0001 This application claims priority from U.S. Provisional Application No. 60/362,307 filed on Mar. 7, 2002 and No. 60/366,710 filed Mar. 22, 2002, the entire disclosures of which are hereby incorporated by reference.

DESCRIPTION 0002 The present is directed to fast melt multiparticulate formulations for oral use. The multiparticulates can be used in a multiple dose delivery device which dispenses a unit dose of the powder upon actuation, or can be packaged for dispensation in sachets or like unit dose containers. 0003 The most prominent mode of delivery of therapeutic agents is by the oral route by means of solid dosage forms such as tablets and capsules. Oral administration of solid dosage forms is more convenient and accepted than other modes of administration, e.g., parenteral administration. However, the manufacture, dispensing and administration of solid dosage forms are not without associated problems and drawbacks. 0004 With the manufacture of solid dosage forms, in addition to the active agent, it is necessary to combine other ingredients in the formulations for various reasons, such as to enhance physical appearance, to provide necessary bulk for tableting or capsuling, to improve stability, to improve compressibility or to aid in disintegration after administration. However, these added excipients have been shown to adversely influence the release, stability and bioavailability of the active ingredient. The added excipients are a particular problem with drugs which require a high dose in order to provide a therapeutic effect, e.g., biphosphonate drugs. The inclusion of the additional excipient can make the final tablet extremely large which could result in esophogeal damage due to the physical characteristics of the dosage form if it is not swallowed properly. Esophogeal damage can also be caused by toxicity caused by the drug itself, if the tablet becomes lodged in the throat or has an increased transit time through the esophagus, due to its increased size. 0005 Further, the tableting of certain drugs has many associated production problems. In particular, many drugs, e.g., paracetamol (acetaminophen), have poor compressibility and cannot be directly compressed into solid dosage forms. Consequently, such drugs must either be wet granulated or manufactured in a special grade in order to be tableted which increases manufacturing steps and production costs. 0006 The adherence to good manufacturing practices and process controls is essential in order to minimize dosage form to dosage form and batch to batch variations of the final product. Even strict adherence to these practices still is not a guarantee that acceptable variation will occur. 0007 With the high cost of industrial scale production and governmental approval of solid dosage forms, such formulations are often available in a limited number of strengths, which only meet the needs of the largest sectors of the population. Unfortunately, this practice leaves many patients without acceptable means of treatment and physicians in a quandary with respect to individualizing dosages to meet the clinical needs of their patients. 0008 The dispensing of oral solid dosage forms also makes the formulations susceptible to degradation and contamination due to repackaging, improper storage and manual handling. 0009 There are also many patients who are unable or unwilling to take conventional orally administered dosage forms. For some patients, the perception of unacceptable taste or mouth feel of a dose of medicine leads to a gag reflex action that makes swallowing difficult or impossible. Other patients, e.g., pediatric and geriatric patients, find it difficult to ingest typical solid oral dosage forms, e.g., due to tablet size. 0010 Other patients, particularly elderly patients, have conditions such as achlorhydria which hinders the successful use of oral solid dosage forms. Achlorhydria is a condition wherein there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This condition hinders the disintegration and/or dissolution of oral solid dosage forms, particularly dosage forms with high or insoluble excipient payloads. Thus, as the present dosage form is in fast melt multiparticulate form, it does not need to undergo disintegration and/or dissolution to the same extent as solid dosage forms 0011 Flavoured solutions/suspensions of some therapeutic agents have been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. While liquid formulations are more easily administered to the problem patient, liquid/suspension formulations are not without their own significant problems and restrictions. The liquid dose amount is not as easily controlled compared with tablet and capsule forms and many therapeutic agents are not sufficiently stable in solution/suspension form. Indeed, most suspension type formulations are typically reconstituted by the pharmacist and then have a limited shelf life even under refrigerated conditions. Another problem with liquid formulations which is not as much a factor with tablets and capsules is the taste of the active agent. The taste of some therapeutic agents is so unacceptable that liquid formulations are not a viable option. Further, solution/suspension type formulations are typically not acceptable where the active agent must be provided with a protective coating, e.g. a taste masking coating or an enteric coating to protect the active agent from the strongly acidic conditions of the stomach. 0012 Fast melt drug formulations have also been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. Fast melt formulations are typically in the form of tablets or lozenges that dissolve or disperse in a patient's mouth within a minute without the need of water or chewing. Drug delivery formulations which exhibit fast melt properties can improve patient compliance due to the ease of swallowing as well as the absence of a need for the co-administration of water or another fluid. Further, fast melt systems can be formulated as to have a superior taste and improved accuracy of dosing as compared to liquid preparations. 0013 Other formulations which have been contemplated in order to facilitate the oral administration of oral agents and to avoid the associated problems of solid dosage forms are multiparticulate dosage forms as disclosed in WO 01/64182, the contents of which are hereby incorporated by reference. 0014 According to a first aspect of the present invention, there is provided a drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 m to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid. 0015 Thus, the present invention, in its first aspect, provides a formulation which exhibits the benefits of fast melt formulations as well as the benefits of multiparticulate formulations. It also facilitates the delivery of a wide range of therapeutic agents for gastrointestinal deposition and minimizes pulmonary deposition of materials having undesirable or unknown pulmonary toxicology but which are approved for oral delivery. In some embodiments, the formulation can contain minimal excipient and be used in a multiple dose delivery device which dispenses a unit dose of the formulation upon actuation. Such delivery devices are disclosed in WO 01/64182. 0016 In a second aspect, the present invention provides a drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles and including an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 m to about 1 mm, and the excipient has a negative heat of solution. 0017 A significant advantage of formulations in accordance with the second aspect of the invention is that, when administered via the oral cavity, the local cooling caused by the water-soluble excipient dissolving in saliva serves to mask the taste of the active agent in a manner which does not delay the release, or dissolution of the active agent itself. 0018 Preferably, formulations in accordance with the second aspect of the invention are capable of dissolving or dispersing in a patient's mouth within one minute after administration, without the co-administration of a fluid. Such preferred formulations, therefore, are also examples of the first aspect of the invention and will provide all of the aforementioned benefits associated with the first aspect of the invention. 0019 Drug formulations in accordance with either the first or the second aspect of the invention are preferably arranged for direct, un-encapsulated administration to a patient's oral cavity. It is also preferred for the particles to be non-compressed. 0020 In embodiments, the particles each include both active agent and water-soluble excipient. The particles can comprise a core and a coating, with the coating including a quantity of the water-soluble excipient. 