US 2005O106241A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0106241A1 Brewer et al. (43) Pub. Date: May 19, 2005

(54) PHARMACEUTICAL COMPOSITION Mar. 22, 1996 (GB)...... 9517063.5 FORMULATED FOR PRE-GASTRIC ABSORPTION OF MONOAMINE OXDASEB Publication Classification INHIBITORS (51) Int. Cl." ...... A61K 31/137; A61 K 9/20 (76) Inventors: Francesca Mary Brewer, Stoke Poges (52) U.S. Cl...... 424/464; 514/649 (GB); Edward Stewart Johnson, Ruscombe (GB); Anthony Clarke, Checkendon (GB) (57) ABSTRACT Correspondence Address: The invention described herein provides a fast dispersing Andrew G. Rozycki oral Solid dosage form containing monoamine oxidase B Cardinal Health, Inc. inhibitor (MAO-B inhibitor) as the active ingredient, and 7000 Cardinal Place method of treating disease there with, Such as Parkinson's Dublin, OH 43017 (US) disease. In one embodiment, the monoamine oxidase B inhibitor Selegiline or its analogue can be the Sole active (21) Appl. No.: 10/957,947 ingredient in the composition administered. The dosage form composition is formulated to promote absorption (22) Filed: Oct. 4, 2004 through the buccal, Sublingual, pharyngeal and/or esoph Related U.S. Application Data ageal mucous membrane tissue, Such that at least 5% of the active ingredient is absorbed within one minute of place (63) Continuation-in-part of application No. 10/610,613, ment in the oral cavity, as determined by a buccal absorption filed on Jul. 1, 2003, which is a continuation of test. Monoamine oxidase B inhibitor compounds adminis application No. 08/894,764, filed on Nov. 17, 1997, tered in accordance with the invention decrease the amount now abandoned, filed as 371 of international appli of undesirable metabolites associated with first pass effect of cation No. PCT/GB96/00484, filed on Jan. 3, 1996. Selegiline, for example, Such as amphetamine and metham phetamine. The invention provides a number of other advan (30) Foreign Application Priority Data tages over conventional orally administered tablet forms, including administration of monoamine oxidase B inhibitor Feb. 3, 1995 (GB)...... 95.04235.4 compounds to patients that have difficulty Swallowing. Patent Application Publication May 19, 2005 Sheet 1 of 10 US 2005/0106241 A1

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PHARMACEUTICAL COMPOSITION effect”, and results in a decrease in the bioavailability of FORMULATED FOR PRE-GASTRIC ABSORPTION Selegiline administered in the conventional manner. See, for OF MONOAMINE OXDASE B INHIBITORS example, Heinonen et al., Clinical Pharmacology & Thera peutics, Vol. 56, No. 6 (1994), pp. 742-749. RELATED APPLICATION DATA 0006 Another problem with conventional selegiline is its 0001. This application is a continuation-in-part of U.S. undesired metabolites. It is known that Selegiline is metabo patent application Ser. No. 10/610,613 filed Jul. 1, 2003, lized to produce N-deSmethylselegiline, methamphetamine now pending, which is a continuation of U.S. patent appli and amophetamine according to the following metabolic cation Ser. No. 08/894,764, filed Nov. 17, 1997, now aban pathway: doned, which is the U.S. national filing of International Patent Application No. PCT/GB96/00484 (WO 96/26720 published Sep. 6, 1996) with an international filing date of Selegiline Jan. 3, 1996, which claims benefit of priority to Great Britain Selegiline Patent Application No. 9504235.4 filed Feb. 3, 1995 and Great Britain Patent Application No. 9517063.5 filed Mar. CH 22, 1996. (O)-at-i- FIELD OF THE INVENTION CH, CHCECH L-(-)-Methamphetamine 0002 The invention relates to a pharmaceutical compo Sition for the treatment of diseaseS Such as Parkinson's L-(-)-Methamphetamine disease. In particular, the invention pertains to a fast disin tegrating oral Solid dosage form containing monoamine oxidase B inhibitor compounds as the active ingredient, and (O)-cis-- methods of treatment therewith. CH, CH L-(-)-Desmethylselegiline BACKGROUND OF THE INVENTION L-(-)-Desmethylselegiline 0003) Selegiline, or (-)-N, C-dimethyl-N-2-propynyl phenethylamine, is known to be useful in the treatment of Parkinson's disease. The mechanism of action of Selegiline has not been fully elucidated. Selegiline, however, is a (O)-a-ti-CH, CHCECHt potent irreversible inhibitor of monoamine oxidase, with a L-(-)-Amphetamine greater affinity for the type B form of the enzyme. Monoam ine oxidase is known to play an important role in the L-(-)-Amphetamine breakdown of biological amines, Such as dopamine, norad renaline and 5-hydroxytryptamine (Serotonin) in the brain. It is thought that the inhibition of monoamine oxidase type B (MAO-B) may lead to enhancement of the effects of dopam (O)-cis--CH NH2 ine and phenethylamine in the brain of patients with Par kinson's disease, thus leading to improved control of move ment. See for example, Gaal and Hermez, Inhibitors of 0007 Although it has been suggested that N-desmeth Monoamine Oxidase B, Pharmacology and Clinical Use in ylselegiline may contribute to the desired inhibition of Neurodegenerative Disorders, (edited by I. Szelenyi, monoamine oxidases (see, for example, Heinonen et al. in Birkhauser Verlag, Basel, Switzerland), Chapter 4 (1993) Chapter 10 of Szelenyi), methamphetamine and amphet (hereinafter referred to as Szelenyi). amine exhibit no useful effect in Parkinson's disease. 0004 Selegiline is currently administered orally in the Indeed, since methamphetamine and amphetamine are both form of conventional tablet design and to be swallowed Stimulants of the central nervous System and of the heart, whole. Alternatively, Selegiline is also administered in a their presence produces undesirable Side-effects Such as measure amount of Syrup for rapid Swallowing. Accordingly, insomnia and cardiac arrhythmias. In order to minimize the Selegiline administered this way is absorbed from the gas central nervous System Stimulant effect, currently available trointestinal tract, that is, the Stomach, Small intestine and dosage forms of Selegiline must be administered by no later the proximal large intestine (colon), into the hepatic portal than mid-day so that the unwanted stimulant effect will System and is presented to the liver before reaching Systemic subside at the end of the day. Clearly, this situation is far circulation. from Satisfactory. 0005 One problem associated with the administration of 0008. Yet another problem associated with conventional conventional tablet forms of selegiline is that the liver is Selegiline administration is that which is associated with its known to be the principal Site for conversion of active co-administration with levodopa. Co-administration of Sel Selegiline into metabolites, Some of which are undesirable. egiline with levodopa has even been associated with fatali Consequently, this first pass of absorbed Selegiline through ties, and unadjusted (unreduced) amounts of levodopa can the liver results in extensive metabolism of the drug, and a cause dyskenesias (defects in the ability to perform volun Significant proportion of the absorbed dose of intact Sel tary movement). egiline never reach Systemic circulation or, therefore, the 0009. Yet another undesired side-effect of conventional brain. This phenomenon is generally known as the “first pass Selegiline administration is orthostatic hypotension and Syn US 2005/0106241 A1 May 19, 2005

