferred disintegrant . Crospovidone is cross-linked polyvinyl pyrrolidone.

Pantoprazole containing tablets should disintegrate rapidly when leaving the stomach and reaching the upper part of the intestine where the physiological pH raises to values higher than 5.5 and

where the polymer of the enteric coating dissolves. It has surprisingly been found that the disintegration of coated tablets can be improved by using a disintegrant having a defined particles size. By using a combination of disintegrant with an average particle size 10 to 60 μm (Type A) , preferably crospovidone, and disintegrant with an average particle size 80 to 200 μm (Type B) , preferably crospovidone, the disintegration time can be significantly reduced. Mixtures comprising 1 part by weight of disintegrant Type A and 1 to 5 parts by weight of disintegrant Type B, preferably 2 to 4 parts by weight of disintegrant of Type B proved to be particularly advantageous.

The compositions of the present invention preferably release more than 50 % of the active ingredient within 45 minutes and more than 80 % of the active ingredient within 60 minutes, determined in phosphate buffer of pH 6.4, USP apparatus 1, 100 rpm, after storage in 0.1 M HCL solution of pH 1 for 1 hour.

The tablet cores preferably also contain a lubricant. Preferred lubricants are stearic acid, hydrogenated vegetable oils, paraffin or alkali or alkaline earth stearates, aluminum stearate, sodium stearyl fumarate or mixtures of two or more of these compounds. The most preferred lubricants are magnesium stearate and calcium stearate.

The tablet cores may also comprise a binder, such as microcrystalline cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone (povidone) or mixtures of two or more of these compounds .

The tablet cores preferably comprise

15 to 50 % by weight, preferably 20 to 30 % by weight, more preferably 25 to 30 % by weight of the active ingredient,

2 to 25 % by weight, preferably 5 to 20 % by weight, more preferably 5 to 15 % by weight of the alkalizing substance,

10 to 50 % by weight, preferably 20 to 40 % by weight, more preferably 25 to 35 % by weight of the filler, and

10 to 50 % by weight, preferably 20 to 40 % by weight, more preferably 25 to 40 % by weight of the disintegrant .

According to a preferred embodiment the film-coated tablet according to the invention contain on the surface of the tablet core a sub-coating or separating layer. The optional water- soluble separating layer applied on the tablet core may contain film-forming substances generally used for the preparation of film-coated tablets. A preferred water-soluble film-forming substance is hydroxypropyl-methyl cellulose alone or in combination with other water soluble polymers such as polyvinylpyrolidone . Besides the film-forming polymer optionally further auxiliary agents, such as plasticizers, e.g. polyethylene glycol, propylene glycol, titanium dioxide and talc can be used in the coating. The sub-coating is used to separate gastro-resistant coating from direct contact with tablet core.

The sub-coating is preferably applied in an amount of 2 to 20 % by weight, preferably 5 to 15 % by weight (related to the total weight of the composition) .

The optional separating layer has preferably a thickness of 20 to 120 μm, more preferably of 50 to 90 μm.

The enteric coating layer preferably comprises film-forming substances such as cellulose acetate phthalate, polyvinyl- acetate phthalate, hydroxypropyl-methyl cellulose phthalate, hydroxypropyl-methyl cellulose acetate succinate, ethylacrylate methacrylic acid copolymer, methylmethacrylate methacrylic acid

copolymer, shellac, more preferably copolymers of methacrylic acid and methacrylic acid esters, such as anionic polymer of methacrylic acid and methacrylates with -COOH groups, e.g. L- form Eudragits . These polymers can be used as organic solutions or preferably as aqueous dispersions, and optionally plasticizers, e.g. triacetin, polyethyleglycole (macrogol) or triethyl citrate, or talc may be added to them. The enteric coating is insoluble in acidic medium. It prevents a disintegration of the tablets in the acidic medium of the stomach which would cause degradation of the pantoprazole and consequently diminishing of therapeutic effect of such the composition .

The enteric coating layer is preferably applied in an amount of 8 to 20 % by weight, more preferably 10 to 15 % by weight (related to the total weight of the composition) .

The enteric coating layer has preferably a thickness of 85 to 150 μm or more, more preferably of 90 to 120 μm.