0021 Preferably, and in accordance with either aspect of the invention, the particles are formed by melt-coating core particles with a coating material that includes (and may consist of) a quantity of the excipient, at a temperature below that at which the active agent melts or decomposes. Forming the particles in this manner is considered to provide them with surface properties that render them easily wetted and capable of rapidly absorbing water from their environment and, thus, able to facilitate the rapid dissolution or dispersion of the formulation, especially the active agent, when the formulation is exposed to an aqueous environment, such as in the oral cavity. 0022 A quantity of the active agent can be included in the core or core particles and/or in the coating or coating material. In some preferred embodiments, the coating or coating material is substantially free of active agent, whereas in others, the core is substantially free of active agent. 0023 In further embodiments of either aspect of the invention, the coating or coating material comprises a water-soluble or hydrophilic binder. Preferably, the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. In further embodiments, the water-soluble excipient melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. In further preferred arrangements, the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the water-soluble excipient melts or decomposes. In some embodiments of the invention, the coating or coating material substantially completely covers the surface of the core or core particles. 0024 Thus, particles in accordance with the present invention can comprise a core that consists substantially or entirely of active agent surrounded by a coating that comprises water-soluble excipient either alone, or in combination with a water-soluble or hydrophilic binder. When the water-soluble excipient is employed alone in such particles, it is preferred for it to be capable of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. Where a binder is employed, the water-soluble excipient need not be capable of melting or softening at a temperature below the melting or decomposition temperature of the active agent. However, when such a high melting point water-soluble excipient is employed, the binder should be capable both of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes, and of binding the water-soluble excipient in the coating. 0025 The core or core particles, in addition to including active agent, can also include a quantity of the water-soluble excipient and/or an additional excipient, which may also be water soluble, but which does not necessarily qualify as a water-soluble excipient in accordance with the present invention. For example, the core can comprise a granulation of such an additional excipient (e.g. polyvinyl alcohol, or polyvinylpyrrolidine) and active agent, or consist of a particle (e.g. a microcrystalline cellulose sphere) of additional excipient coated with active agent. 0026 In other embodiments in accordance with the invention, the core can consist entirely of water-soluble excipient. In such embodiments, the coat or coating material comprises active agent and either an additional quantity of water-soluble excipient, or a binder. When the coat or coating material comprises active agent and binder, additional water-soluble excipient can also be present in therein. 0027 It is preferred that formulations in accordance with either aspect of the present invention are formed by a process in which the active agent is not raised to or above its melting point, or a temperature at which a significant proportion thereof is caused to decompose. 0028 The melting point of the water-soluble excipient is preferably equal to or below 150, 120 or 110 C., and is preferably at least 40 or 50 C. Preferably, the excipient melts at around or below 100 C. The melting point of the binder, if employed, is preferably equal to or below 150, 120 or 110 C., and is preferably at least 40 or 50 C. 0029 More preferably, the binder melts at around or below 100 C. In certain embodiments, the melting point of the excipient exceeds that of the binder. 0030 The water-soluble excipient, preferably, has a heat of solution equal to or below 7 KCal/Kg. More preferably, the heat of solution of the water-soluble excipient is equal to or below 10, 15, 20, 25, or 30 KCal/Kg. The solubility in water of the water-soluble excipient is preferably at least 20, 30 or 40% w/w at 25 C. 0031 The water-soluble excipient is preferably a sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide, and is preferably not lactose. Formulations in accordance with the invention, preferably, are lactose free. The preferred water-soluble excipients are the sugar alcohols including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combinations thereof. The preferred sugar is glucose. Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof. 0032 Preferred binders include polyethylene glycols (PEG) and polyethylene oxides. 0033 In further preferred embodiments, the core or core particles include an additional excipient for controlling or delaying the release of the active agent. In this regard, the core or core particles can include a layer or coating of such an additional excipient encapsulating an inner core comprising the active agent. The additional excipient can be selected from those known to persons skilled in the art to be capable of controlling the release of an encapsulated active agent. Such excipients include those commonly used to provide enteric and sustained release coatings. Examples of the former include cellulose acetate phthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates, such as Eudragit L 100-55 or L 30 D-55, and Shellac. Examples of the latter include ethylcellulose, hydroxypropyl-celluose, hydroxypropylmethylcelluose, and polymethacrylates, such as Eudragit RL and RS film-coating systems. 0034 In alternative embodiments, formulations in accordance with the invention can provide rapid release of the active agent. In this regard, the term rapid release should be understood to mean that such formulations release at least 80% of their active agent within 45 minutes in standard dissolution tests. In the case of poorly soluble active agents, such formulations typically release at least 80% of their active agent within 40, 30, 20, 15 and preferably 10 minutes after being administered to a patient's oral cavity. In the case of more soluble active agents, such formulations typically release at least 80% of their active agent within 10, 7 and preferably 5 minutes after being administered to a patient's oral cavity. In particularly preferred embodiments of the invention, the active agent will dissolve into an aqueous environment more rapidly from a formulation in accordance with the invention than it would if it had not been incorporated in such a formulation. 0035 In a third aspect, the present invention provides a method of preparing a drug formulation in accordance with the first or second aspect of the invention, comprising forming the particles by melt-coating core particles with a coating material that includes a quantity of the water-soluble excipient, at a temperature below the melting point or decomposition temperature of the active agent. 0036 In a further aspect, the invention provides the use of a drug formulation in accordance with the first or second aspect of the invention, or a drug formulation prepared by a method in accordance with the third aspect of the invention, for the preparation of a medicament for treating a human or animal patient, wherein the formulation is administered directly and in an un-encapsulated form to the patient's oral cavity. The invention also provides a method of treating a human or animal patient, wherein a formulation in accordance with the first or second aspect of the invention, or prepared by a method in accordance with a third aspect of the invention, is administered in a un-encapsulated form directly into the patient's oral cavity. 0037 It is also possible for formulations in accordance with either the first aspect or the second aspect of the invention to include additional particles with different properties to those described above. For example, the additional particles may not include any active agent. 0038 Certain embodiments of the invention comprise a fast melt multiparticulate formulation which contains a salivary stimulant to facilitate hydration of the formulation and the swallowing of a unit dose of the multiparticulates upon oral delivery. 0039 Certain embodiments of the invention comprise a fast melt multiparticulate formulation which has a desired particle range in order to minimize pulmonary aspiration of particles. 