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-

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 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: , 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. progesterone 20 to 40 mg daily as found with creams. hairs, linen cloth, and troche trays. Clinical experience shows that the doses of progesterone 0008 Today the computer has replaced the marble slabs, needed in troches is usually between 200 to 400 mg daily the wooden trays and brushes, etc. with complex electronic which indicates a great deal of the dose is not being absorbed mixers, poly-glycol flavoured bases, accurate electronic by the buccal mucosa thus supporting the evidence that a US 2008/031 7850 A1 Dec. 25, 2008

majority of the dose is being swallowed. Perhaps a buccal where there is an actual reduction or risk of reduction in bone patch would provide better absorption characteristics than mineral density and osteolysis from a normal reference range troches but are currently unavailable. In addition, there is no as a consequence of the disease or physiological state, such as real benefit using buccal administration over oral administra menopause, hypogonadism, osteogenesis imperfecta, Paget’s tion for those hormones such as the and DHEA disease, myeloma bone disease, cancers metastatic to bone, which already possess good oral bioavailability (over 90%). primary hyperparathyroidism, fibrous dysplasia and hyper 0014 Troches also exhibit poor pharmacokinetic param calcemia of malignancy. eters. This means that there are great fluctuations in hormone 0022. For example, an estimated 44 million people in the serum levels after taking a troche dose. Soon after taking a United States over the age of 50 currently have either troche serum hormone levels rise rapidly, sometimes to very osteoporosis or low bone mass. This number could rise to high levels, and then rapidly fall to low levels within 4 to 5 over 61 million by 2020 (National Osteoporosis Foundation hours. They therefore require at least twice daily administra America's Bone Health: The State of Osteoporosis and Low tion or for optimal results three to four times a day to maintain Bone Mass, 2002). adequate levels longer however compliance becomes a major 0023 Sufferers of osteoporosis face long-term drug problem with this type of dosing schedule. This wide fluctua therapy with anti-resorptive agents to prevent further bone tion in hormone levels is not the ideal situation. Creams and loss. As indicated above, alendronate and risedronate are slow release capsules release hormones into the blood stream generally prescribed as anti-resorptive agents. more gradually achieving steadier serum levels for a longer 0024 However, both agents are poorly absorbed (about period of time thus generally requiring only once a day dos 1% of the ingested dose), and this rate can be even lower if the 1ng. drugs are not taken as directed. Non-compliance with current 0015 Troches are made from two different types of bases administration protocols is a common problem due to the both of which have several drawbacks: gastrointestinal irritation of bisphosphonates which often (0016 polyethylene glycol (PEG) PEG bases are well leads to nausea and even vomiting in some subjects. known to cause allergic and sensitivity reactions and can 0025 Bisphosphonates are also often prescribed in con cause the buccal mucosa to become inflamed. In addi junction with hormone replacement therapy (HRT) to counter tion PEG's can contain Small amounts of dioxin, an the effects of declining sex hormone production around the industrial Solvent shown to cause cancer, and time of menopause. Sex hormone Supplementation generally 0017 gelatin is a hydrophilic (water loving) base employs the gastrointestinal administration route, where sig which causes hydrophobic (fat loving) particles such as nificant amounts of hormone are degraded by the digestive bioidentical hormones to aggregate together. This aggre environments encountered prior to absorption. As such, larger gation of particles further reduces mucosal absorption than required amounts of hormones must be used in the manu thus increasing the amount Swallowed and also does not facture of oral hormone dosage forms to ensure a therapeutic allow for an even dispersion of the hormones throughout dose reaches the circulation. the slurry causing greater dose variation between each 0026. A number of HRT regimens specific for female troche made. menopausal symptoms have been devised, which have met 0018. In conclusion troches are currently being widely with varying rates of clinical Success. The majority of these used to administer bioidentical hormones to women however treatments are based on the use of natural 17-B-oestradiol, they possess many drawbacks and are not considered the conjugated equine oestrogen, or other conjugated oestrogens optimal choice. Transdermal creams are considered the first in combination with synthesised Such as nor choice by many as they require lower doses compared to ethisterone, levonorgestrel and dydrogesterone. Although troches and capsules and they are the only route of adminis Such therapeutic combinations are highly successful in con tration that truly bypasses the stomach and first pass metabo trolling symptoms, again patient compliance is often a limit lism. They provide better release parameters providing steady ing factor in their overall clinical efficiency. Side-effects such serum levels without wild fluctuations seen with troches. as gastrointestinal irritation and bloating