AU2012238330B1 - Fast Dissolving Solid Dosage Form - Google Patents

Abstract

There is provided a fast dissolving solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises at 5 least one biologically active material, and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. A method of producing the same and a kit comprising the same are also provided. NO SUITABLE FIGURE

Description

r-/u/u I laWWI I Regulation 3.2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT (Patent of Addition) Name of Applicant: iX Biopharma Pte Ltd Actual Inventors Chin Beng Stephen Lim Vivian Bruce Sunderland Yip Hang Eddy Lee Address for service is: WRAYS Ground Floor, 56 Ord Street West Perth WA 6005 Attorney code: WR Invention Title: Fast Dissolving Solid Dosage Form The following statement is a full description of this invention, including the best method of performing it known to me: 1/1 FAST DISSOLVING SOLID DOSAGE FORM FIELD OF THE INVENTION This invention relates to dosage forms adapted for administration to a subject. Preferably, the dosage forms have rapid dissolution rates. 5 BACKGROUND Tablets are a common dosage form to deliver an agent to human beings via oral administration. Drug delivery via the oral cavity mucosa, for example the sublingual mucosa, allows a rapidly dissolving drug to be absorbed by simple diffusion, directly into the systemic circulation via the jugular vein, bypassing the gastrointestinal tract 10 and the hepatic first-pass effect. The sublingual route usually produces a fast and reliable onset of action, and is more suitable for fast dissolving dosage forms of administration. There is an unmet need in the medical field for dosage forms, which have a rapid dissolution rate in the oral cavity. The previous attempts to overcome the problems 15 associated with solid dosages forms include effervescent tablets, films, chewable tablets, disintegrants and wicking agents. These dosage forms are particularly useful for patients who have difficulty in swallowing e.g. children and elderly people. There are several technologies used for preparing such dosage forms, including freeze drying, spray-drying, tablet molding and tablet compression. 20 Freeze drying processes have been used to prepare fast dissolving solid dosage forms. Depending on the manufacturing process, the product obtained is characterised by a highly porous microstructure of the supporting matrix (i.e. mannitol, glycine, lactose, gelatins etc.) in which the active agent is homogeneously dispersed. This technology produces a product which rapidly dissolves in water or in 25 the oral cavity; however, the poor physical integrity of its physical structure severely limits further manufacturing operations such as forming blister packs. Moreover, the freeze drying technology in manufacturing such dosage forms leads to the high production costs because of the lengthy duration of each freeze drying cycle (normally from 24 to 48 hours). The complexity of the industrial plants is another 30 important factor which prejudices the large scale use of this technology for the development of rapidly dissolving tablets. In addition, the thermal shocks, as a direct consequence of each freeze drying cycle, might physically modify the physical chemical properties of the outer membrane of microencapsulated particles. 1/2 In the freeze-drying processes, gelatin and other gelatin-related materials have been used to formulate agents in fast dissolving dosage forms. Gelatin is carrier or structure-forming agent, and it is commonly used in preparing fast dissolving forms for a wide range of drugs. Gelatin provides strength to the dosage form, thus 5 preventing cracking and break-up of the dosage form. This is especially a problem when the dosage form is being removed from the blister package. Gelatin is advantageous in fast dissolving drugs because once the dosage form is placed in the oral cavity it provides rapid dissolution of the dosage form. Gelatin is a protein which is obtained by the partial hydrolysis of animal collagenous 10 tissue, such as skins, tendons, ligaments and bone. However, one significant problem with mammalian-derived gelatin is that it has a bland taste. This results in the fast dissolving dosage form requiring the use of sweeteners and flavours to hide and mask the taste of the gelatin component. A further problem with conventional mammalian derived gelatin is that it requires the use of heat to affect the gelatin 15 solution. This additional step adds time and cost to the process of manufacture. An additional problem with the use of gelatin-based material as fast dissolving dosage form matrices is that the gelatin can increase in the viscosity of the solution with time. This can lead to processing difficulties. Moreover, the gelatin can lead to homogeneity and sedimentation problems associated with the gelatin solution during 20 the holding period. Other disadvantages of gelatin formulations include being prone to bacterial growth and some individuals dislike the fact it is from animal origin. Other agents which have been used to replace gelatin in fast dissolving dosage forms are starch and modified starches. One problem with starch is that it has a particulate feel for the patient when in the mouth and can lead to dissatisfaction for 25 the patient. Many modified starches also result in this problem. Furthermore, they are expensive. Ketamine is a rapid-acting, general anaesthetic approved only for intravenous injection. In recent years there has been increasing interest in its use at non anaesthetic doses as an adjunct in acute and chronic pain management. Its pain 30 modifying properties are attributed to its antagonism at the N-methyl-D-aspartate (NMDA) receptor, binding non-competitively to the phencyclidine binding site. When administered at sub-anaesthesia levels, ketamine is effective at producing analgesia and also demonstrates opioid sparing activity, although the mechanisms behind this remain poorly understood. Ketamine's analgesic efficacy correlates well with its 35 inhibiting action on N-methyl-D-aspartate receptor-mediated pain facilitation and a J decrease in activity of brain structures that respond to noxious stimuli. Therefore its utility in the management of acute pain is of interest. The racemic formulation of ketamine is a mixture of two enantiomers R-(-) and S-(+). Ketamine undergoes extensive hepatic metabolism in humans and is mediated by 5 various isoforms of cytochrome P450 to its major metabolite, norketamine, which also has antagonist properties. Although parenteral administration of ketamine might provide almost instant pain relief, this route may not be suitable or convenient for the patient. There is a need in the art for a fast dissolving dosage form which delivers an N 10 methyl-D-aspartate receptor antagonist to a patient via oral administration, wherein the dosage form rapidly dissolves in the oral cavity of the patient, and wherein the dosage form does not use substantial amounts of mammalian gelatin or starch or modified starch material. It is an object of the invention to overcome some or all of the deficiencies in the prior art. 15 SUMMARY OF THE INVENTION In a first aspect, the invention is a dosage form adapted for the release of an N methyl-D-aspartate receptor antagonist in the oral cavity of a patient comprising at least one matrix forming agent. Preferably, the invention is a fast dissolving dosage form adapted for the release of 20 an N-methyl-D-aspartate receptor antagonist in the oral cavity of a patient comprising at least one matrix forming agent. Preferably, the said dosage form is adapted to substantially dissolve in the oral cavity. More preferably, the said dosage form is adapted to not leave a residue of said dosage form in the oral cavity that is detectable by the patient. 25 Preferably, the dosage form is solid and not a liquid. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the group consisting of dextromethorphan, dextrorphan or ketamine. In one embodiment, the N-methyl-D-aspartate receptor antagonist is ketamine, which has a IUPAC name of RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone. 30 In one embodiment, the N-methyl-D-aspartate receptor antagonist is a pharmaceutically acceptable salt of compounds selected from the group consisting of dextromethorphan, dextrorphan or ketamine.

