US 20080299.199A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0299199 A1 Bar-Shalom et al. (43) Pub. Date: Dec. 4, 2008

(54) SWELLABLE DOSAGE FORM COMPRISING Publication Classification GELLAN GUMI (51) Int. Cl. A6II 47/36 (2006.01) (75) Inventors: Daniel Bar-Shalom, Kokkedal A6II 47/38 (2006.01) (DK); Lillian Slot, Virum (DK); A6II 47/32 (2006.01) Gina Fischer, Vaerlose (DK); A6II 47/02 (2006.01) Pernille Hoyrup Hemmingsen, A6IR 9/00 (2006.01) Bagsvaerd (DK) (52) U.S. Cl...... 424/484: 514/777: 514/779; 514/781; 424/400: 514/772.4: 514/769 Correspondence Address: (57) ABSTRACT FOLEY AND LARDNER LLP SUTESOO A novel dosage form. The dosage form is presented in par 3OOOK STREET NW ticulate form and before oral ingestion the particulate mate WASHINGTON, DC 20007 (US) rial is subjected to an aqueous medium, whereby it is con Verted to a semi-solid form by Swelling or gelling of one or (73) Assignee: Egalet a?s more of the components, especially of a gellan gum, of the particulate matter. The invention also relates to a vehicle for oral administration of one or more active Substances, the (21) Appl. No.: 111596,123 vehicle comprising a gellan gum arranged in a configuration allowing optimal water diffusion so that upon addition of a (22) PCT Filed: May 11, 2005 predetermined amount of an aqueous medium, without the necessity of applying shear forces or other mixing forces, (86). PCT No.: PCT/DKOS/OO317 within a time period of 5 minutes or less swells and/or gels and the texture of the swelled vehicle being similar to that of S371 (c)(1), a soft pudding and having a viscosity of at least about 10,000 (2), (4) Date: Aug. 14, 2007 cps as measured by a Brookfield Viscometer with a #4 LV spindle at 6 rpm and at 20-25°C. In one embodiment of the (30) Foreign Application Priority Data invention, the particulate matter can be moulded into a desired shape or pressed onto a dispensing unit such as a May 11, 2004 (DK) ...... PA 2004 OO755 Spoon. (1) \-7 (1a) - N-27 (1b) Patent Application Publication Dec. 4, 2008 Sheet 1 of 10 US 2008/0299.199 A1

Patent Application Publication Dec. 4, 2008 Sheet 2 of 10 US 2008/0299.199 A1

Dissolution of 200 mg Paracetamol parvulet

120 - - - -0-61% coated 100 Paracetamol -- 200 mg Paracetamol 80 parvulet -A-200 mg Paracetamol ?a parvulet SSo 60 -X-200 mg Paracetamol 40 parvulet -- 200 mg Paracetamol parvulet 20 -e-200 mg Paracetamol parvulet O - O 5 10 15 20 25 30 35 40 45 50 55 time min

Fig. 2 Patent Application Publication Dec. 4, 2008 Sheet 3 of 10 US 2008/0299.199 A1

Patent Application Publication Dec. 4, 2008 Sheet 4 of 10 US 2008/0299.199 A1

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Fig. 4 Patent Application Publication Dec. 4, 2008 Sheet 5 of 10 US 2008/0299.199 A1

Patent Application Publication Dec. 4, 2008 Sheet 6 of 10 US 2008/0299.199 A1

Patent Application Publication Dec. 4, 2008 Sheet 7 of 10 US 2008/0299.199 A1

Fig. 7 Patent Application Publication Dec. 4, 2008 Sheet 8 of 10 US 2008/0299.199 A1

F8 i

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8 & s

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Fig. 8 Patent Application Publication Dec. 4, 2008 Sheet 9 of 10 US 2008/0299.199 A1

20 —

100

8O

--Wessel 1 -H-Wessel 2 -A-Wessel 3 re-vessel 4 --vesses se-Wessel 6

4. o

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0 10 20 30 4. 50 SO 70 Time (min)

Fig. 9 Patent Application Publication Dec. 4, 2008 Sheet 10 of 10 US 2008/0299.199 A1

US 2008/0299.199 A1 Dec. 4, 2008

SWELLABLE DOSAGE FORM COMPRISING then be formulated into tablets or capsules meant to be swal GELLAN GUMI lowed whole. Those tablets and capsules as Such are inappro priate for patients with Swallowing difficulties. Patients (or FIELD OF THE INVENTION they providers in the case of children) are often instructed to open the capsules (or crush the tablets) and to sprinkle the 0001. The present application relates to a novel dosage powder on syrup or pudding or applesauce or similar and then form. The dosage form is presented in particulate form and administered. This approach has limitations. The carrier before oral ingestion the particulate material is subjected to (syrup, pudding, applesauce) is not a well defined entity and an aqueous medium, whereby it is converted to a semi-solid different carriers might interact differently with the multi form by Swelling or gelling of one or more of the components, particles and/or drug and thereby compromise the treatment. especially of a gellan gum, of the particulate matter. The Also, children might object to the grittiness in the material. invention also relates to a vehicle for oral administration of Syrups do not necessarily resemble types of food or bever one or more active Substances, the vehicle comprising a gel ages that children are used to consume. langum arranged in a configuration allowing optimal water 0005. Alternatively the powder can be formulated into diffusion so that upon addition of a predetermined amount of effervescent granules or tablets. These granules or tablets are an aqueous medium, without the necessity of applying shear intended to be dissolved in an aqueous liquid requiring the forces or other mixing forces, within a time period of 5 provision of a glass of liquid and a waiting period sufficient to minutes or less swells and/or gels and the texture of the allow the tablet to completely dissolve and the resulting vol swelled vehicle being similar to that of a soft pudding and ume might be considerable. Often, these dosage forms leave having a viscosity of at least about 10,000 cps as measured by an objectionable deposit in the glass, which may represent a a BrookfieldViscometer with a #4 LV spindle at 6 rpm and at non-ingested part of the drug. Effervescent formulations are, 20-250 C. in general more appropriate for adults although some com 0002. In one embodiment of the invention, the particulate mercial vitamin preparations for children use this approach. matter can be moulded into a desired shape or pressed onto a 0006 Another category is the fast-melting tablets meant to dispensing unit Such as a spoon. be put on the tongue and disintegrate upon contact with saliva. The might be effervescent or non-effervescent. Yet another BACKGROUND OF THE INVENTION Solution is to dispense the multi-particles in lozenges, chew 0003. A recurring problem in the treatment of patients, in able tablets and chewing gum. particular children and the elderly, is their inability or unwill 0007. One example of these approaches was described in ingness to Swallow solid oral dosage forms such as tablets or Wehling et al., U.S. Pat. No. 5,178.878, which relates to capsules. The problem is, however, not uncommon in healthy certain effervescent dosage forms including microparticles. adults as well. This problem is not trivial, the inability or The effervescent dosage forms of Wehling et al. provide a unwillingness of some people to take Solid oral dosage forms significant advance over the art in that they provide an effer can severely compromise the patient's compliance with a Vescent dosage form for direct oral administration. The dos prescribed treatment protocol. Moreover, due to embarrass age form is designed to disintegrate rapidly in the mouth ment, many patients are unwilling to tell their doctor of their releasing its microparticles as a slurry for ingestion. The problem so that the doctor can consider other drugs and/or dosage forms produced in accordance with Wehling et al. can alternate dosage forms. Such a lack of compliance can com be placed in the patient's mouth and the effervescence con promise treatment or cure. tained therein will be activated by contact with the patient’s 0004 Ifan orally administered drug has such a taste that is saliva. The tablet will then disintegrate in a number of sec acceptable to the patient and the pharmacokinetic character onds. However, the effervescence on the tongue may be istics allow reasonable administration regimens, such as once unpleasant to Some adults and to many children. or twice daily, the drug might be formulated in a sirup, elixir, 0008 Kallstrand, et al., U.S. Pat. No. 4,994.260 relates to Suspension or other liquid dosage forms. Unfortunately, in a pharmaceutical mixture. The mixture is used for the con many cases the native taste of the drug is unpleasant and not trolled release of a Substance. According to Kallstrand et al., amenable to taste-masking by the addition of Sweeteners of a liquid dosage form is produced using either a dry powder or flavours. Also, many drugs have such pharmacokinetic microcapsules, which are Suspended in a solution of a release parameters that demand administration at short intervals, dis controlling Substance, also referred to as a "sink. Alterna rupting sleep and other activities. The taste and/or pharma tively, it is possible to encapsulate the release-controlling cokinetic deficiencies can be corrected by the use of various Substance, together with a drug, within an encapsulating coating and/or matrices and/or by modifying the crystalline shell. The release-controlling Substance may include, inter structure, etcetera. U.S. Pat. No. 6,589,955 illustrates such an alia, carbohydrates and carbohydrate-related compounds, approach. The resulting material after micro-encapsulation or disaccharides, monosaccharides, glycerol, glycol, glycosides crystallization or other strategies might be a monolithical of monosaccharides and Substances derived from ethyleneg unit, one unit containing the whole dose, or multi-particles, lycol. each particle containing a fraction of the total dosage. The 0009 Boder et al., U.S. Pat. No. 5,126,151 relates to an monolithical units are often unacceptable to people having encapsulation mixture. Boder et al. refers to the construction the swallowing problems described above. The multi-par of gums and candies in oral dosage forms. According to ticles must be further processed into finished dosage forms Boder et al., microcapsules are produced including a core Such as tablets and capsules with the same limitation as the material which can be selected from a wide variety of mate monolithical units or other forms specifically designed for rials including Sweeteners, medicaments, drugs, flavoring children and/or adults unable to swallow oral solid dosage agents and the like. These materials can be used, either sin forms. Finally, some substances are administered in Such high gularly or in combination, in either a single or multiple part doses that the resulting tablets or capsules are either very delivery systems. That is, one or more of these materials may large or that many tablets or capsules must be administered be present within one coating matrix or maybe separately simultaneously, in either case, causing discomfort. The multi coated by the matrix and employed alone or in combination in particles may be presented as a powder. This powder might the final product. The resulting formulations are said to be US 2008/0299.199 A1 Dec. 4, 2008

able to provide a masking of unpleasant tasting drugs such as cps as measured by a Brookfield Viscometer with a #4 LV potassium chloride and the like, making consumption of the spindle at 6 rpm and at 20-25°C. drug more appealing to the public. The dosage forms may be 0017 Dispersing, wetting/hydrating, dissolving gelling prepared in chewable tablet form. agents in water to form colloidal dispersions is a notoriously 0010 Schobel et al., U.S. Pat. No. 4,824,681, and Wei et difficult procedure A discussion of the general properties of al., U.S. Pat. No. 4,590,075. Encapsulated sweeteners have colloidal dispersions and their preparation can be found in: also been used to provide an extended release of Sweetening Remington; The Science and Practice of Pharmacy, 20" Edi in, for example, chewing gum, see for example European tion, A. R. Gennaro et al editors, published in 2000 by Lip patent application EPO 87-810747 to Schobel et al. and in pincott Williams and Wilkins (Chapter 21). Diverse tech bakery products such as disclosed in WO 91-US9434 filed niques are involved, among them stirring, shaking, heating/ Dec. 17, 1991 to Redding et al. cooling, slow and gradual addition of the gelling agent to the 0011. Further, in WO 01/76610 Simek et al describe a liquid, etcetera. This explains why the in the directions of use pharmaceutical composition containing calcium or mixture of the so called “Instant Puddings” or “Instant Creams' or of calcium and vitamin D or mixture of calcium and magne “Instant Sauces instructions such as “add the powder slowly sium and adjuvants, presented in the form of soluble powder, to the boiling water or “stir vigorously” or “let it stand for 30 which by addition of liquids and mechanical mixing, forms a minutes' are often found. gelatinous Suspension resembling a pudding. 0018. In another aspect, the invention relates to a pharma 0012 U.S. Pat. No. 6,709,678 discloses an oral pharma ceutical composition for oral administration comprising one ceutical composition to be dispersed in an aqueous carrier or more active Substances and a gellan gum arranged in a prior to administration comprising a multiplicity of particles configuration allowing optimal water diffusion so that upon consisting of a drug core individually coated with one or more addition of a predetermined amount of an aqueous medium, layers with a hydratable polymer. The preferred hydratable without the necessity of applying shear forces or other mixing polymers are preferably alginates, carboxymethylcellulose, forces, within a time period of 5 minutes or less, the compo hydroxypropylmethylcellulose and polyvinylpyrrolidone. sition swells and/or gels and the texture of the swelled com The coating is applied by conventional coating methods with position being similar to that of a soft pudding and having a a powder mixture in a spheronizer or by spraying on a solu viscosity of at least about 10,000 cps as measured by a Brook tion or Suspension of the coating materials to the core. The field Viscometer with a #4 LV spindle at 6 rpm and at 20-25° aim of the hydrated formulation is to obtain a formulation in C a single, slippery, non disintegrating mouldable coherent vis 0019. In a still further aspect, the invention relates to a cous plastic mass, which does not adhere to the mucosa. dispensing unit comprising a pharmaceutical composition for 0013 WO2004/096906 A1 discloses a thickenable com oral administration comprising one or more active substances position in water-containing liquid form which upon addition and a gellan gum arranged in a configuration allowing opti of further water increases in viscosity. The composition com mal water diffusion so that upon addition of a predetermined prises different anionic polymers such as Xanthan together amount of an aqueous medium, without the necessity of withalginate, carboxymethylcellulose, carrageenan, an acry applying shear forces or other mixing forces, within a time late polymer or pectin. period of 5 minutes or less, the composition Swells and/or gels 0014 WO 2005/007074 A2 published on 27 Jan. 2005 and the texture of the swelled composition being similar to discloses a gellan gum based oral controlled release dosage that of a soft pudding and having a viscosity of at least about form for gastric retention. The formulation is swallowed in a 10,000 cps as measured by a Brookfield Viscometer with a #4 non hydrated form such as a tablet and it is expected that the LV spindle at 6 rpm and at 20-25°C. formulation when reaching the aqueous environment of the 0020. The pharmaceutical composition and the dispensing stomach would form a strong gel. unit according to the invention are intended to be contacted 0015 The present invention proposes an improvement with a small amount of water before administration and the over the art by providing a Substantially water free dosage water induces the Swelling of the gellan gum, which makes form, containing particulate material Such as, e.g., particulate the composition easy to ingest and at the same time provides units, that is/are designed for the purpose of masking the taste an acceptable mouth-feel. of drug Substance(s) and/or to provide controlled release of a 0021. In the context of the present invention relatively drug Substance or drug Substances. In turn the particulate Small Volumes are contemplated for the ready-to-administer material may be coated and/or mixed with components that, unit (meaning after exposure to water), typically in the range upon exposure to water will Swell into a soft pudding-like, of 1 to 100 mL, in particular 1 to 20 mL. Stirring/shaking or mousse-like or souffle-like semisolid mass that has a sensory any type of mixing would be difficult and often result in loss acceptable mouth-feel and taste as determined and judged by of material thus compromising the accuracy of dosing. There a professional taste panel. Further, the invention provides a fore it is desirable to have a composition, which, upon expo vehicle to be combined prior to administration with particu sure to water, will swell without shaking. It was found that if late matter Such as microencapsulated drugs. steps are taken to ensure rapid diffusion of water into the bulk, then the desired result is achieved. The steps include: (1) SUMMARY OF THE INVENTION Addition of very soluble Substances such as soluble Sugars. (2) Using gelling agents presenting as fine powders (3) 0016. In one aspect, the invention relates to a vehicle for Granulating the ingredients with Small amounts of binding oral administration of one or more active Substances, the Solutions and (4) Packing the granulate (if desired) loosely. vehicle comprising a gellan gum arranged in a configuration 0022. Other possible techniques are forming the compo allowing optimal water diffusion so that upon addition of a nents, typically either the gelling agents and/or the Sugars into predetermined amount of an aqueous medium, without the threads which can be subsequently formed into non-woven necessity of applying shear forces or other mixing forces, tissues or forming the gelling agents into films where readily within a time period of 5 minutes or less swells and/or gels soluble substance are embedded to ensure channel of diffu and the texture of the swelled vehicle being similar to that of sion for the water. The last mentioned techniques might, in a soft pudding and having a viscosity of at least about 10,000 turn, be combined with granulated matter. US 2008/0299.199 A1 Dec. 4, 2008

0023. In accordance with the present invention, a pharma preparation in order to intake the composition is easy and ceutical unit dosage form is provided that is dispensed as a convenient for the patient and do not require specific equip Solid, but which upon contact with a measured amount of ment. water and without application of a shear force Such as mixing 0028. As it will appear from the description herein, the quickly Swells to provide a semi-solid mass that easily can be ready-to-use composition is intended to adhere to the dis orally ingested by a patient, in particular patients with Swal pensing unit Such as e.g. a spoon. Furthermore, it is advanta lowing difficulties. geous that the ready-to-use composition does not fall off the dispensing unit and accordingly, the vehicle and/or the phar 0024. The unit dosage form includes a plurality of par maceutical composition must have a certain viscosity as men ticles or a plurality of units. In the following the drug-con tioned above. In specific embodiments, a vehicle and/or com taining particle or unit is commonly denoted "drug-contain position of the invention has a viscosity in a range from about ing micro-particle'. The drug-containing micro-particle 10,000 to about 99,000 cps. The viscosity can be measured carries at least one therapeutically, prophylactically and/or using a Brookfield Viscometer with a #4 LV spindle at 6 RPM diagnostically active Substance and, optionally, components and at 20-25 degrees C., or equivalent. Viscosity decreases providing taste masking and/or controlled release function slightly with increasing temperature. ality. Further, the dosage form contains one or more Sub 0029. The inventive formulations may also have a Brook stances that are able to swell upon contact with water. Yet field viscosity within the range of about 10,000 cps to about further the dosage form may contain taste modifiers such as 99,000 cps at room temperature. Below about 20,000 cps, Sweeteners, flavors, preserving Substances, texture modifiers, formulations tend to spill but formulations less viscous might color modifiers and other additives such as binders. Impor be appropriate in Some instances, such as reclining patients. tantly, the dosage form according to the invention has prop Formulations exhibit desirable spill-resistant properties at a erties that are acceptable to the patient from a sensory aspect, viscosity greater than about 20,000 cps. i.e. when ingested, it does not have an unpleasant mouth-feel 0030 The ready-to-use compositions are non-Newtonian and/or a bad taste or odor. These properties are tested by a and time independent fluids. Non-Newtonian refers to a fluid professional taste panel consisting of at least 6 persons that whose behaviour departs from that of an ideal Newtonian have been specifically selected due to their tasting ability as fluid. These fluids have different viscosities at different shear well as to children age 5-6 years to evaluate whether the rates and fall under two groups: time independent and time children would have any objections to a repetitive placebo dependent. In contrast, for a Newtonian fluid the rate of shear dosage according to the present invention. in the fluid under isothermal conditions is proportional to the 0025. The drug-containing micro-particles can be pre corresponding stress at the point under consideration. pared following any of the conventional methods used e.g. in (McGraw-Hill Encyclopedia of Science & Technology, micro-encapsulation, in incorporation into matrices or by 6

COOH CHOH CH2OH O O O O |-o OH CH O Y KSH O

HO OH HO OH OH OH Low Acyl form

Comparison of Physical Properties of High Acyl and Low hydroxyl groups in the other plus one strongly bound water Acyl Gellan Gum molecule. Pairs of helices may form antiparallel junction 0045 Zones with Ca2+. Functionality:

Kelcogel LT100 Kelcogel F 0048. The functionality depends on the degree of acyla (High Acyl) (LOW acyl) tion and the ions present. If low acylated, gellan forms soft, Molecular Weight 1-2 x 106 Daltons 2-3 x 105 Daltons elastic, transparent and flexible gels but once de-acylated it Solubility Hot water Hot or cold water forms hard, non-elastic brittle gels. An important feature is Set temperature 70-80° C. 30°-50 the irrevasible gelling properties where gellangum may form Thermo reversibility Thermo-reversible Heat stable an irrevasible film after dehydration, which will prevent gel ling on rehydration. A gel sol transition occurs at about 50° C. 0046. The molecular structure of gellan gum is straight dependent on concentration. Thermoreversible gels form on chain based on repeating glucose, rhamose and glucuronic cooling in the presence of cations even at low (0.1% w/w) to acid units. In its native or high acyl form, two acyl Substitu very low (0.005% w/w) concentrations. ents—acetate and glycerate—are present. Both Substituents 0049 Gellan is unique in that it forms gels with all ions, are located on the same glucose residue, and on average, there including hydrogen. Gellan is compatible with a number of is one glycerate per repeat and one acetate per every two other gums (Xanthan, locust bean), starches and gelatin to repeats. In low acylgellan gum, the acyl groups are removed manipulate the type of gel, elasticity and stability. Gellan may completely. The acyl groups have a profound influence on gel be combined in mixtures producing synergistic properties characteristics. The high acyl form produces soft, elastic, which mixtures may also include natural seaweeds, natural non-brittle gels, whereas the low acyl form produces firm, seed gums, natural plant exudates, natural fruit extracts, bio non-elastics, and brittle gels. The acylated form is shown synthetic gums, bio-synthetic processed starch or cellulosic below. materials. More specifically, the mixture may include algi

US 2008/0299.199 A1 Dec. 4, 2008

nates, agar gum, guar gum, locust bean gum (carob), carrag (aq.) from the environment of use into the matrix. Exemplary eenan, tara gum, gum arabic, ghatti gum, Khaya grandifolia osmotic agents are water swell able or water soluble. The gum, tragacanth gum, karayagum, pectin, arabian (araban). vehicle or composition according to the invention may Xanthan, starch, konjak mannan, galactomannan, funoran. include water-swell able hydrophilic polymers, both ionic 0050. Another preferred swelling and swelling improving and non-ionic, often refers to as "osmopolymers' and hydro agent is konjak. Konjak contains 50%-60% glucomannan, gels. Exemplary materials includehydrophilic vinyl and acryl 20-30% starch, 2-5% fiber, 5-10% crude protein, 3-5% polymers, poly saccharides, PEO, PEG, PPG, poly(2-hy soluble Sugars (monosaccharide and oligosaccharide) and droxyethyl methacrylate), poly(acrylic)acid, poly(meth 3-5% ash (minerals). Chemical Structure of Konjac Gluco acrylic)acid, PVP, PVA, PVA/PVP copolymers, HEC, HPC, mannan (KGM) is shown below. The molecular weight of HPMC, CMC, CEC, sodium alginate, polycarbophil, gelatine KGM varied from 1,000,000 to 2,000,000 daltons according to konjac species or variety, processing method and storage and sodium starch glycolate. Other materials include hydro time of the raw material. gels comprising interpenetrating networks of polymers, 0051. In a preferred embodiment, the gellan gum has a which may be formed by addition or by condensation poly mean particle size within 25 mesh to 300 mesh in order to merization, the components of which may comprise hydro allow a suitable distribution of water into the vehicle. philic and hydrophobic monomers. Preferred polymers for 0052 Furthermore, in a specific embodiment, the gellan use at the water-swellable hydrophilic polymers include gum is acylated within a degree of 0 to 4 per every two repeats PEO, PEG, PVP HPMC and polyacrylic acid. of the glucose-rhamnose-glucose-glucuronic acid unit of the 0.058 By “osmotically effective solutes' is meant any polymer. The vehicle or composition may contain a mixture water-soluble compound that is commonly referred to in the of gellan gums having different degrees of acylation and/or pharmaceutical arts as an “osmogen' oran “oSmagent'. Typi different mean particle sizes. cally classes of Suitable osmogens are water-soluble organic 0053. In a specific embodiment, the gellan gum has a acids, salts and Sugars that are capable of imbibing water to degree of acylation of one glycerate per repeat and one acetate thereby affect an osmotic pressure gradient across the barrier per every two repeats. of the Surrounding matrix. Typical useful osmogens include 0054 As mentioned above, the presence of gellan gum in magnesium Sulfate, magnesium chloride, calcium chloride, a vehicle or a composition according to the invention may Sodium chloride, lithium chloride, potassium Sulfate, sodium lead to a porous hydrogel when contacted with water Such as, carbonate, Sodium sulfite, lithium Sulfate, potassium chlo e.g., a micro-porous hydrogel havingapore size of at the most ride, Sodium sulfate, mannitol, Xylitol, urea, Sorbitol, inositol, 4. A or a macro-porous hydrogel having a pore size of from raffinose, Sucrose, glucose, fructose, lactose, inulin, instant about 4 to about 15 A. Sugar, citric acid, Succinic acid, tartaric acid, and mixtures

Konjak:

CH2OH CH2OH

O OH OH O O

Mannose Mannose Glucose Glucose

0055 Some of the factors there can effect the swelling thereof. Particularly preferred osmogens are glucose, lactose, include pH, ionic strengths, and temperature. The behaviours Sucrose, mannitol, Xylitol and sodium chloride. of the different hydrogels as drug carrier, is well known. The behaviour of e.g. Gellan gum is quite different from that of Electrolytes PVP and PEO, respectively. In fact, although the gel Gellan Gum with cations shows a very well ordered and regular 0059. The electrolyte's greater hydrophilicity than the structure both in the solid state and in solution, when it is other formulation components allows it to hydrate preferen tested as a matrix it swells up and it is rapidly dispersed, tially in comparison to the Surrounding polymers and the drug leading to a quite fast release of the API (active substance). molecules. This peripheral matrix-hardening creates a con 0056. As mentioned above, a vehicle or a composition trollable micro-environment within the hydrated layer, and according to the invention may further comprise an agent that make the formulation robust again variable ion strengths from improves Swelling of the gellangum. Such an agent may be a added water to the matrix. hydrophilic agent selected from the group consisting of elec trolytes, organic acids and osmotic agents, and mixtures 0060. The use of e.g. alkalizing agents to preserve internal thereof. dosage form pH though the acid regions of the upper gas trointestinal tract is well established. Osmotic Agents 0061. One advantage of maintaining a constant internal 0057 By the term “osmotic agent' is meant any agent pH is that a very soluble drug in 0.1M HCl may be made less which creates a driving force for transport of water or media soluble if the environmental pH is above the pKa-value of the US 2008/0299.199 A1 Dec. 4, 2008

drugs. Through the application of colloidal chemistry prin between different ionic groups with the same charges. The ciples, it is possible to provide pH-control via a formulation nature of the counter ions is thus of extremely importance for component that is also active as a release controlling excipi the degree of Swelling of Such charged gel-like systems. ent within a hydrophilic matrix. Changing the ionic content in the formulation will affect the 0062) A vehicle or composition according to the invention water uptake. The nature of the ions (ion pair) has a profound may also comprise a pH-adjusting agent selected from the effect on the characteristics of the water adsorption due to the group consisting of any material which is suitable to adjust different ability of the ion pair to dissociate. the pH of an aqueous gel Such as, e.g., Sodium bicarbonate, 0069. The ion pairs will compete with the hydrogel about Sodium phosphate, sodium hydroxide, ammonium hydrox the water molecules, and can thereby increase the hydration ide, Sodium Stannate, triethanolamine, citric acid, hydrochlo and decrease the solubility of the hydrogel, respectively, ric acid, sodium citrate, and combinations thereof. Generally, which can stabilise the gel formation. if present, the pH adjusting agentis present in an amount So as to adjust the pH of the gel formed upon addition of an aqueous Physical and Chemical Properties of Hydrogels medium to about 4.5 to about 11, preferably from about 5 to 0070 The cross linking ratio is one of the most important about 9, and more preferably from about 5 to about 8. A factors that effects the swelling of hydrogels. It is defined as Suitable amount is normally in an amount of from about the ratio of moles of cross linking agent to the moles of 0.01% to about 15% w/w such as, e.g., from about 0.05% to polymer repeating units. The higher the cross linking ratio, about 5% w/w. the more cross linking agent is incorporated in the hydrogel 0063. Upon ingestion, gastric fluid enter into the dosage structure. Highly cross linked hydrogels have a tighter struc form, causing the composition to hydrate and activates the pH ture, and will swell less compared to the same hydrogel with and release-controlling characteristics of the excipients. lower cross linking ratios. Cross linking hinders the mobility 0064. A suitable electrolyte for use according to the inven of the polymer chains, hence lowering the Swelling ratio. The tion is a ionizable Substance that is selected from the group chemical structure of the polymer may also affect the swell consisting of monovalent, divalent, or multivalent ionizable ing ratio of the hydrogels. Hydrogel contains hydrophilic salts. More specifically, the salt is selected from inorganic groups Swell to a higher degree compare to those containing salts, including various alkali metal and/or alkaline earth hydrophobic groups. Hydrophobic groups collapse in the metal Sulfates, chlorides, borates, bromides, etc., and ioniz presence of water, thus minimizing their exposed to the water able alkaline earth organic salts such as citrates, acetates, molecule. lactates, etc. pH-Sensitive Hydro Gels 0065. In specific embodiments, the salt is selected from 0071. The hydrogels which exhibiting pH dependent calcium sulfate, Sodium chloride, potassium Sulfate, sodium Swelling behaviour will in aqueous media of appropriate pH carbonate, lithium chloride, tripotassium phosphate, sodium and ionic strengths be ionized. As a result in of the electro borate, potassium bromide, potassium fluoride, Sodium bicar static repulsions, the uptake of water in the network is bonate, calcium chloride, magnesium chloride, Sodium cit increased. Ionic hydrogels are Swollen polymer networks rate, Sodium acetate, calcium lactate, magnesium Sulfate, containing pendant groups, such as carboxylic acid, which alkali metal chlorides, sodium fluoride, organic acids such S show Sudden or gradual changes in their dynamic and equi citric, succinic, fumaric, malic, maleic, glutaric, lactic and the librium behaviour as a result of changing the external pH. In like: alkali metal Sulfates such as Sodium Sulfate; dihydrogen these gels, ionization occurs when the ph of the environment Sodium phosphate, monohydrogen Sodium phosphate, diso is above the pKa of the ionisable group. As degree of ioniza dium hydrogen phosphate, and mixtures thereof, and multi tion increases the number offixed charges increases resulting valent metal cations. Notably, the salt is calcium sulfate or in increased electrostatic repulsions between the chains. This sodium chloride. in turn, results in an increased hydrophilicity of the network, and greater Swelling ratio. The Swelling of polyelectrolyte Organic Acids gels is significantly affected by the ionic strengths of the 0066. The present formulations may also contain organic Swelling agent. As the ionic strengths of the Swelling agent acids to delay dissolution rate in the acid media and/or to increases, the concentration of ions within the gel must increase the dissolution rate in buffer at pH 6.8 or to ensure increase in order to satisfy the Donnan equilibrium. drug stability with time and provide a substantially pH inde 0072 A vehicle or composition according to the invention pendent dissolution profile. may also comprise one or more pharmaceutically acceptable 0067. The organic acids are chosen to cover a solubility excipients or additive. and pKa-values range, in order to cover a range of pH and to help controlling the release mechanism. The aim is to obtain Excipients the same release time in both buffer 6.8 and in 0.1M HCl. 0073. A wetting agent may be used such as one or more Pharmaceutically acceptable organic acids are e.g. Benzoic selected from the group consisting of pharmaceutically acid, Succinic acid, Citric acid and Adipic acid but can acceptable anionic Surfactants, cationic Surfactants, amphot include other pharmaceutically approved organic acids. eric (amphipathic/amphophilic) Surfactants, and non-ionic surfactants including poloxamer, PEG, and PEO; alkane Ionic Strengths metal sulfates, wherein the alkyl group is from 1 to 14 carbon 0068 An increase in electrostatic repulsion, by adding e.g. atoms, such as sodium methyl sulfate, sodium lauryl Sulfate monovalent or/and divalent metal ions (natively present or and the like as well as dioctyl sodium sulfo Succinate. introduced in the formulation) also promotes a Swelling until 0074. In a specific embodiment of the invention, a vehicle a saturation point. The driving force necessary to expand the or composition further comprises glycerol, cf. the examples material during Swelling is the electrostatic repulsion herein. US 2008/0299.199 A1 Dec. 4, 2008

0075 Suitable excipients and/or additives may be selected gel particles are right next to each other then they all try to from the group consisting of Surfactants, coloring agents, Swell at the same time, and weld themselves together into one Sweetening agents, taste-masking agents, antioxidants, large, slow to hydrate lump. If the pectin particles are all polysaccharides, Sugars, wetting agents, UV-absorbers, Sus slightly separated from each other when they contact the pending agents, stabilizers, Solubilizers, preservatives, pro water, then they all have enough room to go through their cessing aids, pH controlling agents, plasticizers, odor mask initial expansion. To achieve a fast hydration, and thereby ing agents, nutrients, flavouring agents, flavour masking swelling for the matrix system it is preferable to added hydro agents, emulsifiers, thickening agents, dispersing agents, philic or/and ion pair formation excipients. crystal grow inhibitors, crystallization promoters, chelating agents, buffers, bases, and antimicrobials, and mixtures Hydrophilic Excipients: thereof. 0076. In order to ensure an effective interaction of the I0085 Known excipients can be blended with the molecu water with the gelling agent or agents, the addition of a cation lar or dispersed dosage form to provide a controllable water and/or sequestering agent to the mixture might be desirable diffusion/drug release mechanism. and is generally depending on the Swelling agent or mixtures hereof. Examples of Suitable cations and sequestering agents Vehicle Form which may be added to cause this gelling agent to gel are well I0086 A vehicle according to the invention may have any known to persons skilled in the art and include Na+, Ca", K" Suitable form such as, e.g., in the form of a powder blend, in and H. sodium hexametaphosphate, sodium tripolyphos the form of granules, beads, oblates or pellets, or in the form phate, EDTA, citric acid, sodium citrate and other citric acid of a granulate. Any additive or excipient, if present, may be salts, phosphoric acid, dicalcium phosphate and tetrasodium incorporated e.g. in the granules etc, or it may be loosely pyrophosphate. added e.g. after formation of a granulate. As mentioned here 0077. An excipient for use in a dosage form according to inbefore, the vehicle may be admixed with one or more active the present invention may also include one or more other Substances, i.e. the active Substance may be incorporated in components generally known for use in food products, such the granules etc., or it may be added after formation e.g. of a as flavourings, colourings, Sugar and/or other Sweeteners, granulate. The active Substance may also be present in a preservatives, buffering agents, texturing agents, fats, col coated and/or microencapsulated form or embedded in a loids, Suspended solids, etc., to give the a desired texture matrix, or in a form that allows for controlled release of the and/or appearance. The amounts of such components are not active Substance. critical to the invention and may be adjusted according to taste and according to the flavour/texture characteristics desired of Compositions the mixture of the invention. The pH of the mixture might be I0087 As mentioned above, the present invention also adjusted to the requirements of the active Substance(s). relates to a pharmaceutical composition for oral administra Excipients Used to Change the Hydration and Diffusion of tion comprising one or more active Substances and a gellan Water into the Matrix System gum arranged in a configuration allowing optimal water dif 0078 While the slow swelling property is the one that also fusion so that upon addition of a predetermined amount of an made hydrogels useful in controlled drug delivery, many aqueous medium, without the necessity of applying shear applications required fast Swelling (i.e. Swelling in a matter of forces or other mixing forces, within a time period of 5 minutes or seconds rather than hours) of dried hydrogels. minutes or less, the composition Swells and/or gels and the 0079 Being a water soluble polysaccharide e.g. Gellan texture of the swelled composition being similar to that of a gum can be difficult to disperse in water due to the formation soft pudding and having a viscosity of at least about 10,000 of a film layer around each Gellangum particle. This leads to cps as measured by a Brookfield Viscometer with a #4 LV the formation of large agglomerates (lumps), which, due to spindle at 6 rpm and at 20-25°C. the protective film layer, are very difficult for the water mol I0088 All the details and particulars mentioned hereinbe ecules to penetrate. fore relating to other aspects of the invention apply mutatis 0080. The less soluble the Gellan gum is the easier the mutandis to this aspect. dispersion, other factors which decrease the solubility of I0089. The pharmaceutical composition or the dosage form Gelangum will improve the dispersibility. of the invention includes a plurality of drug-containing 0081. Different formulation initiative, by e.g. incorpora micro-particles. Each micro-particle carries at least one tion of hydrophilic excipients, can change the hydration, and active Substance and, optionally, components providing taste Swelling rate: masking and/or controlled release functionality. The micro 0082 Fast swelling is usually done by making very small particles can be produced using know micro-encapsulation or particles of dried hydrogels. The extremely short diffusion by integration into a matrix or by crystallization. The particles path length of micro particles makes it possible to complete may be further fragmented to reduce the particle size. The Swelling in a matter of seconds or minutes. preferred embodiments are those where the particles are 0083. By creating pores that are interconnected to each small so as to be imperceptible or nearly imperceptible to the other throughout the hydrogel matrix. The interconnected patient, visually and/or tactilely, in particular on the tongue. pores allow for fast absorption of water by capillary force. A The preferred embodiments are those where the particle size simple method of making porous hydrogel includes, produce is less than 500 micrometers and best less than 200 microme gas bubbles by adding sodium bicarbonate to generate carbon ters. However, if the retention in the mouth of even a few dioxide bubbles, and generation of gas bubbles makes the particles after a few minutes is not desired (because, for foam rise. example, the taste being masked leaks), the particles should 0084 Another approach is to separate the hydrogel par not be smaller than 100 micrometers so they are not retained ticles from each other before contact with water. If the hydro in crevices in the pouth or between papillae on the tongue, US 2008/0299.199 A1 Dec. 4, 2008

unless the cohesivness of the semisolid vehicle ensures that Dekker, Inc., 1989), and to Ansel et al., Pharmaceutical Dos all particles are swallowed with the vehicle. age Forms and Drug Delivery Systems, 6' Ed. (Media, Pa. 0090. In another aspect of this invention, the active sub Williams & Wilkins, 1995). stances do not require controlled release or taste masking but, Drug Delivery (Release) from the Composition because of stability problems, in particular hydrolysis they can not be formulated in water containing dosage forms; also Swelling-Controlled System: the approach may be useful if very large doses are to be administered. Accordingly, in one aspect of the invention a 0097. Formulations consisting of hydrophilic matrixes, dosage form is provided having a water content of at the most and from which the drug release is controlled by the inward about 5% w/w such as, e.g., at the most about 4% w/w, at the flux of solvent molecules and consequent Swelling of the most about 3% w/w, at the most about 2% w/w, at the most polymer matrix, are often referred to as a Swelling-controlled about 1% w/w or at the most about 0.5% w/w. systems. In these systems, the drug are initially dissolved or 0091. The dosage form may be dispensed as a granulate in dispersed in the glassy polymers. Upon contact with fluids bulk or further processed into discrete units. The discrete units may be capsules or cachets or Sachets filled with a (pre-hydration with water or/and biological fluids), the poly measured amount of granulate meant to be opened and the mer matrix begins to Swell and two distinct phases can be contents poured onto a measured amount of water. However, observed in the polymer: the inner glassy phase and the Swol the capsules or cachets or Sachets may be made from fast len rubbery phase. The drug molecule are able to diffuse out dissolving materials such as water Soluble polymer films, of the out of the rubbery phase of the polymer. Clearly, the woven or non-woven fabrics made of water soluble materials drug release is controlled by the velocity and position of the Such as candy floss. Further, the capsules or cachets or Sachets glass-rubbery interface. A very important phenomenon of might be made of gelling polymers such as those described macromolecular relaxation takes place at the glass-rubbery for the mixture. interface, and significant affects the drug release. 0092. The discrete units may also be tablets meant to be 0098. This is due to the fact that the matrix is exposed to put into a measured amount of water. In producing the tables, continuous changes in its structure and thickness. The gel attention must be paid to the fact that, the more the material is layer is a hydrophilic barrier that can controls water penetra compacted, the more difficult the penetration of water into the tion and drug diffusion. It begins when the polymer becomes unit will be. Therefore, the production method for the tablets hydrated and Swells. Here, the polymer chains are strongly must be adapted. Production methods might include low entangled in a network, and the gel layer is highly resistant. pressure compression, extruding, molding and calendaring. However, moving away from this swelling position, the gel 0093. In a specific embodiment of interest, the discrete layer becomes progressively more hydrated and, when Suffi units may be in the form of a disposable spoon where the cient water has accumulated, the chains disentangle and the granulated is fastened, typically by using a hydrocolloid solu polymer dissolves. tion as a binder and drying. Such a unit is illustrated in FIG.1. 0099. In matrix systems, which are also diffusion-con To this end, it is extremely important that the dosage form of trolled, the drug can be either dissolved or dispersed in the drug-containing micro-particles is designed so that a Suit throughout the network of the hydrogel. able texture of the dosage form is obtained after addition of a 0100. There are different approaches to controlling the predetermined amount of an aqueous medium Such as water release rate from the matrix system. Some of the major for without the necessity of employing any shear force Such as mulation parameters, which can be varied to adjust the result e.g. mechanical mixing or stirring. ing release patterns to designing a new oral controlled release 0094. The dosage form might also be formed into a tape or system can include: laminate, with or without the help of water soluble polymer The initial drug loading films, woven or non-woven fabrics made of water soluble The API solubility materials such as candy floss. This laminate can then be cut Type of matrix forming polymers into discrete portions or dispensed as such, so the user can cut it to the required dose/size. Type and load of hydrophilic/hydrophobic excipients 0095. In some cases, where the purity of the water is an important factor, Such as when presence or absence of given Release Mechanisms for API Incorporated in a Primary ions might interfere with the gelling process, it might be Based Hydro Gels: desirable to dispense the water alongside the granulate. In the 0101. In development of an a delivery system, three sig case of a satchet it might be dispensed as a two compartment nificant phenomena (simplified) must be taken into account plastic bag, one compartment containing the granulate, the simultaneously, other the water. In the case of the spoon, a reservoir might be built-into the handle of the spoon. Diffusion of water, drug, excipients and disentangled poly 0096 Conventional coating procedures and equipment merchains, may then be used to coat or embed the drug-containing micro Polymer hydration and swelling, particles, i.e., the drug-containing beads or particles. For Drug, excipient and polymer dissolution. example, a delayed release coating composition may be 0102. Furthermore, in a formulation containing an API, applied using a coating pan, an airless spray technique, flu polymer(s), and excipients, three different kinds of interac idized bed coating equipment, or the like. For detailed infor tion may affect the release of the API: (i) the API may interact mation concerning materials, equipment and processes for with the polymer, (ii) the drug may interact with the excipi preparing beads, drug particles, and delayed release dosage ents, and (iii) the excipients may interact with the polymer(s) forms, reference may be made to Pharmaceutical Dosage matrix. The rate of API release can be successfully controlled Forms: Tablets, eds. Lieberman et al. (New York: Marcel by controlling these interactions. US 2008/0299.199 A1 Dec. 4, 2008