are unacceptable to They only require once daily dosing so are more convenient, many patients. dosage adjustments are very easy to make and finally they are 0027 Poor patient compliance is a significant barrier to significantly cheaper with a standard formula costing about the completion of prescription regimens and the cause of S30/month. If creams are deemed unsuitable in certain cases Sub-optimal clinical outcome. There is thus a need to develop then the second choice should be slow release capsules. These drug delivery formulations which reduce the side-effects that capsules provide better release properties than troches, only impact on patient compliance. require once a day dosing, and are fast to administer and no bitter taste. Troches are thought to be suitable for patients SUMMARY OF THE INVENTION where creams are unsuitable and malabsorption syndrome occurs thus making oral administration unsuitable. 0028. The present invention provides a buccal delivery 0019. There is thus a need for improved formulations for system which provides improved bioavailability of active Sublingual or buccal delivery of agents to patients. agents. The buccal delivery system of the present invention is able to deliver up to and sometimes more than 85% of the active ingredient as it circumvents the action of the liver in Bisphosphonates first past metabolism. In this specification, the term “buc 0020. One group of drugs which is particularly beneficial cal' is used in its broadest sense to refer to the mouth as a in a range of conditions are the bisphosphonates. Osteoporo whole and includes Sublingual. sis is one condition for which the bisphosphonate drugs, 0029. Since the buccal delivery system of the present alendronate and risedronate, are frequently prescribed. invention provides improved bioavailability, it is possible 0021 Osteoporosis and selected bone-resorptive condi using the present invention to use less of the active ingredient tions represent a significant medical disorder affecting mil in the manufacture of dosage forms. lions of sufferers worldwide. Examples of other bone-resorp 0030. In addition, the buccal delivery system of the present tive conditions include other diseases or physiological states invention may reduce the severity of gastrointestinal side US 2008/031 7850 A1 Dec. 25, 2008 effects of particular agents such as indigestion, pain, nausea, emulsify, solubilize, complex or deliver any biologically Vomiting, constipation, cramps, diarrhoea and flatulence. active lipophilic or hydrophilic compound across a mem 0031. The present invention also provides a buccal deliv brane. ery system which can be manufactured more easily and more economically as it can be made using a dry manufacturing 0043. The person skilled in the art will know which poly process with all actives blended in a normal dry powder ethylene glycol (PEG) is suitable to provide the desired phar process and compressed using a standard tabletting machine. macokinetics for the delivery system. For example, the choice Such dry formulations can be manufactured in commercial of PEG will be related to whether Zero or first order release is numbers and provided in conventional blister packaging. The desired. In a particularly preferred embodiment, the base is active ingredients and excipients are similar to those used in PEG 1450. the prior art troche, however the excipients are modified so 0044) The polyethylene glycol can be used in the form of that there is no need to use the special wet formulating plant a PEG- having surfactant properties. Examples and equipment and manual processing required for the tro of suitable PEG-fatty acid include PEG-10 laurate, ches (soft gel products) of the prior art which are costly and PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 time intensive. dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, 0032. According to a first aspect of the invention there is PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 provided a buccal delivery system capable of being blended in oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, a normal dry powder process and compressed using a stan PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl tri dard tabletting machine, said buccal delivery system com oleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 prising a matrix of glyceryl laurate, PEG-20 glyceryl Stearate, PEG-20 glyceryl 0033 (a) an effective amount of one or more active oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, ingredients; PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 0034 (b) an amount of one or more polyethylene gly hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor cols or derivatives thereof having a molecular weight oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG between 1000 to 8000 sufficient to provide the required 60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/ hardness and time for dissolution of the matrix; caprylate glycerides, PEG-8 caprate/caprylate glycerides, 0035 (c) 0.05-2%by weight of the total matrix of one or polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto more Suspending agents; sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbi 0036) (d) 0.05-2% by weight of the total matrix of one tan oleate, PEG-80 sorbitan laurate, PEG-1450, polysorbate or more flowing agents; and 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, 0037 (e)0.05-2%by weight of the total matrix of one or POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl more SWeetenerS. ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, 0038. The effective amount of the active ingredient is typi polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose cally an amount up to about 60% by weight of the total matrix. monostearate. Sucrose monolaurate. Sucrose monopalmitate, 0039. The matrix may release the active ingredient from PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol within seconds to hours of application depending on the desired release profile. Typically, the active ingredient is series, a poloxamer, and mixtures thereof. releasable from the matrix within at least two hours following 0045. A person skilled in the art will understand that application to one or more membranes in the buccal cavity, amount of the Suspending agent is Sufficient to improve the preferably within one hour of application and even more texture and consistency of the delivery system. Suitable preferably within 40 minutes of application. Most preferably, examples of Such suspending agents are those in the gum dissolution occurs within 12 to 15 minutes. For acute treat yielding plant group Such as tetragonolobus, Acacia glauco ments, preferably the matrix should be dissolved within 5 phylla, Acacia abyssinica, Acacia nilotica, Acacia gum minutes of application. mifera and Acacia arabica. Other Suitable Suspending agents 0040. The term “buccal delivery system as used herein include silica gel and Suspension polymers such as kollidon, refers to a delivery system wherein an active ingredient is cremaphor, kollicoat, Solutol and ludipress. provided for absorption across one or more membranes in the 0046. The person skilled in the art will understand that the mouth, including the buccal mucosa, buccal gingiva, mucous flowing agent (also known as lubricant) is present in an membrane of the tongue, Sublingual membrane and the soft amount Sufficient for the prevention of adhesion, especially palate. The term encompasses all Suitable dosage forms during the manufacturing process. A Suitable example of a capable of manufacture using a normal dry powder process flowing agent is magnesium Stearate. and compression using a standard tabletting machine. 0047. The buccal delivery system comprises a sufficient 0041 Reference to an “active ingredient' includes athera amount of a Sweetener to improve the organoleptic properties peutic or prophylactic agent, drug, pro-drug, drug complex, of the dosage form. Examples of suitable sweeteners include drug intermediate, diagnostic agent, enzyme, medicine, plant Sucrose. Sucralose; Zinc gluconate; ethyl maltitol; glycine; extract, herbal concoction, phytochemical, proteins, anti acesulfame-K; aspartame; saccharin, fructose; Xylitol; body, nanobody, antibody fragment, antibody directed honey; corn syrup, golden syrup, misri, spray dried licorice enzyme pro-drug therapy (ADEPT), bioactive compound, root; glycerrhizine; dextrose; sodium gluconate; Stevia pow nutraceutical or dietary Supplement. der; glucono delta-lactone; ethyl Vanillin; Vanillin; normal 0042. The term “matrix” as used herein refers to a solid or and high-potency Sweeteners or syrups or salts thereof. Pref semi-solid monolithic material containing one or more dis erably, a high-intensity Sweetener selected from the group Solved or dispersed active ingredients closely associated with consisting of aspartame. Sucralose, and acesulfame-K is used. a Surrounding, rate-controlling heterogenous material where 0048. In another aspect, the present invention provides a the active ingredient(s) are released when the matrix is placed method of manufacturing a dosage formulation capable of in direct contact with a moist diffusion membrane. The solid delivering one or more active ingredients across one or more or semi solid monolithic material can include a range of membranes within the buccal cavity, said method comprising materials known in the art of pharmaceutical drug delivery to the steps of: US 2008/031 7850 A1 Dec. 25, 2008

0049 (a) preparing a matrix by blending bisphosphonic acids (or salts thereof) with one or more hor 0050 (i) an effective amount of one or more active mones used in hormone replacement therapy, such as estra ingredients; diol, progesterone, testosterone and/or dehydroepiandroster 0051 (ii) an amount of one or more polyethylene one (DHEA). glycols or derivatives thereof having a molecular 0061 The art of efficient drug delivery also requires that a weight between 1000 to 8000 sufficient to provide the drug be both soluble in the aqueous biological medium and in required hardness and time for dissolution of the an appropriate form to permit transport of either individual matrix; drug molecules or very Small aggregates of the drug mol 0052 (iii) 0.05-2% by weight of the total matrix of ecules. The buccal delivery system may further comprise one one or more Suspending agents: or more other pharmaceutically acceptable carriers and/or 0053 (iv) 0.05-2% by weight of the total matrix of excipients. Such as but not limited to binding agents, flavour one or more flowing agents; and ing agents, colouring agents, solubility enhancers, disinte 0054 (v) 0.05-2% by weight of the total matrix of grants, fillers, proteins, co-factors, emulsifiers, and solubiliz One Or more SWeetenerS. ing or complexing agents. In a preferred embodiment, these 0055 (b) compressing the matrix into a suitable tablet excipients will improve delivery of the active ingredient format for administration to the one or more membranes across a membrane. Suitable excipients will be known to in the buccal cavity; those skilled in the art. One typical example