USOO88284.35B2 (12) United States Patent (10) Patent No.: US 8,828,435 B2 Hewitt et al. (45) Date of Patent: Sep. 9, 2014 (54) BUCCAL DELIVERY SYSTEM 2002/0114833 A1 8/2002 Abu-IZZa et al. 2004/0019026 A1 1/2004 Schwartz ...................... 514,177 2004/0028732 A1 2/2004 Falkenhausen et al. (75) Inventors: Ernest Alan Hewitt, Windsor Downs 2004/0037878 A1 2/2004 Szamosi et al. (AU); Richard James Stenlake, Double 2006, O141027 A1 6, 2006 Cioli Day (AU) FOREIGN PATENT DOCUMENTS (73) Assignee: Lingual Consegna Pty Ltd (AU) EP 215635 3, 1987 (*) Notice: Subject to any disclaimer, the term of this GB 1248.189 9, 1971 patent is extended or adjusted under 35 W. wo: iii. U.S.C. 154(b) by 85 days. WO WO9904758 2, 1999 WO WOO189485 11, 2001 (21) Appl. No.: 13/021,578 WO 2004075877 A1 9, 2004 (22) Filed: Feb. 4, 2011 OTHER PUBLICATIONS (65) Prior Publication Data Velaz I., et al., “Effect of PEG 4000 on the Dissolution Rate of Naproxen”, European Journal of Drug Metabolism & US 2011 FO123619 A1 May 26, 2011 Pharmacokinetics, vol. 23, No. 2, pp. 103-108 (Apr.-Jun. 1998). Runkel, R., et al., "Naproxen Oral Absorption Characteristics'. Related U.S. Application Data Chem. Pharm. Bull. vol. 70, No. 7, pp. 1457-1466 (197p). Ranucci E. et al., “Pharmacokinetic Results on Naproxen Prodrugs (63) Continuation of application No. 1 1/910.902, filed as Based on Poly(ethyleneglycol)s', J Biomater Sci Polymer Edn, vol. application No. PCT/AU2006/000472 on Apr. 7, 2006, 6, No. 2, pp. 141-147 (1994). now abandoned. Ali, J., et al., “Formulation and Characterisation of a Buccoadhesive Erodible Tablet for the Treatment of Oral lesions'. Dept. of (51) Int. Cl. Pharmaceutics, Faculty of Pharmacy, Hamdard University, New A6 IK 9/14 (2006.01) Delhi, India, pp. 329-334 (1998). A6 IK9/20 (2006.01) Extended European Search Report for corresponding International A69/ (2006.01) Application PCT/AU06/000472, Dec. 16, 2011. (52) U.S. Cl. * cited by examiner CPC ............. A61 K9/0056 (2013.01); A61 K9/2031 y (2013.01); A61 K9/2095 (2013.01) Primary Examiner — Adam C Milligan USPC ........................................... 424/484: 514/108 (74) Attorney, Agent, or Firm — Maryellen Feehery Hank; (58) Field of Classification Search Reed Smith LLP CPC. A61 K9/2031: A61 K9/2095; A61 K9/0056 USPC .......................................................... 424/484 (57) ABSTRACT See application file for complete search history. A buccal delivery system capable of being blended in a nor (56) References Cited mal dry powder process and compressed using a standard tabletting machine, said buccal delivery system comprising a U.S. PATENT DOCUMENTS matrix of: (a) an effective amount of one or more active ingredients; (b) an amount of one or more polyethylene gly 14: A ck $8. E.al 424/435 cols orderivatives thereofhaving a molecular weight between 5.244,668 A 9/1993 Snipes . 1000 to 8000 sufficient to provide the required hardness and 5,324,746 A * 6/1994 McKee et al. ................. 514,530 time for dissolution of the matrix; (c) 0.05-2% by weight of 5,891.465 A * 4, 1999 Keller et al. .................. 424/450 the total matrix of one or more Suspending agents; (d) 0.05 5,945,117 A 8/1999 El-Rashidy et al. 2% by weight of the total matrix of one or more flowing 3. 6. f 3. Ea agents; and (e) 0.05-2% by weight of the total matrix of one or 6,193.992 B1 2/2001 El-Rashidy et al. more SWeetenerS. 6,319,510 B1 * 1 1/2001 Yates ............................ 424/404 6,372,728 B1 * 4/2002 Ungell .......................... 514f109 8 Claims, 4 Drawing Sheets U.S. Patent Sep. 9, 2014 Sheet 1 of 4 US 8,828,435 B2 Figure 1 Hormone Replacement Clinical Trial - Oestradio 1800 1600 1400 1200 ----- 1000 --- -0- Blood Oestradiol 800 + -- Saliwa Oestradio 400 --- / 4. 12 hr. 16 hr 24 hr Time Figure 2 Hormone Replacement Clinical Trial - Progesterone -- Blood Progesterone -- Saliva Progesterone Pre r 4 8 12 hr. 16 Dose Time U.S. Patent Sep. 9, 2014 Sheet 2 of 4 US 8,828,435 B2 Figure 3 Hormone Replacement Clinical Trial-Testosterone 25OOO 2OOOO 15OOO --Blood Testosterone 1OOOO - . -- Saliva Testosterone 5000 O - Pre- r 4 hr 3r 12 hr 16 hr 24 hr Dose Time Figure 4 Hormone Replacement Clinical Trial - DHEAS 3000 2500 2000 S --Blood DHEAS 9. 1500 E -- Saliwa DHEAS 1OOO 500 - O Pre- r 4 8 r 12 in 16 ir 24 hr Dose Te U.S. Patent Sep. 9, 2014 Sheet 3 of 4 US 8,828,435 B2 Figure 5 Hormone Replacement Clinical Trial 25000 20OOO -0- Blood Oestradio 15000 -- Saiva Oestradiol - Blood Progesterone .x. Saliva Progesterone 10000 -be-Blood Testosterone -o- Saliva Testosterone 5000 : Pre h 8 12 hr. 16 hr 24 hr Dose Time US 8,828,435 B2 1. 