0040 Fast melt multiparticulate formulations in accordance with the invention are, preferably, divisable into unit doses (e.g. with the use of a multiple unit dosing device) with a weight uniformity which is within the acceptable range of weight uniformity for tablets or capsules. A detailed discussion of weight uniformity can be found in the USP/NF 23/18 section 905, which is hereby incorporated by reference in its entirety for all purposes. 0041 The invention also provides methods of preparing fast melt multiparticulate dosage forms and systems disclosed herein. The invention further provides methods of preparing fast melt multiparticulate dosage forms without the use of an aqueous fluid as a processing aid. 0042 The invention additionally provides methods of preparing multiple unit delivery systems containing fast melt multiparticulate dosage forms in accordance with the invention. 0043 The invention also provides methods of preparing fast melt multiparticulate dosage forms having a desired particle size range. 0044 The invention further provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form. 0045 The invention additionally provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form via the use of a multiple unit delivery system. 0046 In certain embodiments, the present invention is directed to a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 m to about 1 mm, the particles comprising at least about 50% drug and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid. 0047 In certain embodiments, the invention is directed to a method of treating a patient with an active agent for gastrointestinal deposition comprising administering a formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 m to about 1 mm, and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid. 0048 In certain embodiments, the invention is directed to a drug delivery system for delivery of a drug for gastrointestinal deposition. The system comprises a multiple unit dosing device comprising a housing and an actuator, the device containing multiple doses of a fast melt multiparticulate formulation, the device upon actuation delivering a unit dose of the fast melt multiparticulates for gastrointestinal deposition, the multiparticulates having a mean particle size of greater than 10 m and preferably less than about 1 mm in order to minimize pulmonary deposition of the multiparticulates and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient. The drug delivery system can be used to administer the unit dose of fast melt multiparticulates into the oral cavity of the patient (in-vivo) or to dispense the unit dose into an intermediate receptacle (ex-vivo) for subsequent gastrointestinal deposition. Oral drug delivery systems and devices for oral powders are disclosed in WO01/64182, hereby incorporated by reference in its entirety for all purposes. 0049 In certain embodiments, the invention provides a method of preparing a drug delivery system for delivering multiple doses of a drug for gastrointestinal deposition comprising preparing a fast melt multiparticulate drug formulation in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs; and placing multiple unit doses of the fast melt drug formulation in a device which meters a single unit dose for delivery. 0050 In certain embodiments, the invention provides a method of treating a patient in need of multiple doses of a drug for gastrointestinal deposition comprising preparing fast melt multiparticulates in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs and dissolve or disperse in the mouth within 1 minute after administration, placing multiple unit doses of the fast melt multiparticulates in a device which meters a single unit dose for delivery and either (a) administering the unit dose into the oral cavity of a patient or(b) dispensing the unit dose into an intermediate receptacle and thereafter administering the unit dose into the oral cavity of the patient. 0051 In certain embodiments, the particles of the invention comprise at least about 50% drug; at least about 60% drug; at least about 70% drug; at least about 80% drug; or at least about 90% drug. In others, low doses of up to 20%, 10% or 5% of drug or active agent are carried by the inventive particles. In certain embodiments, the invention provides a method for delivery of a drug comprising delivering fast melt multiparticulates comprising drug particles via the use of a multiple unit dosing device comprising a housing and an actuator, the device upon actuation delivering a unit dose of the fast melt multiparticulates, and thereafter re-using the device to deliver additional unit doses of the fast melt multiparticulates at appropriate dosing intervals. 0052 In preferred embodiments of the invention, the unit dose comprises a discreet collection of fast melt multiparticulates. For purposes of the invention, a discreet collection means that the fast melt multiparticulates are in the form of a non-compressed free flowing unit and not dispersed in a cloud or mist, which effectively minimizes inhalation of the active agent into the lungs of the patient. The unit dose can be include from about 0.01 mg to about 1.5 g of active agent. For example, the dose of active agent can be from about 1 mg to about 100 mg, or from about 10 mg to about 50 mg. 0053 In certain embodiments of the invention, the mean diameter of the fast melt multiparticulates is of a size which minimizes their capacity to be inhaled into the lower lung. Typically, the mean particle size of the drug particles (or agglomerates) is greater than 10 m, preferably greater than about 50 m or greater than about 75 m. In certain embodiments of the invention, the mean particle size range of the drug particles is from about 100 m to about 1 mm, preferably from about 50 m to about 500 m. In preferred embodiments, greater than 80% of the particles have the above disclosed diameter (not mean diameter), e.g. 80% of the drug particles have a diameter of greater than 10 m, or a diameter of from about 100 m to about 1 mm. In other embodiments, greater than about 90% of the particles have the above disclosed diameter. 0054 In certain embodiments of the invention, the mean diameter of the fast melt multiparticulates does not vary by greater than about 20%, preferably not greater than about 15% and most preferably not greater than about 10%. 0055 In certain embodiments of the invention, the multiple doses of the fast melt formulation are contained in a reservoir. The reservoir can contain an amount of multiparticulates to provide any number of unit doses, e.g. from about 2 doses to about 400 doses. For ease in patient compliance, the reservoir has a sufficient quantity of to provide e.g. a days supply, a months supply or a years supply of doses, e.g. 30 or 365 for once daily dosing for a month or year, respectively. 0056 In order to aid in patient compliance, certain embodiments of the invention include a counter or indicator to display the number of doses remaining in the system or the number of doses actuated. 0057 In certain embodiments of the invention, the unit doses are individually metered prior to actuation, e.g., in the form of capsules or blisters or preferably in the form of sachets, wherein each sachet contains one individual unit dose. The system can be capable of containing any multiple of pre-metered unit doses, e.g. from about 2 to about 400 sachets. 0058 For purposes of the present invention, the term device refers to an apparatus capable of delivering a unit dose of drug. 0059 The term system refers to a drug delivery device in combination with a fast melt multiparticulate formulation having the specifications disclosed herein, e.g. drug particle size, excipient type, etc. 0060 The term discreet collection refers to a non-compressed free flowing unit of multiparticulates with minimal particulate matter being dispersed in the surrounding environment (e.g., as a cloud or mist). 0061 The term drug refers to any agent which is capable of providing a therapeutic effect to a patient upon gastrointestinal deposition. This encompasses all drugs which are intended for absorption for a systemic effect (regardless of their actual bioavailability) as well as drugs intended for a local effect in the gut and/or oral cavity, e.g. nystatin, antibiotics or local anaesthetics. 0062 The term particle size refers to the diameter of the particle. 0063 The term deposition means the deposit of the unit dose at the intended point of absorption and/or action. For example, gastrointestinal deposition means the intended deposit of the unit dose in the gastrointestinal system for e.g., absorption for a systemic effect or to exert a local effect. Pulmonary deposition means the intended deposit of drug into the lungs in order to provide a pharmaceutical effect, regardless that the unit dose may enter the oral cavity prior to pulmonary deposition. 