cope is Some patients, which has been linked to non lowing the tablet because no water is needed to administer selective MAO inhibition. Conventional selegiline can also MAO-B inhibitors in the invention. cause undesirable and capricious Side effects due to Sudden 0015. Further, no advanced preparation, measuring or changes in plasma concentration of Selegiline itself and/or mixing, etc. is needed. Thus, the inaccuracies of measuring its known metabolites. The presence or absence of food in out liquid doses are eliminated. AS a Solid dosage form, it the digestive tract may also contribute to the unpredictabil can Still be packaged, handled and manipulated by both ity. caregiver and patient as easily as a conventional tablet. 0010. One analogue of selegiline, para-fluoroselegiline, is also a monoamine oxidase B inhibitor and exhibits very 0016 Surprisingly, it has been discovered that an equiva Similar pharmacological activity to that of Selegiline. Many lent efficacy of Selegiline can be obtained with oral admin other compounds, Some of which are not chemically related istration in accordance with the invention as with conven to Selegiline, also have monoamine oxidase B-inhibiting tional Selegiline tablets by administering a fraction of the properties. A number of these have also demonstrated utility amount of the MAO-B inhibitor within the rapid disinte for treatment of Parkinson's disease, treatment of depres grating Solid oral dosage form of the invention. Sion, and/or treatment or prophylaxis of Alzheimer's dis 0017. The invention provides a fast disintegrating oral ease. Among such MAO-B inhibitors are: lazabemide (N-(2- Solid dosage form formulated for pre-gastric absorption of aminoethyl)-5-chloropyridine-2-carboxamide monoamine oxidase B inhibitor, Said dosage form compris hydrochloride); rasagiline (2,3-dihydro-N-2-propynyl-1H ing a monoamine oxidase B inhibitor and a carrier. Preferred inden-1-amine); 2-BUMP (N-(2-butyl)-N-methylpropargy monoamine oxidase B inhibitor compounds that can be used lamine); M-2-PP (N-methyl-N-(2-pentyl)-propargylamine); in accordance with the invention include those having the MDL-72145 (beta-(fluoromethylene)-3,4-dimethoxy-ben following general formula: Zeneethanamine); and mofegiline (E)-4-fluoro-3-(fluorom ethylene) benzene butanamine hydrochloride). (I) 0.011 Clinical studies have shown that up to 82% of X patients suffering with Parkinson's disease have difficulty Swallowing and tend to dribble. Conventional Selegiline tablets, Syrups, and the like, Still require the patient to v-O-cr-in-l-al-ch attempt Swallowing. Moreover, conventional tablets need to CH be administered with water, requiring another difficult Swal lowing act for Such patients. 0018 or acid addition salt thereof, wherein X represents 0012 From a clinical perspective, it would be highly hydrogen or methyl group, and Y represents hydrogen or desirable to administer MAO-B inhibitors while enhancing fluorine. Preferably, Y is hydrogen. In an even more pre the bioavailability of the active ingredient and avoiding first ferred embodiment, X is methyl and Y is hydrogen, which pass effect and its undesirable metabolites, hence affording is also known as the MAO-B inhibitor selegiline. a comparatively rapid onset and prolonged duration of effect 0019. In a preferred embodiment of the invention, the fast as compared to conventional administration forms. Even disintegrating oral Solid dosage form is formulated for more desirable would be the ability to administer MAO-B in pre-gastric absorption Such that at least 5% of the active a dosage form that does not present difficulty in ingestion in monoamine oxidase B inhibitor is absorbed within one those patients that have difficulty Swallowing, can be minute of placement in the oral cavity. In an even more handled easily, and affords assurance and greater predict preferred embodiment, the dosage form is also formulated to ability of its administration and effect. disintegrate within 10 Seconds after placement in the oral cavity. SUMMARY OF THE INVENTION 0020. In one embodiment, the invention provides a fast 0013 The invention provides a pharmaceutical compo disintegrating oral Solid dosage form formulated for pre Sition as a rapidly disintegrating Solid oral dosage form gastric absorption wherein the active ingredient consists of comprising a carrier and monoamine oxidase B inhibitor Selegiline, and Said dosage form comprises a carrier. compound as an active ingredient. It has been discovered that an oral Solid pharmaceutical dosage form containing a 0021. The invention also provides a method for treatment monoamine oxidase B inhibitor, Such as Selegiline, can be of Parkinson's disease comprising administering to a patient prepared that permits effective pre-gastric oral administra in need of treatment therefore, a fast dispersing oral Solid tion and avoids the disadvantages associated with conven dosage form formulated for pre-gastric absorption, Said tional Swallowed tablet forms of the drug and permits its dosage form comprising a pharmaceutically effective administration without other active ingredients and their amount of monoamine oxidase B inhibitor and carrier, Said asSociated risks. dosage form being formulated for pre-gastric absorption. 0.014. The invention presents a number of significant 0022. The invention further provides a method for treat improvements over conventional Selegiline administration. ment or prophylaxis of Alzheimer's disease comprising The administration of monoamine oxidase B inhibiting administering to a patient in need of treatment thereof a fast compounds in fast dissolving oral Solid dosage form disintegrating oral Solid dosage form formulated for pre improves ease and convenience of administration for prac gastric absorption comprising a pharmaceutically effective titioners and patients alike. This is especially the case in amount of monoamine oxidase B inhibitor and carrier, dysphagic patients with Parkinson's disease, wherein the wherein Said dosage form is formulated for pre-gastric invention avoids coordination of Sipping water and Swal absorption. US 2005/0106241 A1 May 19, 2005

0023. Further provided is a method for treatment or therefore preferred that the composition of the invention be prophylaxis of depression comprising administering to a formulated which Sustains the active ingredient in contact patient in need of Said treatment a fast disintegrating oral with the buccal, Sublingual, pharyngeal and/or esophageal Solid dosage form containing a pharmaceutically effective mucous membranes. amount of monoamine oxidase B inhibitor and carrier, Said 0038 Pre-gastric absorption of MAO-B inhibitors can be dosage form being formulated for pre-gastric absorption. assessed using the method described for Selegiline in 0024. Another method of increasing the level of phen Example 3 below. This test is similar to the “buccal absorp ethylamine in the body comprising administering to a patient tion test” cited by Harris and Robinson, J. Pharm. Sci., Vol. in need of Said treatment a fast disintegrating oral Solid 81 (1992), p. 1-10, as a well-recognized method for evalu dosage form containing a pharmaceutically effective amount ating buccal absorption of drugs. Thus, the test formulation of monoamine oxidase B inhibitor and carrier, Said dosage containing the clinically effective dose of the MAO-B form being formulated for pre-gastric absorption. inhibitor is retained in the mouth for one (1) minute before it is expectorated. The mouth is then rinsed with 3 aliquots 0.025. Other advantages associated with the invention of 25 ml water, which are then similarly expectorated. The will become apparent from the following description. total amount of MAO-B inhibitor is then determined from the expectorated mouth Washings using a Suitable analytical BRIEF DESCRIPTION OF THE DRAWINGS technique, such as HPLC. The recovered quantity of 0.026 FIG. 1 is a graph showing plasma concentration MAO-B inhibitor is subtracted from the total amount of drug Versus time curve for the Specific compound Selegiline. initially placed in the mouth to determine the total amount of the drug which has been pre-gastrically absorbed. For 0.027 FIG. 2 is a graph showing plasma concentration Significant buccal absorption to have occurred, it is generally Versus time curve for the Specific compound N-deSmeth preferred that at least 5% of the MAO-B inhibitor be ylselegiline. absorbed in one (1) minute in this test, more preferably at 0028 FIG. 3 is a graph showing plasma concentration least 10% is absorbed in one (1) minute and most preferably Versus time curve for the Specific compound methamphet at least 15% of the MAO-B inhibitor within one (1) minute. amine. 