The tablets preferably comprise 20 to 40 mg, in particular 20 mg or 40 mg of pantoprazole, calculated as pure pantoprazole. This means that e.g. 20 mg or 40 mg of pure pantoprazole are incorporated into each tablet. If pantoprazole is used in the form of a salt and or a hydrate, the mass of the active ingredient which is actually used is calculated such that it corresponds to 20 to 40 mg of pure pantoprazole. According to a preferred embodiment of the invention the enteric coating of these tablets has the same thickness even if the tablets differ in strengths, size or quantities of ingredients. The same thickness means, that the thickness of the enteric coating layer of the tablets does not differ by more than 5 % measured by SEM on the cross-section of the tablets. If the surface area of the cores of the tablets is not the same the quantity of enteric coating material which is applied to the cores is adjusted such

that the same thickness of the enteric coating layer is achieved.

The thickness of the enteric coating layer of different tablets can be adjusted such that the same functionality is achieved. The functionality of enteric coating layers for different tablets is determined by comparing the results of dissolution testing of the active ingredient (% of released pantroprazole in phosphate buffer solution, pH 6.8, USP Apparatus 2, 50 rpm, at 37°C; tablets are first exposed for two hours to 0.1 M solution of HCl and then the medium is exchanged for phosphate buffer solution of pH 6.8; similarity factors for the dissolution profiles of different tablets can then be calculated and compared) . The similarity of the dissolution profiles is compared by calculating the similarity factor (according to the EMEA guideline CPMP/QWP/604/96 NOTE FOR GUIDANCE ON QUALITY OF MODIFIED RELEASE PRODUCTS: A: ORAL DOSAGE FORMS B: TRANSDERMAL DOSAGE FORMS SECTION I (QUALITY) ) .

The similarity factor is defined as follows:

f ₂ = 50 x log{ [l+(l/n)∑ _t =i ⁿ (Rt-Tt) ² ] ^"0 - ⁵ x 100}

In this equation f ₂ is the similarity factor, n is the number of time points, R(t) is the mean percent drug dissolved of e.g. the current formulation, and T(t) is the mean percent drug dissolved of e.g. the changed composition.

The evaluation of similarity is based on the condition of (i) a minimum of three time points, (ϋ) 12 individual values for every time point, (iii) not more than one mean value of > 85 % dissolved; (iv) that the standard deviation of the mean should be less than 10 % from the second to last time point. An f ₂ value between 50 and 100 suggests that two dissolution profiles are similar.

The thickness of the sub-coating and the enteric coating is measured on the scanning electron microscope of the cross- section of coated tablets .

The film-coated tablet according to the invention containing pantoprazole can be prepared as follows. First a tablet core is provided by mixing of the active ingredient, a disintegrant, a filler, an alkalizing agent and any optional components, and compressing the homogenous mixture to tablets without the addition of water. Mixing is preferably performed in a biconical mixer and tablets are preferably formed on a rotary tabletting machine. The thus-obtained tablets are then coated first with a water-soluble coating, then with an enteric coating resistant to gastric acid and finally with a further optional water-soluble coating.

The compositions can optionally be subjected to a curing step. The curing step is preferably performed after application of the dispersion of the acid insoluble polymer (gastro resistant coating) . The curing step is preferably performed in the coating equipment such as a perforated coating pan known in the state of the art (e.g. Manesty types, Accela Cota, GS coating pan or Glatt coater) and/or in a drying chamber. Curing is preferably performed at a composition temperature of 30 to 50 ⁰ C, more preferably 35 to 45 ⁰ C, and the preferred curing time is in the range of 1 to 16 hours, more preferably 2 to 8 hours.

The pantoprazole particles used for preparing the pharmaceutical compositions can be prepared e.g. by crystallization. It is preferred to produce the particles by agglomeration of smaller particles which are commercially available. Agglomeration is performed by wetting pantoprazole with water, passing the wet pantoprazole through a sieve having a mesh size in the range 0.8 to 2 mm, preferably 0.8 to 1.2 mm, more preferably 1.0 mm, and

drying the mass in a fluid bed dryer preferably at product temperatures 35 to 50 ⁰ C. The order of the sieving step and the drying step is optional.

The water is preferably adjusted to a pH of 10 to 12 by the addition of an alkalizing agent such as sodium hydroxide, sodium carbonate, trisodium phosphate, meglumine or glucosamine. Mixing is preferably performed in a high shear mixer. As the starting material commercially available pantoprazole can be used, preferably pantoprazole having an average particle size of at least 25 μm is used. Drying is preferably performed at a temperature of 35 to 5O ⁰ C.

