AU2013200682B1 - Fast Dissolving Solid Dosage Form - Google Patents

Abstract

FAST DISSOLVING SOLID DOSAGE FORM Abstract 5 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 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

1 FAST DISSOLVING SOLID DOSAGE FORM FIELD OF THE INVENTION 5 This invention relates to dosage forms adapted for administration to a subject. Preferably, the dosage forms have rapid dissolution rates. BACKGROUND 10 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 and the hepatic first-pass effect. The sublingual route usually produces a fast and 15 reliable onset of action, and is more suitable for fast dissolving dosage forms. 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 associated with solid dosages forms include effervescent tablets, films, chewable 20 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. 25 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 30 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 is 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 important factor which 35 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 2 freeze drying cycle, might physically modify the physical-chemical properties of the outer membrane of microencapsulated particles. 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 5 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 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 drug from the dosage form because once the dosage 10 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 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 15 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 solution. This additional step adds time and cost to the process of manufacture. 20 An additional problem with the use of gelatin-based material as fast dissolving dosage form matrices is that the gelatin can increase in 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 the holding period. Other disadvantages of gelatin formulations include being prone 25 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 30 the patient. Many modified starches also result in this problem. Furthermore, they are expensive. Therefore, there is a need in the art for a fast dissolving dosage form which delivers an agent to a patient via oral administration, wherein the dosage form rapidly 35 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.

3 SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a fast dissolving 5 solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises: (i) at least one biologically active material, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. 10 According to another aspect of the present invention, there is provided a method to produce the fast dissolving solid dosage form of the present invention comprising the steps of combining at least one matrix forming agent with a biologically active material to form a homogeneous mixture and then freeze drying the mixture to prepare the solid dosage form of the present invention. 15 According to another aspect of the present invention, there is provided a kit comprising the fast dissolving solid dosage form wherein the dosage form comprises: (i) at least one biologically active material, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for 20 its use. According to another aspect of the present invention, there is provided a solid dosage form adapted for the release of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitors in the oral cavity wherein the dosage 25 form comprises: (i) sildenafil, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. In particular, the pharmaceutical composition may be, for example, designed for buccal or sublingual delivery. 30 The fast dissolving solid dosage form may be provided in the form of a pharmaceutical composition for transmucosal delivery. According to another aspect of the present invention, there is provided an inclusion complex of sildenafil and a matrix forming agent. Preferably, one matrix forming 35 agent is sodium carboxymethylcellulose. When at least one matrix forming agent is 4 sodium carboxymethyl cellulose, the polymer is present in a concentration of from about 0.1% to about 19% by dry weight of the solid dosage form. According to another aspect of the present invention, there is provided a method to 5 produce the fast dissolving solid dosage form of the present invention comprising the steps of combining at least one matrix forming agent with sildenafil to form a homogeneous mixture and then freeze drying the mixture to prepare the solid dosage form of the present invention. 10 According to a further aspect of the present invention there is provided a kit comprising the fast dissolving solid dosage form of the invention wherein the dosage form comprises: (i) sildenafil, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 15 According to another aspect of the invention there is provided a solid dosage form adapted for the release of a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an oral cavity wherein said dosage form comprises: (a) at least one cyclic guanosine monophosphate (cGMP) 20 phosphodiesterase type 5 (PDE5) inhibitor; and (b) at least one matrix forming agent; wherein said dosage form substantially dissolves in the oral cavity. Further features of the invention provide for a solid dosage form according to the 25 invention, wherein the dosage form is fast dissolving. Further features of the invention provide for a solid dosage form according to the invention, 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, 30 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, less than 2 seconds. 35 Further features of the invention provide for a solid dosage form according to the invention, wherein said dosage form substantially dissolves in the oral cavity without 5 leaving a residue of said dosage form in the oral cavity that is detectable by a subject. Further features of the invention provide for a solid dosage form according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase 5 type 5 (PDE5) inhibitor is sildenafil. Further features of the invention provide for a solid dosage form according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate. 10 Further features of the invention provide for a solid dosage form according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is present in an amount from 0.02 to 95 weight % by dry weight of the composition of the dosage form. 15 Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one matrix forming agent comprises sodium carboxymethylcel lylose. 20 Further features of the invention provide for a solid dosage form according to the invention, wherein sodium carboxymethylcellylose is present in an amount from 0.1 to 19 weight % by dry weight of the composition of the dosage form. The solid dosage form according to the invention, wherein the at least one matrix 25 forming agent comprises amylopectin. Further features of the invention provide for a solid dosage form according to the invention, wherein amylopectin is present in an amount from 2 to 17 weight % by dry weight of the composition of the dosage form. 30 Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one matrix forming agent comprises microcrystalline cellulose. 35 Further features of the invention provide for a solid dosage form according to the invention, wherein microcrystalline cellulose is present in an amount from 1 to 10 weight % by dry weight of the composition of the dosage form.

6 Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one matrix forming agent comprises glycine. Further features of the invention provide for a solid dosage form according to the 5 invention, wherein the glycine is present in an amount from 0.5 to 5 weight % by dry weight of the composition of the dosage form. Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one matrix forming agent comprises mannitol. 10 Further features of the invention provide for a solid dosage form according to the invention, wherein the mannitol is present in an amount from 5 to 80 weight % by dry weight of the composition of the dosage form. 15 Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one lubricant. Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one lubricant comprises polyethylene glycol (PEG) 20 2000. Further features of the invention provide for a solid dosage form according to the invention, wherein PEG 2000 is present in an amount from 0.05 to 5 weight % by dry weight of the composition of the dosage form. 25 Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one buffer reagent. Further features of the invention provide for a solid dosage form according to the 30 invention, wherein the at least one buffer reagent comprises sodium carbonate. Further features of the invention provide for a solid dosage form according to the invention, wherein sodium carbonate is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form. 35 Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one absorption enhancer.

7 Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one absorption enhancer comprises #-cyclodextrin. Further features of the invention provide for a solid dosage form according to the 5 invention, wherein #-cyclodextrin is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form. Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one flocculating agent. 10 Further features of the invention provide for a solid dosage form according to the invention, wherein the at least one flocculating agent comprises xanthan gum. Further features of the invention provide for a solid dosage form according to the 15 invention, wherein xanthan gum is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form. Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one surfactant. 20 Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one additive. Further features of the invention provide for a solid dosage form according to the 25 invention, further comprising at least one colouring agent. Further features of the invention provide for a solid dosage form according to the invention, wherein 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. 30 Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one flavoring agent. Further features of the invention provide for a solid dosage form according to the 35 invention, wherein the at least one flavoring agent is selected from the group consisting of orange, mint, raspberry, caramel, aspartame, saccharin, and mixture therein.

8 Further features of the invention provide for a solid dosage form according to the invention, wherein the dosage form is a wafer, tablet, capsule, pill, powder, pellet, granule, or film. 5 Further features of the invention provide for a solid dosage form according to the invention, 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 10 than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds. Further features of the invention provide for a solid dosage form according to the invention, wherein the dosage form substantially dissolves after oral administration to 15 a subject thereby avoiding the urge for the subject to swallow the dosage form. Further features of the invention provide for a solid dosage form according to the invention, further comprising at least one pharmaceutically acceptable carrier. 20 According to another aspect of the invention there is provided a method of producing a solid dosage form adapted for the release of a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an oral cavity, comprising the steps of: (i) combining at least one matrix forming agent with a cyclic guanosine 25 monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor to form a homogeneous mixture; and (ii) freeze drying the mixture to form the solid dosage form. Further features of the invention provide for a method according to the invention, 30 wherein the dosage form is fast dissolving. Further features of the invention provide for a method according to the invention, wherein the dosage form is fast dissolving. 35 Further features of the invention provide for a method according to the invention, 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 9 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, less than 2 seconds. 5 Further features of the invention provide for a method according to the invention, 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 a subject. Further features of the invention provide for a method according to the invention, 10 wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. Further features of the invention provide for a method according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 15 (PDE5) inhibitor is sildenafil citrate. Further features of the invention provide for a method according to the invention, further comprising measuring the mixture in a preformed plastic or aluminium blister mould. 20 Further features of the invention provide for a method according to the invention, wherein the freeze drying technique is used to remove the solvent from the blister mould. 25 Further features of the invention provide for a method according to the invention, further comprising sealing the solid dosage form with a plastic or aluminium foil to prevent moisture absorption. Further features of the invention provide for a method according to the invention, 30 further comprising adding a pH adjuster to maintain the pH of the mixture within the range of between 3.0 and 8.0. Further features of the invention provide for a method according to the invention, further comprising adding a solvent. 35 According to another aspect of the invention there is provided a kit comprising a dissolving solid dosage form adapted for the release of a biologically active material in an oral cavity, wherein the dosage form comprises: (i) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , and 10 (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. Further features of the invention provide for a kit according to the invention, wherein 5 the dosage form is fast dissolving. Further features of the invention provide for a kit according to the invention, wherein the dosage form is fast dissolving. 10 Further features of the invention provide for a kit according to the invention, 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 15 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds. Further features of the invention provide for a kit according to the invention, 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 a subject. 20 Further features of the invention provide for a kit according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. 25 Further features of the invention provide for a kit according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate. According to another aspect of the invention there is provided a wafer comprising a 30 dissolving solid dosage form adapted for the release of a biologically active material in an oral cavity, wherein the dosage form comprises: (i) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 35 Further features of the invention provide for a wafer according to the invention, wherein the dosage form is fast dissolving.