Preferably, the N-methyl-D-aspartate receptor antagonist is ketamine hydrochloride. In one embodiment, the ketamine is in the form of a racemic mixture of the R and S enantiomers. Preferably, the ketamine is a mixture of two enantiomers R-(-) and S (+. 5 In one embodiment, the N-methyl-D-aspartate receptor antagonist is present in an amount by dry weight of the composition of the dosage form selected from the group consisting of; 0.01 to 95%; 0.1 to 75% and 1 to 45%. Preferably, the dosage form is a form selected from the group consisting of: a wafer; tablet; capsule; pill; powder; pellet; granule; and film. 10 Preferably, the dosage form is a pharmaceutical. In one embodiment, the least one matrix forming agent is selected from the group consisting of: non-mammalian gelatin, dextrin, soy protein, wheat protein, psyllium seed protein, acacia gum, guar gum, agar gum, xanthin gum, polysaccharides; alginates; sodium carboxymethylcellulose; carrageenans; dextrans; pectins; sugars; 15 amino acids; starch; modified starches; carboxymethylcellulose; hydroxypropylmethylcellulose; hydroxypropyl cellulose and methyl cellulose inorganic salts; synthetic polymers; amylopectin; polypeptide/protein; and poly-saccharide complexes. Preferably, the carbohydrate is selected from the group consisting of: mannitol; 20 dextrose; lactose; galactose; trehalose; and cyclodextrin. Preferably, the inorganic salt is selected from the group consisting of: sodium phosphate; sodium chloride; and aluminium silicates. Preferably, the amino acid is selected from the group consisting of: glycine; L alanine; L-aspartic acid; L-glutamic acid; L-hydroxyproline; L-isoleucine; L-leucine; 25 and L-phenylalanine. In one preferred embodiment, the at least one matrix forming agent comprises sodium carboxymethylcellulose. Preferably, the sodium carboxymethylcellulose is present in an amount by dry weight of the composition of the dosage form selected from the group consisting of: 0.05% to 19%; 0.1% to 15%; and 0.1% to 10%. 30 In another preferred embodiment, the at least one matrix forming agent is amylopectin. Preferably, amylopectin is present in an amount by dry weight of the composition of the dosage form selected from the group consisting of: 2% to 17%; and 2% to 15%. In another preferred embodiment, the at least one matrix forming agent comprises microcrystalline cellulose. Preferably, the microcrystalline cellulose is present in an 5 amount by dry weight of the composition of the dosage form selected from the group consisting of: about 1% to about 10%, and preferably from about 1% to about 5% by dry weight of the dosage form. Preferably, the microcrystalline cellulose may act as a filler and binder in the dosage form of the present invention. Microcrystalline cellulose has the ability to compact with minimum compression pressures, and 10 results in a hard, stable and fast dissolving dosage form. Due to its large surface area and high internal porosity, microcrystalline cellulose is able to absorb and retain large amounts of water, which is desirable in the dosage form of the invention. In another preferred embodiment, the dosage form does not comprise gelatin. In another preferred embodiment, the at least one matrix forming agent comprises 15 glycine. Preferably, the glycine is present in an amount from 0.5 to 5 weight % by dry weight of the composition of the dosage form. Glycine is an amino acid with excellent wetting properties and is suitable for the fast dissolving formulation. Low amounts of glycine may be used in the formulation of the present invention to control the dissolution rate of the dosage form. Furthermore, glycine may also be used as an 20 anti-collapsing agent, which maintains the dosage form from shrinking either during the manufacture process or after packing. In another preferred embodiment, the at least one matrix forming agent comprises mannitol. Preferably, mannitol is present in an amount by dry weight of the composition of the dosage form selected from the group consisting of: from about 5% 25 to about 80%, and preferably from about 10% to about 50% by dry weight of the dosage form. Mannitol aids in the crystalline structure and can impart hardness of the dosage form. In another preferred embodiment, the dosage form comprises at least one diluent. Preferably, the diluent is selected from the group consisting of: microcrystalline 30 cellulose (such as Avicel PH 101* and Avicel PH 102*); lactose; starch; and sorbitol. In one embodiment, the diluent is present in an amount of about 1% to about 80%, preferably about 2% to about 50%, either individually or cumulatively. In another preferred embodiment, the dosage form comprises at least one lubricant. Preferably, the at least one lubricant is selected from the group consisting of: 0 polyethylene glycol (PEG) 1000; polyethylene glycol (PEG) 2000; polyethylene glycol (PEG) 4000; polyethylene glycol (PEG) 6000; sodium lauryl sulphate; fats; and oils. These lubricants may be present in the dosage form either alone or as a mixture in different ratios, and may be between 0.05% to 5%, preferable between 0.1% and 2%, 5 preferable about 1.5%, either individually or cumulatively. In one embodiment, the composition includes between 0.05% to 5% PEG 2000, preferably between 0.1% and 2% PEG 2000, most preferably about 1.5% PEG 2000 by dry weight of the dosage form, or as mixtures of the various glycols. In another preferred embodiment, the dosage form comprises at least one buffer 10 reagent. Preferably, the at least one buffer reagent comprises sodium carbonate. Preferably, the solid buffer reagent provides a saliva pH of 7.0 to 7.8 when dissolved in oral cavity. Increasing the pH of the solution of ketamine can increase the ratio of unionized to ionized, which will lead to enhanced transmucosal absorption. The solid buffer reagent includes sodium dihydrogen phosphate dehydrate, sodium hydrogen 15 phosphate, sodium hydrogen carbonate and sodium carbonate, which may be present in the dosage form either alone or as a mixture in different ratios in a concentration of about 0.01% to about 10% by weight of the composition. Preferably, the buffer reagent is sodium carbonate, which may be present in a concentration of about 0.01% to about 10% by weight of the composition, more preferably between 0.1% 20 to 1%, most preferably about 0.5%. In one embodiment, sodium carbonate is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form. In another preferred embodiment, the dosage form comprises at least one absorption enhancer. Preferably, the at least one absorption enhancer comprises #-cyclodextrin. 25 The p-cyclodextrin or derivative may be present in a concentration of from about 0.01% to about 10% by dry weight of the dosage form, more preferably between 0.2% to 2%, and most preferably about 1%. In another preferred embodiment, the dosage form comprises at least one flocculating agent. Preferably, the at least one flocculating agent comprises xanthan 30 gum. The xanthan gum may be present in a concentration of about 0.01% to about 10% by dry weight of the composition, preferably from about 0.2% to 2%, and most preferably about 1%. In another preferred embodiment, the dosage form comprises at least one surfactant. Suitable surfactants include anionic detergents such as sodium lauryl sulfate, dioctyl ( sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents may be used and include benzalkonium chloride or benzethomium chloride. The list of possible non ionic detergents includes lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 5 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants may be present in the dosage form either alone or as a mixture in different ratios. Additives which potentially enhance uptake of the compounds are fatty acids such as oleic acid, linoleic acid and linolenic acid. 10 In another preferred embodiment, the dosage form comprises at least one additive. In another preferred embodiment, the dosage form comprises at least one colouring agent. Preferably, the at least one colouring agent is selected from the group consisting of FD & C dyes Blue No.2 and Red No. 40, and mixture therein. In another preferred embodiment, the dosage form comprises at least one flavoring 15 agent. Preferably, the at least one flavoring agent is selected from the group consisting of orange, mint, raspberry, caramel, aspartame, saccharin, and mixture therein. In another preferred embodiment, the dosage form substantially dissolves once placed in the oral cavity in a time period selected from the group consisting of: less 20 than 2 minutes; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds. Preferably, the fast dissolving dosage form's dissolution rate is higher than the dissolution rates of conventional dosage forms. 25 Preferably, the dosage form completely dissolves after sublingual administration to the patient thereby avoiding the urge for the patient to swallow the dosage form. In another preferred embodiment, the dosage form comprises at least one pharmaceutically acceptable carrier. The medicaments of the present invention may include one or more pharmaceutically acceptable carriers. The use of such media 30 and agents for the manufacture of medicaments is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable material, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated.

0 Pharmaceutical acceptable carriers according to the invention may include one or more of the following examples: (1) surfactants and polymers, including, however not limited to polyethylene glycol (PEG), polyvinylpyrrolidone, polyvinylalcohol, crospovidone, 5 polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl 10 acetate; and/or (2) binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and/or (3) filling agents such as lactose monohydrate, lactose anhydrous, mannitol, microcrystalline cellulose and various starches; and/or 15 (4) lubricating agents such as agents that act on the flowability of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and/or (5) sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and accsulfame K; and/or 20 (6) flavouring agents; and/or (7) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quarternary compounds such as benzalkonium chloride; 25 antioxidants such as ascorbic acid, potassium sorbate, sodium bisulfate sodium metabisulfite and sorbic acid; and/or (8) buffers; and/or (9) diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, 30 and/or mixtures of any of the foregoing; and/or (10) wetting agents such as corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crosspovidone, sodium starch glycolate, and mixtures thereof; and/or (11) disintegrants; and/or 5 (12) effervescent agents such as effervescent couples such as an organic acid (e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts), or a carbonate (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L lysine carbonate, and arginine carbonate) or bicarbonate (e.g. sodium 10 bicarbonate or potassium bicarbonate); and/or (13) other pharmaceutically acceptable excipients. The actual dosage strengths of the N-methyl-D-aspartate receptor antagonist in the medicament of the invention may be varied in accordance the nature of the antagonist, as well as the potential increased efficacy due to the advantages of 15 providing and administering the antagonist. Thus, as used, herein "therapeutically effective amount" will refer to an amount of antagonist required to effect a therapeutic response in a patient. Amounts effective for such a use will depend on: the desired therapeutic effect; the potency of the antagonist; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of 20 health of the patient; and the judgment of the prescribing physician. In another embodiment, the N-methyl-D-aspartate receptor antagonist may be combined into a medicament with another biologically active material. In one embodiment, a medicament may be achieved which provides for different release characteristics - early release from ketamine, and later release from a larger average 25 size ketamine. In another embodiment, medicaments of the invention can be orally administered to a patient. Preferably, the medicaments are administered sub-lingually. The pharmaceutical composition may be formulated as wafers, capsules, tablets, pills, powders, pellets, films and granules for oral administration. Further, incorporating 30 any of the normally employed excipients, such as those previously listed, and generally 0.1% to 95% of an N-methyl-D-aspartate receptor antagonist (preferably ketamine), and more preferably at a concentration of 0.1% to 75% will form a pharmaceutically acceptable non-toxic oral administration.

'u In one embodiment of the present invention, the method may require that the pH of the mixture is adjusted to a pH within the range of between 4.0 and 8.0, preferably between 6.4 and 7.8. If required, the pH may be adjusted by using an acid, such as hydrochloric acid, phosphoric acid or citric acid; or a basic compound such as sodium 5 hydroxide, sodium dihydrogen phosphate dehydrate, sodium hydrogen phosphate, sodium hydrogen carbonate and sodium carbonate. In another embodiment, the method may include the step of using a solvent, such as water. If water is used as a solvent, it is preferable to be removed by freeze drying. The pharmaceutical composition in the present invention can also be formulated to 10 additionally contain conventional additives or supplementary ingredients in the usual amounts of such materials. The composition can be in the form of a solid, a liposome, or other ordered structures suitable to high drug concentration adapted for oral delivery. The composition may, in one embodiment, be formulated to be substantially free of 15 preservatives, physiological or mucosal absorption enhancers, or propellants. The composition may, in an alternative embodiment, be formulated to contain preservatives, physiological or mucosal absorption enhancers, or propellants. In another embodiment, the dosage form comprises: (a) 0.01 to 95 (dry) weight % of an N-methyl-D-aspartate receptor antagonist 20 (such as ketamine); (b) between 2 to 17% (dry) weight % of amylopectin; (c) between 0.01 to 50) (dry)weight % of at least one matrix forming agent; (d) between 0.01 to 40 (dry) weight % of a filling agent; (e) between 0.01 to 10 (dry) weight % of an amino acid; and 25 (f) between 0.01 to 20 (dry) weight % of a glycol/surfactant (g) between 0.01 to 60 (dry) weight % carbohydrate; (h) between 0.1 to 1 (dry) weight % of a solid buffer reagent. In a highly preferred embodiment, the present invention provides a rapidly dissolving solid dosage form adapted for the release of an N-methyl-D-aspartate receptor 30 antagonists in the oral cavity wherein the dosage form comprises: (i) at least one N methyl-D-aspartate receptor antagonist, preferably ketamine and (ii) at least one I 'I matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, wherein the dosage form comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylcellulose, 1.25% PEG 2000, 2.49% glycine, 2.49% microcrystalline cellulose; 12.49% amylopectin, 24.98% lactose and 37.46% mannitol as a dry weight 5 of the solid dosage form, and which does not result in substantial detectable levels of residue left over in the oral cavity of the patient. Applicant also found that PEG 2000 could be replaced with PEG 1000 with the same advantages as the oral dosage form described above. The patient receiving the fast dissolving dosage form of the present invention may be 10 an animal or human being. When the patient is a human being, it may be an adult or a child, including elderly adults and infants. In particular the patient is a patient that is unable to or has difficulties in swallowing. In another embodiment, the dosage form comprises a quantity of an N-methyl-D aspartate receptor antagonist selected from the group consisting of: 5mg; 10mg; 15 15mg; 20mg; 25mg; 50mg; and 100mg. In another embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 20 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In another embodiment, the dosage form has a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. 25 In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 30 3 minutes; within 2 minutes; and within 1 minute. Preferably, the dosage form provides a median bioavailability of an N-methyl-D aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an 1z N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In an alternative embodiment, the dosage form provides a bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group 5 consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. Preferably, the dosage form provides a median half life of an N-methyl-D-aspartate 10 receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In another embodiment, the dosage form provides an effective plasma concentration of an N-methyl-D-aspartate receptor antagonist in a patient which is reached within a 15 period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In another embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 20 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In another embodiment, the dosage form provides reduced burning, irritation and/or discomfort compared to convention dosage forms. In another embodiment, the dosage form is adapted for delivery via the oral cavity 25 mucosa and into the systemic blood circulation system. In another embodiment, the dosage form is adapted to be delivered directly into the systemic circulation via the jugular vein, bypassing the gastrointestinal tract and the hepatic first-pass effect. In a second aspect, the invention is a pharmaceutical composition comprising the 30 dosage form of the invention. In a third aspect, the invention is a method of producing the dosage form of the invention, comprising the steps of: (i) combining at least one matrix forming agent with an N-methyl-D aspartate receptor antagonist to form a homogeneous mixture; and (ii) freeze drying the mixture to form the solid dosage form. Preferably, the method comprises measuring the mixture in a preformed plastic or 5 aluminium blister mould. Preferably, the freeze drying technique is used to remove the solvent from the blister mould. In one embodiment, the method comprises sealing the solid dosage form with a plastic or aluminium foil to prevent moisture absorption. In a further embodiment, the method comprises adding a pH adjuster to maintain the 10 pH of the mixture within the range of between 3.0 and 8.0. In a further embodiment, the method comprises adding a solvent. In a fourth aspect, the invention is a kit comprising a fast dissolving solid dosage form of the invention and instructions for its use. Therapeutic uses of the medicaments of the invention include pain relief, epileptic 15 seizure relief, migraine, antidepressants, and other disorders that require ketamine to be administered with a high bioavailability. One of the main areas when rapid absorption and higher bioavailability of an N-methyl-D-aspartate receptor antagonist (especially ketamine) is required is in the relief of pain. In a fifth aspect, the invention is a method of treating pain, comprising the steps of 20 administering to a patient in need thereof a dosage form of the invention. Preferably, the method comprises administering to the patient a dosage form of the invention, wherein the dosage form is administered sublingually. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from 25 the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/m; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 30 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes.

