US008383155B2 (12) United States Patent (10) Patent No.: US 8,383,155 B2 Bar-Shalom et al. (45) Date of Patent: Feb. 26, 2013 (54) SWELLABLE DOSAGE FORM COMPRISING FOREIGN PATENT DOCUMENTS GELLAN GUMI EP O272220 6, 1993 EP 1371 360 B1 12/2003 JP 11-187827 7, 1999 (75) Inventors: Daniel Bar-Shalom, Kokkedal (DK); JP 2004-97114 4/2004 Lillian Slot, Virum (DK); Gina Fischer, WO WO92f1 1084 7, 1992 Vaerlose (DK); Pernille Hoyrup WO WO97/38679 A2 10, 1997 Hemmingsen, Bagsvaerd (DK) WO WO 98.23292 A1 6, 1998 WO WO99/62498 A1 12/1999 WO WOO1,76610 10, 2001 (73) Assignee: Egalet A/S, Vaerlose (DK) WO WOO2,46571 A2 6, 2002 WO WO O2/49571 A2 6, 2002 (*) Notice: Subject to any disclaimer, the term of this WO WO 03/043638 A1 5, 2003 patent is extended or adjusted under 35 WO WO 2004/096906 11, 2004 WO WO 2004/096906 A1 11, 2004 U.S.C. 154(b) by 0 days. WO WO 2005/007074 1, 2005 (21) Appl. No.: 13/212,679 WO WO 2005/007074 A 1, 2005 OTHER PUBLICATIONS (22) Filed: Aug. 18, 2011 JECFA, “Gellan Gum.” FNP 52 Addendum 4 (1996). (65) Prior Publication Data JECFA, “Talc.” FNP 52 Addendum 1 (1992). Alterna LLC, “ElixSure, Allergy Formula', description and label US 2012/OO39969 A1 Feb. 16, 2012 directions, online (Feb. 6, 2007). Hagerström, H., “Polymer gels as pharmaceutical dosage forms'. comprehensive Summaries of Uppsala dissertations from the faculty Related U.S. Application Data of pharmacy, vol. 293 Uppsala (2003). Lin, “Gellan Gum', U.S. Food and Drug Administration, www. (62) Division of application No. 1 1/596,123, filed as inchem.org, online (Jan. 17, 2005). application No. PCT/DK2005/000317 on May 11, Miyazaki, S., et al., “In situ-gelling gellan formulations as vehicles 2005. for oral drug delivery”. J. Control Release, vol. 60, pp. 287-295 (1999). (30) Foreign Application Priority Data Rowe, Raymond C. et al., “Handbook of Pharmaceutical Excipients'. Pharmaceutical Press, Fourth Edition, 2003, pp. 257 May 11, 2004 (DK) ................................. 2004 OO755 258. “Gellan Gum Wins IFT's Food Technology Industrial Achievement (51) Int. Cl. Award.” Food Technology, Institute of Food Technologists, vol. 47. A6 IK 8/02 (2006.01) No. 9, Sep. 1, 1993, pp. 94-96. A6 IK9/48 (2006.01) Monsanto, “Kelcogel Gellan Gum.” Kelcogel, 1998. A6 IK3I/546 (2006.01) (Continued) A6 IK3I/44 (2006.01) A 6LX3L/295 (2006.01) A 6LX3L/75 (2006.01) Primary Examiner – Walter Webb A6 IK 8/00 (2006.01) (74) Attorney, Agent, or Firm — Foley & Lardner LLP A6 IK3I/67 (2006.01) A6 IK9/00 (2006.01) (57) ABSTRACT A6 IK3I/92 (2006.01) A61O I/00 (2006.01) A novel dosage form. The dosage form is presented in par A61O II/00 (2006.01) ticulate form and before oral ingestion the particulate mate A6IP 43/00 (2006.01) rial is subjected to an aqueous medium, whereby it is con A6IP 29/00 (2006.01) Verted to a semi-solid form by Swelling or gelling of one or (52) U.S. Cl. ........................................ 424/485; 426/573 more of the components, especially of a gellan gum, of the (58) Field of Classification Search ................... 424/484 particulate matter. The invention also relates to a vehicle for See application file for complete search history. oral administration of one or more active Substances, the vehicle comprising a gellan gum arranged in a configuration (56) References Cited allowing optimal water diffusion so that upon addition of a predetermined amount of an aqueous medium, without the U.S. PATENT DOCUMENTS necessity of applying shear forces or other mixing forces, 4,590,075 A 5, 1986 Wei et al. within a time period of 5 minutes or less swells and/or gels 4,824,681 A 4, 1989 Schobel et al. and the texture of the swelled vehicle being similar to that of 4,882,169 A 11, 1989 Ventouras a soft pudding and having a viscosity of at least about 10,000 4,994.260 A 2f1991 Kallstrand et al. 5,126,151 A 6, 1992 Boder et al. cps as measured by a Brookfield Viscometer with a #4 LV 6,102.254. A 8, 2000 ROSS spindle at 6 rpm and at 20-25°C. In one embodiment of the 6,395,298 B1 5/2002 Flanagan et al. invention, the particulate matter can be molded into a desired 6,488.962 B1 12/2002 Berner et al. shape or pressed onto a dispensing unit such as a spoon. 