WO2005051348A2

WO2005051348A2 - Enteric-coated tablets of pantoprazole

Info

Publication number: WO2005051348A2
Application number: PCT/HU2004/000111
Authority: WO
Inventors: Pál FEKETE; Zsuzsa SZLÁVYNÉ SZÉLL; Cecília BURESNÉ PAPP; Éva FURDYGA
Original assignee: EGIS Gyógyszergyár Rt.
Priority date: 2003-11-25
Filing date: 2004-11-24
Publication date: 2005-06-09
Also published as: HUP0303791A3; WO2005051348A3; HU0303791D0; HUP0303791A2; HU227317B1

Abstract

The invention relates to enteric-coated tablets containing pantoprazole as active ingredient and a process for the preparation thereof. The tablets according to the invention comprise a.) a core consisting of 20-50% by weight (related to the weight of the tablet core) of the active ingredient, spray-dried or granulated mannitol having an average particle size between 100 µm and 500 µm, an alkalizing agent, a disintegrant and a lubricant conventionally applied in the pharmaceutical industry; b.) a water-soluble separating film coating; c.) an enterosolvent film coating insoluble in gastric juices; and d.) an optional water-soluble protecting film coating, and show increased stability during storage.

Description

ENTERIC-COATED TABLETS OF PANTOPRAZOLE

Field of the invention

The invention relates to enteric-coated tablets containing pantoprazole as active ingredient and a process for the preparation thereof.

Technical background of the invention Pantoprazole (5- (difluoromethoxy) -2 { [ (3,4-di- methoxγ-2-pγridinyl) -methyl] -sulphinyl} -lH-benz- imidazole) of the formula (I)

is a proton pump inhibitor belonging to the group of benzimidazoles . Similarly to other members of this group (omeprazole, lansoprazole, perprazole, etc.) this compound also 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 is, however, well known that in acidic medium these compounds are liable to decomposition. Similarly to other molecules belonging to this group, pantoprazole rs also instable in acidic medium. In aqueous media more acidic than pH 4 it suffers a practically complete decomposition within- a period shorter than 10 minutes. Even in solid state it is sensitive to heat, to humidity, to light and especially to substances containing an acidic group. That is why when benzimidazole derivatives are formulated into oral pharmaceutical compositions the above characteristics of the compounds are always to be- taken^' into consideration. _ It is not sufficient ^"to ^' protect^"' t e primary formulation containing the active ingredient (crystal, granule, pellet, tablet, capsule) from the decomposing effect of the gastric acid by using a coating insoluble in acids, but the active ingredient itself is also to be protected from the effects of the coating material and other excipients being present in the composition, furthermore from environmental elements causing decompositio .

Taking into account the highly important role of the benzimidazole derivatives in the therapy together with the above considerations, it is not surprising that the first patent application concerned with oral dosage forms of the ^'•compounds, (European 'patent No. 244, 380) -.was followed ^'by a number of further ^'applications. According .to Hungarian* patent^* No. 198,385 "corresponding to EP 244,380 stable pharmaceutical formulations containing as active ingredient an acid-sensitive compound of benzimidazole type should consist of the following 3. parts :

1. - A- -core containing -either the^-1 '-active ingredient together- with -an .alkaline . ^'substance or an alkaline salt ---of- the active -i'ngred-ient . Said core may be formulated into granules, pellets, tablets or fillers of capsules. In case of tablets polyvinylpyrrolidone or hydroxypropyl cellulose is used as excipient.

2. A water-soluble interim film coating, which separates the „core" from the acidic coating material. This may also contain an alkaline component, or it may be the shell of the capsule .

3. A film coating resistant to gastric acid dissolving in the small intestine (enterosolvent) . Its material contains acid groups .

The ^• term "pellet" used throughout - this- specification relates . to nearly. ^• - spherical agglomerates* 0.3-2.0 mm in diameter.

The novelty or inventive step of the later patent applications concerned with oral pharmaceutical compositions containing acid- sensitive benzimidazole derivatives in general or ^•' certain -members of them or with a manufacturing process ^•• -thereof • is_..;:_., practically always determined in"^' relation to EP ..2-44 _f-

The first patent application concerned with the preparation of a pantoprazole composition is International patent WO 92/22284. The number of the corresponding Hungarian patent is 219,247.

According to this patent specification the pharmaceutical compositions containing acid- sensitive benzimidazole derivatives described in EP 244,380 contain several components incompatible with pantoprazole. According to the specification the lactose, microcrystalline cellulose and hydroxypropyl cellulose being present in the composition cause an increased decomposition of the pantoprazole. Instead of these components polyvinylpyrrolidone and/or hydroxypropyl-methyl cellulose are used as excipients, and mannitol is applied as an" optional inert filler. As a ^' result of the modification of the composition pharmaceutical compositions of favourable stability can be produced. In Hungarian patent specification No. 219,247 it is described that whenever mannitoli is used as filler, the use of an appropriate polymeric binder is also' required. '-•.*

According to the literature the.-_^ pantoprazole compositions being on the market are prepared as contemplated in Hungarian patent No. 219,247. As to the quality of the ingredients, said compositions are identical with the enterosolvent tablet described in Example 1 of the patent specification.

