EP1028719A1

EP1028719A1 - Treatment of attention deficit hyperactivity disorder and narcolepsy

Info

Publication number: EP1028719A1
Application number: EP98967116A
Authority: EP
Inventors: Edward Stewart Johnson
Original assignee: RP Scherer Technologies LLC
Current assignee: RP Scherer Technologies LLC
Priority date: 1997-07-17
Filing date: 1998-07-17
Publication date: 2000-08-23
Also published as: AU1645699A; WO1999003458A1; GB9715082D0

Abstract

This invention relates to the use of a pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a monoamine oxidase B inhibitor, characterised in that the composition is formulated to promote pre-gastric absorption of said monoamine oxidase B inhibitor, for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy. A method of treating Attention Deficit Hyperactivity Disorder and/or narcolepsy is also provided.

Description

TREATMENT OF ATTENTION- DEFICIT HYPERACTIVITY DISORDER

AND NARCOLEPSY

This invention relates to the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy and a method of treating these conditions.

Attention Deficit Hyperactivity Disorder (ADHD) is a behavioural disorder of unknown cause characterised by inattention, impulsiveness and hyperactivity (see K.A. Calis et al, Clinical Pharmacology, (1990) , 9_., 632-642) . The behaviour, which may be manifested at home, school or in social situations, is generally worse in settings requiring sustained attention. As a result, academic underachievement is frequently an associated problem. Although the onset usually occurs before the age of 4 years, ADHD is most commonly diagnosed when a child enters school. This condition is six times more common in boys than in girls and nearly one third of all children with ADHD continue to show symptoms of the disorder in adulthood.

There is currently no cure for ADHD. However, psychostimulant medications, such as methylphenidate, amphetamine and pemoline, are used to manage the behavioural manifestations of ADHD. Methylphenidate and amphetamine are equally effective but methylphenidate (20-60 mg daily) causes fewer side effects. Thus, according to a Baltimore County Health Department Survey in 1987, methylphenidate accounted for 93% of the medications prescribed for children in the county' s public and private schools. Methylphenidate decreases hyperactivity in about 80% of affected children, allows more purposeful activity and improved learning capacity. However, the long-term use of methylphenidate in doses greater than 20mg daily may be associated with reversible impaired growth and development (see S. Safer et al , New England Journal of Medicine, (1972) 287. 217-220) . Thus, methylphenidate is often beneficially accompanied by behavioural education and psycho counselling.

Narcolepsy is a disorder characterised by uncontrollable sleepiness which begins in late childhood or adolescence. Several times a day, usually while sitting in class, the subject is overcome by an uncontrollable desire to sleep. Somnolence may occur in unusual situations, for instance, while standing or carrying on conversations. Also, in about 70% of patients cataplexy sometimes occurs. This is usually brought on by laughter (occasionally by excitement, sadness or anger) and causes the patient's head to fall forward, his jaw to drop, his knees to buckle, even with falling to the ground, all with perfect preservation of consciousness. Such attacks only last a minute or two. Sleep paralysis and hallucinations on waking may also occur but these are rare.

No form of therapy will control all the symptoms of narcolepsy but methylphenidate (20-60 mg daily in clinical dosage) controls the sleep attacks and accompanying tension. This beneficial response is maintained on long-term treatment (see Y. Honda et al, Current Therapeutic Research, (1979) 25., 288-298) . However, such long-term treatment with methylphenidate is also associated with undesirable side effects as discussed above.

Methylphenidate acts on the brain in an analogous way to amphetamine, the 1-enantiomer (less active form) of which is produced by the liver as a metabolite of selegiline when administered orally in the form of a conventional tablet or syrup according to the following metabolic pathway:-

L-(-)-Desmethyiselegiline L-(-)-Amphetamine

( ) CH?— CH— NH (C ) CH₂ — CH— H₂

CH₃ CH₂C≡CH CH₃

Accordingly, it has been suggested in WO 95/11016 that selegiline, which is a monoamine oxidase B (MAO-B) inhibitor, may be useful in the treatment of ADHD. However, in a double-blind study in adults, selegiline has been shown to be inactive clinically (see M. Ernst et al, Psychopharmacology Bulletin, (1996) , 3_2, 327-334) . It is believed that this is probably because lOmg conventional tablets administered daily give rise to too little 1-amphetamine to have any beneficial effect and the 20-60mg dose used by Ernst et al causes the inhibition of monoamine oxidase A (MAO-A) as well as MAO- B which reverses any potential beneficial effect.

