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Pharmaceutical Composition for Sublingual Administration (19) TZZ_ __T (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 BIOADHESIVE PROPERTIES OF CALCIUM MC NL PT SE ALGINATE GEL 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 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 652 518 B1 • 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 SOLUBILITY COMPOUNDS", tablet 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.
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