The above composition, which is provided in Hungarian patent No. 219,247 ensures that the stability of the composition containing pantoprazole as active ingredient is suitable even if the humidity content of the composition is between 5 and 8% by weight, contrary to the maximum value of 1.5% by weight raised as a requirement^' i^'n ^" Hungarian ^' patent specification No. 198,385. Meeting said requirement would demand expensive technical measures (e.g. drying;,^• air with a^' low humidity content cooled below -15 °C, tabletting and packing room with 20% relative humidity content) .

An all-out examination of the qualitative" characteristics of the compositions revealed that while- ^'the chemical stability of the composition manufactured according ■■ ,to the process- -specified in Hungarian patent-**, No. 219,247 is really suitable, the in vitro dissolution of the active ingredient after storage lasting only - one week at a relative humidity content of 75% considerably decreases (from a value of above 80% to about 20%) , and practically does not meet the pharmacopoeial requirements . The dissolution of the active ingredient in case of solid pharmaceutical compositions is a highly important qualitative parameter, as without the dissolution of the active ingredient in an appropriate extent and at a suitable rate the absorption of the active ingredient could not occur, and thus a therapeutic effect could not be^' -achieved.^' In case of. ehterosόlvent • (enteric- - coated) compositions resistant to gastric ^■ acid the dissolution of the active ingredient is to be examined and ^• evaluated according to the specifications of The United States Pharmacopoeia as follows (The United States Pharmacopeia Ed. 26, 2003, US Pharmacopeial Convention, Inc, Rockville, p. 2160-216.1.): .

The dissolution characteristics of the film- coated enterosolvent tablets according to the prior art containing pantoprazole or a salt thereof suffer a change during storage.

The dissolution rate of the .active ingredient from a pharmaceutical composition containing an appropriate alkalizing '. substance in order ^■ to -stabilize the active ingredient, -a polymeric binder and other auxiliary agents in order to meet the physical requirements . concerning the tablet core, becomes slower during storage, and does not meet the above pharmacopoeial requirements .

The aim of the present invention was to elaborate a film-coated . enterosolvent. ^". tablet- containing pantoprazole, which comprises a core containing the stabilized----active ingredient- of suitable mechanical stability, a separating layer surrounding the core and an enterosolvent coating, which tablet keeps its favourable dissolution characteristics under storage • and thus ensures the proper delivery of the active ingredient. Summary of the invention The invention is based on the recognition that by using appropriately chosen excipients compatible with the active ingredient it is not necessary to use a polymeric binder in order to prepare pantoprazole tablets possessing mechanical characteristics suitable for the formation of a film coating, and the -dissolution of the active ingredient from said tablets following storage meets even the strictest pharmacopoeial requirements.

Details of the invention

According to an aspect of the present invention there are provided enteric-coated tablets containing pantoprazole, that is 5- (difluoro-

■methoxy) -2{ [ (3,4-dimethoxy-2-pyridinyl) -ritiethyl] - sulphinyl} -lH-benzlmidazole as active ingredient, which comprise • a.) a core consisting of 20-50% by weight (related to the weight of the tablet core) of the 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 generally applied in the pharmaceutical industry; b.) a water-soluble separating film coating; c.) an enterosolvent film coating insoluble in gastric juices; and d.) an optional water-soluble protecting film coating.

The decrease in the dissolution of the active ingredient from pantoprazole tablets manufactured as specified in Hungarian patent No. 219,247 during storage at a relative humidity content of 75% is attributed to thepolymeric - polyvinylpyrrolidone (povidone) type - binder, which may cause a serious carburiz- ation of the structure of the tablet upon the effect of humidity absorbed during storage. This considerable decrease in the dissolution could not be expected on the basis of the composition provided in Example 1 of Hungarian patent No. 219,247, since it contains the usual amount, that is 2.58% of polyvinylpyrrolidone binder (Povidone K90) , and at the same time a high amount, that is 32.3% of cross-linked polyvinyl pyrrolidone (Crospovidone) as disintegrant . Namely for the persons skilled in the art it is known that in the compositions in form of tablets povidone as excipient is usually used in an amount between 0,5 and 5%, while crospovidone as disintegrant is generally applied in an amount between 2 and 5% (Pharmaceutical Excipients 2000, Windows Version, American Pharmaceutical Association and Pharmaceutical Press; Povidone, Crospovidone).

Up to now no method has been described in the literature for the preparation of tablets devoid of ^' polymeric, binder -^'containing pantopr.azole as active ingredient. Hungarian patent No. 219,-247 teaches as follows:- „If only mannitol is used for the tablets as filler, the application of an appropriate binder is necessary, which renders the core appropriately hard". Despite of this statement it has been found that there is a composition enabling the preparation of the tablet core of suitable physical and chemical ■stability even withoαt ^:- the application _.-.of 'polymeric binders....- ..„*:_. - . *. - ^. .