14 In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 5 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute. In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. 10 In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. 15 In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% 20 wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. 25 In a sixth aspect, the invention is a method of induction of anaesthesia, comprising the steps of administering to a patient in need thereof a dosage form of the invention. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 30 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from 5 the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute. In a further embodiment, the effective plasma concentration of an N-methyl-D 10 aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 15 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; 20 between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: 25 between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In a seventh aspect, the invention is a method of treating depression, comprising the steps of administering to a patient in need thereof a dosage form of the invention. In one embodiment, the dosage form provides the patient with a peak plasma 30 concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/m; 180ng/ml; 190ng/ml; and 200ng/ml.

In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. 5 In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 10 3 minutes; within 2 minutes; and within 1 minute. In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective 15 therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N 20 methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. 25 In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In an eighth aspect, the invention is a method of treating addiction, comprising the 30 steps of administering to a patient in need thereof a dosage form of the invention. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; I f 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 5 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; 10 within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute. In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the 15 group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 20 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median 25 bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 30 hours; and 3.4 hours. In a ninth aspect, the invention is a method of treating an epileptic seizure, comprising the steps of administering to a patient in need thereof a dosage form of the invention. In one embodiment the epileptic seizure is caused by epilepsy. In a further embodiment, the epilepsy is selected from the group consisting of: benign 10 Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (pyknolepsy), hot water epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's 5 syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease, and photosensitive epilepsy. In a further embodiment, the epileptic seizure is selected from the group consisting of: nonconvulsive status epilepticus and convulsive status epilepticus. 10 In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 11Ong/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. 15 In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable 20 plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute. 25 In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a 30 period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group 10 consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. 5 In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In a tenth aspect, the invention is the use of a dosage form of the invention in the 10 manufacture of a medicament for the treatment of pain. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cma) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 15 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tm" selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. 20 In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a 25 period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from 30 the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute.

LU In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median 5 bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 10 hours; and 3.4 hours. In an eleventh aspect, the invention is the use of a dosage form of the invention in the manufacture of a medicament for induction of anesthesia. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from 15 the group consisting of: 25ng/ml; 30ng/ml; 4Ong/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 20 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; 25 within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute. In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the 30 group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group 5 consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl 10 D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In an twelfth aspect, the invention is the use of a dosage form of the invention in the manufacture of a medicament for the treatment of addiction. 15 In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. 20 In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable 25 plasma concentration of an N-methyl-D-aspartate receptor antagonist within 2 minutes In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. 30 In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours. In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group 5 consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably the dosage form has an in vivo median bioavailability of 28% for a 25mg ketamine dose administered to a human patient. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: 10 between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours. In a thirteenth aspect, the invention is the use of a dosage form of the invention in the manufacture of a medicament for the treatment of depression. In one embodiment, the dosage form provides the patient with a peak plasma 15 concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 25ng/ml; 30ng/ml; 4Ong/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax 20 selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist within 2 25 minutes In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective 30 therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours.

1-5 In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median 5 bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 10 hours; and 3.4 hours. In a fourteenth aspect, the invention is the use of a dosage form of the invention in the manufacture of a medicament for the treatment of an epileptic seizure. In one embodiment, the dosage form provides the patient with a peak plasma concentration (Cmax) of an N-methyl-D-aspartate receptor antagonist selected from 15 the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml. In a further embodiment, the dosage form provides the patient with a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 20 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. In a highly preferred embodiment, the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist within 2 minutes 25 In a further embodiment, the effective plasma concentration of an N-methyl-D aspartate receptor antagonist in a patient is reached within a period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes. In a further embodiment, the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a 30 period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours.

In a further embodiment, the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%. Preferably, the dosage form provides a median 5 bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient of 28% wherein the dose of the antagonist is 25mg. In a further embodiment, the dosage form provides a median half life of an N-methyl D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 10 hours; and 3.4 hours. Medicaments of the invention suitable for use in animals and in particular in human beings typically must be sterile and stable under the conditions of manufacture and storage. The medicaments of the invention comprising ketamine can be formulated as a solid, a liposome, or other ordered structures suitable to high drug concentration 15 adapted for oral delivery. Actual dosage strengths of the biologically active material in the medicament of the invention may be varied in accordance with the nature of the biologically active material, as well as the potential increased efficacy due to the advantages of providing and administering the biologically active material. Thus as used herein 20 "therapeutically effective amount" will refer to an amount of biologically active material required to effect a therapeutic response in a subject. Amounts effective for such a use will depend on: the desired therapeutic effect; the potency of the biologically active material; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; 25 and the judgment of the prescribing physician. The present invention will now be described with reference to the following non limiting Examples. The description of the Examples is in no way limiting on the preceding paragraphs of this specification, however is provided for exemplification of the methods and compositions of the invention. 30 BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 Scanning electron micrographs of the surface of wafers from batch numbers 071501 B and 071502B. FIGURE 2 Scanning electron micrographs of the surface of wafers from batch numbers 0820A and 0820B.

FIGURE 3 Scanning electron micrograph of the surface of wafer from batch number 0905MD. FIGURE 4 Scanning electron micrographs of the cross section of wafers from batch numbers 0715016 and 071502B. 5 FIGURE 5 Scanning electron micrographs of the cross section of wafers from batch numbers 0820A and 0820B. FIGURE 6 Scanning electron micrograph of the cross section of wafer from batch number 0905MD. FIGURE 7 Powder X-ray diffraction spectra of wafers from batch number 10 071501A and 071502B. FIGURE 8 Powder X-ray diffraction spectra of wafers from batch numbers 0820A and 0820B. FIGURE 9 Powder X-ray diffraction spectrum of wafer from batch number 0905MD. 15 FIGURE 10 [A] Typical HPLC chromatograms of standard midazolam sample at 4.05 pg/mL (n=3); [B] Midazolam powder dissolution samples at 1 minute and 5 minutes; [C] Midazolam powder dissolution sample at 10 minutes; [D] Midazolam powder dissolution sample 15 minutes; and [E] standard midazolam sample at 8.1 pg/ml. 20 FIGURE 11 Typical HPLC chromatograms of dissolution wafer Sample S1 at 45 seconds and 1 minute. FIGURE 12 Typical HPLC chromatogram of dissolution wafer Sample S1 at 10 minutes. FIGURE 13 Typical HPLC chromatograms of dissolution wafer Sample S2 at 5 and 25 10 minutes. FIGURE 14 Typical HPLC chromatograms of dissolution wafer Sample S2 at 30 seconds and 2 minutes. FIGURE 15 Typical HPLC chromatograms of dissolution wafer Sample S3 at 20 seconds and at 1 minute. 30 FIGURE 16 Typical HPLC chromatograms of standard midazolam sample at 1.01 pg/mL.

FIGURE 17 Typical HPLC chromatograms of Midazolam powder dissolution sample at 30 seconds. FIGURE 18 Typical HPLC chromatograms of dissolution wafer 1 at 1 minute and 5 minutes. 5 FIGURE 19 Typical HPLC chromatograms of dissolution wafer 1 at 5, 10 and 15 minutes. FIGURE 20 Typical HPLC chromatogram of drug loading test wafer sample No.1. FIGURE 21 Typical HPLC chromatograms of dissolution wafer 2 at 30 seconds. FIGURE 22 Typical HPLC chromatograms of dissolution wafer 2 at 1 minute and 5 10 minutes. FIGURE 23 Typical HPLC chromatograms of dissolution wafer 2 at 10, 15 and 30 minutes. FIGURE 24 Typical HPLC chromatograms of drug loading test wafer sample No. 2. FIGURE 25 Typical HPLC chromatograms of dissolution wafer 3 at 30 seconds. 15 FIGURE 26 Typical HPLC chromatograms of dissolution wafer 3 at 1 minute and 5 minutes. FIGURE 27 Typical HPLC chromatograms of dissolution wafer 3 at 10 and 15 minutes. FIGURE 28 Typical HPLC chromatograms of dissolution wafer 3 at 30, 45 and 60 20 minutes. FIGURE 29 Typical HPLC chromatograms of drug loading test wafer sample No. 3. FIGURE 30 Standard HPLC calibration curve of midazolam (1 to 32.4 pg/mL). FIGURE 31 Cumulative concentration of midazolam released from wafer and midazolam powder in phosphate buffer solution (pH 6.8) at 37 0 C. 25 FIGURE 32 Standard HPLC calibration curve of fentanyl (0.5 to 10 ig/mL). FIGURE 33 Dissolution profiles of fentanyl wafer in phosphate buffer solution (pH 6.8) at 37*C, (n=4). FIGURE 34 A to E Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at sampling times of 0.5, 1, 5, 10, 15 and 20 minutes.

