US 20080299.199A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0299199 A1 Bar-Shalom et al. (43) Pub. Date: Dec. 4, 2008 (54) SWELLABLE DOSAGE FORM COMPRISING Publication Classification GELLAN GUMI (51) Int. Cl. A6II 47/36 (2006.01) (75) Inventors: Daniel Bar-Shalom, Kokkedal A6II 47/38 (2006.01) (DK); Lillian Slot, Virum (DK); A6II 47/32 (2006.01) Gina Fischer, Vaerlose (DK); A6II 47/02 (2006.01) Pernille Hoyrup Hemmingsen, A6IR 9/00 (2006.01) Bagsvaerd (DK) (52) U.S. Cl. ......... 424/484: 514/777: 514/779; 514/781; 424/400: 514/772.4: 514/769 Correspondence Address: (57) ABSTRACT FOLEY AND LARDNER LLP SUTESOO A novel dosage form. The dosage form is presented in par 3OOOK STREET NW ticulate form and before oral ingestion the particulate mate WASHINGTON, DC 20007 (US) rial is subjected to an aqueous medium, whereby it is con Verted to a semi-solid form by Swelling or gelling of one or (73) Assignee: Egalet a?s more of the components, especially of a gellan gum, of the particulate matter. The invention also relates to a vehicle for oral administration of one or more active Substances, the (21) Appl. No.: 111596,123 vehicle comprising a gellan gum arranged in a configuration allowing optimal water diffusion so that upon addition of a (22) PCT Filed: May 11, 2005 predetermined amount of an aqueous medium, without the necessity of applying shear forces or other mixing forces, (86). PCT No.: PCT/DKOS/OO317 within a time period of 5 minutes or less swells and/or gels and the texture of the swelled vehicle being similar to that of S371 (c)(1), a soft pudding and having a viscosity of at least about 10,000 (2), (4) Date: Aug. 14, 2007 cps as measured by a Brookfield Viscometer with a #4 LV spindle at 6 rpm and at 20-25°C. In one embodiment of the (30) Foreign Application Priority Data invention, the particulate matter can be moulded into a desired shape or pressed onto a dispensing unit such as a May 11, 2004 (DK) ........................... PA 2004 OO755 Spoon. (1) \-7 (1a) - N-27 (1b) Patent Application Publication Dec. 4, 2008 Sheet 1 of 10 US 2008/0299.199 A1 Patent Application Publication Dec. 4, 2008 Sheet 2 of 10 US 2008/0299.199 A1 Dissolution of 200 mg Paracetamol parvulet 120 - - - -0-61% coated 100 Paracetamol -- 200 mg Paracetamol 80 parvulet -A-200 mg Paracetamol ?a parvulet SSo 60 -X-200 mg Paracetamol 40 parvulet -- 200 mg Paracetamol parvulet 20 -e-200 mg Paracetamol parvulet O - O 5 10 15 20 25 30 35 40 45 50 55 time min Fig. 2 Patent Application Publication Dec. 4, 2008 Sheet 3 of 10 US 2008/0299.199 A1 Patent Application Publication Dec. 4, 2008 Sheet 4 of 10 US 2008/0299.199 A1 jeg Fig. 4 Patent Application Publication Dec. 4, 2008 Sheet 5 of 10 US 2008/0299.199 A1 Patent Application Publication Dec. 4, 2008 Sheet 6 of 10 US 2008/0299.199 A1 Patent Application Publication Dec. 4, 2008 Sheet 7 of 10 US 2008/0299.199 A1 Fig. 7 Patent Application Publication Dec. 4, 2008 Sheet 8 of 10 US 2008/0299.199 A1 F8 i sts' Ea 8 & s 3.s; : :3. S8. 8 3. Fig. 8 Patent Application Publication Dec. 4, 2008 Sheet 9 of 10 US 2008/0299.199 A1 20 — 100 8 O --Wessel 1 -H-Wessel 2 -A-Wessel 3 re-vessel 4 --vesses se-Wessel 6 4. o 2 O 0 10 20 30 4. 50 SO 70 Time (min) Fig. 9 Patent Application Publication Dec. 4, 2008 Sheet 10 of 10 US 2008/0299.199 A1 US 2008/0299.199 A1 Dec. 4, 2008 SWELLABLE DOSAGE FORM COMPRISING then be formulated into tablets or capsules meant to be swal GELLAN GUMI lowed whole. Those tablets and capsules as Such are inappro priate for patients with Swallowing difficulties. Patients (or FIELD OF THE INVENTION they providers in the case of children) are often instructed to open the capsules (or crush the tablets) and to sprinkle the 0001. The present application relates to a novel dosage powder on syrup or pudding or applesauce or similar and then form. The dosage form is presented in particulate form and administered. This approach has limitations. The carrier before oral ingestion the particulate material is subjected to (syrup, pudding, applesauce) is not a well defined entity and an aqueous medium, whereby it is converted to a semi-solid different carriers might interact differently with the multi form by Swelling or gelling of one or more of the components, particles and/or drug and thereby compromise the treatment. especially of a gellan gum, of the particulate matter. The Also, children might object to the grittiness in the material. invention also relates to a vehicle for oral administration of Syrups do not necessarily resemble types of food or bever one or more active Substances, the vehicle comprising a gel ages that children are used to consume. langum arranged in a configuration allowing