According to a preferred embodiment of the invention the film-coated enterosolvent tablet containing pantoprazole as active ingredient comprises a.) a core consisting of 20-50% by weight (related to the weight of the tablet core) of the active ingredient, 30-75% by weight of spray-dried or granulated mannitol having an ι: average particle size between 100 μm and 500 μm, 2-20% by weight of an alkalizing substance, a disintegrant and a lubricant usually applied in the pharmaceutical industry; b.) a water-soluble separating film coating; c.) an enterosolvent film coating insoluble in gastric juices; and d.) an optional wa-ter.-sαlύblev ^• protecting .film coating. ^{• ' ■■ •} .. ,

More specifically, according to a ^• preferred embodiment of the ■ invention the film-coated enterosolvent tablet containing pantoprazole as active ingredient comprises a.) a core consisting of 20-50% by weight (related to the weight of the tablet core) , preferably- - 25-35%. by weight-, of the sodium-, salt of pantoprazole^', . 30-^-75% by ".<wei,ght.> preferably -30-55%- by^' weight , -- more' - pre erably- ^• 30^-40%.. -.by weight of spray-dried or granulated mannitol having an average particle size between 100 μm and 500 μm, 2-20% by weight, preferably 10-20% by weight of a disintegrant, 2-20% by weight, preferably 5-10% by weight of an alkalizing substance and 1-5% by weight, preferably 2-4% by weight of a lubricant; b.) a water-soluble separating film coating; c.) an enteric film coating insoluble in gastric juices; and d.) an optional water-soluble protecting film coating.

The tablet according to the invention contains as active ingredient pantoprazole, preferably the sodium salt of pantoprazole._., more, preferably the sesquihydrate ■ of the - sodium salt ^■ of pantoprazole.

The tablet according to the invention contains as alkalizing substance an alkali hydroxide, an alkali carbonate, an alkali hydrocarbonate or mixtures thereof, preferably an alkali hydro- carbonate, more preferably sodium hydroxide, sodium ca bonate,, ., . sodiμm hydrocarbonate or a mixture thereof. The most, .preferable ,is the application of sodium carbonaφe . , *.

As disintegrant the tablet according to the invention contains sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, crospovidone or a mixture thereof. The most preferable is the application of crospovidone. As anti-friction agent and lubricant stearic acid, hydrogenated vegetable oils, paraffme or alkali earths stearates, preferably magnesium or potassium stearate, more preferably potassium stearate can be used.

A preferred embodiment of the film-coated tablet according to the invention containing pantoprazole as active ingredient contains, on the surface of the tablet core, 5-20% by weight (related to the total weight of the composition) of a water-soluble coating, on the outer surface of said coating 5-20 % by weight of an enteric coating insoluble in gastric acid and, if desired, 0,5-5% by weight of a further coating soluble in water.

According to another aspect of the present invention there is provided a process for the preparation of enteric-coated tablets containing pantoprazole as active ingredient, which comprises a.) providing a tablet core consisting of 20 - 50% by weight of the active ingredient, spray- dried or granulated mannitol having a particle size between 100 μm and 500 μm, an alkalizing agent and optionally other auxiliary agents generally applied in the pharmaceutical industry; b.) applying to the core a water-soluble film- coating; c.) applying an enterosolvent film coating insoluble in gastric juices; and optionally d*. ) applying a -water-soluble protecting film coating.

More particularly, the process according to the invention for the preparation of enteric-coated tablets containing pantoprazole as active ingredient comprises a.) providing a tablet core consisting of 20-50% by weight, preferably 25-35% by weight of the active ingredient, 30-75% by* weight, preferably30-50% by weight, more preferably ..30-40% by- weight of spray-dried mannitol having an average particle size between 100 μm and 500 μm, 2-20% by weight, preferably 5-10% by weight of an alkalizing agent, 2-20% by weight, preferably 10-20% by weight of a disintegrant and 1-5% by weight, preferably 2-4% by weight of- a lubricant, b.) applying to the core 5-20% by weight (related to the final weight of the composition) a water-soluble film-coating; c.) applying 5-20% by weight (related to the final weight of the composition) of an enteric film coating insoluble in gastric juices; and optionally d.) applying 0,5-5 % by weight (related to the final weight of the composition)^' - of a water- soluble protecting film, coating.

The film-coated tablet according to the invention containing pantoprazole can also be prepared as follows. First a tablet core is provided by granulating a mixture of 20-50% by weight (related to the^' weight, of the tablet core) of the active ingredient, a disintegrant.and an alkalizing agent with an aqueous _. solution: of .mannitol- and the alkalizing- agent, optionally drying the .granulate,^'., adding to the granulate spray-dried mannitol . having an average particle size between 100 μm and 500 ^'μm, optionally a disintegrant and a lubricant and compressing the homogenizate to tablets. The thus-obtained tablets are then coated first with a water- soluble coating, then with an enterosolvent coating resistant to gastric acid and finally 18 and optionally with a water-soluble film coating.

More particularly, the film-coated tablet according to the invention containing pantoprazole can also be prepared as follows: the mixture of 20-50% by weight, preferably 25- 35% by -weight -.(related ••to" -the --weight- , of the tablet core) of the active- ingredient, . ■ 2-20% by weight, preferably 10-20% by weight of a disintegrant and' 2-20 % .by weight, preferably 5- 10% by weight of an alkalizing agent is granulated with an aqueous solution of 2-20% by weight of mannitol and 1-3% by weight of an alkalizing agent, the granulate is. optionally dried, 30-55% by weight, preferably 20-40% by weight ,of spray-dried mannitol having.'.;-an. average particle "*-,.S_'i-ze between" 100 ^' μm ^" and -500 ^' μm-, '^•'optionally"-' 2-20-% -by -weight', -preferably 10 2U^'%^^'by^"'" weight of a disintegrant^' and 1-5% by weight, preferably 2-4% by weight of a lubricant are added to it, the homogenizate is compressed to tablets and the tablets are coated subsequently with the following layers: 1. 5-20% by weight (related to the total weight of the composition) of a water-soluble coating, 2. 5-20% (related to the total weight of the composition) of an enterosolvent coating insoluble in gastric acid, and finally and optionally

3. 0,5-5% by weight of a water-soluble film coating.

