Multi-Layered Compositions Containing Histamine Or Serotonin Antagonists

(1 9) J Eur°Pean Patent Office <*S Office europeen des brevets (11) EP 0 546 593 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int. CI.6: A61 K 9/20, A61K9/24 of the grant of the patent: 03.09.1997 Bulletin 1997/36

(21) Application number: 92203262.8

(22) Date of filing: 23.10.1992

(54) Multi-layered compositions containing histamine or serotonin antagonists Mehrschichtzusammensetzungen enthaltend Histamin- oder Serotonin- Antagonisten Compositions multicouches contenant d'antagonistes de I'histamine ou de la serotonine

(84) Designated Contracting States: • Huckle, Paul Derrick DE DK ES NL PT SE Ware, Hertfordshire, SG1 2 ODP (GB)

(30) Priority: 30.10.1991 GB 9123044 (74) Representative: Filler, Wendy Anne, Dr. et al 30.10.1991 GB 9123026 Glaxo Wellcome pic 18.02.1992 GB 9203364 Glaxo Wellcome House, Berkeley Avenue (43) Date of publication of application: Greenford, Middlesex UB6 0NN (GB) 16.06.1993 Bulletin 1993/24 (56) References cited: (73) Proprietor: GLAXO GROUP LIMITED EP-A- 0 299 21 1 EP-A- 0 384 514 Greenford, Middlesex UB6 0NN (GB) GB-A- 2 230 185

(72) Inventors: Remarks: • Dandiker, Yogendra The file contains technical information submitted Ware, Hertfordshire, SG1 2 ODP (GB) after the application was filed and not included in this specification

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).

Printed by Rank Xerox (UK) Business Services 2.14.12/3.4 1 EP 0 546 593 B1 2

Description active ingredient followed by an immediate dose of active ingredient. Dosage forms for pulsed delivery are The invention relates to pharmaceutical composi- described, for example, in United Kingdom Patent tions for the controlled release of one or more active Specification No. 2230441 A. The described dosage ingredients. In particular, the invention relates to phar- s form comprises a two-part capsule containing a water- maceutical compositions for the controlled release of swellable material to separate the capsule parts on H2-antagonists or serotonin agonists or antagonists. swelling. Dosage forms of this type are relatively expen- Cimetidine, N-cyano-N'-methyl-N"-[2-[[(5-methyl- sive and difficult to manufacture. 1 H-imidazol-4-yl)methyl]thio]ethyl]guanidine, and its One major problem has been the provision of a pharmaceutical^ acceptable salts are described in Brit- 10 pulsed release dosage form which uses conventional ish Patent Specification No. 1397436. Delayed-release excipients and which can be prepared in a simple man- oral dosage forms of cimetidine and its pharmaceuti- ner using conventional tabletting machinery.A further cal^ acceptable acid addition salts are described in problem arises when aiming to prepare pulsed release European Patent Application No. 431877. Cimetidine is dosage forms containing highly water-soluble active a histamine H2-antagonist. 15 ingredients such as ranitidine. Some pulsed release Ranitidine, N-[2-[[[5-(dimethylamino)methyl-2-fura- devices rely on an outer layer comprised of a polymer nyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1 ,1 -ethenedi- which hydrates to form a gel matrix on coming into con- amine, and its pharmaceutical^ acceptable salts are tact with gastro-intestinal fluid. European Patent Appli- described in British Patent Specification No. 1565966, cation No. 384514 describes such a device. In this and a particular crystalline form of ranitidine hydrochlo- 20 device, once the outer layer has partially dissolved, ride is described and claimed in GB-B-2084580. In both leaving a loose gel network, gastrointestinal fluid wets of these specifications there is reference to a variety of the inner tablet. If the inner tablet contains a highly formulations including preparations for oral, topical, water-soluble active ingredient, this will leach out parenteral or rectal administration. Oral preparations of through the partially dissolved outer gel layer giving pre- ranitidine are further described in GB-B-21 42820, GB- 25 mature and unpredictable release and a non-distinct B-2198352, GB-B-2218336, GB-B-2219940, GB-B- pulse, which in turn can lead to reduced absorption and 2222772 and GB-A-2229094. insufficient plasma levels. Ranitidine is a potent histamine H2-antagonist There is also a problem with preparing pulsed which, in the form of its hydrochloride salt, is widely release dosage forms where relatively large doses of used in the treatment of conditions where there is an 30 active ingredient are required, especially in the case of advantage in lowering gastric acidity. Such conditions oral dosage forms. The cores of such dosage forms are include duodenal and gastric ulceration, reflux necessarily large which in turn limits the thickness of the oesophagitis and Zollinger-Ellison syndrome. Ranitidine outer layer if the tablets are to remain easy to swallow. may also be used prophylactically in surgical proce- The problem is multiplied if the active ingredient is dures, and in the treatment of allergic and inflammatory 35 water-soluble since, if the outer layer is thin, the drug conditions where histamine is a known mediator. can leach out through the thin outer layer again giving The serotonin S2-agonist sumatriptan, 3-[2- unpredictable and premature release. (dimethylamino)ethyl]-N-methyl-1H-indole-5-meth- We have now found that, using conventional excipi- anesulphonamide, is described in British Patent Specifi- ents and conventional tabletting machinery, it is possi- cation No. 2162522 and is a compound having a 40 ble to prepare dosage forms which allow for; for combination of highly advantageous properties for the example: treatment of migraine. Sumatriptan is preferably administered in the form of its succinate. i) pulsed release of an active ingredient; ii) immedi- The preparation of immediate release and sus- ate release of a first active ingredient followed by tained release dosage forms is well known. Recently 45 pulsed release of a second active ingredient; iii) dosage forms which provide for rapid release of an delayed sustained release of an active ingredient; active ingredient after an initial time delay have been iv)sustained release of a first active ingredient and described. These latter have become known as pulsed delayed sustained release of a second active ingre- release dosage forms. United Kingdom Patent Applica- dient; v) immediate release of a first active ingredi- tion No. 22301 85A describes a tablet for oral adminis- so ent followed by sustained release of a second tration which comprises two layers, one of which active ingredient, optionally followed by pulsed contains a drug for immediate release and the other release of a further active ingredient. contains a drug for sustained release. Thus the tablet essentially consists of two dosage forms bonded The pharmaceutical compositions of the invention together. A problem with this type of tablet is that it is not 55 have the advantages associated with pulsed release, simple to prepare efficiently using conventional tablet- sustained release and/or delayed release dosage ting machinery. European Patent Application No. forms. Thus the pharmaceutical compositions of the 384514 relates to a "tablet-within-a-tablet" pharmaceuti- invention allow for a reduction in the frequency of cal composition which provides for a sustained dose of administration of an active ingredient, enhancing patient