optimal water 0005. Alternatively the powder can be formulated into diffusion so that upon addition of a predetermined amount of effervescent granules or tablets. These granules or tablets are an aqueous medium, without the necessity of applying shear intended to be dissolved in an aqueous liquid requiring the forces or other mixing forces, within a time period of 5 provision of a glass of liquid and a waiting period sufficient to minutes or less swells and/or gels and the texture of the allow the tablet to completely dissolve and the resulting vol swelled vehicle being similar to that of a soft pudding and ume might be considerable. Often, these dosage forms leave having a viscosity of at least about 10,000 cps as measured by an objectionable deposit in the glass, which may represent a a BrookfieldViscometer with a #4 LV spindle at 6 rpm and at non-ingested part of the drug. Effervescent formulations are, 20-250 C. in general more appropriate for adults although some com 0002. In one embodiment of the invention, the particulate mercial vitamin preparations for children use this approach. matter can be moulded into a desired shape or pressed onto a 0006 Another category is the fast-melting tablets meant to dispensing unit Such as a spoon. be put on the tongue and disintegrate upon contact with saliva. The might be effervescent or non-effervescent. Yet another BACKGROUND OF THE INVENTION Solution is to dispense the multi-particles in lozenges, chew 0003. A recurring problem in the treatment of patients, in able tablets and chewing gum. particular children and the elderly, is their inability or unwill 0007. One example of these approaches was described in ingness to Swallow solid oral dosage forms such as tablets or Wehling et al., U.S. Pat. No. 5,178.878, which relates to capsules. The problem is, however, not uncommon in healthy certain effervescent dosage forms including microparticles. adults as well. This problem is not trivial, the inability or The effervescent dosage forms of Wehling et al. provide a unwillingness of some people to take Solid oral dosage forms significant advance over the art in that they provide an effer can severely compromise the patient's compliance with a Vescent dosage form for direct oral administration. The dos prescribed treatment protocol. Moreover, due to embarrass age form is designed to disintegrate rapidly in the mouth ment, many patients are unwilling to tell their doctor of their releasing its microparticles as a slurry for ingestion. The problem so that the doctor can consider other drugs and/or dosage forms produced in accordance with Wehling et al. can alternate dosage forms. Such a lack of compliance can com be placed in the patient's mouth and the effervescence con promise treatment or cure. tained therein will be activated by contact with the patient’s 0004 Ifan orally administered drug has such a taste that is saliva. The tablet will then disintegrate in a number of sec acceptable to the patient and the pharmacokinetic character onds. However, the effervescence on the tongue may be istics allow reasonable administration regimens, such as once unpleasant to Some adults and to many children. or twice daily, the drug might be formulated in a sirup, elixir, 0008 Kallstrand, et al., U.S. Pat. No. 4,994.260 relates to Suspension or other liquid dosage forms. Unfortunately, in a pharmaceutical mixture. The mixture is used for the con many cases the native taste of the drug is unpleasant and not trolled release of a Substance. According to Kallstrand et al., amenable to taste-masking by the addition of Sweeteners of a liquid dosage form is produced using either a dry powder or flavours. Also, many drugs have such pharmacokinetic microcapsules, which are Suspended in a solution of a release parameters that demand administration at short intervals, dis controlling Substance, also referred to as a "sink. Alterna rupting sleep and other activities. The taste and/or pharma tively, it is possible to encapsulate the release-controlling cokinetic deficiencies can be corrected by the use of various Substance, together with a drug, within an encapsulating coating and/or matrices and/or by modifying the crystalline shell. The release-controlling Substance may include, inter structure, etcetera. U.S. Pat. No. 6,589,955 illustrates such an alia, carbohydrates and carbohydrate-related compounds, approach. The resulting material after micro-encapsulation or disaccharides, monosaccharides, glycerol, glycol, glycosides crystallization or other strategies might be a monolithical of monosaccharides and Substances derived from ethyleneg unit, one unit containing the whole dose, or multi-particles, lycol.