As active ingredient for _: the process according to the invention pantoprazole, preferably the sodium salt of pantoprazole, more particularly the sesquihydrate of the . sodium salt of pantoprazole is used.

As alkalizing agent an alkali hydroxide, an alkali carbonate, an alkali hydrocarbonate or mixtures thereof, preferably an alkali hydrocarbonate-, more preferably, .sodium: hydroxide, - sodium carbonate,., sodium hydrocarbonate or a mixture thereof . can be us d.. The. ost., preferable is the application of sodium carbonate. - -^•

As disintegrant sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, crospovidone, or a mixture thereof. The most preferable is the application of crospovidone. As lubricant stearic acid, hydrogenated vegetable oils, paraf ine or alkali earths stearates, preferably magnesium or potassium stearate, more preferably potassium stearate can be used.

It has been found that when using as filler granulated or spray-dried mannitol having an average particle size of 100 μm or above and optionally mannitol applied from the aqueous solution, as alkalizing agent sodium hydrogen carbonate, as disintegrant crospovidone and as lubricant potassium stearate, quickly disintegrating tablet cores of an appropriate mechanical stability can be provided, which enable a quick dissolution of the active ingredient. When coating the thus-obtained tablet cores with. an intermediate layer optionally consisting of hydroxypr.opyl-methyl cellulose and with a further layer insoluble in gastric acid but soluble in enteric juices and optionally with a water-soluble outer layer, pantoprazole compositions can be prepared which are much more favourable in respect of the dissolution requirements than those prepared according to the state of the art. Pantoprazole used as active ingredient for the composition according to the invention is known from the European patent No. 166,287. Among the physiologically acceptable salts of pantoprazole provided in the same patent the use of the sodium salt is particularly preferable.

Granulated . or ..spray-dried mannitol having an average particle size of -100 μm or -above used for the preparation of the tablet core belongs to the so-called direct compressing auxiliary? agents. These substances are characterized by favourable flow properties resulted by the particle size of 100 μm or above, the nearly symmetric or spherical shape of the granules'?:-; furthermore by a good compressibility. Such^* substances comprising mannitol are: marketed by' the firm Roquette under the name Pearlitol (e.g.

Pearlitol- 300 DC, Pearlj tol 400: DC.,., ..Pearlitol

500 DC, Pearlitol SD 200, Pearlitol SD 100), or by the firm SPI Pharma (e.g. Mannitol granular 2080, Mannitol granular 3215) .

In certain cases, depending on the particle size of the active ingredient or the excipient used for the composition (e.g. sodium carbonate, crospovidone) or on the amount of the granulated 48

22

or spray-dried mannitol having a particle size of 100 μm or above being present in the tablet core, it may be necessary to improve the flowability of the mixture. This can be achieved by increasing the particle size of the active ingredient. For this purpose granulation may be carried out with an aqueous solution Of mannitol-.' The amount of mannitol used- for the granulation - may ^■ be ■ between 2^' and 20%-by^' weight related to the total weight of the tablet core;"" Granulation can be carried out ■ ^■ either by kneading or by fluidization spraying methods.

In the compositions according to the invention dislntegrants are also used in order to ensure a^'1" quick decomposition of the tablet core in an aqueous .. medium^r . -and a quick and " complete dissolution "-^'of^* --the active*-*- -ingredient:^" As diajlntegrant ^"it .'is- ^"expedient to.-^' use* a«»^'s-o-called „super disintegrant", such as sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose or crospovidone (cross-linked polyvinylpyrrolidone) . The quantity of the disintegrants in the composition may be 2-20% by weight. As these substances can absorb a considerable amount of water, it is expedient to use these substances in the smallest possible quantity in order to decrease water-uptake of the compositions during storage.

In the composition according to the invention the pH of the tablet core is to be raised to a value above pH 7 in order to ensure the chemical stability Of pantoprazole-. "--'As -alkalizing 'a'gent sodium ^• hydroxide,•^• potassium Tydroxidey ^•■■sodium hydrogen carbonate or sodium carbonate may ' be us.ed.- These substances may be admixed- with the active ingredient and the mannitol in powdered form, or may be applied in the form of solutions. In the composition preferably sodium carbonate is applied. The amount of the alkalizing agents in the tablet core is 2-20% by weight. A part, of ^• he alkalizing agent may -ais' - be- applied together "with -the aqueou-s.-.-solution of the ...mannitol . ^" "...--^'* ^'■■ ,--- . ■ "... -*■-.- .,,, ,-,-*>'.<;,• ....-•-

In the composition according to the invention it is preferable to use a lubricant, that is an anti-friction substance for the preparation of the tablet core. The role of this substance is to decrease the friction and adhesion between the tablet core and the compressing dies. For this purpose substances generally used for the manufacture of tablets, such as stearic acid, hydrogenated vegetable oils, paraffine or alkaline earth stearates, preferably magnesium or potassium stearate, more preferably potassium stearate are used in an amount between 1-5% related to the weight of the composition.

