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(11) EP 1 652 518 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: A61K 31/19 (2006.01) A61K 31/34 (2006.01) of the grant of the patent: A61K 31/44 (2006.01) A61K 38/16 (2006.01) 07.08.2013 Bulletin 2013/32 A61K 9/16 (2006.01) A61K 31/445 (2006.01)

(21) Application number: 05077875.2

(22) Date of filing: 24.09.1999

(54) Pharmaceutical composition for sublingual administration Pharmazeutische Zusammensetzung für die sublinguale Verabreichung Composition pharmaceutique pour administration par voie sub-linguale

(84) Designated Contracting States: • GASEROD O ET AL: "THE ENHANCEMENT OF AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU THE PROPERTIES OF CALCIUM MC NL PT SE ALGINATE BEADS BY COATING WITH CHITOSAN" INTERNATIONAL JOURNAL OF (30) Priority: 24.09.1998 SE 9803240 PHARMACEUTICS, AMSTERDAM, NL, vol. 175, 1998, pages 237-246, XP002964881 ISSN: (43) Date of publication of application: 0378-5173 03.05.2006 Bulletin 2006/18 • DUCHENE D ET AL: "Bioadhesion of solid oral dosage forms, why and how?" EUROPEAN (60) Divisional application: JOURNAL OF PHARMACEUTICS AND 10001406.7 / 2 236 132 BIOPHARMACEUTICS, ELSEVIER SCIENCE 10001408.3 / 2 236 133 PUBLISHERS B.V., AMSTERDAM, NL, vol. 44, no. 1, July 1997 (1997-07), pages 15-23, XP004256896 (62) Document number(s) of the earlier application(s) in ISSN: 0939-6411 accordance with Art. 76 EPC: • WESTERBERG M ET AL: "Physicochemical 99952867.2 / 1 115 383 aspects of drug release. XVIII. The use of a surfactant and a disintegrant for improving drug (73) Proprietor: Orexo AB dissolution rate from ordered mixtures" S.T.P. 751 05 Uppsala (SE) PHARMA SCIENCES 1993 FRANCE, vol. 3, no. 2, 1993, pages 142-147, XP009062599 ISSN: (72) Inventors: 1157-1489 • Pettersson, Anders • FARRAR J T ET AL: "ORAL TRANSMUCOSAL 442 97 Kode (SE) FENTANYL CITRATE: RANDOMIZED, DOUBLE- • Nyström, Christer BLIND, PLACEBO-CONTROLLED TRIAL FOR SE-18134 Lidingö (SE) TREATMENT OF BREAKTHROUGH PAIN IN CANCER PATIENTS" JOURNAL OF THE (74) Representative: McNeeney, Stephen Phillip NATIONAL CANCER INSTITUTE, US DEPT. OF Potter Clarkson LLP HEALTH, EDICATIONAND WELFARE, PUBLIC The Belgrave Centre HEALTH, US, vol. 90, no. 8, 15 April 1998 Talbot Street (1998-04-15), pages 611-616, XP001058154 ISSN: Nottingham NG1 5GG (GB) 0027-8874

(56) References cited: EP-A- 0 144 243 EP-A- 0 324 725 WO-A-90/04962

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 652 518 B1

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• NYSTROM C ET AL: "THE USE OF ORDERED • VOORSPOELS J ET AL: "Buccal absorption of MIXTURES FOR IMPROVING THE DISSOLUTION testosterone and its esters using a bioadhesive RATE OF LOW COMPOUNDS", in dogs.", PHARMACEUTICAL RESEARCH JOURNAL OF PHARMACY AND AUG 1996 LNKD- PUBMED:8865317, vol. 13, no. PHARMACOLOGY, ROYAL PHARMACEUTICAL 8, August 1996 (1996-08), pages 1228-1232, ISSN: SOCIETY OF GREAT BRITAIN, GB, vol. 38, no. 3, 0724-8741 1 January 1986 (1986-01-01), pages 161-165, • Harris, A. S.: "opportunities provided by the XP009062597, ISSN: 0022-3573 buccal and nasal administration of peptides" In: • NYSTROM C ET AL: "Studies on direct Dominique Duchéne (Editor): "Buccal and nasal compression of tablets. I. The effect of particle administration as an alternative to parental size in mixing finely divided powders with administration", 1992, Editions de Santé, Paris granules", ACTA PHARMACEUTICA SUECICA pages 204-225, 1980 SE, vol. 17, no. 5, 1980, pages 282-287, ISSN: • "Disintegration of tablets ans capsules" In: 0001-6675 "European Pharmcopoeia", 2006, Council of • DATABASE EMBASE [Online] ELSEVIER Europe, Strasbourg ISBN: 92-871-5837-1 pages SCIENCE PUBLISHERS, AMSTERDAM, NL 3351-3353, January 1996 TAYLAN B ET AL: ’Design and evaluation of sustained-release and buccal Remarks: adhesive propranolol hydrochloride tablets’ Thefile contains technical information submitted after Database accession no. EMB-1996021583 & the application was filed and not included in this JOURNAL OF CONTROLLED RELEASE 199601 specification NL LNKD- DOI:10.1016/0168-3659(95)00094-1, vol. 38, no. 1, January 1996 (1996-01), pages 11-20, ISSN: 0168-3659