2 3 EP 0 546 593 B1 4 acceptability, and enable it to be released at a time active ingredient is present or when the inner layer or when it would be inconvenient to the patient to adminis- layers is gradually removed by a combination of dissolu- ter medication, for example, when the patient is asleep, tion and erosion once exposed, the outer layer com- and also enable medication to be administered prior to prises a pH independent hydrophilic polymer together the onset of symptoms. Further, when administered 5 with one or more fillers and an active ingredient. orally such dosage forms enable the site of drug deliv- In a preferred or alternative aspect the outer layer ery to be controlled and enable an optimal plasma con- comprises a pH independent hydrophilic polymer centration of active ingredient to be maintained. The together with one or more fillers and substantially free of dosage forms of the present invention allow the advan- any active ingredient. tages of pulsed release, sustained release and/or 10 In a preferred or alternative aspect the pharmaceu- delayed release dosage forms to be combined. In par- tical composition of the invention is additionally provided ticular, the dosage forms of the invention allow quite with an enteric coating surrounding the pH independent complex dosage regimens to be implemented without hydrophilic polymer layer. the need for administration of many different dosage The pharmaceutical compositions of the invention forms. This is particularly useful where the active ingre- 15 may be presented in any suitable dosage form, in partic- dients are to be self-administered as it avoids reliance ular in dosage forms suitable for oral, rectal or vaginal on the patient remembering to take a number of differ- administration such as tablets, suppositories and pes- ent dosage forms at varying intervals. saries. The pharmaceutical compositions of the invention Suitable active ingredients for use in the pharma- are also able to provide a distinct pulse with no prema- 20 ceutical compositions of the invention include, for exam- ture leakage of the active ingredient from the core, even ple analgesics, anti-inflammatories, bronchodilators, when highly water-soluble active ingredients such as such as salbutamol, hypnotics, hypotensives, steroids, ranitidine are employed. The pharmaceutical composi- anti-migraine compounds such as serotonin agonists, tions of the invention can readily be adapted to provide e.g. sumatriptan and H2-antagonists. the specific "time-to-pulse" required. Batches of tablets 25 Further suitable active ingredients include agents having the same composition will have a predictable for treating lower gastrointestinal tract diseases such as release profile with little batch-to-batch variation. The irritable bowel syndrome for example the serotonin pharmaceutical compositions of the invention are able antagonist compounds described in EP-A-0501322 in to provide reliable pulsed-release even when the thick- particular [1 -[2-[(methylsulphonyl)amino]ethyl]-4-pipe- ness of the outer coating is limited, i.e. when large 30 ridinyl]methyl 5-f luoro-2-methoxy-1 H-indole-3-carboxy- doses of active ingredient are required, and the active late and pharmaceutical^ acceptable salts and solvates ingredient is highly water-soluble. thereof. Thus, according to the present invention there is Yet further suitable active ingredients include the provided a pharmaceutical composition comprising: 5HT3 serotonin antagonists ondansetron and pharma- 35 ceutically acceptable salts and solvates thereof, e.g. the (a) an outer layer comprising a pH independent hydrochloride dihydrate, 2,3,4,5-tetrahydro-5-methyl-2- hydrophilic polymer together with one or more fillers [(5-methyl-1H-imidazol-4-yl)methyl]-1H- selected from microcrystalline cellulose and dibasic pyrido[4,3b]indol-1-one and pharmaceutical^ accepta- calcium phosphate; and ble salts and solvates thereof, e.g. the hydrochloride (b) one or more inner layers each comprising an H2 40 salt, (+)-1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H- antagonist, a serotonin agonist or a serotonin imidazol-4-yl)methyl]-4H-carbazol-4-one and pharma- antagonist as active ingredient; wherein the outer ceutical^ acceptable salts and solvates thereof, e.g. the layer is gradually removed by a combination of dis- hydrochloride salt, 6-fluoro 2,3,4,5-tetrahydro-5-methyl- solution and erosion following administration and 2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3- the inner layer or layers disintegrates rapidly once 45 b]indol-1-one, and pharmaceutical^ acceptable salts exposed. and solvates thereof. The pharmaceutical compositions according to the In a preferred or alternative aspect the inner layer or invention may contain a 5HT3antagonist, e.g. ondanset- layers disintegrate rapidly once exposed. Preferably, the ron, in combination with one or more other antiemetic pharmaceutical compositions of the invention have one so compounds such as dexamethasone. or two or, more preferably, a single inner core layer com- Preferably, the pharmaceutical compositions of the prising an active ingredient. invention comprise salbutamol or, more preferably, a In a preferred or alternative aspect the pharmaceu- serotonin agonist, e.g. sumatriptan, a serotonin antago- tical composition of the invention is additionally provided nist, e.g. [1-[2-[(methylsulphonyl) amino]ethyl]-4-pipe- with a rapidly disintegrating outer coating, surrounding 55 ridinyl]methyl 5-fluoro-2-methoxy-1H-indole-3- the pH independent hydrophilic polymer layer, compris- carboxylate and pharmaceutical^ acceptable salts and ing an active ingredient. solvates thereof, or an H2-antagonist, such as sufotidine In a preferred or alternative aspect, when an addi- or ranitidine as active ingredient. tional rapidly disintegrating outer coating comprising an In a preferred or alternative aspect the H2-antago-