The water-soluble ^'separating, layer applied on the tablet ^■ .core . may^' ' contain film-forming substances generally used for the preparation of film-coated tablets. Such water-soluble film- forming substance is e.g. hydroxypropyl-methyl cellulose, which is suggested to be used as a substance for the separating layer in compositions . containing benzimidazole derivatives in several publications according to the state of the -art (e"".^"g. ^'European .patent No. 244,380, Hungarian patent No..- - 247 ,^'9-83) v. Besidesthe film-forming polymer*,-* ,- optionally -further-' auxiliary agents, plasticizers (such as polyethylene glycol) and optionally further additives (e.g. titanium ■ dioxide, talc) can be used in the coating. The separating coating should be relatively thick in order to provide an effective protection for the active ingredient in the core against the acidic, film- forming polymer resistant to gastric acid. That 48

25

is why the amount of the separating layer is between 5 and 20% by weight related to the total amount of the composition. As coating substance preferably ready-made coating substances, such as the product under the trademark Opadry can be used.

The gastric acid resistant enteric coating may contain film-forming substances known for the persons skilled in the art. Such substances are e.g. cellulose acetate phtalate, polyvinyl- acetate phtalate, hydroxypropyl-methyl cellulose phtalate, hydroxypropyl-methyl cellulose acetate succinate, ethylacrylate methacrylic acid copolymer, methylmethacrylate methacrylic acid copolymer, shellac. These polymers may be used as organic solutions or preferably as aqueous dispersions, and optionally plasticizers, e.g. triacetine or triethyl citrate may be added to them. This coating should also be relatively thick in order to ensure the intact character of the film-coated tablet while the composition is in the stomach, and thus to ensure an efficient protection for the active ingredient in the core against the decomposing effect of the acidic gastric juice. That is why the amount of the separating layer is 5 to 20% by weight related to the total weight of the composition.

The outer protecting layer serving to prevent the film-coated tablets from sticking together during storage at higher temperatures may also contain water-soluble film-forming substances generally applied for the manufacture of film- coated tablets .- Such a . water-soluble *:^• film- forming substance is e.g. hydroxypropyl-methyl cellulose. Besides the film-forming polymer optionally further excipients, plasticizers , e.g. polyethylene glycol may be used in the coating. This protecting layer is relatively thin, it is used in an amount between 0,5 and 5% by weight related, to the total weight of the composition. As coating substance ready-made coating systems, such as the substances marketed under the trade name Opadry can preferably be applied. • . . ' ^■. -^•...^• .

A particularly advantage of the enteric-coated tablets according to the invention over other enterosolvent, pantoprazole-containing film- coated tablets according to the state of the art is that the rate of the dissolution of the active ingredient does not drop off during storage of the film-coated tablets in a room having a relative humidity content of 75%, as the tablet core does not contain hygroscopic, hydrofil polymeric binders, such as polyvinylpyrrolidone or hydroxymethyl cellulose, and at the same time the amount of the highly hygroscopic disintegrant is considerably lower.

In--^, order ^■• to . demonstrate ' the..-- -favourable properties - — of- ^' the enteric-coated tablets according to' the invention, the :.^' qualitative parameters .of. the composition prepared according to Example 1 and those of the composition prepared according to comparative Example 2 (which corresponds to the composition provided in Example 1 of the Hungarian patent specification No. 219,247B) measured immediatelyaf er the -manufacture ' and following -a: .storage lasting one week at" a temperature of ^*40°C--under a relative... humidity -content (RH) of 75% -are shown as follows :

*Karl Fischer's method On the basis of the experiments it can be seen that the in vitro dissolution of the active ingredient from the composition according to the invention during storage in a room having a relative humidity content of 75% decreases only in a small extent, compared to the dissolution from a composition according to the state of the art, which is considerable. After^"" storage^' • the

^•dissolution value of the-' composition' according to - the state of the art does hot^' meet the requirements of the USP. ^' • The^" considerable difference between the dissolution data of the two compositions can be attributed to the difference between the water-uptake (water content) of the two compositions and . the presence of the polymeric binding agent in the

^■'Composition.* according to '.HU"-'No. ^• 219_/-247B"".- The ' water content, of-..- the' film tablets according to the invention, - that -i-s- the water-' content determined according to the method of Karl Fischer rose from 6,1% by weight to 8,1% by weight during storage, while the water content of the reference composition rose from 7,7% by weight to 12,4% by weight. The difference in the water-uptake may be attributed to the difference in the compositions of the tablet cores. Namely the tablet core according to the invention contains 16.1% by weight of hygroscopic crospovidone, while the tablet core of the composition according to the literature contains 32.2% by weight of crospovidone and further 2,6% by weight of povidone K90 polymer,, which is also a hygroscopic substance. This latter polymer may increase the strength of the binding between the granules in the. tablet core^' having a high humidity content due to further ' physical changes, which may finally lead to^"' a slow dissolution of the active ingredient.

Further details of the invention are illustrated by the following Examples without limiting the scope of protection, that is the claimed composition or the manufacturing method to the Examples .