2 1 EP 1 652 518 B1 2

Description the pharmaceutical composition is placed under tongue, and the active component is absorbed through the sur- Field of the invention rounding mucous membranes. However, with this way of administration, the risk that the patient swallows the [0001] The present invention relates to a rapidly acting 5 medication by swallowing saliva is well known. pharmaceutical composition for sublingual administra- [0007] For the treatment of acute pain may be used tion of a pharmaceutical agent, to a method for preparing fentanyl, N-(1-phenethyl-4-piperidyl)-propioanilide, or such a composition, and to the use of such a composition one of its pharmaceutically acceptable salts. This com- in the treatment of acute disorders. pound is an opioid agonist and shares many of the phar- 10 macodynamic effects of opiates such as morphine and Background of the invention meperidine. However, compared to these opiates, fen- tanyl exhibits little hypnotic activity, rarely induces hista- [0002] Acute and/or severe disorders are a common mine release, and respiratory depression is more short- cause of emergency treatment or hospitalization. One of lived. Fentanyl is commercially available for intravenous, the most common disorders of this type is acute or break- 15 intrabucchal (lozenge-transmucosal) and transdermal through pain. In cancer patients, pain is usually treated administration. with non-steroid anti-inflammatory drugs (NSAIDs) and [0008] Following parenteral administration of fentanyl, opiates alone or in combination. Opioid- requiring cancer the analgesic action is more prompt and less prolonged pain patients are usually given slow-release opiates than that of morphine and meperidine. The onset of an- (slow-release morphine or ketobemidone or transdermal 20 algesia following i.v. administration is rapid. Peak anal- fentanyl). A characteristic feature of cancer pain are pe- gesia is obtained within a few minutes. Following trans- riods of inadequate analgesia (breakthrough pain) . Most bucchal administration by a lozenge, consumption of the often they are due to increased physical activity of the lozenge is usually complete within 30 min and peak plas- patient. However, treatment of breakthrough pain by ad- ma concentrations appear after around 20 minutes, as ministration of increased time contingent doses of long- 25 described by e.g. Farrar et al., J. Natl. Cancer Inst., 1998, acting analgesics causes adverse side effects such an 90(8), p. 611-616. Analgesia is apparent within 5-15 min excess sedation, nausea, and constipation. and peaks at about 20-50 min. While this is an improve- [0003] Other disorders and conditions which require a ment over oral administration for gastrointestinal uptake, fast-acting treatment are, for example, pulmonary ede- a quicker onset of analgesia would be of substantial ben- ma, gastroesophageal reflux, insomnia and nephrolitia- 30 efit to the patient. In addition, substantial amounts of loz- sis. enge-administered fentanyl are swallowed by the patient. [0004] Presently available oral, rectal, or sublingual This is not desirable and results in the administration of formulations have relatively lengthy onset times or erratic excessive amounts of the drug, which may give rise to absorption characteristics that are not well suited to con- side effects. trol acute disorders. 35 [0005] Conditions of acute operative/postoperative or Objects of the invention traumatic/ posttraumatic pain as well as pain due to se- vere disease (e.g. myocardial infarction, nephrolithiasis, [0009] It is one object of the invention to provide for etc.) is usually treated with opioid analgesics which are the treatment of acute disorders by perorally administer- administered parenterally (by intravenous or intramus- 40 ing at least one pharmaceutically active agent in a man- cular administration) to obtain a rapid onset of analgesia. ner giving rise to pharmacologically effective plasma lev- In such cases, rapid-onset oral alternatives are of con- els of said agent or agents within a short time after ad- siderable therapeutic interest. Also for the treatment of ministration. other acute disorders, it is of considerable interest to pro- [0010] It is another object of the invention to provide a vide fast-acting therapeutic compositions which may be 45 pharmaceutical composition suitable for that purpose. administered orally instead of parenterally or rectally. [0011] It is a further object of the invention to provide [0006] However, many pharmaceutically active agents a method of making such a composition. which would be advantageous to adminster orally are not [0012] It is an additional object of the invention to pro- suitable to be swallowed. They may, for example, be in- vide a method of manufacture of a medicament for sub- activated by the gastro- intestinal liquids, have a slow ac- 50 lingual administration containing a physiologically effec- tion because of a low solubility in the aqueous medium, tive dose of at least one pharmaceutically active com- or be highly susceptible to metabolism by gastro-intesti- pound useful in the treatment of acute disorders. nal enzymes and have poor absorptiom properties, as exemplified for peptide hormones. It is therefore more Description of the drawing preferable to arrange for the active component to be tak- 55 en up through the mucous membranes of the oral cavity. [0013] The sole figure of the drawing shows the result Here, the most preferred way of administration is via the of a test of the bioavailability of the active agent in a com- sublingual route. In this administration, a dosage unit of position according to the invention. It is a diagram show-

3 3 EP 1 652 518 B1 4 ing the plasma concentration of the agent against the stances coated with the pharmaceutically active agent time after administration. or agents in a fine particulate form. [0019] It is preferred to formulate the composition ac- Summary of the invention cording to the invention by use of the technology for for- 5 mulating rapidly dissolving ordered-mixture composi- [0014] According to the invention there is provided a tionsdisclosed in Europeanpatent EP 0324 725. Inthese bioadhesive and/or mucoadhesive pharmaceutical com- compositions, the drug in a finely dispersed state covers position for the treatment of acute disorders by sublingual the surface of substantially larger carrier particles. Such administration, comprising an essentially water-free, or- compositions disintegrate rapidly in water, thereby dis- dered mixture of microparticles of at least one pharma- 10 persing their contents of microscopic drug particles. ceutically active agent adhered to the surfaces of carrier [0020] However, this prior art technique of using an particles, said particles being substantially larger than ordered mixture for rapid drug dissolution has hitherto said microparticles and being water-soluble, and a bio- only been reported to be suitable for conventional oral and/or mucoadhesion promoting agent present drug therapy, i.e. for solid dosage forms which are to be on the surfaces of the carrier particles. The peroral treat- 15 swallowed. For such preparations, the dissolution of the ment of acute disorders comprises sublingual adminis- drug particles takes place in the stomach, i.e. in an en- tration of an ordered mixture comprising a pharmacolog- vironment where there exists a relatively large volume of ically effective amount of at least one pharmaceutically liquid which can dissolve the drug particles. In the entire active agent. Said agent or agents is administered sub- prior art literature, dissolution testing of ordered mixtures lingually in combination with a bioadhesion and/or mu- 20 has been conducted with a large volume of water, typi- coadhesion promoting compound. cally 1 litre. The possibility to use ordered mixtures for [0015] Further according to the invention, there is also sublingual administration, where the volume of liquid provided a single-dose pharmaceutical composition for available as a solvent is limited to a few millilitres, has sublingual administration, comprising a pharmacologi- not been considered as a feasible approach. It was there- cally effective amount ofat least one pharmaceutically 25 fore unexpected that the present form of a solid dosage active agent. Said composition also contains a bioadhe- form preparation and administration route gives positive sion or mucoadhesion promoting compound. This com- and useful results. position reduces erratic drug absorption via swallowed In such an ordered mixture, the active agent or agents saliva and enables the administration of small amounts have a mean particle size below 10 mm. This size is de- of said agent or agents. Therefore, it substantially reduc- 30 termined on a weight basis, as obtained directly by e.g. es the risk of side effects and intrapatient as well as in- dry sieving analysis, as is known by those skilled in the terpatient variation of therapeutic response. Thereby the art. risk of drug accumulation is reduced, making the phar- [0021] A bioadhesion and/or mucoadhesion promoting maceutical preparation well suited for repeated dosing agent is additionally added to the carrier particles accord- in patients suffering from acute disorders. 35 ing to the invention. The bioadhesion and/or mucoadhe- [0016] The amount of active agent or agents contained sion promoting agent is effective in making the active in the pharmaceutical composition of the invention is ob- agent or agents adhere to the oral mucosa and may, in viously dependent on a number of factors, which are to addition, possess properties to swell and expand in con- be evaluated by the treating physician. Among such fac- tact with water and thus make the tablet or the carrier tors may be mentioned the specific agent used and the 40 particles disintegrate when wetted with saliva. The bio/ type of disorder being treated, the medical status of the mucoadhesion promoting agent must then be present on patient, and others. the surface of the carrier particles, but it may optinally [0017] When fentanyl is used for the treatment of acute also be present within these particles, as described be- or breakthrough pain, the composition of the invention low. should contain from 0.05 up to 20 weight percent of fen- 45 [0022] Theexpression "mucoadhesion" ismeant to de- tanyl or one of its pharmaceutically acceptable salts. note an adhesion to mucous membranes which are cov- More preferably, the composition contains from 0.05 to ered by , such as those in the oral cavity, while 5 weight percent of fentanyl, and especially from 0. I to the expression "bioadhesion" is meant to denote an ad- 1 weight percent. The contents can also be expressed hesion to biological surfaces more in general, including as the amount of fentanyl in a dose unit of the composi- 50 mucous membranes which are not covered by mucus. tion, such as a tablet. In this case, a dose unit should These expressions generally overlap as definitions, and contain from 0.05 to 20 mg, and preferably 0.1 to 5 mg may usually be used interchangeably, although the ex- of fentanyl. When the fentanyl is used in the form of a pression "bioadhesive" has a somwhat wider scope. In salt, these percentages and amounts should be recalcu- the present specification and claims, the two expressions lated accordingly. 55 serve the same purpose as regards the objects of the [0018] Still further according to the invention, the sub- invention, and this has been expressed by the use of the lingual composition comprises an ordered mixture of one common term "bio/mucoadhesion". or more bioadhesive and/or mucoadhesive carrier sub- [0023] Suitably the carrier particles contain from 0.1