The preferred substrate for MAO-B is phenylethylamine, a chemical which occurs naturally in the brain. Phenylethylamine is structurally very closely related to amphetamine and is often referred to as the "endogenous amphetamine". It is known from WO 96/26720 that, if selegiline or, by implication, another MAO-B inhibiting compound which is susceptible to a high first pass effect is formulated in a composition to promote pre-gastric absorption of the MAO-B inhibitor, an increase in the amount of phenylethylamine occurs in the body to a far greater extent than with conventional oral formulations containing the same amount of active ingredient. Moreover, an earlier onset of effect is likely to be achieved and, in the case of selegiline, the low dose levels result in lower levels of unwanted metabolites and therefore a reduction in their associated side effects. It has now been discovered that the use of a composition which is formulated to promote pre-gastric absorption of an MAO-B inhibitor increases the amount of endogenous phenylethylamine in the brain to levels which are effective to activate the brain to combat ADHD or narcolepsy without all the side effects associated with high dose selegiline or synthetic amphetamines, such as nervousness, restlessness, insomnia, anorexia, palpitations, tachycardia, nausea, dizziness, weight loss and abdominal pain. Moreover, in the case of selegiline, lower doses can be administered since it is the endogenous phenylethylamine and not the 1-amphetamine metabolite of selegiline which produces the desired therapeutic effect .

According to the present invention there is therefore provided use of a pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a monoamine oxidase B inhibitor characterised in that the composition is formulated to promote pre-gastric absorption of said monoamine oxidase B inhibitor, for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy.

The term "pre-gastric absorption" is used to refer to absorption of the active ingredient from that part of the alimentary canal prior to the stomach and includes buccal, sublingual, oropharyngeal and oesophageal absorption.

The potential for the pre-gastric absorption of compositions containing MAO-B inhibitors can be assessed using the method described for selegiline in Example 3 below. This test is similar to the "buccal absorption test" which is said by Harris and Robinson in a review article (J..Pharm. Sci., 1992, vol 81, p 1-10) to be a well recognised method for evaluating buccal absorption of drugs. Thus, the test formulation containing the clinically effective dose of the MAO-B inhibitor is retained in the mouth for 1 minute before it is expectorated. The mouth is then rinsed with 3 aliquots of 25 ml of water which are similarly expectorated. The total amount of MAO-B inhibitor is then determined in the expectorated mouth washings, using a suitable analytical technique such as HPLC, and the recovered quantity of MAO-B inhibitor is subtracted from the total amount of drug initially placed in the mouth to determine the total amount of drug which has been absorbed pre-gastrically . For significant buccal absorption to have occurred it is generally preferred that at least 5% of the MAO-B inhibitor has been absorbed in 1 minute in this test, more preferably that at least 10% has been absorbed in 1 minute and most preferably at least 15% of the MAO-B inhibitor has been absorbed in 1 minute.

It is envisaged that such pre-gastric absorption will occur primarily across the mucous membranes in the mouth, pharynx and oesophagus. Accordingly, it is preferred that the composition of the invention is formulated to promote absorption of the active ingredient through the buccal, sublingual, pharyngeal and/or oesophageal mucous membranes.

It is therefore preferred that the composition of the invention should be in a form which sustains the active ingredient in contact with the buccal, sublingual, pharyngeal and/or oesophageal mucous membranes .

Preferably, the composition of the invention is in the form of a viscous emulsion, syrup or elixir, a sub-lingual tablet, a suckable or chewable tablet, softgel, lozenge, aqueous or non-aqueous drops or other dosage form designed to release the active ingredient in a controlled manner to saliva or to the buccal, pharyngeal and/or oesophageal mucous membranes, a fast- dispersing dosage form designed rapidly to release the active ingredient in the oral cavity, or a bioadherent system.

The term "bioadherent system" refers to a solid or liquid dosage form which, at body temperature, exhibits controlled release and bioadherence characteristics. This type of dosage form may be an emulsion which is water in oil in nature and whose internal phase is greater than that of the external phase. Examples of such bioadherent systems may be found in U.S. Patent No. 5055303.