0103) The dissolution rate is often influenced by a) com on the resulting drug release rate than in the case of higher position and level of drugs and other additives within the drug solubility. Consequently, the critical initial drug loading matrix, and b) composition and ionic strengths of electrolytes (above which the relative release rate increases) increases in the dissolution medium. with decreasing drug solubility. These phenomena are not 0104. It is possible to control or/and change the release straightforward and have to be taken into account when rate of the drug from the polymer by varying e.g. the physical designing the new formulation. chemical properties of the active drug, excipients or/and the polymer system. Extremely simplified, by adding more 0112. With respect to the blending of the vehicle accord soluble excipients compared to the API solubility, will to ing to the present invention it should be noticed whether any Some extent increase the release rate of the matrix system, and of the desires excipients or active drugs have a solubility opposite for more hydrophobic excipients the release rate will considerable below that of gellan gum as the Substance may be slowed down. When e.g. adding very soluble excipients, decrease the hydration of the gellan gum. In Such cases the the network becomes more and more porous upon drug deple substance should be added to a premixture of other ingredi tion. Consequently, the free Volume increases, and thus poly ents, which pre mixture or blend preferable is granulated mer disentanglement increases giving rise to higher diffusion before adding the substance with lower solubility. In cases constants and thus faster dissolution. where one of the ingredients is capable of solubilizing the 0105. The physical-chemical properties of the matrix gellan gum, the same procedure is to be used in order to (composition) components will alter the intermolecular prevent any solubilizing of the gellan gum which will other forces, free Volume, glass transition temperature, and conse wise result in decreased gelling capacity. quently, can alter the transport mechanisms. 0106. In general, solubility of drug molecule itself cru Particle and Granular Sizes: cially governs the rate and extent of diffusion release in both the matrix system, and the delivery sites. For diffusion to 0113 Although it is not required, it is preferred that the occur, the first step is wetting of the drug by water, followed API, gellangum, hydrogel(s), and excipients is in particulate by its dissolution to enable the drug molecule to be available form. The particles should, as a general rule, be of a size. Such in molecular. Hence, the net release rate observed is a cumu that, the matrix can hydrate Sufficiently, and equally through lative effect of drug solubility (influence by its structure, out the matrix. To prevent segregation, and consequently molecular weight, pKa), polymer property (hydrophilicity/ inhomogen products it would be preferable to formulate with lipophilicity, molecular weight, tortuosity), excipients (struc uniform particle sizes, with exception of PVP, wherein it can ture, molecular weight, solubility, pKa) and the relative ratio also be an advantage to have Smaller particles. A Suitable of drug/polymer, and excipient/polymer in the unit. granular size should be between 350-500 um. Furthermore it is an advantage to seal the material after fastened the discrete Initial Load/Dissolution Profiles units on a delivering device. The fastening is easily done by 0107 Various factors contribute to the overall control of spraying the device with a glue to adhere the discrete unit to drug release, such as the solubility of the drug within the bulk the device. Such glue may be produced by mixing a volatile fluid, drug load, the size of the drug molecule, and it's mobil liquid with a binder until a clear solution is achieved, and the ity within the swollen polymeric network. formulation is transferred to e.g. by use of an aerosol can to 0108. In the case of poorly water-soluble drugs (solubility the device. Such as a spoon the Volatile liquid is evaporated <1 g drug/100 mL solution) or high initial loadings of mod from the spoon in an oven, and thus the device Surface is erately water soluble drugs (1 g drug/10 mL solution), dis Sticky. Solved and non-dissolved drug coexist within the composi tion. If the total amount of drug exceeds the amount, which is 0114. The layer thickness of the applied mixtures varies soluble under the actual conditions, it exceeds the amount greatly and depends on the processing method or the quantity soluble under the actual conditions, the excess is considered of additional substances. The thickness ranges from 1-100 to be non-dissolved and thus not available for diffusion. um, preferably from 10-50 um. This corresponds to a binder 0109. With decreasing drug solubility the concentration application of 0.1-5 wt.%. difference during drug release (matrix position vs. bulk fluid) 0115 The desired dose of the formulation to be applied to decreases, and thus the driving force for drug diffusion out of the device is weight out separately and distributed by pressing the matrix decreases. Under theses conditions a decrease of the granules against the spoon with a stopper to a thin layer. the porosity of the matrix upon drug depletion (due to an The layer thickness will dependent on the formulation, but increase initial drug loading) has probably a more pro preferable approximately 2 mm in height in the bottom, and nounced effect on the resulting absolute drug release rate than sides of the spoon. The glue attaches the material to the in the case of e.g. freely soluble drugs, and thus higher diffu device. When the composition is applied to the device, the sion driving forces. Consequently, the critical initial drug glue may be in liquid form or in solution selected from the loading increases with decreasing drug solubility. group consisting of Sugar alcohols, Sugars, polyvinylpyrroli 0110. The effect of the initial drug loading of the tableton done (PVP), gums. Other binders may be employed. Nor the resulting release kinetic is more complex in the case of mally, the binder is dissolved in a volatile solvent. As it poorly soluble drugs compared to freely water soluble drugs. appears from the examples herein, an especially suitable glue 0111. With decreasing drug solubility the concentration or adhesive agent comprises a mixture of PVP and glycerol. difference during drug release (matrix position vs. bulk fluid) 0116. The composition of the invention may be dispensed decreases, and thus the driving force for drug diffusion out of in any suitable device. Preferably the device is made of a the matrix decreases. Under these conditions, decrease of the Suitable material Such as a plastic based material or glass or porosity of the matrix upon depletion (due to an increased metal, preferable a disposable material. In order to adhere to initial drug loading) has probably a more pronounced effect the device it is preferred that the device has a concave surface. US 2008/0299.199 A1 Dec. 4, 2008

Spoons or devices having similar shape and function are muscle relaxants; narcotic antagonists; nutritional agents, Suitable in the present context. Such as vitamins, essential amino acids and fatty acids; para sympatholytics; peptide drugs; psychoStimulants; sedatives; Active Substances steroids; sympathomimetics; and tranquilizers. 0117. In a specific embodiment the vehicle according to I0121 Several known drugs are substantially insoluble or the invention comprises one or more active Substances. The only slightly soluble in water and accordingly difficult to active Substance may be present in admixture with the formulate in Solutions and Suspensions for administration to vehicle, it may be present in the granulate comprising the children, elderly or other subjects having difficulties in Swal Swelling and/or gelling agent, it may be present in microen lowing and Such drugs are therefore of particular interest capsulated form or embedded in a matrix, and/or it may be according to the present invention and include, by way of present in a form that allows for controlled release of the example, the following: active Substance. 0.122 Gastrointestinally active substances. Gastrointesti 0118 “Drug substances” or “active substances” in accor nally active Substances are particularly preferred drugs that dance with the present invention include systematically dis can be administered using the present dosage forms. These tributable therapeutically, prophylactically and/or diagnosti types of drugs include agents for inhibiting gastric acid secre cally active Substances, vitamins, minerals, dietary tion, Such as the H. Sub.2 receptor antagonists cimetidine, Supplements, as well as non-systemically distributable active ranitidine, famotidine, and nizatidine, the H. Sup.+, K. Sup.+- Substances. Therapeutically, prophylactically and/or diag ATPase inhibitors (also referred to as “proton pump inhibi nostically active Substances may include, without limitation, tors') omeprazole and lanSoprazole, and antacids such as antacids, analgesics, anti-inflammatories, antibiotics, laxa calcium carbonate, aluminum hydroxide, and magnesium tives, anorexics, antihistamines, antiasthmatics, antidiuretics, hydroxide. Also included within this general group are agents antiflatuents, antimigraine agents, antispaspodics, sedatives, for treating infection with Helicobacter pylori (H. pylori), antihyperactives, antihypertensives, tranquilizers, deconges Such as metronidazole, tinidazole, amoxicillin, clarithromy tants, beta blockers and combinations thereof. Also encom cin, tetracycline, thiamphenicol, and bismuth compounds passed by the terms “drug substances” and “active sub (e.g., bismuth subcitrate and bismuth subsalicylate). Other stances are the drugs and pharmaceutical active ingredients gastrointestinally active Substances administrable using the described in Mantelle U.S. Pat. No. 5,234,957 includes 18 present dosage forms include, but are not limited to, penta through 21. This text is hereby incorporated by reference. gastrin, carbenoXolone, Sulfated polysaccharides such as 0119. With respect to the individual dosages of the active Sucralfate, prostaglandins such as misoprostol, and muscar to be incorporated in the novel dosage form this will follow inic antagonists such as pirenzepine and telenzepine. Addi the general recommendations knownto the skilled personand tionally included are antidiarrheal agents, antiemetic agents are generally calculated based on the body weight or body and prokinetic agents such as ondansetron, granisetron, meto Surface, especially for children, and the daily dosage may clopramide, chlorpromazine, perphenazine, prochlorpera naturally be divided in several dosages according to conven Zine, promethazine, thiethylperazine, triflupromazine, dom tional treatment regimens for the active Substance in question. peridone, trimethobenzamide, cisapride, motilin, Depending of the actual amount, a dosage may be present in loperamide, diphenoxylate, and octreotide. a single spoon or similar dosing device or in several spoons to I0123 Anti-microbial agents. These include: quinolone be ingested. Alternatively, the actual dosage can be measured antibiotics such as nalidixic acid, and particularly fluorinated based the content per Volume of a pre-prepared product simi quinolone antibiotics Such as ciprofloxacin, clinafloxacin, lar with dosing from bottles of mixtures generally employed enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lom with liquid formulations. efloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, 0120. The active substance administered may be any com sparfloxacin, and trovafloxacin, tetracycline antibiotics and pound that is Suitable for oral drug administration; examples related compounds (chlortetracycline, Oxytetracycline, of the various classes of active Substances that can be admin demeclocycline, methacycline, doxycycline, minocycline, istered using the present dosage forms include, but are not rolitetracycline); macrollide antibiotics such as erythromycin, limited to: analgesic agents; anesthetic agents; antiarthritic clarithromycin, and azithromycin; streptogramin antibiotics agents; respiratory drugs; anticancer agents; anticholinergics; Such as quinupristin and dalfopristin; beta-lactamantibiotics, anticonvulsants; antidepressants; antidiabetic agents; antidi including penicillins (e.g., penicillin G, penicillin VK), anti arrheals; antihelminthics; antihistamines; antihyperlipidemic staphylococcal penicillins (e.g., cloxacillin, dicloxacillin, agents; antihypertensive agents; anti-infective agents such as nafcillin, and oxacillin), extended spectrum penicillins (e.g., antibiotics and antiviral agents; antiinflammatory agents; aminopenicillins such as amplicillin and amoxicillin, and the antimigraine preparations; antinauseants; antineoplastic antipseudomonal penicillins such as carbenicillin), and agents; antiparkinsonism drugs; antipruritics; antipsychotics; cephalosporins (e.g., cefadroxil, cefepime, cephalexin, cefa antipyretics; antispasmodics; antitubercular agents; antiulcer Zolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazi agents and other gastrointestinally active agents; antiviral dime, and ceftriaxone), and carbapenems such as imipenem, agents; anxiolytics; appetite Suppressants; attention deficit meropenem and aztreonam, aminoglycoside antibiotics Such disorder (ADD) and attention deficit hyperactivity disorder as streptomycin, gentamicin, tobramycin, amikacin, and neo (ADHD) drugs; cardiovascular preparations including cal mycin; glycopeptide antibiotics such as teicoplanin; Sulfona cium channel blockers, CNS agents, and vasodilators; beta mide antibiotics Such as Sulfacetamide, Sulfabenzamide, Sul blockers and antiarrhythmic agents; central nervous system fadiazine, Sulfadoxine, Sulfamerazine, Sulfamethazine, stimulants; cough and cold preparations, including deconges Sulfamethizole, and Sulfamethoxazole; anti-mycobacterials tants; diuretics; genetic materials; herbal remedies; hor Such as isoniazid, rifampin, rifabutin, ethambutol, pyraZina monolytics; hypnotics; hypoglycemic agents; immunosup mide, ethionamide, aminosalicylic, and cycloserine; sys pressive agents; leukotriene inhibitors; mitotic inhibitors; temic antifungal agents such as itraconazole, ketoconazole, US 2008/0299.199 A1 Dec. 4, 2008 fluconazole, and amphotericin B; antiviral agents such as reuptake inhibitors citalopram, fluoxetine, fluvoxamine, par acyclovir, famcicylovir, ganciclovir, idoxuridine, Sorivudine, oxetine, Sertraline, and Venlafaxine, (c) monoamine oxidase trifluridine, Valacyclovir, Vidarabine, didanosine, stavudine, inhibitors such as phenelzine, tranylcypromine, and (-)-sel Zalcitabine, Zidovudine, amantadine, interferon alpha, ribavi egiline, and (d) other, "atypical antidepressants such as nefa rin and rimantadine; and miscellaneous antimicrobial agents Zodone, traZodone and Venlafaxine, and wherein antimanic Such as chloramphenicol, spectinomycin, polymyxin B and antipsychotic agents include (a) phenothiazines Such as (colistin), bacitracin, nitrofurantoin, methenamine mandelate acetophenazine, acetophenazine maleate, chlorpromazine, and methenamine hippurate. chlorpromazine hydrochloride, fluphenazine, fluphenazine 0.124 Anti-diabetic agents. These include, by way of hydrochloride, fluiphenazine enanthate, fluphenazine example, acetohexamide, chlorpropamide, ciglitaZone, gli decanoate, mesoridazine, mesoridazine besylate, perphena clazide, glipizide, glucagon, glyburide, miglitol, pioglita zine, thioridazine, thioridazine hydrochloride, trifluopera Zone, tolaZamide, tolbutamide, triampterine, and troglita zine, and trifluoperazine hydrochloride, (b) thioxanthenes ZO. Such as chlorprothixene, thiothixene, and thiothixene hydro 0125 Analgesics. Non-opioid analgesic agents include chloride, and (c) other heterocyclic drugs such as carbam apaZone, etodolac, difenpiramide, indomethacin, meclofe azepine, clozapine, droperidol, haloperidol, haloperidol namate, mefenamic acid, Oxaprozin, phenylbutaZone, piroxi decanoate, loxapine Succinate, molindone, molindone hydro cam, and tolmetin; opioid analgesics include alfentanil, chloride, olanzapine, pimozide, quetiapine, risperidone, and buprenorphine, butorphanol, codeine, drocode, fentanyl. sertindole. hydrocodone, hydromorphone, levorphanol, meperidine, 0.130 Hypnotic agents and sedatives include clomethiaz methadone, morphine, nalbuphine, oxycodone, oxymor ole, ethinamate, etomidate, glutethimide, meprobamate, met phone, pentazocine, propoxyphene, Sufentanil, and tramadol. hyprylon, Zolpidem, and barbiturates (e.g., amobarbital, 0126 Anti-inflammatory agents. Anti-inflammatory apropbarbital, butabarbital, butalbital, mephobarbital, agents include the nonsteroidal anti-inflammatory agents, methohexital, pentobarbital, phenobarbital, secobarbital, e.g., the propionic acid derivatives as ketoprofen, flurbipro thiopental). fen, ibuprofen, naproxen, fenoprofen, benoxaprofen, I0131 Anxiolytics and tranquilizers include benzodiaz indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, epines (e.g., alprazolam, brotizolam, chlordiazepoxide, clo Suprofen, alminoprofen, butibufen, and fenbufen, apaZone; bazam, clonazepam, cloraZepate, demoxepam, diazepam, diclofenac; difenpiramide; diflunisal: etodolac, indometha estazolam, flumazenil, flurazepam, halazepam, lorazepam, cin; ketorolac, meclofenamate; nabumetone; phenylbuta midazolam, nitrazepam, nordazepam, oxazepam, prazepam, Zone; piroXicam, Sulindac; and tolmetin. Steroidal anti-in quazepam, temazepam, triazolam), buspirone, chlordiazep flammatory agents include hydrocortisone, hydrocortisone oxide, and droperidol. 21-monoesters (e.g., hydrocortisone-21-acetate, 0132 Anticancer agents, including antineoplastic agents: hydrocortisone-21-butyrate, hydrocortisone-21-propionate, Paclitaxel, docetaxel, camptothecin and its analogues and hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-di derivatives (e.g., 9-aminocamptothecin, 9-nitrocamptoth esters (e.g., hydrocortisone-17,21-diacetate, hydrocortisone ecin, 10-hydroxy-camptothecin, irinotecan, topotecan, 17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate, 20-O-beta.-glucopyranosyl camptothecin), taxanes (bacc etc.), alclometasone, dexamethasone, flumethasone, pred atins, cephalomannine and their derivatives), carboplatin, cis nisolone, and methylprednisolone. platin, interferon-alpha. Sub.2A, interferon-alpha. Sub.2B, 0127. Anti-convulsant agents. Suitable anti-convulsant interferon-alpha. Sub.N3 and other agents of the interferon (anti-seizure) drugs include, by way of example, aZetazola family, levamisole, altretamine, cladribine, tretinoin, procar mide, carbamazepine, clonazepam, cloraZepate, ethoSuxim bazine, dacarbazine, gemcitabine, mitotane, asparaginase, ide, ethotoin, felbamate, lamotrigine, mephenyloin, porfimer, mesna, amifostine, mitotic inhibitors including mephobarbital, phenyloin, phenobarbital, primidone, tri podophyllotoxin derivatives such as teniposide and etoposide methadione, vigabatrin, topiramate, and the benzodiaz and Vinca alkaloids Such as Vinorelbine, Vincristine and Vin epines. BenZodiazepines, as is well known, are useful for a blastine. number of indications, including anxiety, insomnia, and nau 0.133 Antihyperlipidemic agents. Lipid-lowering agents, SCa or “hyperlipidemic agents, include HMG-CoA reductase 0128 CNS and respiratory stimulants. CNS and respira inhibitors such as atorvastatin, simvastatin, pravastatin, lov tory stimulants also encompass a number of active agents. astatin and cerivastatin, and other lipid-lowering agents such These stimulants include, but are not limited to, the follow as clofibrate, fenofibrate, gemfibrozil and tacrine. ing: Xanthines such as caffeine and theophylline; amphet I0134) Anti-hypertensive agents. These include amlo amines such as amphetamine, benzphetamine hydrochloride, dipine, benazepril, darodipine, dilitazem, diazoxide, dox dextroamphetamine, dextroamphetamine Sulfate, levamphet aZosin, enalapril, eposartan, losartan, Valsartan, felodipine, amine, levamphetamine hydrochloride, methamphetamine, fenoldopam, fosinopril, guanabenz, guanadrel, guanethidine, and methamphetamine hydrochloride; and miscellaneous guanfacine, hydralazine, metyrosine, minoxidil, nicardipine, stimulants such as methylphenidate, methylphenidate hydro nifedipine, nisoldipine, phenoxybenzamine, praZosin, chloride, modafinil, pemoline, Sibutramine, and Sibutramine quinapril, reserpine, and teraZosin. hydrochloride. 0.135 Cardiovascular preparations. Cardiovascular prepa 0129. Neuroleptic agents. Neuroleptic drugs include anti rations include, by way of example, angiotensin converting depressant drugs, antimanic drugs, and antipsychotic agents, enzyme (ACE) inhibitors such as enalapril, 1-carboxym wherein antidepressant drugs include (a) the tricyclic antide ethyl-3-1-carboxy-3-phenyl-(1S)-propylamino-2,3,4,5-tet pressants such as amoxapine, amitriptyline, clomipramine, rahydro-1H-(3S)-1-benzazepine-2-one, amino-1-carboxy desipramine, doxepin, imipramine, maprotiline, nortrip 1S-pentyl)amino-2,-3,4,5-tetrahydro-2-oxo-3S-1H-1- tyline, protriptyline, and trimipramine, (b) the serotonin benzazepine-1-acetic acid or 3-(1-ethoxycarbonyl-3-phenyl US 2008/0299.199 A1 Dec. 4, 2008