L FIGURE 35 A to J Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at sampling times of 1, 2, 3, 4, 5, 7 and 10 minutes. FIGURE 36 Scanning electron micrographs of the surface of a blank fast dissolving dosage form. 5 FIGURE 37 Scanning electron micrographs of the surface of ketamine fast dissolving dosage form. FIGURE 38 Powder X-ray diffraction spectra of a blank fast dissolving dosage form. FIGURE 39 Powder X-ray diffraction spectra of ketamine powder. 10 FIGURE 40 Powder X-ray diffraction spectrum of ketamine fast dissolving dosage form. FIGURE 41 Typical HPLC chromatograms of dissolution ketamine wafer Sample S2 at 1 minute. FIGURE 42 Typical HPLC chromatogram of dissolution ketamine wafer Sample S2 15 at 3 minutes. FIGURE 43 Typical HPLC chromatograms of dissolution ketamine wafer Sample S2 at 5 minutes. FIGURE 44 Typical HPLC chromatograms of dissolution ketamine wafer Sample S2 at 7 minutes. 20 FIGURE 45 Typical HPLC chromatograms of dissolution ketamine wafer Sample S2 at 10 minutes. FIGURE 46 Typical HPLC chromatograms of dissolution ketamine wafer Sample S2 at 15 minutes. FIGURE 47 Typical HPLC chromatograms of dissolution ketamine wafer Sample 25 S2 at 20 minutes. FIGURE 48 Typical HPLC chromatograms of dissolution ketamine wafer Samples S2 at 30 minutes. FIGURE 49 Standard HPLC calibration curve of ketamine hydrochloride (5 to 100ptg/mL).

zo FIGURE 50 Typical HPLC chromatogram of drug loading test ketamine wafter sample No.1. FIGURE 51 Dissolution profiles of ketamine wafer in phosphate buffer solution (pH 6.8) at 37*C, (n=3). 5 FIGURE 52 Geometric mean with overlay of individual RS ketamine plasma concentrations for the entire sampling period, following a 10 mg dose given during a 30 minute intravenous infusion to eight healthy volunteers. FIGURE 53 Geometric mean with overlay of individual RS ketamine plasma 10 concentrations during the first 12 hours following a 10 mg dose given during a 30 minute intravenous infusion to eight healthy volunteers. FIGURE 54 Geometric mean with an overlay of individual RS ketamine plasma concentrations for the entire sampling period, following a 25 mg sublingual dose to eight healthy volunteers. 15 FIGURE 55 Geometric mean with overlay of individual RS ketamine plasma concentrations during the first 12 hours following a 25 mg sublingual dose to eight healthy volunteers. FIGURE 56 Individual (S=Subject randomization number) tma for RS ketamine following 25 mg sublingual dose to eight healthy volunteers. 20 FIGURE 57 Individual (S=Subject randomization number) AUCINF for RS ketamine following a 10 mg dose given during a 30 minute intravenous infusion (IV, open bars) or 25 mg sublingually (SL, filled bars) to eight healthy volunteers. FIGURE 58 Individual (Subject randomization number) clearance (CL) for RS 25 ketamine following a 10 mg dose given during a 30 minute intravenous infusion to eight healthy volunteers. FIGURE 59 Individual (S=Subject randomization number) terminal half life t 1

/

2 for RS ketamine following a 10 mg dose given during a 30 minutes intravenous infusion (IV, open circles) or 25 mg sublingually (SL, filled 30 circles) to eight healthy volunteers.

FIGURE 60 Individual estimates for all subjects (S=subject number) of bioavailability (F) % following administration of 25 mg RS ketamine to eight healthy volunteers. FIGURE 61 Mood rating scale profile for IV administration. The mean (SD) scores 5 for Factors "alertness" (Factor 1), "contentedness" (Factor 2) and "calmness" (Factor 3) observed following a 30 minute intravenous infusion of 10 mg ketamine to healthy volunteers. FIGURE 62 Mood rating scale profile for sublingual administration. The mean (SD) scores for Factors "alertness" (Factor 1), "contentedness" (Factor 2) 10 and "calmness" (Factor 3) observed following sublingual administration of a 25 mg ketamine wafer to healthy volunteers. FIGURE 63 Total modified Likert Scales of Local Tolerability DETAILED DESCRIPTION OF THE INVENTION General 15 Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively and any and all 20 combinations or any two or more of the steps or features. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein. 25 The invention described herein may include one or more ranges of values (e.g. size, concentration etc). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range. 30 The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. Inclusion does not constitute an admission is OU made that any of the references constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates. Throughout this specification, unless the context requires otherwise, the word "comprise" or variations, such as "comprises" or "comprising" will be understood to 5 imply the inclusion of a stated integer, or group of integers, however not the exclusion of any other integers or group of integers. It is also noted that in this disclosure, and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in US Patent law; e.g., they can mean "includes", "included", "including", and the 10 like. "Therapeutically effective amount" as used herein with respect to methods of treatment and in particular drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that "therapeutically 15 effective amount," administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a "therapeutically effective amount" by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood. 20 The term "inhibit" is defined to include its generally accepted meaning which includes prohibiting, preventing, restraining, and lowering, stopping, or reversing progression or severity, and such action on a resultant symptom. As such the present invention includes both medical therapeutic and prophylactic administration, as appropriate. The term "biologically active material" is defined to mean a biologically active 25 compound or a substance which comprises a biologically active compound. In this definition, a compound is generally taken to mean a distinct chemical entity where a chemical formula or formulas can be used to describe the substance. Such compounds would generally, however not necessarily be identified in the literature by a unique classification system such as a CAS number. Some compounds may have 30 a more complex and have a mixed chemical structure. For such compounds they may only have an empirical formula or be qualitatively identified. A compound would generally be a pure material, although it would be expected that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities and the like. Examples of biologically active compounds are, however not limited to, 35 fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, 1l complementary medicines, natural products, vitamins, nutrients, neutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, additives, foods and food ingredients and analogs, homologs and first order derivatives thereof. A substance that contains a biological active compound is 5 any substance which has as one of its components a biological active compound. Examples of substances containing biologically active compounds are, however not limited to, pharmaceutical formulations and products, cosmetic formulations and products, industrial formulations and products, agricultural formulations and products, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, 10 minerals, animal products, shells and other skeletal material. Any of the terms, "biological(ly) active", "active", "active material" shall have the same meaning as biologically active material. As used herein "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and 15 absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for oral administration. Detailed Description of the Invention Example I A formulation of the present invention was prepared in accordance with the method 20 and ingredients as set out below in Table 1: Table 1: Compositions of Fast Dissolving Solid Dosage Form Formulation Ingredient Amount (g) % by weight Sodium carbonate 10 0.075 BP/USP Sodium 20 0.149 carboxymethylcellulose BP/USP Polyethylene glycol 2000 50 0.374

BP/USP

Glycine BP/USP 100 0.747 Microcrystalline cellulose 200 1.495 BP/USP Amylopectin BP/USP 500 3.737 Lactose BP/USP 1000 7.474 Mannitol BP/USP 1500 11.211 Purified water BP/USP 10000 74.738 Sodium carboxymethylcellulose and amylopectin were added in a portion of purified water by mixing thoroughly with a stirrer. The mixture was then heated to 50* C for ten minutes to allow dissolving of the polymers. Once the solution cooled down to room temperature, polyethylene glycol 2000, glycine, sodium carbonate, 5 microcrystalline cellulose, lactose and mannitol were added individually, under stirring to obtain a homogenously solution. The viscosity of the solution was measured at 25 0 C using a Brookfield Digital Viscometer (Brookfield Engineering Laboratories Inc, MA, USA). The resulting mixture was transferred by pipette and accurately weighed into pre 10 formed blister packs, and then transferred into a freezer (-30 0 C) for approximately 24 hours. After freezing, the sample was freeze-dried (DYNAVAC, Australia) for 24 hours. The prepared sample was stored in desiccator over silica gel at room temperature. The following additional formulations were prepared by the method as set out above. 15 Essentially Samples 1 to 6 are based on the formulation described above, with the addition of flavour and/or colour agents. Sample 1. Sample 1 additionally contained a flavour. Ingredient Amount (g) % by weight Sodium carbonate 1 0.08 J J Sodium 2 0.15 carboxymethylcellulose Polyethylene glycol 2000 5 0.37 Orange flavor 10 0.74 Glycine 10 0.74 Microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 150 11.13 Purified water 1000 74.18 Sample 2. Additional contained a flavour and a pH adjuster (citric acid). Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose Citric acid 5 0.37 Polyethylene glycol 2000 5 0.37 Mint flavor 10 0.74 Glycine 10 0.74 Microcrystalline cellulose 20 1.48 Amylopectin 50 3.70 Lactose 100 7.39 Mannitol 150 11.09 Purified water 1000 73.91 Sample 3. Additionally contained flavour and a colouring agent Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose Polyethylene glycol 5 0.37 2000 Grape flavor 9.9 0.74 Glycine 10 0.74 Microcrystalline 20 1.48 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 150 11.13 Purified water 1000 74.18 Sample 4. Additionally contained flavour, a colouring agent and an absorption enhancer. Ingredient Amount (g) % by weight FD & C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose p-Cyclodextrin 5 0.37 Polyethylene glycol 5 0.37 2000 Grape flavor 9.9 0.73 Glycine 10 0.74 Microcrystalline 20 1.48 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 145 10.76 Deionsed water 1000 74.19 Sample 5. Additionally contained a colouring agent and a sweetener Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose Aspartame 5 0.37 Polyethylene glycol 5 0.37 2000 Cherry flavor 9.9 0.73 Glycine 10 0.74 Microcrystalline 20 1.48 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 145 10.76 Deionsed water 1000 74.19 Sample 6. Additionally contained a colouring agent and a pH adjuster Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose Sodium hydrogen 5 0.37 carbonate Polyethylene glycol 5 0.37 2000 Raspberry flavor 9.9 0.73 Glycine 10 0.74 Microcrystalline 20 1.48 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 145 10.76 Deionsed water 1000 74.19 Various batches of fast dissolving solid dosage form were then prepared based on the formulation shown in Table 1 and prepared as set out in Example 1 above. The batch number and the ingredients are listed in Table 2. Table 2: Compositions of the Formulations Used for Investigations Batch Batch Batch Batch Batch Batch 071501 071502B 0820B 0820A 0905MD 1003FEN B Ingredient Amount Amount Amount Amount Amount Amount (g) (g) (g) (g) (g) (g) Amylopectin 1.0 1.0 1.0 0.00 1.0 0.5 Mannitol 3.0 3.0 3.0 3.0 3.0 1.5 Lactose 2.0 2.0 2.0 2.0 2.0 1.0 Glycine 0.2 0.2 0.5 0.3 0.2 0.1 PEG 2000 0.1 0.1 0.1 0.1 0.1 0.05 Sodium 0.04 0.04 0.04 0.04 0.04 0.02 Carboxymethyl cellulose Sodium 0 0.02 0 0 0.02 0.01 carbonate Starch 1.0 0 0 0 0 0 Avicel 0.2 0.2 0.00 0.2 0.2 0.1 Active 0 0 0 0 0.255 0.004 pharmaceutical midazolam fentanyl ingredient (base) citrate (2.5 mg fentanyl base) Purified water 40 40 40 40 40 20 General observations The procedure of Example 1 was repeated, except that polyethylene glycol 1000 was employed instead of polyethylene glycol 2000, to thereby yield a fast dissolving dosage form. Applicant found that there was no significant difference between the use of polyethylene glycol 1000 or polyethylene glycol 2000 (results not shown). Applicant found the addition of starch resulted in a hard wafer and was less suitable for the fast dissolving solid dosage form of the present invention. 5 Uniformity of Weight The uniformity of the weight of the fast dissolving dosage form (wafer) was tested in accordance with the British Pharmacopoeia (BP) 2009 test. That is, 20 wafers from each of the formulations listed in the above Table 2 were individually weighed, and the average weight and relative standard was calculated. All the prepared wafers 10 from different formulations were within the accepted weight variation from between 0.25 to 2%. Hardness The hardness of the dosage formulations listed in Table 2 was also tested. The mechanical strength of tablet is referred to as "hardness". The hardness of the wafer 15 was determined using an Erweka Hardness Tester (Germany). The values of hardness from different formulations ranged from 0.5 to 4.0 kg. It was observed that the hardness of the formulation increased when Avicel was added to the formulation (results not shown). Friability 20 The strength of the fast dissolving solid dosage forms (wafers), i.e. their ability to be reduced from a solid substance into smaller pieces was measured. The test was conducted according to BP 2009 method (i.e. friability of uncoated tablets), using the Erweka friability tester (Germany). A sample of 20 wafers was weighed accurately and placed in the apparatus. A rotation time of four minutes at 25 rpm was used. 25 Wafers were removed and reweighed and the percentage weight loss was calculated. It was found that the weight loss of 20 wafters ranged from 8 to 20%. Although this weight loss does not comply with the BP 2009 standard of about 1% weight loss for compressed tablets, there is no such standard for wafers in either the BP or USP monograph. 30 Moisture Analysis The moisture content of the wafers was analysed after lyophilisation using the 870 Karl Fisher Titrino Plus (Metrohm Ag, Germany). The results show that the residual moisture content was varied from 1% to 5% for different formulations.