of an emulsifier 0056 wherein the ratio of active ingredients and excipi which may be suitable is tocopherol polyethylene glycol ents enables dissolution and absorption of the active 1000 succinate (TPGS). Examples of complexing agents are ingredient within a desired time period. compounds containing amine groups or other nitrogen func 0057 Examples of suitable active ingredients include, but tional groups such as amino acids, proteins, amine functional are not limited to, anti-infective agents (antibiotics), eye, ear, sterols and phospholipids containing amine functional nose and throat preparations, anti-neoplastic agents including groups. Suitable Surfactants may be amphoteric, Zwitterionic, antibody, nanobody, antibody fragment(s), antibody directed or cationic. Preferred complexing agents of this type include enzyme pro-drug therapy (ADEPT), gastrointestinal drugs, water-soluble cationic polymers with a quaternary ammo respiratory agents, arthritic agents, blood formation and nium functional group on the polymer backbone and water coagulation agents, diagnostic agents, photosensitisers (eg Soluble, cationic guarjaguar gums). porphyrins and agents which stimulate natural porphyrin pro 0062. In a preferred embodiment, the buccal delivery sys duction), statins, naproxyn, indole-3-, hormones tem comprises a binding and gelling agent such as hydrox and synthetic Substitutes, cardiovascular drugs, skin and ypropyl methocellulose. mucous membrane preparations, NSAIDs, analgesics, 0063. In another embodiment, the buccal delivery system muscle spasm , anti-inflammatory agents, central further comprises a colouring agent which may be a dye or a nervous system drugs, dietary Supplements, diabetic agents, pigment. Suitable colouring agents are well known in the art and electrolyte and water balance agents, mixtures thereof and include curcumin, carotenoids, Sunset yellow, tartrazine, and pro-drugs, drug complexes, drug intermediates, enzyme, indigo dyes, quino-phthalene dyes and triphenyl methane Vitamins and protein complexes thereof. dyes. 0058 Other active ingredients include for example hor 0064. In a preferred embodiment, the buccal delivery sys mones of natural or synthetic origin selected from the hor tem further comprises a flavouring agent for improving orga mone group comprising insulin, triamcinolone, testosterone, noleptic properties. Suitable flavouring agents are well levonorgestrel, , phytoestrogen, , dexametha known in the art and include almond oil; babassu oil; borage Sone, ethynodiol, prednisone, desogestrel, cyproterone, nore oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; thindrone, megestrol, hydrocortisone, , cortisone corn oil; cottonseed oil; evening primrose oil; grapeseed oil; acetate, aviane, , , fludrocorti groundnut oil; mustard seed oil, olive oil; palm oil; palm Sone, fluoxymesterone dexamethasone levora fludrocorti kernel oil; peanut oil; grapeseed oil; Safflower oil; sesame oil; Sone low-ogestrel methylprednisolone, necon, levonorg shark liver oil; soybean oil; Sunflower oil; hydrogenated cas estrel, , levOXyl, methimazole, propylthiouracil tor oil; hydrogenated coconut oil; hydrogenated palm oil; desmopressin, prednisolone orgestrel norethindrone triamci hydrogenated Soybean oil; hydrogenated vegetable oil; nolone trivora Zovia gestodene, alfacalcidol, 1,25-dihydrox hydrogenated cottonseed and castor oil; partially hydroge yvitamin D3, clomiphene, finasteride and or any nated Soybean oil; soy oil; glyceryl tricaproate; glyceryl tri biologically relevant intermediate or combination thereof. caprylate; glyceryl tricaprate; glyceryl triundecanoate; glyc 0059. In one preferred embodiment, the active ingredient eryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; is a bisphosphonic acid or a bisphosphonate salt useful in the glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl treatment of a bone resorptive condition. Reference to “a tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/li bisphosphonic acid' includes one or more acids as well as noleate; glyceryl tricaprylate/caprate/stearate; Saturated pharmaceutically acceptable salts and derivatives thereof. polyglycolized glycerides; linoleic glycerides; caprylic/ca This term may be used to refer to a salt form such as “biphos pric glycerides; modified triglycerides; fractionated triglyc phonate'. Preferred bisphosphonic acids and their salts erides; Safrole, Vanillin, citric acid, malic acid and phosphoric include the group comprising alendronate, etidronate, pam acid or salts and/or mixtures thereof. idronate, tiludronate and risedronate compounds. Even more 0065. In an alternative embodiment, the buccal dosage preferably, the bisphosphonate is alendronate selected from forms are useful as Sustained release compositions. The term the group comprising anhydrous alendronate or hydrated “sustained release' (also referred to as “extended release') is alendronate salts, such as Sodium alendronate. used in its conventional sense to refer to a drug formulation 0060. The buccal delivery system of the present invention that provides for gradual release of a drug over an extended may contain two or more active agents. The active ingredients period of time, and that preferably, although not necessarily, may be released at the same time, ie simultaneously, or at results in Substantially constant blood levels of a drug over an differential rates. A preferred combination is one or more extended time period. US 2008/031 7850 A1 Dec. 25, 2008