11 Further features of the invention provide for a wafer according to the invention, wherein the dosage form is fast dissolving. Further features of the invention provide for a wafer according to the invention, 5 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 than 3 seconds, less than 2 seconds. 10 Further features of the invention provide for a wafer according to the invention, 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 a subject. 15 Further features of the invention provide for a wafer according to the invention, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. Further features of the invention provide for a wafer according to the invention, 20 wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate. According to another aspect of the invention, there is pharmaceutical composition comprising the solid dosage form of the invention. 25 According to another aspect of the invention, there is a method of treating a disease or disorder in a patient, comprising the step of administering to said patient a pharmaceutical composition of the invention. Preferably, the disease or disorder is selected from the group consisting of: erectile dysfunction, pulmonary hypertension, 30 central nervous disorders, cardiovascular disorders and high altitude pulmonary edema. Preferably the disease or disorder is erectile dysfunction or pulmonary hypertension. According to another aspect of the invention, there is a use of a pharmaceutical 35 composition of the invention in the manufacture of a medicament to treat a disease or disorder. Preferably, the disease or disorder is selected from the group consisting of: 12 erectile dysfunction, pulmonary hypertension, central nervous disorders, cardiovascular disorders and high altitude pulmonary edema. 5 DISCLOSURE OF INVENTION According to one aspect of the present invention, 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: (i) at least one biologically active 10 material, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. The biologically active material includes active compounds, and compounds for veterinary and human use, such as however not limited to, pharmaceutical actives, 15 neutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, foods, vitamins, nutrients, biologics, amino acids, proteins, peptides, nucleotides, and nucleic acids. In a preferred form the biologically active material is adapted for oral administration. 20 In a preferred embodiment of the invention, the biologically active material is an organic compound. In a highly preferred embodiment of the invention, the biologically active material is an organic, therapeutically active compound for human use. In another embodiment of the present invention, the biologically active material is an inorganic compound. When the biological active material is a drug, it can be of 25 a neutral species, basic or acidic as well as salts of an acid or base. This invention is not limited to any drug specific class, application type, chemical type or function grouping. The biologically active material is ordinarily an agent for which one of skill in the art 30 desires improved fast dissolution for oral administration. The biologically active material may be a conventional active agent or drug. Examples of biologically active materials suitable for use in the invention include actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and 35 analogs, homologs and first order derivatives thereof. The biologically active material can be selected from a variety of known classes of drugs, including, however not 13 limited to: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including 5 penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood 10 products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-Parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, 15 radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. A description of these classes of active agents and a listing of species within each 20 class can be found in Martindale's The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press, London, 1996), specifically incorporated by reference. Another source of active agents is the Physicians Desk Reference ( 6 0 th Ed., 2005), familiar to those of skill in the art. The active agents are commercially available and/or can be prepared by techniques known in the art. 25 Additionally, examples of suitable drugs include, however are not limited to those listed below: Analgesics and anti-inflammatory agents: aloxiprin, auranofm, azapropazone, 30 benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac. Anthelmintics: albendazole, bephenium hydroxynaphthoate, cambendazole, 35 dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.

14 Anti-arrhythmic agents: amiodarone HCI, disopyramide, flecainide acetate, quinidine sulphate. 5 Anti-bacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin HCI, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim. 10 Anti-coagulants: dicoumarol, dipyridamole, nicoumalone, phenindione. Anti-depressants: amoxapine, ciclazindol, maprotiline HCI, mianserin HCI, nortriptyline HCI, trazodone HCI, trimipramine maleate. 15 Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide. Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin, methoin, 20 methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, valproic acid. Anti-fungal agents: amphotericin, butoconazole nitrate, clotrimazole, econazole 25 nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCI, terconazole, tioconazole, undecenoic acid. Anti-gout agents: allopurinol, probenecid, sulphinpyrazone. 30 Anti-hypertensive agents: amlodipine, benidipine, darodipine, dilitazem HCI, diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCI, nifedipine, nimodipine, phenoxybenzamine HCI, prazosin HCI, reserpine, terazosin HCI. 35 15 Anti-malarials: amodiaquine, chloroquine, chlorproguanil HCI, halofantrine HCI, mefloquine HCI, proguanil HCI, pyrimethamine, quinine sulphate. Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate, 5 methysergide maleate, pizotifen maleate, sumatriptan succinate. Anti-muscarinic agents: atropine, benzhexol HCI, biperiden, ethopropazine HCI, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, oxyphencylcimine HCI, tropicamide. 10 Anti-neoplastic agents and Immunosuppressants: aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCI, tamoxifen citrate, testolactone. 15 Anti-protazoal agents: benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole. 20 Anti-thyroid agents: carbimazole, propylthiouracil. Anxiolvtic, sedatives, hypnotics and neuroleptics: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam, 25 clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone. 30 Beta-Blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol. Cardiac Inotropic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, 35 medigoxin.

16 Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone. 5 Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene. Anti-Parkinson agents: bromocriptine mesylate, lysuride maleate. 10 Gastro-intestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCI, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCI, ranitidine HCI, sulphasalazine. 15 Histamine H,-Receptor Antagonists: acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCI, dimenhydrinate, flunarizine HCI, loratadine, meclozine HCI, oxatomide, terfenadine, triprolidine. Lipid regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol. 20 Local anaesthetics: Neuro-muscular agents: pyridostigmine. Nitrates and other anti-anginal agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate. 25 Nutritional agents: betacarotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K. Opioid analgesics: codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, 30 meptazinol, methadone, morphine, nalbuphine, pentazocine, medazolam, fentanyl. Oral vaccines: Vaccines designed to prevent or reduce the symptoms of diseases of which the following is a representative however not exclusive list: Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, 35 Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease, Travellers' Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies, Parainfluenza, 17 Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina Haemorrhagic Fever, Caries, Chagas Disease, Urinary Tract Infection caused by E. coli, Pneumoccoccal Disease, Mumps, and Chikungunya. 5 Vaccines to prevent or reduce the symptoms of other disease syndromes of which the following is a representative, however not exclusive list of causative organisms: Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondii, Cytomegalovirus, Chlamydia species, Streptococcal species, 10 Norwalk Virus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Neisseria meningiditis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridia species, Respiratory Syncytial Virus, Klebsielia species, Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross 15 River Virus, J. C. Virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica. Further specific examples include opioids such as fentanyl or midazolam. Vaccines directed to non-infections immuno-modulated disease conditions such as 20 topical and systematic allergic conditions such as Hayfever, Asthma, Rheumatoid Arthritis and Carcinomas. Vaccines for veterinary use include those directed to Coccidiosis, Newcastle Disease, Enzootic pneumonia, Feline leukaemia, Atrophic rhinitis, Erysipelas, Foot 25 and Mouth disease, Swine, pneumonia, and other disease conditions and other infections and auto-immune disease conditions affecting companion and farm animals. Proteins, peptides and recombinant drugs: insulin (hexameric/dimeric/monomeric 30 forms), glucagon, growth hormone (somatotropin), polypeptides or their derivatives, (preferably with a molecular weight from 1000 to 300,000), calcitonins and synthetic modifications thereof, enkephalins, interferons (especially Alpha-2 interferon for treatment of common colds), LHRH and analogues (nafarelin, buserelin, zolidex),GHRH (growth hormone releasing hormone), secretin, bradykin antagonists, 35 GRF (growth releasing factor), THF, TRH (thyrotropin releasing hormone), ACTH analogues, IGF (insulin like growth factors), CGRP (calcitonin gene related peptide), 18 atrial natriurectic peptide, vasopressin and analogues (DDAVP, lypressin), factorVill, G-CSF (granulocyte-colony stimulating factor), EPO (erythropoitin). Sex hormones: clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone 5 acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated oestrogens, progesterone, stanozolol, stiboestrol, testosterone, tibolone. Spermicides: nonoxynol 9. Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, 10 mazindol, pemoline. Notwithstanding the general applicability of the method of the invention, more specific examples of biologically active materials include, however are not limited to: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride (p-adrenergic 15 agonist), terfenadine (H1-antagonist), propranolol hydrochloride (p-adrenergic antagonist), desipramine hydrochloride (antidepressant), sildenafil citrate, tadalafil and vardenafil. Minor analgesics (cyclooxygenase inhibitors), fenamic acids, Piroxicam, Cox-2 inhibitors, and Naproxen, and others, may all benefit from being prepared. 20 Further examples include, however are not limited to: alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin, benzocaine and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, binovum, 25 biperiden, bromazepam, bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan, cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin, cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate, ciglitazone, clonidine, cortexolone, 30 corticosterone, cortisol, cortisone, cyclophosphamide, cyclosporin A and other cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone esters such as the acetate, dezocine, diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digitoxin, digoxin, dihydroergotamine, dihydroergotoxin, diltiazem, dopamine antagonists, doxorubicin, econazole, endralazine, enkephalin, enalapril, 35 epoprostenol, estradiol, estramustine, etofibrate, etoposide, factor ix, factor viii, felbamate, fenbendazole, fenofibrate, fexofenedine, flunarizin, flurbiprofen, 5- 19 fluorouracil, flurazepam, fosfomycin, fosmidomycin, furosemide, gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide, glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine, hydralazine, hydrochlorothiazide, hydrocortisone, ibuprofen, ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray contrast agents such as 5 iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifen, ketotifen fumarate, K-strophanthin, labetalol, lactobacillus vaccine, lidocaine, lidoflazin, lisuride, lisuride hydrogen maleate, lorazepam, lovastatin, mefenamic acid, melphalan, memantin, mesulergin, metergoline, methotrexate, methyl digoxin, methylprednisolone, metronidazole, metisoprenol, metipranolol, metkephamide, 10 metolazone, metoprolol, metoprolol tartrate, miconazole, miconazole nitrate, minoxidil, misonidazol, molsidomin, nadolol, nafiverine, nafazatrom, naproxen, natural insulins, nesapidil, nicardipine, nicorandil, nifedipine, niludipin, nimodipine, nitrazepam, nitrendipine, nitrocamptothesin, 9-nitrocamptothesin, olanzapine, oxazepam, oxprenolol, oxytetracycline, penicillins such as penicillin G benethamine, 15 penecillin 0, phenylbutazone, picotamide, pindolol, piposulfan, piretanide, piribedil, piroxicam, pirprofen, plasminogenici activator, prednisolone, prednisone, pregnenolone, procarbacin, procaterol, progesterone, proinsulin, propafenone, propanolol, propentofyllin, propofol, propranolol, raloxifene, rifapentin, simvastatin, semi-synthetic insulins, sobrerol, somastotine and its derivatives, somatropin, 20 stilamine, sulfinalol hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulproston, synthetic insulins, talinolol, taxol, taxotere, testosterone, testosterone propionate, testosterone undecanoate, tetracane HI, tiaramide HCI, tolmetin, tranilast, triquilar, tromantadine HCI, urokinase, valium, verapamil, vidarabine, vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine, vincristine, vindesine, vinpocetine, 25 vitamin A, vitamin E succinate, and X-ray contrast agents. In addition, it is also expected that new chemical entities (NCE) and other actives for which the methods of the invention are suitable, and will be created or become commercially available in the future. 30 The present invention also relates to a pharmaceutical composition for transmucosal delivery comprising a fast dissolving solid dosage form adapted for of specific cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitors in the oral cavity wherein the dosage form comprises: (i) at least one of the specific 35 cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) 20 inhibitor, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. As used herein, the term of the specific cyclic guanosine monophosphate (cGMP) 5 phosphodiesterase type 5 (PDE5) inhibitor includes sildenafil, tadalafil, vardenafil. In a preferred embodiment of the invention, the antagonist is sildenafil or its pharmaceutically acceptable salt thereof. Preferably, the antagonist is sildenafil citrate. 10 The sildenafil may be generally present in an amount from 0.02 to 95%, preferably 0.1 to 75% or preferably 1 to 45%, by dry weight of the composition of the dosage form. 15 The sildenafil may be generally present in an amount selected from the group consisting of: 5mg; 10mg; 15mg; 20mg; 25mg; 30mg; 35mg, 40mg, 45mg, 50 mg, 60mg and 100mg. According to another aspect of the invention, there is provided a pharmaceutical 20 composition for oral transmucosal administration, the composition comprising at least one matrix forming agent. The method may include the step of selecting other polymer materials suitable for forming a matrix for specific application in the field of drug delivery, especially for 25 site-specific drug delivery system such as in the oral cavity. Matrix forming agents of the present invention may be 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; amino acids; 30 starch; modified starches; carboxymethylcellylose; hydroxypropylmethylcellulose; hydroxypropyl cellulose and methyl cellulose inorganic salts; synthetic polymers; amylopectin, polypeptide/protein or poly-saccharide complexes. In another embodiment of the invention, the solid dosage form is substantially free of 35 starch.