2 BUCCAL DELVERY SYSTEM Troches first appeared in the Edinburgh Pharmacopoeia in 1841 and then in 1864 in the British Pharmacopoeia. In the RELATED APPLICATION 1800s, troche making was an art way and required a lot of practical experience. The apparatus required to make troches This instant application is a continuation of application Ser. 5 was a Smooth marble slab to mix them, a rolling pin, troche No. 1 1/910,902 filed on Oct. 5, 2007, with a 371(c) filing date cutters, a palette knife, a badger brush with long soft hairs, of Feb. 5, 2008, which is a U.S. National Phase Application of linen cloth, and troche trays. International Application Serial No. PCT/AU2006/000472, Today the computer has replaced the marble slabs, the filed Apr. 7, 2006, which claims priority to Australian Appli wooden trays and brushes, etc. with complex electronic mix ers, poly-glycol flavoured bases, accurate electronic scales cation Serial No. AU 2005901758 filed Apr. 8, 2005. 10 (capable of measuring milligram doses) and miniature elec tric hot plates that make the finished troche an accurate and FIELD OF THE INVENTION precise dosage form. The finished troches are dispensed in plastic calibrated moulds. The troches are available in a wide The invention relates to a buccal delivery system which 15 variety of flavours to assist compliance by even the fussiest provides improved delivery of therapeutic agents. In particu patient. lar, the present invention relates to buccal dosage formula The troches provide a means to deliver custom made medi tions. The present invention further provides easier and more cation in small doses directly into the blood stream. Today economic methods of manufacturing a dosage formulation many drugs, both natural and synthetic, can be used in troche capable of delivering one or more active ingredients via buc- 20 form to gain rapid onset of action and bypass the usual cal membranes. absorption into the blood stream, thus bypassing the liver. This reduces the load upon the liver and is especially good for BACKGROUND OF THE INVENTION liver toxic drugs. Troches are currently used in hormone replacement In this specification where a document, act or item of 25 therapy mainly because of the ease in which ingredients in knowledge is referred to or discussed, this reference or dis each prescription can be altered and the buccal absorption cussion is not an admission that the document, act or item of does not involve gastric metabolism. Troches can also be knowledge or any combination thereof was at the priority mixed so that each individual troche contains a combination date, publicly available, known to the public, part of common of various natural hormones in Small doses. For example, a general knowledge; or known to be relevant to an attempt to 30 troche can be made containing a mixture of any of the bio solve any problem with which this specification is concerned. identical natural hormones, eg: estrogen, progesterone, test The ability to effectively deliver therapeutic agents to ani osterone and DHEA in any possible dosage. This combina mals and, in particular, humans is frequently dependent on tion is used to treat the symptoms of menopause. For male compliance of the recipient. Compliance is also often con andropause, a combination of testosterone and DHEA is most nected or associated with the formulation used to deliver the 35 commonly used. Troches containing natural progesterone agent. The formulations provided are also dependent on the alone are helpful for premenstrual syndrome and can be taken ease of manufacture. during the latter half of the menstrual cycle to alleviate In addition, the formulation itself is often critical to the depression, migraine, nausea and basically all those PMT efficacy of the drug to be delivered. This is particularly the symptoms that occur in the premenstrum. case for the delivery of pain relief agents such as paracetamol. 40 They are also used for anaesthetics, antibiotics, analgesics, One of the rate limiting steps in paracetamol delivery to the antimicrobials, antitussives, demulcents and other combina blood stream is the rate of gastric emptying. Various formu tions of medicines. lations which provide paracetamol at an alkaline pH have Troches are being marketed as a method of administering been proposed. agents that bypass the stomach and first pass metabolism of There is a continual need to develop more improved drug 45 the liver as they are supposedly absorbed directly into buccal delivery formulations which efficaciously deliver therapeutic circulation. Claims are made that this places less stress on the agents quickly yet without inducing unwanted side effects. liver and therefore is better for the patient. In reality, more A major objective in drug delivery is to obtain a specific than 50% (up to 70%) of the troche dose is actually swallowed biological effect at a targeted site of action with minimal side by the normal salivation process which will encounter the effects.