0064 The term dispense, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose ex vivo with the intent of subsequent administration to a mammal. For example, the device or system can dispense the unit dose into a food, a liquid, a spoon, or another intermediate receptacle. 0065 The term administer, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose in vivo, i.e., directly into the gastrointestinal tract of a mammal. 0066 The term deliver is meant to cover all ex vivo and in vivo delivery, i.e., dispensing and administering, respectively. 0067 The term patient refers to humans as well as other mammals in need of a therapeutic agent, e.g., household pets or livestock. This term also refers to humans or mammals in need of or receiving prophylactic treatment. 0068 The term fast melt means a formulation which dissolving or disperses in a patient's mouth within 1 minute after administration without the co-administration of a fluid. Preferably, the formulation dissolving or disperses in a patient's mouth within 30 seconds, or 15 seconds after administration without the co-administration of a fluid 0069 The term disperses means that the administered formulation becomes hydrated in the mouth and the particles of the formulation become suspended is saliva, such that the multiparticulate formulation is wetted and easily swallowed. 0070 In certain embodiments, the particulates are defined functionally with respect to the fact that they are of a size such that an effective dose cannot be delivered into the lower lung of a human patient. However, this definition should be understood to mean that a small percentage of drug (but not an amount effective to render a therapeutic effect) may in fact be inadvertently delivered to the lungs of the patient. Also, this definition is meant to define the particles, but not to limit the use of the invention to the treatments of humans only. The invention may be used for delivering doses of drugs to other mammals as well. 0071 In this specification, there are references to the temperature at which the active agent or the water-soluble excipient decomposes. This temperature should be understood to be the temperature at and above which the active agent or excipient would decompose to a significant extent, if held there for sufficient time for the active agent or excipient to be processes by melt granulation. 0072 In general, it has been recognized in the art that dry powder inhalation or insufflation formulations must consist of particles of a size of about 2 microns in diameter in order for the particles, when inhaled, to reach the peripheral or deep lung, including alveoli. Particles larger than 10 microns in diameter are not able to reach the deep lung when inhaled because they are collected on the back of the throat and upper airways in humans. Therefore, known powder delivery systems have been formulated with particle sizes of less than 10 microns in order for the particles to reach the intended site of action, the pulmonary system. Known powder delivery devices have not contemplated delivery of particles from a multi-dose delivery device to achieve gastrointestinal deposition, and therefore have avoided the use of drug particles having a large size, e.g. greater than 10 microns. By virtue of the invention disclosed in Applicants co-pending application, WO01/64182, it has been a surprising discovery that drug particles greater than 10 microns can be delivered from a multi-use drug delivery device for gastrointestinal deposition in a patient in order to minimize the inhalation of the drug particles into the lungs, in order to have substantially all of the dose deposited in the gastrointestinal system. By virtue of the present invention, powders that can be used in such devices can exhibit fast melt properties in order to provide the benefits of such formulations. The powders can be used in the device or can be administered without the use of the device, e.g., by using a sachet. 0073 As the fast melt multiparticulates of the present invention are not intended to be compressed, a high load formulation of the active agent is ascertainable. This is due to the fact that excipients which must be included in prior art fast melt tablets (e.g., fillers in order to provide bulk for tableting and disintegrants to provide a breakdown of the tablet upon administration) need not be included in the present formulations, or included to a lesser extent. As the fast melt formulations can have lower excipient and a higher drug load, the resultant unit dose is smaller which decreases the necessary time for the dissolution or dispersion of the formulation upon oral delivery. 0074 The water-soluble excipient of the formulation can be a sugar alcohol including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combination thereof. Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof. 0075 The formulations of the present invention preferably include a salivary stimulant including, but not limited to citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof. 0076 The salivary stimulant can also be an effervescent agent, such as wherein the effervescence is the result of a reaction of a soluble acid source and an alkali metal carbonate or carbonate source. The carbonate sources can be selected from the group consisting of dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate. 0077 The drug formulations of the present invention preferably comprise a sweetener such as a water-soluble artificial sweetener, including but not limited to soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof. The sweetener can also comprise a dipeptide based sweetener such as L-aspartyl L-phenylalanine methyl ester. 0078 The formulations of the present invention can also comprise further pharmaceutical excipients such as polyvinyl alcohol, polyvinylpyrrolidine, acacia or a combination thereof. 0079 The dissolution or dispersion of the formulation can be improved with the use of a surfactant, such as sodium lauryl sulphate (Texapon K 12), various polysorbates known under the trade name Tween, ethers of polyhydroxy ethylene fatty acids known under the trade name Brij, esters of polyhydroxy ethylene fatty acids known under the trade name Myrj, sodium desoxycholate, glycerol polyethylene glycol ricinoleate (Cremophor EL), polyoxyethylene-polyoxypropylene polymers known under the trade name Pluronic, and various polyalkoxy alkylene sterol ethers. 0080 The fast melt formulations of the present invention can also comprise starches, e.g., corn starch, or modified starches, e.g., sodium starch glycolate or mixtures thereof, in any proportions. Starches can provide increased salivation due to the porous nature of the starch. Increased salivation favours rapid dissolution or dispersion of the formulation upon oral administration. 0081 When a starch is present in the formulation, the formulation can further comprise a starch degrading enzyme will have a synergistic effect with the starch with respect to dissolution or dispersion. The enzymes upon being contacted with an aqueous solution will initiate conversion of the starch to mono and polysaccharides which quickly dissolve in the aqueous environment and further contribute to improving the taste of the multiparticulate formulation and increasing salivation. 0082 The enzymes can be chosen for their degradation effect on the starch and also for their stability over time, i.e. during the shelf-life of the fast melt multiparticulate formulation. Advantageously, the enzyme will be chosen from the group of starch degrading enzymes comprising alpha-amylase, beta-amylase, amyloglucosidase, debranching enzymes and glucose-fructose isomerase. In certain embodiments, the enzymes can be an equal mixture of amyloglucosidase and a-amylase. 0083 In certain embodiments, drug formulations in accordance with the invention are prepared by a process comprising melt granulating the water soluble excipient and the active agent to form a homogenous mixture. In an alternate embodiment, the process comprises melt coating the water-soluble excipient onto the active agent which can be optionally pregranulated with a pharmaceutically acceptable excipient. 0084 In such processes, the water-soluble excipient is preferably a water-soluble alcohol such as xylitol. 