21 In a further embodiment of the invention, the pharmaceutical composition is substantially free of starch. The precise quantity of biologically active material will depend on the material, such 5 as a drug, selected. However, the active material is generally present in an amount from 0.02 to 95%, preferably 0.02 to 20% or preferably 0.1 to 75%, by dry weight of the composition of the dosage form. The fast dissolving solid dosage form of the present invention also comprises at least 10 one matrix forming agent. In the freeze-dried systems of the prior art, gelatin is the most commonly used carrier or structure forming agent due to its wall-forming ability. Gelatin is a water soluble polymer, and as such, when mixed with active pharmaceutical ingredients in water; the increasing viscosity of the solution over time may cause a decreasing solubility of poorly soluble drugs in the mixture, and lead to 15 a suspension of the drug in gelatin matrix. This can cause phase separation to occur; and the drug in amorphous or crystalline forms may not be homogenously dispersed in the matrix, which will eventually affect the dissolution and absorption of the final product. 20 Applicant has found that other polymer materials suitable for forming a matrix may be selected for specific application in the field of drug delivery, especially for site-specific drug delivery system such as in the oral cavity. Matrix forming agents of the present invention may be selected from the group consisting of: non-mammalian gelatin, dextrin, soy protein, wheat protein, psyllium seed protein, acacia gum, guar gum, 25 agar gum, xanthin gum, polysaccharides; alginates; sodium carboxymethylcellulose; carrageenans; dextrans; pectins; sugars; amino acids; starch; modified starches; carboxymethylcel lylose; hydroxypropylmethylcell ulose; hydroxypropyl cellulose and methyl cellulose inorganic salts; synthetic polymers; amylopectin, polypeptide/protein or poly-saccharide complexes. 30 Applicant has also found that the solid dosage form or pharmaceutical composition of the invention may be substantially free of starch. Examples of at least one matrix forming agent that are carbohydrates include 35 mannitol, dextrose, lactose, galactose and trehalose and cyclodextrin. Examples of matrix forming agents that are inorganic salts may be selected from the group 22 consisting of: sodium phosphate, sodium chloride and aluminium silicates. The at least one matrix forming agent may also be an amino acid. Examples of suitable amino acids include glycine, L-alanine, L-aspartic acid, L-glutamic acid, L hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. 5 In a highly preferred embodiment, at least one matrix forming agent is sodium carboxymethylcellulose. When at least one matrix forming agent is sodium carboxymethyl cellulose, the polymer is present in a concentration of from about 0.05% to about 19% by dry weight of the solid dosage form. In a preferred 10 embodiment, the polymer is present in a concentration of from about 0.1% to about 19% by dry weight of the solid dosage form. In a preferred embodiment the sodium carboxymethylcellulose is present in an amount of about 0.1% to about 15% by dry weight of the dosage form. In a highly preferred embodiment of the present invention, the sodium carboxymethyl cellulose is present in an amount of about 0.1% 15 to about 10% by dry weight of the solid dosage form. In another highly preferred embodiment of the present invention, the sodium carboxymethyl cellulose is present in an amount of about 0.1% to about 1.0% by dry weight of the solid dosage form. In another embodiment of the present invention, the fast dissolving dosage form 20 comprises amylopectin as at least one matrix forming agent. Amylopectin is capable of increasing the release of the biologically active agent by promoting formulation disintegration. Amylopectin may be present in the dosage form at a concentration about 2% up to no great than 20% by dry weight of the solid dosage form. In a highly preferred form of the present invention, amylopectin is present in an amount of about 25 2% to about 15% dry weight of the dosage form. To achieve a rapid dissolution of drugs, diluents, may be added as at least one matrix forming material. Diluents include microcrystalline cellulose (e.g., Avicel PH 30 101* and Avicel PH 102*), lactose, starch and sorbitol. These diluents may be present in the dosage form either alone or as a mixture in different ratios, and may be about 1% to about 80%, preferably about 2% to about 50%, either individually or cumulatively. 35 Alternatively, the solid dosage form or the pharmaceutical composition of the invention may be substantially free of Avicel.

23 In one embodiment of the present invention, the fast dissolving dosage form comprises microcrystalline cellulose as the at least one matrix forming agent. Microcrystalline cellulose may act as a filler and binder in the dosage form of the 5 present invention. Microcrystalline cellulose has the ability to compact with minimum compression pressures, and 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. When the solid dosage form of the present 10 invention comprises microcrystalline cellulose, it is present in an amount of about 1% to about 10%, and preferably from about 1% to about 8% by dry weight of the dosage form. The effectiveness of the fast dissolving dosage form of the present invention relies on 15 the drug dissolving in a small volume of fluid, such as in the oral cavity, prior to absorption into the systemic circulation. Therefore, the rate of dissolution of the dosage form is important. In a preferred embodiment of the present invention, the dosage form comprises a super-disintegrant as at least one matrix forming material. 20 In a highly preferred embodiment, the fast dissolving dosage form of the present invention comprises glycine. 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 anti-collapsing 25 agent, which maintains the dosage form from shrinking either during the manufacture process or after packing. In one embodiment, the dosage form of the present invention comprises from about 0.5% to about 5% dry weight of the dosage form. According to another embodiment of the invention, the fast dissolving solid dosage 30 form may include a matrix forming agent such as mannitol. Mannitol is a component that may aid in the crystalline structure and impart hardness of the dosage form. When mannitol is present in the dosage form, it occurs in a concentration of from about 5% to about 80%, and preferably from about 10% to about 60% by dry weight of the dosage form, most preferably from about 10% to about 50% by dry weight of 35 the dosage form.

24 In addition, the fast dissolving dosage form of the present invention may include lubricants, such as polyethylene glycol (PEG) 1000, 2000, 4000 and 6000, sodium lauryl sulphate, fats or oils. One advantage of the use of these lubricants is to aid in the removal of the dosage form from the mould. These lubricants may be present in 5 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%, preferable about 1.5%, either individually or cumulatively. In one embodiment, the composition includes between 0.05% to 5% polyethylene glycol 2000, preferably between 0.1% and 2% polyethylene glycol 2000, preferably about 1.5% polyethylene glycol 2000 by dry 10 weight of the dosage form, or as mixtures of the various glycols. The invention extends, in another aspect thereof, to improve sublingual absorption of weak base compounds, the composition comprising a solid buffer reagent that affords to produce a saliva pH of 7.0 to 7.8 when dissolved in oral cavity. Increasing 15 the pH of the solution of a weak base compound can increase the ratio of unionized to ionized, which will lead to enhanced sublingual absorption. The solid buffer reagent include sodium dihydrogen phosphate dehydrate, sodium hydrogen 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 20 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, preferably between 0.1% to 1%, most preferably about 0.3%. 25 The invention extends, in another aspect thereof, to improved transmucosal absorption of sildenafil, the composition comprising a solid buffer reagent that affords to produce a saliva pH of 7.0 to 7.8 when dissolved in oral cavity. Increasing the pH of the solution of sildenafil can increase the ratio of unionized to ionized, which will lead to enhanced transmucosal absorption. The solid buffer reagent includes sodium 30 dihydrogen phosphate dehydrate, sodium hydrogen 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 35 composition, more preferably between 0.1% to 1%, most preferably about 0.5%.