3 5 EP 0 546 593 B1 6

nist-containing pharmaceutical compositions of the line cellulose, dibasic calcium phosphate, tribasic cal- invention are additionally provided with a rapidly disinte- cium phosphate, calcium carbonate, calcium sulphate, grating outer coating, surrounding the pH independent dextrose, kaolin, lactose, powdered cellulose, pregelati- hydrophilic polymer layer, comprising an H2-antagonist nised starch, starch, sucrose and mixtures thereof. Pre- to provide an immediate release of drug. 5 ferred fillers include microcrystalline cellulose and In a preferred aspect the H2-antagonist is ranitidine, dibasic calcium phosphate. cimetidine, sufotidine, famotidine, roxatidine or nizati- Other excipients which may be used in the polymer dine, preferably cimetidine or, more preferably, raniti- layer include lubricants conventional to the art, such as dine. The term 'ranitidine' encompasses magnesium stearate, zinc stearate, calcium stearate, pharmaceutical^ acceptable salts thereof. Such salts 10 stearic acid, sodium stearyl fumerate, hydrogenated include salts with inorganic acids, such as hydrochlo- vegetable oils, glyceryl palmitostearate, glyceryl behen- rides, hydrobromides and sulphates, and organic acids, ate, sodium benzoate, sodium lauryl sulphate, magne- such as acetates, maleates, succinates, fumarates and sium lauryl sulphate, mineral oil, talc and mixtures ascorbates. A particularly preferred salt is the hydro- thereof; glidants conventional to the art such as colloidal chloride. 15 silicon dioxide; disintegrants conventional to the art, The H2-antagonist-containing pharmaceutical com- such as carboxymethylcellulose calcium, carboxymeth- positions of the invention may be presented in any suit- ylcellulose sodium, magnesium aluminium silicate, able dosage form, in particular in dosage forms suitable microcrystalline cellulose, polacrilin potassium, prege- for oral administration such as tablets. latinized starch, sodium alginate, sodium starch glyco- In a preferred or alternative aspect the sumatriptan- 20 late, and mixtures thereof; surfactants conventional to containing pharmaceutical compositions of the inven- the art, such as anionic (e.g. sodium lauryl sulphate), tion are additionally provided with a rapidly disintegrat- cationic or neutral surfactants; ionic salts conventional ing outer coating, surrounding the pH independent to the art (e.g. sodium chloride); and dyes and pigments hydrophilic polymer layer, comprising sumatriptan to conventionally used in the art of pharmacy. provide an immediate release of drug. 25 A preferred lubricant for inclusion in the polymer The sumatriptan-containing pharmaceutical com- layer is sodium stearyl fumerate. positions of the invention may be presented in any suit- A preferred glidant for inclusion in the polymer layer able dosage form, in particular in dosage forms suitable is colloidal silicon dioxide. for oral or rectal administration such as tablets and sup- In a preferred aspect the outer polymer layer com- positories. 30 prises a pH independent hydrophilic polymer (e.g. When in the compositions according to the inven- hydroxypropylmethylcellulose), one or more fillers (e.g. tion, a layer or layers is "gradually" removed, this means microcrystalline cellulose, dibasic calcium phosphate), that the layer is removed over a time period of, for exam- a lubricant (e.g. sodium stearyl fumerate), and a glidant ple, 1-8 hours, such as 1-3.5 hours, 2-5 hours or 4-6 (e.g. colloidal silicon dioxide). hours following administration. 35 Preferably the outer layer will comprise from 20 to When in the compositions according to the inven- 85% w/w of a pH independent hydrophilic polymer, pref- tion, a layer or layers disintegrates "rapidly", this means erably hydroxypropylmethyl cellulose, e.g. 20 to 40% that the layer disintegrates over a time period of, for w/w. example, less than 30 minutes, for example less than 1 0 The rapidly disintegrating inner layer or layers and minutes once exposed. 40 the rapidly disintegrating outer coating may comprise, in It will be appreciated that the rapidly disintegrating addition to the active ingredient, excipients such as fill- inner layer or layers in the compositions according to ers, binders, disintegrants and lubricants. Suitable fill- the invention will only start to disintegrate once the outer ers, disintegrants and lubricants are those mentioned pH independent hydrophilic polymer layer has been above. Suitable binders include methylcellulose, sodium removed to expose a portion or all of the inner layer. 45 carboxymethylcellulose, hydroxypropyl methylcellulose, The term "pH independent hydrophilic polymer" will alginic acid, ethylcellulose, acacia, gelatin, pregelati- be well-understood by those skilled in the art. Such pol- nized starch, sucrose syrup, polyvinylpyrrolidone and ymers dissolve/erode after administration at a rate guar gum. which is independent of the pH of the surrounding fluid. In a preferred aspect the rapidly disintegrating inner Such polymers include, for example, cellulose so layer or layers and the rapidly disintegrating outer layer ethers, polyvinylpyrrolidone, mixtures of natural comprises, in addition to the active ingredient, one or hydrophilic gums, e.g. guar gum, gum Karaya, traga- more fillers (e.g. microcrystalline cellulose, lactose), canth and xanthan gum, and mixtures thereof. Prefera- binders (e.g. polyvinylpyrrolidone, pregelatinised bly cellulose ethers will be employed, most preferably starch), disintegrants (e.g. microcrystalline cellulose, hydroxypropylmethylcellulose. ss pregelatinised starch) and lubricants (e.g. sodium Fillers for use in the tablets of the invention will be stearyl fumerate, magnesium stearate). those fillers known to those skilled in the art. The rapidly disintegrating inner layer or layers and Such fillers may be soluble or insoluble and swelling the rapidly disintegrating outer coating may conven- or non-swelling and include, for example microcrystal- iently have the same composition.

4 7 EP 0 546 59393 B1 8

When the pharmaceutical compositions of the between individual preparations; and invention (i.e. tablets) are provided with an enteric coat- ii) the weight of polymer coat on each preparation ing, this will delay the initiation of the erosion/disintegra- should be effectively constant as between individ- tion of the underlying pH independent hydrophilic ual preparations. polymer layer until the tablet reaches a region of the 5 gastrointestinal tract where a specific pH prevails. The pharmaceutical compositions of the invention Such enteric coated tablets allow targeting of drugs can be conveniently coated with an accurately known to the colon for either a direct local action, or to provide weight of polymer using conventional tabletting meth- a preferred site for drug delivery. ods. Enteric coatings for use in the tablets of the inven- 10 Thus in a further or alternative aspect the present tion will be those coatings known to those skilled in the invention provides a plurality of pharmaceutical prepa- art. Such coatings include cellulose acetate phthalate, rations wherein the maximum variation in weight of the polyvinyl acetate phthalate, shellac, styrene maleic acid outer polymer layer does not exceed ± 5% (e.g. ±2%) of copolymers, methacrylic acid copolymers and hydroxy- the mean weight of the outer polymer layer. propyl methylcellulose phthalate. 15 In a further or alternative aspect the present inven- When the pharmaceutical compositions of the tion also provides a plurality of pharmaceutical prepara- invention are enterically coated they are particularly tions wherein the maximum variation in thickness of the useful for treating diseases of the lower gastrointestinal outer polymer layer does not exceed ± 5% (e.g. ±2%) of tract such as irritable bowel syndrome. the mean thickness of the outer polymer layer. Thus when the pharmaceutical compositions of the 20 A plurality of pharmaceutical preparations means a invention contain the compounds described in EP-A- production run of such preparations, or a course pre- 0501322 as active ingredient, e.g. [1 -[2-[(methylsulpho- scribed by a medical practitioner, or a bottle, container, nyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-meth- packet or batch of such preparations. oxy-1H-indole-3-carboxylate and pharmaceutical^ Using conventional tabletting methods pharmaceu- acceptable salts and solvates thereof, they are prefera- 25 tical compositions of the invention may conveniently be bly enterically coated. provided such that the outer polymer layer of each indi- When the pharmaceutical compositions of the vidual pharmaceutical preparation can be evenly distrib- invention contain an H2-antagonist or sumatriptan, they uted over the surface of that preparation. will not have an enteric coating. Thus the invention further provides a pharmaceuti- The concentration of active ingredient in the inner 30 cal composition wherein the difference in thickness or outer layers or outer coating depends on the active between the thinnest part of the outer layer and the ingredient employed and is conveniently from 30 to thickest part of the outer layer is no more than 5% (e.g. 100% w/w, with respect to the other excipients in the 2%) of the mean outer layer thickness. layer. Thus, for example, in the case of sumatriptan, a It should be appreciated that predictable and uni- suitable concentration is 50% w/w (as succinate) and, 35 form release profiles may be obtained even when the for ranitidine, a suitable concentration is 95% w/w (as outer polymer layer of the pharmaceutical preparation is hydrochloride). not evenly distributed over the surface of the prepara- The weight ratio of inner layer or layers to outer pol- tion, for example the core of the device may be off-set ymer layer is conveniently in the range of 1:1 to 1 :5, for from the centre, in which case the time-to-pulse will example 1 :1 .3 to 1 :4.3. The weight ratio of inner layer or 40 depend upon the thickness of the outer polymer layer at layers to outer rapidly disintegrating coating (when its thinnest point. present) is conveniently 1:1. Thus the invention further provides plurality of phar- Where pulsed release dosage forms are provided maceutical compositions wherein the maximum varia- the active ingredient is contained within a rapidly disin- tion in thickness of the thinnest part of the outer layer tegrating inner layer. 45 does not exceed ± 5 % (e.g. ± 2 %) of the mean thick- It is a further advantage of the invention that phar- ness of the thinnest part of the outer layer. maceutical compositions (e.g. pulsed release composi- In a further or alternative aspect the invention pro- tions) are produced having a predictable and uniform vides a plurality of pulsed-release dosage forms release profile (i.e. the time-to-pulse is predictable and wherein the maximum variation in time-to-pulse does does not vary between individual dosage forms). For a so not exceed ± 5% (e.g. ± 2%) of the mean time-to-pulse. fixed composition of outer layer and inner layer accord- In a preferred aspect the pulse release pharmaceu- ing to the invention, the release profile of the prepara- tical compositions according to the invention provide a tion will depend upon the thickness of the outer distinct pulse i.e. the release of active ingredient from hydrophilic polymer coating. Thus if pharmaceutical the core after the initial predetermined time delay compositions are to be produced having a uniform 55 occurs over a relatively short time period (i.e. less than release profile, it is important that: 30 minutes, e.g. less than 10 minutes) and there is no premature leakage of the active ingredient from the i) the coating thickness on each individual prepara- core. tion should be uniform and effectively constant as The pharmaceutical compositions according to the