0085 The melt granulation and melt coating processes are particularly preferred processes of the present invention as it is not necessary to use an aqueous fluid as a processing aid. This results in a process which can be used for a wide variety of active agents, including those agents which would be susceptible to degradation upon contact with water. Accordingly, such processes provide advantages over many prior art processes for making fast melt systems which rely on water as a processing aid. These prior art processes would not be suitable for water liable drugs as such processes would result in degradation of the drug during the manufacturing process and during storage due to residual moisture in the final product. 0086 In certain embodiments, formulations in accordance with the invention can be prepared by subliming solvent from a composition comprising the active agent and the water soluble excipient and reducing the sublimed composition to the particles. In such embodiments, the composition can further comprises an excipient selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, acacia or a combination thereof. The sublimation is preferably by freeze-drying and the solvent can be an aqueous solvent or a co-solvent comprising an aqueous solvent and an alcohol. A surfactant can also be included in such a formulation. 0087 In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and a solvent, freezing the mixture, vacuum drying the frozen mixture above a collapse temperature of the mixture to form a partially collapsed matrix network and reducing the sublimed composition to the particles. Preferably, the mixture comprises the active agent, a gum, a carbohydrate base, and a solvent, wherein the gum is selected from the group consisting of acacia, guar, xanthan, tragacanth gum, and mixtures thereof, and the carbohydrate is selected from the group consisting of mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrup solids, and mixtures thereof. 0088 In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and an agar aqueous solution, solidifying the mixture into a jelly form, drying the jelly and reducing the dried composition into the particles. The drying can be effected by reduced pressure drying, aeration drying or freeze-drying. 0089 In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises melt spinning the active agent with the saccharide to form a mass of spun fibres and reducing the spun fibres to the particles. The saccharide can be sucrose or glucose. 0090 In order to achieve the desired lower limit of the particles size of the fast melt multiparticulate formulation of the invention, air jet sieving can be used to remove fine particles. In particular embodiments, the invention is directed to a method of preparing a multiparticulate drug formulation for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient as disclosed herein and air jet sieving the particles to separate the cores from fine particles; and thereafter overcoating the core with a functional coating as disclosed herein. 0091 The invention is also directed to compositions obtained using these methods. 0092 The compositions of multiparticulates obtained using air jet sieving and methods thereof are not limited to the particular embodiments disclosed herein. The use of an air jet sieve is beneficial as the standard sieving techniques used with screens and meshes may not separate all of the desired fine particles as the fine particles may adhere to the surface of larger particles and thus not separate during the sieving process. The air jet sieving process utilizes a negative pressure to draw particles below a particular size range down through an appropriate screen or mesh. In another embodiment, there is a combination of a downward negative pressure and an upward positive pressure which facilitates the de-agglomeration of the different particle sizes. In other embodiments, the upward pressure can be introduced upwards from a rotating wand. An apparatus utilizing a negative downward pressure and an upward positive pressure through a rotating wand is a Micron Air Jet Sieve MAJS I/II manufactured by Hosakawa. 0093 The effect of humidity can have a negative impact of the flowability of particles (e.g., due to cohesiveness). This can be a particular problem with the present invention, which is directed to fast melt multiparticulates which are designed to absorb water. Accordingly, in preferred embodiments, the unit doses of fast melt multiparticulates are premetered prior to actuation of the device. This reduces the contamination of the unit doses as compared to having the formulation in a multiple dose reservoir. Preferably, the premetered unit doses are contained in sachets which minimize the effect of humidity and moisture on the formulation. 0094 Other multiple unit oral dosing devices, adapted contain the formulation in a reservoir or as premetered unit doses, which are useful in the present invention are disclosed in WO01/64182 hereby incorporated by reference. 0095 Classes of drugs which are suitable in the present invention include antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, anti-manics, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, bronchodilators, expectorants, cough suppressants, mucolytics, drugs affecting calcification and bone turnover and anti-uricemic drugs. Specific drugs include gastro-intestinal sedatives such as metoclopramide and propantheline bromide; antacids such as aluminum trisilicate, aluminum hydroxide, ranitidine and cimetidine; anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid; anti-infective substances such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucloxacillin sodium, hexamine mandelate and hexamine hippurate; neuroleptic drugs such as flurazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine; central nervous stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride; antihistamic drugs such as diphenhydramine, diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrheal drugs such as bisacodyl and magnesium hydroxide; the laxative drug, dioctyl sodium sulfosuccinate; nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugs such as dicyclomine and diphenoxylate; drugs affecting the rhythm of the heart such as verapamil, nifedipine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate; drugs used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; drugs used in the treatment of migraine such as ergotamine; drugs affecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate; analgesic drugs such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid; anti-epileptic drugs such as phenytoin sodium and sodium valproate; neuromuscular drugs such as dantrolene sodium; substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insulin; drugs used in the treatment of thyroid gland dysfunction such as triiodothyronine, thyroxine and propylthiouracil, diuretic drugs such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and triamterene; the uterine relaxant drug ritodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride; anti-asthmatic and bronchodilator drugs such as aminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate; expectorant drugs such as guaiphenesin; cough suppressants such as dextromethorphan and noscapine; mucolytic drugs such as carbocisteine; anti-septics such as cetylpyridinium chloride, tyrothricin and chlorhexidine; decongestant drugs such as phenylpropanolamine and pseudoephedrine; hypnotic drugs such as dichloralphenazone and nitrazepam; anti-nauseant drugs such as promethazine theoclate; haemopoietic drugs such as ferrous sulphate, folic acid and calcium gluconate; uricosuric drugs such as sulphinpyrazone, allopurinol and probenecid; and calcification affecting agents such as biphosphonates, e.g., etidronate, pamidronate, alendronate, residronate, teludronate, clodronate and alondronate. 0096 Particularly preferred agents include antibiotics such as clarithromycin, amoxicillin erythromycin, ampicillin, penicillin, cephalosporins, e.g., cephalexin, pharmaceutically acceptable salts thereof and derivatives thereof. 0097 A particularly preferred agent is paracetamol (acetaminophen). Other preferred agents are NTHES such as ibuprofen, indomethacin, aspirin, diclofenac and pharmaceutically acceptable salts thereof. 0098 In certain preferred embodiments, however, formulations in accordance with the invention do not include any non-steroidal anti-inflammatory drug (NSAID). 0099 The size of the unit dose is dependent on the amount of drug needed to provide the intended therapeutic effect and the amount of any pharmaceutically acceptable excipient which may be necessary. Typically, a unit dose of from about 0.01 mg to about 1.5 g would be sufficient to contain a therapeutically effective amount of the drug to be delivered, however, this range is not limiting and can be smaller or higher, depending on the amount of drug and excipient that is necessary. 0100 The following examples serve to illustrate the invention, but should not be understood to be limiting in any respect.