25 The molecular structure of sildenafil has both weakly acid centre and weakly basic centre. It means sildenafil solubility in water is affected by the solution pH value and two optimum pH (pHmax) values are 4.5 and 10.24 (29). Therefore, to improve transmucosal absorption of sildenafil, the composition comprising a solid buffer 5 reagent that affords to produce a saliva pH of 5.0 to 6.0 when dissolved in oral cavity. Increasing the pH of the solution of sildenafil can decrease the ratio of unionized to ionized, which will lead to enhanced transmucosal absorption. The solid buffer reagent includes alginic acid, ascorbic acid, citric acid malic acid, succinic acid and tartaric acid, which may be present in the dosage form either alone or as a mixture in 10 different ratios in a concentration of about 0.01% to about 10% by weight of the composition. Preferably, the buffer reagent is citric acid, which may be present in a concentration of about 0.01% to about 10% by weight of the composition, more preferably between 0.1% to 5%, most preferably about 2.0%. 15 The composition may, in one embodiment, be formulated to be substantially free of preservatives, physiological or mucosal absorption enhancers, or propellants. When mannitol is present in the dosage form, it occurs in a concentration of from about 5% to about 80%, and preferably from about 10% to about 60% by dry weight 20 of the dosage form. The composition may, in certain embodiments, include an absorption enhancer. The absorption enhancer may be a polysaccharide and may be positively charged. Preferably, the absorption enhancer is p-cyclodextrin or its derivatives. The p 25 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%. The fast dissolving solid dosage form of the present invention may comprise 30 flocculating agents to maintain disbursement of the biologically active material evenly dispersed in the matrix during the manufacture process. The flocculating agent may be gums. Preferable, the gum is xanthan 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%. 35 26 The fast dissolving solid dosage form of the present invention may comprise flocculating agents to maintain disbursement of sildenafil evenly dispersed in the matrix during the manufacture process. The flocculating agent may be gums. Preferable, the gum is xanthan gum. The xanthan gum may be present in a 5 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%. To aid dissolution of the biologically active material into the aqueous environment, a surfactant may be added to the solution as a wetting agent. Suitable surfactants include 10 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 and 80, sucrose fatty acid 15 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. 20 In order to enhance the aesthetic and taste appeal of the fast dissolving dosage form to the subject, the dosage form may also contain colouring agents, such as FD & C dyes Blue No. 2 and Red No. 40; flavoring agents, such as orange, mint, raspberry and caramel; and/or sweeteners such as aspartame and saccharin. 25 The fast dissolving solid dosage form of the present invention is suitable for oral administration to a subject. As discussed above, the dosage form comprises at least one biologically active agent or material. The active agent is therefore delivered to the subject via the oral cavity mucosa and into the systemic blood system within a 30 relatively short period of time. In a preferred embodiment, an effective plasma concentration of the biologically active agent is reached within a period of no more than two hours, preferable within 30 minutes, and most preferably within 10 minutes. As discussed above, the dosage form comprises at least one specific cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, 35 preferably sildenafil. The sildenafil is therefore delivered to the subject via the oral cavity mucosa and into the systemic blood system within a relatively short period of 27 time. In a preferred embodiment, an effective plasma concentration sildenafil is reached within a period of no more than one hour, preferable within 30 minutes, and most preferably within 10 minutes. 5 Furthermore, an advantage of the present invention is that the fast dissolving solid dosage form completely dissolves within 2 seconds to 60 seconds, preferably 2 seconds to 30 seconds, more preferably within 2 seconds to 10 seconds, and most preferably within 2 seconds to 15 seconds after administration of the dosage form. In a highly preferred embodiment of the present invention, there is no residue remaining 10 of the dosage form of the present invention after administration that is detectable by the patient. As such, the subject has no urge to swallow the dosage form. Preferably, there is no unpleasant task in the mouth of the subject. Preferably, the patient can engage in kissing with their partner shortly after taking the solid dosage form without having an unpleasant taste in their mouth. 15 The subject receiving the fast dissolving dosage form of the present invention may be an animal or human being. When the subject is a human being, it may be an adult or a child, including elderly adults and infants. In particular the subject is a subject that is unable to or has difficulties in swallowing. 20 The inventors have surprisingly found that the addition of sodium carboxymethylcellulose improves the dissolution rate of the fast dissolving dosage form. When the amount of sodium carboxymethylcellulose is between about 0.1% and 15% by dry weight of the dosage form, the wafer releases the active agent 25 rapidly, without leaving a residue in the oral cavity. In addition, the use of gelatin was avoided by the inventors, and therefore prevents the unwanted residue left in the oral cavity after administration. The addition of lactose and or mannitol was also found to be advantageous in the dosage formulation of the present invention. When the amount of sodium carboxymethylcellulose is between about 0.1% and 10% by dry 30 weight of the dosage form, it releases sildenafil rapidly, without leaving a residue in the oral cavity. In addition, the use of gelatin was avoided, and therefore prevents the unwanted residue left in the oral cavity after administration. The addition of lactose and or mannitol was also found to be advantageous in the dosage formulation of the present invention. 35 28 Thus, in a highly preferred embodiment, the present invention provides a rapidly dissolving solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises: (i) at least one biologically active material and (ii) at least one matrix forming agent, wherein the dosage form 5 substantially dissolves in the oral cavity, wherein the dosage form comprises 0.29% sodium carbonate, 0.59% sodium carboxymethylcellulose, 1.48% PEG 2000, 2.97% glycine, 5.93% microcrystalline cellulose; 14.84% amylopectin, 29.67% lactose and 44.23% mannitol as a dry weight 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. 10 Applicant also found that PEG 2000 could be replaced with PEG 1000 with the same advantages as the oral dosage form described above. As discussed above, the medicaments of the present invention may include one or more pharmaceutically acceptable carriers. The use of such media and agents for 15 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. 20 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, polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose derivatives, 25 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 acetate; and/or 30 (2) binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and/or (3) filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches; and/or (4) lubricating agents such as agents that act on the flowability of the powder to 35 be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and/or 29 (5) sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and accsulfame K; and/or (6) flavouring agents; and/or (7) preservatives such as potassium sorbate, methylparaben, propylparaben, 5 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; antioxidants such as ascorbic acid, potassium sorbate, sodium bisulfate sodium metabisulfite and sorbic acid; and/or 10 (8) buffers; and/or (9) diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing; and/or (10) wetting agents such as corn starch, potato starch, maize starch, and 15 modified starches, croscarmellose sodium, crosspovidone, sodium starch glycolate, and mixtures thereof; and/or (11) disintegrants; and/or (12) effervescent agents such as effervescent couples such as an organic acid (e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and 20 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 bicarbonate or potassium bicarbonate); and/or (13) other pharmaceutically acceptable excipients. 25 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 the biologically active material can be formulated as a solid, a liposome, or other ordered structures 30 suitable to high drug concentration adapted for oral delivery. The medicaments of the invention comprising sildenafil can be formulated as a solid, a liposome, or other ordered structures suitable to high drug concentration adapted for oral delivery. Actual dosage strengths of the biologically active material in the medicament of the 35 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 30 providing and administering the biologically active material. Thus as used herein "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 5 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; and the judgment of the prescribing physician. Actual dosage strengths of sildenafil in the medicament of the invention may be 10 varied in accordance with its nature, as well as the potential increased efficacy due to the advantages of providing and administering sildenafil. Thus, as used herein, "therapeutically effective amount" will refer to an amount of sildenafil 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 sildenafil; the desired 15 duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician. In another embodiment, the biologically active material may be combined into a 20 medicament with another biologically active material, or even the same biologically active material. In the latter embodiment, a medicament may be achieved which provides for different release characteristics - early release from the biologically active material, and later release from a larger average size biologically active material. 25 In another embodiment, sildenafil may be combined into a medicament with another biologically active material, or even with an alternative formulation of sildenafil. In the latter embodiment, a medicament may be formulated to include to formulations which provide for different release characteristics - a first formulation providing for early 30 release of sildenafil, and a second formulation providing for later release of sildenafil. Medicaments of the invention can be orally administered to a subject. Solid dosage forms for oral administration include wafers, capsules, tablets, pills, powders, pellets, films and granules. Further, incorporating any of the normally employed excipients, 35 such as those previously listed, and generally 0.1% to 95% of the biologically active 31 agent, and more preferably at a concentration of 0.1% to 75% will form a pharmaceutically acceptable non-toxic oral administration. Although the fast dissolving dosage form of the present invention may be administered 5 orally, the oral dosage form of the present invention is also suitable for use with a nebulizer, either jet or ultrasonic, and will typically comprise the dosage form suspended in water. The dosage form of the present invention may also include a buffer and a simple sugar (e.g., for protein stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface 10 induced aggregation of the compounds caused by atomization of the solution in forming the aerosol. As described above, the biologically active material can be formulated into a solid dosage form (e.g., for oral, dermal or suppository administration). In this case there 15 may be little or no need to add stabilizing agents since the grinding matrix may effectively act as a solid-state stabilizer. As described above, sildenafil can be formulated into a solid dosage form (e.g., for oral, dermal or suppository administration). In this case there may be little or no need 20 to add stabilizing agents since the grinding matrix may effectively act as a solid-state stabilizer. Therapeutic uses of the medicaments of the invention include pain relief, anti inflammatory, migraine, asthma, and other disorders that require the active agent to 25 be administered with a high bioavailability. One of the main areas when rapid bioavailability of a biologically active material is required is in the relief of pain. The minor analgesics, such as cyclooxgenase inhibitors (aspirin related drugs) or opioids may be prepared as medicaments according to the present invention. 30 Therapeutic uses of the medicaments of the invention include erectile dysfunctions, pulmonary hypertension, central nervous disorders, cardiovascular disorders, high altitude pulmonary edema, and other disorders that require sildenafil to be administered with a high bioavailability. One of the main areas when rapid bioavailability of sildenafil is required is in the erectile dysfunctions of etiologies. 35 32 Treatment of cardiovascular disease may also benefit from biologically active materials according to the invention, such as treatment of angina pectoris and, in particular, molsidomine may benefit from improved bioavailability. Other therapeutic uses of the medicaments of the present invention include treatment of hair loss, 5 sexual dysfunction, or dermal treatment of psoriasis. According to a further aspect of the present invention, there is provided a method to produce the fast dissolving dosage form of the present invention comprising the steps of combining at least one matrix forming agent with a biologically active 10 material to form a mixture and then freeze drying the mixture to form the solid dosage form. In a preferred embodiment of the present invention, the mixture is measured (by weight or volume) into a preformed plastic or aluminium blister mould (individual dose). The blister mould is placed into a freeze dryer for 24 hours and the resultant solid dosage form (wafer) is then sealed with aluminium or plastics foil to prevent 15 moisture absorption. According to a further aspect of the present invention, there is provided a method to produce the fast dissolving dosage form of the present invention comprising the steps of combining at least one matrix forming agent with sildenafil to form a mixture 20 and then freeze drying the mixture to form the solid dosage form. In a preferred embodiment of the present invention, the mixture is measured (by weight or volume) into a preformed plastic or aluminium blister mould (individual dose). The blister mould is placed into a freeze dryer for 24 hours and the resultant solid dosage forms (film and/or wafer) is then sealed with aluminium or plastics foil to prevent moisture 25 absorption. 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 3.0 and 8.0, preferably between 6.4 and 7.8. If required, the pH may be adjusted by using an acid, such as 30 hydrochloric acid, phosphoric acid or citric acid; or a basic compound such as sodium hydroxide, sodium dihydrogen phosphate dehydrate, sodium hydrogen phosphate, sodium hydrogen carbonate and sodium carbonate. In another embodiment of the invention, the moisture content of the competition may 35 be between 4% and 20%. More specifically, the moisture content may be around 4%.

33 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 5 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. 10 In a further aspect of the present invention, there is provided a kit comprising the fast dissolving oral dosage form wherein the dosage form comprises: (i) at least one biologically active material, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 15 In a further aspect of the present invention, there is provided a kit comprising the fast dissolving oral dosage form wherein the dosage form comprises: (i) sildenafil, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 20 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. 25 BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 Scanning electron micrographs of the surface of wafers from batch numbers 071501B and 071502B. 30 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 35 batch numbers 071501B and 071502B.

34 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. 5 FIGURE 7 Powder X-ray diffraction spectra of wafers from batch number 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 10 0905MD. 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; 15 and [E] standard midazolam sample at 8.1 pg/ml. 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. 20 FIGURE 13 Typical HPLC chromatograms of dissolution wafer Sample S2 at 5 and 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 25 seconds and at 1 minute. 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. 30 FIGURE 18 Typical HPLC chromatograms of dissolution wafer 1 at 1 minute and 5 minutes. 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. 35 FIGURE 21 Typical HPLC chromatograms of dissolution wafer 2 at 30 seconds.