5 9 EP 0 546 593 B1 10

invention may be adapted to provide a variety of unit immediate dose of cimetidine (e.g. 200 or 400mg) fol- doses depending on the active ingredient, the route of lowed by a further dose of cimetidine (e.g. 200 or administration and the age and condition of the patient. 400mg) after a predetermined time delay. Suitable doses will be readily appreciated by those The H2-antagonist-containing pharmaceutical com- skilled in the art. 5 positions according to the invention are of particular Thus, in the case of sumatriptan, a suitable unit benefit in the treatment of reflux oesophagitis or dis- dose is 0. 1 mg to 1 0Omg, e.g. 2mg to 40mg of the active eases resulting in a very high gastric acid secretion e.g. ingredient per unit dose, e.g. 50mg of sumatriptan as its Zollinger-Ellison syndrome. succinate. Such unit doses may be administered one to When the pharmaceutical compositions according four times a day, preferably twice a day. 10 to the invention contain agents for treating lower gas- When the pharmaceutical compositions according trointestinal tract diseases, for example the compounds to the invention contain ranitidine, a convenient unit described in EP-A-0501322 in particular [1-[2-[(methyl- dose of ranitidine is 50-800mg, preferably 75-600mg, sulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2- e.g. 150mg, expressed as the weight of the free base. methoxy-1 H-indole-3-carboxylate and pharmaceutical^ Such unit doses may be administered one to four times is acceptable salts and solvates thereof, they may be a day, preferably twice a day. designed to deliver a suitable unit dose after a predeter- When the pharmaceutical compositions according mined time delay of, for example, 6 to 8 hours when the to the invention contain cimetidine, a convenient unit device has been enterically coated, or 4 to 6 hours dose of cimetidine is 200mg or 400mg expressed as the when the device has not been enterically coated. weight of free base. 20 In designing dosage forms according to the inven- When the pharmaceutical compositions according tion in order to tailor the rate and manner of release of to the invention contain a compound described in a EP- the active ingredients, certain factors are important and A-0501322 convenient unit dose of the active ingredient such factors include; is 1 mg to 1 0Omg expressed as the weight of free base, which may be administered, for example, 1 to 4 times 25 1 . Polymer hydration rates. A pH independent poly- per day. mer will conveniently be selected which will wet rap- The pharmaceutical compositions of the invention idly to form a gel layer, fast enough to protect the may be designed to deliver multiple unit doses, for interior of the dosage form from either dissolving or example the pulsed release pharmaceutical composi- disintegrating. If the polymer is too slow to hydrate, tions of the invention may provide an immediate dose of 30 fluids may penetrate to the core, resulting in prema- active ingredient followed by a subsequent dose after a ture release of the drug. Another result of inade- predetermined time delay, thus the frequency of admin- quate polymer hydration speed can be accelerated istration of medication is reduced. dissolving of the water soluble excipients in the pol- The time-to-pulse will depend upon the active ymer layer resulting in premature disintegration of ingredient employed and the conditions being treated. 35 the dosage form. Thus, in the case of sumatriptan the pharmaceuti- Polymer hydration rates can be manipulated by cal compositions of the invention conveniently provide altering the methoxyl and hydroxypropyl ratios of an immediate dose of sumatriptan followed by a further the polymer. dose after a time-delay of 1 to 6 hours (e.g. 1 to 3.5 For example, among the family of hydroxypro- hours). Alternatively, a pulsed release sumatriptan dos- 40 pyl methylcelluloses, there are significant differ- age form may be taken simultaneously with a conven- ences in the rate at which polymers will hydrate. tional sumatriptan tablet to achieve the same This is due to varying proportions of the two chem- immediate/delayed-release profile. ical substituents attached to the cellulose backbone Sumatriptan pulsed-release compositions of the of HPMC, the hydroxypropyl and methoxyl substitu- invention are of particular use in the treatment of 45 tion. The methoxy substituent is a relatively hydro- patients suffering from predictable nocturnal cluster phobic component and does not contribute as headaches where the patient can be administered with greatly to the hydrophilic nature of the polymer and pulsed release dosage forms which deliver a dose of the rate at which it will hydrate. The hydroxypropyl sumatriptan at an appropriate time during the night, for group however, does contribute greatly to the rate example 6 hours after administration. so of polymer hydration. Thus by altering the methoxyl When the pharmaceutical compositions according and hydroxypropyl ratio of the polymer, the polymer to the invention contain ranitidine, they may be designed hydration rates can be altered. to deliver a suitable unit dose (e.g. 150mg) of ranitidine, for example immediately, followed by a subsequent suit- 2. Particle size. The particle size of the polymer can able unit dose of ranitidine (e.g. a further dose of 55 greatly influence the rate of polymer hydration. In 150mg) after a predetermined time delay (e.g. 2 to 5 general it will be preferable to use pH independent hours). polymers (e.g. hydroxypropyl methylcellulose) of When, the pharmaceutical compositions according small particle size to ensure rapid polymer hydra- to the invention contain cimetidine, they may provide an tion. The particle size of the polymer will also allow