4 5 EP 1 652 518 B1 6 up to 25 weight percent of bio/mucoadhesion promoting used as bio/ mucoadhesion promoting agents. In addition compound, based on the total composition. In practice, to their polymeric nature, their ability to swell is important. contents below 1 weight percent have been found to give On the other hand, it is also important that they are sub- an insufficient bio/mucoadhesive effect. The preferred stantially insoluble in water. Their swelling factor by vol- range of bio/mucoadhesion promoting agent content is 5 ume whenbrought intocontact with water or saliva should from 1 to 15 weight percent. preferably be at least 10, while a factor of at least 20 is [0024] It is preferred that the bio/mucoadhesion pro- more preferred. Examples of such bio/mucoadhesion moting agent is a polymeric substance, preferably a sub- promoting agents include cellulose derivatives such as stance with an average molecular weight above 5,000 hydroxypropylmethyl cellulose (HPMC), hydroxyethyl (weight average) . The level of hydration of the mucosa 10 cellulose (HEC), hydroxypropyl cellulose (HPC), methyl adhesion promoting agent interface is of importance in cellulose, ethyl hydroxyethyl cellulose, carboxymethyl the development of bio/ mucoadhesive forces. Therefore, cellulose and sodium carboxymethyl cellulose (NaCMC); the faster the swelling of the polymer, the faster is the starch derivatives such as moderately cross-linked initiation of bio/mucoadhesion. The hydration of bioad- starch; acrylic polymers such as carbomer and its deriv- hesive compounds also makes them useful as absorption 15 atives (Polycarbophyl, Carbopol®, etc.); polyethylene enhancers according to the invention. oxide (PEO); chitosan (poly-(D-glucosamine)); natural [0025] Preferably, the carrier particle size is from 50 to polymers such as gelatin, sodium alginate, pectin; scle- 750 mm, and more preferredly from 100 to 600 mm. Al- roglucan; xanthan gum; guar gum; poly co-(methylvinyl though particle sizes outside the indicated range can be ether/maleic anhydride); and crosscaramellose. Combi- used, practical difficulties are experienced when formu- 20 nations of two or more bio/mucoadhesive polymers can lating pharmaceutical preparations from particles having also he used. More generally, any physiologically accept- such sizes. The carrier used may comprise any sub- able agent showing bio/mucoadhesive characteristics stance which is pharmaceutically acceptable, is highly may be used successfully to be incorporated in the car- soluble in water, and which can be formulated into par- rier. Bio/mucoadhesiveness can be determined in vitro, ticles fit for incorporating a bio/ mucoadhesion promoting 25 e.g.according to G. Salaet al., Proceed.Int. Symp. Contr. agent. A number of such substances are known to the Release. Bioact. Mat. 16:420, 1989. person skilled in this art. As suitable examples may be [0030] Some suitable commercial sources for repre- mentioned carbohydrates, such as sugar, mannitol and sentative bio/mucoadhesive polymers include: lactose, or pharmaceutically acceptable inorganic salts, such as sodium chloride or calcium phosphate. 30 Carbopol® acrylic copolymer - BF Goodrich Chem- [0026] In accordance with one particularly preferred ical Co, Cleveland, 08, USA; aspect of the invention, the carrier also comprises a frag- HPMC - Dow Chemical Co., Midland, ), MI, USA; mentation promoting agent. By a fragmentation promot- NEC (Natrosol) - Hercules Inc., Wilmington, DE., ing agent is meant a brittle material which is readily USA; crushed or broken up when a pharmaceutical composi- 35 HPC (Klucel®) - Dow Chemical Co., Midland, MI, tion of which it forms a part is compacted into tablets. If USA; a bio/mucoadhesion promoting agent also is incorporat- NaCMC - Hercules Inc. Wilmington, DE.. USA; ed within the carrier as well as being added to the carrier PEO - Aldrich Chemicals, USA; surface, further surfaces of bio/ mucoadhesion promoting Sodium Alginate, - Edward Mandell Co., Inc., Car- agent may then exposed for hydration. This effect is es- 40 mel, NY, USAi pecially pronounced when the bio/mucoadhesion pro- Pectin - BF Goodrich Chemical Co., Cleveland, OH, moting agent also serves as a disintegrant. Mannitol and USA.’ lactose have been found to be particularly suitable as Ac-Di-Sol® (modified cellulose gum with a high fragmentation promoting agents. swellability) - FMC Corp., USA; [0027] The addition of a pharmaceutically acceptable 45 Actigum, - Mero-Rousselot-Satia, Baupte, France; surfactant to the composition is also a preferred feature Satiaxane - Sanofi BioIndustries, Paris, France; of the invention. The increased effect of the sur- Gantrez® - ISP, Milan, Italy; factant enhances the hydration of the carrier particles, Chitosan-Sigma, St Louis, MS, USA; which results in faster initiation of the bio/ mucoadhesion. The surfactant should be in a finely dispersed form and 50 [0031] Depending on the type and the proportion of the intimately mixed with the active agent or agents. The bio/mucoadhesion promoting agent used, the rate and amount of surfactant should be from 0.5 to 5 weight per- intensity of bio/mucoadhesion may be varied. According cent of the composition, and preferably then from 0.5 to to one of the preferred aspects of the invention, substanc- 3 weight percent. es with high and rapid capacity for swelling are preferred. [0028] As examples of suitable surfactants may be55 [0032] In order for the pharmaceutical composition of mentioned sodium lauryl sulfate, polysorbates, bile acid the invention to function properly when a bio/ mucoadhe- salts and mixtures of these. sion promoting agent is added thereto, this agent must [0029] A variety of polymers known in the art can be be positioned at the surfaces of the carrier particles. The