0039 Fast-Disintegrating Oral Solid Dosage Forms 0029 FIG. 4 is a graph showing plasma concentration 0040 AS used herein, the terms “fast dissolving”, “fast Versus time curve for the Specific compound amphetamine. disintegrating”, “rapid dissolving”, “rapid disintegrating” 0030 FIG. 5 is a graph of comparative concentration of when used to describe the dosage form are meant to refer to Selegiline in a blood plasma Sample versus time for expec the property of the Solid form disintegrating or dissolving torated Example 1 formulation, Swallowed Example 1 for upon placement within the oral cavity (and saliva contact) mulation, and the Eldepryl(R) tablet. within a relatively shortened time period of about 60 sec onds. 0.031 FIG. 6 is a chart showing comparative cumulative 5-hydroxyindoleacetic acid excretion in urine over 24 hours 0041) A variety of fast-dispersing Solid dosage forms can for the FIG. 5 samples. be used in accordance with the invention. One example of such a dosage form is described in U.S. Pat. No. 4,855,326. 0.032 FIG. 7 shows the comparative cumulative phen This reference describes a melt Spinnable carrier agent, Such ethylamine excretion in urine over 24 hours for the FIG. 5 as Sugar, that is combined with an active ingredient and spun Samples. into a resultant “candy floss' preparation. The Spun "candy 0.033 FIG. 8 is a graph containing plot data for mea floSS' is the compressed into a rapidly dispersing, highly Surements of plasma Selegiline and 24 hour urinary excre porous Solid dosage form. tion of phenethylamine. 0042 U.S. Pat. No. 5,120,549 describes a fast-dispersing 0034 FIG. 9 is a table containing comparative urinary matrix System which is prepared by first Solidifying a excretion data for phenethylamine following administration matrix-forming System dispersed in a first Solvent and of Zydis(R) Selegiline and commercial Selegiline tablet. Subsequently contacting the Solidified matrix with a Second solvent that is substantially miscible with the first solvent at 0.035 FIG. 10 is a graph showing comparative pre-dose a temperature lower than the Solidification point of the first plasma levels over time for Zydis(R) Selegiline and conven Solvent, the matrix-forming elements and active ingredient tional Selegiline. being Substantially insoluble in the Second Solvent. Upon Substantial removal of the first Solvent, a fast-dispersing DETAILED DESCRIPTION OF THE matrix results. INVENTION 0043 U.S. Pat. No. 5,079,018 describes a fast dispersing 0.036 AS used herein, the phrase “pre-gastric absorption” dosage form which comprises a porous Skeletal Structure of is meant to refer to absorption of the active ingredient from a water Soluble, hydratable gel or foam material that has that part of the alimentary canal prior to the Stomach, and been hydrated with water, rigidified in the hydrated State includes buccal, Sublingual, oropharyngeal and eSophageal with a rigidifying agent and dehydrated with a liquid organic absorption. solvent at a temperature of about 0° C. or lower to leave 0037 According to the invention, the composition is Spaces in place of hydration liquid. formulated Such that pre-gastric absorption of the monoam 0044) Published International Application No. WO ine oxidase B inhibitor occurs primarily across the mucous 93/12769 (PCT/JP93/01631) describes a fast dispersing dos membranes in the mouth, pharynx and esophagus. It is age form of very low density formed by gelling, with agar, US 2005/0106241 A1 May 19, 2005 aqueous Systems containing the matrix-forming elements cially advantageous in the case of active agents that are not and active ingredient, and then removing water by forced air Sufficiently Soluble in water and, therefore, must be Sus or vacuum drying. pended rather than dissolved. 0045 U.S. Pat. No. 5,298,261 describes a fast-dispersing 0052 Secondary components can also be incorporated dosage form comprising a partially collapsed matrix net into the composition of the invention. Suitable Secondary work that has been vacuum-dried above the collapse tem components include preservatives, antioxidants, Surfactants, perature of the matrix. However, the matrix is preferably at Viscosity enhancers, coloring agents, flavoring agents, pH least partially dried below the equilibrium freezing point of modifiers, SweetenerS and taste masking agents. Coloring the matrix. agents that can be used include red, black and yellow iron 0046) Published International Application No. WO oxides, and FD&C dyes such as FD&C blue no. 2 and 91/04757 (PCT/US90/05206) describes a fast dispersing FD&C red no. 40 (available from Ellis & Edward). Flavor dosage form that contains an effervescent disintegration ing agents that can be used include mint, raspberry, licorice, agent designed to effervesce on contact with Saliva to orange, lemon, grapefruit, caramel, Vanilla, cherry and grape provide rapid disintegration of the dosage form and disper flavors, and combinations thereof. Suitable pH modifiers Sion of the active ingredient in the oral cavity. that can be used include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Sweeteners that can 0047 Compositions of then invention can be prepared be used include aspartame, aceSulfame K and thaumatin. using processes for preparing the fast dispersing oral Solid Suitable taste masking agents include Sodium bicarbonate, dosage form, in which the carrier is associated with the ion eXchange resins, cyclodextrin inclusion compounds, active monoamine oxidase B inhibitor compound, utilizing adsorbates and microencapsulated actives. the procedures Set forth in the above references, the entire texts of which are again incorporated herein by reference. 0053. The fast dispersing oral Solid dosage form of the invention comprises a monoamine oxidase B inhibitor com 0.048 Particularly preferred, however, is the dosage form pound (MAO-B inhibitor) as the active ingredient within the of the type described in UK Patent No. 1,548,022. The pharmaceutical composition component. Preferred dosage form described therein comprises a network of the monoamine oxidase B inhibitor compounds for use in the active ingredient and a water-Soluble or water-dispersible invention are those having the following general formula: carrier which is inert toward the active ingredient. The network is prepared by Subliming a Solvent from the com position in Solid State, wherein the composition comprises (I) the active ingredient and a Solution of the carrier in a Solvent. X When oral Solid dosage forms are prepared in accordance with this technique, the composition can disintegrate within Y CH-CH-N-CHCECH 1 to 10 Seconds, particularly within 2 to 8 Seconds, of being CH placed in the oral cavity. The texts of all of the above references are incorporated herein by reference. 0049. When the preferred fast dispersing oral Solid dos 0054 or an acid addition salt thereof, wherein X repre age form is used, the composition preferably contains, in Sents hydrogen or methyl group, and Y represents hydrogen addition to the active ingredient monoamine oxidase-B or fluorine. Preferably, Y is hydrogen. In a preferred embodi inhibitor, matrix forming agents and Secondary components. ment, X is methyl and Y is hydrogen, or in other words, the Suitable matrix forming agents for use in the invention active MAO-B inhibitor compound is selegiline. include materials derived from animal or vegetable proteins, 0055 Selegiline or para-fluoroselegiline which is Such as gelatins, dextrins and Soy, wheat and psyllium Seed absorbed by pre-gastric absorption from a composition proteins, gums Such as acacia, guar, agar and Xanthan; prepared in accordance with this invention passes Straight polysaccharides, alginates, carboxymethylcelluloses, carra into the Systemic circulatory System, thereby avoiding first geenans, dextrans, pectins, Synthetic polymers, Such as pass metabolism in the liver. Accordingly, the initial rapid polyvinyl pyrrollidone; and polypeptide/protein or polysac production of unwanted metabolites is reduced, and the charide complexes. Such as gelatin-acacia complexes. bioavailability of active Selegiline or para-fluoroSelegiline is 0050. Other matrix forming agents suitable for use in the increased. This produces a number of advantages. For invention include Sugars, Such as mannitol, dextrose, lac example, the increased bioavailability of Selegiline or para tose, galactose and trehalose, cyclic SugarS Such