0066. The present invention further contemplates methods 0080. Once Base A is melted, the other ingredients are of treatment and/or prophylaxis of medical conditions in added and stirred with a spatula. mammals and, in particular, humans by the administration of a drug using a delivery system according to the invention. TABLE 2 DRAWINGS Approx 1 Approx 25 Approx 50 Approx. 75 Approx 100 troches troches troches troches troches 0067 Various embodiments/aspects of the invention will (29 mls) (725 mls) (1450 mls) (2175 mls) (2900 mls) now be described with reference to the following drawings in Base A 28.10 g 702.5 g 1405 g 2107.5 g 2810.0 g which: Stevia 0.605 g 15.125 g 30.25 g 45.375g 60.50 g 0068 FIG. 1 is a diagrammatic representation showing the Acacia 0.483g 12.075 g 24.15 g 36.225g 48.3 g results obtained for oestradiol using a buccal delivery system Metho- 1.450 g 36.25 g 72.50 g 108.57g 145.0 g according to the invention in Example 3. cel 0069 FIG. 2 is a diagrammatic representation showing the results obtained for progesterone using a buccal delivery sys tem according to the invention in Example 3. 0070 FIG.3 is a diagrammatic representation showing the Making the Troche results obtained for testosterone using a buccal delivery sys 0081. A 400 mL beaker is placed on the scales and tem according to the invention in Example 3. tared. The active ingredients are added. The PEG base 0071 FIG. 4 is a diagrammatic representation showing the prepared above is then added up to a total weight of 30.0 results obtained for -Sulphate using a 9. buccal delivery system according to the invention in Example 0082. The beaker is placed onto a hotplate and the stirrer 3. 0072 FIG.5 is a diagrammatic representation showing the bar allowed to spin. The required flavour is added, and results obtained for all of the hormones tested using a buccal the mixture allowed to spin until all active ingredients delivery system according to the invention in Example 3. are dissolved. 0073 FIG. 6 is a tabular representation showing the results 0.083. The troche mixture is then poured into a mould obtained for all of the hormones tested using abuccal delivery and evened out with a spatula and allowed to dry. system according to the invention in Example 3. 0084. The top of the troche is slowly heated using a hair dryer until it begins to melt. EXAMPLES 0085) Any excess is scraped away evenly with a clean bent spatula using the grids of the mould as a guide. The 0074 Various embodiments/aspects of the invention will excess is used to fill any holes and even out each lozenge now be described with reference to the following non-limit to an even dosage form. This may need to be repeated 2-3 ing examples. times. Example 1 I0086 Once even, the surface is slightly heated to finish. The mould is then cleaned outside with a damp cloth. Comparative Example Discussion 0075. This example shows the process for preparation of troches as per the prior art. I0087. It can be seen that this methodology is not ideal for 0076. The ingredients used for 28 Troches is shown in commercial scale manufacture. It would be preferable to be Table 1. able to use the standard dry tabletting process for commercial scale manufacture. TABLE 1. Example 2 Ingredients I0088. This example demonstrates the manufacture of Drug Amounts LINGUET tablets according to the invention. Release pow Stevia powder 130 mg ders containing the equivalent of 5, 10 and 40 mg of the active Methocel E4M 1.45 g ingredient sodium alendronate were blended together with Base APEG 1450 q.S to 30 g the following excipients: Flavour 60 uL-800 uL I0089 PEG 1000-8000 molecular weight, varied according to required hardness and time for dissolution of tablet Preparation of Components 0077. The required quantity of active ingredients is cal culated (e.g. 200 mg progesterone for 30 lozenges Magnesium Stearate: 0.05-2% by weight requiring 6.0 g of progesterone). Kollidon: 0.05-2% by weight Stevia: 0.05-2% by weight 0078 Required components are weighed out and Active Ingredient: up to 60% by weight placed into clean labelled weigh trays (eg 0.01 g). Preparation of PEG Base 0090 Standard dry blending was performed in a horizon tallow-energy laboratory blender for 60 mins. Powder mix 0079. In a large 4 litre beaker, the base required for the tures were subsequently blended with PEG for 5 mins, and day is calculated (see Table 2) and placed on the hotplate directly compressed via TabletPress Inc Benchtop single to melt inside a water bath. The bath is set at 60° C. press tablet punch. US 2008/031 7850 A1 Dec. 25, 2008

0091 Dissolution times for these LINGUET tablets range their mouths thoroughly with water and waited 5-10 min from 10 to 20 mins, while a slightly longer period of 15-20 before swallowing any saliva in the mouth. Subjects then mins was required for complete dissolution following buccal expressed saliva directly into the collection tubes. administration. 0100 Saliva samples were obtained for single dose esti mation at the following times: pre-dose (O), and 1.0, 4.0, 8.0, Example 3 12.0, 16.0 and 24 h after dosing. For steady-state analysis, saliva was collected at pre-dose (O), and 1.0, 4.0, 8.0 and 12.0 0092. This example investigated the bioavailability of hor h after LINGUET tablet administration. mone replacement therapy active ingredients using the buccal delivery system of the invention in a clinical trial in a hospital. Analytical Methods The trial was conducted with approval of an ethics committee within the hospital. 