5 7 EP 1 652 518 B1 8 bio/mucoadhesion promoting agent can then be admixed butazolidine (analgetic), phenylbutazone (analgetic), di- to the carrier particles in several ways. In a preferred azepam (insomnia), oxazepam (insomnia), zopiclone (in- embodiment of the invention, a fine particulate quality of somnia), zolpidem (insomnia), propiomazine (insomnia), the bio/mucoadhesion promoting agent is mixed together valeriana (insomnia), levomepromazin (insomnia), cy- with the coarse carrier for a sufficient time to produce an 5 clizine (allergy), cetirizine (allergy), terfenadine (allergy), ordered mixture, where the finer particles exist as dis- acrivastine (allergy), fexofenadine (allergy) and furosem- crete primary particles adhered to the surfaces of the ide (diuretic). carrier particles. Thus, the bio/ mucoadhesion promoting [0036] Other drugs which benefit from an enhanced agent is admixed in the same way as the active com- absorption and which may be used for medical conditions pound described in European patent No. 0 324 725. 10 where a rapid onset of the action is desirable include, [0033] In yet another embodiment of the invention, the without any limiting sense, various peptides and en- bioJmucoadhesion promoting agent may, besides it pe- zymes, such as atrial natriuretic peptides (ANP, ANF, ripheral orientation on the surfaces of the carrier parti- auriculin) (diuretics), brain natriuretic peptides (diuret- cles, also be incorporated into the carrier particles in var- ics), platelet aggregation inhibitors (anticoagulants), ious ways. For example, the finely dispersed carrier can 15 streptokinase (antocoagulant), heparin (anticoagulant), be granulated together with finely dispersed bio/ mucoad- urokinase (anticoagulant), renin inhibitors (hyperten- hesive in a liquid which does not dissolve the bio/mu- sion), insulin (antidiabetic), and sleep inducing peptide coadhesive agent or cause it to swell. In this case, the (insomnia). dry constituents are first mixed, and the resultant mix is [0037] Further examples of drugs where exposure to thenmoistened with a non- dissolving/non-swelling liquid, 20 gastric acid has to be avoided and where the swallowing such as absolute ethanol. The resultant mass is granu- of active drug containing saliva can be minimised by lated, for instance by forcing it through a filter. It is then means of the bio/ mucoadhesive properties of the present dried and finely ground. Alternatively, the moist mass can formulations include, without any limiting sense, benzim- he dried and then granulated. Another way of producing idazole derivatives used as H +, K+ and ATPase inhibitors the carrier particles according to the invention is by dis- 25 (gastric acid reduction), such as omeprazole, pantopra- solving the carrier agent in a solvent which will not dis- zole, perprazole and lansoprazole. Other H +, K+ and AT- solve the bio/mucoadhesion promoting agent or cause it Pase inhibitors include alyll isothiocyanate, trifluorper- to swell, followed by the addition or the bio/mucoadhe- azide, nolinium bromide and fenoctimine. sion promoting agent to the solution, evaporation of the [0038] The invention is particularly suitable for the ad- solvent, and granulation of the residue. Other methods 30 ministration of fentanyl and its pharmacologically accept- are also conceivable to the person skilled in this art. Ir- able salts, such as the citrate or maleate, which are not respective of the method applied, a suitable grain size readily soluble in water. The particles of fentanyl or salt fraction of the carrier agent containing bio/ mucoadhesion thereof will suitably have a maximum particle size of promoting agent is prepared in a final stage, e.g. by pass- about 24 mm but will preferably not be greater than about ing the particulate mixtures through an screen or sieve 35 10 mm Fentanyl is caused to adhere to the carrier par- of an appropriate mesh size, for instance a U.S. mesh tieles by dry mixing of the ingredients during a period of size from 35 to 170. time of sufficient length. This time period can vary ac- [0034] The bio/mucoadhesion promoting agent suita- cording to the mixing equipment used. A person skilled bly has a particle size between 1 and 100 mm. When the in the art will have no difficultly in determining by exper- particles of this agent are to be mixed with the carrier 40 imentation a suitable mixing time for a given combination particles to form an ordered mixture, their size lies within of active substance, bio/ mucoadhesion promoting agent. the lower part of the size interval, and suitably their size and carrier, by using a particular mixing equipment. is then below 10 mm. When the bio/mucoadhesion pro- [0039] Another preferred aspect of the invention com- moting agent is to be incorporated in the carrier particles, prises the incorporation of a disintegrating agent in the its particle size may be within the upper part of the size 45 composition of the invention. Such an agent which will interval. accelerate the dispersion of the carrier particles. Exam- [0035] The invention is particularly directed to the ad- ples of disintegrating agents according to the invention ministration of drugs which are used for the treatment of include cross- linked polyvinylpyrrolidone, carboxymethyl medical conditions where a rapid and transient effect is starch, natural starch, microcrystalline cellulose, cellu- desirable, such as pain, insomnia, allergic conditions and 50 lose gum and mixtures of these. A preferred content of pulmonary oedema. As non-limiting examples of such disintegrating agent is from 1 % to 10 % of the composi- drugs may be mentioned morphine (analgetic), fentanyl tion. As can be seen, the definitions of the disintegrating (analgetic), alfentanyl (analgetic), sufentanyl (analgetic), agent and the bio/mucoadhesion promoting agent over- buprenorphine (analgetic), pizotifen (analgetic), su- lap somewhat, and it may be preferred that both functions matriptan (analgetic), indomethacin (analgetic), sulindac 55 are served by the same substance. However, it is impor- (analgetic), diclofenac (analgetic), ketorolac (analgetic), tant to note that these two categories of excipients are piroxicam (analgetic), tenoxicam (analgetic), ibuprofen not equivalent, and there are efficiently functioning dis- (analgetic), naproxen (analgetic), ketoprofen (analgetic), integrants which do not possess bio/ mucoadhesive prop-