35 FIGURE 22 Typical HPLC chromatograms of dissolution wafer 2 at 1 minute and 5 minutes. FIGURE 23 Typical HPLC chromatograms of dissolution wafer 2 at 10, 15 and 30 minutes. 5 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. 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 10 minutes. FIGURE 28 Typical HPLC chromatograms of dissolution wafer 3 at 30, 45 and 60 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 g/mL). 15 FIGURE 31 Cumulative concentration of midazolam released from wafer and midazolam powder in phosphate buffer solution (pH 6.8) at 37'C. FIGURE 32 Standard HPLC calibration curve of fentanyl (0.5 to 10 g/mL). FIGURE 33 Dissolution profiles of fentanyl wafer in phosphate buffer solution (pH 6.8) at 37'C, (n=4). 20 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. 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 25 dosage form. 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. 30 FIGURE 39 Powder X-ray diffraction spectra of ketamine powder. 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. 35 FIGURE 42 Typical HPLC chromatogram of dissolution ketamine wafer Sample S2 at 3 minutes.

36 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. 5 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 10 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 1 00 g/mL). 15 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). FIGURE 52 Geometric mean with overlay of individual RS ketamine plasma 20 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 concentrations during the first 12 hours following a 10 mg dose given 25 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. FIGURE 55 Geometric mean with overlay of individual RS ketamine plasma 30 concentrations during the first 12 hours following a 25 mg sublingual dose to eight healthy volunteers. FIGURE 56 Individual (S=Subject randomization number) tmax for RS ketamine following 25 mg sublingual dose to eight healthy volunteers. FIGURE 57 Individual (S=Subject randomization number) AUCINF for RS ketamine 35 following a 10 mg dose given during a 30 minute intravenous infusion 37 (IV, open bars) or 25 mg sublingually (SL, filled bars) to eight healthy volunteers. FIGURE 58 Individual (Subject randomization number) clearance (CL) for RS ketamine following a 10 mg dose given during a 30 minute intravenous 5 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 circles) to eight healthy volunteers. 10 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 for Factors "alertness" (Factor 1), "contentedness" (Factor 2) and 15 "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) and "calmness" (Factor 3) observed following sublingual administration 20 of a 25 mg ketamine wafer to healthy volunteers. FIGURE 63 Total modified Likert Scales of Local Tolerability FIGURE 64 Scanning electron micrographs of the surface of a blank fast dissolving dosage form. FIGURE 65 Powder X-ray diffraction spectra of a blank fast dissolving dosage 25 form. FIGURE 66 Powder X-ray diffraction spectra of sildenafil powder. FIGURE 67 Powder X-ray diffraction spectrum of sildenafil fast dissolving dosage form. FIGURE 68 Typical HPLC chromatograms of dissolution sildenafil wafer Sample 30 S1 at 1 minute FIGURE 69 Typical HPLC chromatogram of dissolution sildenafil wafer Sample S1 at 3 minutes FIGURE 70 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 5 minutes 35 FIGURE 71 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 7 minutes 38 FIGURE 72 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 10 minutes FIGURE 73 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 15 minutes 5 FIGURE 74 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 20 minutes FIGURE 75 Typical HPLC chromatograms of dissolution sildenafil wafer Sample S1 at 30 minutes FIGURE 76 Typical HPLC chromatogram of drug loading test sildenafil wafter 10 sample No.1. FIGURE 77 Standard HPLC calibration curve of sildenafil 5 to 100 g/mL). FIGURE 78 Dissolution profiles of sildenafil wafer in phosphate buffer solution (pH 6.8) at 37'C, (n=4). FIGURE 79 Table showing the demographic characteristics of the study volunteers 15 according to example 4. FIGURE 80 Graph showing the mean (±SEM) plasma concentration (pg/mL) over time profiles for sublingual fentanyl water and IV fentanyl. Inset figure is an expanded profile for the initial two-hour period. FIGURE 81 Graph showing the plasma concentration data (pg/mL) over time 20 profiles for sublingual fentanyl wafer for each volunteer (n=22). FIGURE 82 Table showing the mean values (±1 SD) of fentanyl plasma pharmacokinetic parameters. FIGURE 83 Table showing the comparative literature pharmacokinetic data (mean 1 SD) for buccal and sublingual (SL) fentanyl dosage forms. 25 39 DETAILED DESCRIPTION OF THE INVENTION General 5 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 10 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 15 scope of the invention as described herein. 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 20 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. The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are 25 hereby incorporated by reference. Inclusion does not constitute an admission is 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 30 "comprise" or variations, such as "comprises" or "comprising" will be understood to 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 35 to it in US Patent law; e.g., they can mean "includes", "included", "including", and the like.

40 "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 5 number of subjects in need of such treatment. It is emphasized that "therapeutically 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 10 oral dosages, or with reference to drug levels as measured in blood. 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 15 includes both medical therapeutic and prophylactic administration, as appropriate. The term "biologically active material" is defined to mean a biologically active 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 20 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 a more complex and have a mixed chemical structure. For such compounds they may only have an empirical formula or be qualitatively indentified. A compound would 25 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, fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, neutraceuticals, 30 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 any substance which has as one of its components a biological active compound. Examples of substances containing biologically active compounds are, however not 35 limited to, pharmaceutical formulations and products, cosmetic formulations and products, industrial formulations and products, agricultural formulations and products, 41 foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material. Any of the terms, "biological(ly) active", "active", "active material" shall have the same 5 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 absorption delaying agents, and the like that are physiologically compatible. 10 Preferably, the carrier is suitable for oral administration. Detailed Description of the Invention Example 1 A formulation of the present invention was prepared in accordance with the method 15 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 carboxymethylcel lulose 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 20 water by mixing thoroughly with a stirrer. The mixture was then heated to 500C for ten minutes to allow dissolving of the polymers. Once the solution cooled down to room temperature, polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose and mannitol were added individually, under stirring to obtain a homogenously solution. The viscosity of the solution was 42 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 5 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. 10 The following additional formulations were prepared by the method as set out above. 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 Sodium 2 0.15 carboxymethylcel lulose 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 15 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 carboxymethylcel lulose 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 43 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 2000 5 0.37 Grape flavor 9.9 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 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 carboxymethylcel lulose 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 5 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 44 carboxymethylcel lulose 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 carboxymethylcel lulose 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 5 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 0820A 0820B 0905MD 1003FEN

B

45 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 5 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. 10 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 46 from different formulations were within the accepted weight variation from between 0.25 to 2%. Hardness 5 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 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 10 (results not shown). Friability 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 15 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. 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%. 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. Moisture Analysis 25 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. Scanning electron microscopic analysis 30 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 of the wafer using a scalpel. Samples were coated with carbon prior to examination. The accelerating voltage was 10 kV. 35 47 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 excipients used influence the microstructure of the wafer. In addition, the 5 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) 10 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. 15 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 20 2-theta of 9.580, 19, 680 and 20.050, which indicating a crystalline nature. This finding 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. 25 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'C. 30 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. 35 For the dissolution testing: 48 (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 5 rotation speed at 75 rpm. At given interval (e.g., 0.5, 1, 2, 3, 5 10 15, 20 and 30 min), 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. 10 The HPLC system consisted of a Waters 1525 pump, a Waters Symmetry C18 column (5 rim, 150 x 4.6 mm), and Waters UV 484 detector. The mobile phase was 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 15 concentrations 1-32.4 g/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 samples]. A standard HPLC calibration curve for Midazolam is shown in Figure 30. The results 20 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 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 25 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 in accordance with Table 1 are shown in Figures 11 to 29. Figures 10 A to 10 E 30 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 35 contains midazolam as a model drug.

49 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 wafer containing test drug midazolam was measured. Samples were taken at 0.5 minute, 1 minute, 5, minutes, 10 minutes and 15 minutes. 5 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 15 method. The dissolution rates of the wafer were determined in a small volume (10 mL phosphate buffer solution, pH 6.8) with a basket rotation speed at 50 rpm. At 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. 20 The mobile phase was methanol: 0.4% phosphoric acid (50 : 50, v/v, pH 2.3) and the 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 g/mL (eight-point calibration) was linear [y=316668x+4675.7, (r=0.9999), y representing the peak area 25 of fentanyl and x the concentration of the samples]. The assay standard curve is shown in Figure 32. 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 30 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 profiles are presented in Figure 33. 35 The HPLC chromatograms of six dissolution samples of fentanyl wafers were collected and is shown in Figures 34 A to E (samples 1 to 3) and Figures 35 A to J.

50 (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. 5 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 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 10 effect. Example 2 A formulation of the present invention was prepared in accordance with the method and ingredients as set out below in Table 3: 15 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 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'C for 20 ten minutes to allow dissolving of the polymers. Once the solution cooled down to room temperature, PEG 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose, mannitol and ketamine hydrochloride were added individually, under stirring 51 to obtain a homogenously solution. The viscosity of the solution was measured at 25'C using a Brookfield Digital Viscometer (Brookfi eld Engineering Laboratories Inc, MA, USA). 5 The resulting mixture was transferred by pipette and accurately weighed into pre 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. 10 The following additional formulations were prepared by the method as set out above. 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. 15 Sample 1. Sample 1 additionally contained a flavour. Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.14 carboxymethylcel lulose 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 carboxymethylcel lulose Citric acid 5 0.35 52 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 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 carboxymethylcel lulose 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. 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 53 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 54 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. 5 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 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 55 Purified water 40 40 40 General observations The procedure of Example 2 was repeated, except that PEG 1000 was employed 5 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. 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. 10 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. 15 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 deviation was calculated. All the prepared wafers from different formulations were 20 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 referred to as "hardness", which was determined using an Erweka Hardness Tester 25 (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 a fast dissolution rate and allows for easy handling. 30 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 35 (Germany). A sample of 20 ketamine wafers was weighed accurately and placed in 56 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%. 5 Moisture Analysis 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%. 10 Scanning electron microscopic analysis Surface morphology and cross-section of samples selected wafer formulations were 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. 15 The accelerating voltage was 10 kV. The SEM images shown in Figures 36 and 37 illustrate the highly porous nature of the wafers for both surface and the inner structures. 20 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 mA. The samples were scanned over a 2 theta range of 7.5 to 70, and counting 25 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 30 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. 35 However, all became amorphous after freeze-drying.