Example 1

Composition :

Manufac.turing process

Into the container of a fluidization granulating machine of Glatt GPCG 1 type 586.3 g of pantoprazole, 104.0 g of sodium carbonate and 130.0 g of crospovidone are introduced, and the mixture of the ingredients is granulated with a solution of 260.0 g of mannitol and 26.0 g of sodium carbonate in 500 g of water. The has decreased below 3%, and then 648.7 g of spray-dried mannitol, the residual 195.0 g of crospovidone and ' 65.0 g of potassium stearate are subsequently mixed to it. The homogen-izate is compressed into tablets weighting 155 mg on a tabletting machine of Manesty B3B^'"-type using-.leήtifiørm- dies" of' -8 -itim*- In- _.diameter . --, The^; tablet- cores ^"are coated-^' first '^•'with a -^'-dispersion of 2.6-0 :-.P -,.g, of Opardy I-. in- 2300. g "d -'.-water , then with " a coating dispersion prepared from an aqueous dispersion of 416.0 g of Eudragit L 30D containing 124.8 g of Eudragit ^' L-55 , ^'36.4 ^'g of triethyl citrate, 89.7 g of talc and 9.1 g of Tween 80, finally with a solution of 26.0 g of Opadry 'clear in 143.0- g of water using a coating apparatus o .Glatt GC 250 type. ^{• '}

Example 2 (comparative: example) ^"". •^{' '} -^•

Composition :

Manufacturing process

Into the container of a fluidization granulating machine of Glatt GPCG 1 type 676.5 g of pantoprazole, 540.5 g of mannitol, 120.0 g of sodium carbonate and 400 g of crospovidone are introduced, and the mixture of the ingredients is granulated with a solution of 60.0 g of Povidon K90, 100.0 g of mannitol and 30.0 g of sodium carbonate in 750 g of water. The granulate is dried until the humidity content has decreased below 3%, and then 350.0 g of crospovidone - and-- 48.0 g of -potassium stearate are_. mixed to- it. The homogenizate is compressed into tablets weighting 155 mg on a tabletting machine of Manesty B3B type using lentiform dies of 8 mm in diameter. The tablet cores are coated first with a coating dispersion prepared from 237.5 g of 3 cP hydroxypropyl-methyl cellulose (Pharmacoat 603), 4,8 g of Povidon K 25, 4.2 g of titanium dioxide, 53.1 g of propylene glycol and 2130. ¹ of water, then with a coating dispersion prepared from an aqueous .dispersion of 682.0 g of Eudragit L 30D containing 204.6 g of Eudragit -55 and 20.4 g of triethyl citrate in 1330 g of water.

Example 3

Composition:

,1

Manufacturing process Into the mixing pan of a Turbula mixer 250.0 g of pantoprazole, 55.4 g of g of sodium carbonate, 138.5 g of crospovidone and 415.0 g of mannitol granulate are measured. The substances are . homogenizated for -10 minutes, ^{j ■} 2J7-. -7 ; g of potassium stearate -are_*..added to^' them and,■-■the homogenizatio.n is continued for- -^'-further

_;. 2-_. minutes. The homogenizate is compressed to tablets weighting 155 mg on a tabletting machine of EXI type using len-tiform dies of 8 mm in diameter. The tablet cores are coated as specified in Example 1 in a coating apparatus of Glatt GC 250 type first with a dispersion of 1.10.8 g of Opadry I in 1000 g of water, then with a coating dispersion prepared from 17_.7.3 g of an aqueous Eudragit L .30D dispersion containing -53.2 g of Eudragit '. L-55 , 15.5 g of triethyl citrate, 38.2 g of talc and^' 3.9 g of ^' ween 80.

Example 4 Composition:

Protecting layer Opadry clear 1.00 mg 2.00 mg 0.064 kg 0.20 kg ( Hydroxypropyl - methyl cellulose , polyethylene glycol 400 ) Purified 0.58 kg 1.80 kg water

Manufacturing process

To the container of a fluidization granulating equipment of Glatt GPCG 15 type 6.77 kg of pantoprazole, 1.2 kg of sodium carbonate and 1.5 kg of crospovidone are introduced, and the mixture is granulated with a solution of 3.0 kg of mannitol and 0.30 kg of sodium carbonate in 5.0 kg of water. The granulate is dried until the water content has decreased below 3% and 7.48 kg of spray-dried mannitol, the residual 2.25 kg of crospovidone and finally 0.75 kg of potassium stearate are added to it. A part of the ho ogenizate is compressed to tablets on a tabletting machine of Manesty Betapress type using lentiform dies of 8 mm in diameter. In this- way 100,000 pieces of tablets weighting 155 mg and containing 40 mg of the active agent each are produced. The residual homogenizate is compressed to tablets using lentiform dies of 6 mm in diameter. Thus about 100,000 pieces of tablets weithing 77.5 mg and containing 20 mg of the active ingredient are produced.

15 kg of the tablets weighting 40 mg and 5 kg of the tablets weighting 20 mg are coated^" in a coating apparatus of Driam 500/600 Vario type by using a coating liquid having a- composition provided in the above Table.

Claims

41What we claim is

1. Enteric-coated tablets containing pantoprazole, that is 5- (difluoromethoxy) - 2{ [ (3, -dimethoxy-2-pyridinyl) -methyl] - sulphinyl } -lH-benzimidazole

as active ingredient, which comprise a.) a core consisting -of 20-50% by weight (related to the weight of the tablet core) of the active ingredient, spray-dried or granulated mannitol having an average particle size between

100 μm and 500 μm, an alkalizing agent, a disintegrant and a lubricant conventionally applied in the pharmaceutical industry; b.) a water-soluble separating film coating; c.) an enterosolvent film coating insoluble in gastric juices; and d.) an optional water-soluble protecting film coating .