6 11 EP 0 546 593 B1 12 some control over the compression characteristics tion. of the dosage form. Inclusion of surfactants such as anionic sur- The particle size of the f iller(s) or any additional factants, for example sodium lauryl sulphate, can excipients in the polymer layer may also have a sig- give rise to higher viscosities and slower release nificant impact on release characteristics. In gen- s that might otherwise be expected. eral, a fine particle size for insoluble fillers will be preferred and will contribute to a more uniform ero- 7. Thickness of the outer polymer layer. As the sion of the polymer layer. thickness of the outer polymer layer is increased, the delay time for release of the active ingredient in 3. Polymer solution viscosity. The rate at which the to the inner core increases. Modification of the surface surface gel layer penetrates the interior of the dos- to volume ratio of the dosage form may also sub- age form is governed to some extent by the viscos- stantially alter the release characteristics. ity of the gel as well as its erosion. Release of the The pharmaceutical compositions according to active ingredient can be controlled by selecting pH the invention may be prepared according to con- independent hydrophilic polymers with different ts ventional methods known in the art using conven- chain lengths and differing viscosities. Higher vis- tional tabletting machinery. cosity polymers result in more delayed release of Thus, for example, the pH independent the active ingredient. Polymers having a normal vis- hydrophilic polymer may be blended with one or cosity of around 100cps at 2% concentration in more fillers, and optionally other excipients, and water are preferred. 20 compressed onto a core of one or more inner layers each comprising an active ingredient. 4. Polymer concentration. Increasing the concen- Cores of active substance may be prepared, for tration of the pH independent hydrophilic polymer example, by compression of material produced by relative to the other constituents of the outer layer dry slugging, wet granulation or dry blending. increases the viscosity of the gel that forms on the 25 Blends for rapidly disintegrating outer coatings surface of the dosage form. Therefore, an increase may be prepared in the same way and compressed in the level of polymer used will generally lead to a onto the pH independent hydrophilic polymer greater delay in release of the active ingredient. coated cores. An increase in the concentration of polymer also tends to decrease the sensitivity of the formu- 30 The invention is further illustrated by the following lation to changes in particle size or hydration rates examples, which are non-limiting. The following exam- of polymers. ples relate specifically to tablets for oral administration, however by altering the shape of the dosage forms, sup- 5. Presence of soluble/insoluble and swelling/non- positories and pessaries suitable for rectal and vaginal swelling fillers. Soluble fillers in the polymer layer 35 administration may be obtained using the same core may affect gel viscosity on the surface of the dos- and coating compositions. age form. The soluble materials will compete with the polymer for the available water. Example 1 Release of insoluble fillers occurs through an erosion mechanism. As the polymer dissolves away 40 Tablet for pulsed release exposing new layers, the insoluble filler will be released. Preferably the combination of swelling and non-swelling fillers in the outer polymer layer Tablet Core % w/w will be controlled to avoid stress fractures occurring Sufotidine 20 in the polymer layer leading to premature disinte- 45 gration of the core. Generally, the insoluble fillers Microcrystalline Cellulose 59 should be used at relatively low concentrations, for Pregelatinized Starch 1 5 example less than 15% by weight of the dosage form. Polyvinylpyrrolidone 5 Conveniently an insoluble but swelling filler, so Sodium Stearyl Fumerate 1 such as microcrystalline cellulose, is used so that release characteristics are modified due to a change in the rate of swelling, but no stress fractures occur. Sufotidine was dry mixed with microcrystalline cel- 55 lulose, pregelatinized starch and polyvinylpyrrolidone 6. Presence of surfactants and ionic salts. When and the mixture granulated using isopropyl alcohol as ionic salts are used in the formulation of the poly- the granulation fluid. The granulate was air dried, sieved mer layer they can compete with the polymer for the and blended with sodium stearyl fumerate before com- available water altering the rate of polymer hydra- pression on a suitable tablet press to produce 50mg

7 13 EP 0 546 593 B1 14 core tablets containing 10mg of sufotidine which were 4.76mm in diameter and 3.0mm in thickness. Outer layer % w/w Hydroxypropyl Methylcellulose * 77 Outer layer % w/w Microcrystalline Cellulose 12 Hydroxypropyl Methylcellulose * 35 Dibasic Calcium Phosphate 9 Microcrystalline Cellulose 40 Colloidal Silicon Dioxide 1 Dibasic Calcium Phosphate 23 10 Sodium Stearyl Fumerate 1 Colloidal Silicon Dioxide 1 * normal viscosity 2% in water = 1 Sodium Stearyl Fumerate 1 0Ocps * normal viscosity 2% in water = 1 0Ocps 15 Pulsed release tablets were prepared and tested as for Example 1 . The excipients were dry mixed and the core tablet Pulsatile release of the active ingredient was compression coated using the resulting blend to pro- obtained after a period of about 9.2 hours in simulated duce 265mg tablets, 8.7mm in diameter and 4.0mm in intestinal fluid and about 6.2 hours in distilled water or thickness. 20 simulated gastric fluid. The release of the drug from the tablets was monitored using a dissolution tester which conforms to the Example 3 requirements of the USP, in which 500ml of distilled water or simulated gastric fluid or simulated intestinal Tablet for pulsed release fluid was maintained at 37°C and used as the dissolu- 25 tion medium. The USP 1 dissolution method was used at a rotation speed of 250rpm. Tablet core % w/w Pulsatile release of sufotidine is obtained after a Salbutamol Sulphate 19.28 period of about 3.5 hours in each of the dissolution media. 30 Microcrystalline Cellulose 64.72 In the following examples numbered 2 to 9 the Pregelatinized Starch 15.00 dimensions of the tablet cores and polymer coat are identical to those in Example 1 . Sodium Stearyl Fumerate 1 .00

Example 2 35

Tablet for Pulsed release Salbutamol sulphate was mixed with the excipients and the mixture compressed on a suitable tablet press to produce tablet cores of containing 8mg of salbutamol Tablet Core % w/w 40 base. Sufotidine 20 Microcrystalline Cellulose 59 Outer layer % w/w Pregelatinized Starch 1 5 * 30 45 Hydroxypropyl Methylcellulose Polyvinylpyrrolidone 5 Microcrystalline Cellulose 43 Sodium Stearyl Fumerate 1 Dibasic Calcium Phosphate 25 Colloidal Silicon Dioxide 1 50 Sodium Stearyl Fumerate 1 * normal viscosity 2% in water = 1 0Ocps