6 9 EP 1 652 518 B1 10 erties, and vice versa. was investigated in accordance with USP XXIII (Paddle [0040] The ordered mixtures prepared in accordance Method) at two different stirring speeds, 25 and 100 rpm. with the present invention can be incorporated into var- ious kinds of pharmaceutical preparations intended for Example 2. Preparation of a rapidly disintegrating tablet sublingual administration. Irrespective of the form given 5 with bio/mucoadhesion promoting properties. to the preparation, it is important that the preparation is essentially free from water, since its bio/mucoadhesion [0046] A batch of 1000 tablets was produced from the promoting character results from its practically instanta- following composition: 91.0 g of mannitol (granular qual- neous hydration when brought into contact with water or ity of a particle size from 250 to 450m m) and 1.0 g of saliva. Premature hydration would drastically decrease 10 sodium lauryl sulfate and 500 mg of micronized fentanyl the mucoadhesion promoting properties and result in a were mixed in a V- mixer over a period of 24 hours. There- premature dissolution of the active substance. after, 5.0 g ofAvicel ® PH101 and 2.0 g of Ac-Di-Sol® [0041] A pharmaceutical composition for the preferred (here used both as a disintegrant and as a bio/ mucoad- sublingual can be obtained by hesion promoting agent) was admixed for an additional combining an aforementioned ordered mixture with con- 15 2 hours. Finally, 0.5 g of magnesium stearate was ad- ventional pharmaceutical additives and excipients used mixed for 2 minutes. The resulting tablet mass was com- in the art for sublingual preparations. Appropriate formu- pacted into tablets at a compaction pressure of 130 Mpa, lation methods are well known to the person skilled in each tablet containing 0.5 mg of fentanyl. the art; see, for instance, Pharmaceutical Dosage Forms: [0047] The disintegration time was tested with the use Tablets. Vohune 1, 2nd Edition, Lieberman H A et al.; 20 of the apparatus described in Ph.Eur. (latest edition) Eds.; Marcel Dekker, New York and Basel 1989, p. [0048] It was found that the disintegration time was less 354-356, and literature cited therein. Suitable additives than 15 seconds. comprise additional carrier agents, preservatives, lubri- [0049] For comparison, conventional rapidly dissolv- cants, gliding agents, disintegrants, flavorings, and dye- ing tablets were also produced. Dry mannitol having a stuffs. 25 particle size of 250-450 microns was dry mixed with mi- [0042] Thus, the invention provides a dosage form cronized fentanyl without any further addition of excipi- which is easy and inexpensive to manufacture, enables ents.The mixing timewas 50 hours.The resulting mixture rapid active substance release, promotes a rapid uptake was compacted into tablets at a compaction pressure of of the active agent or agents through the oral mucosa, 200 MPa, each tablet containing 0.5 mg of fentanyl. and enhances the upptake of otherwise poorly soluble 30 [0050] The results from this investigation showed that substances, such as peptides.. The use of a low dose of the ordered mixture with bio/mucoadhesive properties active agent is provided for, supporting a short duration according to the invention (Example 1) has a dissolution of action while enabling a repeated dosing schedule for rate equal to that of a conventional rapidly dissolving tab- patients in need of treatment of recurrent acute disorders. let formulation. The entire tablet was dissolved within 2 [0043] The invention will now be illustrated in more de- 35 minutes. Furthermore, the rapid disintegration found for tail by reference to examples showing preferred but not the tablets of Example 2 was equal to or better than for limiting embodiments. the conventional tablets.

Example 1. Preparation of a rapidly disintegrating tablet Example 3. Evaluation of uptake in sublingual adminis- with bio/mucoadhesion promoting properties. 40 tration

[0044] A batch of 1000 tablets was produced from the [0051] To one patient suffering from breakthrough pain following compositions: 81.5 g of mannitol and 2.0 g of due to cancer was administered 400 mg of fentanyl as a Ac-Di-Sol® (disintegrant and bio/ mucoadhesion promot- sublingual tablet formulated as described in Example 1. ing agent) were mixed with about 170 ml of absolute eth- 45 The plasma concentration of fentanyl was monitored for anol The dried mixture was forced through a metal sieve a time of 240 minutes after the administration, and the of 1 mm mesh width and the resultant fraction, having a results are shown in the accompanying figure. It will be particle size from about 250 to 450 microns, was mixed seen that the uptake of fentanyl was rapid, with the max- with 500 mg of micronized fentanyl and with 1.0 g of finely imum value attained already after 5 minutes. This shows ground sodium lauryl sulfate (surfactant) over a period 50 that a sublingual preparation according to the invention of 50 hours. The resulting mixture was admixed with 5.0 gives a rapid uptake of the active agent, even though a g of Avicel® Ph 101 and 10.0 g sodium alginate (bio/ very small volume of liquid is available for dissolution in mucoadhesion promoting agent and disintegrant) over a this route of administration. period of 60 minutes. The resulting mixture was com- pacted into tablets at a compaction pressure of 200 MPa, 55 Example 4. Evaluation of bio/mucoadhesive properties. each tablet having a weight of 100 mg and containing 0.5 mg of fentanyl. [0052] For in vitro evaluation of the bio/ mucoadhesive [0045] The dissolution rate of the tablets thus produced properties of the formulation according to the present in-

7 11 EP 1 652 518 B1 12 vention, a method permitting evaluation of bio/mucoad- an enhanced uptake of ANP through the oral mucosa in hesion promoting properties directly on finished dosage comparison with conventional peroral formulations. The forms (Sala, G.E. et al., Proc. Int. Symp . Contr. Release preparation may be used for the treatment of pulmonary Bioact.Mat. 16: 420, 1989) was used. The evaluation was edema. based on measurements of the flow of water required to 5 remove the active substance from a rabbit intestinal Example 7. Preparation of rapidly disintegrating tablets membrane. A strip of rabbit mucosa was placed horizon- for the administration of omeprazole tally in a suitable temperature controlled chamber set at 37°C. The tissue was first washed with predetermined [0055] Rapidly disintegrating tablets with bio/ mucoad- volumes of water by means of a peristaltic pump. Pre- 10 hesive properties for sublingual administration were pre- compressed compositions according to Example 1 (5-15 pared according to example 1, each tablet containong mg) were then placed on the tissue and allowed to remain 10 mg of omeprazole. The tablets show a rapid release there for 2 minutes to ensure proper dissolution. Upon of omeprazole and an enhanced uptake of omeprazole this followed an elution with water fed by a peristaltic through the oral mucosa, as well as a reduced swallowing pump during 10 minutes. Rinsed- off fentanyl was collect- 15 of omeprazole in the saliva, in comparison with conven- ed, and its amount determined by radioimmunoassay tional peroral formulations. The preparation may be used (RIA) in order to establish the percentage of fentanyl re- for the treatment of gastroesophageal reflux. moved. Subsequent tests were carried out using increas- ing elution flow rates. The results are shown in Table 2; Example 8. Preparation of rapidly disintegrating tablets percentages of removal at a high flow rate are listed for: 20 for the administration of diclofenac

A Bio/mucoadhesive mixture according to the inven- [0056] Rapidly disintegrating tablets with bio/ mucoad- tion (Example 1); hesive properties for sublingual administration were pre- pared according to example 1, each tablet containinh 50 B Bio/mucoadhesive mixture according to the inven- 25 mg of diclofenac. The tablets show a rapid release of tion (Example 2); diclofenac and an enhanced uptake of diclofenac through the oral mucosa in comparison with conventional peroral C Conventional mixture for rapid dissolution contain- formulations. The preparation may be used for the treat- ing no bio/mucoadhesion promoting agent. ment of painful conditions such as neprolithiasis. 30 [0057] In the foregoing specification, the present in- vention has been described with reference to various ex- Table 2: amples and preferred embodiments. However, for a per- % fentanyl removed son skilled in the art, it is clear that the scope of the in- Flow rate (ml/min) ABC vention is not limited to these examples and embodi- 35 ments. >15 <50 <50 > 95