EXAMPLE 1 0101 The following materials were employed in this example. 1Material% CompositionParacetamol75Xylitol24Aspartame0.5Acesulphame K0.5

0102 Method 0103 Granular paracetamol, aspartame fine, acesulphame potassium and 12% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0104 Results 0105 The formulation had a sweet taste and good mouthfeel. The dissolution of the paracetamol from the formulation was measured using a modified version of the standard USP test for measuring paracetamol (acetaminophen) dissolution. The test conditions involved stirring 333 mg of the formulation in 900 ml of water, buffered to pH 5.8 with a potassium phosphate buffer, at 37 C., using a paddle speed of 100 RPM (the standard USP paddle speed is 50 RPM). The results are set out below.

EXAMPLE 2 0106 The following materials were employed in this example. 2Material% CompositionParacetamol77Xylitol20Aspartame0.5Acesulphame K0.5Maltodextrin M1002

0107 Method 0108 Granular paracetamol, aspartame fine, maltodextrin M100, acesulphame potassium and 10% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0109 Results 0110 It was found that incorporation of certain grades maltodextrin improved mouthfeel and reduced aftertaste without impeding drug release. The dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.

EXAMPLE 3 0111 The tastemasking properties of xylitol result from its negative heat of solution, which confers a cooling effect on dissolution on the oral cavity. This example details the use of erythritol, which has a greater negative heat of solution, to improve the degree of tastemasking. Formulations were prepared using erythritol as the melt binder from the following materials. 3Material% CompositionParacetamol87Erythritol10Aspartame0.5Acesulphame K0.5Maltodextrin M1002

0112 Method 0113 Granular paracetamol, aspartame fine, maltodextrin M100, acesulphame potassium and 5% erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121 C. The blend was mixed at an impellar speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0114 Results 0115 Upon melt granulation it was observed that the formulation developed a slight brown discoloration. This was attributed to the thermal degredation of Maltodextrin M100. This was confirmed by the preparation of Example 4 in which there was no evidence of browning.

EXAMPLE 4 0116 The following materials were employed in this example. 4Material% CompositionParacetamol89Erythritol10Aspartame0.5Acesulphame K0.5

0117 Method 0118 Granular acetaminophen, aspartame fine, acesulphame potassium and 5% erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder (erythritol) was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0119 Dissolution profiles were not obtained for examples 3 and 4.

EXAMPLE 5 0120 The following materials were employed in this example. 5Material% CompositionParacetamol82Erythritol5Xylitol10Maltodextrin M1002Aspartame0.5Acesulphame K0.5

0121 Method 0122 Granular acetaminophen and erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The temperature was then reduced to 95 C. and the xylitol, aspartame fine, acesulphame potassium and maltodextrin added to the blend. The impeller speed was increased as required to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0123 Results 0124 Example 5 exhibited improved tastemasking over example 2, with improved masking of the slight aftertaste which was evident in example 3 and minimal evidence of the aftertaste which was evident in example 4. The browning of the formulation which was observed in example 3 was not evident in this formulation due to the incorporation of maltodextrin in the second stage of melt coating. The dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below. 0125 The drug release profiles of the formulation of Example 5 versus that of the unformulated raw drug, i.e., granular acetaminophen, are shown in FIG. 1. The particle size distributions of the formulation of Example 5 (Special Granulate APAP) versus that of the unformulated raw drug (Paracetamol Special Granular) are shown in FIG. 2.

EXAMPLE 6 0126 Example 6 describes the use of materials capable of liberating carbon dioxide in aqueous conditions to facilitate tastemasking. The following materials were employed in this example. 6Material% CompositionParacetamol77Xylitol20Sodium Glycine Carbonate1.2Citric Acid Monohydrate0.8Acesulphame K0.5Aspartame0.5

0127 Method 0128 Granular paracetamol, aspartame fine, sodium glycine carbonate, citric acid monohydrate, acesulphame potassium and 10% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95 C. The blend was mixed at an impellar speed sufficient to keep the whole powder bed moving (i.e. 222 RPM using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM. The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0129 Results 0130 The formulation exhibited acceptable tastemasking. However, the addition of Maltodextrin M100, as shown in example 7, improved its mouthfeel.