as cyclo fluoroSelegiline means that the dose amount of Selegiline or dextrin; inorganic Salts. Such as Sodium phosphate, Sodium para-fluoroselegiline can be reduced while producing the chloride and aluminum Silicates, amino acids having from 2 Same or Similar beneficial therapeutic effect as compared to to 12 carbon atoms Such as a glycine, L-alanine, L-aspartic conventional oral administration means. Further, there is a acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, decrease in the amount of unwanted MAO-B inhibitor L-leucine and L-phenylalanine. metabolites. In the case of Selegiline, this means a reduction in the Stimulatory effect of methamphetamine and amphet 0051. In preparing the composition, one or more matrix amine on the central nervous System and heart. Conse forming agents can be incorporated into the Solution or quently, no restrictions on administration or dosage timing Suspension prior to Solidification. The matrix forming agent are required for compositions of the invention. can be present in addition to, or to the exclusion of, a Surfactant. Aside from forming the matrix, the matrix form 0056 According to the invention, a therapeutically effec ing agent may aid in maintaining the dispersion of the active tive amount of monoamine oxidase B inhibitor is present in ingredient within the Solution or Suspension. This is espe the dosage form. By the phrases “pharmaceutically effec US 2005/0106241 A1 May 19, 2005 tive” and “therapeutically effective', it is meant that the 0061 Alternatively, administration of lower doses of amount of active ingredient to be administered is known to Selegiline (10 mg or less) in conjunction with phenylalanine provide the desired effect with respect to the intended (250 mg) (dietary precursor to phenethylamine) has been treatment in accordance with pharmacological Standards, proposed. In this combination, Selegiline inhibits the pro principles and/or research. In the case of Selegiline and its duction of monoamine oxidase B thereby inhibiting the analogues of Formula I above, the active ingredient is deamination of phenethylamine, and phenylalanine Stimu preferably present in an amount ranging from about 1 to lates phenethylamine Synthesis. This results in increased about 30% by weight of the composition. Preferably, the levels of phenethylamine in the brain and, therefore, con active ingredient is present in an amount of from 1% to comitant elevation of mood. However, two active agents about 20% of the composition. In is also preferred that the need to be given, and the onset of anti-depressant effect is active ingredient is present in the composition in an amount still slow. of from about 0.25 mg to about 30 mg, more preferably 0.50 0062) To date, no studies have shown consistent anti mg to about 10 mg and, especially preferred, an amount depressant activity using low doses of Selegiline by itself from 1 to 5 mg. In the case wherein other MAO-B inhibitors using conventional administration. Accordingly, another are used, the active ingredient can be formulated in concen aspect of the invention is a method of treatment and/or trations and amounts which are likewise clinically effective. prophylaxis of depression comprising administering to a 0057 The invention includes a method of treating Par patient in need of Such treatment a fast dispersing oral Solid kinson's disease comprising administering to a patient in dosage form comprising a pharmaceutically effective need of treatment thereof, the fast dispersing oral Solid amount of monoamine oxidase B inhibitor and carrier. It has dosage form comprising monoamine oxidase B inhibitor now been found that if Selegiline, or by implication other compound as the active ingredient present in a pharmaceu monoamine oxidase B inhibitors, are formulated in accor tically effective amount, and a carrier. In another aspect of dance with the present invention, an increase in the amount the invention, the method of treatment by administering the of phenethylamine occurs in the body and thereby a good composition of the invention can be performed using a anti-depressant effect can be achieved at dose levels asso composition containing an active ingredient consisting ciated with selective inhibition of monoamine oxidase B. essentially of a monoamine oxidase B inhibitor, e.g., Sel Moreover, an earlier onset of effect is likely to be achieved egiline or a Selegiline analogue alone, without the co than with existing formulation and, in the case of Selegiline, administration of a Second or other active ingredient for said the low dose levels result in lower levels of unwanted treatment. This is one of the important advantages associated metabolites and therefore a reduction in their associated Side with the invention. effects. 0.058 Treatment of Depression 0063) Alzheimer's Disease 0059 AS mentioned above, selegiline and para-fluorosel 0064. Another aspect of the invention provides a method egiline are both inhibitors of monoamine oxidase B. The for treatment and/or prophylaxis of Alzheimer's disease preferred Substrate for monoamine oxidase B is phenethyl comprising administering to a patient in need of Such emine-a chemical which occurs naturally in the brain. treatment a fast dispersing oral Solid dosage form containing Phenethylemine is structurally very similar to amphetamine, a therapeutically effective amount of monoamine oxidase B and recent Studies have indicated that phenethylaine can act inhibitor and a carrier. Recent Studies have also Suggested as a neuromodulator promoting elevation of mood. This is that selegiline and other MAO-B inhibitors have a positive borne Out of the fact that patients Suffering from depression effect in the treatment and/or prophylaxis of Alzheimer's have been found to have sub-normal levels of phenethy disease, Since this condition is also associated with a marked lamine in the brain. increase in levels of monoamine oxidase B in the brain when compared with age-matched controls. Accordingly, Since 0060. In view of these findings, it has been suggested that formulation of Selegiline and, by implication other monoam monoamine oxidase B inhibitors, Such as Selegiline, may be ine oxidase B inhibitors, when prepared in accordance with useful in the treatment of depression, Since the inhibition of the invention, have been shown to increase bioavailability of monoamine oxidase B produces increased levels of phen the active ingredient, Such compositions can be especially ethylamine. In conventional practice, however, it has gen erally been found that high doses, typically 30 to 60 g per effective in the treatment and/or prophylaxis of Alzheimer's day for long periods (e.g., 6 weeks) or Selegiline are required disease while minimizing unwanted metabolites and asso to elevate mood in depressed patients. Such high doses are ciated Side effects. asSociated with non-specific inhibition of monoamine oxi 0065 Since it is well known that patients suffering from dase A and B, whereas Selective inhibition of monoamine Alzheimer's disease may not comply with their treatment oxidase B occurs at low doses (e.g., 10 mg or less) of regimen cooperatively, for example Spitting out tablets, fast Selegiline. Although monoamine oxidase A has very little dispersing oral Solid dosage form of the invention is par effect on the metabolism of phenethylamine, it has been ticularly advantageous because of their rapid disintegration Suggested that inhibition of monoamine oxidase A may in the mouth reduces the opportunity to eject the complete produce an anti-depressant effect by inhibiting deamination intact dosage form. Furthermore, Since a significant portion of norepinephrine and 5 hydroxytryptamine (serotonin), of the active ingredient is rapidly absorbed into the body deficits of which are also associated with depression. How using the dosage form of the invention, a significant amount ever, inhibition of monoamine oxidase A can produce unde of the active ingredient can reach Systemic circulation even Sirable cardiovascular effects and tyramine-induced hyper if a portion is expectorated. tensive crisis (the So-called "cheese effect”). Accordingly, 0066. The invention is further illustrated by the following the use of such high doses of selegiline or other MAO-B examples, none of which are to be construed as necessarily inhibitors to combat depression is clearly far from ideal. limiting the invention: US 2005/0106241 A1 May 19, 2005