According to the process of the present invention granulation of the active ingredient can be achieved without the addition of other ingredients such as sugar alcohols and disintegrants . The granulate of the present invention can be dried in significantly shorter time than granulate prepared according to the prior art e.g. by use of an aqueous solution of mannitol . A granulate of agglomerated pantoprazole sodium sesquihydrate prepared according to the present invention can be dried to a residual moisture content below 1 % by weight in less than 1 hour while the moisture content of a granulate prepared with an aqueous solution of mannitol is just below 3 % by weight after 2 to 3 hours of drying at identical conditions. The residual moisture is determined by a halogen moisture analyzer (Mettler HR 73; 20 min at 85 ⁰ C) . Thus the present invention provides a granulate containing less moisture than prior art granulates, preferably less than 1 % by weight, and less degradation products since drying of prior art granulates down to a moisture content of less than 1 % by weight unavoidably results in the formation of degradation products. Furthermore, due to the reduced moisture content the granulate shows improved stability during storage.

The agglomerated drug can be used in the preparation of tablet cores either by direct compression or further granulation with excipients such as fillers, stabilizers and disintegrants .

Examples

Example 1: Preparation of agglomerated pantoprazole sodium sesquihydrate

6.14 kg of pantoprazole sodium sesquihydrate were transferred into the high sheare mixer (Collet Gral 75) and wetted while mixing with 1.9 kg purified water. The wet mass was transferred to a fluid bed dryer (Glatt WSG 5) and dried with inlet air temperature (60 ⁰ C) for 25 minutes. After drying the granulate was sieved through a 1.0 mm sieve and dried for an additional 20 minutes. The residual moisture of the dried granulate was 0.6% as determined by a halogen moisture analyzer (Mettler HR 73; 20 min at 85°C) .

The average particle size of the product was determined by laser light scattering. 100 to 800 mg of the particles were dispersed in 5 to 8 ml of vegetable oil (sunflower oil) . No solubilizers or surfactants were used. Then the obtained suspension was subjected to size determination (Malvern Mastersizer MS 2000) . According to the manufacturer's information, the Malvern Mastersizers allows for a measurement of particle size distributions in the range of 20 nm to 2000 μm, with a precision of better than 0.5%. The product had an average particle size of

141 μm. This product was used in the following examples.

Example 2 :

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 315.7 g

(Example 1)

Sodium carbonate 140.0 g

Mannitol (granulated) 153.3 g

Crosspovidone (type A) ¹ 350.0 g

Microcrystalline cellulose 245.0 g

(Avicel PH 200)

Magnesium stearate 21.0 g

cross-linked polyvinyl pyrrolidone, average particle size < 60 μm

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose ¹ 3 176.0 g cp

Kollidon K25 ² 4.4 g

Propylenglycole 44.0 g

Water 1375.0 g

hydroxypropyl methyl cellulose polyvinylpyrrolidone (not cross-linked)

Hypromellose and Kollidon were dissolved in water. Propylenglycole was added to the solution. Tablet cores obtained under A were coated by spraying the solution obtained under B onto the tablet cores using a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D ¹ 176 . 0 g ² Triethycitrate 17 . 6 g Water 583 . 0 g

anionic polymer of methacrylic acid and methacrylates with a -COOH group expressed as dry substance weight

Eudragit dispersion was diluted with water and triethylcitrate was dispersed into the diluted Eudragit dispersion. The coating dispersion containing Eudragit L30D, triethylcitrate and water was sprayed onto coated tablets obtained under B using the same equipment as in step B.

Example 3:

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 315.7 g

(Example 1)

Sodium carbonate 140.0 g

Lactose (spray dryed) 153.3 g

Crosspovidone (Type B) 350.0 g

Microcrystalline cellulose 245.0 g

(Avicel PH 200)

Magnesium stearate 21.0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycole was added to the solution. Tablet cores obtained under A were coated by spraying the solution obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 211. 2 g ¹

Macrogole ² 6000 21.1 g

Talc 79.2 g

Water 700. o g

¹ expressed as dry substance weight

² polyethylenglycol

Eudragit dispersion was diluted with a part of the water and Macrogole was dissolved in rest of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. The obtained suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B.