2. Enteric-coated tablets containing pantoprazole as claimed in claim 1, which comprise , , a.) a core- consisting of 20-50% by weight of the activ - ingredient, - -30-75% by ^'weight of -spray- dried or ^'granulated mannitol^" having an average particle size between-100 μm and;- 500 -μm, • 2-20 % by weight of an alkalizing agent, a disintegrant and a lubricant conventionally applied in the pharmaceutical industry; b.) a water-soluble separating film coating; c.) an enterosolvent film coating insoluble in gastric juices; and d.) an optional water-soluble protecting film coating. .. .

3. Enteric-coated tablets containing pantoprazole as claimed in claim 2 , wherein the core contains 2-20% by weight (related to the weight of the tablet core) of a disintegrant and 1-5% by weight of a lubricant.

4. Enteric-coated tablets containing pantoprazole as claimed in claim 3 , wherein the core consists of 25-35% by weight of the active ingredient, 30-55% by weight of spray-dried or granulated mannitol having an average particle size between 100 μm and 500 μm, 5-10% by weight of an alkalizing agent, as excipient 2-20% by weight of a disintegrant and 2-4% by weight of a lubricant.

5.' ^' . - Eh erie-coated^v...,.^{~ '}, tablets , containing •pantoprazole :as-..;claimed in .claim . 4 , . wherein the core consists of 25-35% by weight of the active ingredient, 30-40% by weight of spray-dried or granulated mannitol having an average - particle size between 100 μm and 500 μm, 5-10% by weight of an alkalizing agent, as excipient 10-20% by weight, of a disintegrant and 2-4% by weight of a lubricant.

6. Enteric-coated ^• tablets containing pantoprazole as claimed in claim 1, which comprise a.) a core consisting of 25-25% by weight of the sodium salt of pantoprazole, preferably the sesquihydrate of the sodium salt of pantoprazole, as filler 30-40% by weight of spray-dried mannitol having an average particle size between 100 μm and 500 μm, as alkalizing agent 5-10% by weight of sodium carbonate, as disintegrant 10-20% by weight of crospovidone and as lubricant 2-4% by weight of calcium stearate; b.) 2-20% (related to the total weight of the composition) of ^■ a water-soluble film coating; c.) 5-20% (related to the total weight of the

.composition) ,.of- an enterosolvent film- coating resi-&tant to gastric juices; and optionally d.) 0.5'-5% (related to the total weight of the composition) of a water-soluble protecting film coating.

7. A process for the preparation of enteric- coated tablets containing pantoprazole as claimed in claim 1, which comprises a.) providing a tablet core consisting of 20 - 50% by weight, of the active ingredient, spray- dried or. granulated mannitol having, a particle size between 100 μm and 500 μm, an alkalizing agent, a disintegrant and a lubricant conventionally applied in the pharmaceutical industry; b.) applying to the core a water-soluble film- coating; c.) applying an enterosolvent film coating insoluble in gastric juices; and d.) optionally applying a water-soluble protecting film coating.

8. A process as claimed in claim 7, wherein 30- 75% by weight (related to the weight of the tablet core) of spray-dried mannitol having a particle ^'size between 100 μm and 500 μm" and 2-

^•"•20%^' by weight of an alkalizing agent is used.

9. A process as claimed in claim 8, wherein 2- 20% by weight (related to the weight of the tablet core) of a disintegrant and 1-5% by weight of a lubricant are used.

10. A process as claimed in claim 9, wherein 25- 35% by weight (related to the weight of the tablet core) of the active ingredient, 30-55% by weight, preferably 30-40% by weight of spray- dried mannitol having a particle size between 100 μm and 500 μm, 5-10 % by weight of an alkalizing agent and 10-20 % by weight of a disintegrant are used.

11. A process as claimed in claim 10, which comprises a.) providing a tablet core consisting of 25-35% by weight (related to the weight of the tablet core) of the sodium salt of pantoprazole, preferably the sesquihydrate of the sodium salt of pantoprazole, 30-40 % by weight of spray- dried mannitol having a particle size between 100 μm and 500 μm, as alkalizing agent 5-10% by weight of sodium carbonate, as disintegrant 10- 20%: ό-f crospovidone and as lubricant 2-^'-4% ^"by weight- of potassium stearate, ■ b.) applying to the core 5-20% (related to the final weight of the composition) of a water- soluble film-coating; c.) applying 5-20% of an enterosolvent film coating insoluble in gastric juices; and d.) optionally applying 0.5-5% by weight (related to the final weight of_. the composition) of a water-soluble protecting film coating.

12. A process as claimed in claim 11, which comprises a.) providing a tablet core by granulating the mixture of 20-50% by weight (related to the weight of the tablet core) of the active ingredient, a disintegrant and an alkalizing agent with an aqueous solution of mannitol and the alkalizing agent, optionally drying the granulate, adding spray-dried mannitol having an average particle size between 100 μm and 500 μm and optionally a disintegrant and a lubricant and compressing the homogenizate to tablets, b.) applying to the core a water-soluble film- coating;^{* •}- ^{•• ■' •} -i;

.c-;. ) .. -applying an enterosolvent' film " coatrih-g ^■insoluble in ^■ gastric juices; and- ■^' "' "^■•'• * d.-) optionally applying again- a water-soluble protecting film coating.