EXAMPLES -continued Example 1 % by wt of Preparation of a Fast-Dispersing Dosage Form Ingredient Weight (mg) composition Comprising Selegiline Citric acid EP/USP 1.250 OSO Opatint TM AD-22901 yellow 0.750 O.3 0067 (a) Preparation of Selegiline Hydrochloride 2.0% Dispersion Total 2SO.OOO 1OO.O 0068 Gelatin (720 g) and mannitol (540 g) were dis *Signifies removed during the lyophilization process. persed in a portion of purified water (15.75 kg) by mixing thoroughly in the bowl of a vacuum mixer. The remaining Example 2 water (1.5 liters) was added under vacuum while mixing using an anchor stirrer. The mix was then heated to 40 C.2 C. and homogenized for ten minutes. When cooled, a Comparative Pharmacokinetic Study of Selegiline 4500g portion of the mix was removed into a stainless steel Dosage Forms vessel and glycine (360 g) aspartame (90 g), grapefruit 0072 The aim of this experiment was to compare the flavor (54g), OpatintTM yellow (54 g), citric acid (90 g) and bioavailability of the selegiline hydrochloride formulation Selegiline hydrochloride (360 g) were then added sequen of Example 1 prepared according to the invention, with the tially to this portion while homogenizing using a bench top commercially available tablet form of selegiline hydrochlo homogenizer. The remainder of the mix was transferred into ride sold under the trademark MoverganTM (available from a Second Stainless Steel vessel. The mix was homogenized Asta Medica AG, Weismullerstrasse 45, 6000 Frankfurt am for ten minutes using a bench top homogenizer to dissolve Main, Germany). the drug. Once dispersion of the coloring agent was com plete, the homogenized portion of the mix in the first vessel 0073. An open label, randomized, 2-way crossover, vol was returned to the mixer bowl together with the mix from unteer study was performed as follows. Twenty-four Sub the second vessel. The combined mixes were then mixed for jects of either Sex, aged between 45 and 71 years, giving at least 20 minutes. The bulk dispersion was then homog written informed consent, underwent a thorough medical enized to ensure that mixing was complete. examination to establish their fitness to participate in the Study. Subjects received Study treatment in the order dictated 0069 (b) Preparation of Selegiline Hydrochloride 5 mg by a pre-determined randomization Schedule. Subjects were Units given either the formulation of Example 1, or the Mover 0070 250 mg of the selegiline hydrochloride 2.0% dis ganTM formulation. Blood samples for determination of persion formed in Step (a) above was dosed into each one of pharmacokinetic parameters were taken at baseline (imme a Series of pre-formed blister pockets having a pocket diately before drug administration), then after 0.25, 0.5, diameter of 12 mm. The blister laminate comprised 200 um 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 and 96 PVC/30 um PE/PVDC 90 g per square meter. The product hours. The Study procedures were repeated two weeks later, was frozen immediately in a liquid nitrogen freeze tunnel. when Subjects were crossed-over to receive their Second The frozen product was then stored below -20° C. for a drug administration. Selegiline hydrochloride was adminis minimum of 24 hours prior to freeze-drying in a freeze drier tered as Single 10 mg doses (made up from 2x5 mg tablets) using a drying temperature of +20 C. and a chamber of the formulation of Example 1 or of the MoverganTM pressure of 0.5 mbar. The freeze-dried units were then formulation. inspected for the presence of critical defects and the remain 0074 Assays were performed to determine the concen der of the batch sealed with lidding foil consisting of trations of Selegiline, N-deSmethylselegiline, meth paper/foil laminate (20 um aluminum). Each blister was then ampgetamine, and amphetamine in each of the blood plasma coded with a batch number and overwrapped in a preformed Samples. The following pharmacokinetic parameters were Sachet by placing the blister in the Sachet and Sealing the determined for all four analyzed substances: bioavailability open end of the Sachet completely. Each Sachet was then (as measured as the area under the curve (AUC) of the drug labeled with the product name, batch number, date of concentrations/time plot), Cmax (the maximum plasma con manufacture and Supplier's name. centration achieved and Tmax (the time point at which 0.071) Each unit dosage form had the following compo Cmax was observed). Sition: 0075) The results are shown in graphical form in FIGS. 1 to 4 where each figure is a plot of the concentration of a Specific compound in a blood plasma Sample versus the time % by wt of at which the sample was taken for the formulation of Ingredient Weight (mg) composition Example 1, and the tablet formulation sold under the trade mark MoverganTM. In FIG. 1, the specific compound is Purified water USP/EP* 218.5OO 87.4 Selegiline Hydrochloride S.OOO 2.O Selegiline. In FIG. 2, the specific compound is N-desmeth Gelatin EP/USNF 1O.OOO 4.0 ylselegiline. In FIG. 3, the specific compound is metham Mannitol BP/USP 7.500 3.0 phetamine. In FIG. 4, the Specific compound is amphet Aspartame EP/USN 1.250 0.5 amine. Grapefruit flavor 502.106/A 0.750 O.3 Glycine USP S.OOO 2.O 0076. The results are shown in numerical form in Table 1 below. In this table, the references to N-desmethylsel US 2005/0106241 A1 May 19, 2005 egiline, methamphetamine and amphetamine are to the L-(- ing to Example 1. The pharmacokinetic profile of Selegiline )-isomers of these compounds. hydrochloride from the commercially available US tablet formulation should under the registered trademark TABLE 1. Eldepryl(R) (available from Somerset Pharmaceuticals, Inc. 777 South Harbor Island Boulevard, Suite 880, Tampa Fla. N-desmethyl- Metham 33602) served as a control for the degree of gastrointestinal Selegiline selegiline phetmine Amphetamine absorption of Selegiline. In addition, the Study was designed AUC to compare the urinary excretion over 24 hours of phen Example 1 6.93 36.58 215.43 104.85 ethylamine and 5-hydroxyindoleacetic acid (5-HIAA) from Movergan TM O.83 35.60 234.91 108.01 the Subjects to whom Such formulations had been adminis Cmax tered. Example 1 5.17 14.47 8.90 3.01 0082) This study was an open-labeled randomized 3-way Movergan TM O.86 17.36 10.59 3.54 croSSOver Volunteer Study and was performed as follows: Tmax 0083 Eleven subjects of either sex aged between 45 and Example 1 O.33 0.71 2.40 5.40 62 years giving written informed consent underwent a Movergan TM O.58 0.72 2.16 4.16 thorough medical examination to establish their fitness to Key participate in the Study. Subjects received each of the AUC = area under the plasma concentration-time curve (ngh/ml) following treatments in the order dictated by a pre-deter Cmax = maximum plasma concentration (ng/ml) mined randomization Schedule: Tmax = time to maximum plasma concentration (h) 0084) 1) 2x5 mg Eldepryl tablets taken with 150 ml 0077 Results: water (Eldepryl (10 mg)). 0078 From FIG.1 to 4 and Table 1, it is apparent that the 0085 2) 2x5 mg selegiline tablets produced according bioavailability of selegiline from the formulation of to Example 1 kept in the mouth for 1 minute and then Example 1 is more than eight times that of Selegiline from expectorated and the mouth rinsed with 3x25ml water the Movergan formulation, despite the fact that both formu and then expectorated (Example 1 (2.96 mg)). lations contained the same amount of active ingredient. 