55 Pulsed release of salbutamol is obtained after a period of about 3 hours in each of the dissolution media.

8 15 EP 0 546 593 B1 16

Example 4 cellulose and lactose and the mixture was granulated using a granulating fluid composed of polyvinylpyrro- Sufotidine core tablets (manufactured as in Exam- lidone dissolved in isopropyl alcohol. The granulate was ple 1) were compression coated using a blend com- dried in a fluid bed drier, sieved and blended with posed of 74.4% w/w HPMC (nominal viscosity, 2% in 5 sodium stearyl fumerate before compression on a suita- water = 100 cps), 1 1 .6% w/w microcrystalline cellulose, ble tablet press to produce 100mg core tablets contain- 8.2% w/w dibasic calcium phosphate, 3.3% w/w piroxi- ing 50mg of sumatriptan (as succinate) which were cam, 0.97% w/w/ colloidal silicon dioxide and 0.97% 5.5mm in diameter and 3.0mm in thickness. w/w sodium stearyl fumerate. The release of the drug from the tablets was moni- 10 tored using a dissolution tester which conforms to the Intermediate Polymer Layer % w/w of the USP, in which 500ml of simulated requirements * Hydroxypropyl Methylcellulose 35 gastric fluid was maintained at 37° and used as the dissolution medium. The USP1 dissolution method was Microcrystalline Cellulose 40 used at a rotation speed of 250rpm. 15 Dibasic calcium phosphate 23 Sustained release of piroxicam and pulsed release of sufotidine was obtained. Colloidal silicon dioxide 1 Sodium stearyl fumerate 1 Example 5 * 20 normal viscosity 2% in water = 1 0Ocps. Sufotidine pulse release tablets were prepared as described in Example 1 . These tablets were given an enteric coating by spraying onto the tablets a solution The excipients for the intermediate layer were dry containing methacrylic acid copolymer and triacetin mixed and the core tablet was compression coated (90:10) in isopropyl alcohol. This enteric coat is insolu- 25 using the resulting blend to produce 230mg tablets, ble below pH6.0 and also in natural and simulated gas- 8.7mm in diameter and 4.0mm in thickness. tric fluid. The coat, however, is soluble in the region of the digestive tract where the pH is above 7.0. Outer Sumatriptan Layer The release of the drug from the tablets was monitored in vitro using a dissolution tester which conforms 30 Same formulation as the core tablet. to the requirements of the USP, in which either simu- The compression coated tablets were further lated gastric fluid (pH1 .2) or intestinal fluid (pH7.2) were coated with 100mg of the tablet core blend by compres- maintained at 37°. The USP1 dissolution method was sion. used at a rotation speed of 250 rpm. The release of the drug was monitored using disso- When tested in simulated gastric fluid (pH1.2) 35 lution equipment which conforms to the requirements of release of drug from the device was prevented through- the USP, in which 900ml of simulated gastric fluid was out the period of testing (6.5 hours). When transferred maintained at 37°C and used as the dissolution to simulated intestinal fluid (pH 7.2) however, a pulsed medium. The USP 1 dissolution method was used at a release of sufotidine was achieved after 4.5 hours. rotation speed of 250rpm. 40 Initial immediate release of sumatriptan was Example 6 obtained followed by pulsatile release of the drug after a period of about 1 .5 hours. Tablet for immediate release and pulsed release The core tablets described above were also coated with the above intermediate polymer blend to give tablets of 1 1 .0mm in diameter which were further coated Tablet Core % w/w with the outer sumatriptan layer blend (100mg). The resulting tablets (720mg) gave initial immediate release Sumatriptan (as succinate) 50 of sumatriptan followed by pulsatile release of the drug Microcrystalline cellulose 23 after a period of 3 hours. Lactose 23 Polyvinylpyrrolidone 2 Sodium stearyl fumerate 2 * Isopropyl Alcohol qs * not present in the final product.

Sumatriptan was dry mixed with microcrystalline

9 17 EPO 16 593B1 18

Example 7 a period of 3.5 hours in each of the above media.

Tablet for pulsed release Example 8

5 Tablet for pulsed release Tablet Core % w/w Sumatriptan (as succinate) 50 Tablet Core % w/w Microcrystalline cellulose 23 Ranitidine hydrochloride 95 Lactose 23 Polyvinylpyrrolidone 4 Polyvinylpyrrolidone 2 Magnesium Stearate 1 Sodium stearyl fumerate 2 * Isopropyl Alcohol qs * Isopropyl Alcohol qs * not present in the final product * not present in the final product. The ranitidine hydrochloride was granulated using a Sumatriptan was dry mixed with microcrystalline granulating fluid composed of polyvinylpyrrolidone dis- cellulose and lactose and the mixture was granulated 20 solved in isopropyl alcohol. The granulate was dried in a using a granulating fluid composed of polyvinylpyrro- fluid bed drier, sieved and blended with magnesium lidone dissolved in isopropyl alcohol. The granulate was stearate before compression on a suitable tablet press dried in a fluid bed drier, sieved and blended with to produce 1 77mg core tablets containing 1 50mg of ran- sodium stearyl fumerate before compression on a suita- itidine (as base) which were 7.5mm in diameter and ble tablet press to produce 100mg core tablets contain- 25 4.5mm in thickness. ing 50mg of sumatriptan (as succinate) which were 5.5mm in diameter and 3.0mm in thickness. Outer Layer % w/w * Hydroxypropyl Methylcellulose 23.0 Polymer Layer % w/w 3o Microcrystalline Cellulose 40.6 * Hydroxypropyl Methylcellulose 35 Dibasic calcium phosphate 35.0 Microcrystalline Cellulose 40 Colloidal silicon dioxide 0.7 Dibasic calcium phosphate 23 35 Sodium stearyl fumerate 0.7 Colloidal silicon dioxide 1 * normal viscosity 2% in water = 1 0Ocps. Sodium stearyl fumerate 1 * normal viscosity 2% in water = 1 0Ocps. 40 The excipients of the outer layer were dry mixed and the core tablet was compression coated using the The excipients for the polymer layer were dry mixed resulting blend to produce 730mg tablets, 12mm in and the core tablet was compression coated using the diameter and 5.6mm in thickness. resulting blend to produce 340mg tablets, 9.0mm in The release of the drug was monitored using disso- diameter and 4.1mm in thickness. 45 lution equipment which conforms to the requirements of The release of the drug was monitored using disso- the USP, in which 900ml of simulated gastric fluid was lution equipment which conforms to the requirements of maintained at 37°C and used as the dissolution the USP in which either, distilled water, simulated intes- medium. The USP 1 dissolution method was used at a tinal fluid or simulated gastric fluid was maintained at rotation speed of 250rpm. A pulsatile release of drug 37°C and used as the dissolution medium. The USP 1 so was obtained after a period of about 3 hours. dissolution method was used at a rotation speed of 250rpm. Example 9 Pulsatile release of sumatriptan was obtained after a period of about 2.5 hours in each of the dissolution Tablet for immediate release and pulsed release media. 55 The core tablets described above were also coated Pulse delivery devices containing ranitidine were with the above polymer blend to give 460mg tablets, manufactured as described in Example 1 . 1 1 mm in diameter and 4.5mm in thickness. The compression coated tablets were further Pulsatile release of sumatriptan was obtained after coated with 177mg of the tablet core blend by compres-