(1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo-(-3S)- esters formed from the hydroxyl group present at the C-17 benzazepine-1-acetic acid monohydrochloride; cardiac position, including, but not limited to, the enanthate, propi glycosides such as digoxin and digitoxin; inotropes such as onate, cypionate, phenylacetate, acetate, isobutyrate, buci aminone and milrinone; calcium channel blockers such as clate, heptanoate, decanoate, undecanoate, caprate and isoca Verapamil, nifedipine, nicardipene, felodipine, isradipine, prate esters; and pharmaceutically acceptable derivatives of nimodipine, bepridil, amlodipine and diltiazem; beta-block testosterone Such as methyl testosterone, testolactone, erS Such as atenolol, metoprolol; pindolol, propafenone, pro oxymetholone and fluoxymesterone. pranolol, esmolol, Sotalol, timolol, and acebutolol; antiar 0.138 Muscarinic receptoragonists and antagonists. Mus rhythmics such as moricizine, ibutilide, procainamide, carinic receptoragonists include, by way of example: choline quinidine, disopyramide, lidocaine, phenyloin, tocamide, esters such as acetylcholine, methacholine, carbachol, mexiletine, flecamide, encamide, bretylium and amiodarone; bethanechol (carbamylmethylcholine), bethanechol chloride, and cardioprotective agents such as dexraZoxane and leuco cholinomimetic natural alkaloids and synthetic analogs Vorin; and vasodilators such as nitroglycerin; and diuretic thereof, including pilocarpine, muscarine, McN-A-343, and agents such as hydrochlorothiazide, furosemide, bumetanide, oxotremorine. Muscarinic receptor antagonists are generally ethacrynic acid, torsemide, azosemide, muZolimine, piret belladonna alkaloids or semisynthetic or synthetic analogs anide, and tripamide. thereof. Such as atropine, Scopolamine, homatropine, homa 0.136 Anti-viral agents. Antiviral agents that can be deliv tropine methyl bromide, ipratropium, methantheline, meth ered using the present dosage forms include the antiherpes Scopolamine and tiotropium. agents acyclovir, famciclovir, foScamet, ganciclovir, idoxuri 0.139. Peptide drugs. Peptidyl drugs include the peptidyl dine, sorivudine, trifluridine, Valacyclovir, and Vidarabine; hormones activin, amylin, angiotensin, atrial natriuretic pep the antiretroviral agents didanosine, stavudine, Zalcitabine, tide (ANP), calcitonin, calcitonin gene-related peptide, cal and Zidovudine; and other antiviral agents such as amanta citonin N-terminal flanking peptide, ciliary neurotrophic fac dine, interferon alpha, ribavirin and rimantadine. tor (CNTF), corticotropin (adrenocorticotropin hormone, 0137 Sex steroids. The sex steroids include, first of all, ACTH), corticotropin-releasing factor (CRF or CRH), epi progestogens such as acetoxypregnenolone, allylestrenol, dermal growth factor (EGF), follicle-stimulating hormone anagestone acetate, chlormadinone acetate, cyproterone, (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-re cyproterone acetate, desogestrel, dihydrogesterone, dime leasing peptide, gonadotropin-releasing factor (GnRF or thisterone, ethisterone (17.alpha.-ethinyltestoster-one), GNRH), growth hormone releasing factor (GRF, GRH), ethynodiol diacetate, fluorogestone acetate, gestadene, human chorionic gonadotropin (hCH), inhibin A, inhibin B, hydroxyprogesterone, hydroxyprogesterone acetate, hydrox insulin, luteinizing hormone (LH), luteinizing hormone-re yprogesterone caproate, hydroxymethylprogesterone, leasing hormone (LHRH), alpha.-melanocyte-stimulating hydroxymethylprogesterone acetate, 3-ketodesogestrel, hormone, beta.-melanocyte-stimulating hormone, gamma.- levonorgestrel, lynestrenol, medrogestone, medroxyprogest melanocyte-stimulating hormone, melatonin, motilin, oxyto erone acetate, megestrol, megestrol acetate, melengestrol cin (pitocin), pancreatic polypeptide, parathyroid hormone acetate, norethindrone, norethindrone acetate, norethister (PTH), placental lactogen, prolactin (PRL), prolactin-release one, norethisterone acetate, norethynodrel, norgestimate, inhibiting factor (PIF), prolactin-releasing factor (PRF), norgestrel, norgestrienone, normethisterone, and progester secretin, Somatotropin (growth hormone, GH). Somatostatin one. Also included within this general class are estrogens, (SIF, growth hormone-release inhibiting factor, GIF), thy e.g.: estradiol (i.e., 1,3,5-estratriene-3,17.beta.-diol, or “ 17. rotropin (thyroid-stimulating hormone, TSH), thyrotropin beta.-estradiol) and its esters, including estradiol benzoate, releasing factor (TRH or TRF), thyroxine, vasoactive intesti Valerate, cypionate, heptanoate, decanoate, acetate and diac nal peptide (VIP), and vasopressin. Other peptidyl drugs are etate; 17.alpha.-estradiol; ethinylestradiol (i.e., 17.alpha.- the cytokines, e.g., colony stimulating factor 4, heparin bind ethinylestradiol) and esters and ethers thereof, including ethi ing neurotrophic factor (HBNF), interferon-a, interferon al nylestradiol 3-acetate and ethinylestradiol 3-benzoate; estriol pha.-2a, interferon alpha.-2b, interferon alpha.-n3, inter and estriol Succinate; polyestrol phosphate; estrone and its feron-beta., etc., interleukin-1, interleukin-2, interleukin-3, esters and derivatives, including estrone acetate, estrone Sul interleukin-4, interleukin-5, interleukin-6, etc., tumor necro fate, and piperazine estrone sulfate; quinestrol; mestranol: sis factor, tumor necrosis factor-alpha., granuloycte colony and conjugated equine estrogens. Androgenic agents, also stimulating factor (G-CSF), granulocyte-macrophage included within the general class of sex steroids, are drugs colony-stimulating factor (GM-CSF), macrophage colony Such as the naturally occurring androgens androsterone, stimulating factor, midkine (MD), and thymopoietin. Still androsterone acetate, androsterone propionate, androsterone other peptidyl drugs that can be advantageously delivered benzoate, androstenediol, androstenediol-3-acetate, andros using the present systems include endorphins (e.g., dermor tenediol-17-acetate, androstenediol-3,17-diacetate, andros phin, dynorphin, alpha.-endorphin, beta.-endorphin, tenediol-17-benzoate, androstenediol-3-acetate-17-ben gamma.-endorphin, ..sigma.-endorphin, Leu. Sup.5en Zoate, androstenedione, dehydroepiandrosterone (DHEA: kephalin, Met. Sup.5enkephalin, Substance P), kinins (e.g., also termed “prasterone'), sodium dehydroepiandrosterone bradykinin, potentiator B, bradykinin potentiator C. kallidin), sulfate, 4-dihydrotestosterone (DHT; also termed LHRH analogues (e.g., buserelin, deslorelin, fertirelin, gos 'stanolone'), 5.alpha-dihydrotestosterone, dromostanolone, erelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), dromostanolone propionate, ethylestrenol, nandrolone phen and the coagulation factors, such as alpha. Sub. 1-antitrypsin, propionate, nandrolone decanoate, nandrolone furylpropi ..alpha. Sub.2-macroglobulin, antithrombin III, factor I (fi onate, nandrolone cyclohexanepropionate, nandrolone ben brinogen), factor II (prothrombin), factor III (tissue pro Zoate, nandrolone cyclohexanecarboxylate, Oxandrolone, thrombin), factor V (proaccelerin), factor VII (proconvertin), stanozolol and testosterone; pharmaceutically acceptable factor VIII (antihemophilic globulin or AHG), factor IX esters of testosterone and 4-dihydrotestosterone, typically (Christmas factor, plasma thromboplastin component or US 2008/0299.199 A1 Dec. 4, 2008

PTC), factor X (Stuart-Power factor), factor XI (plasma Remifentanil, Repaglinide; Ribavirin/Interferon alfa-2B, thromboplastin antecedent or PTA), factor XII (Hageman recombinant, Rifapentine; Risedronate; Risperidone; factor), heparin cofactor II, kallikrein, plasmin, plasminogen, Ritonavir; Rocuronium; Rofecoxib; Ropivacaine; Rosiglita prekallikrein, protein C, protein S, and thrombomodulin and Zone; RosiglitaZone; Salmeterol, Saquinavir, Sertraline; combinations thereof. Sevelamer; Sevoflurane; Sibutramine; Sildenafil; Simvasta 0140 Genetic material may also be delivered using the tin; Sirolimus; Sodium ferric gluconate complex: Sotalol; present dosage forms, e.g., nucleic acids, RNA, DNA, recom Stavudine: Sumatriptan; Tacrolimus; Tamoxifen: Temozolo binant RNA, recombinant DNA, antisense RNA, antisense mide; Tenofovir, Terbinafine; Testosterone; Timolol;Toltero DNA, ribozymes, ribooligonucleotides, deoxyribonucle dine; Topiramate; Topotecan; Tramadol; Valacyclovir; Val otides, antisense ribooligonucleotides, and antisense deox ganciclovir, Valproate; Valsartan; Venlafaxine, Verapamil; yribooligonucleotides. Representative genes include those Vinorelbine; Voriconazole; Zafirlukast; Zanamivir; Ziprasi encoding for vascular endothelial growth factor, fibroblast done; Zoledronic acid; Zolmitriptan; Zonisamide. growth factor, Bcl-2, cystic fibrosis transmembrane regulator, 0142. As incorporated be reference according to Mantelle nerve growth factor, human growth factor, erythropoietin, U.S. Pat. No. F,234,957: tumor necrosis factor, and interleukin-2, as well as histocom 1. Analgesic anti-inflammatory agents such as, acetami patibility genes such as HLA-B7. nophen, aspirin, salicylic acid, methyl salicylate, choline Sali 0141. In a preferred embodiment for a pediatric product cylate, glycol salicylate, 1-menthol, camphor, mefenamic and use according to the invention, the active drug is selected acid, fluiphenamic acid, indomethacin, diclofenac, alclofenac, from Abacavir; Acetazolamide; Adefovir, Albuterol; ibuprofen, ketoprofen, naproxene, pranoprofen, fenoprofen, Albuterol; Alendronate; Almotriptan; Alosetron: Alpra Sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, pro Zolam; Amiodarone; Amlexanox: Amlodipine; the combina tizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, tion Amlodipine/Benazepril; Ammonium Lactate; Amphet bufexamac, piroxicam, phenylbutaZone, oxyphenbutaZone, amine (including mixed salts); Amprenavir, Anagrelide; clofeZone, pentazocine, mepirizole, and the like; AnastroZole; Argatroban; Aripiprazole; Atazanavir, Atomox 2. Drugs having an action on the central nervous system, for etine; Atorvastatin; the mixture Atovaquone/Proguanil; example sedatives, hypnotics, antianxiety agents, analgesics Azelastine; Baclofen; Balsalazide. Beclomethasone; and anesthetics, such as, chloral, buprenorphine, naloxone, Beclomethasone; Benazepril; Betamethasone; Betaxolol; haloperidol, fluphenazine, pentobarbital, phenobarbital, Betaxolol; Bicalutamide; Bisoprolol; Brimonidine: Brinzola secobarbital, amobarbital, cyclobarbital, codeine, lidocaine, mide: Budesonide; Buproprion; Buspirone; Busulfan; tetracaine, dyclonine, dibucaine, cocaine, procaine, mepiv C-Urea; Calcitriol: Candesartan; Carboplatin: Carteolol, acaine, bupivacaine, etidocaine, prilocaine, benzocaine, fen Carvedilol; Caspofungin: Celecoxib; Cerivastatin: Cetiriz tanyl, nicotine, and the like; ine: Cilostazol; Cimetidine: Ciprofloxacin: Ciprofloxacin: 3. Antihistaminics or antiallergic agents such as, diphenhy Cisatracurium; Citalopram; Clopidogrel; Colesevelam: Cro dramine, dimenhydrinate, perphenazine, triprolidine, pyril molyn; Cromolyn; Cytarabine; Desflurane; Desloratadine: amine, chlorcyclizine, promethazine, carbinoxamine, tripe Dexrazoxane; Dichlorphenamide; Didanosine; Dorzola lennamine, brompheniramine, hydroxyZine, cyclizine, mide, Efavirenz: Eletriptan; Emtricitabine: Enalapril; Enfu virtide (T-20); Enoxaparin: Epirubicin; Eplerenone; Ertap meclizine, clorprenaline, terfenadine, chlorpheniramine, and enem, Esmolol; Esomeprazole; Etodolac. Famciclovir; the like: Famotidine: Felodipine: Fenoldopam; Fentanyl: Fentanyl: 4. Acetonide anti-inflammatory agents, such as hydrocorti Fexofenadine: Fluconazole; Fludarabine, Iuocinolone; Flu Sone, cortisone, dexamethasone, fluocinolone, triamcino oxetine: Fluticasone; Fluvastatin: Fluvoxamine; Formoterol; lone, medrysone, prednisolone, flurandrenolide, prednisone, Fosinopril; Fosphenyloin: Fulvestrant; Gabapentin; Gati halcinonide, methylprednisolone, fludrocortisone, corticos floxacin; Gatifloxacin; Gemcitabine; Gemtuzumab; Gen terone, paramethasone, betamethasone, ibuprophen, tamicin; Glatiramer; Glimepiride; Glipizide/Metformin; naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen, Glyburide/Metformin: Granisetron; Hydrocortisone, ketoprofen, Suprofen, indomethacin, piroXicam, aspirin, Sali Hydroxyurea; Ibuprofen; Ibuprofen/pseudoephedrine: Ima cylic acid, diflunisal, methyl salicylate, phenylbutaZone, tinib. Imiquimod; Indinavir, Insulin glargine; Irbesartan; Sulindac, mefenamic acid, meclofenamate Sodium, tolmetin, Irinotecan; Isotretinoin, Itraconazole; Ketoconazole, Ketoro and the like; lac; Labetalol; Lamivudine, Lamotrigine; Lansoprazole; 5. Steroids such as, androgenic steroids, Such as, testosterone, Leflunomide; Levalbuterol; Levetiracetam; Levobetaxolol; methyltestosterone, fluoxymesterone, estrogens such as, con Levobunolol; Levofloxacin; Levofloxacin; Linezolid; Lisino jugated estrogens, esterified estrogens, estropipate, 17-beta. pril; Lisinopril; Lopinavir/Ritonavir, Loratadine; Losartan; estradiol, 17-.beta.estradiol Valerate, equilin, mestranol, Lovastatin; Mesalamine; Metformin; Methazolamide; Meth estrone, estriol, 17-beta.ethinyl estradiol, diethylstilbestrol, ylphenidate; Metipranolol; Metoprolol; Midazolam: Mil progestational agents, such as, progesterone, 19-norprogest rinone; Minoxidil; Mirtazapine: Modafinil; Moexipril; erone, norethindrone, norethindrone acetate, melengestrol, Mometasone; Montelukast; Morphine; Moxifloxacin; Nabu chlormadinone, ethisterone, medroxyprogesterone acetate, metone; Nateglinide; Nefazodone; Nelfinavir. Nevirapine; hydroxyprogesterone caproate, ethynodiol diacetate, nor Nicotine; Nizatidine; Norfloxacin; Norgestimate/ethinyl ethynodrel, 17-.alpha.hydroxyprogesterone, dydrogesterone, estradiol; Octreotide: Ofloxacin; Olanzapine; Olmesartan; dimethisterone, ethinylestrenol, norgestrel, demegestone, Omeprazole; Ondansetron; Orlistat; Oseltamivir; Oxaprozin; promegestone, megestrol acetate, and the like; Oxcarbazepine; Oxybutynin. Oxybutynin. Oxycodone; Pan 6. Respiratory agents such as, theophilline and beta. Sub.2- toprazole; Paricalcitol; Paroxetine; Pegvisomant; Pemirolast; adrenergic agonists, such as, albuterol, terbutaline, metapro Pimecrolimus: Pioglitazone; Pravastatin: Propofol; Quetiap terenol, ritodrine, carbuterol, fenoterol, quinterenol, rimit ine Fumerate; Quinapril; Rabeprazole; Ramipril; Ranitidine: erol, Solmefamol, Soterenol, tetroquinol, and the like; US 2008/0299.199 A1 Dec. 4, 2008