0.086 3)2x5 mg selegiline tablets produced according Also, the bioavailability of N-desmethylselegiline is very to Example 1 kept in the mouth for 1 minute and then similar to for both formulations. The bioavailability of Swallowed (Example 1 (10 mg)). methamphetamine and amphetamine, which are known not to contribute to the therapeutic effect, are very Similar to 0087 Blood samples for determination of pharmacoki Example 1 and the MoverganTM formulation. However, in netic parameters were taken at baseline (immediately before view of the much greater bioavailability of selegiline from drug administration) and then after 0.08, 0.16, 0.25, 0.5, the Example 1 formulation, it is envisaged that the dose of 0.75, 1, 1.5, 2, 3, 4, 6 and 12 hours. Urine samples were Selegiline could be significantly reduced thereby signifi taken immediately before drug administration and during the cantly reducing the quantity of unwanted central nervous periods 0-2 hours, 2-4 hours, 4-6 hours, 6-12 hours and System and cardiac Stimulant metabolites and undesired side 12-24 hours. effects caused by them while still achieving the desired 0088 Assays were performed to determine the concen levels of Selegiline in plasma and hence the desired thera tration of Selegiline in each of the blood plasma and urine peutic effect associated with monoamine oxidase B inhibi Samples and the concentration of phenethylamine and 5-hy tion. droxyindoleacetic acid (5-HIAA) was measured in each of 0079. In Table 1, the ratio of the area under the plasma the urine Samples. Selegiline was also measured in Saliva concentration-time curve (AUC) for selegiline and the AUC and mouth Washings. for N-desmethylselegiline was 0.0233 for the MoverganTM 0089 Phenethylamine is the preferred substrate for formulation, indicating clearly the extensive metabolism of monoamine oxidase B (MAO-B) and consequently its excre Selegiline when administered in an existing dosage form. tion has been shown to rise when MAO-B is inhibited. 0080. The corresponding AUC ratio for Example 1 in 5-HIAA is a breakdown product formed by the action of Table 1 was 0.1894. This demonstrates that pre-gastric MAO-A on 5-hydroxytryptamine (serotonin). When absorption of Selegiline results in a greater proportion of the MAO-A is inhibited, the 5-HIAA level excreted has been administered dose being absorbed in the unmetabolized shown to decline. form. It demonstrates further that the selegiline:N-desmeth ylselegiline AUC ratio can be used as another indicator of 0090 Results the degree of pre-gastric absorption in Selegiline-containing 0091. The results from the study are shown in graphical compositions in accordance with this invention. It is gener form in FIGS. 5, 6 and 7. When the tablets produced ally preferred that the ratio of selegiline AUC to the N-des according to Example 1 were kept in the mouth for 1 minute methylselegiline AUC should be greater than 0.05, more and the Saliva expectorated, an average concentration preferably greater than 0.075, and most preferably greater equivalent to 7.04 mg. Selegiline hydrochloride was mea than 0.10. Sured in the mouth Washings. Thus an average of 2.96 mg Example 3 Selegiline hydrochloride was absorbed pre-gastrically with this treatment. Subjects therefore received 2.96 mg, or 10 Pre-Gastric Absorption Study mg of Selegiline hydrochloride from the 10 mg formulation 0081. The aim of this study was to assess the Sublingual produced according to Example 1 and 10 mg Selegiline from absorption of Selegiline hydrochloride formulations accord the Eldepryl(R) formulation. US 2005/0106241 A1 May 19, 2005

0092 FIG. 5 is a plot of concentration of selegiline in a Example 4 blood plasma Sample versus the time at which the Sample was taken for both expectorated and Swallowed formulations Fast Dispersing Oral Solid Dosage Formulation of example 1 (Example 1 (equivalent to 2.96 mg) and Containing Selegiline Example 1 (10 mg) respectively) and the 10 mg tablet formulation sold under the trademark Eldepryl(R). FIG. 6 0098) shows the cumulative 5-hydroxyindoleacetic acid excretion in urine over 24 hours. FIG. 7 shows the cumulative phenethylamine excretion in urine over 24 hours. % by weight of 0093. From FIG. 5, it is apparent that the bioavailability Ingredient Weight (mg) composition of Selegiline from both the 2.96 mg (expectorated) equiva Purified water EP/USP* 221.625 88.65 lent and 10 mg (Swallowed) doses prepared according to Selegiline hydrochloride S.OOO 2.OO Example 1 is much greater than that of Selegiline from the Gelatin EP/USNF 11.250 4.50 Eldepryl(R) formulation, despite the fact that one formulation Mannitol EP/USP 8.125 3.25 Aspartame EP/USNF 1.250 OSO (Example 1 (10 mg Swallowed) contained the same amount Grapefruit Flavor 502.106/A 0.750 O.30 of active ingredient as the Eldepryl(R) formulation and the Citric acid EP/USP 1.250 OSO expectorated treatment contained less than one third of the Opatint AD-22901 yellow 0.750 O.30 amount of active ingredient as the Eldepryl(R) formulation. Total 1OOOO 0094) Moreover, it is apparent from FIG. 7 that this enhanced bioavailability is associated with a dose-related *signifies removed during the lyophilization process. increase in the urinary excretion of phenethylamine. This was an unexpected result as increased phenethylamine Example 5 excretion is caused by inhibition of monoamine oxidase B and it as hitherto believed that 10 mg of selegiline in standard tablet form (i.e., Eldepryl(R) would be sufficient to Fast Dispersing Oral Solid Dosage Formulation cause maximal inhibition of monoamine oxidase B during Containing Selegiline the first 24 hours. In addition, the higher rate of excretion of phenethylamine in FIG. 7 for Example 1 (10 mg Swallowed) 0099) and Example 1 (2.96 mg expectorated) than for the Eldepryl(R) formulation indicates a faster rate of monoamine oxidase B inhibition than with the former compositions and % by weight of consequently a possible earlier alleviation of Symptoms of Ingredient Weight (mg) composition Parkinson's disease, Alzheimer's disease and depression Purified water EP/USP* 224.125 89.65 than for the Eldepryl(R) formulation. Selegiline hydrochloride S.OOO 2.OO Gelatin EP/USNF 9.375 3.75 Mannitol EP/USP 7.500 3.OO 0.095 Lack of inhibition of monoamine oxidase A by the Grapefruit Flavor 502.106/A 0.750 O.30 Example 1 (10 mg Swallowed) and Example 1 (2.96 mg Citric acid EP/USP 1.250 OSO expectorated) treatments was confirmed by analysis of the Opatint AD-22901 yellow 0.750 O.30 urine Samples for concentration of 5-hydroxyindoleacetic Acesulfame K 1.250 OSO acid, which is the metabolite of 5-hydroxutryptamine (sero Total 1OOOO tonin) which is a principal Substrate for monoamine oxidase A (see FIG. 6). Urinary concentrations of 5 hydroxyin *signifies removed during the lyophilization process. doleacetic acid were similar for the Example 1 (10 mg Swallowed), Example 1 (2.96 expectorated) and the standard Eldepryl tablet formulations, showing that the Selegiline Example 6 formulations produced according to Example 1 did not cause greater MAO-A inhibition than standard tablets despite the Fast Dispersing Oral Solid Dosage Formulation much increased Selegiline bioavailability. Containing Selegiline 0096. Once again, in view of the greater bioavailability of 01.00 Selegiline from the Example 1 (10 mg Swallowed) and example 1 (2.96 expectorated) formulations, it is envisaged that the dose of Selegiline could be significantly reduced % by weight of thereby significantly reducing the quantity of unwanted Ingredient Weight (mg) composition metabolites with their associated side effects, while still achieving the desired therapeutic effects associated with Purified water EP/USP* 219.5OO 87.8O inhibition of monoamine oxidase B. Selegiline hydrochloride S.OOO 2.OO Gelatin EP/USNF 1O.OOO 4.00 Mannitol EP/USP 7.500 3.OO 0097. The following examples further exemplify formu Aspartame EP/USNF 1.OOO O40 lations which can be prepared using the proceSS described in Glycine USP 2.5OO 1.OO Example 1 which will promote pre-gastric absorption of Citric acid EP/USP 1.250 OSO Selegiline and other MAO-B inhibitors: US 2005/0106241 A1 May 19, 2005

Example 9 -continued Fast Dispersing Oral Solid Dosage Formulation Containing Selegiline % by weight of Ingredient Weight (mg) composition 0103)

Opatint AD-22901 yellow 0.750 O.30 Lemon Lime flavor 59.15/AP 2.5OO 1.OO % by weight of Ingredient Weight (mg) composition