10 19 EP 0 546 593 B1 20 sion on a suitable tablet press. Example 1 1 The release of the drug was monitored using dissolution equipment which conforms to the requirements of Tablet for pulsed release the USP in which 900ml of simulated gastric fluid was maintained at 37°C and used as the dissolution s medium. The USP 1 dissolution method was used at a Tablet Core % w/w rotation speed of 250rpm. Ranitidine hydrochloride 95 Initial immediate release of ranitidine was obtained followed by pulsatile release of the drug after a period of Polyvinylpyrrolidone 4.5 about 3 hours. 10 Magnesium Stearate 0.5 Example 10 * Isopropyl Alcohol qs * not present in the final product Tablet for pulsed release

The ranitidine hydrochloride was granulated using a Tablet Core % w/w granulating fluid composed of polyvinylpyrrolidone dissolved in isopropyl alcohol. The granulate was dried in a Ranitidine hydrochloride 95 fluid bed drier, sieved and blended with magnesium Polyvinylpyrrolidone 4.5 stearate before compression on a suitable tablet press to produce 1 77mg core tablets containing 1 50mg of ran- Magnesium Stearate 0.5 itidine (as base) which were 7.5mm in diameter and * Isopropyl Alcohol qs 4.5mm in thickness. * not present in the final product 25 Outer Layer % w/w The ranitidine hydrochloride was granulated using a * Hydroxypropyl Methylcellulose 33.3 granulating fluid composed of polyvinylpyrrolidone dissolved in isopropyl alcohol. The granulate was dried in a Microcrystalline Cellulose 38.1 fluid bed drier, sieved and blended with magnesium 30 Dibasic calcium phosphate 26.7 stearate before compression on a suitable tablet press to produce 1 77mg core tablets containing 1 50mg of ran- Colloidal silicon dioxide 0.95 itidine (as base) which were 9.0mm in diameter and Sodium stearyl fumerate 0.95 3.4mm in thickness. * normal viscosity 2% in water = 1 0Ocps.

Outer Layer % The excipients of the outer layer were dry mixed * Hydroxypropyl Methylcellulose 3 and the core tablet was compression coated using the Microcrystalline Cellulose 4 40 resulting blend to produce 530mg tablets, 12mm in diameter and 5.1mm in thickness. Dibasic calcium phosphate 2 The release of the drug was monitored using disso- Colloidal silicon dioxide 1 lution equipment which conforms to the requirements of Sodium stearyl fumerate 1 the USP, in which 900ml of simulated gastric fluid was 45 maintained at 37°C and used as the dissolution * normal viscosity 2% in water = 1 0Ocps. medium. The USP 1 dissolution method was used at a rotation speed of 250rpm. A pulsatile release of drug was obtained alter a period of about 3 hours. The excipients of the outer layer were dry mixed and the core tablet was compression coated using the so Claims resulting blend to produce 530mg tablets, 12mm in diameter and 5.1mm in thickness. 1 . A pharmaceutical composition comprising: The release of the drug was monitored using dissolution equipment which conforms to the requirements of (a) an outer layer comprising a pH independent the USP, in which 900ml of simulated gastric fluid was 55 hydrophilic polymer together with one or more maintained at 37°C and used as the dissolution fillers selected from microcrystalline cellulose medium. The USP 1 dissolution method was used at a and dibasic calcium phosphate; and rotation speed of 250rpm. A pulsatile release of drug was obtained after a period of about 2 hours. (b) one or more inner layers each comprising

11 21 EP 0 546 593 B1 22

an H2 antagonist, a serotonin agonist or a pendent hydrophilic polymer together with one or serotonin antagonist as active ingredient; more fillers is compression coated onto a core of one or more inner layers each comprising an active wherein the outer layer is gradually removed by a ingredient. combination of dissolution and erosion following 5 administration and the inner layer or layers disinte- 1 1 . A process as claimed in Claim 1 0 wherein the phar- grates rapidly once exposed. maceutical composition is further compression coated with a blend comprising an active ingredi- 2. A pharmaceutical composition as claimed in Claim ent. 1 having a single inner core layer comprising an 10 active ingredient. Patentanspruche

3. A pharmaceutical composition as claimed in Claim 1. Pharmazeutische Zusammensetzung, umfassend: 1 or Claim 2 having an additional rapidly disintegrating outer coating, surrounding the pH independent 15 (a) eine auBere Schicht, die ein pH-unabhangi- hydrophilic polymer layer, comprising an active ges hydrophiles Polymer zusammen mit einem ingredient. oder mehreren Fullstoffen, ausgewahlt aus mikrokristalliner Cellulose und zweibasigem 4. A pharmaceutical composition as claimed in Claim Calciumphosphat, umfaBt; und 1 wherein the H2-antagonist is ranitidine or a phar- 20 maceutical^ acceptable salt thereof. (b) eine Oder mehrere innere Schichten, die jeweils einen H2-Antagonisten, einen Seroto- 5. A pharmaceutical composition as claimed in Claim nin-Agonisten oder einen Serotonin-Antagoni- 1 wherein the serotonin agonist is sumatriptan or a sten als Wirkstoff umfassen; pharmaceutical^ acceptable salt thereof and the 25 serotonin antagonist is [1 -[2-[(methylsulpho- worin die auBere Schicht allmahlich durch eine nyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2- Kombination von Auflosung und Erosion nach der methoxy-1 H-indole-3-carboxylate; ondansetron; Verabreichung entfernt wird und die innere Schicht 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imida- oder Schichten, wenn sie exponiert werden, rasch zol-4-yl)methyl]-1 H-pyridol[4,3b]indol-1 -one; (+)- 30 zerfallen. 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4-one; 6-fluoro- 2. Pharmazeutische Zusammensetzung gemaB 2,3,4,5-tetrahydro-5-methyl~2-[(5-methyl-1H-imi- Anspruch 1 mit einer einzigen inneren Kernschicht, dazol-4-yl) -methyl] - 1 H-pyrido[4, 3-b] indol - 1 -one ; die einen Wirkstoff umfaBt. or a pharmaceutical^ acceptable salt or solvate 35 thereof. 3. Pharmazeutische Zusammensetzung nach Anspruch 1 oder Anspruch 2 mit einem zusatzli- 6. A pharmaceutical composition as claimed in any chen, rasch zerfallenden auBeren Uberzug, der die one of Claims 1 to 5 wherein the pH independent pH-unabhangige hydrophile Polymerschicht umgibt hydrophilic polymer has a normal viscosity of 100 40 und einen Wirkstoff umfaBt. cps at 2% concentration in water. 4. Pharmazeutische Zusammensetzung gemaB 7. A pharmaceutical composition as claimed in any Anspruch 1, wobei der H2-Antagonist Ranitidin one of Claims 1 to 6 wherein the pH independent oder ein pharmazeutisch akzeptables Salz davon hydrophilic polymer is a cellulose ether; polyvi- 45 iSt. nylpyrrolidone; a mixture of natural hydrophilic gums; or mixtures thereof. 5. Pharmazeutische Zusammensetzung gemaB Anspruch 1, wobei der Serotonin-Agonist Suma- 8. A pharmaceutical composition as claimed in any triptan oder ein pharmazeutisch akzeptables Salz one of Claims 1 to 7 wherein the cellulose ether is so davon ist und der Serotonin-Antagonist [1-[2- hydroxypropylmethylcellulose. [(Methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl- 5-fluor-2-methoxy-1 H-indol-3-carboxylat; Ondan- 9. A pharmaceutical composition as claimed in any setron; 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- one of Claims 1 to 8 wherein the outer layer addi- 1 H-imidazol-4-yl)methyl]-1 H-pyridol[4,3b]indol-1 - tionally comprises a lubricant and a glidant. 55 on; (+)-1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl- 1 H-imidazol-4-yl)methyl]-4H-carbazol-4-on; 6- 1 0. A process for the preparation of a pharmaceutical Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H- composition as claimed in any one of Claims 1 to 9 imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-on; wherein an outer layer blend comprising a pH inde- oder ein pharmazeutisch akzeptables Salz oder