0101 Plasma concentrations of hormones were deter 0093. LINGUET tablets were generated containing 17-p- mined using routine validated, radioimmunoassay techniques oestradiol (0.5 mg), progesterone (200 mg), testosterone (2.0 in the hospital laboratory (Sydpath, St Vincent's Hospital, mg) and DHEA (10.0 mg). The excipients in the LINGUET Sydney). The laboratory is an accredited pathology provider tablets consisted of silica gel, magnesium Stearate, acacia, that participates in national quality assurance programmes for Stevia and polyethylene glycol with a wildberry flavour. The hormonal analysis. LINGUET tablets employed in this trial were formulated in a 0102 Hormone concentrations in saliva were conducted single batch for the study using the process according to the by the Analytical Reference Laboratories (Melbourne) using invention as described in example 2 above. The LINGUET validated, commercial radioimmunoassays. This laboratory tablets were provided by Richard Stenlake Compounding is similarly an accredited pathology provider. Pharmacist (Bondi Junction, Australia). 0103 DHEA was monitored as the sulphate metabolite (DHEAS), not as the administered hormone. Study Protocol 0104 Oestradiol: Single and multiple dosing of the LINGUET tablet produced very similar mean concentration 0094. The study was an open-label investigation in six time profiles for Oestrogen in plasma. Substantial intersubject post-menopausal women. Before entry into the trial, Subjects variability on concentrations was evident (Tables 3 and 4). gave informed consent, and underwent medical and bio 0105 Testosterone: Single and multiple dosing of the chemical screening. Subjects were in general good health, LINGUET tablet also produced virtually super-imposable and at least one year post-menopausal. The Subjects ranged in mean concentration-time profiles for testosterone in plasma age from 45 to 60 years (mean, 56 yr), had a mean weight of with markedly increased concentrations for up to 4 hours, and 69 kg (range, 64-76 kg), mean height of 166 cm (range 157 a return to pre-treatment values within approximately 8 178 cm) and mean body mass index of 25.2 (range 23.4-27.6). hours. Absorption of this hormone was more rapid than for 0095 Subjects did not have a history of cancer of the the others with peak concentrations occurring at a mean of 0.6 breast or uterus, thrombosis, embolism, hypertension, diabe hr (Tables 3 and 4). tes, hyperlipidaemia, obesity or were Smokers. They also did 0106 Progesterone: Progesterone demonstrated the great not have any clinically significant abnormalities on routine est accumulation on dosage to steady-state (Table 3). Elimi biochemical and haematological Screening. nation of this hormone appeared to be biphasic with a sec 0096. Subjects discontinued their prescribed HRT therapy ondary peak evident at approximately 4 hr both following as well as any herbal or alternative medicines not less than single and multiple dosing. Concentrations decreased to three days prior to the first study day. Subjects presented to the below those generally associated with biological activity in Clinical Trials Centre on the morning of each study day after the endometrium within five hours. an overnight fast. An indwelling cannula was inserted into a 0107 Dehydroepiandrosterone (DHEA): Single dose forearm vein and a baseline blood specimen collected. administration of one-half LINGUET tablet (5 mg DHEA) 0097. On the first day, a half-LINGUET tablet was placed resulted in a doubling of blood concentrations of DHEAS in the buccal cavity (between the cheek and the gum) and over 5-10 hours with a subsequent return to pretreatment allowed to dissolve. Subjects were instructed not to swallow concentrations within 24hr. Inter-subject variability was high the formulation. Dissolution of the formulation in the buccal (Tables 3 and 4). cavity took up to 40 min. Subjects rinsed their mouths with water at 45 min. Blood samples were collected via the can Results and Discussion nula at timed intervals over 24 h. Subjects were discharged, but continued to take half a LINGUET tablet, twice daily, for 0.108 Concentration Profiles of Hormones in Saliva: the following two weeks. Subjects then re-presented to the Before the single application of a LINGUET tablet, the sali Clinical Trials Centre where the morning dose was taken and vary concentrations of all four hormones appeared to be further blood samples were collected at timed intervals over elevated compared to blood concentrations. The concentra the dosage interval of 12 h. tions of oestradiol and progesterone in Saliva were elevated 0098 Blood samples were schedule for collection follow many times higher than in blood following use of the ing the single dose at the following times: Pre-dose (O), 0.25, LINGUET tablet. This elevation was maintained over the 0.5,0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0 and following 8-12 hours suggesting that the massive increase 24.0h following the single dose, and at pre-dose (O), 0.25. 0.5, was not due solely to residual hormone within the buccal 0.75, 1.0, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 and 12 h after the cavity (Table 5 see FIG. 6). two-week dosing interval (steady-state). Actual times were 0109 At steady-state, the concentrations of salivary hor recorded, and these were used for the pharmacokinetic cal mones were found to be elevated to unexpectedly high con culations. centrations. Ratios of saliva top plasma was very variable 0099 Saliva was collected according to the standardized (Table 5 see FIG. 6). directions provided by the laboratory, Australian Reference 0110 Plasma hormones: Each of the four hormones, Laboratories (Melbourne), and stored frozen (-20°C.) prior oestradiol, progesterone, testosterone and dehydroepiandros to shipping for hormonal analysis. In brief. Subjects rinsed terone (the latter monitored as the active sulphate metabolite) US 2008/031 7850 A1 Dec. 25, 2008