In view of the psychostimulatory nature of the drugs currently of preference in the treatment of ADHD and narcolepsy, it is common for children to remove the drug from the mouth after administration by a teacher or parent for later illegal sale. Accordingly, of the dosage forms listed above, fast-dispersing dosage forms are particularly preferred since they will disintegrate rapidly in the mouth thereby safeguarding against potential abuse of selegiline and actual abuse of methylphenidate, amphetamine etc. Moreover, the ease of administration of such fast-dispersing dosage forms would be advantageous to school nurses, teachers, parents and children.

One example of a fast -dispersing dosage form is described in U.S. Patent No. 4855326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a "candy-floss" preparation. The spun "candy-floss" product is then compressed into a rapidly dispersing, highly porous solid dosage form.

U.S. Patent No. 5120549 discloses a fast- dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix- forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.

U.S. Patent No. 5079018 discloses a fast- dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.

Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and ^• then removing water by forced air or vacuum drying.

U.S. Patent No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.

Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.

The term "fast-dispersing dosage form" therefore encompasses all the types of dosage -form described in the preceding paragraphs. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.

It is preferred that the composition of the invention disintegrates within 1 to 10 seconds, particulary 2 to 8 seconds, of being placed in the oral cavity.

In the case of the preferred type of fast- dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components . Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses ; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes .

Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L- hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine .

One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.

Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, colouring agents, flavouring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard. Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include asparta e, acesulfame K and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives .

Selegiline has already been mentioned above as an MAO-B inhibitor which can be used in the treatment of ADHD and narcolepsy according to the present invention.

Para-fluoroselegiline is an analogue of selegiline which is also a monoamine oxidase B inhibitor and exhibits very similar pharmacological activity to that of selegiline.

Many other compounds, which are often not chemically related to selegiline, also have monoamine oxidase B-inhibiting properties, and a number of these are also envisaged to have utility for the treatment of ADHD and narcolepsy. Among such MAO-B inhibitors may be mentioned: lazabemide [N- (2-aminoethyl) -5-chloropyridine- 2-carboxamide hydrochloride]; rasagiline [2 , 3-dihydro-N- 2-propynyl-lH-inden-l-amine] ; 2-BUMP [N- (2 -butyl) -N- methylpropargylamine; M-2-PP [N-methyl-N- (2-pentyl) - propargylamine] ; MDL-72145 [beta- (fluoromethylene) -3 , 4- dimethoxy-benzeneethanamine] ; and mofegiline [(E) -4- fluoro-β- (fluoromethylene) benzene butanamine hydrochloride] .

Preferred compositions in accordance with this invention include as the active MAO-B inhibitor a compound of the general formula :

or an acid addition salt thereof, in which X represents a hydrogen atom or, preferably, a methyl group and Y represents a fluorine or, preferably, a hydrogen atom. It is particularly preferred that X is methyl and Y is hydrogen i.e. that the active MAO-B inhibitor is selegiline .

Selegiline or para-fluoroselegiline which is absorbed by pre-gastric absorption from a composition in accordance with this invention passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, the initial rapid production of unwanted metabolites is reduced and the bioavailability of active selegiline or para-fluoroselegiline is increased. This results in a number of advantages. For instance, the increased bioavailability of active selegiline or para-fluoroselegiline means that the dose of selegiline or para-fluoroselegiline may be reduced whilst still producing the desired beneficial effect. This will result in a further decrease in the production of unwanted metabolites and, in the case of selegiline, a corresponding reduction in the stimulatory effect of methamphetamine and amphetamine on the central nervous system and heart. Consequently, no restrictions on dose timing are required for the compositions of the invention.

In the case of selegiline and its analogues of formula I above, the active ingredient preferably is present in the composition in an amount of from 1 to 30%, more preferably 1 to 20%, by weight of the composition. It is also preferred that the active ingredient is present in the composition in an amount of from 0.25 to 20 mg, more preferably 0.5 to 10 mg and, most preferably, 1.25 to 5 mg.

In the case of other MAO-B inhibitors these also will be present in concentrations which are clinically effective .

According to another aspect of the invention there is provided a method of treating Attention Deficit Hyperactivity Disorder and/or narcolepsy which comprises introducing into the oral cavity of a patient a therapuetically effective amount of a pharmaceutical composition as described above.