Example 5. Preparation of rapidly disintegrating tablets Claims for the administration of furosemide 40 1. A bioadhesive and/or mucoadhesive pharmaceuti- [0053] Rapidly disintegrating tablets with bio/ mucoad- cal composition for the treatment of acute disorders hesive properties for sublingual administration were pre- by sublingual administration, comprising an essen- pared according to Example 1, each tablet containing 20 tially water-free, ordered mixture of microparticles of mg of furosemide. The tablets show a rapid release of at least one pharmaceutically active agent adhered furosemide and a promoted uptake of furosemide45 to the surfaces of carrier particles, said particles be- through the oral mucosa in comparison with conventional ing substantially larger than said microparticles and peroral formulations. The preparation may be used for being water-soluble, and a bioadhesion and/or mu- the treatment of pulmonary edema. coadhesionpromoting agent present on thesurfaces of the carrier particles. Example 6. Preparation of rapidly disintegrating tablets 50 for the administration of atrial natriuretic peptide (ANP) 2. A composition according to claim 1, wherein the mi- croparticles of said active agent or agents have a [0054] Rapidly disintegrating tablets with bio/ mucoad- weight based mean diameter of less than 10 mm. hesive properties which in addition enhance absorption of large molecules in sublingual administration were pre- 55 3. A composition according to claim 1 or 2, wherein the pared according to Example 1, each tablet containing 0.7 mean sieve diameter of the carrier particles is less mg ANP. The tablets show a rapid release of ANP and than 750 mm.

8 13 EP 1 652 518 B1 14

4. A composition according to claim 3, wherein the di- 15. A composition according to claim 14, wherein the ameter is from 100 to 600 mm. carrier particles comprise at least one of the materi- als mannitol, lactose, calcium phosphate and sugar. 5. A composition according to any one of claims 14, wherein the carrier particles comprise a brittle ma- 5 16. A composition according to any one of claims 1-15, terial which will fragmentize easily when com- wherein the carrier particles contain at least one pressed. pharmaceutical disintegrating agent promoting the dispersion of the microparticles of the active agent 6. A composition according to any one of claims 1-5, or agents over the sublingual mucosa. wherein the carrier particles contain from 0.1 to 25 10 weight percent of the bio-mucoadhesion promoting 17. A composition according to claim 16, wherein the agent based on the total composition. disintegrating agent is selected from the group con- sisting of cross-linked polyvinylpyrrolidone, car- 7. A composition according to claim 6, wherein the car- boxymethyl starch, natural starch, microcrystalline rier particles contain from 1 to 13 weight percent. 15 cellulose, cellulose gum, and mixtures thereof.

8. A composition according to claim 6 or 7, wherein the 18. A composition according to claim 16 or 17, wherein bio/mucoadhesion promoting agent is selected from the disintegrating agent is present in an amount from the group consisting of acrylic polymers, cellulose 1 to 10 weight percent of the composition. derivatives, natural polymers having bio/ mucoadhe- 20 sive properties, and mixtures thereof. 19. A composition according to any one of claims 1-18, for use in the treatment of acute disorders by sub- 9. A composition according to claim 8, wherein the bio/ lingual administration. mucoadhesion promoting agent is selected from the group consisting of cellulose derivatives and com- 25 20. A composition according to any one of claims 1 to prising hydroxypropylmethyl cellulose, hydroxyethyl 18, wherein the active agent is morphine, alfentanyl, cellulose, hydroxypropyl cellulose, sodium car- sufentanyl, buprenorphine, pizolifen, sumalriptan, boxymethyl cellulose, methyl cellulose, ethyl hydrox- indomethacin, sulindac, diclofenac, ketorolac, pirox- yethyl cellulose, carboxymethyl cellulose and mod- icam, tanoxicam, ibuprofen, naproxen, ketaprofen, ified cellulose gum; crosscaramellose; modified30 butazolidine, phenylbulazone, cyclizine, cetirizine, starch; acrylic polymers comprising carbomer and terfenadine, acrivastine or fexofenadine. its derivatives; polyethylene oxide; chitosan; gelatin; sodium alginate; pectin; scleroglucan; xanthan gum; 21. A composition according to claim 20, wherein the guar gum; poly-co-(methyl vinyl ether-maleic anhy- active agent is affentanyl or sufentanyl. dride); and mixtures thereof. 35 22. A composition according to any one of claims 1 to 10. A composition according to any one of claims 1-9, 18, wherein the active agent is furosemide, an atrial further comprising a pharmaceutically acceptable natriuretic peptide or a brain natriuretic peptide. surfactant in a finely dispersed form and intimately mixed with the active agent or agents. 40 23. A composition according to any one of claims 1 to 18, wherein the active agent is a platelet aggregation 11. A composition according to claim 10, wherein the inhibitor, streptokinase, heparin or urokinase. surfactant is present in an amount from 0.5 to 5 weight percent of the composition. 24. A composition according to any one of claims 1 to 45 18, wherein the active agent is a renin inhibitor. 12. A composition according to claim 11, wherein the amount is from 0.5 to 3 weight percent 25. A composition according to any one of claims 1 to 18, wherein the active agent is insulin. 13. A composition according to claims 10 to 12, wherein the surfactant is selected from the group consisting 50 26. A composition according to any one of claims 1 to of sodium lauryl sulfate, polysorbates, bile acid salts 18, wherein the active agent is a +H, K+ ATPase and mixtures thereof. inhbitor.

14. A composition according to any one of claims 1-13, 27. The composition according to claim 16, wherein the wherein the carrier particles comprise a water-solu- 55 active agent is omeprazole, pantoprazole, perpra- ble, pharmaceutically acceptable carbohydrate zole, lansoprazole, alyll isothiocyanate, trifluore- and/or an inorganic salt. razide, nolinium bromide or fenoctimine.

9 15 EP 1 652 518 B1 16

Patentansprüche reanhydrid); und Gemischen hiervon ausgewählt ist.