Total 2SO.OOO 1OOOO Purified water EP/USP* 216.750 86.7O Selegiline hydrochloride S.OOO 2.OO Gelatin EP/USNF 1O.OOO 4.OO *signifies removed during the lyophilization process. Mannitol EP/USP 7.500 3.OO Aspartame EP/USNF 1.250 OSO Glycine USP 3.750 1.50 Citric acid EP/USP 1.250 OSO Example 7 Opatint AD-22901 yellow 0.750 O.30 Acesulfame K 1.250 OSO Fast Dispersing Oral Solid Dosage Formulation Lemon lime flavor 59.15/AP 2.5OO 1.OO Containing Selegiline Total 2SO.OOO 1OOOO 01.01 *signifies removed during the lyophilization process. Example 10 % by weight of Fast Dispersing Oral Solid Dosage Formulation Ingredient Weight (mg) composition Containing Mofegiline Purified water EP/USP* 223.625 89.45 Selegiline hydrochloride 5.OOO 2.00 01.04] Gelatin EP/USNF 1O.OOO 4.00 Mannitol EP/USP 7.500 3.00 % by weight of Aspartame EP/USNF 0.750 O.30 Ingredient Weight (mg) composition Grapefruit Flavor 502.106/A 0.750 O.30 Citric acid EP/USP 1.2SO O.SO Purified water EP/USP* 215.875 86.35 Opatint AD-22901 yellow 0.750 O.30 Mofegiline 12.OOO 4.8O Sodium methyl parabens EP/USNF O.250 O.10 Gelatin EP/USNF 1O.OOO 4.OO Sodium propyl parabens EP/USNF O.125 O.OS Mannitol EP/USP 8.125 3.25 Aspartame EP/USNF 1.250 OSO Grapefruit Flavor 502.106/A 0.750 O.30 Total 2SO.OOO 1OO.OO Glycine USP 1.250 OSO Opatint AD-22901 yellow 0.750 O.30 *signifies removed during the lyophilization process. Total 2SO.OOO 1OOOO Example 8 *signifies removed during the lyophilization process. Fast Dispersing Oral Solid Dosage Formulation Example 11 Containing Selegiline Fast Dispersing Oral Solid Dosage Formulation 0102) Containing LaZabe,ode 01.05 % by weight of Ingredient Weight (mg) composition % by weight of Purified water EP/USP* 219.125 87.65 Ingredient Weight (mg) composition Selegiline hydrochloride S.OOO 2.OO Gelatin EP/USNF 10.625 4.25 Purified water EP/USP* 797.500 79.75 Mannitol EP/USP 6.875 2.75 Lazabemide 1OOOOO 1O.OO Aspartame EP/USNF 1.250 OSO Gelatin EP/USNF 45.OOO 4.50 Glycine USP S.OOO 2.OO Mannitol EP/USP 35.OOO 3.50 Grapefruit Flavor 502.106/A 0.750 O.30 Lemon lime flavor 59.15/AP S.OOO OSO Citric acid EP/USP O.625 O.25 Glycine USP 1O.OOO 1.OO Opatint AD-22901 yellow 0.750 O.30 Aspartame EP/USNF 7.500 O.75

Total 2SO.OOO 1OOOO Total 1OOOOOO 1OOOO *signifies removed during the lyophilization process. *signifies removed during the lyophilization process. US 2005/0106241 A1 May 19, 2005

0106 Additional clinical studies were performed pertain cardiovascular threshold after each treatment was deter ing to the therapeutic efficacy and Safety of Selegiline in the mined, the mean doses as follows: Zydis(R (Cardinal Health, Inc., Dublin, Ohio) fast dispersing oral Solid dosage form. The Zydis(E) fast-dispersing oral Solid dosage form containing Selegiline was prepared in a Conventional tablet control 400 mg (73.9) manner Similar to that Set forth in Example 1. Conventional selegiline 131.3 mg (65.0) Zydis control 408.3 mg (131.1) Example 12 Zydis selegiline 120.8 mg (49.8) Selegiline Inhibition of MAO-B 0112 From this mean (ESD) the tyramine pressor end 0107. In four pharmacokinetic studies, the Log10 AUC point ratio for 10 mg Zydis(R) Selegiline was calculated to be plasma Selegiline was significantly correlated with the 24 3.67 (1.3) and the ratio for 10 mg conventional selegiline hour cumulative urinary excretion of phenethylamine was calculated to be 4.5 (4.1). Thus, as far as the effects on (PEA). By contrast, the same studies showed there was no MAO-A were concerned, 10 mg Zydis(E) selegiline was Significant correlation between Log10 plasma N-desmeth equivalent to 10 mg of conventional Selegiline tablets. These ylselegiline (and therefore 1-amphetamine or 1-metham ratios were also in close agreement with the observations of phetamine) and 24 hour phenethylemine excretion. This others (Table 2) and showed that both treatments had similar indicates that Selegiline, and not its metabolites, was respon and probable minimal or no effects on MAO-A. Further as Sible for the MAO-B inhibition. a result, no new Safety concerns had emerged from the 0108). The data from the studies is set forth in FIG. 8, repeated use of 10 mg Zydis(R selegiline over those from the which is a graph containing plot data for measurements of use of 10 mg conventional selegiline. If MAO-A been fully plasma Selegiline and 24 hour urinary excretion of phen inhibited, the tyramine pressor endpoint ratio would have ethylamine. Upon inspecting the graph, it can be clearly Seen been expected to exceed 20. that there exists a remarkably consistent relationship between plasma Selegiline concentrations and MAO-B inhi TABLE 2 bition, despite the route used to administer Selegiline or at what dose. Tyramine Pressor Endpoint Ratios for Selegiline Doses Over 2-3 Weeks Example 13 Tyramine Pressor Selegiline daily dose Endpoint Ratio Comparative MAO-B Inhibition of Zydis(R) mg (n) (Tyramine route) Selegiline and Commercial Selegiline 5 (8) 1.7 (oral) 5 (8) 2.8 (oral) 0109 Two studies were conducted using 1.25 mg doses 10 (7) 3.7 (iv) of Zydis(E) fast dispersing oral Solid Selegiline dosage form. 10 (2) 1.7 (i.vii) The first of these Studies used a quartered Zydis Selegiline 5 15* (4) 2.1 (i.v.) 20 (7) 3.8 (oral) mg unit, with the remaining three-quarters made up with 20 (7) 4.5 (oral) placebo to ensure a constant dosage of excipients. In the 30+ k (7) 3.1 (oral) Second study, Zydis Selegiline 1.25 mg units were used. Again, cumulative urinary excretion of phenethylamine was *indicates ascending dose over 3 weeks (5-15 mg) measured over 24 hours for the 1.25 mg Zydis Selegiline and **indicates ascending dose over 1 week (5030 mg) 10 mg commercial Selegiline tablets. AS can be seen from i.v. i. indicates intravenous infusion the data in FIG. 9, the cumulative phenethylamine urinary 0113. The results demonstrate that despite higher con excretion is Similar. Therefore, it can be reasonably assumed centrations of unchanged Selegiline occurring in plasma that both formulations are equally efficacious despite the after 10 mg Zydis(E) Selegiline compared with 10 mg con difference in dose amount. In other words, Zydis(R fast ventionally administered selegiline, the MAO-B selectivity dispersing Solid oral dosage form for Selegiline 1.25 mg is had been retained. The fact that the tyramine pressor end equally efficacious to the 10 mg commercial tablet. point ratio was Similar for tyramine given orally or intrave nously strongly Suggests that gastro-intestinal MAO-A inhi Example 14 bition played little part in the change of threshold, and that the potentiation of tyramine was brought about by intravas Selective Inhibition of MAO-B by Zydis Selegiline cular actions, possibly through platelet MAO-B inhibition, 0110. An experiment to test for non-selective MAO inhi although an effect on MAO-A in Sympathetic nerve endings bition was conducted using the oral tyramine pressor test. cannot be eliminated. Accordingly, it is reasonable to The oral tyramine pressor test is the clinically relevant assume that the chance of non-Selectivity occurring with model for detecting a lowering of the threshold of the Zydis(R) Selegiline 1.25 mg is very Small. cardiovascular effects of tyramine (i.e., “cheese reaction”). This test was therefore carried out before Selegiline dosing Example 15 and after treatment on day 14 in all 24 Subjects used in the study. Of the 24 subjects, 12 received 10 mg Zydis(R) Comparative MHPG Plasma Levels Selegiline and 12 received 10 mg conventional Selegiline. 0114. In another study, plasma MHPG was measured at 0111. A “survival-type” analysis was performed and the baseline and 24 hours following treatment using 10 mg mean dose of tyramine (tSD) required to achieve the ZydiscE) Selegiline and conventional Selegiline (Deprenyl(R) US 2005/0106241 A1 May 19, 2005