The invention is further illustrated by the following examples. Example 1

Preparation of a fast-dispersing dosage form of selegiline (a) Preparation of selegiline hydrochloride 2.0% dispersion

Gelatin (720g) and mannitol (540g) were dispersed in a portion of purified water (15.73kg) by mixing thoroughly in the bowl of a vacuum mixer. The remaining water (1.5 litres) was added under vacuum while mixing using an anchor stirrer. The mix was then heated to 40°C + 2°C and homogenised for ten minutes . The mix was cooled down to room temperature. When cooled, a 4500g portion of the mix was removed into a stainless steel vessel and glycine (360g) , aspartame (90g) , grapefruit flavour (54g) , Opatint yellow (54g) , citric acid (90g) and selegiline hydrochloride (360g) were then added sequentially to this portion while homogenising using a bench top homogeniser. The remainder of the mix was transferred into a second stainless steel vessel. The mix was homogenised for ten minutes using a bench top mixer to dissolve the drug. Once dispersion of the colouring agent was complete, the homogenised portion of the mix in the first vessel was returned to the mixer bowl together with the mix from the second vessel . The combined mixes were then mixed for at least 20 minutes. The bulk dispersion was then homogenised to ensure that mixing was complete.

(b) Preparation of selegiline hydrochloride 5 mg units

250mg of the selegiline hydrochloride 2.0% dispersion formed in (a) above was dosed into each one of a series of pre-formed blister pockets having a pocket diameter of 12 mm. The blister laminate comprised 200μm PVC/30μm PE/PVDC 90g per square metre. The product was frozen immediately in a liquid nitrogen freeze tunnel, The frozen product was then stored below - 20°C for a minimum of 24 hours prior to freeze-drying in a freeze drier using a drying temperature of + 20°C and a chamber pressure of 0.5 mbar. The freeze-dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20μm aluminium) . Each blister was then coded with a batch number and over- wrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely. Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.

Each unit dosage form had the following composition:

Ingredient Weight (mg) % bv wt of composition

Purified Water USP/EP* 218.500 87.4

Selegiline Hydrochloride 5.000 2.0

Gelatin EP/USNF 10.000 4.0

Mannitol BP/USP 7.500 3.0

Aspartame EP/USN 1.250 0.5

Grapefruit Flavour 502.106/A 0.750 0.3

Glycine USP 5.000 2.0

Citric Acid EP/USP 1.250 0.5

Opatint AD-22901 yellow 0.750 0.3

250.000 100.0

* Signifies removed during the lyophilisation process.

Example 2

Comparative pharmacokinetic study

The aim of this experiment was to compare the bioavailability of the selegiline hydrochloride formulation of Example 1 with the commercially available tablet formulation of selegiline hydrochloride sold under the registered Trade Mark "Movergan" by Asta Medica AG, Weismύllerstrasse 45, 6000 Frankfurt am Main, Germany.

An open label, randomised, 2 -way crossover, volunteer study was performed as follows. Twenty four subjects of either sex, aged between 45 and 71 years, giving written informed consent underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received study treatment in the order dictated by a pre-determined randomisation schedule. Subjects were given either the formulation of Example 1 or the "Movergan" formulation. Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration), then after 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 and 96 hours. The study procedures were repeated two weeks later, when subjects were crossed-over to receive their second drug administration. Selegiline hydrochloride was administered as single lOmg doses (made up from 2 x 5 mg tablets) of the formulation of Example 1 or of the "Movergan" formulation.

Assays were performed to determine the concentrations of selegiline, N-desmethylselegiline, methamphetamine and amphetamine in each of the blood plasma samples. The following pharmacokinetic parameters were determined for all four analysed substances: bioavailability (as measured as the area under the curve (AUC) of the drug concentrations/time plot) , Cmax (the maximum plasma concentration achieved and Tmax (the time- point at which Cmax was observed) .

The results are shown in graphical form in Figures 1 to 4 where each figure is a plot of the concentration of a specific compound in a blood plasma sample versus the time at which the sample was taken for the formulation of Example 1 (Example 1) and the tablet formulation sold under the registered Trade Mark "Movergan" (Movergan) . In Figure 1, the specific compound is selegiline. In Figure 2, the specific compound is N-desmethylselegiline. In Figure 3, the specific compound is methamphetamine. In Figure 4, the specific compound is amphetamine.