1. Bioadhäsive und/oder mucoadhäsive pharmazeuti- 10. Zusammensetzung nach einem der Ansprüche 1-9, sche Zusammensetzung zur Behandlung von aku- die ferner ein pharmazeutisch akzeptables grenzflä- ten Störungen durch sublinguale Verabreichung, 5 chenaktives Mittel in einer fein dispergierten Form wobei die Zusammensetzung ein im Wesentlichen und mit dem Wirkstoff bzw. den Wirkstoffen innig wasserfreies geordnetes Gemisch aus Mikroteil- vermischt umfasst. chen von mindestens einem pharmazeutischen Wirkstoff, die an den Oberflächen von Trägerteil- 11. Zusammensetzung nach Anspruch 10, wobei das chen haften, wobei die Teilchen wesentlich größer 10 grenzflächenaktive Mittel in einer Menge von 0,5 bis als die Mikroteilchen und wasserlöslich sind, und ei- 5 Gew.-% der Zusammensetzung vorhanden ist. nem die Bioadhäsion und/oder die Mucoadhäsion fördernden Mittel, das auf den Oberflächen der Trä- 12. Zusammensetzung nach Anspruch 11, wobei die gerteilchen vorhanden ist, umfasst. Menge 0,5 bis 3 Gew.-% beträgt. 15 2. Zusammensetzung nach Anspruch 1, wobei die Mi- 13. Zusammensetzung nach den Ansprüchen 10 bis 12, kroteilchen des Wirkstoffs bzw. der Wirkstoffe einen wobei das grenzflächenaktive Mittel aus der Gruppe massebasierten mittleren Durchmesser von weniger von Natriumlaurylsulfat, Polysorbaten, Gallensäure- als 10 mm aufweisen. salzen und Gemischen hiervon ausgewählt ist. 20 3. Zusammensetzung nach Anspruch 1 oder 2, wobei 14. Zusammensetzung nach einem der Ansprüche der mittlere Siebdurchmesser der Trägerteilchen 1-13, wobei die Trägerteilchen ein wasserlösliches, weniger als 750 mm beträgt. pharmazeutisch akzeptables Kohlehydrat und/oder ein anorganisches Salz umfassen. 4. Zusammensetzung nach Anspruch 3, wobei der25 Durchmesser 100 bis 600 mm beträgt. 15. Zusammensetzung nach Anspruch 14, wobei die Trägerteilchen mindestens eines der Materialien 5. Zusammensetzung nach einem der Ansprüche 1-4, Mannit, Lactose, Calciumphosphat und Zucker um- wobei die Trägerteilchen ein sprödes Material, das fassen. ohne Weiteres zerbricht, wenn es zusammenge-30 drückt wird, umfassen. 16. Zusammensetzung nach einem der Ansprüche 1-15, wobei die Trägerteilchen mindestens ein phar- 6. Zusammensetzung nach einem der Ansprüche 1-5, mazeutisches Desintegrationsmittel enthalten, das wobei die Trägerteilchen 0,1 bis 25 Gew.- % an dem die Verteilung der Mikroteilchen des Wirkstoffs bzw. die Bio/Mucoadhäsion fördernden Mittel, bezogen 35 der Wirkstoffe über die sublinguale Mucosa fördert. auf die Gesamtzusammensetzung, enthalten. 17. Zusammensetzung nach Anspruch 16, wobei das 7. Zusammensetzung nach Anspruch 6, wobei die Trä- Desintegrationsmittel aus der Gruppe von vernetz- gerteilchen 1 bis 13 Gew.-% enthalten. tem Polyvinylpyrrolidon, Carboxymethylstärke, na- 40 türlicher Stärke, mikrokristalliner Cellulose, Cellulo- 8. Zusammensetzung nach Anspruch 6 oder 7, wobei sekautschuk und Gemischen hiervon ausgewählt das die Bio/Mucoadhäsion fördernde Mittel aus der ist. Gruppe von Acrylpolymeren, Cellulosederivaten, natürlichen Polymeren mit bio/mucoadhäsiven Ei- 18. Zusammensetzung nach Anspruch 16 oder 17, wo- genschaften und Gemischen hiervon ausgewählt ist. 45 bei das Desintegrationsmittel in einer Menge von 1 bis 10 Gew.-% der Zusammensetzung vorhanden 9. Zusammensetzung nach Anspruch 8, wobei das die ist. Bio/Mucoadhäsion fördernde Mittel aus der Gruppe von Cellulosederivaten, die Hydroxypropylmethyl- 19. Zusammensetzung nach einem der Ansprüche 1-18 cellulose, Hydroxyethylcellulose, Hydroxypropylcel- 50 zur Verwendungbei der Behandlung von akutenStö- lulose, Natriumcarboxymethylcellulose, Methylcel- rungen durch sublinguale Verabreichung. lulose, Ethylhydroxyethylcellulose, Carboxymethyl- cellulose und modifizierten Cellulosekautschuk um- 20. Zusammensetzung nach einem der Ansprüche 1 bis fassen; Crosscarmellose; modifizierter Stärke; 18, wobei der Wirkstoff Morphin, Alfentanyl, Sufen- Acrylpolymeren, die Carbomer und dessen Derivate 55 tanyl, Buprenorphin, Pizotifen, Sumatriptan, Indo- umfassen; Polyethylenoxid; Chitosan; Gelatine; Na- methacin, Sulindac, Diclofenac, Ketorolac, Piroxi- triumalginat; Pektin; Skleroglucan; Xanthangummi; cam, Tenoxicam, Ibuprofen, Naproxen, Ketoprofen, Guargummi; Poly-co(methylvinylether-maleinsäu- Butazolidin, Phenylbutazon, Cyclizin, Cetirizin, Ter-