were readily absorbed from the LINGUET tablet and 0115 Modifications and improvements to the invention achieved concentrations found in normal young menstruating will be readily apparent to those skilled in the art. Such women. Peak concentrations were achieved quite quickly, modifications and improvements are intended to be within the with a return to baseline between 4 and 8 hours after the single Scope of this invention. dose. The profiles at steady-state were very similar for oestro 1. A buccal delivery system capable of being blended in a gen and testosterone reflecting their short half-lives with respect to the dosing interval. By contrast, at Steady-state normal dry powder process and compressed using a standard progesterone was sustained at concentrations usually associ tabletting machine, said buccal delivery system comprising a ated with physiological and biological activity in young nor matrix of: mal women. If this Sustained concentration of progesterone is (a) an effective amount of one or more active ingredients; shown to produce inhibition of mitosis in the endometrium or (b) an amount of one or more polyethylene glycols or result in develop of secretory change, then this route of deliv derivatives thereof having a molecular weight between ery of progesterone could be utilised for management of 1000 to 8000 sufficient to provide the required hardness post-menopausal symptoms. and time for dissolution of the matrix; 0111. The advantage of the buccal route of delivery is that (c) 0.05-2% by weight of the total matrix of one or more it allowed rapid absorption of the hormones and physiological Suspending agents; concentrations were achieved. This formulation avoids the (d) 0.05-2% by weight of the total matrix of one or more first-pass metabolism associated with oral administration, flowing agents; and while also obviating the difficulties commonly associated (e) 0.05-2% by weight of the total matrix of one or more with transdermal application, namely erratic and poor SWeetenerS. absorption. 2. The buccal delivery system according to claim 1 wherein the effective amount of the active ingredient is an amount up TABLE 3 to about 60% by weight of the total matrix. 3. The buccal delivery system according to claim 1 wherein Baseline hormone concentrations of six postmenopausal the time for dissolution of the matrix is within at least two women prior to troche administration and after hours following administration to a patient. two weeks of twice daily administration 4. The buccal delivery system according to claim3 wherein Prior to Trough concentration at the time for dissolution of the matrix is within 40 minutes. Hormone administration steady-state 5. The buccal delivery system according to claim 4 wherein Oestradiol (pmol/L) 71.5 + 114.2 96.O 33.8 the time for dissolution of the matrix is within 12 to 15 Testosterone (nmol/L) O38 O.O8 O.67 + 0.28 minutes. Progesterone (nmol/L) 1.35 0.73 6.35 - 2.82 DHEA-Sulphate (nmol/L) 1.29 O.80 2.56 - 1.99 6. The buccal delivery system according to claim 5 wherein the time for dissolution of the matrix is within 5 minutes. 7. The buccal delivery system according to claim 1 wherein the buccal delivery system is suitable for sublingual admin TABLE 4 istration. Maximum hormone concentrations (Cmax) and the time 8. The buccal delivery system according to claim 1 wherein they occurred (Tmax) after the first dose (Day 1) the buccal delivery system is suitable for sustained release and after two weeks of treatment (steady-state administration. 9. The buccal delivery system according to claim 1 wherein Day 1 Steady-state the polyethylene glycol (PEG) is PEG 1450. Hormone Cmax Tmax Cmax Tmax 10. The buccal delivery system according to claim 1 wherein the polyethylene glycol (PEG) derivative is a PEG Oestradiol (pmol/L) 1685 - 1071 1.1 h 1821 - 581 1.0h Testosterone (nmol/L) 31.6 10.9 0.6h 31.6 5.0 0.6h fatty acid ester having Surfactant properties. Progesterone (nmol/L) 22.96.9 1.5h 26.1 + 7.6 1.0 h. 11. The buccal delivery system according to claim 1 DHEA-Sulphate (nmol/L) 2.2 + 1.1 6.0h 4.0+2.0 1.5h wherein the Suspending agent is selected from the group consisting of tetragonolobus, Acacia glaucophylla, Acacia abyssinica, Acacia nilotica, Acacia gummifera, Acacia Ara 0112 Table 5 shows the results of a single dose LINGUET bica, silica gel. kollidon, cremaphor, kollicoat, Solutol, tableton day 1 when testing mean hormone concentrations in ludipress and mixtures thereof. blood and saliva. 