57 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'C. 5 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. 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. For the dissolution testing: Dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). 15 The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37 ± 0.50C. A wafer (Batch 20110528) containing ketamine was used to determine the level of drug release from the 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 20 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 25 wavelength was at 210 nm. The HPLC chromatograms of dissolution ketamine wafer were shown In Figures 41 to 48. The calibration curve for the concentrations 5 to10O g/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 30 49. 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. 35 The average disintegration times (BP disintegration apparatus) were less than 5 seconds; and the dissolution studies also indicated a fast release rate of ketamine.

58 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. 5 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 10 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 potential to provide an alternate route of drug administration and results in lower rates of side effect. IN VIVO STUDIES 15 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 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. 20 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). 25 Study Subiects 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 30 presence of drug or alcohol dependence or abuse, and who had normal findings on 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 35 enrolled in this study.

59 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 5 plan, subjects were divided into two groups, in a 1:1 ratio using a computer 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 10 (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 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 15 screening period and a seven-day wash-out period. Measurements of pharmacokinetics, tolerability and safety were carried out for 24 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. 20 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 25 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 30 mL. After collection, the blood samples were immediately centrifuged at 4'C, 2000-2500g for 15 minutes and the plasma extracted and placed into polypropylene storage tubes. The plasma was stored at -80'C ± 1 0'C until transfe r to the bioanalytical laboratory. Pharmacokinetic Analysis 35 60 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. 5 Standard non-compartmental analysis was used to derive Pharmacokinetic variables, except for Cmax, tmax and tfrist, which were taken as observations from the plasma 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 Xz = -1* slope. The linear 10 regression in the terminal phase used the last three to six data points, at a minimum three points. The terminal ti, was calculated as ti, =ln(2) / Xz. The area under the plasma concentration time curve to the last quantifiable plasma concentration (AUCiast) was obtained using the linear up and log down method and 15 extrapolated to infinity with Clasit/z (last quantifiable plasma concentration divided by Xz) to obtain the total AUC, AUCINF. The extrapolated portion of the AUC, AUCextr, was obtained by (1-AUCast/AUCINF)*100. The total area under the first moment curve, AUMCINF, was calculated in a similar manner to AUCINF and MRT was obtained as AUMCINF/AUCINF correcting mean residence time (MRT.V.) for the 20 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 latter is unknown. The volume of distribution, Vz, was calculated as CL/Xz. The MAT for the sublingual administration was obtained as the difference between the MRT for 25 the two routes of administration as, MRTSL- MRTv. The bioavailability (F) of ketamine was calculated as the ratio of the dose adjusted AUCINF following IV and sublingual dosing according to AUCSL/AUCv * doselv/doseSL. Safety and Tolerability 30 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 examination was performed before the first dosing occasion and 24 hours after the second dosing occasion. 35 61 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", "contentedness" and "calmness", were performed at pre dose, 30 minutes post dose 5 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. 10 RESULTS The individual values and summary statistics for volunteer characteristics are reported in Table 5. 15 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 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 20 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 shown separately in Figure 53. The geometric mean with an overlay of individual RS 62 ketamine plasma concentrations for all subjects for the entire sampling period following SL administration are shown in Figure 54 and the first 12 hours are shown in Figure 55. 5 The IV and SL plasma concentration time curves were similar in shape, except for four subjects having 2-3 peaks for the SL route. Following Cmax, concentrations declined biphasically for both IV and SL although the trend was more prominent for IV. 10 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 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. 15 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. 20 For the SL dose, the median time of the main peak i.e. tmax, was 0.75 hour with the 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 56. 25 Table 6 presents individual estimates and summary statistics for the main pharmacokinetic variables. Individual AUCINF values for both routes of administration are shown in Figure 57. The extrapolated portion of the AUC, AUCextr, was very small for both routes of administration, which is indicative of a high quality in the estimation 30 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 58. Following SL 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. 35 63 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 the terminal phase of the plasma concentration time curve and hence show a 5 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 10 and 25 mg SL to eight healthy volunteers. Subject Cmax,iv tmax,iv Cmax,SL tmax,SL AUCINFIV AUCINF_SL CL V. t 112 ,iv tl12,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 a 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- 1.8 226.68 0.60 128.28 1.00 299.44 211.33 59.80 385 7.0 5.5 CV(%) 16 NA 14 21 8 4 8 18 16 17 a gmean is provided for all variables except for tmax and t 1

/

2 where medians are shown NA Not applicable 15 Bioavailability and Absorption In a majority of subjects, the SL wafer dissolved within 30 seconds to one minute. Individual estimates of bioavailability are shown in Figure 60 and individual 20 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, 64 and a double peak for the SL dose. The median and 90% CI [lower, upper] for bioavailability was 29 [27, 31] %, showing the very low inter subject variability. Table 7: Individual (Subject=randomization number), median, minimum and 5 maximum of RS ketamine bioavailability (F) and mean absorption time (MAT) following SL administration of 25 mg to eight healthy volunteers. Subject F (%) MAT (hr) 1 28 1.1 2 27 -0.83 3 29 -1.1 4 30 0.86 5 23 -1.1 6 29 -0.56 7 29 0.20 8 38 0.64 Median 29 -0.18 Min-Max 23-38 -1.1 - 1.1 90%CI [27, 31] NA* [lower, upper] * Not applicable 10 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 hours for SL, indicating a fast absorption. A small difference, i.e. a small MAT, 15 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 20 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.

65 Pharmacodynamic Results Bond and Lader Mood Rating Scales The Bond and Lader scales comprise a total of 16 100-mm lines anchored at either 5 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 analysis were isolated. These have been described by Bond and Lader as representing the following: 10 0 Factor1 : "alertness" (represented by lines anchored by alert-drowsy, attentive-dreamy, lethargic-energetic, muzzy-clearheaded, well coordinated-clumsy, mentally slow-quick witted, strong-feeble, interested bored, incompetent-proficient); e Factor 2 : "contentedness" (contented-discontented, troubled-tranquil, 15 happy-sad, antagonistic-friendly, withdrawn-sociable) and e Factor 3 : "calmness" (calm-excited, tense-relaxed); Scores for each factor represent the unweighted average number of millimeters (maximum 100 mm) from the negative antonym for the individual scales contributing to the factor. Hence the maximum score for Factor 1 is 900; for Factor 2, 500 and for Factor 3, 20 200. 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 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 25 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 Factor of the mood rating scales following IV and SL dosing are depicted in Figure 61 and Figure 62, respectively. 30 Modified Likert 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 for all values following IV administration although there were sporadic values of one 35 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 66 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 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 5 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 minutes. All values had returned to zero by one hour (Figure 63). 10 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 15 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 20 and transient CNS-type symptoms, as expected based on the existing clinical 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. Example 3 A formulation of the present invention was prepared in accordance with the method 25 and ingredients as set out below in Table 8: Table 8: Compositions of Fast Dissolving Solid Dosage Form Formulation Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 BP/USP Sodium 2 0.14 carboxymethylcel lulose BP/USP Polyethylene glycol 2000 5 0.34

BP/USP

67 Glycine BP/USP 10 0.68 Microcrystalline cellulose 10 0.68 BP/USP Citric acid BP/USP 10 0.68 Amylopectin BP/USP 50 3.42 Lactose BP/USP 100 6.84 Mannitol BP/USP 150 10.25 Sildenafil BP/USP 125 8.54 Purified water BP/USP 1000 68.35 Sodium carboxymethylcellulose and amylopectin were added in a portion of purified water by mixing thoroughly with a stirrer. The mixture was then heated to 500C for ten minutes to allow dissolving of the polymers. Once the solution cooled down to 5 room temperature, polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, citric acid, lactose and mannitol 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). 10 The resulting mixture was transferred by pipette and accurately weighed into pre 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 15 temperature. The following additional formulations were prepared by the method as set out above. Essentially Samples 1 to 6 are based on the formulation described above, with the addition of flavour and/or colour agents. 20 Sample 1. Sample 1 additionally contained a flavour. Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium 2 0.15 carboxymethylcel lulose Polyethylene glycol 2000 5 0.37 Orange flavor 10 0.74 68 Glycine 10 0.74 Citric acid 10 0.74 Microcrystalline cellulose 20 1.47 Amylopectin 50 3.68 Lactose 100 7.63 Mannitol 150 11.05 Purified water 1000 73.64 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 carboxymethylcel lulose Polyethylene glycol 2000 5 0.37 Citric acid 10 0.74 Mint flavor 10 0.74 Glycine 10 0.74 Microcrystalline cellulose 20 1.47 Amylopectin 50 3.68 Lactose 100 7.63 Mannitol 150 11.05 Purified water 1000 73.64 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 carboxymethylcel lulose Polyethylene glycol 5 0.37 2000 Grape flavor 9.9 0.73 Glycine 10 0.74 Microcrystalline 20 1.48 69 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 150 11.05 Purified water 1000 73.64 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 carbonare 1 0.07 Sodium 2 0.15 carboxymethylcel lulose p-Cyclodextrin 5 0.37 Polyethylene glycol 5 0.37 2000 Grape flavor 9.9 0.73 Glycine 10 0.74 Citric caid 10 0.74 Microcrystalline 20 1.47 cellulose Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 145 11.05 Deionsed water 1000 73.64 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 carboxymethylcel lulose Aspartame 5 0.37 Polyethylene glycol 5 0.37 70 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 74.18 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 carboxymethylcel lulose 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 74.18 Various batches of fast dissolving solid dosage form were then prepared based on the formulation shown in Table 8 and prepared as set out in Example 3 above. The 5 batch number and the ingredients are listed in Table 9. Table 9: Compositions of the Formulations Used for Investigations 71 Batch Batch Batch Batch Batch 071501B 071502B 0820A 0820B 0628K Ingredient Amount Amount Amoun Amount Amount (g) (g) (g) t (g) (g) Amylopectin 1.0 1.0 1.0 0.00 1.0 Mannitol 3.0 3.0 3.0 3.0 3.0 Lactose 2.0 2.0 2.0 2.0 2.0 Glycine 0.2 0.2 0.5 0.3 0.2 PEG 2000 0.1 0.1 0.1 0.1 0.1 Sodium 0.04 0.04 0.04 0.04 0.04 carboxymethyl cellulose Sodium 0 0.02 0 0 0.02 carbonate Starch 1.0 0 0 0 0 Citric acid 0 0 0 0 0.2 Avicel 0.2 0.2 0.00 0.2 0.2 Active 0 0 0 0 2.5 pharmaceutica sildenafil I ingredient (base) Purified water 40 40 40 40 40 General observations The procedure of Example 2 was repeated, except that polyethylene glycol 1000 was employed instead of polyethylene glycol 2000, to thereby yield a fast dissolving 5 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. 10 Formulation of Sildenafil Fast Dissolving Dosage Form for the In Vitro Study Uniformity of Weight The uniformity of the weight of the sildenafil wafer was tested in accordance with the British Pharmacopoeia (BP) 2009 test. Twenty wafers from the formulations listed in 72 Table 3 were individually weighed, and the average weight and relative standard deviation was calculated. All the prepared wafers from different formulations were within the accepted weight variation of 0.25 to 2%. 5 Hardness The hardness of the wafer was also tested. The mechanical strength of tablet is 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 10 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 a fast dissolution rate and allows for easy handling. Friability 15 The strength of sildenafil wafers (including 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 Erwreka friability tester (Germany). A sample of 20 sildenafil wafers was weighed accurately and placed in the apparatus. A rotation time of four minutes at 25 rpm was used. Sildenafil wafers 20 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 The moisture content of the sildenafil wafers was analyzed after lyophilisation using 25 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 30 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.