The results are shown in numerical form in Table 1 below. In this table, the references to N- desmethylselegiline, methamphetamine and amphetamine are to the L-(-)- isomers of these compounds. Table I

O) c

CD O)

H

C H m

(0 x m rπ

H c r m- t

From Figure 1 to 4 and Table 1, it is apparent that the bioavailability of selegiline from the formulation of Example 1 is more than eight times that of selegiline from the "Movergan" formulation despite the fact that both formulations contained the same amount of active ingredient. Also, the bioavailability of N- desmethylselegiline is very similar for both formulations. The bioavailabilities of methamphetamine and amphetamine are very similar for Example 1 and the "Movergan" formulation. However, in view of the much greater bioavailability of selegiline from the formulation of Example 1, it is envisaged that the dose of selegiline could be significantly reduced thereby significantly reducing the quantity of unwanted central nervous system and cardiac stimulant metabolites and undesired side-effects caused by them whilst still achieving the desired levels of selegiline in plasma and hence the desired therapeutic effect associated with monoamine oxidase B inhibition.

In Table 1, the ratio of the area under the plasma concentration-time curve (AUC) for selegiline and the AUC for N-desmethylselegiline was 0.0233 for the "Movergan" formulation, indicating clearly the extensive metabolism of selegiline when administered in an existing dosage form. The corresponding AUC ratio for Example 1 in Table 1 was 0.1894. This demonstrates that pre- gastric absorption of selegiline results in a greater proportion of the administered dose being absorbed in the unmetabolised form. It demonstrates further that the selegiline :N-desmethylselegiline AUC ratio can be used as another indicator of the degree of pre-gastric absorption in selegiline-containing compositions in accordance with this invention. It is generally preferred that the ratio of the selegiline AUC to the N-desmethylselegiline AUC should be greater than 0.05, more preferably greater than 0.075 and most preferably greater than 0.10. Example 3

Pre-gastric Absorption Study

The aim of this study was to assess the sublingual absorption of selegiline hydrochloride formulations produced according to Example 1. The pharmacokinetic profile of selegiline hydrochloride from the commercially available US tablet formulation sold under the registered trademark "Eldepryl" by Somerset Pharmaceuticals Inc. 777 South Harbour Island Boulevard, Suite 880, Tampa, Florida 33602, served as a control for the degree of gastro-intestinal absorption of selegiline. In addition, the study was designed to compare the urinary excretion over 24 hours of phenylethylamine and 5-hydroxyindoleacetic acid (5-HIAA) from the subjects to whom such formulations had been administered.

This study was an open-label randomised 3 -way crossover volunteer study and was performed as follows:

Eleven subjects of either sex aged between 45 and 62 years giving written informed consent underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received each of the following treatments in the order dictated by a predetermined randomisation schedule : -

1) 2 x 5mg Eldepryl tablets taken with 150ml water (Eldepryl (lOmg) )

2) 2 x 5mg selegiline tablets produced according to Example 1 kept in the mouth for 1 minute and then expectorated and the mouth rinsed with 3 x 25ml water and then expectorated (Example 1 (2.96mg))

3) 2 x 5mg selegiline tablets produced according to Example 1 kept in the mouth for 1 minute and then swallowed (Example 1 (lOmg) ) .

Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration) and then after 0.08, 0.16, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 12 hours . Urine samples were taken immediately before drug administration and during the periods 0-2 hours, 2-4 hours, 4-6 hours, 6-12 hours and 12-24 hours.

Assays were performed to determine the concentration of selegiline in each of the blood plasma and urine samples and the concentration of phenylethylamine and 5-hydroxyindoleacetic acid (5HIAA) was measured in each of the urine samples. Selegiline was also measured in saliva and mouth washings.

Phenylethylamine is the preferred substrate for monoamine oxidase B (MAO-B) and consequently its excretion has been shown to rise when MAO-B is inhibited. 5HIAA is a breakdown product formed by the action of MAO- A on 5-hydroxytryptamine (serotonin) . When MAO-A is inhibited, the 5HIAA level excreted has been shown to decline .

The results from the study are shown in graphical form in Figures 5, 6 and 7. When the tablets produced according to Example 1 were kept in the mouth for 1 minute and the saliva expectorated, an average concentration equivalent to 7.04mg selegiline hydrochloride was measured in the mouth washings . Thus an average of 2.96mg selegiline hydrochloride was absorbed pregastrically with this treatment. Subjects therefore received 2.96mg or lOmg of selegiline hydrochloride from the lOmg formulation produced according to claim 1 and lOmg selegiline from the Eldepryl formulation. Figure 5 is a plot of concentration of selegiline in a blood plasma sample versus the time at which the sample was taken for both expectorated and swallowed formulations produced according to Example 1 (Example 1 (equivalent to 2.96mg) and Example 1 (lOmg) respectively) and the lOmg tablet formulation sold under the registered Trade Mark "Eldepryl". Figure 6 shows the cumulative 5-hydroxyindoleacetic acid excretion in urine over 24 hours. Figure 7 shows the cumulative phenylethylamine excretion in urine over 24 hours.