7. Sympathomimetics Such as, dopamine, norepinephrine, 24 Non-steroidal hormones or antihormones such as, corti phenylpropanolamine, phenylephrine, pseudoephedrine, cotropin, oxytocin, vasopressin, salivary hormone, thyroid amphetamine, propylhexedrine, arecoline, and the like; hormone, adrenal hormone, kallikrein, insulin, Oxendolone, 8. local anesthetics such as, benzocaine, procaine, dibucaine, and the like; lidocaine, and the like; 25. Vitamins such as, vitamins A, B, C, D, E and K and 9. Antimicrobial agents including antibacterial agents, anti derivatives thereof, calciferols, mecobalamin, and the like for fungal agents, antimycotic agents and antiviral agents; tetra dermatologically use: cyclines such as, oxytetracycline, penicillins, such as, ampi 26. Antitumor agents such as, 5-fluorouracil and derivatives cillin, cephalosporins such as, cefalotin, aminoglycosides, thereof, krestin, picibanil, ancitabine, cytarabine, and the Such as, kanamycin, macrollides such as, erythromycin, like: chloramphenicol, iodides, nitrofrantoin, nystatin, amphoteri 27. Enzymes Such as, lysozyme, urokinaze, and the like; cin, fradiomycin, Sulfonamides, purrolnitrin, clotrimazole, 28. Herb medicines or crude extracts such as, glycyrrhiza, miconazole chloramphenicol, Sulfacetamide, SulfamethaZ aloe, Sikon (Lithospermi Radix), and the like: ine, Sulfadiazine, Sulfamerazine, Sulfamethizole and Sulfisox 29. Miotics such as pilocarpine, and the like; lo 30. Cholin azole; antivirals, including idoxuridine, clarithromycin; and ergic agonists such as, choline, acetylcholine, methacholine, other anti-infectives including nitrofuraZone, and the like; carbachol, bethanechol, pilocarpine, muscarine, arecoline, 10. Antihypertensive agents such as, clonidine, alpha.-meth and the like; yldopa, reserpine, Syrosingopine, rescinnamine, cinnarizine, 31. Antimuscarinic or muscarinic cholinergic blocking hydrazine, praZosin, and the like; agents such as, atropine, Scopolamine, homatropine, meth 11. Antihypertensive diuretics such as, chlorothiazide, hydro Scopolamine, homatropine methylbromide, methantheline, chlorothrazide, bendoflumethazide, trichlormethiazide, furo cyclopentolate, tropicamide, propantheline, anisotropine, semide, tripamide, methylclothiazide, penfluzide, hydrothi dicyclomine, eucatropine, and the like; azide, spironolactone, metolaZone, and the like; 32. Mydriatics Such as, atropine, cyclopentolate, homatro 12. Cardiotonics such as, digitalis, ubidecarenone, dopamine, pine, Scopolamine, tropicamide, eucatropine, hydroxyam and the like; phetamine, and the like; 13. Coronary vasodilators such as, organic nitrates Such as, 33. Psychic energizers such as 3-(2-aminopropy)indole, 3-(2- nitroglycerine, isosorbitol dinitrate, erythritol tetranitrate, aminobutyl)indole, and the like: and pentaerythritol tetranitrate, dipyridamole, dilaZep, trapi 34. Humoral agents such as, the prostaglandins, natural and dil, trimetazidine, and the like: synthetic, for example PGE. Sub.1, PGE. Sub.2.alpha., and 14. Vasoconstrictors such as, dihydroergotamine, dihydroer PGF.Sub.2.alpha., and the PGE. sub.1 analog misoprostol. gotoxine, and the like; 35. Antispasmodics Such as, atropine, methantheline, papav 15...beta.-blockers or antiarrhythmic agents such as, timolol erine, cinnamedrine, methScopolamine, and the like; pindolol, propranolol, and the like; 36. Antidepressant drugs such as, isocarboxazid, phenelzine, 16. Calcium antagonists and other circulatory organ agents, tranylcypromine, imipramine, amitriptyline, trimipramine, Such as, aptopril, diltiazem, nifedipine, nicardipine, Vera doxepin, desipramine, nortriptyline, protriptyline, amoxap pamil, bencyclane, ifenprodil tartarate, molsidomine, cloni ine, maprotiline, traZodone, and the like; dine, praZosin, and the like; 37. Anti-diabetics such as, insulin, and anticancer drugs such 17. Anti-convulstants such as, nitrazepam, meprobamate, as, tamoxifen, methotrexate, and the like; phenyloin, and the like; 38. Anorectic drugs such as, dextroamphetamine, metham 18. Agents for dizziness such as, isoprenaline, betahistine, phetamine, phenylpropanolamine, fenfluramine, diethylpro Scopolamine, and the like; pion, mazindol, phentermine, and the like; 19. Tranquilizers such as, reserprine, chlorpromazine, and 39. Anti-allergenics Such as, antazoline, methapyrilene, chlo antianxiety benzodiazepines such as, alprazolam, chlordiaz rpheniramine, pyrilamine, pheniramine, and the like; epoxide, cloraZeptate, halazepam, oxazepam, prazepam, 40. Decongestants such as, phenylephrine, ephedrine, nap clonazepam, flurazepam, triazolam, lorazepam, diazepam, hazoline, tetrahydrozoline, and the like: and the like; 41. Antipyretics such as, aspirin, Salicylamide, and the like; 20. Antipsychotics such as, phenothiazines including thio 42. Antimigrane agents such as, dihydroergotamine, pizoty propazate, chlorpromazine, triflupromazine, mesoridazine, line, and the like: piperracetazine, thioridazine, acetophenazine, fluphenazine, 43. Anti-malarials such as, the 4-aminoquinolines, alphami perphenazine, trifluoperazine, and other major tranquilizers noquinolines, chloroquine, pyrimethamine, and the like; Such as, chlorprathixene, thiothixene, haloperidol, bromperi 44. Anti-ulcerative agents such as, misoprostol, omeprazole, dol, loxapine, and molindone, as well as, those agents used at enprostil, and the like; lower doses in the treatment of nausea, vomiting, and the like; 45. Peptides such as, growth releasing factor, and the like; 21. Muscle relaxants such as, tolperisone, baclofen, dant 46. Anti-estrogen or anti-hormone agents such as, tamoxifen rolene Sodium, cyclobenzaprine; or human chorionic gonadotropin, and the like; 22. Drugs for Parkinson's disease, spasticity, and acute 47. Antiulcer agents such as, allantoin, aldioxa, alcloxa, muscle spasms such as levodopa, carbidopa, amantadine, N-methylscopolamine methylsuflate, and the like: apomorphine, bromocriptine, selegiline (deprenyl), trihex 48. Antidiabetics, and the like. yphenidyl hydrochloride, benztropine mesylate, procyclidine 0143. The drugs mentioned above can be used in combi hydrochloride, baclofen, diazepam, dantrolene, and the like; nation as required. Moreover, the above drugs may be used 23. Respiratory agents such as, codeine, ephedrine, isoprot either in the free form or, if capable of forming salts, in the erenol, dextromethorphan, orciprenaline, ipratropium bro form of a salt with a suitable acid or base. If the drugs have a mide, crom glycic acid, and the like; carboxyl group, their esters can be employed. US 2008/0299.199 A1 Dec. 4, 2008

0144. The acid mentioned above may be an organic acid, Midecamycin, Oleandomycin, Pristinamycin, Quinupristin/ for example, methanesulfonic acid, lactic acid, tartaric acid, Dalfopristin, Rokitamycin, Roxithromycin, Spiramycin, fumaric acid, maleic acid, acetic acid, oran inorganic acid, for Tilmicosin, Troleandomycin, Tylosin, Virginiamycin, example, hydrochloric acid, hydrobromic acid, phosphoric acid or Sulfuric acid. The base may be an organic base, for Penicillins example, ammonia, triethylamine, or an inorganic base, for example, sodium hydroxide or potassium hydroxide. The 0153. The beta-lactamase inhibitors clavulanic acid, sul esters mentioned above may be alkyl esters, aryl esters, bactam, and taZobactam are used to extend the antimicrobial aralkyl esters, and the like. range of certain beta-lactam antibiotics. Amoxicillin, Ampi cillin, Aspoxicillin, AZidocillin, AZlocillin, Bacampicillin, 0145. In one embodiment of the invention, the active sub Benethamine Penicillin, BenZathine Benzylpenicillin, Ben stance is selected from the following: Zathine Phenoxymethylpenicillin, Benzylpenicillin, Carbeni Antibacterials Including Metronidazole cillin, Carfecillin, Carindacillin, Ciclacillin, Clavulanic Acid, Clemizole Penicillin, Clometocillin, Cloxacillin, Dicloxacil 0146 Although antibiotics and other antibacterials are a lin, Flucloxacillin, Mecillinam, Metampicillin, Meticillin, very diverse class of compounds they are often classified and Meziocillin, Nafcillin, Oxacillin, Penethamate, Pheneticillin, discussed in groups. They may be classified according to their Phenoxymethylpenicillin, Piperacillin, Pivampicillin, Piv mode of action or spectrum of antimicrobial activity, but mecillinam, Procaine Penicillin Procaine Benzylpenicillin, generally those with similar chemical structures are grouped Propicillin, Sulbactam, Sulbenicillin, Sultamicillin, Tazobac together. tam, Temocillin, Ticarcillin, Aminoglycosides Quinolones 0147 Amikacin, Apramycin, Arbekacin, Astromicin, 0154 Acrosoxacin Rosoxacin, Alatrofloxacin, Balof Bekanamycin, Dibekacin, Dihydrostreptomycin, Framyce loxacin, Cinoxacin, Ciprofloxacin, Clinafloxacin, Danof tin, Gentamicin, Isepamicin, Kanamycin, Micronomicin, loxacin, Difloxacin, Enoxacin, Enrofloxacin, Fleroxacin, Neomycin, Netilmicin, Sisomicin, Streptomycin, Tobramy Flumequine, Gatifloxacin Gemifloxacin, Grepafloxacin, C1. Levofloxacin, Lomefloxacin, Marbofloxacin, Moxifloxacin, Nadifloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Orbi Antimycobacterials Drug Groups: Antimycobacterials floxacin, Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piro 0148 Aminosalicylic Acid, Capreomycin, Clofazimine, midic Acid, Prulifloxacin, Rufloxacin, Sarafloxacin, Spar Cycloserine, Dapsone, Ethambutol, Ethionamide, Isoniazid, floxacin, Temafloxacin, ToSufloxacin, Trovafloxacin, Methaniazide, Morinamide, Protionamide, Pyrazinamide, Rifabutin, Rifampicin, Rifamycin, Rifapentine, Rifaximin, Sulfonamides and Diaminopyrimidines Thioacetazone. 0155 Baquiloprim, Brodimoprim, Calcium Sulfaloxate, Co-tetroxazine, Co-trifamole, Co-trimazine, Co-trimox Cephalosporins and Related Beta Lactams azole, Formosulfathiazole Mafenide, Ormetoprim, Phthalyl 0149 Drug Groups: Cephalosporins, related Beta Lac sulfathiazole. Succinylsulfathiazole, Sulfabenzamide, Sulfa tams or cephem antibiotics Aztreonam, Betamipron, Biap clozine, Sulfachrysoidine, Sulfadicramide, Sulfadoxine, enem, Carumonam, Cefaclor, Cefadroxil, Cefalexin, Cefalo Sulfamerazine, Sulfamethylthiazole, Sulfametopyrazine, nium, Cefaloridine, Cefalotin, Cefamandole, Cefazolin, Sulfametrole, Sulfamonomethoxine, Sulfaquinoxaline, Sul Cefapirin, Cefatrizine, Cefcapene, Cefdinir, Cefditoren, fasuccinamide, Sulfatroxazole, Sulfacetamide, Sulfachlorpy Cefepime, Cefetamet, Cefixime, Cefluprenam, Cef ridazine, Sulfadiazine, Sulfadiazine Silver, Sulfadimethox menoxime, Cefnmetazole, Cefninox, Cefodizime, Cefonicid, ine, Sulfadimidine, Sulfafurazole, Sulfaguanidine, CefoperaZone, Ceforamide, Cefoselis, Cefotaxime, Sulfamethizole, Sulfamethoxazole, Sulfamethoxypy Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Ce?piramide, ridazine, Sulfamoxole, Sulfanilamide, Sulfapyridine, Sulfi Cefpirome, Cefpodoxime, Cefprozil, Cefauinome, Cefsulo somidine, Sulfathiazole, Sulfacarbamide, Tetroxoprim, Tri din, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftiofur, methoprim, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefradine, Cilasta tin, Faropenem, Flomoxef. Imipenem, Latamoxef, Loracar Tetracyclines bef, Meropenem, Panipenem, 0156 Chlortetracycline, Demeclocycline, Doxycycline, Chloramphenicols Lymecycline, Meclocycline, Methacycline, Minocycline, Oxytetracycline, Rolitetracycline, Tetracycline, 0150 AZidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol, Avoparcin, Ramoplanin, Teicoplanin, Van comycin, Miscellaneous Antibacterials 0157 Acediasulfone, Arsanilic Acid, Avilamycin, Baci Lincosamides tracin, Bambermycin, Carbadox, Chlorquinaldol, Clio quinol, Clofoctol, Colistin, Daptomycin, Evernimicin, Fos 0151 Clindamycin, Lincomycin, Pirlimycin, fomycin, Furaltadone, Fusafungine, Fusidic Acid, Macrollides Gramicidin, Halquinol, Methenamine, Linezolid, Magainins, Mandelic Acid, Mupirocin, Nifuroxazide, Nifurtoinol, 0152 Azithromycin, Clarithromycin, Dirithromycin, Nifurzide, Nisin, Nitrofurantoin, Nitrofurazone, Nitroxoline, Erythromycin, Flurithromycin, Josamycin, Kitasamycin, Novobiocin, Polymyxin B. Spectinomycin, Sulfamazone, US 2008/0299.199 A1 Dec. 4, 2008

Taurolidine, Telithromycin, Terizidone. Thenoic Acid, Thios poses of the present invention, the term vitamin(s) include, trepton, Tiamulin, Trospectomycin, Tyrothricin, Valnemulin, without limitation, thiamine, riboflavin, nicotinic acid, pan Xibornol, tothenic acid, pyrdoxine, biotin, folic acid, vitamin B. Sub.12, lipoic acid, ascorbic acid, vitamin A, vitamin D. Vitamin E Anthelmintics and vitamin K. Also included within the term vitamin are the coenzymes thereof. Coenzymes are specific chemical forms 0158 Albendazole, Diethylcarbamazine, Ivermectin, of vitamins. Coenzymes include thiamine pyrophosphates Levamisole, Mebendazole, Niclosamide, Oxamniquine, pip (TPP), flavin mononucleotide (FMM), flavin adenine erazine, Praziquantel, Pyrantel. Thiabendazole. dinucleotive (FAD), Nicotinamide adenine dinucleotide Antimalarial Drugs (NAD), Nicotinamide adenine dinucleotide phosphate (NADP) Coenzyme A (CoA) pyridoxal phosphate, biocytin, 0159) 4-methanolduinoline derivatives such as the cin tetrahydrofolic acid, coenzyme B.Sub.12, lipoyllysine, chona alkaloids and mefloquine. The 4-aminoquinolines, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term Such as chloroquine, hydroxychloroquine, and amodiaquine. Vitamin(s) also includes choline, carnitine, and alpha, beta, The 8-aminoquinolines such as primaquine and tafenoquine. and gamma carotenes. The biguanides. Such as proguanil and chlorproguanil. The (0170 As used in this disclosure, the term “mineral refers diaminopyrimidines such as pyrimethamine. The dichlo to inorganic Substances, metals, and the like required in the robenzylidine lumefantrine. The hydroxynaphthoduinones, human diet. Thus, the term “mineral as used herein includes, Such as atovaquone. The 9-phenanthrenemethanols such as without limitation, calcium, iron, Zinc, Selenium, copper, halofantrine. The sesquiterpene lactones such as artemisinin iodine, magnesium, phosphorus, chromium and the like, and and its derivatives. The sulfonamides sulfadoxine and sul mixtures thereof. fametopyrazine. The tetracyclines, such as doxycycline and 0171 The term "dietary supplement’ as used herein tetracycline. The lincosamide, clindamycin. The Sulfones means a Substance, which has an appreciable nutritional Such as dapsone. effect when administered in Small amounts. Dietary Supple ments include, without limitation, such ingredients as bee Antiprotozoals pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino acids, proteins and mixtures thereof. As will be 0160 The antimony compounds including meglumine appreciated, dietary Supplements may incorporate vitamins antimonate and Sodium Stibogluconate, the aromatic dia and minerals. midines including pentamidine, the arsenicals including the 0172. In general, the amount of the active substance incor pentaValent compounds acetarSol and tryparsamide, and porated in the dosage form according to the invention may be melarsoprol which is trivalent, the dichloroacetamides selected according to known principles of pharmacy. An including diloxanide, the halogenated hydroxyquinolines effective amount of pharmaceutical ingredient is specifically including diiodohydroxyquinoline, the nitrofurans including contemplated. By the term effective amount, it is understood furazolidone, nifuratel, and nifurtimox, and the 5-nitroimida that, with respect to for example pharmaceuticals, a therapeu Zoles including metronidazole, nimorazole, ornidazole, sec tically, prophylactically and/or diagnostically effective nidazole, and tinidazole. Other drugs include atovaquone, amount is contemplated. An effective amount is the amount or benZnidazole, dehydroemetine, eflornithine, mepacrine, and quantity of a drug Substance, which is sufficient to elicit the Suramin. required or desired therapeutic response, or in other words, the amount, which is sufficient to elicit an appreciable bio Antivirals logical response when administered to a patient. As used Anti-Asthma Drug Groups herein the term “effective amount’ means an amount at least about 10% of the United States Recommended Daily Allow 0161 Antimuscarinics and Beta Agonists. ance (“RDA) of that particular ingredient for a patient. For 0162 Such as the quaternary ammonium compounds ipra example, if an intended ingredient is vitamin C, then an tropium bromide and oxitropium bromide, Salmeterol, effective amount of vitamin C would include an amount of Albuterol, Bitolterol, Isoetharine, Metaproterenol, Pir vitamin C sufficient to provide 10% or more of the RDA. buterol, Terbutaline, Isoproterenol, Ephedrine, Epinephrine Typically, where the tablet includes a mineral or vitamin, it Salbutamol. will incorporate higher amounts, preferably about 100% or more of the applicable RDA. The amount of active agent used Corticosteroids. can vary widely from a few milligrams to 100,000 milligrams 0163 Beclomethasone dipropionate, Budesonide Turbu O. O. haler, Flunisolide, Fluticasone, Triamcinolone acetonide. Preparation of a Pharmaceutical Composition 0164 Leukotriene Inhibitors and Antagonists. 0173 A pharmaceutical composition according to the 0165 Zafirlukast, Montelukast. invention may be prepared by blending of at least: 1) One or more active substances as particulate matter. Either Mast Cell Stabilisers. as pure material (crystals or amorphous, in powder form) or 0166 Sodium cromoglicate and Nedocromil sodium. encapsulated by a coat or trapped in a matrix or bound to an ion-exchange resin. Xanthines. 2) One or more Swelling/gelling materials 0167. Theophylline and its derivatives. and, optionally: 3) Sweetening agents Antifungals 0168 Flucytosine, Griseofulvin, Ketoconazole, Micona 4) Flavours 5) Colorants folio As used herein, the term vitamin refers to trace 0.174. In one embodiment it is possible to use the gelling organic Substances that are required in the diet. For the pur agent in Solution as a binder in granulating and as a glue for US 2008/0299.199 A1 Dec. 4, 2008