12 23 EP 0 546 593 B1 24

Solvat davon ist. 3. Composition pharmaceutique suivant la revendication 1 ou la revendication 2, possedant un revete- 6. Pharmazeutische Zusammensetzung gemaB ment externe supplemental se desagregeant einem der Anspriiche 1 bis 5, wobei das pH-unab- rapidement, qui enveloppe la couche de polymere hangige hydrophile Polymer eine Normalviskositat 5 hydrophile independant du pH, comprenant un von 1 00 cps bei 2 % Konzentration in Wasser hat. ingredient actif.

7. Pharmazeutische Zusammensetzung gemaB 4. Composition pharmaceutique suivant la revendica- einem der Anspriiche 1 bis 6, wobei das pH-unab- tion 1 , caracterisee en ce que I'antagoniste d'H2 est hangige hydrophile Polymer ein Celluloseether, 10 la ranitidine ou un sel pharmaceutiquement accep- Polyvinylpyrrolidon, eine Mischung aus natiirlichen table de celle-ci. hydrophilen Gummen oder eine Mischung davon ist. 5. Composition pharmaceutique suivant la revendication 1 , caracterisee en ce que I'agoniste de seroto- 8. Pharmazeutische Zusammensetzung gemaB 15 nine est le sumatriptan ou un sel einem der Anspriiche 1 bis 7, wobei der Cellulosee- pharmaceutiquement acceptable de celui-ci et ther Hydroxypropylmethylcellulose ist. I'antagoniste de serotonine est I'un des composes qui suivent : [1-[2-[(methylsulfonyl)amino]ethyl]-4- 9. Pharmazeutische Zusammensetzung gemaB piperidinyl]methyl-5-fluoro-2-methoxy-1H-indole-3- einem der Anspriiche 1 bis 8, wobei die auBere 20 carboxylate; ondansetron; 2,3,4,5-tetrahydro-5- Schicht auBerdem ein Schmiermittel und ein Gleit- methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H- mittel umfaBt. pyridol[4,3]indole-1 -one; (+)-1 ,2,3,9-tetrahydro-9- methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-4H- 10. Verfahren zur Herstellung einer pharmazeutischen carbazole-4-one; 6-fluoro-2,3,4,5-tetrahydro-5- Zusammensetzung gemaB einem der Anspriiche 1 25 methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H- bis 9, wobei eine Mischung fur die auBere Schicht, pyrido[4,3]indole-1 -one; umfassend ein pH-unabhangiges hydrophiles Poly- ou un solvate ou sel pharmaceutiquement accepta- mer zusammen mit einem oder mehreren Fullstof- ble d'un de ses composes. fen, auf einen Kern aus einer oder mehreren inneren Schichten, die jeweils einen Wirkstoff 30 6. Composition pharmaceutique suivant I'une quel- umfassen, kompressionsbeschichtet wird. conque des revendications 1 a 5, caracterisee en ce que le polymere hydrophile independant du pH 11. Verfahren gemaB Anspruch 10, wobei die pharma- possede une viscosite normale de 1 00 cps en une zeutische Zusammensetzung auBerdem mit einer concentration de 2% dans de I'eau. Mischung kompressionsbeschichtet wird, die einen 35 Wirkstoff umfaBt. 7. Composition pharmaceutique suivant I'une quelconque des revendications 1 a 6, caracterisee en Revendications ce que le polymere hydrophile independant du pH est un ether de cellulose, la polyvinylpyrrolidone, un 1 . Composition pharmaceutique comprenant : 40 melange de gommes hydrophiles naturelles, ou des melanges de ces produits. (a) une couche externe comprenant un polymere hydrophile independant du pH, en meme 8. Composition pharmaceutique suivant I'une quel- temps qu'une ou plusieurs charges choisies conque des revendications 1 a 7, caracterisee en parmi la cellulose microcristalline et le phos- 45 ce que Tether de cellulose est I'hydroxypropylme- phate de calcium dibasique et thylcellulose. (b) une ou plusieurs couches internes comprenant chacune un antagoniste d'H2, un agoniste 9. Composition pharmaceutique suivant I'une quel- de serotonine, ou un antagoniste de seroto- conque des revendications 1 a 8, caracterisee en nine, a titre d'ingredient actif, so ce que la couche externe comprend en outre un lubrifiant et un agent assurant le glissement. ou la couche externe est graduellement eliminee par une combinaison de dissolution et d'erosion 1 0. Procede de preparation d'une composition pharma- apres administration et la ou les couches internes ceutique suivant I'une quelconque des revendica- se desagregent rapidement une fois exposees. 55 tions 1 a 9, caracterise en ce que Ton enveloppe un noyau constitue d'une ou plusieurs couches inter- 2. Composition pharmaceutique suivant la revendica- nes, comprenant chacune un ingredient actif, d'un tion 1 , comportant une seule couche formant noyau melange formant couche interne comprenant un interne, comprenant un ingredient actif. polymere hydrophile independant du pH ainsi

13 25 EP 0 546 593 B1 qu'une ou plusieurs charges, par compression.

Procede suivant la revendication 10, caracterise en ce que la composition pharmaceutique est en outre enveloppee d'un melange comprenant un ingre- s dient actif par compression.