From Figure 5, it is apparent that the bioavailability of selegiline from both the 2.96mg (expectorated) equivalent and lOmg (swallowed) doses produced according to Example 1 is much greater than that of selegiline from the "Eldepryl" formulation despite the fact that one formulation (Example 1 (lOmg "swallowed")) contained the same amount of active ingredient as the "Eldepryl" formulation and the expectorated treatment contained less than one third of the amount of active ingredient as the "Eldepryl" formulation. Moreover, it is apparent from Figure 7 that this enhanced bioavailability is associated with a dose-related increase in the urinary excretion of phenylethylamine. In addition, the higher rate of excretion of phenylethylamine in Figure 7 for Example 1 (lOmg "swallowed") and Example 1 (2.96mg "expectorated") than for the "Eldepryl" formulation indicates a faster rate of monoamine oxidase B inhibition than with the former compositions and consequently a possible earlier alleviation of symptoms of ADHD and narcolepsy than for the "Eldepryl" formulation.

Lack of inhibition of monoamine oxidase A by the Example 1 (lOmg "swallowed") and Example 1 (2.96mg "expectorated") treatments was confirmed by analysis of the urine samples for concentration of 5- hydroxyindoleacetic acid, which is the metabolite of 5- hydroxytryptamine (serotonin) which is a principal substrate for monoamine oxidase A (see Figure 6) . Urinary concentrations of 5-hydroxyindoleacetic acid were similar for the Example 1 (lOmg "swallowed"), Example 1 (2.96mg "expectorated") and the standard "Eldepryl" tablet formulations, showing that the selegiline formulations produced according to Example 1 did not cause greater MAO-A inhibition than standard tablets despite the much increased selegiline bioavailability. Once again, in view of the greater bioavailability of selegiline from the Example 1 (lOmg "swallowed") and Example 1 (2.96mg "expectorated") formulations, it is envisaged that the dose of selegiline could be significantly reduced thereby significantly reducing the quantity of undesired metabolites with their associated side effects whilst still achieving the desired therapeutic effects associated with inhibition of monoamine oxidase B .

Example 4

Comparative pharmacokinetic study

The aim of this experiment was to determine and compare the bioavailability of selegiline from a single tablet of the selegiline hydrochloride formulation of Example 1 with that from two tablets of the commercially available UK tablet formulation sold under the registered trade mark "Eldepryl" by Britannia Pharmaceuticals Ltd. of 41-75 Brighton Road, Redhill, Surrey RH1 6YS .

An open label randomised, 2 -way crossover, volunteer study was performed as follows . Twelve healthy volunteers of either sex, aged between 40 and 75 years, giving written informed consent underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received each study treatment in an order dictated by a pre-determined randomisation schedule. Subjects were given either one tablet of the formulation of Example 1 (5mg selegiline hydrochloride) or two tablets of the "Eldepryl" formulation (lOmg selegiline hydrochloride) after an overnight fast .

Blood samples for determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration) , and then after 5, 10, 15, 30, 45, 60 minutes and 1.5, 2, 3, 4, 6, 22 and 24 hours post-dose) . Urine samples were collected in 6 hourly aliquots for 24 hours prior to and 24 hours after each selegiline dose. The study procedures were repeated three weeks later, when subjects were crossed over to receive their second drug administration.

Assays were performed to determine the concentration of selegiline in each of the blood plasma samples and the concentration of phenylethylamine (PEA) in each of the urine samples .

The results are shown in graphical form in Figures 8 and 9 where Figure 8 is a plot of concentration of selegiline in a blood plasma sample versus the time at which the sample was taken for the formulation of Example 1 (Example 1) and the tablet formulation sold under the registered Trade Mark "Eldepryl" (Eldepryl) and Figure 9 shows the cumulative phenylethylamine excretion in urine over 24 hours prior to and after each selegiline dose.

From Figure 8, it is apparent that the bioavailabilty of selegiline from the 5mg dose produced according to Example 1 is much greater than that of selegiline from the lOmg dose of the "Eldepryl" formulation despite the fact that the dose of the formulation of Example 1 contained only half the amount of active ingredient of the dose of the "Eldepryl" formulation. Moreover, the maximum plasma concentration (Cmax) was greater for the formulation of Example 1, despite the quantity of active ingredient in this formulation being lower and the time to maximum plasma concentration (Tmax) was less for the formulation of Example 1 indicating a more rapid onset of effect.