10 17 EP 1 652 518 B1 18

fenadin, Acrivastin oder Fexofenadin ist. comprennent un matériau fragile qui se fragmentera facilement lors d’une compression. 21. Zusammensetzung nach Anspruch 20, wobei der Wirkstoff Alfentanyl oder Sufentanyl ist. 6. Composition selon l’une quelconque des revendica- 5 tions 1 à 5, dans laquelle les particules porteuses 22. Zusammensetzung nach einem der Ansprüche 1 bis contiennent entre 0,1 et 25 pour cent en poids 18, wobei der Wirkstoff Furosemid, ein atriales na- d’agent activateur de bio/ mucoadhésion par rapport triuretisches Peptid oder ein natriuretisches Peptid à la composition totale. Typ B ist. 10 7. Composition selon la revendication 6, dans laquelle 23. Zusammensetzung nach einem der Ansprüche 1 bis les particules porteuses contiennent entre 1 et 13 18, wobei der Wirkstoff ein Plättchenaggregations- pour cent en poids. inhibitor, Streptokinase, Heparin oder Urokinase ist. 8. Composition selon la revendication 6 ou 7, dans la- 24. Zusammensetzung nach einem der Ansprüche 1 bis 15 quelle l’agent activateur de bio/mucoadhésion est 18, wobei der Wirkstoff ein Renininhibitor ist. choisi dans le groupe constitué par les polymères acryliques, les dérivés cellulosiques, les polymères 25. Zusammensetzung nach einem der Ansprüche 1 bis naturels ayant des propriétés bio-mucoadhésives, 18, wobei der Wirkstoff Insulin ist. et des mélanges de ceux-ci. 20 26. Zusammensetzung nach einem der Ansprüche 1 bis 9. Composition selon la revendication 8, dans laquelle 18, wobei der Wirkstoff ein H+/K+-ATPase-Inhibitor l’agent activateur de bio/mucoadhésion est choisi ist. dans le groupe constitué par les dérivés cellulosi- ques et comprenant l’hydroxypropylméthylcellulose, 27. Zusammensetzung nach Anspruch 26, wobei der 25 l’hydroxyéthylcellulose, l’hydroxypropylcellulose, la Wirkstoff Omeprazol, Pantoprazol, Perprazol, carboxyméthylcellulose sodique, la méthylcellulose, Lansoprazol, Allylisothiocyanat, Trifluorperazid, No- l’éthylhydroxyéthylcellulose, la carboxyméthylcellu- liniumbromid oder Fenoctimin ist. lose et la gomme cellulosique modifiée; la croscarmellose ; l’amidon modifié ; les polymères 30 acryliques comprenant un carbomère et ses dérivés; Revendications l’oxyde de polyéthylène ; le chitosane ; la gélatine; l’alginate de sodium ; la pectine; le scléroglucane ; 1. Composition pharmaceutique bioadhésive et/ou la gomme xanthique ; la gomme guar ; le poly-co mucoadhésive pour le traitement des troubles aigus (éther méthylvinylique-anhydride maléique) ; et des par administration sublinguale, comprenant un mé- 35 mélanges de ceux-ci. lange ordonné, essentiellement anhydre de micro- particules constituées d’au moins un principe phar- 10. Composition selon l’une quelconque des revendica- maceutiquement actif fixé aux surfaces de particules tions 1 à 9, comprenant en outre un agent tensioactif porteuses, lesdites particules étant sensiblement pharmaceutiquement acceptable sous une forme fi- plus grosses que lesdites microparticules et étant 40 nement dispersée et soigneusement mélangé avec hydrosolubles, et d’un agent activateur de bioadhé- le ou les principes actifs. sion et/ou de mucoadhésion présent sur les surfaces des particules porteuses. 11. Composition selon la revendication 10, dans laquelle l’agent tensioactif est présent en une quantité com- 2. Composition selon la revendication 1, dans laquelle 45 prise entre 0,5 et 5 pour cent en poids de la compo- les microparticules dudit ou desdits principes actifs sition. ont un diamètre moyen basé sur le poids inférieur à 10 mm. 12. Composition selon la revendication 11, dans laquelle la quantité est comprise entre 0,5 et 3 pour cent en 3. Composition selon la revendication 1 ou 2, dans la- 50 poids. quelle le diamètre particulaire moyen des particules porteuses est inférieur à 750 mm. 13. Composition selon les revendications 10 à 12, dans laquelle l’agent tensioactif est choisi dans le groupe 4. Composition selon la revendication 3, dans laquelle constitué par le sodium laurylsulfate, les polysorba- le diamètre est compris entre 100 mm et 600 mm. 55 tes, les sels d’acides biliaires et des mélanges de ceux-ci. 5. Composition selon l’une quelconque des revendica- tions 1 à 4, dans laquelle les particules porteuses 14. Composition selon l’une quelconque des revendica-

11 19 EP 1 652 518 B1 20

tions 1 à 13, dans laquelle les particules porteuses inhibiteur de la rénine. comprennent un carbohydrate hydrosoluble phar- maceutiquement acceptable et/ou un sel inorgani- 25. Composition selon l’une quelconque des revendica- que. tions 1 à 18, dans laquelle le principe actif est l’insu- 5 line. 15. Compositionselon la revendication 14, danslaquelle les particules porteuses comprennent au moins un 26. Composition selon l’une quelconque des revendica- des matériaux suivants : mannitol, lactose, phos- tions 1 à 18, dans laquelle le principe actif est un phate de calcium et sucre. inhibiteur d’ATPase H+, K+. 10 16. Composition selon l’une quelconque des revendica- 27. Composition selon la revendication 26, dans laquelle tions 1 à 15, dans laquelle les particules porteuses le principe actif est l’oméprazole, le pantoprazole, le contiennent au moins un agent désintégrant phar- perprazole, le lansoprazole, l’isothiocyanate d’allyle, maceutique activant la dispersion des microparticu- la trifluoropérazine, le bromure de nolinium, ou le les du ou des principes actifs sur la muqueuse su- 15 fénoctimine. blinguale.

17. Compositionselon la revendication 16, danslaquelle l’agent désintégrant est choisi dans le groupe cons- titué par la polyvinylpyrrolidone réticulée, l’amidon 20 carboxyméthylique, l’amidon naturel, la cellulose mi- crocristalline, la gomme cellulosique, et des mélan- ges de ceux-ci.

18. Composition selon la revendication 16 ou 17, dans 25 laquelle l’agent désintégrant est présent dans une quantité de 1 à 10 pour cent en poids de la compo- sition.

19. Composition selon l’une quelconque des revendica- 30 tions 1 à 18, pour utilisation dans le traitement des troubles aigus par administration sublinguale.

20. Composition selon l’une quelconque des revendica- tions 1 à 18, dans laquelle le principe actif est la35 morphine, l’alfentanyle, le sufentanyle, la buprénor- phine, le pizotifène, le sumatriptan, l’indométhacine, le sulindac, le diclofénac, le kétorolac, le piroxicam, le ténoxicam, l’ibuprofène, le naproxène, le kétopro- fène, la butazolidine, la phénylbutazone, la cyclizine, 40 la cétirizine, la terfénadine, l’acrivastine ou la fexo- fénadine.

21. Compositionselon la revendication 20, danslaquelle le principe actif est l’alfentanyle ou le sufentanyle. 45

22. Composition selon l’une quelconque des revendica- tions 1 à 18, dans laquelle le principe actif est le furosémide, un peptide natriurétique auriculaire ou un peptide natriurétique cérébral. 50

23. Composition selon l’une quelconque des revendica- tions 1 à 18, dans laquelle le principe actif est un inhibiteur d’agrégation plaquettaire, la streptokina- se, l’héparine ou l’urokinase. 55

24. Composition selon l’une quelconque des revendica- tions 1 à 18, dans laquelle le principe actif est un

12 EP 1 652 518 B1

13 EP 1 652 518 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• EP 0324725 A [0019] [0032]

Non-patent literature cited in the description

• FARRAR et al. J. Natl. Cancer Inst., 1998, vol. 90 • Pharmaceutical Dosage Forms: Tablets. Marcel (8), 611-616 [0008] Dekker, New York, 1989, vol. 1, 354-356 [0041] • G. SALA et al. Proceed. Int. Symp. Contr. Release. •SALA,G.E.al.et Proc. Int. Symp . Contr. Release Bioact. Mat., 1989, vol. 16, 420 [0029] Bioact. Mat., 1989, vol. 16, 420 [0052]

14