giving the formulation the desired shape, however once the 0180 FIG. 2 shows the dissolution curve according to the gelling agent has beenhydrated, the gelling properties may be formulation of Example 17 of a Paracetamol dosage unit in reduced, accordingly sometimes the gelling agent used in simulated gastric fluid demonstrating a very fast release of at Solution as a binder is identical with the bulk gelling agent least 96% within 5 minutes. (example Kelcogel(R) LT100), sometimes it is a different 0181 FIG.3 shows the stomach recorded by in vivo ultra grade of the same gelling agent (Kelcogel(R) LT 100 bulk, Sonic measures after ingestion of water and before ingestion Kelcogel(R) F as binder) and sometimes a different binder of the formulation according to Example 19. altogether (Kelcogel(R) LT100 as bulk, Keltrol as binder). The 0182 FIG. 4 shows the subsequent ultrasonic pictures just desired shape mentioned could be, for example, granulating after ingestion of the formulation according to Example 19. the mixture of active substances, gelling agent, Sweetenerand 0183 FIG. 5 shows the complete dispersion of the formu flavour and Subsequently moulding and gluing the granules to lation according to Example 19 and as shown in FIG. 4. 0.184 FIG. 6 shows the dissolution at low pH of the for the concave surface of a spoon, preferable in a relative thin mulation according to Example 24 demonstrating disintegra layer of 0.5 to 5 mm thick. This strategy contributes to that the tion into material with individual flakes varying in size from powder/particulate material obtained as the novel dosage approximately 1 to 5 mm. form can be converted into a pudding-like mass without appli 0185 FIG. 7 demonstrates the dissolution similar to FIG. cation of any shear force and within the desired time period. 6 in a media at pH 4.8 demonstrating complete disintegration This feature is very advantageous in that it is possible to use of the material the novel dosage form also for very Small amounts of active 0186 FIG. 8 demonstrates the dissolution similar to FIG. substances as there is no risk that active substance will be lost 6 in a media at pH 6.8 demonstrating complete disintegration e.g. on a spoon or stirrer during stirring or mechanical mixing. of the material into very small and fluffy material represent In other words, the dose form presents the active substance in ing the non soluble material of the formulation. a form that ensures the right dose to be ingested. To the best of 0187 FIG. 9 shows the dissolution of the formulation the inventors knowledge this is the first comparable semi according to Example 24 resulting in a fast dissolution rate of liquid alternative in this respect to a tablet or capsule dosage the paracetamol at different pH values. Similar effect is also form. obtained with simulated gastric fluid. 0175 More specifically, the invention relates to a method 0188 FIG. 10 shows 3 different spoons for use as delivery for preparing a pharmaceutical composition according to the devices according to the present invention. All spoons are invention, the method comprising blending the dry compo prepared in order to be able to be left on a table or similar nents to a homogeneous mixture and optionally granulating place without tilting and at the same time easy to pick up the mixture with a binder. providing an easy handling during administration. The means 0176). In a specific embodiment, the invention relates to a for preventing the spoons for tilting when left is self-explana method for preparing a pharmaceutical composition accord tory from the drawings in that either the shaft is bend or more ing to the invention comprising one or more excipients and/or times and or the “floor of the spoon is flattened. The latter active ingredients which have a solubility substantial lower may further be provided with an ordinary concave inner lin than the solubility of the gellan gum, wherein the method ing of the spoon to avoid material to be left on the spoon after comprises application to the mouth. i) granulating a first blend comprising gellan gum but essen MATERIALS AND METHODS tially not containing the one or more excipients and/or active 0189 Several of the below Examples have been produced ingredients which have a solubility substantial lower than the without an active ingredient and used for demonstrating dif solubility of the gellan gum, ferent compositions to which an active can be added (i.e. they ii) adding the one or more excipients and/or active ingredients are vehicles). Several of these formulations have been used which have a solubility substantiallower than the solubility of for consumer testing. The term Parvulet as used herein rep the gellan gum to the granulated first blend. resents any formulation according to the invention and is a 0177. In a subsequent step, the one or more excipients trademark for the products. and/or active ingredients which have a solubility substantial 0190. The following materials have been employed: lower than the solubility of the gellan gum is added to the Absolute alcohol 99.9%, De danske spritfabrikker, pharma granulated first blend as a blend or granulate with additional ceutical grade excipients. Aerosil, Unikem, pharmaceutical grade 0.178 The foregoing will be better understood with refer Caramel flavour, Frutarom ence to the following examples which detail certain proce CefuximeAxetil, Stragen Nordic dures for manufacture of tablets in accordance to the present (0191 Chocolate flavour, Kiranto food invention. All references made to these examples are for the Ferrous fumarate coated, Ferrosan, pharmaceutical grade purposes of illustration. They are not to be considered limit Gellan, Kelcogel LT 100, CpKelco ApS, pharmaceutical ing as to the scope and nature of the present invention. grade Gellan, Kelcogel F. CpKelco ApS, pharmaceutical grade FIGURES Glycerol, Uniqema, pharmaceutical grade Ibuprofen Coated, Nycomed DK, pharmaceutical grade 0179 FIG. 1 shows a (A) spoon with the dryg composition Instant Sugar, Danisco Oy, pharmaceutical grade adhering to it and covered with a "peel off film which in (B) Inulin instant, Fibruline is remove and water (C) is added whereupongelling (D) takes place with expansion of the material which do no not slip the Ispaghulae Husks, Vi-siblin, Pfizer spoon (E) when this is tipped the other way round. Maize Starch Ultrasprese HV. National Starch & Chemical US 2008/0299.199 A1 Dec. 4, 2008

0.192 Medium Chain Triglyceride EP (Labrafac cc), Gat the material is dispersed/dissolved, and after about 5 min the tefossé SAS, pharmaceutical grade Viscosity and the temperature are measured. PVP (Plastdone(R) K-25, ISP (Switzerland) AG Sensory Test 0193 Pyridoxine Coated, Ferrosan, pharmaceutical grade 0205 Tapped water is added to the formulation and when Sodium Citrate, Unikem, pharmaceutical grade all the liquid is absorbed (visually confirmed), the test can Sodium hydrogen carbonate, Unikem, pharmaceutical grade start. Taste the formulation and rank the taste from 1-10, Sodium starch glycolate, Explotab, JRS Pharma where 10 is the most pleasant taste. Strawberry flavour, Kiranto food Tutti-frutti flavour, Frutarom EXAMPLE 1. Vanilla flavour, Keranto food A/S Xanthan gum, Keltrol CpKelco ApS. pharmaceutical grade A Composition According to the Invention Contain ing 250 mg Coated Cefuxime Dosage Unit Xylitol, Danisco Sweeteners LtD 0206. A composition that has a shape as outlined in FIG. 1 Coat: containing cefuXime as active Substance was prepared as (0194 Eudragite EPO, Rohm follows: 0.195 Lauryl sulphate, Sigma 0196. Altalc 500V. Luzenac America 0.197 Eudragit NE30D, Rohm % Wiw 9. Granulation Blend 1: Explotab 46.3 0.97 0198 Performed by hand mixing until homogenous Instant Sugar 46.32 0.97 slightly sticky relative small particles are present Suitable Aerosil O.53 O.O11 equipment includes High Shear mixer Such as in a Zanchetta Vanilla flavor 4.6 O.096 Glycerol 2.3 (binder) O.048 Roto P100-100 liter capacity or a MTI mixer. Blend 2: Drop Down Test Blend 1 60 2.1 Coated Cefuxime 40 1.4 0199 The drop down test apparatus is a medical plastic spoon obtained from Nomeco (DBI Plastic type 1 15022) with markings for 2/2 and 5 ml liquid) see FIG. 1, e.g. drawing E. 0207. The ingredients (1-4) of Blend 1 are mixed /2 min (depending on the amount of powder) in a mortar, transferred Test Method to a Philips Food processor, Electronic type HR 2377/D, ingredient 5 is added and mixed for about /2 min (depending 0200. In a test spoon 0.5g-0.7 g test material is accurately on the amount of powder) at speed 4. The ingredients from weighed. 3 ml-5 ml tapped water is added. Wait /2 min, turn blend 2 are mixed in a mortar for about/2 min (depending on the spoon around, and if the test material does not drop down the amount of powder). (fall off the spoon) within 2 min, the material has passed the teSt. 0208. In this example, Explotab is used as a gelling agent that is granulated with glycerol. Viscosity Test 0209. The granules are divided into 570 mg/dose. The dose is weight out into a medical spoon and moulded by Apparatus: gently pressing the granules against the spoon with a mortar Brookfield Viscometer Model LVF, Serie 56779 pistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature. 0201 Spindel No. #4 diameter 3.2 mm, length 33.96 mm Beaker 500 ml low form (approximately 90 mm internal Drop Down Test: diameter) 0210. To the above dosage form, 4 ml tapped water is Termometer added. After about/2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test Parameter: material did not fall out and passed the test. (0202 Speed: 6 rpm 0203 Spindle: The Viscometer spindle is centered in the EXAMPLE 2 test sample container. The spindle is properly immersed to the mid-point of the shafts narrow portion. A Composition According to the Invention Contain ing 250 mg Coated Cefuxime in the Dosage Unit Test Method 0211 A composition that has a shape as outlined in FIG. 1 0204 Into a 500 ml beaker 22-88 g test material is accu containing CefuXime as active Substance, was prepared as rately weighed, 500 ml tapped water is added. Mix until all follows (given as % w/w): Dec. 4, 2008 20

0217. The granules are divided to 700 mg/dose. The dose is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortarpistil to % Wiw 9. a thin layer about 1-3 mm in high in the bottom of the spoon. Blend 1: The water is evaporated at ambient temperature. Explotab 46.3 O.87 Drop Down Test: Instant Sugar 46.32 O.87 Aerosil O.53 O.OO94 0218. To the above dosage form 4 ml tapped water is Vanilla flavour 4.6 O.O86 Glycerol 2.35 O.O43 added. After about/2 min the liquid is absorbed. The spoon is Blend 2: turned around and held upside down for 2 min. The test material did not fall out and passed the test. Blend 1 S3.6 1.87 Coated Cefuxime 35.7 1.25 EXAMPLE 4 Vi-siblin 10.7 O.38 A Composition According to the Invention Contain ing 150 mg Coated Pyridoxine in the Dosage Unit 0212. The ingredients (1-4) of Blend 1 are mixed /2 min (depending on the amount of powder) in a mortar transferred 0219. A composition that has a shape as outlined in FIG. 1 to a Philips Food processor Electronic type HR 2377/D, containing coated pyridoxine as active Substance was pre ingredient 5 is added and mixed for about /2 min (depending pared as follows: on the amount of powder) at speed 4. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). 0213. The granules are divided into 700 mg/dose. The % Wiw 9. dose is weight out into a medical spoon and moulded by Blend 1: gently pressing the granules against the spoon with a mortar Kelcogel LT100 5O1 O.938 pistil to a thin layer about 1-3 mm in high in the bottom of the Xylitol 47.52 O.89 spoon. The water is evaporated at ambient temperature. Vanilla flavour 2.53 O.O47 Blend 2: Drop Down Test: Blend 1 75 1875 0214) To the above dosage form 4 ml tapped water is Pyridoxine coated 25 O.625 added. After about/2 min the liquid is absorbed. The spoon is Blend 3: turned around and held upside down for 2 min. The test Blend 2 71.4 2.50 material did not fall out and passed the test. Kelcogel F 14.32 O.S Water 14.33 O.S EXAMPLE 3 A Composition According to the Invention Contain 0220. The ingredients (1-3) of Blend 1 are mixed /2 min ing 250 mg Coated Cefuxime Dosage Unit (depending on the amount of powder) in a mortar. The ingre dients from blend 2 are mixed in a mortar for about /2 min 0215. A composition that has a shape as outlined in FIG. 1 (depending on the amount of powder). containing cefuXime as active substance was prepared as 0221) The ingredients (2-3 (binding solution) from blend 3 follows% w/w: are mixed /2 min and ingredient 1 is added to the blend and mixed for about% min (depending on the amount of powder) and forming the granules. 0222. The granules are divided to 700 mg/dose. The dose % Wiw 9. is weight out into a medical spoon and moulded by gently Blend 1: pressing the granules against the spoon with a mortarpistil to Kelcogel LT100 23.1 O.S2 a thin layer about 1-3 mm in high in the bottom of the spoon. Xylitol 69.12 1.55 The water is evaporated at ambient temperature. Aerosil O.53 O.O11 Vanilla flavour 54 O112 Drop Down Test: Glycerol 2.35 Blend 2: 0223) To the above dosage form 3 ml tapped water is Blend 1 64.3 2.25 added. After about/2 min the liquid is absorbed. The spoon is Coated Cefuxime 35.7 1.24 turned around and held upside down for 2 min. The test material did not fall out and pass the test. 0216. The ingredients (1-4) of Blend 1 are mixed /2 min EXAMPLE 5 (depending on the amount of powder) in a mortar transferred to a Philips Food processor Electronic type HR 2377/D, A Composition According to the Invention Contain ingredient 5 is added and mixed for about /2 min (The gran ing 150 mg Coated Ferro Fumarate in the Dosage ules are made by adding in this case glycerol to the dry mixed Unit powder, i.e. Kelcogel LT 100 is pre-swelled in glycerol) at 0224. A composition that has a shape as outlined in FIG. 1 speed 4. The ingredients from blend 2 are mixed in a mortar containing coated Ferro fumarate as active Substance was for about /2 min (depending on the amount of powder). prepared as follows: US 2008/0299.199 A1 Dec. 4, 2008 21

0231. The ingredients (2-3) from blend 3 are mixed 96 min and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). % Wiw 9. 0232. The granules are divided to 700 mg/dose. The dose Blend 1: is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortarpistil to Kelcogel LT100 501 O.938 Xylitol 47.52 O.89 a thin layer about 1-3 mm in high in the bottom of the spoon. Vanilla flavour 2.53 O.O47 The water is evaporated at ambient temperature, or moulded Blend 2: to a sphere or stripe. The water is evaporated in an oven at 70° C. to constant temperature. Blend 1 75 1875 Ferro fumarate 25 O.625 Drop Down Test: Blend 3: 0233. To the above dosage form 3 ml tapped water is Blend 2 71.4 2.50 added. After about/2 min the liquid is absorbed. The spoon is Kelcogel F 14.32 O.S turned around and held upside down for 2 min. The test Water 14.3 O.S material did not fall out and pass the test. EXAMPLE 7 0225. The ingredients (1-3) of Blend 1 are mixed /2 min (depending on the amount of powder) in a mortar. The ingre A Composition According to the Invention Contain dients from blend 2 are mixed in a mortar for about /2 min ing 125 mg Coated Ibuprofen in the Dosage Unit (depending on the amount of powder). 0234. A composition that has a shape as outlined in FIG. 1 0226. The ingredients (2-3) from blend 3 are mixed/2 min containing coated ibuprofen dosage as active Substance was and ingredient 1 is added to the blend and mixed for about/2 prepared as follows: min (depending on the amount of powder). 0227. The granules are divided into 700 mg/dose. The dose is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortar % ww 9. pistil to a thin layer about 1-3 mm in high in the bottom of the Blend 1: spoon. The water is evaporated at ambient temperature. Kelcogel LT100 52.6 O.95 Xylitol 47.42 O.86 Drop Down Test: Blend 2:

0228 To the above dosage form 3 ml tapped water is Blend 1 69.7 1.81 added. After about/2 min the liquid is absorbed. The spoon is Ibuprofen coated 22.7 O.S8 turned around and held upside down for 2 min. The test Tutti-frutti flavour 7.6 O.20 material did not fall out and pass the test. Blend 3: Blend 2 74.21 2.59 EXAMPLE 6 Kelcogel F 12.92 O.45 A Composition According to the Invention Contain Water 12.9 O.45 ing 125 mg Coated Ibuprofen in the Dosage Unit 0235. The ingredients of Blend 1 are mixed /2 min (de 0229. A composition that has a shape as outlined in FIG. 1 pending on the amount of powder) in a mortar. The ingredi containing coated ibuprofen as active Substance was prepared ents from blend 2 are mixed in a mortar for about 9% min as follows: (depending on the amount of powder). 0236. The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about% % Wiw 9. min (depending on the amount of powder). 0237. The granules are divided into 700 mg/dose. The Blend 1: dose is weight out into a medical spoon and moulded by Kelcogel LT100 52.6 O.87 gently pressing the granules against the spoon with a mortar Xylitol 47.42 0.79 pistil to a thin layer about 1-3 mm in high in the bottom of the Blend 2: Spoon. Blend 1 64.1 1.66 Drop Down Test: Ibuprofen 20.9 O.S4 Vanilla flavour 15 O.39 0238. To the above dosage form 3 ml tapped water is Blend 3: added. After about/2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test Blend 2 742 2.59 Kelcogel F 12.92 O.45 material did not fall out and pass the test. Water 12.93 O.45 EXAMPLE 8 A Composition According to the Invention Contain 0230. The ingredients of Blend 1 are mixed /2 min (de ing 125 mg Coated Ibuprofen in the Dosage Unit pending on the amount of powder) in a mortar. The ingredi 0239. A composition that has a shape as outlined in FIG. 1 ents from blend 2 are mixed in a mortar for about 9% min containing coated ibuprofen as active Substance was prepared (depending on the amount of powder). as follows: US 2008/0299.199 A1 Dec. 4, 2008 22

-continued

% Wiw 9. % ww 9. Blend 1: Blend 3: Kelcogel LT100 52.6 Blend 2 742 2.59 Xylitol 47.42 Kelcogel F 12.92 O.45 Blend 2: Water 12.93 O.45

Blend 1 71 1.83 Ibuprofen coated 23.2 O.6 0245. The ingredients of Blend 1 are mixed /2 min (de Caramel flavour 5.8 O.15 pending on the amount of powder) in a mortar. The ingredi Blend 3: ents from blend 2 are mixed in a mortar for about /2 min Blend 2 74.21 2.59 (depending on the amount of powder). Kelcogel F 12.92 O.45 0246 The ingredients (2-3) from blend 3 are mixed/2 min Water 12.9 O.45 and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). 0247 The granules are divided into 700 mg/dose. The 0240. The ingredients of Blend 1 are mixed /2 min (de dose is weight out into a medical spoon and moulded By pending on the amount of powder) in a mortar. The ingredi gently pressing the granules against the spoon with a mortar ents from blend 2 are mixed in a mortar for about /2 min pistil to a thin layer about 1-3 mm in high in the bottom of the (depending on the amount of powder). spoon. The water is evaporated at ambient temperature to a 0241 The ingredients (2-3) from blend 3 are mixed/2 min final amount of approximately 575 mg/dose. and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). Drop Down Test: 0242. The granules are divided into 700 mg/dose. The 0248. To the above dosage form 3 ml tapped water is dose is weight out into a medical spoon and moulded by added. After about/2 min the liquid is absorbed. The spoon is gently pressing the granules against the spoon with a mortar turned around and held upside down for 2 min. The test pistil to a thin layer about 1-3 mm in high in the bottom of the material did not fall out and pass the test. spoon. The water is evaporated at ambient temperature to a 0249. The average absorption rate of water by the dosage final amount of approximately 575 mg/dose per second measured in gram water absorb per gram dosage per second is 3 g/0.575 g/120 sec corresponding to a water Drop Down Test: absorption rate of 0.0435 g/g/s 0243 To the above dosage form 3 ml tapped water is EXAMPLE 10 added. After about/2 min the liquid is absorbed. The spoon is A Placebo Composition According to the Invention turned around and held upside down for 2 min. The test 0250) A composition that has a shape as outlined in FIG. 1 material did not fall out and pass the test. The average absorp was prepared as follows: tion rate of water by the dosage per second measured in gram water absorb per gram dosageper second is 3 g/0.575 g/30sec corresponding to a water absorption rate of 0.1739 g/g/s % ww 9. EXAMPLE 9 Blend 1: Kelcogel LT100 22.51 0.675 A Composition According to the Invention Contain Xylitol 67.52 2.025 ing 125 mg Coated Ferro Fumarate in the Dosage Ultrasperse HV 10.03 O.3 Unit Blend 2:

Blend 1 94.0 3.0 0244. A composition that has a shape as outlined in FIG. 1 Strawberry flavour 6.O O.2 containing coated ferro fumarate dosage as active Substance Blend 3: was prepared as follows: Blend 2 91.4 3.2O Sodium citrate 122 O.042 Water 8.43 O.294