73 The SEM images shown in Figures 64 and 65 illustrate the highly porous nature of the wafers for both surface and the inner structures. Clearly, there were morphological differences between blank and sildenafil wafers. 5 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 mA. The samples were scanned over a 2 theta range of 7.5 to 70, and counting 10 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 9 are shown in Figures 66, 67 and 68. It was observed that all the powder 15 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. 20 However, it seemed 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 25 used for both tests. The temperature of the medium was kept at 37 ± 0.5'C. For the disintegration test, a sildenafil 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. 30 It was shown that the wafers of the present invention were able to completely dissolve in about 15 seconds and did not leave behind residue. For the dissolution testing: Dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). 35 The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37 ± 0.50C. A wafer (Batch 20120628) 74 containing sildenafil was used to determine the level of drug release from the formulation. The dissolution rates of the sildenafil 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 5 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 calibration curve for the concentrations 5 to100 10 g/mL (seven-point calibration) was linear [Y=32.973X-36538, (r=0.9999), Y representing the peak area of sildenafil and X the concentration of the samples]. The assay standard curve is shown in Figure 77. The prepared sildenafil wafer (Batch 20120628) showed a weight variation of 15 2.55%, and the mean percentage sildenafil content of the wafer was 98.67% (BP standard for uniformity content limits 85 to 115%). The average disintegration times (BP disintegration apparatus) were less than 5 seconds; and the dissolution studies also indicated a fast release rate of sildenafil. Almost 95% of sildenafil had dissolved within one minute. This may indicate the changing of sildenafil crystal form in the 20 wafer, which was also evident in the X-ray. The X-ray spectrum pointed to an amorphization of sildenafil during the freeze-drying process. The dissolution profiles are presented in Figure 78. The sildenafil wafer is a solid dispersion of sildenafil hydrochloride into a porous 25 matrix. After administration, this dosage form is quickly disintegrates in oral cavity, and allows rapidly dissolving sildenafil 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. 30 The fast dissolving dosage forms is a solid dispersion of drug into a porous matrix. After administration, this dosage form is quickly disintegrates in oral cavity, and 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 35 provide an alternate route of drug administration and results in lower rates of side effect.

75 Example 4 A Phase I Pharmacokinetic and Bioavailability Study of a Sublinqual Fentanyl Wafer in Healthy Volunteers 5 Methods Study Subjects Healthy volunteers gave written informed consent on an approved subject consent 10 form, before undergoing trial procedures. Subjects between 19 and 32 years of age who had a body mass index between 18 and 30 kg/m 2 , had no history or evidence of drug or alcohol dependence or abuse, had normal findings after a clinical history and laboratory testing, were free of SL (sublingual) or buccal ulceration or disease, and had negative findings for human immunodeficiency virus, hepatitis B, and hepatitis C 15 viral testing were included in the study. Twenty-four volunteers who met the study inclusion and exclusion criteria were enrolled in this study. On the basis of an SD of the area under the curve (AUC), values of 35% and a 20% difference being significant gives a power of 84% (a= 20 0.05). Study Design This was a single-center (Linear Clinical Research Ltd., Perth, Australia), randomized, open-label, single-dose, 2-treatment, 2-period, 2-way crossover study. 25 According to the randomization plan, subjects were divided into 2 groups, in a 1:1 ratio using a computer-generated table of random numbers. The volunteers were given either IV fentanyl citrate or an SL fentanyl citrate wafer (equivalent to 100 pg of fentanyl). Each volunteer subsequently received the alternative route after a 7-day washout period. 30 The wafer was administered by placing it under the tongue. The volunteer was requested to avoid swallowing for as long as possible, at least for 10 minutes. A naltrexone tablet (50 mg) was administered orally every 12 hours from before day 1 to the evening of day 2 (12 hours after the last fentanyl dose), so as to block any 35 systemic effects of fentanyl.

76 Before commencement of the study, a dedicated IV cannula was placed in the forearm for subsequent venous blood sampling. Blood samples (7 mL) were taken predose before the commencement of wafer administration and then at 2, 5, 10, 15, 20, 30, 45, 60, 120, 180, 360, 460, 600, 720, 960, and 1440 minutes after 5 administration commencement. For IV infusion, blood samples were taken at predose, at 2 and 3 minutes after commencement, and at 5 minutes (end infusion), then at 7, 10, 15, 20, 25, 30, 45, 60, 120, 180, 360, 460, 600, 720, 840, 960, and 1440 minutes from infusion commencement. 10 After collection, the blood samples were immediately centrifuged at 4'C, 2000 to 2500 g for 15 minutes and the plasma extracted and placed into polypropylene storage tubes. The plasma was stored at -80C ± 10 C until transfer to the bioanalytical laboratory. Sample extracts were analyzed on an API 4000 LC-MS/MS system (Applied Biosystems, Foster City, CA), preceded by a Shimadzu Prominence 15 high-performance liquid chromatography system with d5-fentanyl as the internal standard. The assay had a limit of detection of 10 pg/mL. Precision was determined by duplicate analyses of plasma containing 10, 40, and 400 pg/mL fentanyl. The results were precise to within ±6.2%, ±3.3%, and ±1.7% of the mean measured concentration values of 10, 40, and 400 pg/mL, respectively, and accurate to within 20 102%, 99.9%, and 101.4% of the nominal concentrations of 10, 40, and 400 pg/mL, respectively. At each concentration the number of replicates was 6. Pharmacokinetics The pharmacokinetic parameters were determined using Phoenix WinNonlin version 25 6.1 (Pharsight, A Certara T M Company, St. Louis, MO). The pharmacokinetic data were Cmax, tmax, AUCo to 12, AUCo.

1 , AUCo_, kei, and t 1

/

2 . First detectable fentanyl plasma concentration after SL administration (Cfirst) and the time to Cfirst (tfirst) were read directly from the plasma fentanyl concentration-time curves. The terminal elimination rate constant (kei) was determined as the slope of the regression line of 30 best fit to the approximately log-linear terminal elimination phase. All fitting was performed with unity weighting of the data. The terminal elimination half-life (t 1

/

2 ) was obtained from kei and equaled In 2/kei. The AUCo to 12 and AUCo-t values were obtained using the trapezoidal rule. The extrapolation to AUCo_. was calculated from AUCo-i + Ct/kei. 35 Safety and Tolerability 77 Safety and tolerability were assessed by monitoring vital signs (arterial blood pressure and heart rate) after fentanyl administration. A full physical examination was performed before and 48 hours after drug administration. Laboratory tests and a 12 lead electrocardiogram were performed at baseline and completion of the study. 5 Adverse events were assessed using direct observation, spontaneous reporting, and nonspecific questioning. Statistical Analysis Summary statistics were computed by treatment of each pharmacokinetic parameter. 10 Bioavailability of SL fentanyl was determined separately for each subject as the ratio of Cmax, AUCo to 12, AUCo.

1 , and AUC 0 . for SL administration in comparison with IV administration. Overall bioavailability was estimated as the back-transform of the difference between treatments for log-transformed Cmax, AUCo to12, AUCo.

1 , and AUC 0 - values using a linear model with terms for treatment, period, sequence, and subject 15 within sequence. The 90% confidence interval (CI) was also calculated, and P values <0.05 were considered statistically significant. All analyses were conducted using SAS version 9.2 (SAS Institute Inc., 2008). Differences in formulations were evaluated using Student t tests. 20 Results Twenty-four patients were randomized, 12 to the SL:IV sequence and 12 to the IV:SL sequence. Two volunteers did not complete the SL or the IV administration arm of the study and were eliminated from all analyses. The volunteer characteristics are reported in Figure 79. 25 Pharmacokinetic Results Mean plasma (±SEM) fentanyl concentration versus time curves for the IV and SL routes are shown in Figure 80. Individual subject plasma concentration profiles are shown for the SL route in Figure 81. The mean values (±1 SD) for the plasma 30 pharmacokinetic parameters Cmax, tmax, AUCo to 12, AUCo-i, and AUC 0 . for fentanyl are shown in Figure 82. The first detectable plasma fentanyl concentration (Cfirst), after SL administration, was observed between 2 and 10 minutes after administration. The cumulative percentage of the 22 volunteers with tfrist at 2, 5, and 10 minutes and their mean plasma fentanyl concentration (Cfirst) were 12.5% (32.4 pg/mL), 62.5% (30.7 35 pg/mL), and 100.0% (49.0 pg/mL), respectively.

78 The mean time to peak plasma concentrations (tmax) after commencing IV and SL administration was 0.12 hour and 0.92 hour, respectively (P < 0.0001) (Figure 82). The mean (±SD) terminal half-life (t 1

/

2 ) for IV and SL administration was 13.07 ± 3.00 hours and 12.49 ± 5.24 hours, respectively (P = 0.889). The mean (±SD) terminal 5 elimination rate constant (kei) for IV and SL administration was 0.055 ± 0.012 h- and 0.064 ± 0.025 h-W, respectively (P = 0.317). Bioavailability was assessed by the percentage ratios of SL/IV for AUCo to 12, AUCo-i, and AUCo_. values. The mean bioavailability of SL fentanyl was estimated to be 10 72.1% (CI, 65.3% to 79.6%) from AUCo to 12, and 73.2% (Cl, 66.3% to 80.9%) from AUCO-I. Absolute bioavailability was 78.9% (Cl, 51.1% to 121.7%) on the basis of the AUCo_. values. The Cmax of SL fentanyl was 18.8% (Cl, 14.4% to 24.6%) of the IV administration 15 value, with the average time to maximum concentration being 0.9 hour. For IV administration, Cmax generally occurred at the end of the infusion, with a rapid reduction over the half hour immediately postdose. From approximately 2 hours postdose, the mean concentration-time profiles were similar for the 2 modes of administration. 20 Tolerability All reported adverse events were mild to moderate. The mean (±SD) time for the wafer to dissolve in the SL pouch was 73 ± 76 seconds. 25 This study was designed as a phase I study to determine the basic pharmacokinetic parameters of a recently developed rapidly dissolving fentanyl wafer. It also collected some data on subject acceptance of the product. It was found that the Cmax and tmax values for the SL fentanyl (100 pg) wafer were 30 comparable (Figure 83) to data reported from a previously studied SL fentanyl (100 pg) tablet. The Cmax and tmax values provide an indication of the rate of absorption of drugs. The wafer has similar Cmax, tmax, and AUC values, in comparison with the SL tablet (P = 0.573, 0.331, and 0.103, respectively); no absolute bioavailability data were available for the SL tablet. It was noted that the SL tablet was evaluated in 35 cancer patients over a 10-hour collection period, which causes different t 1

/

2 values of 6.1 and 12.5 hours for the tablet and wafer, respectively (P = 0.0013).