qu Scanning electron microscopic analysis Surface morphology and cross-sections of selected wafer formulations were observed using scanning electron microscope (SEM) (Zeiss, EVO 40 XVP, the Oxford Instrument, UK). Cross-section sample were prepared by cutting a thin slice 5 of the wafer using a scalpel. Samples were coated with carbon prior to examination. The accelerating voltage was 10 kV. The SEM images shown in Figures 1 to 6 illustrate the highly porous nature of the wafers on both surface and the inner structure. Clearly, there were morphological differences between different formulations. These differences indicated that the 10 excipients used influenced the microstructure of the wafer. In addition, the microstructure might give an explanation about the different hardness, friability, disintegration time, and even the dissolution profiles of wafer prepared from different formulations. Powder X-ray diffraction (XRD) 15 X-ray diffraction experiments were performed using Bruker D8 Advance (Germany) with detector LynEye. The radiation used was nickel filtered CuKa, which was generated using an acceleration voltage of 40 kV and a cathode current of 40 mA. The samples were scanned over a 2 theta range of 7.5 to 70 degree, and counting time at 1 second per 0.02 degree. 20 The physical state of the materials in the wafer was evident in the X-ray diffraction spectra. Spectra for three different formulations as prepared in accordance with Table 2 are shown in Figures 7 to 9. It was observed that all the powder patterns of wafer prepared are dominated by intense scattering peaks approximately located at 2-theta of 9.580, 19, 68* and 20.05*, which indicated a crystalline nature. This finding 25 was also supported by the data generated from the SEM (see Figures 1-6). Indeed, the excipients used in the formulations, such as glycine, lactose, mannitol and microcrystalline cellulose are crystalline in nature. It was observed that there was minimal physical state change in the solid dispersion. Disintegration and Dissolution Analysis 30 Disintegration and dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37 ± 0.5 0

C.

4~I For the disintegration test, a wafer was placed in the cylindrical basket and wetted on the underside by contact with distilled water in the cylindrical vessel. The time of total dissolution of each wafer was noted, and a mean value was calculated. For the dissolution testing: 5 (i) a wafer (Batch 0905MD) containing midazolam as a model drug was used to determine the mechanism of drug release from the system following the both BP basket and USP paddle methods (see Figure 17). Dissolution medium was 500 mL phosphate buffer solution (pH value is closed to saliva fluid at 6.8), with a paddle rotation speed at 75 rpm. At given interval (e.g., 0.5, 1, 2, 3, 5 10 15, 20 and 30 min), 10 2 mL of solution was sampled and replaced with an equal volume of fresh medium to maintain a constant total volume. Samples were filtered through a 0.2 pm Millipore filter. The drug released was measured by HPLC. The HPLC system consisted of a Waters 1525 pump, a Waters Symmetry C 18 column (5 ptm, 150 x 4.6 mm), and Waters UV 484 detector. The mobile phase was 15 acetonitrile: 10 mM ammonium acetate buffer (40: 60, v/v, pH 4.10) and the flow rate was 1.2 ml/min at ambient temperature. The peaks were recorded at 220 nm, and the limit of quantitation was approximately 1 ng/ml. The calibration curve for the concentrations 1-32.4 pg/mL (six-point calibration) was linear [y=870714x+52057 (r=0.9998), y representing the peak area of midazolam and x the concentration of the 20 samples]. A standard HPLC calibration curve for Midazolam is shown in Figure 30. The results as shown in Figure 31 demonstrate that the average disintegration times were less than 15 seconds; and the dissolution studies also indicated a fast release rate of midazolam. Almost 75% of midazolam had dissolved in one minute. The raw 25 midazolam powder was considerably slower. This may indicate the changing of midazolam crystal form in the wafer, which was also evident in the X-ray. The X-ray spectrum pointed to an amorphization of midazolam during the freeze-drying process. The results of the HPLC analysis on various samples of the formulation as prepared 30 in accordance with Table 1 are shown in Figures 11 to 29. Figures 10 A to 10 E illustrate the HPLC of standard midazolam sample, and midazolam powder dissolution samples. Figures 11 to 16 are HPLC chromatograms of dissolution wafer samples 1 to 3 (S1, S2 and S3, BP basket method). Briefly, the samples 1, 2 and 3 were prepared according to Table 1 and are triplicate samples of the same formulation. Figure 17 illustrates the HPLC chromatogram of Batch 0905MD, which contains midazolam as a model drug. Figures 18 to 29 reflect the HPLC chromatograms of another three dissolution wafer samples (USP paddle methods). As discussed above, the dissolution rate of the 5 wafer containing test drug midazolam was measured. Samples were taken at 0.5 minute, 1 minute, 5, minutes, 10 minutes and 15 minutes. The results of wafers 1 to 3 (Batch 0905MD) are shown over these time limits in Figures 18 to 29. A drug loading test was also conducted for another three wafers (Batch 0905MD). 10 It was shown that the wafers of the present invention were able to completely dissolve in about 15 seconds and did not leave behind any residue. (ii) a wafer (Batch 1003FEN) containing fentanyl as a model drug was used to determine the mechanism of drug release from the system following the BP basket method. The dissolution rates of the wafer were determined in a small volume (10 15 mL phosphate buffer solution, pH 6.8) with a basket rotation speed at 50 rpm. At a given interval (e.g., 0.5, 1, 2, 3, 4, 5, 7, 10 and 15 min), 0.5 mL of solution was sampled and replaced with an equal volume of fresh medium. The drug released was measured by HPLC. The mobile phase was methanol: 0.4% phosphoric acid (50 : 50, v/v, pH 2.3) and the 20 flow rate was 1.2 ml/min at ambient temperature. The monitoring wavelength was at 210 nm. The calibration curve for the concentrations 0.5-10 pg/mL (eight-point calibration) was linear [y=316668x+4675.7, (r=0.9999), y representing the peak area of fentanyl and x the concentration of the samples]. The assay standard curve is shown in Figure 32. 25 The prepared fentanyl wafer (batch 1003FEN) showed a weight variation of ± 2.55%, and the mean percentage fentanyl content of the wafer was 91.32% (BP standard for uniformity content limits 85 to 115%). The average disintegration times were less than 15 seconds; and the dissolution studies also indicated a fast release rate of fentanyl. Almost 90% of fentanyl had dissolved in one minute. The dissolution 30 profiles are presented in Figure 33. The HPLC chromatograms of six dissolution samples of fentanyl wafers were collected and are shown in Figures 34 A to E (samples 1 to 3) and Figures 35 A to J. (samples 4 to 6). The sampling of each test wafer was conducted at time of 0.5, 1, 5, 10, 15 and 20 minutes for dissolution samples 1 to 3, and at 1, 2, 3, 4, 5, 7 and 10 minutes for dissolution samples 4 to 6. The fast dissolving dosage form is a solid dispersion of drug into a porous matrix. After administration, this dosage form quickly disintegrates in the oral cavity, and 5 allows rapidly dissolving drug to be absorbed by diffusion directly into the systemic circulation, and the first-pass effect is avoided. This invention has the potential to provide an alternate route of drug administration and results in lower rates of side effect. Example 2 10 A formulation of the present invention was prepared in accordance with the method and ingredients as set out below in Table 3: Table 3: Compositions of Ketamine Fast Dissolving Solid Dosage Form (Strength equivalent of 25 mg of ketamine base) Ingredient (BP/USP) Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcellulose Polyethylene glycol 2000 5 0.36 Glycine 1 0.07 Microcrystalline cellulose 2 0.15 Amylopectin 50 3.64 Ketamine 62.5 4.55 Lactose 100 7.28 Mannitol 150 10.92 q4 Purified water 1000 72.81 Sodium carboxymethylcellulose and amylopectin were added in a portion of purified water by mixing thoroughly with a stirrer. The mixture was then heated to 50 0 C for ten minutes to allow dissolving of the polymers. Once the solution cooled down to room temperature, PEG 2000, glycine, sodium carbonate, microcrystalline cellulose, 5 lactose, mannitol and ketamine hydrochloride were added individually, under stirring to obtain a homogenously solution. The viscosity of the solution was measured at 25*C using a Brookfield Digital Viscometer (Brookfield Engineering Laboratories Inc, MA, USA). The resulting mixture was transferred by pipette and accurately weighed into pre 10 formed blister packs, and then transferred into a freezer (-30*C) for approximately 24 hours. After freezing, the sample was freeze-dried (DYNAVAC, Australia) for 24 hours. The prepare sample was stored in desiccator over silica gel at a room temperature. The following additional formulations were prepared by the method as set out above. 15 Samples 1 to 6 are based on the formulation described above (strength equivalent of 25 mg ketamine base), with the addition of flavour and/or colour agents. Sample 1. Sample 1 additionally contained a flavour. Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose Polyethylene glycol 2000 5 0.35 Orange flavor 10 0.71 Glycine 10 0.71 Microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Ketamine 62.5 4.43 Lactose 100 7.09 Mannitol 150 10.63 Purified water 1000 70.90 Sample 2. Additional contained a flavour and a pH adjuster (citric acid). Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose Citric acid 5 0.35 Polyethylene glycol 2000 5 0.35 Mint flavor 10 0.71 Glycine 10 0.71 Microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.50 4.42 Lactose 100 7.06 Mannitol 150 11.09 40 Purified water 1000 70.65 Sample 3. Additionally contained flavour and a colouring agent Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose Polyethylene glycol 2000 5 0.35 Grape flavor 9.9 0.70 Glycine 10 0.71 Microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Ketamine 62.5 4.43 Lactose 100 7.09 Mannitol 150 10.43 Purified water 1000 70.90 Sample 4. Additionally contained flavour, a colouring agent and an absorption enhancer. 5 141 Ingredient Amount (g) % by weight FD & C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose p-Cyclodextrin 5 0.35 Polyethylene glycol 2000 5 0.35 Grape flavor 9.9 0.70 Glycine 10 0.71 Microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 Lactose 100 7.06 Mannitol 145 10.24 Deionsed water 1000 70.65 Sample 5. Additionally contained a colouring agent and a sweetener Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose Aspartame 5 0.35 Polyethylene glycol 2000 5 0.35 Cherry flavor 9.9 0.70 Glycine 10 0.71 Microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 Lactose 100 7.06 Mannitol 145 10.24 Deionsed water 1000 70.65 Sample 6. Additionally contained a colouring agent and a pH adjuster Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcellulose Sodium hydrogen carbonate 5 0.35 Polyethylene glycol 2000 5 0.35 Raspberry flavor 9.9 0.70 Glycine 10 0.71 Microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 Lactose 100 7.06 Mannitol 145 10.24 Deionsed water 1000 70.65 Various strength of ketamine fast dissolving solid dosage form were then prepared based on the formulation shown in Table 3 and prepared as set out in Example 2 above. The batch number and the ingredients are listed in Table 4. Table 4: Compositions of the Ketamine Used for Investigations Batch 20110323K Batch 20110528 Batch 20110820 (strength equivalent of (strength equivalent of (strength equivalent of 25 mg ketamine base) 25 mg ketamine base) 50 mg ketamine base) Ingredient Amount (g) Amount (g) Amount (g) Amylopectin 1.0 1.0 1.2 Mannitol 3.0 3.0 2.9 Lactose 2.0 2.0 1.9 ou Glycine 0.2 0.2 0.3 Polyethylene 0.1 0.1 0.1 glycol 2000 Sodium 0.04 0.04 0.04 carboxymethyl cellulose Sodium 0.02 0.02 0.05 carbonate Avicel 0.2 0.2 0.2 Active 1.250 ketamine (base) 1.250 ketamine (base) 2.50 ketamine (base) pharmaceutical ingredient Purified water 40 40 40 General observations The procedure of Example 2 was repeated, except that PEG 1000 was employed instead of PEG 2000, to thereby yield a fast dissolving dosage form. Applicant found that there was no significant difference between the use of PEG 1000 or PEG 2000. 5 Applicant found the addition of starch resulted in a hard wafer, and was less suitable for the fast dissolving solid dosage form of the present invention. IN VITRO STUDIES The in vitro studies were to describe the physicochemical properties of freeze-dried ketamine (equivalent to 25 mg of ketamine base) fast dissolving solid dosage form. 10 Uniformity of Weight The uniformity of the weight of the ketamine wafer was tested in accordance with the British Pharmacopoeia (BP) 2009 test. That is, 20 wafers from the formulations listed in Table 3 were individually weighed, and the average weight and relative standard 0I1 deviation was calculated. All the prepared wafers from different formulations were within the accepted weight variation of 0.25 to 2%. Hardness The hardness of the wafer was also tested. The mechanical strength of tablet is 5 referred to as "hardness", which was determined using an Erweka Hardness Tester (Germany). The hardness values from different formulations ranged from 0.5 to 4.0 kg. It was observed that the hardness increased when Avicel was included in the formulation (results not shown). The hardness of the wafer at 0.5 to 1.0 kg is prepared (Batch 20110528) and used in the clinical trial. This formulation will enable 10 a fast dissolution rate and allows for easy handling. Friability The strength of ketamine wafers, i.e. their ability to be reduced from a solid substance into smaller pieces was measured. The test was conducted according to BP 2009 method (i.e. friability of uncoated tablets), using the Erweka friability tester 15 (Germany). A sample of 20 ketamine wafers was weighed accurately and placed in the apparatus. A rotation time of four minutes at 25 rpm was used. Ketamine wafers were removed and reweighed and the percentage weight loss was calculated. It was found that the weight loss of 20 wafers ranged from 8 to 20%. Moisture Analysis 20 The moisture content of the ketamine wafers was analysed after lyophilisation using the 870 Karl Fisher Titrino Plus (Metrohm Ag, Germany). The results showed that the residual moisture content was around 4%. Scanning electron microscopic analysis Surface morphology and cross-section of samples selected wafer formulations were 25 observed using a scanning electron microscope (SEM) (Zeiss, EVO 40 XVP, the Oxford Instrument, UK). Cross-section samples were prepared by cutting a thin slice of the wafer using a scalpel. Samples were coated with carbon prior to examination. The accelerating voltage was 10 kV. The SEM images shown in Figures 36 and 37 illustrate the highly porous nature of 30 the wafers for both surface and the inner structures.

