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(12) Patent Application Publication (10) Pub. No.: US 2008/0317850 A1 Hewitt Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0317850 A1 Hewitt Et Al US 20080317850A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317850 A1 Hewitt et al. (43) Pub. Date: Dec. 25, 2008 (54) BUCCAL DELIVERY SYSTEM Publication Classification (51) Int. Cl. (76) Inventors: Ernest Alan Hewitt, New South A69/20 (2006.01) Wales (AU); Richard James A6II 47/34 (2006.01) Stenlake, New South Wales (AU) A 6LX 3/57 (2006.01) A6II 3/565 (2006.01) Correspondence Address: A6II 3/568 (2006.01) REED SMITH LLP A6II 3/66 (2006.01) P.O. BOX 488 (52) U.S. Cl. ......... 424/464; 424/486; 514/177: 514/182: PITTSBURGH, PA 15230-0488 (US) 514/178; 514/108 (57) ABSTRACT (21) Appl. No.: 11/910,902 A buccal delivery system capable of being blended in a nor 1-1. mal dry powder process and compressed using a standard (22) PCT Filed: Apr. 7, 2006 tabletting machine, said buccal delivery system comprising a matrix of: (a) an effective amount of one or more active (86). PCT No.: PCT/AU2OO6/OOO472 ingredients; (b) an amount of one or more polyethylene gly cols orderivatives thereofhaving a molecular weight between S371 (c)(1), 1000 to 8000 sufficient to provide the required hardness and (2), (4) Date: Feb. 5, 2008 time for dissolution of the matrix; (c) 0.05-2% by weight of the total matrix of one or more Suspending agents; (d) 0.05 (30) Foreign Application Priority Data 2% by weight of the total matrix of one or more flowing agents; and (e) 0.05-2% by weight of the total matrix of one or Apr. 8, 2005 (AU) ................................ 2005901 758 more SWeetenerS. Patent Application Publication Dec. 25, 2008 Sheet 1 of 4 US 2008/0317850 A1 Figure 1 Hormone Replacement Clinical Trial - Oestradiol 1800 1600 1400 1200 1OOO -0-Blood Oestradiol 800 -- Saliwa Oestradiol 600 400 200 Pre- ir 4 hr 8 hr 12 hr 16 hr 24 hr Dose Time Figure 2 Hormone Replacement Clinical Trial-Progesterone 25000 20000+ 15000 --Blood Progesterone 10000 -- Saliva Progesterone 5000. Pre- hr 4 hr 8 hr 12 hr 16 hr 24 hr Dose Time Patent Application Publication Dec. 25, 2008 Sheet 2 of 4 US 2008/0317850 A1 Figure 3 Hormone Replacement Clinical Trial-Testosterone 25000 20000 - 15OOO - - - --Blood Testosterone 10000 --- - - - - - --Saliva Testosterone 5000 Pre hr 4 hr 8 hr 12 hr 16 hr 24 h. Dose Time Figure 4 Hormone Replacement Clinical Trial-DHEAS --Blood DHEAS -- Saliva DHEAS Pre hr 4.hr 8 r 12 hr 16 hr 24 hr Dose Time Patent Application Publication Dec. 25, 2008 Sheet 3 of 4 US 2008/031785.0 A1 Figure 5 Hormone Replacement Clinical Trial 25000 20000 s. -- Blood Oestradio 15000 -- Saiva Oestradiol S o ... Blood Progesterone S o -é. Saliva Progesterone 10000 - -be-Blood Testosterone -e-Saliva TestOSterOne 5000 o 2-SEESS as . Pre- hr 4 8 hr 12 hr 16 hr 24 hr Dose Time Patent Application Publication Dec. 25, 2008 Sheet 4 of 4 US 2008/031 7850 A1 |(100LLDOEZII Les 000Z I-I? prepue?S 007IZ |09&z. ©5-T-U-T-OOST-55 prepue?S |000||FŒT prepue?S [×] US 2008/031785.0 A1 Dec. 25, 2008 BUCCAL DELIVERY SYSTEM scales (capable of measuring milligram doses) and miniature electric hot plates that make the finished troche an accurate FIELD OF THE INVENTION and precise dosage form. The finished troches are dispensed in plastic calibrated moulds. The troches are available in a 0001. The invention relates to a buccal delivery system wide variety of flavours to assist compliance by even the which provides improved delivery of therapeutic agents. In fussiest patient. particular, the present invention relates to buccal dosage for 0009. The troches provide a means to deliver custom made mulations. The present invention further provides easier and medication in small doses directly into the blood stream. more economic methods of manufacturing a dosage formu Today many drugs, both natural and synthetic, can be used in lation capable of delivering one or more active ingredients via troche form to gain rapid onset of action and bypass the usual buccal 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. 0002. In this specification where a document, act or item 0010 Troches are currently used in hormone replacement of knowledge is referred to or discussed, this reference or therapy mainly because of the ease in which ingredients in discussion is not an admission that the document, actor item each prescription can be altered and the buccal absorption of knowledge or any combination thereof was at the priority does not involve gastric metabolism. Troches can also be date, publicly available, known to the public, part of common mixed so that each individual troche contains a combination general knowledge; or known to be relevant to an attempt to of various natural hormones in Small doses. For example, a solve any problem with which this specification is concerned. troche can