W I AUSTRALIA Patents Act 1990 PATENT REQUEST : STANDARD PATENT The person identified below as the Applicant requests the grant of a patent to the person identified below as the Nominated Person, for an invention described in the accompanying standard complete specification. Applicant: THE WELLCOME FOUNDATION LIMITED Address: Unicorn House, 160 Euston Road, LONDON NW1 2BP, ENGLAND Nominated Person: THE WELLCOME FOUNDATION LIMITED Address: Unicorn House, 160 Euston Road, LONDON NW1 2BP, ENGLAND Invention Title: WATER-DISPERSIBLE TABLETS c . '*’’t Name of Actual ί*ί ί Inventor: Krystyna Elzbieta Fielden t : «ίίί ■ c « ε « *<· Address for Service: GRIFFITH HACK & CO 168 WALKER STREET c e ε CCS1 Ci «t NORTH SYDNEY NSW 2060 Attorney Code: GH fi . ' C C t- C c Ci c “”t DIVISIONAL APPLICATION DETAILS i c Original Appln No: 11863/92 t 1 rr. cr. / t . C t < f. f- C ■ f t fi C . ' . ■ c t » t ci·c « ■ . ' DATED this 12th day of July 1994 ? ettm t « ' . THE WELLCOME FOUNDATION LIMITED By their Patent Attorney 3047719 13/07/94 GRIFFITH HACK & CO I Τ1 -----------Τ 'ί . Π Ρ/00/008 Section 29(1) Regulation 3.1(2) AUSTRALIA Patents Act 1990 NOTICE OF ENTITLEMENT We THE WELLCOME FOUNDATION LIMITED of Unicorn House, 160 Euston Road, London NW1 2BP, ENGLAND being the Applicant and Nominated Person, in respect of Application No. 67454/94, entitled Water-Dispersible Tablets state the following: Krystyna Elzbieta Fielden is the actual inventor of the invention. This application is a divisional application of Australian Patent Application No. 11863/92, filed 29 January 1992 in the name of THE WELLCOME FOUNDATION LIMITED. The inventor made the invention for and on behalf of the nominated person in the course of her duties as an employee of the nominated person. DATED this 8th day of January 1995 CCCft tec® < < c c I « « » * « THE WELLCOME FOUNDATION LIMITED • · » « « · OUR REF: Ρ15431-ΕΟ.ΆΜΡ -.1 Ct* V ' ·! AU9467454 (12) PATENT ABRIDGMENT (11) Document No, AU-B-67454/94 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance no. 659581 (54) Title WATER-DISPERSIBLE TABLETS International Patent Classification(s) (51)5 A61K 031/53 A61K 009/20 A61K 047/46 (21) Application No. : 67454/94 (22) Application (30) Priority Data (31) Number (32) Date (33) Country 9102019 30.01.91 GB UNITED KINGDOM 9124807 22.11.91 GB UNITED KINGDOM 9124803 22.11.91 GB UNITED KINGDOM 9125005 25.11.91 GB UNITED KINGDOM (43) Publication Date: 08.09.94 (44) Publication Date of Accepted Application : 18.05.95 (62) Related to Division(s) :11863/92 (71) Applicant(s) t THE WELLCOME FOUNDATION LIMITED (72) Inventor(s) KRYSTYNA ELZBIETA FIELDEN (74) Attorney or Agent GRIFFITH HACK & CO., GPO Box 4164, SYDNEY NSW 2001 (57) Claim 1) A water-dispersible tablet having 2.5 to 500mg lamotrigine and comprising 3% w/w to 90% w/w lamotrigine, 0.25 to 40% w/w of a pharmaceutically acceptable swellable clay which is present within the granules of the tablet, and an effective amount of an additional pharmaceutically acceptable disintegrating agent which is present within the granules of the tablet to provide a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710um in accordance with the test for dispersible tablets defined in the British Pharmaeopoea 1988, volume Π, page 895. ' 23) A process for the preparation of a water-dispersible tablet having 2.5 to 500mg lamotrigine and comprising 3% to 90% w/w lamotrigine, 0.25 to 40% of a pharmaceutically acceptable swellable clay and an additional pharmaceutically acceptable disintegrating agent; said process comprising bringing lamotrigine into association with said swellable clay and additional disintegrating agent to form granules, and then compressing the granules to form a tablet which is capable of dispersing in water within a period of 3 minutes to provide a dispersion which is capable of passing through a sieve screen with a mesh aperture of 710μπι in accordance with the test for dispersible tablets defined in the British Pharmacopaeia, 1988, volume H, page 895. ‘ ../2 (11) AU-B-67454/94 -2- (10)659581 26) A method for the treatment in a human being of a disorder of the central nervous system which comprises administration of a water-dispersible compressed tablet comprising lamotrigine as defined in any one of claims 1 to 22. r ::::. r 65958 1 P/00/011 Regulation 3.2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT »e·· • · · · Invention Title: WATER-DISPERSIBLE TABLETS ···• ·ft » e « · • « · ft • ft • ft · » ft • • ft · · ft I ·♦ » ft ί ft ft ft · « « · ft ft ft The following statement is a full description of this invention, including (j the best method of performing it known to us: cC c ft C Γ * <■ f. - t f ft ft ft ■ft ft c ft ft ft ft ft € ft C ft ft GH&CO REF: P15431-EO:AMP ? 