Powder X-ray diffraction (XRD) Powder X-ray diffraction experiments were performed using Bruker D8 Advance (Germany) with detector LynEye. The radiation used was nickel filtered CuKa, which was generated using an acceleration voltage of 40 kV and a cathode current of 40 5 mA. The samples were scanned over a 2 theta range of 7.5 to 70*, and counting time at 1 second per 0.02 degree. The physical state of the materials in the wafer was evident in the X-ray diffraction spectra. Spectra for three different formulations as prepared in accordance with Table 4 are shown in Figures 38, 39 and 40. It was observed that all the powder 10 patterns of wafers prepared were dominated by intense scattering peaks approximately located at 2-theta of 9.580, 19, 680 and 20.05*, which indicating a crystalline nature of the excipient Avicel. This finding was also supported by the data generated from the SEM. Indeed, the excipients used in the formulations, such as glycine, lactose, mannitol and microcrystalline cellulose are crystalline in nature. 15 However, all became amorphous after freeze-drying. Disintegration and Dissolution Analysis Disintegration and dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37 ± 0.5 0 C. 20 For the disintegration test, a ketamine wafer was placed in the cylindrical basket and wetted on the underside by contact with distilled water in the cylindrical vessel. The time of total dissolution of each wafer was noted, and a mean value was calculated. It was shown that the wafers of the present invention were able to completely dissolve in about 15 seconds and did not leave behind any residue. 25 For the dissolution testing: Dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37 ± 0.5"C. A wafer (Batch 20110528) containing ketamine was used to determine the level of drug release from the 30 formulation. The dissolution rates of the ketamine wafer were determined in a large volume (200 mL phosphate buffer solution, 25 mM, pH 6.8) with a basket rotation speed at 75 rpm. At given intervals (e.g., 1, 3, 5, 7, 10, 15, 20 and 30 min), 1.0 mL of solution was sampled and replaced with an equal volume of fresh medium. The drug released was measured by HPLC with a C18 column (150 x 4.6 mm, 5 pm), a mobile phase of 15% v/v acetonitrile in 85% of 50 mM H 3

PO

4 , 20mM triethylamine HCI (pH 3.00) and the flow rate was 1.5 ml/min at ambient temperature. The monitoring wavelength was at 210 nm. The HPLC chromatograms of dissolution ketamine wafer 5 were shown In Figures 41 to 48. The calibration curve for the concentrations 5 to100 pg/mL (seven-point calibration) was linear [Y=16225X+3328.9, (R 2 =1), Y representing the peak area of ketamine and X the concentration of the samples]. The assay standard curve is shown in Figure 49. 10 The prepared ketamine wafer (Batch 20110528) showed a weight variation of ± 2.55%, and the mean percentage ketamine content of the wafer was 98.67% (BP standard for uniformity content limits 85 to 115%). The HPLC chromatogram is shown in Figure 50. The average disintegration times (BP disintegration apparatus) were less than 5 15 seconds; and the dissolution studies also indicated a fast release rate of ketamine. Almost 95% of ketamine had dissolved within one minute. This may indicate the changing of ketamine crystal form in the wafer, which was also evident in the X-ray. The X-ray spectrum pointed to an amorphization of ketamine during the freeze-drying process. 20 The dissolution profiles are presented in Figure 51. The ketamine wafer is a solid dispersion of ketamine hydrochloride into a porous matrix. After administration, this dosage form is quickly disintegrates in the oral cavity, and allows rapidly dissolving ketamine to be absorbed by diffusion directly into the systemic circulation, and the first-pass effect is avoided. This invention has the 25 potential to provide an alternate route of drug administration and results in lower rates of side effect. IN VIVO STUDIES The aims of the in vivo study were: 1) to investigate the pharmacokinetic profile of ketamine wafer (equivalent to 25 mg of ketamine base); 2) to determine the absolute 30 bioavailability of a single 25 mg sublingual dose of ketamine wafer; and 3) to evaluate the clinical characteristics and acceptability of the present invention using modified Likert, and Bond and Lader scales.