79 After SL administration, rapid absorption of fentanyl was evidenced by detectable plasma concentrations within 2 to 10 minutes (tfirst), occurring in most cases within 5 minutes. The wafer formulation had a Cfirst similar to that of the SL tablet. This reflects 5 fentanyl's high permeability into the rich bloodflow (and good venous outflow) of the SL mucosa, which bypasses the hepatic "first-pass" effect. The SL mucosa (100 to 200 pm) is thicker than the nasal mucosa (40 to 80 pm); hence a slower absorption rate was expected in comparison with that reported after IN administration (tmax for IN fentanyl 4.2 to 11.4 minutes versus 54.6 minutes for SL fentanyl in this study). 10 The high bioavailability of fentanyl from the wafer suggests that wafer fentanyl is reliably absorbed sublingually and less likely to be partially swallowed, hence avoiding first-pass metabolism. No attempt was made to apportion bioavailability to these routes of absorption in this study. The analgesic efficacy of the wafer 15 formulation appears satisfactory, on the basis of an earlier pilot study conducted among postoperative surgical patients. This SL fentanyl wafer resulted in rapidly detectable plasma fentanyl concentrations in healthy volunteers, within 10 minutes of administration, indicating potential for the 20 treatment of breakthrough pain. The bioavailability was 78.9% in relation to IV administration.

Claims (72)

1. A solid dosage form adapted for the release of a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an oral 5 cavity wherein said dosage form comprises: (a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor; and (b) at least one matrix forming agent; wherein said dosage form substantially dissolves in the oral cavity. 10

2. The solid dosage form according to claim 1, wherein the dosage form is fast dissolving.

3. The solid dosage form according to either claim 1 or claim 2, wherein the 15 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 than 3 seconds, less 20 than 2 seconds.

4. The solid dosage form according to any one of the preceding claims, 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 a subject. 25

5. The solid dosage form according to any one of the preceding claims, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. 30

6. The solid dosage form according to any one of the preceding claims, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate.

7. The solid dosage form according to any one of the preceding claims, wherein 35 the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is present in an amount from 0.02 to 95 weight % by dry weight of the composition of the dosage form. 81

8. The solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises sodium carboxymethylcel lylose. 5

9. The solid dosage form according to claim 8, wherein sodium carboxymethylcellylose is present in an amount from 0.1 to 19 weight % by dry weight of the composition of the dosage form.

10 10. The solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises amylopectin.

11. The solid dosage form according to claim 10, wherein amylopectin is present in an amount from 2 to 17 weight % by dry weight of the composition of the 15 dosage form.

12. The solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises microcrystalline cellulose. 20

13. The solid dosage form according to claim 12, wherein microcrystalline cellulose is present in an amount from 1 to 10 weight % by dry weight of the composition of the dosage form.

14. The solid dosage form according to any one of the preceding claims, wherein 25 the at least one matrix forming agent comprises glycine.

15. The solid dosage form according to claim 14, wherein the glycine is present in an amount from 0.5 to 5 weight % by dry weight of the composition of the dosage form. 30

16. The solid dosage form according to any one of the preceding claims, wherein the at least one matrix forming agent comprises mannitol.

17. The solid dosage form according to claim 16, wherein the mannitol is present in 35 an amount from 5 to 80 weight % by dry weight of the composition of the dosage form.

18. The solid dosage form according to any one of the preceding claims, further comprising at least one lubricant. 82

19. The solid dosage form according to claim 18, wherein the at least one lubricant comprises polyethylene glycol (PEG) 2000. 5

20. The solid dosage form according to claim 19, wherein PEG 2000 is present in an amount from 0.05 to 5 weight % by dry weight of the composition of the dosage form.

21. The solid dosage form according to any one of the preceding claims, further 10 comprising at least one buffer reagent.

22. The solid dosage form according to claim 21, wherein the at least one buffer reagent comprises sodium carbonate. 15

23. The solid dosage form according to claim 22, wherein sodium carbonate is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form.

24. The solid dosage form according to any one of the preceding claims, further 20 comprising at least one absorption enhancer.

25. The solid dosage form according to claim 21, wherein the at least one absorption enhancer comprises #-cyclodextrin. 25

26. The solid dosage form according to claim 25, wherein #-cyclodextrin is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form.

27. The solid dosage form according to any one of the preceding claims, further 30 comprising at least one flocculating agent.

28. The solid dosage form according to claim 21, wherein the at least one flocculating agent comprises xanthan gum. 35

29. The solid dosage form according to claim 28, wherein xanthan gum is present in an amount from 0.01 to 10 weight % by dry weight of the composition of the dosage form. 83

30. The solid dosage form according to any one of the preceding claims, further comprising at least one surfactant.

31. The solid dosage form according to any one of the preceding claims, further 5 comprising at least one additive.

32. The solid dosage form according to any one of the preceding claims, further comprising at least one colouring agent. 10

33. The solid dosage form according to claim 32, wherein 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.

34. The solid dosage form according to any one of the preceding claims, further 15 comprising at least one flavoring agent.

35. The solid dosage form according to claim 34, wherein the at least one flavoring agent is selected from the group consisting of orange, mint, raspberry, caramel, aspartame, saccharin, and mixture therein. 20

36. The solid dosage form according to any one of the preceding claims, wherein the dosage form is a wafer, tablet, capsule, pill, powder, pellet, granule, or film.

37. The solid dosage form according to any one of the preceding claims, wherein 25 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 than 3 seconds, less 30 than 2 seconds.

38. The solid dosage form according to claim 37, wherein the dosage form substantially dissolves after oral administration to a subject thereby avoiding the urge for the subject to swallow the dosage form. 35

39. The solid dosage form according to any one of the preceding claims, further comprising at least one pharmaceutically acceptable carrier. 84

40. A method of producing a solid dosage form adapted for the release of a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an oral cavity, comprising the steps of: combining at least one matrix forming agent with a cyclic guanosine 5 monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor to form a homogeneous mixture; and freeze drying the mixture to form the solid dosage form.

41. The method according to claim 40, wherein the dosage form is fast dissolving. 10

42. The method according to either claim 40 or claim 41, wherein the dosage form is fast dissolving.

43. The method according to any one of claims 40 to 42, wherein the dosage form 15 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 than 3 seconds, less than 2 20 seconds.

44. The method according to any one of claims 40 to 43, 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 a subject. 25

45. The method according to any one of claims 40 to 44, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. 30

46. The method according to any one of claims 40 to 45, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate.

47. The method according to claim 40, further comprising measuring the mixture in 35 a preformed plastic or aluminium blister mould. 85

48. The method according to claim 47, wherein the freeze drying technique is used to remove the solvent from the blister mould.

49. The method according to claim 48, further comprising sealing the solid dosage 5 form with a plastic or aluminium foil to prevent moisture absorption.

50. The method according to any one of claims 48 to 49, further comprising adding a pH adjuster to maintain the pH of the mixture within the range of between 3.0 and 8.0. 10

51. The method according to any one of claims 48 to 50, further comprising adding a solvent.

52. A kit comprising a dissolving solid dosage form adapted for the release of a 15 biologically active material in an oral cavity, wherein the dosage form comprises: (i) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 20

53. The kit according to claim 52, wherein the dosage form is fast dissolving.

54. The kit according to either claim 52 or claim 53, wherein the dosage form is fast dissolving. 25

55. The kit according to any one of claims 52 to 54, 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 30 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, less than 2 seconds.

56. The kit according to any one of claims 52 to 55, wherein said dosage form 35 substantially dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject. 86

57. The kit according to any one of claims 52 to 56, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil. 5

58. The kit according to any one of claims 52 to 57, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate.

59. A wafer comprising a dissolving solid dosage form adapted for the release of a 10 biologically active material in an oral cavity, wherein the dosage form comprises: (i) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, and instructions for its use. 15

60. The wafer according to claim 59, wherein the dosage form is fast dissolving.

61. The wafer according to either claim 59 or claim 60, wherein the dosage form is fast dissolving. 20

62. The wafer according to any one of claims 59 to 61, 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 25 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, less than 2 seconds.

63. The wafer according to any one of claims 59 to 62, wherein said dosage form 30 substantially dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject.

64. The wafer according to any one of claims 59 to 63, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor 35 is sildenafil. 87

65. The wafer according to any one of claims 59 to 64, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil citrate. 5

66. A solid dosage form, a method, a kit, or a wafer substantially as herein described with reference to the accompanying examples and figures.

67. A pharmaceutical composition comprising the solid dosage form of any one of claims 1 to 39. 10

68. A method of treating a disease or disorder in a patient, comprising the step of administering to said patient a pharmaceutical composition of claim 67.

69. The method of claim 68, wherein the disease or disorder is selected from the 15 group consisting of: erectile dysfunction, pulmonary hypertension, central nervous disorders, cardiovascular disorders and high altitude pulmonary edema.

70. Use of a pharmaceutical composition of claim 67 in the manufacture of a 20 medicament to treat a disease or disorder.

71. The use of a pharmaceutical composition of claim 70, wherein the disease or disorder is selected from the group consisting of: erectile dysfunction, pulmonary hypertension, central nervous disorders, cardiovascular disorders 25 and high altitude pulmonary edema.

72. A solid dosage form according to claim 1, a method according to claim 40, a kit according to claim 52, a wafer according to claim 59, a pharmaceutical composition of claim 67, a method of treating according to claim 68 or use of a 30 pharmaceutical composition of claim 70 substantially as herein described with reference to the accompanying examples and figures.