% Wiw 9. 0251. The ingredients of Blend 1 are mixed /2 min (de Blend 1: pending on the amount of powder) in a mortar. The ingredi Kelcogel LT100 52.6 O.91 ents from blend 2 are mixed in a mortar for about /2 min Xylitol 47.42 O.83 (depending on the amount of powder). Blend 2: 0252. The ingredients (2-3) from blend 3 are mixed/2 min Blend 1 67.2 1.74 and ingredient 1 is added to the blend and mixed for about/2 Ferro fumerate coated 21.9 O.S6 min (depending on the amount of powder). Chocolate flavour 10.9 O.29 0253) The granules are divided into 550 mg/dose. The dose is weight out into a medical spoon and moulded by US 2008/0299.199 A1 Dec. 4, 2008

gently pressing the granules against the spoon with a mortar EXAMPLE 12 pistil to a thin layer about 1-3 mm in high in the bottom of the A Placebo Composition According to the Invention spoon. The water is evaporated at ambient temperature to a 0262. A composition that has a shape as outlined in FIG. 1 final amount of approximately 502 mg/dose. was prepared as follows: Drop Down Test: 0254 To the above dosage form 3.5 ml tapped water is % Wiw 9. added. After about/2 min the liquid is absorbed. The spoon is Blend 1: turned around and held upside down for 2 min. The test Kelcogel LT100 501 1.2 material did not fall out and pass the test. Xylitol 502 1.2 0255. The average absorption rate of water by the dosage Blend 2: per second measured in gram water absorb per gram dosage Blend 1 8O 2.4 per second is 3.5 g/0.502 g/120 sec corresponding to a water Keltrol 2O O.6 absorption rate of 0.0581 g/g/s Blend 3: Blend 2 71.4 3.0 EXAMPLE 11 Caramel flavour 14.32 O.S Water 14.33 O.S A Placebo Composition According to the Invention 0263. The ingredients (1-2) of Blend 1 are mixed /2 min 0256 A composition that has a shape as outlined in FIG. 1 (depending on the amount of powder) in a mortar. The ingre was prepared as follows: dients from blend 2 are mixed in a mortar for about /2 min (depending on the amount of powder). 0264. The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/2 % Wiw 9. min (depending on the amount of powder). Blend 1: 0265. The granules are divided into 500 mg/dose. The dose is weight out into a medical spoon and moulded by Kelcogel LT100 251 O.65 gently pressing the granules against the spoon with a mortar Xylitol 752 1.94 pistil to a thin layer about 1-3 mm in high in the bottom of the Blend 2: spoon. The water is evaporated at ambient temperature to a Blend 1 80.3 2.59 final dosage of 429 mg Inulin 13.1 O.42 Caramel flavour 6.6 O.21 Drop Down Test: Blend 3: 0266 To the above dosage form 3 ml tapped water is Blend 2 92 3.22 added. After about/2 min the liquid is absorbed. The spoon is Water 8 O.28 turned around and held upside down for 2 min. The test material did not fall out and pass the test. 0257 The ingredients of Blend 1 are mixed /2 min (de EXAMPLE 13 pending on the amount of powder) in a mortar. The ingredi A Composition According to the Invention Contain ents from blend 2 are mixed in a mortar for about /2 min ing 120 mg Coated Cefuxime in the Dosage Unit (depending on the amount of powder). 0267 A composition in percentage having a shape as out 0258 Blend 3 is mixed for about /2 min (depending on the lined in FIG. 1 containing cefuXime as active substance was amount of powder). prepared as follow: 0259. The granules are divided into 550 mg/dose. The dose is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortar % Wiw 9. pistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature to a Blend 1: final dosage of 506 mg. Sodium citrate 251 0.157 Dem. water 752 O.470 Drop Down Test: Blend 2: Blend 1 98.04 O627 0260 To the above dosage form 3.5 ml tapped water is Keltrol 1962 O.O13 added. After about/2 min the liquid is absorbed. The spoon is Blend 3: turned around and held upside down for 2 min. The test Blend 2 60 O.64 material did not fall out and pass the test. Microencapsulated Cefuxime 40 O42 0261 The average absorption rate of water by the dosage Blend 4: per second measured in gram water absorb per gram dosage Kelcogel LT100 501 O.98 per second is 3.5 g/0.506 g/120 sec corresponding to a water Xylitol 502 O.98 absorption rate of 0.0576 g/g/s US 2008/0299.199 A1 Dec. 4, 2008 24

about 1-3 mm in high in the bottom of the spoon. The water is -continued evaporated at ambient temperature.

% ww 9. Drop Down Test: 0275 To the dosage form 4 ml tapped water (temp. Blend 5 between 15-20°C.) is added. After about 15 sec the liquid is Blend 4 56.1 1.96 absorbed. The spoon is turned around and held upside down Blend 3 30.3 1.06 for 2 min. The test material did not fall out and pass the test. Ketrol 9.1 O.32 Apple fruit 4.5 O16 Viscosity Test: 0276 Transfer 43.75 g test materials Accurately weighed 0268 Blend 1: the ingredients is dissolved in ingredient 2. into a 500 ml beaker, and disperse/dissolve with 500 ml Blend 2: the ingredient 2 is dissolved in ingredient 1. The tapped water. ingredient from blend 3 is mixed in a mortar with a scraperor (0277. The viscosity is measured to 60500 cps. a card until all is blend. EXAMPLE 1.5 0269. The ingredient from blend 4 is mixed in a mortar A Composition According to the Invention Contain with a scraper or a card until all is blend. ing 50 mg Coated Paracetamol in the Dosage Unit 0270. The granules are divided to 600 mg/dose. The dose 0278 A composition in percentage having a shape as out is weight out into a medical spoon and moulded by pressing lined in FIG. 1 containing paracetamol as active Substance the granules against the spoon with a stopper to a thin layer was prepared as follow: about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature. Blend 1 Drop Down Test: Sodium citrate 25 0271 To the above dosage form 4 ml tapped water (temp. Dem. water 75 between 15-20°C.) is added. After about 15 sec the liquid is Blend 2: absorbed. The spoon is turned around and held upside down Kelcogel LT100 50 Xylitol SO for 2 min. The test material did not fall out and pass the test. Blend 3:

EXAMPLE 1.4 Blend 2 75 Keltrol 12.5 Apple fruit 12.5 A Composition According to the Invention Contain Blend 4: ing 120 mg Coated Cefuxime in the Dosage Unit Blend 3 74.22 Blend 1 12.13 0272. A composition in percentage having a shape as out Microencapsulated paracetamol 13.65 (61% pure paracetamol) lined in FIG. 1 containing cefuXime as active substance was prepared as follow: 0279 Blend 1: Sodium citrate is dissolved in dem. water. Blend 2: The ingredient from blend 2 is mixed in a mortar with a scraper or a card until all is blend. Blend 3: The % Wiw 9. ingredient from blend 3 is mixed in a mortar with a scraper or a card until all is blend. Blend 1: 0280. The ingredient from blend 4 is mixed in a mortar Kelcogel LT100 40 1.195 with a scraper or a card until a homogeneous blend is Xylitol 40 1.195 obtained. Ketrol 2O O.6O 0281. The blend 4 is divided to 600 mg/dose. The dose is Blend 2: weight out into a medical spoon and molded by pressing the Sodium citrate 251 O.128 granules against the spoon with a stopper to a thin layer about Dem. water 733 0.372 1-3 mm in high in the bottom of the spoon. The water is Keltrol 22 O.O11 Blend 3 evaporated at ambient temperature.

Blend 1 85.4 2.99 Drop Down Test: Blend 2 14.6 O.S1 0282. To the above dosage form 4 ml tapped water (temp. between 15-20°C.) is added. After about 15 sec the liquid is absorbed. The spoon is turned around and held upside down 0273. The ingredients Blend 1 are mixed in a Braun elec for 2 min. The test material did not fall out and pass the test. tronic mixer type 4202 for about 1 min. The ingredients (1-2) blend 2 are dissolved in ingredient 3. Blend 3 is mixed to EXAMPLE 16 granules in a Braun electronic mixer type 4202 with a dough A Composition According to the Invention Contain shaft. ing 50 mg Coated Paracetamol in the Dosage Unit 0274 The granules are divided to 600 mg/dose. The dose 0283. A composition in percentage having a shape as out is weight out into a medical spoon and moulded by pressing lined in FIG. 1 containing paracetamol as active Substance the granules against the spoon with a stopper to a thin layer was prepared as follow: US 2008/0299.199 A1 Dec. 4, 2008 25

Blend 1: Blend 1:

Sodium citrate 25 Gellan gum (Kelcogel LT100) SO.OO Dem. water 75 Xylitol SO.OO Blend 2: Blend 2:

Blend 1 50 Blend 1 37.5 Sodium citrate 11 Microencapsulated paracetamol 52 (61% pure paracetamol) PEG 200 39 Glycerin 1O.S Blend 3: Kelcogel LT100 42.86 Xylitol 42.86 0292 Blend 2: The ingredients from blend 1 are mixed in Keltrol 14.28 a mortar with a pestle, scraping as needed until homogeneous Blend 4: blend.

Blend 2 8OSO Blend 3 19.50 Blend 5: Blend 3: Blend 4 90.00 Microencapsulated paracetamol 10.00 (61% pure paracetamol) Povidone (kollidon 25k) 9.52 Ethanol 99.9% 85.72 Glycerol 4.76 0284 Blend 1: Sodium citrate is dissolved dem. water. Blend 2: The ingredient is mixed. 0285 Blend 3: the ingredient is mixed in a mortar with a 0293 Blend 3: Povidone (kollidon 25k) is dissolved Etha scraper or a card until all is blend. nol 99.9% and then Glycerol is added and dissolved. Blend 4 0286 The ingredient from blend 4 is mixed in a mortar is poured in a 50 ml spray flask with nozzle. with a scraper or a card until all is blend. Blend 5: The 0294 Prepared spoon: The concave side of the spoons are ingredient from blend 5 is mixed in a mortar with a scraperor sprayed twice with blend 4. The EtOH is evaporated in an a card until homogeneous blend is obtained. oven at 45° C. for one hour. 0295) The blend 2 is divided to 630 mg/dose. The dose is weight out into a prepared medical spoon and moulded by pressing the granules against the spoon with a stopperto a thin Blend 6: layer about 1-3 mm in high in the bottom of the spoon. The PVP (kollidon 25k) 9.52 water is evaporated at ambient temperature. Ethanol 99.9% 85.72 Glycerol 4.76 Drop Down Test: 0296 To the above dosage form 4 ml tapped water (temp. (0287 Blend 6: PVP (kollidon 25k) is dissolved in Ethanol between 15-20°C.) is added. After about 15 sec the liquid is 99.9%, when dissolved Glycerol is added and blend. Blend 6 absorbed. The spoon is turned around and held upside down is poured in a 50 ml spray flask with a nozzle. for 2 min. The test material did not fall out and pass the test. 0288 Prepared spoon: The concave side of the spoons are sprayed twice with blend 4. The EtOH is evaporated in an Dissolution oven at 45° C. for one hour. 0289. The blend 5 is divided to 820 mg/dose. The dose is Material and Methods weight out into a prepared medical spoon and moulded by 0297 Simulated gastric Fluid: For 1 L: 0.1H HCl pressing the granules against the spoon with a stopperto a thin 0298 Dissolution system consists of online system model layer about 1-3 mm in high in the bottom of the spoon. The SOTAX AT7 and UV detector Model PE lambda 2 using water is evaporated at ambient temperature. Disslab version 1.1. 0299. The dissolutions curve was obtain with Temp 37 Drop Down Test: C. Speed 120 rpm, 280 nm and a factor of 108 over a period 0290. To the above dosage form 4 ml tapped water (temp. of 1 h. between 15-20°C.) is added. After about 15 sec the liquid is absorbed. The spoon is turned around and held upside down Results and Discussion for 2 min. The test material did not fall out and pass the test. 0300 FIG. 2 illustrates the dissolutions profile of a Parac etamol dosage unit in simulated gastric fluid. After 5 min at EXAMPLE 17 least 96% of the Paracetamol is released. A Composition According to the Invention Contain 0301 The curve with the dot-line is pure coated paraceta ing 200 mg Coated Paracetamol in the Dosage Unit mol used in the dosage form; After 5 min at least 96% of the Paracetamol is released. 0291. A composition in percentage having a shape as out 0302 Comparing pure coated paracetamol and the Parac lined in FIG. 1 containing paracetamol as active Substance etamol dosage unit no differences between the release profiles was prepared as follow: a Sel. US 2008/0299.199 A1 Dec. 4, 2008 26

EXAMPLE 1.8 EXAMPLE19 A Placebo Composition According to the Invention A Composition According to the Invention Contain ing 250 mg Coated Paracetamol in the Dosage Unit 0311. A composition that has a shape as outlined in FIG. 1 was prepared as follows (given as % w/w): 0303 A composition in percentage having a shape as out lined in FIG. 1 containing paracetamol as active Substance was prepared as follow: Blend 1: Sodium citrate 25 Demineralized water 75 Blend 2: Blend 1: Kelcogel LT100 50 Sodium citrate 25 Xylitol 50 Demineralized water 75 Blend 3: Blend 2, Blend 1 11.2 Blend 2 8O Gellan gum (Kelcogel LT100) SO.OO Sodium hydrogen carbonates 3 Xylitol SO.OO Strawberry flavoribanana flavor 5.8 Blend 3:

Blend 1 42.7 0312 Blend 1: Sodium citrate is dissolved dem. Water. Blend 2 9.8 0313 Blend 2: The ingredients from blend are mixed in a Microencapsulated paracetamol 38.7 mortar with a pestle, Scraping as needed until homogeneous (61% pure paracetamol) blend. Sodium Hydrogen Carbonate 2.9 0314 Blend 3: The ingredients from blend are mixed in a Strawberry flavour 5.8 mortar with a pestle, Scraping as needed until homogeneous blend. 0315. The blend 3 is divided into 250 mg/dose. The dose is 0304 Blend 1: Sodium citrate is dissolved Dem. water. weight out into a medical spoon and molded by gently press 0305 Blend 2: The ingredients from blend are mixed in a ing the granules against the spoon with a mortarpistil to a thin mortar with a pestle, Scraping as needed until homogeneous layer about 1-3 mm in high in the bottom of the spoon. The blend. water is evaporated at ambient temperature. 0306 Blend 3: The ingredients from blend are mixed in a Drop Down Test: mortar with a pestle, Scraping as needed until homogeneous 0316 To the above dosage form 3 ml tapped water is blend. added. After about% min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test material did not fall out and pass the test. Blend 4: In-Vivo Ultra Sound Scanning Test Povidone (kollidon 25k) 9.52 0317. In vivo properties of the above placebo formulations Ethanol 99.9% 85.72 were determined in a subject who had fasted for 8-12 hours Glycerol 4.76 prior to ingesting 250 mL of water and 5 min after having ingested the prepared dosages form. Ultrasound imaging was 0307 Blend 4: Povidone (kollidon 25k) is dissolved Etha performed in sitting position throughout the procedure. nol 99.9% and then Glycerol is added and dissolved. Blend 4 0318 B-mode ultrasound imaging of the gastrointestinal tract was done with a LOGIC (4-10 MHz) linear transducer is poured in a 50 ml spray flask with nozzle. (Linear 10L H40412LG) coupled to a LOGIQ 9 Ultrasound 0308 Prepared spoon: The concave side of the spoons are instrument with software version R3.0.11 abdominal pro sprayed twice with blend 4. The EtOH is evaporated in an gram (8 MHz). Images were videotaped before ingestion of oven at 45° C. for one hour. water and immediately prior to ingestion of the dosage form 0309 The blend 3 is divided to 880 mg/dose. The dose is (time 0) and at five minutes intervals thereafter. 0319 FIG. 3 demonstrates that the ingested water weight out into a prepared medical spoon and moulded by appeared “black” in the ultrasonic image. pressing the granules against the spoon with a stopperto a thin 0320 FIG. 4 demonstrates that the ingested dosages form layer about 1-3 mm in high in the bottom of the spoon. The appeared “white' in the ultrasonic image. water is evaporated at ambient temperature. 0321 Shortly after ingestion of the water the stomach lumen became Sonolucent and non-echogenic and thus Drop Down Test: appeared “black” in the ultrasonic image and after ingestion of the dosage form the stomach lumen became Sonolucent 0310. To the above dosage form 4 ml tapped water (temp. and echogenic and thus appeared “white' in the ultrasonic between 15-20°C.) is added. After about 15 sec the liquid is image. As seen from the picture FIG. 5 the dosage form is absorbed. The spoon is turned around and held upside down spread through out the stomach, which indicate that the dos for 2 min. The test material did not fall out and pass the test. age form is totally disintegrated when reaching the stomach. US 2008/0299.199 A1 Dec. 4, 2008 27

EXAMPLE 20 EXAMPLE 21 A Placebo Composition for Use According to the A Placebo Composition for Use According to the Invention Invention 0331. A composition that has a shape as outlined in FIG. 1 was prepared as follows (given as % w/w): 0322. A composition that has a shape as outlined in FIG. 1 was prepared as follows (given as % w/w): Blend 1: Kelcogel LT100 50 Blend 1: Xylitol 50 Blend 2:

Kelcogel LT100 50 Blend 1 83.3 Xylitol 50 Medium Chain Triglyceride EP S.6 Blend 2: (Labrafiac cc) Povidone (kollidon 25k) S.6 Vanilla flavour S.6 Blend 1 92.4 Povidone (kollidon 25k) O.S 0332 Blend 1: The ingredients from blend are mixed in a Strawberry flavoribanana?vanilla flavor 7.1 mortar with a pestle, Scraping as needed until homogeneous Blend 3: blend. 0333 Blend 2: blend 1 is mixed with Medium Chain Trig Blend 1 93.8 lyceride EP (Labrafiac cc) in a mortar with a pestle, scraping Ethanol 99.9% 6.2 as needed until homogeneous blend and Povidone (kollidon 25k) is added mixed to a homogeneous blend, Vanilla flavour is added to the mixture and blend to a homogeneous mass. 0323 Blend 1: Kelcogel LT100 and Xylitol are mixed in a mortar with a pestle, Scraping as needed until homogeneous blend. Blend 3: 0324 Blend 2: The ingredients from blend 2 are mixed in Povidone (kollidon 25k) 9.52 a mortar with a pestle, Scraping as needed until homogeneous Ethanol 99.9% 85.72 blend. Glycerol 4.76 0325 Blend 3: The ingredients from blend 3 are mixed in a mortar with a pestle, Scraping as needed until homogeneous 0334 Blend 3: Povidone (kollidon 25k) is dissolved in blend. Ethanol 99.9% and Glycerol is added to the mixture and dissolved. Blend 4 is poured in a 50 ml spray flask with nozzle. 0335 Prepared spoon: The concave side of the spoons are Blend 4: sprayed twice with blend 3. The EtOH is evaporated in an oven at 45° C. for one hour. Povidone (kollidon 25k) 9.52 Ethanol 99.9% 85.72 0336. The granules are divided to 250 mg/dose. The dose Glycerol 4.76 is weight out into a prepared medical spoon and moulded by pressing the granules against the spoon with a stopperto a thin layer about 1-3 mm in high in the bottom of the spoon. The 0326 Blend 4: Povidone is dissolved in Ethanol and then water is evaporated at ambient temperature. Glycerol is added and dissolved. Drop Down Test: 0327 Blend 4 is poured in a 50 ml spray flask with nozzle. 0337 To the above dosage form 3 ml tapped water is 0328 Prepared spoon: The concave side of the spoons are added. After about/2 min the liquid is absorbed. The spoon is sprayed twice with blend 4. The EtOH is evaporated in an turned around and held upside down for 2 min. The test oven at 45° C. for one hour. material did not fall out and pass the test. 0329. The granules are divided to 300 mg/dose. The dose EXAMPLE 22 is weight out into a prepared medical spoon and moulded by Oral Hygiene Composition for Use Directly in the pressing the granules against the spoon with a stopperto a thin Mouth Cavity with or without Prehydration layer about 1-3 mm in high in the bottom of the spoon. The 0338 A composition in percentage having a shape as out water is evaporated at ambient temperature. lined in FIG. 1 was prepared as follow: Drop Down Test: 0330. To the above dosage form 3 ml tapped water is Blend 1: added. After about/2 min the liquid is absorbed. The spoon is Xylitol 86.6 turned around and held upside down for 2 min. The test Glycerol 13.4 material did not fall out and pass the test. US 2008/0299.199 A1 Dec. 4, 2008 28

ules against the spoon with a stopper. The final layer of -continued granules lay in the bottom of the spoon and is approximately 2 mm in height. The spoon is sprayed twice with blend 4 Blend 2: (approximately 60 mg) and placed in an oven at 45° C. for 30 Blend 1 S3.6 minutes, evaporating the ethanol. Kelcogel LT100 46.4 Drop Down Test: 0339 Blend 1: Xylitol is mixed with glycerol in a Braun electronic kitchen mixer at level 4, for 2 min. Blend 2: The 0349 To the above dosage form 5 M1 tapped water is ingredient from blend 2 is mixed in the Braun Electronic added. After about 30 seconds the liquid is absorbed. The kitchen mixer until all is blend. Sieved through a sieve mesh. spoon is turned around and held upside down for 2 min. The 0340. The two blends are mixed and pressed into plates test material did not fall out and pass the test. with a thickness of approximately 2 mm and cut into pieces of 1x2 cm. The flakes are dried in an oven (Electrolux) at 45° C. EXAMPLE 24 for /2 h. 0341 The flakes are placed in the oral cavity where the A Composition According to the Invention Contain formulation will be hydrated by the saliva and any local active ing 250 mg Paracetamol released or the formulation can be added conventional toot paste components and dried on tooth brushes or on other 0350 A composition that has a shape as outlined in FIG. 1 devices for mechanical cleaning within the oral cavity. was prepared as follows: EXAMPLE 23