be made containing a mixture of any of the bio 0003. The ability to effectively deliver therapeutic agents identical natural hormones, eg: estrogen, progesterone, test to animals and, in particular, humans is frequently dependent osterone and DHEA in any possible dosage. This combina on compliance of the recipient. Compliance is also often tion is used to treat the symptoms of menopause. For male connected or associated with the formulation used to deliver andropause, a combination of testosterone and DHEA is most the agent. The formulations provided are also dependent on commonly used. Troches containing natural progesterone the ease of manufacture. alone are helpful for premenstrual syndrome and can be taken 0004. In addition, the formulation itself is often critical to during the latter half of the menstrual cycle to alleviate the efficacy of the drug to be delivered. This is particularly the depression, migraine, nausea and basically all those PMT case for the delivery of pain relief agents such as paracetamol. symptoms that occur in the premenstrum. One of the rate limiting steps in paracetamol delivery to the (0.011) They are also used for anaesthetics, antibiotics, blood stream is the rate of gastric emptying. Various formu analgesics, antimicrobials, antitussives, demulcents and lations which provide paracetamol at an alkaline pH have other combinations of medicines. been proposed. 0012 Troches are being marketed as a method of admin 0005. There is a continual need to develop more improved istering agents that bypass the stomach and first pass metabo drug delivery formulations which efficaciously deliver thera lism of the liver as they are supposedly absorbed directly into peutic agents quickly yet without inducing unwanted side buccal circulation. Claims are made that this places less stress effects. A major objective in drug delivery is to obtain a on the liver and therefore is better for the patient. In reality, specific biological effect at a targeted site of action with more than 50% (up to 70%) of the troche dose is actually minimal side effects. It is taught that bioactivity of a pharma swallowed by the normal salivation process which will ceutical will be sub-optimal if it does not possess the correct encounter the stomach acids and first pass metabolism while physiochemical properties to allow release of the biologically the remainder is absorbed by the buccal mucosa (IntJ Pharm active form. For this reason improved drug delivery strategies Comp., 4, 414-420, 2000). With only 30 to 50% of the dose focus on modifying physiochemical properties of active being absorbed through the mucosal lining in the mouth there drugs including solubility, dissolution and dispersion. appears to be only a minimal reduction in the livers first pass metabolism when compared to capsules. The hormones that Troches are eventually absorbed, whetherit is by the buccal mucosa or 0006 Back in the 1800's, medical lozenges were exten the gastrointestinal tract, will eventually encounter the liver sively used to treat mouth and throat infections. These were anyway at some stage through normal circulation so there is small, square shape, mildly medicated solid masses intended no real significant liver sparing effect. Clinical experience to dissolve in the mouth. The finished troches are dispensed in shows that the doses required for troches are within the same plastic calibrated moulds that contain an accurate and precise range as those required for capsules so the overall “total load dosage unit. In England they were called a lozenge, in the on the body is approximately the same so again no real liver USA atroche, in France a tablette, and in Germany a pastillen. sparing benefit is obtained. Creams on the other hand require Troches slowly melt in the mouth and the active ingredients lower doses compared to troches and capsules and actually do are absorbed mostly by the soft lining of the inner cheek. bypass the stomach and first pass metabolism of the liver So Here, blood vessels carry the hormones off to the rest of the are therefore the only way that actually reduces the overall body, similar to an injection with a needle. load on the liver. 0007 Troches first appeared in the Edinburgh Pharmaco 0013 Hormones that possess poor oral bioavailability poeia in 1841 and then in 1864 in the British Pharmacopoeia. such as progesterone and testosterone (10 to 15% bioavail In the 1800s, troche making was an art way and required a lot ability) could potentially be good candidates for buccal of practical experience. The apparatus required to make tro administration. If successful the dosages for buccal adminis ches was a smooth marble slab to mix them, a rolling pin, tration should approach those of normal physiological doses troche cutters, a palette knife, a badger brush with long soft e.g.
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