EXAMPLE 7 0131 The following materials were employed in this example. 7Material% CompositionParacetamol77Xylitol18Maltodextrin M1002.0Sodium Glycine Carbonate1.2Citric Acid Monohydrate0.8Acesulphame K0.5Aspartame0.5

0132 Method 0133 Granular paracetamol, aspartame fine, sodium glycine carbonate, citric acid monohydrate, maltodextrin M100, acesulphame potassium and 9% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0134 Results 0135 The addition of Maltodextrin M100 was shown to improve mouthfeel.

EXAMPLE 8 0136 Example 8 illustrates the use of polyethylene glycols (PEGs) as the water soluble melt binder. 0137 The following materials were employed in this example. 8Material% CompositionParacetamol80Erythritol5PEG6000 Powder10Maltodextrin M1002.0Sodium Glycine Carbonate1.2Citric Acid Monohydrate0.8Acesulphame K0.5Aspartame0.5

0138 Method 0139 Granular paracetamol, erythritol, sodium glycine carbonate and citric acid monohydrate and 5% PEG6000 were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 70 C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend, along with the maltodextrin M100, aspartame and acesulphame potassium, and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete. 0140 Results 0141 The resulting formulation exhibited reasonable tastemasking and a slight aftertaste, but with excellent mouthfeel and rapid dispersibility.

EXAMPLE 9 0142 An additional approach to drug tastemasking is described where the citric acid monohydrate content is increased to locally modify the pH within the oral cavity and therefore limit drug dissolution. 0143 The following materials were employed in this example. 9Material% CompositionParacetamol77.2Erythritol10.0PEG6000 Powder7.0Sodium starch Glycolate2.0Sodium Glycine Carbonate1.2Citric Acid Monohydrate1.5Acesulphame K0.5Aspartame0.5Powdered Lemon Flavour0.1

0144 Method 0145 Using a Diosna P1-6 mixer-granulator equipped with a 1 litre jacketed bowl was heated at 55 C. for 10 minutes before the addition of the granular acetaminophen, erythritol, sodium starch glycolate, sodium glycine carbonate, citric acid monohydrate, aspartame fine, acesulphame potassium and powdered lemon flavour. This material was blended for a further 10 minutes prior to the addition of the PEG6000. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25 C. for 10 minutes. 0146 Results 0147 The resulting formulation exhibited pleasant taste, good mouthfeel and a slight bitter aftertaste; which is attributed to the presence of additional citric acid. The dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.

EXAMPLE 10 0148 Sumatriptan 50 mg (Final Formulation Mass 75.7 mg) A granulation of Sumatriptan was prepared containing 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 m sieve and airjet sieved to remove particles below 1001 m. The resulting granules were then spray coated with an aqueous dispersion of Eudragit RD-100 plasticised with Triacetin. The quantity of coating was sufficient to achieve the required degree of tastemasking of the active (approximately 15% weight gain). The granules were then dried and cooled for hot melt coating with xylitol. The tastemasked Sumatriptan granules were loaded into a 1 litre-jacketed bowl for a modified Diosna P1-6 mixer-granulator (preheated at 95 C. for 10 minutes) with 1% Aspartame (or 0.5% Aspartame and 0.5% Acesulfame potassium) and 10% xylitol. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder (xylitol) through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing, the bowl was cooled to 25 C. over 10 minutes. Once cooled the formulation was tested. It was found that improved tastemasking and drug release could be achieved by further addition of Triacetin to the Eudragit RD100 film coat.

EXAMPLE 11 0149 Lansoprazole 15 mg (Final Formulation Mass 20 mg) 0150 Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75% Lansoprazole, 20% PEG 6000 and 5% Aspartame was prepared using a one litre jacketed mixing bowl heated to a temperature sufficient to melt the PEG 6000 binder (i.e. 70 C.). The Lansoprazole and Aspartame were equilibrated in the bowl for 10 minutes at an impeller speed of 300 RPM and a chopper speed of 150 RPM, after this time the PEG6000 was added and massing continued for another 3 minutes. The material was then emptied from the bowl, cooled on a metal tray at room temperature and then stored in sealed bags. It was found that incorporation of 5% of a low-viscosity Sodium Starch Glycolate into the granules improved the mouthfeel of this formulation without altering drug release or the degree of tastemasking.

EXAMPLE 12 0151 Ranitidine 150 mg (Final Formulation Mass 200 mg) 0152 Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75% Ranitidine, 20% PEG 6000 and 5% Aspartame was prepared using a one litre jacketed mixing bowl heated to a temperature sufficient to melt the PEG 6000 binder (i.e. 70 C.). The Ranitidine and Aspartame were equilibrated in the bowl for 10 minutes at an impeller speed of 300 RPM and a chopper speed of 150 RPM, after this time the PEG6000 was added and massing continued for another 3 minutes. The material was then emptied from the bowl, cooled on a metal tray at room temperature and then stored in sealed bags. It was found that incorporation of molar equivalents of citric acid monohydrate and sodium bicarbonate into the melt granulation improved the degree of tastemasking and aided the dispersion of the granules.

EXAMPLE 13 0153 Domperidone 10 mg (Final Formulation Mass 100 mg) 0154 A 5% w/w aqueous dispersion of maltodextrin containing 5% w/w domperidone was prepared and spray-coated onto microcrystalline cellulose spheres sufficient to achieve a 33% coating wt. gain using and MP-Micro Fluid Bed Dryer. The coated spheres were then dried and cooled for hot melt coating with xylitol. Using a modified Diosna P1-6 mixer-granulator the domperidone-loaded microcrystalline cellulose spheres were blended with 10% wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95 C. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing, the bowl was cooled to 25 C. over 10 minutes. Once cooled, the formulation was tested. It was found that the incorporation of 0.25-0.5% of hydroxypropylmethylcellulose to the xylitol improved the stability of the formulation.