Example 4 :

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 315.7 g

(Example 1)

Sodium carbonate anhydrous 140.0 g

Mannitol 363.3 g

Crosspovidone (type A) ¹ 70.0 g

Crosspovidone (type B) ² 280.0 g

Magnesium stearate 21.0 g

cross-linked polyvinyl pyrrolidone, average particle size < 60 μm cross-linked polyvinyl pyrrolidone, average particle size > 80 μm

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine. Loss on drying of the mixture for tabletting: 1,75% (Mettler halogen dryer: 85°C 20 min . )

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Titanium dioxide 3.7 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycol was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores

obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 125.4 g ¹

Triethycitrate 12.5 g

Macrogole 6000 2.6 g

Talc 57.4 g

Water 415.8 g

expressed as dry substance weight

Eudragit dispersion was diluted with a 1 part of water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. Trietylcitrate was dispersed in 3 ^rd part of water and the obtained dispersion was added to the suspension. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B.

Example 5 :

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 315.7 g

(Example 1)

Sodium carbonate anhydrous 140.0 g

Magnesium carbonate heavy 14.0 g

Sorbitole (granulated) 349.3 g

Crosspovidone (Type B) 350.0 g

Magnesium stearate 21.0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Titanium dioxide 3.7 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycol was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 146 •3 g ¹

Triethycitrate 14. 6 g

Macrogole 6000 3.1 g

Talc 67. o g

Water 485 .0 g expressed as dry substance weight

Eudragit dispersion was diluted with a 1 part of the water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. Trietylcitrate was dispersed in 3 ^rd part of water and the obtained dispersion was added to the suspension. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B.

Example 6:

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 631,4 g

(Example 1)

Sodium carbonate anhydrous 140,0 g

Sorbitole (granulated) 518,0 g

Crospovidone (Type A) 210,0 g

Crospovidone (Type B) 700,0 g

Calcium stearate 14.0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Titanium dioxide 3.7 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycol was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 176,0 g ¹

Macrogole 6000 17,6 g

Talc 66.0 g

Water 583.0 g

expressed as dry substance weight

Eudragit dispersion was diluted with a 1 part of the water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B. After the coating suspension had been sprayed onto the coated tablets, the product was transferred to a drying chamber and kept at 40 ⁰ C for 8 hours .

Example 7:

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate ¹ 315.7 g

Sodium carbonate anhydrous 70.0 g

Crospovidone (Type A) 105.0 g

Mannitol (kristalline) 83.3 g

average particle size 66.0 μm

0.3 g sodium carbonate anhydrous was dissolved in 370 g of water to form solution (I) . The ingredients listed in the above table were placed into a high shear mixer (Collet grail 10) and solution (I) was slowly added to the mixture while mixing.

Kneading was used for 1 min. The wet mass was passed through 18 mesh (1.0 mm) sieve and dried in fluid bed granulator/dryer (Glatt GPCG-3) until the loss on drying was lower than 3%.

To the dry granulate following ingredients were added to obtain a mixture for tabletting:

Ingredient Amount

Sorbitole (granulated) 259,0 g Crosspovidone (Type B) 350.0 g calcium stearate 7.0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Titanium dioxide 3.7 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycol was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 176,0 g ¹

Macrogole 6000 17,6 g

Talc 66.0 g

Water 583.0 g

expressed as dry substance weight

Eudragit dispersion was diluted with a 1 part of water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B. The coated tablets produced in step C were then kept in the coating equipment (Manesty XL) at 45 ⁰ C for 4 hours at periodical slow revolution of the pan (1 revolution every 5 minutes) in order to diminish

mechanical stress on the tablets and to achieve good temperature distribution in the tablet mass in the pan.

Example 8:

A) Tablet core

Ingredient Amount

Pantoprazole sodium sesquihydrate 315.7 g

(Example 1)

Sodium carbonate anhydrous 70.0 g

Crospovidone (TypeA) 105.0 g

Mannitol (kristalline) 83.3 g

0.3 g Anhydrous sodium carbonate was dissolved in 370 g of water to form solution (I) . The ingredients listed in the above table were placed into a high shear mixer (Collet grail 10) and solution (I) was slowly added to the mixture while mixing.