6,709,678 B2 3, 2004 Gruber 2003/0232082 A1 12, 2003 Li et al. 2004/O247675 A1 12, 2004 Gruber et al. 22 Claims, 10 Drawing Sheets US 8,383,155 B2 Page 2 OTHER PUBLICATIONS Office Action issued on Nov. 24, 2010 by the Examiner in U.S. Appl. Bar-Shalom et al., “Opportunities and obstacles in Pediatric Oral No. 1 1/596,123 (US 2008/02991.99). Controlled Release Dosage Forms.” Parvulet Poster, Online, Oct. 28. Office Action issued on Aug. 17, 2010 by the Examiner in U.S. Appl. 2004. No. 1 1/596,123 (US 2008/02991.99). Office Action issued on May 11, 2011 by the Examiner in U.S. Appl. Office Action issued on Oct. 17, 2011 by the Examiner in U.S. Appl. No. 1 1/596,123 (US 2008/02991.99). No. 1 1/596,123 (US 2008/02991.99). U.S. Patent Feb. 26, 2013 Sheet 1 of 10 US 8,383,155 B2 U.S. Patent Feb. 26, 2013 Sheet 2 of 10 US 8,383,155 B2 Dissolution of 200 mg Paracetamol parvulet -- 61%. Coated Paracetamol -s-200 mg Paracetamol parvulet -a-200 mg Paracetamol. parvulet e -X-200 mg Paracetamol parvulet -- 200 mg Paracetamol parvulet -e-200 mg Paracetamol parvulet |- O 5 1 O 15 20 25 30 35 4O 45 5O 55 time min Fig. 2 U.S. Patent Feb. 26, 2013 Sheet 3 of 10 US 8,383,155 B2 Figure 3 U.S. Patent Feb. 26, 2013 Sheet 4 of 10 US 8,383,155 B2 Figure 4 U.S. Patent Feb. 26, 2013 Sheet 5 of 10 US 8,383,155 B2 Figure 5 U.S. Patent Feb. 26, 2013 Sheet 6 of 10 US 8,383,155 B2 Figure 6 U.S. Patent Feb. 26, 2013 Sheet 7 of 10 US 8,383,155 B2 Figure 7 U.S. Patent Feb. 26, 2013 Sheet 8 of 10 US 8,383,155 B2 Figure 8 U.S. Patent Feb. 26, 2013 Sheet 9 of 10 US 8,383,155 B2 -- Wesse 1 w-r- Wessel 2 |-- Wessel 3 reham vesse 4 mer Wesses wam Vesses O y- - mym wn -M -- O 1. 2O 30 4. 50 s 70 Time ?min) - Fig. 9 U.S. Patent Feb. 26, 2013 Sheet 10 of 10 US 8,383,155 B2 CL (O) () | \Ll (1a) - N3-27 (1b) CIT O) (2) -- Ssey (2e) OL (O) (c) / N321 Fig. 10 US 8,383,155 B2 1. 2 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 The present application relates to a novel dosage form. The powder on syrup or pudding or applesauce or similar and then dosage form is presented in particulate form and before oral administered. This approach has limitations. The carrier ingestion the particulate material is subjected to an aqueous (syrup, pudding, applesauce) is not a well defined entity and medium, whereby it is converted to a semi-solid form by different carriers might interact differently with the multi Swelling or gelling of one or more of the components, espe 10 particles and/or drug and thereby compromise the treatment. cially of a gellan gum, of the particulate matter. The invention Also, children might object to the grittiness in the material. also relates to a vehicle for oral administration of one or more Syrups do not necessarily resemble types of food or bever active Substances, the vehicle comprising a gellan gum ages that children are used to consume. arranged in a configuration allowing optimal water diffusion Alternatively the powder can be formulated into efferves so that upon addition of a predetermined amount of an aque 15 cent granules or tablets. These granules or tablets are intended ous medium, without the necessity of applying shear forces or to be dissolved in an aqueous liquid requiring the provision of other mixing forces, within a time period of 5 minutes or less a glass of liquid and a waiting period Sufficient to allow the swells and/or gels and the texture of the swelled vehicle being tablet to completely dissolve and the resulting Volume might similar to that of a soft pudding and having a viscosity of at be considerable. Often, these dosage forms leave an objec least about 10,000 cps as measured by a Brookfield Viscom tionable deposit in the glass, which may represent a non eter with a #4 LV spindle at 6 rpm and at 20-25°C. ingested part of the drug. Effervescent formulations are, in In one embodiment of the invention, the particulate matter general more appropriate for adults although some commer can be molded into a desired shape or pressed onto a dispens cial vitamin preparations for children use this approach.