EXAMPLE 14 0155 Paracetamol (Acetaminophen) 500 mg (Final Formulation Mass 745 mg) 0156 Step 1: Spray Coating With Surelease 0157 Granular paracetamol was tastemasked by spray-coating with an aqueous dispersion of ethylcellulose in an MP-Micro Fluid Bed Dryer. Approximately a 15% wt. gain was required, depending on the degree of tastemasking. Once the desired weight of ethylcellulose had been added to the granules, the material was dried, cooled and then screened through a 250 m sieve and airjet sieved to remove particles below 100 m. Using a modified Diosna P1-6 mixer-granulator, the tastemasked paracetamol granules were then blended with 1% Aspartame and 10% xylitol in a one litre jacketed mixing bowl heated to 95 C. for 10 minutes. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing the bowl was cooled to 25 C. over 10 minutes. Once cooled the formulation was tested. It was found that improved tastemasking and drug release could be achieved by further addition of glycerol to the ethylcellulose film coat.

EXAMPLE 15 0158 Loperamide 2 mg (Final Formulation Mass 50 mg) 0159 A granulation of equal quantities of aspartame and Acesulphame K was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 m sieve and airjet sieved to remove particles below 100 m. The granules were dried and cooled for hot melt coating with xylitol. Using a modified Diosna P1-6 mixer-granulator the aspartame/acesulphame K granules were blended with 4% Loperamide and 10% wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95 C. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing the bowl was cooled to 25 C. over 10 minutes. Once cooled the formulation was tested. It was found that the incorporation of 0.25-0.5% of hydroxypropylmethylcellulose to the xylitol improved the stability of the formulation.

EXAMPLE 17 0160 Co-Beneldopa 12.5 mg/50 mg (Final Formulation Mass 164.8 mg) 0161 A granulation of 19.2% Benserazide Hydrochloride and 76.8% Levodopa was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 m sieve and airjet sieved to remove particles below 100 m. The granules were dried and cooled for hot melt coating with Xylitol. Using a modified Diosna P1-6 mixer-granulator the Co-Beneldopa granulation was blended with 10% xylitol in a one litre jacketed mixing bowl heated to 95 C. for 10 minutes. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. 0162 After another 5 minutes mixing the bowl was cooled to 25 C. over 10 minutes. Once cooled the formulation was tested. It was found that by adding a 5% wt. gain of glyceryl palmitostearate and 1% wt. gain of aspartame, the degree of tastemasking was improved without adversely impeding drug release.

EXAMPLE 18 0163 Enteric coated Aspirin formulation 0164 Method 0165 Granular Aspirin, having a particle size suitable for spray coating (i.e., between 100 and 5001 m) was coated in an MP-Micro fluid bed dryer, using the down-spray coating module. An aqueous dispersion of 15% w/w Opadry was prepared, which was sprayed onto the granular aspirin at a product temperature of between 40 and 45 C. to a weight gain of 10%. The coated material was dried before a 15% weight gain of an aqueous dispersion of 15% w/w Acryl-eze was added to the granules, at a product temperature of 25-35 C. The material was dried and cooled before being placed in a one litre jacketed bowl for the Diosna P1-6 mixer granulator. A blend of 60% enteric coated aspirin, 20% Mannitol, 10% Xyltiol 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and 2% Maltodextrin was equilibrated at 70 C. whilst mixing at an impellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25 C. for 10 minutes. 0166 Results 0167 The formulation met USP requirements for acid phase drug release, i.e., less than or equal to 10% dissolved in 2 hours in 0.1M HCl and greater than 80% released in 90 minutes in pH 6.8 phosphate buffer.

EXAMPLE 19 0168 Controlled Release Chlorpheniramine Maleate Drug-Loaded Spheres 0169 Step 1: Drug Loading 0170 Chlorpheniramine maleate was dissolved in an aqueous dispersion of 10% Opadry. A 15% weight gain of Opadry was applied to 60-40 mesh non-pariel sugar spheres, in order to obtain an active drug content of approximately 8% w/w. The dispersion was applied to the sugar spheres at a product temperature of between 40 and 45 C. in an MP-Micro fluid bed dryer, using the down-spray coating module. 0171 Step 2: Sustained Release Coating 0172 An additional 5% coat of 10% Opadry aqueous dispersion was added to the drug loaded spheres before the application of an aqueous dispersion of 15% w/w Surelease was applied. A weight gain of between 15 and 30% was applied to produce a formulation with the required release profile. 0173 Step 3: Melt Granulation 0174 The dried, 65% drug-loaded spheres were blended in a one litre jacketed bowl for the Diosna P1-6 mixer granulator with 15% Mannitol, 10% Erythritol, 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and 2% Maltodextrin and equilibrated at 70 C. whilst mixing at an impellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25 C. for 10 minutes. 0175 Results 10Time (Hours)% Drug Release220-30435-45645-551260-70

EXAMPLE 20 0176 Immediate release Chlorpheniramine Maleate 0177 A granulation of 8% Chlorpheniramine Maleate, 4% w/w PVP K-30 and 88% Xylitol was prepared in an MP Micro fluid bed dryer. The materials were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 m sieve and airjet sieved to remove particles below 1001 m. A blend containing 50% Chlorpheniramine Granules, 25% Granular Mannitol, 10% Erythritol, 0.5% Aspartame, 0.5% Acesulfame Potassium, 1.2% Citric Acid Monohydrate, 0.8% Sodium Glycine Carbonate and 2% Maltodextrin was equilibrated at 70 C. in a one litre jacketed bowl for a Diosna P1-6 mixer-granulator for 10 minutes at an impellar speed of 50 RPM and a chopper speed of 50 RPM prior to the addition of 10% PEG6000. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25 C. for 10 minutes.

EXAMPLE 21 0178 10 Chronotherapeutic Chlorpheniramine Maleate Blend Method 0179 A blend of 16.7 g of immediate-release chlorpheniramine maleate granules (Example 20) was blended with 83.3 g controlled-release chlorpheniramine maleate drug-loaded spheres (Example 19) at 42 rpm for 30 minutes using an inversion low shear mixer. 11Results (Formulation mass 600 mg: active 24 mg)Time (Hours)Mean Drug Release (mg) n 60.54.249.6612.11215.6