04 Ethical Approval The protocol was approved by the Royal Adelaide Human Research Ethics Committee and also this trial was registered with the Australian Therapeutic Goods Administration under the Clinical Trial Notification Scheme (CTN: 2011/0292). 5 Study Subjects All volunteers gave their written informed consent on an approved subject consent form, prior to undergoing trial procedures. Subjects between 19 to 41 years of age who had a body mass index between 22 and 30kg/m 2 , no history or showed presence of drug or alcohol dependence or abuse, and who had normal findings on 10 the clinical history and laboratory testing, free of sublingual or buccal ulceration or disease, and who had negative findings on HIV, hepatitis B and C viral testing were included in the study. A total of eight healthy males who met the study inclusion and exclusion criteria were enrolled in this study. 15 Study Plan and Design This was a single-centre (Pain and Anaesthesia Research Clinic, Royal Adelaide Hospital, Adelaide, SA 5005, Australia), randomized, open-label, single-dose, two treatment, two-period, two-way crossover study. According to the randomization plan, subjects were divided into two groups, in a 1:1 ratio using a computer 20 generated table of random numbers. The volunteers received both a single 10 mg intravenous (IV) dose (diluted to 30 mL in saline and administered as an IV infusion over 30 min) and a 25 mg sublingual (SL) wafer dose of ketamine. The sequence of treatment periods was balanced and randomised. The wafer was administered by placing it under the tongue. The 25 volunteer was requested to avoid swallowing for at least ten minutes, to minimize loss of ketamine via the oral route and hence through gut and liver metabolism (the first pass effect). The total study duration was four weeks, including a 14-day screening period and a seven-day wash-out period. Measurements of pharmacokinetics, tolerability and safety were carried out for 24 30 hours following both dosing occasions. The total residency period at the Pain and Anaesthesia Research Clinic was 28 hours in Period 1 and 29 hours in Period 2.

Blood samples (5 mL) for quantification of ketamine concentration were taken following both IV and SL administration at pre dose (within 5 minutes of scheduled dosing time), 5, 10, 15, 30, 35 and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post dose. Samples up to and including the 8 hour post-dose sample 5 were to be collected within two minutes of nominal time, thereafter all post-dose samples were to be collected within ten minutes of nominal time. The actual blood collection time was recorded in the source documents. All deviations outside of the windows specified above were to be documented as protocol deviations. The total amount of blood to be taken throughout the study duration was approximately 275 10 mL. After collection, the blood samples were immediately centrifuged at 4 0 C, 2000-2500g for 15 minutes and the plasma extracted and placed into polypropylene storage tubes. The plasma was stored at -80 0 C ± 1 0*C until transfer to the bioanalytical laboratory. Pharmacokinetic Analysis 15 The analysis of the plasma concentrations of racemic ketamine was performed using a validated HPLC method with UV detection, with a lower limit of quantification of 2 ng/mL and <20% bias and imprecision. Standard non-compartmental analysis was used to derive Pharmacokinetic variables, except for Cmax, tmax and tfirst, which were taken as observations from the plasma 20 concentration time profile of each subject. Actual times were used when reporting tmax. The terminal rate constant (Xz) was estimated by log-linear regression, i.e. the slope of the natural log concentration vs. time curve where X, = -1* slope. The linear regression in the terminal phase used the last three to six data points, at a minimum three points. The terminal ti,/ was calculated as t% =ln(2) / X. 25 The area under the plasma concentration time curve to the last quantifiable plasma concentration (AUCast) was obtained using the linear up and log down method and extrapolated to infinity with Clast/Xz (last quantifiable plasma concentration divided by X,) to obtain the total AUC, AUCINF. The extrapolated portion of the AUC, AUCextr, was obtained by (1-AUCtIast/AUCINF)*100. The total area under the first moment 30 curve, AUMCINF, was calculated in a similar manner to AUCINF and MRT was obtained as AUMCINF/AUCINF correcting mean residence time (MRTi.,) for the duration of the 30 minute IV infusion. Clearance (CL) was calculated as dose/AUCINF for IV administration and in the same way for the sublingual dose. The clearance for a non-IV route is expressed as CL/F i.e. a ratio of clearance and bioavailability as the 00 latter is unknown. The volume of distribution, V2, was calculated as CL/Xz. The MAT for the sublingual administration was obtained as the difference between the MRT for the two routes of administration as, MRTSL- MRTv. The bioavailability (F) of ketamine was calculated as the ratio of the dose adjusted AUCNF following IV and sublingual 5 dosing according to AUCSL/AUCv * doselv/doseSL. Safety and Tolerability Safety assessments included scheduled adverse event (AE) probes, spontaneous AE reporting, routine laboratory investigations, 12-lead electrocardiograms (ECGs) and vital sign evaluation during a 24 hour period from start of dosing. A full physical 10 examination was performed before the first dosing occasion and 24 hours after the second dosing occasion. Local tolerability was assessed, by using Likert scales, at pre dose, 5, 10, 15, 30 and 45 minutes and one hour post dose administration. Modified Bond and Lader scales to assess sedation and altered perception, by using the three factors "alertness", 15 "contentedness" and "calmness", were performed at pre dose, 30 minutes post dose and at hours 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post dose administration. Statistical Analysis Standard summary statistics were computed by treatment for each pharmacokinetic variable. The 90% confidence interval (CI) was calculated for the bioavailability. 20 RESULTS The individual values and summary statistics for volunteer characteristics are reported in Table 5. Table 5: Subject Demographics Subject Radoiztin Age Body weight Height BMI n o (years) (kg) (cm) (M 2 ) No. 1 19 74.6 184.0 22.0 2 31 100.0 183.2 29.9 3 23 77.0 173.0 25.7 of 4 19 74.7 168.0 26.4 5 41 87.8 183.5 26.1 6 20 85.0 183.0 25.4 7 21 79.1 185.0 23.1 8 25 108.5 191.0 30.0 n 8 8 8 8 Mean (SD) 25(7.6) 85.8 (12.49) 181.3 (7.29) 26.1 (2.83) Min-Max 19-41 74.6-108.5 168.0-191.0 22.0-30.0 Plasma concentrations of racemic (RS) Ketamine The geometric mean (gmean) with an overlay of individual RS ketamine plasma concentrations for all subjects following IV administration for the entire sampling period is depicted in Figure 52. For clarity, the first 12 hours following dosing are 5 shown separately in FIGURE . The geometric mean with an overlay of individual RS ketamine plasma concentrations for all subjects for the entire sampling period following SL administration are shown in FIGURE 5 and the first 12 hours are shown in FIGURE 5. The IV and SL plasma concentration time curves were similar in shape, except for 10 four subjects having 2-3 peaks for the SL route. Following Cma, concentrations declined biphasically for both IV and SL although the trend was more prominent for IV. The first quantifiable concentration following both IV and SL dosing was at five minutes for all subjects, which indicates a fast absorption for the SL dose. Plasma 15 concentrations were below limit of quantification in six subjects at 24 hours and in one subject at 12 hours for SL dosing. Following IV dosing, all subjects had quantifiable levels at 12 hours and four subjects at 24 hours.

Following IV dosing, Cmax occurred at the end of the infusion in all but one subject (No.6), where the Cmax was observed in the sample taken five minutes after the end of the 30 minutes infusion. For the SL dose, the median time of the main peak i.e. tmax, was 0.75 hour with the 5 earliest peak detected at 0.25 hour and the latest at 1 hour following dosing. Subjects 4, 5, 6 and 7 had multiple minor peaks in their plasma concentration time profile observed during the first three hours following dose administration. Individual tmax values are shown in FIGURE. Table presents individual estimates and summary statistics for the main 10 pharmacokinetic variables. Individual AUCINF values for both routes of administration are shown in FIGURE. The extrapolated portion of the AUC, AUCwr, was very small for both routes of administration, which is indicative of a high quality in the estimation of the AUC values. For IV, the AUCext, was 3-7% and for SL it was 2-9%. Individual estimates of CL for the IV route are presented in FIGURE 8. Following SL 15 dosing the CL is confounded by F, and hence cannot be compared to the values obtained following IV dosing. Median CL for IV dosing was 37.7 L/hr. The terminal half lives following IV and SL dosing were comparable, with medians of 4.5 and 3.4 hours, respectively. Similar half lives for the IV and SL routes indicates that the absorption is fast, or else the slower absorption half life would be governing 20 the terminal phase of the plasma concentration time curve and hence show a considerably longer half life than IV administration. Individual values for both routes of administration are provided in FIGURE 59. Table 6: Individual pharmacokinetic variables and summary statistics of RS ketamine following administration of 10mg as a 30 minute IV infusion 25 and 25 mg SL to eight healthy volunteers. Subject cmaXV tXa'yV CmaxsL taxsL AuCINFIv AUCINF_SL CL v t2V t1I2,SL (ng/mL) (hr) (ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (L/hr) (L) (hr) (hr) 1 226.68 0.5 88.76 0.58 282.73 202.89 35.37 126 2.5 2.9 2 163.26 0.5 128.28 0.25 243.24 162.52 41.11 158 2.7 1.8 3 190.27 0.5 78.72 0.75 254.59 184.28 39.28 283 5.0 3.2 4 124.24 0.5 60.24 1 270.02 203.47 37.03 253 4.7 5.5 5 120.38 0.5 50.02 0.75 289.22 171.90 34.58 300 6.0 3.5 6 101.88 0.6 76.12 1 299.44 211.33 33.40 164 3.4 2.3 7 83.18 0.5 51.79 1 261.00 186.14 38.31 385 7.0 4.6 8 81.12 0.52 61.17 0.5 167.21 161.64 59.81 375 4.3 5.1 Gmean' 128.07 0.50 71.08 0.75 254.98 184.65 39.22 237 4.5 3.4 Min-Max 81.12- 0.50- 50.02- 0.25- 167.21- 161.64- 33.40- 126- 2.5- 1.8 Cv(%) 16 NA 14 21 8 4 8 18 16 17 a gmean is provided for all variables except for tm. and ti, 2 where medians are shown NA Not applicable Bioavailability and Absorption In a majority of subjects, the SL wafer dissolved within 30 seconds to one minute. 5 Individual estimates of bioavailability are shown in FIGURE 660 and individual bioavailability and MAT (mean absorption time) values together with summary statistics are provided in Table 7. Subject No.8 had a noticeably higher bioavailability, 38%, than others. This subject was not markedly different in comparison to other subjects, apart from having the highest extrapolated areas, 9% for SL and 7% for IV, 10 and a double peak for the SL dose. The median and 90% Cl [lower, upper] for bioavailability was 29 [27, 31] %, showing the very low inter subject variability. Table 7: Individual (Subject=randomization number), median, minimum and maximum of RS ketamine bioavailability (F) and mean absorption time (MAT) following SL administration of 25 mg to eight healthy 15 volunteers. Subject F (%) MAT (hr) '1 IQ1 1 9) 97_nA 141)Q .1 1 A n Art X; -1 1 7 90 nAo 8 38 0.64 Median 29 -0.18 Min-Max 23-38 -1.1 - 1.1 90%C1 [27, 31] NA* fou [lower, upper] * Not applicable The MAT represents the average time molecules of ketamine take to pass from the administration site, SL space, to the systemic circulation. The individual MRT values were comparable for the two routes of administration, median of 3.9 for IV and 3.8 5 hours for SL, indicating a fast absorption. A small difference, i.e. a small MAT, between the MRT for IV and SL indicates fast absorption. Taking the difference between two similar values might produce negative values, as is seen in some of the MAT values, due to naturally occurring variability. In summary, the PK of the SL wafer is characterised by fast absorption and low 10 variability in bioavailability. This taken together with low variability in clearance translates into low variability in exposure. Low variability allows for increased accuracy in predicting total exposure and hence pharmacological effect of the SL wafer, which might be expected to increase its utility in the clinical setting. Pharmacodynamic Results 15 Bond and Lader Mood Rating Scales The Bond and Lader scales comprise a total of 16 100-mm lines anchored at either end by antonyms. Participants marked their current subjective state between the antonyms on the line. Each line was scored as millimetres to the mark from the negative antonym. From the resultant scores, three measures derived by factor 20 analysis were isolated. These have been described by Bond and Lader as representing the following: * Factor : "alertness" (represented by lines anchored by alert-drowsy, attentive-dreamy, lethargic-energetic, muzzy-clearheaded, well coordinated-clumsy, mentally slow-quick witted, strong-feeble, interested 25 bored, incompetent-proficient); * Factor 2 : "contentedness" (contented-discontented, troubled-tranquil, happy-sad, antagonistic-friendly, withdrawn-sociable) and * Factor 3 : "calmness" (calm-excited, tense-relaxed); Scores for each factor represent the unweighted average number of millimeters (maximum 100 mm) 30 from the negative antonym for the individual scales contributing to the factor.