2 !SS3 - ΙΑ - WATER-DISPERSIBLE TABLETS ’ The present invention relates to a water-dispersible tablet formulation containing lamotrigine (EP Nos. 021,121 and EP 247,892) . This is a divisional 5 application of application no. 11863/92. Therapeutically active compounds or drugs are frequently administered to patients in tablet form where the drug is intended for oral administration since tablets are an especially convenient pharmaceutical form for manufacture, storage and generally usage. However, problems, may arise with the administration of such tablets to patients who have difficulty in swallowing the tablets (for example, children or more seriously ill patients) especially if the tablets are large in size arising from the amount of drug required in each tablet. A solution to such problems is to formulate the tablets in a form whereby they can be dispersed in water to form a dispersion containing the drug which can then be drunk by the patient. Known water-dispersible tablets include effervescent formulations which rely on the formation of a gas to quickly break up the tablet, but these involve expensive methods of manufacture and strict regulations for such manufacture. Other known water-dispersible tablets use disintegrating agents such as microcrystalline cellulose used in Felders ® dispersible tablets. ί According to a first aspect of the invention there is provided a water-dispersible tablet having 5 to 500mg lamotrigine comprising 2% w/w/ to 90% w/w lamotrigine, 0.25 to 40% k w/w of a pharmaceutically acceptable swellable clay which is present within the granules «- ft * r c »t of the tablet and an effective amount of an additional pharmaceutically acceptable «» ·» ct ·«« ♦ t disintegrating agent which is present within the granules of the tablet to provide a tablet u»< « · « ft which is capab’e of dispersing in water within a period of 3 minutes to provide a dispersion •ft < » I which is capable of passing through a sieve screen with a mesh aperture of 710gm in accordance with the test for dispersible tablets defined in the British Pharmacopoea 1988, I volume II, page 895. fi u £ Swellable clays such as Veegum and other magnesium aluminium silicates have previously been studied and proposed for use as disintegrating agents, binders and t lubricants in the manufacture of tablets, but such studies and proposals were exclusively with respect to tablets intended for swallowing and not for water-dispersible tablets «· (Rubenstein, Pharmaceutics - The Science of Dosage Form Design (1990) for disintegrants « » i »< <· I see p 312 and 314). Moreover, there has never been any suggestion that a clay would be f suitable to meet the more stringent requirements for dispersible tablets. Tablets for I P 1 I EO/8.3.95 ii -2- PA1219AU(i) < swallowing need only have a disintegration time in water of less 15 minutes and be able to form particles on disintegration in water that can pass through a 2.00mm mesh aperture (British Pharmacopia test for swallowable tablets). Such long disintegration times and large particle sizes are entirely unsuitable for a dispersible tablet. Even when swellable clays have been proposed as disintegrating agents for swallowable tablets, they are not regarded as very suitable for such use because their off-white appearance can often discolour the tablet and because they are not as effective as other disintegrating agents (Banker and Anderson - Theory and Practice of Industrial Pharmacy p 328 (1986) and Bhargava et al - Drug Development and Industrial Pharmacy, 17(15), 2093- 2102(1991)). In fact, bentonite is identified in Marshall and Rudnic, Modem Pharmaceutics (1990) p 374, as the least swellable of the ten disintegrants listed. There is no mention in the above text-book references of how the swellable clay should be incorporated - i.e. by intra-granular addition or by extra-granular addition. In the former case, the clay would be included in the mixture from which the granulate is formed; in the latter case the clay would be added to the pre-formed granulate. In J. Pharm. Sci, 55, 1244 (1966), Wai etal. reviewed the following papers relating to swellable clays such as Veegum and bentonite as disintegrating agents: Wai etal., i? J.Pharm.Sci, 55, 1215(1966); Granberg et ah, J.Am.Pharm.Assoc.Sci, 38, 648(1949); Gross et al., J.Am.Pharm.Assoc.Sci, 41, 157(1952); Firouzabadian st al., J.Am.Pharm.Assoc.Sci, ii 43, 248(1954); Ward etal·, Drug Cosmetic Ind, 91, 35(1962); Nair etal., J.Atn.Pharm.Assoc.Sei, 46,131(1957); and Patel et al., Indian J.Pharm., 19, Jan.1957. Wai et al., then compared three grades of Veegum evaluating both extra-granular and intra­ granular addition and concluded that "the clays were not good disintegrating agents when .Ϊ il wet granulated" (i.e.