12. The buccal delivery system according to claim 1 wherein the Sweetener is selected from the group consisting CONCLUSION of sucrose. Sucralose; Zinc gluconate; ethyl maltitol; glycine; 0113. The LINGUET tablets which contained the buccal acesulfame-K; aspartame; saccharin, fructose; Xylitol; delivery system according to the invention delivered the hor honey; corn syrup, golden syrup, misri, spray dried licorice mones via the buccal cavity into the blood. The results root; glycerrhizine; dextrose; sodium gluconate; Stevia pow obtained are comparable with those published for the prior art der; glucono delta-lactone; ethyl Vanillin; Vanillin; normal troches in Wren et al., “Pharmacokinetics of estradiol, proges and high-potency Sweeteners or syrups or salts thereof and terone, testosterone and dehydroepiandrosterone after trans mixtures thereof. buccal administration to postmenopausal women’ Climac 13. The buccal delivery system according to claim 12 teric 2003, 6:104-111. wherein the sweetener is a high-intensity sweetener selected 0114. The word comprising and forms of the word 'com from the group consisting of aspartame. Sucralose, and prising as used in this description and in the claims does not acesulfame-K. limit the invention claimed to exclude any variants or addi 14. The buccal delivery system according to claim 1 tions. wherein the active ingredients are selected from the group US 2008/031 7850 A1 Dec. 25, 2008 consisting of anti-infective agents (antibiotics), eye, ear, nose 22. The buccal delivery system according to claim 21 and throat preparations, anti-neoplastic agents including anti wherein the pharmaceutically acceptable carriers and/or body, nanobody, antibody fragment(s), antibody directed excipients are selected from the group consisting of binding enzyme pro-drug therapy (ADEPT), gastrointestinal drugs, agents, flavouring agents, lubricants, colouring agents, solu respiratory agents, arthritic agents, blood formation and bility enhancers, disintegrants, fillers, proteins, co-factors, coagulation agents, diagnostic agents, photosensitisers, emulsifiers, Solubilising agents, complexing agents and mix tures thereof. statins, naproxyn, indole-3-acetic acid, hormones and Syn 23. The buccal delivery system according to claim 1 thetic Substitutes, cardiovascular drugs, skin and mucous wherein the flowing agent is magnesium Stearate. membrane preparations, NSAIDs, analgesics, muscle spasm 24. The buccal delivery system according to claim 1 further medications, anti-inflammatory agents, central nervous sys comprising a binding and gelling agent. tem drugs, dietary Supplements, diabetic agents, and electro 25. The buccal delivery system according to claim 24 lyte and water balance agents, mixtures thereof and pro wherein the binding and gelling agent is hydroxypropyl drugs, drug complexes, drug intermediates, enzyme, vitamins methocellulose. and protein complexes thereof. 26. A dry process prepared buccal formulation comprising 15. The buccal delivery system according to claim 14 a matrix of: wherein the active ingredients are hormones of natural or (a) an effective amount of one or more active ingredients; synthetic origin selected from the group consisting of insulin, (b) an amount of one or more polyethylene glycols or triamcinolone, testosterone, levonorgestrel, estradiol, phy derivatives thereof having a molecular weight between toestrogen, estrone, dexamethasone, ethynodiol, prednisone, 1000 to 8000 sufficient to provide the required hardness desogestrel, cyproterone, norethindrone, megestrol, hydro and time for dissolution of the matrix; cortisone, danazol, cortisone acetate, aviane, nandrolone, flu (c) 0.05-2% by weight of the total matrix of one or more oxymesterone, fludrocortisone, fluoxymesterone dexametha Suspending agents; SO levora fludrocortisone low-ogestrel (d) 0.05-2% by weight of the total matrix of one or more methylprednisolone, necon, levonorgestrel, estropipate, flowing agents; and levoxyl, methimazole, propylthiouracil desmopressin, pred (e) 0.05-2% by weight of the total matrix of one or more nisolone orgestrel norethindrone triamcinolone trivora Zovia SWeetenerS. gestodene, alfacalcidol, 1,25-dihydroxyvitamin D3, clomi 27. A method of manufacturing a dosage formulation phene, finasteride and tibolone or any biologically relevant capable of delivering one or more active ingredients across intermediate or combination thereof and mixtures thereof. one or more membranes within the buccal cavity, said method 16. The buccal delivery system according to claim 1 comprising the steps of wherein the active ingredient is a bisphosphonic acid or a (a) preparing a matrix by blending bisphosphonate salt selected from the group consisting of (i) an effective amount of one or more active ingredients; alendronate, etidronate, pamidronate, tiludronate and risedr (ii) an amount of one or more polyethylene glycols or onate compounds and mixtures thereof. derivatives thereof having a molecular weight 17. The buccal delivery system according to claim 16 between 1000 to 8000 sufficient to provide the wherein the bisphosphonate is an alendronate selected from required hardness and time for dissolution of the the group consisting of anhydrous alendronate, hydrated matrix; alendronate salts and mixtures thereof. (iii) 0.05-2% by weight of the total matrix of one or more Suspending agents: 18. The buccal delivery system according to claim 17 (iv) 0.05-2% by weight of the total matrix of one or more wherein the bisphosphonate is sodium alendronate. flowing agents; and 19. The buccal delivery system according to claim 16 fur (v) 0.05-2% by weight of the total matrix of one or more ther comprising one or more hormones used in hormone SWeetenerS. replacement therapy. (b) compressing the matrix into a suitable tablet format for 20. The buccal delivery system according to claim 19 administration to the one or more membranes in the wherein the hormones are selected from the group consisting buccal cavity; of estradiol, progesterone, testosterone, dehydroepiandros wherein the ratio of active ingredients and excipients terone (DHEA) and mixtures thereof. enables dissolution and absorption of the active ingredi 21. The buccal delivery system according to claim 1 further ent within a desired time period. comprising one or more other pharmaceutically acceptable carriers and/or excipients. c c c c c