DI Hence the maximum score for Factor 1 is 900; for Factor 2, 500 and for Factor 3, 200. The mood rating scales showed no clear trends for effects. Following SL dosing the Factors "alertness" and "contentedness" were fluctuating around the pre-dose level 5 throughout the 24 hr observation period while "calmness" showed an initial decrease during the first hour after dosing, likely due to excitement caused by dosing and the local tolerability observations during the first 30-60 minutes, followed by a steady increase and full recovery by 2.5 hr post dose. The shapes of the profiles following IV dosing were comparable to that of SL dosing. Profiles of mean (SD) values for each 10 Factor of the mood rating scales following IV and SL dosing are depicted in Figure 61 and Figure 62, respectively. Modified Liked Scales of Local Tolerability Modified Likert scales were used to assess the following symptoms: cheek irritation; burning sensation; bitterness and nausea. As expected, values were generally zero 15 for all values following IV administration although there were sporadic values of one or two. Following SL administration, values were generally zero or sporadically one or two for "cheek irritation" and were similar for "burning sensation" although there was a single value of three reported at 10 minutes by subject 3. For "nausea", values showed the same trend as for IV with mainly zero values but sporadic values of one 20 or two. However values for "bitterness" were different from IV : all subjects reported non-zero post dose values although the peak ranged from 1-9 with one subject each reporting a peak of one and three, with the remainder being five or greater. The highest value was at five minutes in four subjects; at 10 minutes in two subjects; 15 minutes in one subject and one subject reported values of nine at both five and 10 25 minutes. All values had returned to zero by one hour (Figure 63). There were no clinically relevant changes or trends for abnormalities in ECG, vital signs, haematology, clinical chemistry or urinalysis. In summary, the sublingual wafer formulation of ketamine has been developed as a potential adjunct in acute and chronic pain management, and other disorders. The 30 median bioavailability from this example is 29 % with very low inter subject variability, which is favorable for a relatively narrow therapeutic index drug such as ketamine. Low variability also increases the utility of the wafer in terms of reproducible exposure and hence analgesic effect. Ketamine administered as a 25 mg sublingual wafer to healthy volunteers, was safe and well tolerated with the exception of mild 35 and transient CNS-type symptoms, as expected based on the existing clinical oz experience of ketamine. The local tolerability was excellent, and any local irritant effects are expected to be mild and resolve within 30-60 minutes following dosing.

Claims (39)

1. A fast dissolving solid dosage form adapted for the release of an N-methyl-D aspartate receptor antagonist in the oral cavity of a patient wherein said dosage form comprises at least one matrix forming agent and wherein said dosage 5 form substantially dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by the patient.

2. A fast dissolving solid dosage form according to claim 1, wherein the N-methyl D-aspartate receptor antagonist is ketamine.

3. A fast dissolving solid dosage form according to any one of the preceding 10 claims, wherein the at least one matrix forming agent comprises sodium carboxymethylcellulose.

4. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises amylopectin.

5. A fast dissolving solid dosage form according to any one of the preceding 15 claims, wherein the at least one matrix forming agent comprises microcrystalline cellulose.

6. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises mannitol.

7. A fast dissolving solid dosage form according to any one of the preceding 20 claims, wherein the dosage form substantially dissolves once placed in the oral cavity in a time period selected from the group consisting of: less than 2 minutes; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less 25 than 3 seconds; and less than 2 seconds.

8. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form completely dissolves after sublingual administration to the patient thereby avoiding the urge for the patient to swallow the dosage form. 30

9. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylcellulose, 1.25% PEG 2000, 2.49% glycine, 2.49% 04 microcrystalline cellulose; 12.49% amylopectin, 24.98% lactose and 37.46% mannitol as a dry weight of the solid dosage form.

10. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form comprises a quantity of an N-methyl-D 5 aspartate receptor antagonist selected from the group consisting of: 5mg; 10mg; 15mg; 20mg; 25mg; 50mg; and 100mg.

11. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form provides the patient with an N-methyl-D aspartate receptor antagonist peak plasma concentration (Cmax) selected from 10 the group consisting of: 25ng/ml; 30ng/ml; 40ng/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 100ng/ml; 110ng/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml.

12. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form has a median tmax selected from the group 15 consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; 45 minutes.

13. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form provides an effective plasma concentration of 20 an N-methyl-D-aspartate receptor antagonist in a patient, which is reached within a time period selected from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes

14. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form provides the patient with an effective 25 therapeutic plasma level of an N-methyl-D-aspartate receptor antagonist over a time period selected from the group consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours.

15. A fast dissolving solid dosage form according to any one of the preceding 30 claims, wherein the dosage form provides a median bioavailability of an N methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%.

16. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form provides a median half life of an N-methyl-D aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 2.5 and 4.5 hours; between 3 and 4 hours; 5 3.5 hours; and 3.4 hours.

17. A fast dissolving solid dosage form according to any one of the preceding claims, wherein the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; 10 within 12 minutes; within 11 minutes; within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute.

18. A solid dosage form adapted for the release of an N-methyl-D-aspartate receptor antagonist in the oral cavity of a patient wherein said dosage form 15 comprises at least one matrix forming agent and wherein said dosage form substantially dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by the patient.

19. A pharmaceutical composition comprising the fast dissolving solid dosage form of claims 1 - 17.

20 20. A method of producing the fast dissolving solid dosage form of claims 1 - 17, comprising the steps of: (iii) combining at least one matrix forming agent with an N-methyl-D aspartate receptor antagonist to form a homogeneous mixture; and (iv) freeze drying the mixture to form the solid dosage form. 25

21. A kit comprising a fast dissolving solid dosage form of claims 1-17, and instructions for its use.

22. A method of treating pain, comprising the steps of administering to a patient in need thereof a fast dissolving solid dosage form of claims 1 to 17.

23. A method of treating pain according to claim 22, wherein the dosage form 30 comprises a quantity of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 5mg; 10mg; 15mg; 20mg; 25mg; 50mg; and 100mg. oo

24. A method of treating pain according to claim 22, wherein the dosage form provides the patient with an N-methyl-D-aspartate receptor antagonist peak plasma concentration (Cmax) selected from the group consisting of: 25ng/ml; 30ng/ml; 4Ong/ml; 50ng/ml; 60ng/ml; 70ng/ml; 80ng/ml; 90ng/ml; 1O0ng/ml; 5 11Ong/ml; 120ng/ml; 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml; and 200ng/ml.

25. A method of treating pain according to claim 22, wherein the dosage form has a median tmax selected from the group consisting of: between 5 minutes to 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 10 minutes; between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes.

26. A method of treating pain according to claim 22, wherein the dosage form provides an effective plasma concentration of an N-methyl-D-aspartate receptor antagonist in a patient, which is reached within a time period selected 15 from the group consisting of: within 1 hour; within 30 minutes; and within 10 minutes

27. A method of treating pain according to claim 22, wherein the dosage form provides the patient with an effective therapeutic plasma level of an N-methyl D-aspartate receptor antagonist over a time period selected from the group 20 consisting of: 30 minutes; 1 hour; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 7 hours; 8 hours; 9 hours; 10 hours; 11 hours; 12 hours; and 24 hours.

28. A method of treating pain according to claim 22, wherein the dosage form provides a median bioavailability of an N-methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 10 and 25 60%; between 20 and 40%; between 25 and 35%; between 28 and 30%; and 28%.

29. A method of treating pain according to claim 22, wherein the dosage form provides a median half life of an N-methyl-D-aspartate receptor antagonist in a patient, selected from the group consisting of: between 2 and 5 hours; between 30 2.5 and 4.5 hours; between 3 and 4 hours; 3.5 hours; and 3.4 hours.

30. A method of treating pain according to claim 22, wherein the dosage form provides the first detectable plasma concentration of an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes; within 11 minutes; Of within 10 minutes; within 9 minutes; within 8 minutes; within 7 minutes; within 6 minutes; within 5 minutes; within 4 minutes; within 3 minutes; within 2 minutes; and within 1 minute.

31. A method for the induction of anesthesia, comprising the steps of administering 5 to a patient in need thereof a fast dissolving solid dosage form of claims 1 to 17.

32. A method of treating addiction, comprising the steps of administering to a patient in need thereof a fast dissolving solid dosage form of claims 1 to 17.

33. A method of treating depression, comprising the steps of administering to a 10 patient in need thereof a fast dissolving solid dosage form of claims 1 to 17.

34. A method of treating an epileptic seizure, comprising the steps of administering to a patient in need thereof a fast dissolving solid dosage form of claims 1 to 17.

35. Use of fast dissolving solid dosage form of claims 1-17 in the manufacture of a 15 medicament for the treatment of pain.

36. Use of a fast dissolving solid dosage form of claims 1-17 in the manufacture of a medicament for the induction of anesthesia.

37. Use of a fast dissolving solid dosage form of claims 1-17 in the manufacture of a medicament for treating addiction. 20

38. Use of a fast dissolving solid dosage form of claims 1-17 in the manufacture of a medicament for treating depression.

39. Use of a fast dissolving solid dosage form of claims 1-17 in the manufacture of a medicament for treating an epileptic seizure. 25