at intervals over 28 days. The results are shown in FIG. 10. 9. The fast disintegrating oral Solid dosage form according As can be seen from the data in FIG. 10, changes in pre-dose to claim 1, wherein at least 5% of Said monoamine oxidase MHPG plasma levels varied over the 4 week period, but the B inhibitor is absorbed within one minute of placement in effects of both treatments were identical-not only with the oral cavity as measured by a buccal absorption test. respect to change over time, but also that there was no 10. The fast disintegrating oral Solid dosage form accord statistically significant difference between 10 mg Zydis(R) ing to claim 9, wherein at least 10% of said monoamine Selegiline and conventional Selegiline at any time point. AS oxidase B inhibitor is absorbed within one minute of place can be seen from the graph, the measurement of plasma ment in the oral cavity as measured by a buccal absorption MHPG concentrations reveal minimal inhibition of MAO-A teSt. with 10 mg of either Zydis(R selegiline or conventional 11. The fast disintegrating oral Solid dosage form accord Selegiline. ing to claim 10, wherein at least 15% of Said monoamine 0115 Reference has been made herein above to the oxidase B inhibitor is absorbed within one minute of place content of certain documents in the course of describing the ment in the oral cavity as measured by a buccal absorption invention. The full texts of each Such cited reference are teSt. incorporated herein by reference. The invention has been 12. The fast disintegrating oral Solid dosage form accord described herein above with reference to various and Spe ing to claim 4, wherein Said dosage form is formulated Such cific embodiments and techniques. It will be understood by that about 2.96 mg of selegiline hydrochloride is pre one of ordinary skill in the art, however, that reasonable gastrically absorbed within one minute of placement in the modifications and variations can be made from Such oral cavity. embodiments and techniques while remaining within the 13. The fast disintegrating oral Solid dosage form accord spirit and scope of the invention defined by the following ing to claim 1, wherein Said dosage form comprises a claims. network of the monoamine oxidase B inhibitor and water soluble or water dispersible carrier which is inert toward What is claimed is: Said monoamine oxidase B inhibitor, Said network is formed 1. A fast disintegrating oral Solid dosage form formulated by Subliming Solvent from a Solid State composition com for pre-gastric absorption, Said dosage form comprising a prising the monoamine oxidase B inhibitor and a Solution of monoamine oxidase B inhibitor and carrier. the carrier in a Solvent. 2. The fast disintegrating oral Solid dosage form according 14. The fast disintegrating oral Solid dosage form accord to claim 1, wherein the monoamine oxidase B inhibitor has ing to claim 13, wherein said dosage form disintegrates the following formula: within 1 to 10 Seconds of being placed in the oral cavity. 15. The fast disintegrating oral Solid dosage form accord ing to claim 13, wherein Said monoamine oxidase B inhibi (I) tor is Selegiline. X 16. The fast disintegrating oral Solid dosage form accord Y CH-CH-N-CHCECH ing to claim 1, wherein the bioavailability of Said monoam ine oxidase B inhibitor is at least about 8 times that as CH compared to an orally Swallowed Solid tablet dosage form, wherein each of Said dosage forms contain the same amount of monoamine oxidase B inhibitor. or an acid addition Salt thereof, wherein X represents 17. A method of treatment of Parkinson's disease com hydrogen or methyl group, and Y represents hydrogen prising administering to a patient in need of treatment or fluorine. thereof, a fast disintegrating oral Solid dosage form contain 3. The fast disintegrating oral Solid dosage form according ing a pharmaceutically effective amount of monoamine to claim 1, wherein Said monoamine oxidase inhibitor is oxidase B inhibitor, Said dosage form being formulated for Selected from the group consisting of Selegiline, para-fluo pre-gastric absorption and comprising monoamine oxidase roSelegiline, mofegiline, rasagiline, lazabemide, and combi B inhibitor and carrier. nations thereof. 18. The method according to claim 17, wherein said 4. The fast disintegrating oral Solid dosage form according dosage form is formulated to promote absorption of Said to claim 3, wherein said monoamine oxidase B inhibitor is monoamine oxidase B inhibitor through the buccal, Sublin Selegiline. gual, pharyngeal or esophageal mucous membrane. 5. The fast disintegrating oral Solid dosage form according 19. The method according to claim 17, wherein said to claim 4, wherein Selegiline is the only pharmacologically dosage form disintegrates within one minute after placement active ingredient present in Said dosage form. in the oral cavity. 6. The fast disintegrating oral Solid dosage form according 20. The method according to claim 19, wherein said to claim 1, wherein Said dosage form is formulated to dosage form disintegrates within 1 to 10 Seconds after promote absorption of Said monoamine oxidase B inhibitor placement in the oral cavity. through the buccal, Sublingual, pharyngeal or esophageal 21. The method according to claim 17, wherein at least mucous membrane. 5% of said monoamine oxidase B inhibitor is absorbed 7. The fast disintegrating oral Solid dosage form according within one minute of placement in the oral cavity as mea to claim 1, wherein Said dosage form disintegrates within Sured by a buccal absorption test. one minute after placement in the oral cavity. 22. The method according to claim 21, wherein at least 8. The fast disintegrating oral Solid dosage form according 10% of said monoamine oxidase B inhibitor is absorbed to claim 7, wherein Said dosage form disintegrates within 10 within one minute of placement in the oral cavity as mea Seconds after placement in the oral cavity. Sured by a buccal absorption test. US 2005/0106241 A1 May 19, 2005

23. The method according to claim 22, wherein at least thereof, a fast disintegrating oral Solid dosage form contain 15% of said monoamine oxidase B inhibitor is absorbed ing a pharmaceutically effective amount of monoamine within one minute of placement in the oral cavity as mea oxidase B inhibitor, Said dosage form being formulated for Sured by a buccal absorption test. pre-gastric absorption and comprising monoamine oxidase 24. The method according to claim 17, wherein said B inhibitor and carrier. dosage form is formulated Such that about 2.96 mg of 30. The method according to claim 29, wherein said Selegiline hydrochloride is pre-gastrically absorbed within monoamine oxidase B inhibitor is Selegiline. one minute of placement in the oral cavity. 31. A method of treatment of depression comprising 25. The method according to claim 17, wherein said administering to a patient in need of treatment thereof, a fast dosage form comprises a network of the monoamine oxidase disintegrating oral Solid dosage form containing a pharma B inhibitor and water-soluble or water dispersible carrier ceutically effective amount of monoamine oxidase B inhibi which is inert toward said monoamine oxidase B inhibitor, tor, Said dosage form being formulated for pre-gastric said network is formed by Subliming solvent from a solid absorption and comprising monoamine oxidase B inhibitor State composition comprising the monoamine oxidase B and carrier. inhibitor and a Solution of the carrier in a Solvent. 32. The method according to claim 31, wherein said 26. The method according to claim 25, wherein said monoamine oxidase B inhibitor is Selegiline. dosage form disintegrates within 1 to 10 Seconds of being 33. A method of increasing phenethylamine levels in the placed in the oral cavity. body comprising administering to a patient in need of 27. The method according to claim 17, wherein said treatment thereof, a fast disintegrating oral Solid dosage monoamine oxidase B inhibitor is Selegiline. form containing a pharmaceutically effective amount of 28. The method according to claim 17, wherein the monoamine oxidase B inhibitor, Said dosage form being bioavailability of said monoamine oxidase B inhibitor is at formulated for pre-gastric absorption and comprising least about 8 times that as compared to an orally Swallowed monoamine oxidase B inhibitor and carrier. Solid tablet dosage form, wherein each of Said dosage forms 34. The method according to claim 33, wherein said contain the same amount of monoamine oxidase B inhibitor. monoamine oxidase B inhibitor is Selegiline. 29. A method of treatment of Alzheimer's disease com prising administering to a patient in need of treatment