In addition, it is apparent from Figure 9 that this enhanced bioavailability of selegiline is associated with an increase in the urinary excretion of phenylethylamine indicating a faster rate of monoamine oxidase B inhibition for the formulation of Example 1 than the "Eldepryl" formulation despite the quantity of active ingredient in the formulation of Example 1 being only half that administered in the form of the "Eldepryl" formulation.

These results therefore provide further evidence of the clinical effectiveness of lower doses of selegiline administered as the formulation of Example 1.

The following examples further exemplify formulations which can be prepared using the process described in Example 1 which will promote pre-gastric absorption of selegiline and other MAO-B inhibitors:

Example 5

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 221.625 88.65 Selegiline Hydrochloride 5.000 2.00 Gelatin EP/USNF 11.250 4.50 Mannitol EP/USP 8.125 3.25 Aspartame EP/USNF 1.250 0.50 Grapefruit Flavour 502.106/A 0.750 0.30 Citric Acid EP/USP 1.250 0.50 Opatint AD-22901 Yellow 0.750 0.30

Total 250.000 100.00

*Signifies removed during the lyophilisation process

Example 6

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 224.125 89.65 Selegiline Hydrochloride 5.000 2.00 Gelatin EP/USNF 9.375 3.75 Mannitol EP/USP 7.500 3.00 Grapefruit Flavour 502.106/A 0.750 0.30 Citric Acid EP/USP 1.250 0.50 Opatint AD-22901 Yellow 0.750 0.30 Acesulfame K 1.250 0.50

Total 250.000 100.00

*Signifies removed during the lyophilisation process

Example 7

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 219.500 87.80 Selegiline Hydrochloride 5.000 2.00 Gelatin EP/USNF 10.000 4.00 Mannitol EP/USP 7.500 3.00 Aspartame EP/USNF 1.000 0.40 Glycine USP 2.500 1.00 Citric Acid EP/USP 1.250 0.50 Opatint AD-22901 Yellow 0.750 0.30 Lemon Lime 59.15/AP 2.500 1.00

Total 250.000 100.00

*Signifies removed during the lyophilisation process Example 8

Ingredient Weight (mg) ? by wt of composition

Purified Water EP/USP* 223.625 89.45 Selegiline Hydrochloride 5.000 2.00 Gelatin EP/USNF 10.000 4.00 Mannitol EP/USP 7.500 3.00 Aspartame EP/USNF 0.750 0.30 Grapefruit Flavour 502.106/A 0.750 0.30 Citric Acid EP/USP 1.250 0.50 Opatint AD-22901 Yellow 0.750 0.30 Sodium Methyl Parabens EP/USNF 0.250 0.10 Sodium Propyl Parabens EP/USNF 0.125 0.05

Total 250.000 100.00

*Signifies removed during the lyophilisation process

Example 9

Ingredient Weight (mg) > by wt of composition

Purified Water EP/USP* 19.125 87.65

Selegiline Hydrochloride 5.000 2.00

Gelatin EP/USNF 10.625 4.25

Mannitol EP/USP 6.875 2.75

Aspartame EP/USNF 1.250 0.50

Glycine USP 5.000 2.00

Grapefruit Flavour 502.106/A 0.750 0.30

Citric Acid EP/USP 0.625 0.25

Opatint AD-22901 Yellow 0.750 0.30

Total 250.000 100.00

*Signifies removed during the lyophilisation process Example 10

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 216.750 86.7 Selegiline Hydrochloride 5.000 2.0 Gelatin EP/USNF 10.000 4.0 Mannitol EP/USP 7.500 3.0 Aspartame EP/USNF 1.250 0.5 Glycine USP 3.750 1.5 Citric Acid EP/USP 1.250 0.5 Opatint AD-22901 Yellow 0.750 0.3 Acesulfame K 1.250 0.5 Lemon Lime 59.15/AP 2.500 1.0