Kneading was used for 1 min. The wet mass was passed through 18 mesh (1.0 mm) and dried in fluid bed dryer (Glatt GPCG-3) for 3 hours to a residual moisture content of 3% (Halogen moisture analyzer Mettler HR 73; 20 min at 85°C) .

To the dry granulate following ingredients were added to obtain a mixture for tabletting:

Ingredient Amount

Sorbitole (granulated) 259,0 g Crosspovidone (Type B) 350.0 g calcium stearate 7.0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount

Hypromellose 3 cp 176.0 g

Kollidon K25 4.4 g

Titanium dioxide 3.7 g

Propylenglycole 44.0 g

Water 1375.0 g

Hypromellose and Kollidon were dissolved in water. Propylenglycole was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount

Eudragit L-30D 176,0 g ¹

Macrogole 6000 17,6 g

Talc 66.0 g

Water 583.0 g

expressed as dry substance weight

Eudragit dispersion was diluted with a 1 part of water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B.

Example 9 :

A) Tablet core

Ingredient Amount for 20 mg Amount for 40 mg tablets tablets

Pantoprazole sodium 157.85 g 315.7 g sesquihydrate

Sodium carbonate 35.00 g 70.0 g anhydrous

Crospovidone 52.50 g 105.0 g

(Type A)

Mannitol 41.65 g 83.3 g

(kristalline)

Procedure of gralution is the same as in example 7.

Ingredient Amount for 20 mg Amount for 40 mg tablets tablets

Sorbitole (granulated) 126. 0 g 252, 0 g

Crosspovidone (Type B) 175. 0 g 350. 0 g calcium stearate 7. 0 g 14. 0 g

All ingredients were mixed in biconical mixer and pressed into tablets on rotary tabletting machine.

B) Separating layer

Ingredient Amount for 20 mg Amount for 40 mg tablets* tablets*

Hypromellose 3 cp 56.91 g 113.82 g

Kollidon K25 1.40 g 2.80 g

Titanium dioxide 1.05 g 2.10 g

Colouring agent 0.14 g 0.28 g

E172

Propylenglycole 14.00 g 28.00 g

Water 444.60 g 889.20 g

* overage of the suspensions was used due to losses during coating

Hypromellose and Kollidon were dissolved in water. Propylenglycol was added to the solution. Pigment was homogeneously dispersed into the obtained solution. Tablet cores obtained under A were coated by spraying the suspension obtained under B onto the tablet cores in a Manesty coating equipment.

C) Enteric coating

Ingredient Amount for 20 mg Amount for 40 mg tablets ² tablets ²

Eudragit L-30D 70. 00 g ¹ 112. 00 g ¹

Macrogole 6000 7 .00 g 11 20 g

Talc 25 .90 g 42 00 g

Water 235 .00 g 375 00 g

expressed as dry substance weight overage of the suspensions was used due to losses during coating

Eudragit dispersion was diluted with a 1 ^st part of water and Macrogole was dissolved in 2 ^nd part of water. Talc was dispersed into the Macrogole solution and the obtained suspension was added to the diluted Eudragit dispersion. The obtained coating suspension was sprayed onto coated tablets obtained under B using the same equipment as in step B. The coated tablets produced in step C were kept in the coating equipment (Manesty XL) at 40 ⁰ C for 4 hours at periodical slow revolution of the pan (1 revolution every 5 minutes) in order to diminish mechnical stress on the tablets and to achieve good temperature distribution in the tablet mass in the pan.

The gastroresistance and similarity of dissolution profiles of the 20 mg and 40 mg pantoprazole tablets was determined, in 0.1 M HCl, 500 ml, USP apparatus 1 (baskets), 100 rpm, 2 hours. Assay of intact pantoprazole in tablets after 2 hours in 0.1 M HCL was determined by HPLC method and expressed as % of declared amount .

Dissolution of pantoprazole for calculating the similarity factor in buffer stage was determined using phosphate buffer pH 6.8, 900 ml, USP apparatus 1 (baskets), 100 rpm, after acidic stage (0.1 M HCl, 500 ml, USP apparatus 1 (baskets), 100 rpm, 2 hours) . % of release of pantoprazole was followed up to 60 minutes and determined by UV method.

Tablet Gastro-resistance Similarity factor

(buffer stage)

40 mg tablets 102-106%; avg: 104%* 68.1

20 mg tablets 99-104%; avg: 100%*

average value of 6 determinations