13. A process as claimed in claim 12, wherein the tablet core is prepared by granulating a mixture of 20-50% by weight of the active ingredient, 2-20% by weight of a disintegrate and 2-20 % by weight of an alkalizing agent with an-, aqueous .solution of- 2-20%.. by weight of mannitol and- ^• 1-3 % by weight of an alkalizing agent, optionally drying the granulate, adding 30-55% by weight of spray-dried mannitol having an average particle size between 100 μm and 500 μm, 2-20 % by weight of a disintegrant and 1-5% by weight of a lubricant and compressing the homogenizate to tablets.

14. A process as claimed in claim 13. wherein the mixture of 25-35% by weight of the active ingredient, 2-20% by weight of a disintegrant and 5-10% by weight of an alkalizing agent is granulated.

■15. A process as claimed in claim 14, wherein, the tablet core- is prepared •-.•by granulating ••^' a^' mixture- of, 25-35% by weight-'.^'.'..r.el-ated to^'..,, the weighty . of ^'the tablet core) of. the - active ingredient, 10-20% by weight of a disintegrant and 5-10% by weight of an alkalizing agent with an aqueous solution of 2-20% by weight of mannitol and 1-3% by weight of an alkalizing agent, optionally drying the granulate, adding 30-40%* by weight of spray-dried mannitol having an- average particle size between 100 μm and 500 μm, 10-20 % by weight of a disintegrant and 1-5% by weight of a lubricant to it and compressing the homogenizate to tablets.

16. A process as claimed in claim 12, which comprises a.) providing a tablet core by granulating the mixture of 25-35% by weight (related to the weight of the tablet core) of the sodium salt of pantoprazole, preferably the sesquihydrate 10-20 % by weight crospovidone and 5-10% by weight of sodium carbonate with an aqueous solution of 2- 20 % by weight of mannitol and 1-3% by weight of sodium carbonate, optionally drying the granulate, adding 30-40 % by weight of spray- dried mannitol having an average particle size between 100 ,μ-m and- 500 μm, 10-20% .■ by weight of crospovidone and ..1-5% by. weight of calciumstearate and .compressing the homogenizate "to tablets , b.) applying to the core 5-20% by weight (related to the final weight of the composition) a water-soluble film-coating; c.) applying 5-20% by weight of an enterosolvent film coating insoluble in gastric juices; and d.) optionally applying 0.5-5% of a water- soluble film coating..

17. A process as claimed in any -of claims 7-10 or 12-15, wherein the tablet core is coated first with 5-20% by weight (related to the final weight of the composition) of a water-soluble, then with 5-20% by weight (related to the final weight of the composition) of an enterosolvent film coating resistant to gastric juices and finally and optionally with 0.5-5% (related to the final weight of the composition) of a water- soluble film coating.

18. Enteric-coated tablets containing pantoprazole as • claimed in any of claims 1 to 5 , wherein the active ingredient is pantoprazole, preferably the sodium salt of pantoprazole, more preferably the sesquihydrate of the sodium salt of pantoprazole,

19. Enteric-coated tablets containing pantoprazole as claimed in any of claims 1 to 5 , wherein as alkalizing agent an alkali hydroxide, an alkali carbonate, an alkali hydrogen carbonate or the mixtures thereof, - preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate or the .mixtures thereof, more preferably sodium carbonate is used.

20. Enteric-coated tablets containing pantoprazole as claimed in any of claims 1 to 5 , wherein as disintegrant sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, crospovidone or the mixtures thereof, more preferably crospovidone is used.

21. Enteric-coated tablets containing pantoprazole as claimed in any of claims 1 to 5 , wherein as lubricant stearic acid, hydrogenated vegetable oils, paraffine or an alkaline earth stearate, preferably magnesium or potassium stearate, .more preferably potassium -stearate- is used. .^'. . . ... .*.* ^•

22. .. Enteric-coated tablets - containing pantoprazole as claimed in any of claims 1 to 5 , wherein the tablet core is coated a.) with 5-20% by weight (related to the total weight of the composition) of a water-soluble coating, b.) with 2-20% by weight (related to the total weight of the composition) of an enterosolvertt coating resistant to gastric juices, ,and optionally c.) with 0,5-5% by weight (related to the total weight of the composition) of a coating soluble in water.

23. A process as claimed in any of claims 7 to 10 or 12 to 15, wherein as active ingredient pantoprazole, preferably the sodium salt of pantoprazole, more preferably the sesquihydrate of the sodium salt of pantoprazole is used.

24. A process as claimed in any of claims 7 to 10 or 12 to 15, wherein as alkalizing agent an alkali hydroxide, an alkali carbonate, an alkali hydrogen carbonate or the mixtures thereof, preferably sodium hydroxide, sodium . carbonate, sodium hydrogen carbonate or the mixtures th*%r,eof, more preferably sodium carbonate- . is used

25. A process as claimed in any of claims 7 to 10 or 12 to 15, wherein as disintegrant sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, crospovidone or the mixtures thereof, more preferably crospovidone is used.

26. A process as claimed in any of claims 7 to 10 or 12 to 15, wherein as lubricant stearic acid, hydrogenated vegetable oils, paraffine or an alkaline earth stearate, preferably magnesium or potassium stearate, more preferably potassium stearate is used.