Total 250.000 100.00

*Signifies removed during the lyophilisation process

Example 11

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 215.875 86.35

Mofegiline 12.000 4.80

Gelatin EP/USNF 10.000 4.00

Mannitol EP/USP 8.125 3.25

Aspartame EP/USNF 1.250 0.50

Grapefuit Flavour 502.106/A 0.750 0.30

Glycine USP 1.250 0.50

Opatint AD-22901 Yellow 0.750 0.30

Total 250.000 100.00

*Signifies removed during the lyophilisation process Example 12

Ingredient Weight (mg) % by wt of composition

Purified Water EP/USP* 797.500 79.75 Lazabemide 100.000 10.00 Gelatin EP/USNF 45.000 4.50 Mannitol EP/USP 35.000 3.50 Lemon Lime 59.15/AP 5.000 0.50 Glycine USP 10.000 1.00 Aspartame EP/USNF 7.500 0.75

Total 1000.000 100.00

*Signifies removed during the lyophilisation process

Claims

1. Use of a pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a monoamine oxidase B inhibitor, characterised in that the composition is formulated to promote pre-gastric absorption of said monoamine oxidase B inhibitor, for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy.

2. Use of a pharmaceutical composition according to Claim 1, in which the composition is formulated to promote absorption of said monoamine oxidase B inhibitor through the buccal, sublingual, pharyngeal and/or oesophageal mucous membrane .

3. Use of a pharmaceutical composition according to Claim 1 or Claim 2, in which the composition is formulated so that at least 5%, preferably at least 10%, and most preferably at least 15% of said monoamine oxidase B inhibitor is absorbed in one minute in the buccal absorption test described hereinbefore.

4. Use of a pharmaceutical composition according to any one of the preceding claims in which the monoamine oxidase B inhibitor is selected from mofegiline, rasagiline, lazabemide, 2-BUMP, M-2-PP, MDL-72145, compounds of the general formula :

X

^Y (O_/ ^CH2 ΓÇö ^{CH~ N~ CH}2^{CΓëíΓëíCH ( I}

CH₃

in which X represents a hydrogen atom or a methyl group and Y represents a fluorine or hydrogen atom, and pharmaceutically acceptable salts of said monoamine oxidase B inhibitors.

5. Use of a pharmaceutical composition according to Claim 4, in which said monoamine oxidase B inhibitor is a compound of the general formula :

in which X and Y are as defined in Claim 4.

6. Use of a pharmaceutical composition according to Claim 5, in which X represents a methyl group and Y represents a hydrogen atom.

7. Use of a pharmaceutical composition according to Claim 5 or Claim 6, in which the active ingredient is present in an amount of from 1 to 30% by weight of the composition.

8. Use of a pharmaceutical composition according to any one of Claims 5-7, in which the active ingredient is present in an amount of from 0.25 to 30 mg.

9. Use of a pharmaceutical composition according to Claim 6 , or Claim 7 or Claim 8 when appendant to Claim 6 , in which the composition is formulated so that the ratio of the area under the plasma concentration-time curve for selegiline to that for N-desmethylselegiline is greater than 0.05, preferably greater than 0.075 and most preferably greater than 0.10.

10. Use of a pharmaceutical composition according to any one of the preceding claims in which the composition is in the form of a viscous emulsion, syrup or elixir, a sublingual tablet, a suckable or chewable tablet, softgel, lozenge, aqueous or non-aqueous drops or other dosage form designed to release the active ingredient in a controlled manner to saliva or to the buccal, pharyngeal and/or oesophageal mucous membranes, a fast- dispersing dosage form designed rapidly to release the active ingredient in the oral cavity, or a bioadherent system.

11. Use of a pharmaceutical composition according to Claim 10 in which the composition is in the form of a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.

12. Use of a pharmaceutical composition according to Claim 10, in which the composition disintegrates within 1 to 10 seconds of being placed in the oral cavity.

13. Use of a pharmaceutical composition for oral administration comprising a carrier, and selegiline as an active ingredient, characterised in that the composition is in the form of a solid fast-dispersing dosage form comprising a network of selegiline and a water-soluble or water-dispersible carrier which is inert towards selegiline, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising selegiline and a solution of the carrier in a solvent, for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy.

14. Use of a pharmaceutical composition for oral administration comprising selegiline in a solid fast- dispersing dosage form which disintegrates within 1 to 10 seconds of being placed in the oral cavity for the manufacture of a medicament for the treatment of Attention Deficit Hyperactivity Disorder and/or narcolepsy.

15. A method of treating Attention Deficit Hyperactivity Disorder and/or narcolepsy which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a pharmaceutical composition as de ined in any one of claims 1 to 14.