A Placebo Composition According to the Invention % Wiw 9. 0342. A composition that has a shape as outlined in FIG. 1 was prepared as follows: Blend 1: Kelcogel LT100 50 18.78 Xylitol 50 18.78 Blend 2: % Wiw 9. Vanilla Flavour 92.2 2.25 Blend 1 PVPK2 7.8 O.19 end 3: Kelcogel LT100 50 18.78 Xylitol 50 18.78 Blend 1 42.8 6.24 Blend 2 Blend 2 2.76 O4O2 Glycerol 3.42 O499 Vanilla Flavour 92.2 2.25 Paracetamol 40.6 S.92 PVP K25 7.8 O.19 Glycerol 1O.S 1.53 end 3 Blend 4:

Blend 1 88.89 37.56 PVPK25 9.5 4.OO Blend 2 5.78 2.44 Glycerol 4.8 2.00 Glycerol 5.33 2.25 Ethanol 99.9% 85.7 36.O1 Blend 4 PVP K25 9.5 4.OO 0351 Blend 1: Kelcogel LT100 and Xylitol is mixed in a Glycerol 4.8 2.00 Ethanol 99.9% 85.7 36.O1 mortar until a homogeneous blend is formed. 0352 Blend 2: The vanilla flavour is grinded in a mortar (0343 Blend 1: Kelcogel LT100 and Xylitol is mixed in a and the PVP K25 is added stepwise under mixing to form a mortar until a homogeneous blend is formed. homogeneous blend. 0344 Blend 2: The vanilla flavour is grinded in a mortar 0353 Blend 3: Blend 1 is volumetrically mixed stepwise and the PVP K25 is added stepwise under mixing to form a into Blend 2 with a dough scraper or mixing card. Glycerol is homogeneous blend. added stepwise under continuous slow mixing and a uniform 0345 Blend 3: Blend 1 is volumetrically mixed stepwise granulate is formed. Paracetamol is added under continuous into Blend 2 with a dough scraper or mixing card. The Glyc slow mixing and the final part of Glycerol is added to form a erol is added stepwise under continuous slow mixing and a uniform granulate. uniform granulate is formed. 0354 Blend 4: Ethanol and PVP K25 is mixed and stirred 0346 Blend 4: Ethanol and PVP K25 is mixed and stirred until a clear mixture is obtained. The Glycerol is added and until a clear mixture is obtained. The Glycerol is added and stirred until a clear mixture is obtained. Blend 4 is poured into stirred until a clear mixture is obtained. Blend 4 is poured into a 50 ml spray flask with nozzle. a 50 ml spray flask with nozzle. 0347 Medical spoon preparation: The concave side of a 0355 Medical spoon preparation: The concave side of a medical spoon is sprayed twice with Blend 4 (approximately medical spoon is sprayed twice with Blend 4 (approximately 60 mg) and placed in an oven at 45° C. for 30 minutes. 60 mg) and placed in an oven at 45° C. for 30 minutes. (0348 335+17.5 mg/dose of Blend 3 is weight into a pre 0356 616+20 mg/dose is weight into a prepared medicine pared medicine spoon and distributed by pressing the gran spoon and distributed by pressing the granules against the US 2008/0299.199 A1 Dec. 4, 2008 29 spoon with a stopper. The final layer of granules lay in the spoon is turned around and held upside down for 2 min. The bottom of the spoon and is approximately 2 mm in height. test material did not fall out and pass the test. topspray Dissolution Testing: Drop Down Test: 0366 For dissolution spoons prepared as described above 0357 To the above dosage form 5 ml tapped water is was places in a dissolution medium after removal of the added. After about 30 seconds the liquid is absorbed. The handle and aided by a sinker glued to the outer concave spoon is turned around and held upside down for 2 min. The bottom whereby the spoons were located in the bottom of test material did not fall out and pass the test. each of the dissolution vessels comprising 900 ml medium EXAMPLE 25 and equipped with a paddle rotating at 50 rpm. A Composition According to the Invention Contain ing 415 mg Coated Paracetamol (Corresponding to Media: 250 mg Paracetamol) 0367 0.1 NHCl -pH 1 (test media 1): Vessel 5 and 6 0358. A composition that has a shape as outlined in FIG. 1 0368 Ad 1000 ml of purified water in to a 5000 ml blue was prepared as follows: cap flask. 0369 Add carefully 25.5 ml 37 w/w % HC1 in to the 5000 ml blue cap flask. % Wiw 9. 0370 Add purified water until 3000 ml is reached. Blend 1: Measure the pH of the Solution Kelcogel LT100 50 18.78 Xylitol 50 18.78 0371 0.05M Phosphate solution pH 4.5 (test media 2): Blend 2: Vessels 3 and 4 0372. Add 750 ml of a 0.2 M KH2PO4 solution (prepare Vanilla Flavour 92.2 2.25 PVPK2 7.8 O.19 according to QCF026) in to a 5000 ml blue cap flask. end 3: 0373 Add 2250 ml Elix water.

Blend 1 33.2 1O.S 0374. Measure the pH of the solution. The pH changed to Blend 2 2.15 O.678 4.8 after addition of sample. Glycerol 2.66 O840 0375 0.05M Phosphate standard solution pH 6.8 (test Coated Paracetamol 57.1 18.06 Glycerol 4.81 1.52 media 3) Vessel 1 and 2 Blend 4: Dissolution Procedure: PVPK25 9.5 4.OO Glycerol 4.8 2.OO 0376 Place 895 g of degassed dissolution medium inves Ethanol 99.9% 85.7 36.01 sel 1 to 6. 0377 Vessel 1 and 2: Phosphate buffer pH 6.8. 0359 Blend 1: Kelcogel LT100 and Xylitol is mixed in a 0378 Vessel 3 and 4: Phosphate solution pH 4.5. mortar until a homogeneous blend is formed. 0360 Blend 2: The vanilla flavour is grinded in a mortar 0379 Vessel 5 and 6: 0.1N HC1. and the PVP K25 is added stepwise under mixing to form a 0380 Place 200 ml of Diluent buffer in the Standard ves homogeneous blend. sel. 0361 Blend 3: Blend 1 is volumetrically mixed stepwise 0381. After cell diagnostics, replace Diluent buffer from into Blend 2 with a dough scraper or mixing card. Glycerol is the Standard vessel with 250 ml of standard solution (0.2 mg added stepwise under continuous slow mixing and a uniform paracetamol/ml). granulate is formed. Coated Paracetamol is added under con tinuous slow mixing and the final part of Glycerol is added to form a uniform granulate. Analytical principle Online UW 0362 Blend 4: Ethanol and PVP K25 is mixed and stirred API Paracetamol until a clear mixture is obtained. The Glycerol is added and Method USP2 (paddle) Degassing Vacuum filtration at 41° C. stirred until a clear mixture is obtained. Blend 4 is poured into Temperature 37°C. O.S. C. a 50 ml spray flask with nozzle. Volume 900 + 0.2% (895 ml + 4 ml) 0363 Medical spoon preparation: The concave side of a Detection 280 nm. medical spoon is sprayed twice with Blend 4 (approximately Rotation speed 50 rpm 60 mg) and placed in an oven at 45° C. for 30 minutes. Filters 0.7 Full Flow Filter 0364 720+20 mg/dose is weight into a prepared medicine Detection frequency every 5 min. in 60 minutes spoon and distributed by pressing the granules against the spoon with a stopper. The final layer of granules lay in the bottom of the spoon and is approximately 2 mm in height. Sample Preparation: Drop Down Test: 0382 Carefully remove the shaft from the spoon using a 0365. To the above dosage form 5 M1 tapped water is pair of Scissors. added. After about 30 seconds the liquid is absorbed. The 0383 Place sinker on outer bottom of the spoon unit. US 2008/0299.199 A1 Dec. 4, 2008 30

0384 Add 4 ml of tapped water (room temperature) to the EXAMPLE 26 test unit. A Composition According to the Invention Contain ing 200 mg Coated Ibuprofen Results: 0396. A composition that has a shape as outlined in FIG. 1 was prepared as follows: 0385

TABLE 1. % ww 9. Release Time and 90 dissolved material as a function of pH. Blend 1: Release time where less than 0.5% Kelcogel LT100 50 18.72 increase from last Xylitol 50 18.76 measurement % Dissolved, Blend 2: Solution pH (A<0.5% absolute) 60 min. Vanilla Flavour 92.2 2.24 O.1 NHCI 1 35 93.9 PVPK2 7.8 O.19 50 90.4 end 3: O.OSM 4.5 15 90.8 Phosphate 10 90.8 Blend 1 50.7 5.67 O.OSM 6.8 15 85.4 Blend 2 3.29 O.33 Phosphate 10 86.8 Glycerol 6.OO O.60 Coated Ibuprofen 40.O 4.OO Blend 4:

PVPK25 9.5 4.OO Conclusions: Glycerol 4.8 2.00 Ethanol 99.9% 85.7 36.O1 0386 The results demonstrate a fast dissolution rate of the paracetamol from the test product. However, at low pH the 0397 Blend 1: Kelcogel LT100 and Xylitol is mixed in a release is relatively slower compared to pH 4.5 and 6.8. Note mortar until a homogeneous blend is formed. that the gellan gum does not dissolve once gelled hence all 0398 Blend 2: The vanilla flavour is grinded in a mortar dissolution vessels contain a high amount of non-dissolving and the PVP K25 is added stepwise under mixing to form a homogeneous blend. substances. Besides the pH difference of the media the dif 0399 Blend 3: Blend 1 is volumetrically mixed stepwise ference in ionic composition should be noted as this possibly into Blend 2 with a dough scraper or mixing card. Glycerol is could affect drug release. Furthermore, it is noted that drug added stepwise under continuous slow mixing and a uniform release is approx. 91-94% at pH 1 and 4.5 and 85-87% at pH granulate is formed. Ibuprofen is added stepwise under con 6.8. As this test was done on n=2 it is not possible to conclude tinuous slow mixing. 0400 Blend 4: Ethanol and PVP K25 is mixed and stirred if this is significant and it could be related to the specific until a clear mixture is obtained. Glycerol is added and stirred coating of the paracetamol. until a clear mixture is obtained. Blend 4 is poured into a 50 0387 During dissolution it is seen that the formulation ml spray flask with nozzle. 0401 Medical spoon preparation: The concave side of a disintegrates in all 3 media as illustrated in the photographs medical spoon is sprayed twice with Blend 4 (approximately presented in FIGS. 6, 7, and 8 with fine homogeneous mate 60 mg) and placed in an oven at 45° C. for 30 minutes. rial most prominent in buffer solution pH 6.8 (FIG. 8). 0402 500+20 mg/dose is weight into a prepared medicine Slightly bigger, however still homogeneous fluffy flakes of spoon and distributed by pressing the granules against the material are seen at pH 4.8 (FIG. 7). At low pH, the formula spoon with a stopper. The final layer of granules lay in the tion still completely disintegrates into more inhomogeneous bottom of the spoon and is approximately 2 mm in height. The spoon is sprayed twice with blend 4 (approximately 60 mg) material with individual flakes varying in size from approxi and placed in an oven at 45°C. for 30 minutes, evaporating the mately 1 to 5 mm (FIG. 6). ethanol. 0388. The dissolution result appears from FIG.9 Drop Down Test: 0389. A similar result has been obtained with the follow 0403. To the above dosage form 5 M1 tapped water is ing media: added. After about 30 seconds the liquid is absorbed. The 0390 Simulated Gastric Fluid, (0.072M cation)-modified spoon is turned around and held upside down for 2 min. The SGF USP as without enzymes and with 2.1xcations in 6 test material did not fall out and pass the test. vessels: EXAMPLE 27 0391 Add 5000 ml of purified water in to a 25 L plastic Guideline Regarding Effective Ratio Between Gellan container. Gum Granulated with Xylitol with Respect to Gel 0392 Add carefully 70 ml 37 w/w % HCl into the plastic ling Time and Amount of Water Necessary for container. Obtaining an Efficient Gel (300 mg of Mixture) 0393 Weigh 42.07 gi-0.1 g NaCl and add it to the plastic 0404 Xylitol enables water penetration in the granula and container. secure a fast and efficient hydration of the gum. Binder used is glycerol 7.0% weight of total formulation. Granulating 0394 Dissolve the salt and add purified water until 10000 procedure identical with placebo formulation of Example 23. ml is reached. As appears from the Table 2Xylitol decreases the gelling time 0395. Measure the pH of the solution. and increases the range of water resulting necessary for US 2008/0299.199 A1 Dec. 4, 2008

obtaining a sufficient gelling as the 50%/50% mixture is less carboxy methyl cellulose, crosslinked sodium carboxy sensitive to the amount of water added than the mixture com methyl cellulose, enzymatically hydrolysed carboxy methyl prising 20% Xylitol. Clearly the less gellan gum present, the cellulose, gelatine, or mixtures thereof. less water shall be added to avoid inconvenient presence of 60. A vehicle according to claim 57, wherein the gellan excess water in the formulation. gum has a mean particle size within 25 mesh to 300 mesh.

TABLE 2

A. B C D E (blind) Gellan Gum 9.6 1OO 8O 50 2O O Xylitol % O 2O 50 8O 1OO Water 3, 4, 5 ml 4 and 5 ml 4 and 5 ml 3 ml 3 ml added to spoon(s) Gelling Insufficient Sufficient Sufficient Good No gelling quality and gelling for all gelling with gelling with gelling, time 3 spoons as 5 ml only. 4 ml as well however dry granule Gelling time as 5 ml (XCESS is still between 10-12 sec. water added Water present in and present the spoons completed after 30 within 10 Seconds. Seconds.

1-56. (canceled) 61. A vehicle according to claim 57, wherein the gellan 57. A vehicle for oral administration of one or more active gum is acylated within a degree of 0 to 4 per every two repeats Substances, the vehicle comprising a gellan gum, or mixture of the glucose-rhamnose-glucose-glucuronic acid unit of the of gellan gums, arranged in a configuration allowing optimal polymer. water diffusion so that upon addition of a predetermined 62. A vehicle according to claim 61, wherein the gellan amount of an aqueous medium, without the necessity of gum has a degree of acylation of one glycerate per repeat and applying shear forces or other mixing forces, within a time one acetate per every two repeats. period of 5 minutes or less Swells and/or gels; 63. A vehicle according to claim 57, which when con wherein the gellangum is acylated within a degree of up to tacted with water—forms a micro-porous hydrogel having a 4 per every two repeats of the glucose-rhamnose-glu pore size of at the most 4 A. cose-glucoronic acid unit of the polymer, and the vehicle 64. A vehicle according to claim 57, which when con further comprises a hydrophilic agent selected from the tacted with water—forms a macro-porous hydrogel having a group consisting of electrolytes, organic acids and pore size of from about 4 to about 15 A. osmotic agents, and mixtures thereof, that improves 65. A vehicle according to claim 57, wherein the hydro Swelling of the gellan gum; and philic agent is an osmotic agent selected from the group the texture of the swelled vehicle being similar to that of a consisting of hydrophilic vinyl and acryl polymers, poly sac Soft pudding and having a viscosity of at least about charides, PEO, PEG, PPG, poly(2-hydroxyethyl methacry 10,000 cps as measured by a BrookfieldViscometer with late), poly(acrylic)acid, poly(methacrylic)acid, PVP, PVA, a #4 LV spindle at 6 rpm and at 20-25°C.; the Viscom PVA/PVP copolymers, HEC, HPC, HPMC, CMC, CEC, eter spindle is centered in the test sample container, the Sodium alginate, polycarbophil, gelatine and Sodium starch spindle is properly immersed to the mid-point of the glycolate, and mixtures thereof. shafts narrow portion; test method: Into a 500 ml beaker 66. A vehicle according to claim 65, wherein the hydro 22-88 g test material is accurately weighed, 500 ml philic agent is an osmotic agent selected from the group tapped water is added, mix until all the material is dis consisting of PEO, PEG, PVP. HPMC and polyacrylic acid, persed/dissolved, and after about 5 min the viscosity and and mixtures thereof. the temperature are measured. 67. A vehicle according to claim 57, wherein the hydro 58. A vehicle according to claim 57, wherein the viscosity philic agent is an osmotic agent selected from the group is in a range from about 10,000 to about 99,000 cps. consisting of magnesium sulfate, magnesium chloride, cal 59. A vehicle according to claim 57 further comprising a cium chloride, Sodium chloride, lithium chloride, potassium Swelling and/or gelling agent selected from hydrocolloids Sulfate, Sodium carbonate, sodium sulfite, lithium sulfate, and hydrogelling agents such as alginic acid, Sodiumalginate, potassium chloride, Sodium sulfate, mannitol. Xylitol, urea, potassium alginate, ammonium alginate, calcium alginate, Sorbitol, inositol, raffinose, Sucrose, glucose, fructose, lac propane-1,2-diol alginate, agar, carrageenan, processed tose, inulin, instant Sugar, citric acid. Succinic acid, tartaric eucheuma Seaweed, locust bean gum, guar gum, tragacanth, acid, and mixtures thereof. acacia gum, Xanthan gum, karaya gum, tara gum, konjac, 68. A vehicle according to claim 67, wherein the hydro pectins, cellulose derivatives Such as: methyl cellulose, philic agent is an osmotic agent selected from the group hydroxypropyl cellulose, hydroxypropyl methyl cellulose, consisting of glucose, lactose, Sucrose, mannitol. Xylitol and ethyl methyl cellulose, carboxy methyl cellulose, sodium sodium chloride, and mixtures thereof. US 2008/0299.199 A1 Dec. 4, 2008 32

69. A vehicle according to claim 57, wherein the hydro 80. A vehicle according to claim 57 in the form of a powder philic agent is an electrolyte is a ionizable Substance that is blend. selected from the group consisting of monovalent, divalent, or 81. A vehicle according to claim 57 in the form of granules, multivalent ionizable salts. beads, oblates or pellets. 70. A vehicle according to claim 69, wherein the salt is 82. A vehicle according to claim 57, wherein at least one of selected from inorganic salts, including various alkali metal the additives selected from the group consisting of Surfac and/or alkaline earth metal sulfates, chlorides, borates, bro tants, coloring agents, Sweetening agents, taste-masking mides, etc., and ionizable alkaline earth organic salts such as agents, antioxidants, polysaccharides, Sugars, Wetting agents, citrates, acetates, lactates, etc. UV-absorbers, Suspending agents, stabilizers, solubilizers, 71. A vehicle according to claim 70, wherein the salt is preservatives, processing aids, pH controlling agents, plasti selected from calcium Sulfate, sodium chloride, potassium cizers, odor masking agents, nutrients, flavouring agents, fla Sulfate, Sodium carbonate, lithium chloride, tripotassium Vour masking agents, emulsifiers, thickening agents, dispers phosphate, sodium borate, potassium bromide, potassium ing agents, crystal grow inhibitors, crystallization promoters, fluoride, Sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, chelating agents, buffers, bases, and antimicrobials, and mix magnesium sulfate, alkali metal chlorides, sodium fluoride, tures thereof, and/or the hydrophilic agent and/or the swelling organic acids Such as citric, Succinic, fumaric, malic, maleic, and/or gelling agent is added to a granulate material. glutaric, lactic and the like; alkali metal Sulfates such as 83. A vehicle according to claim 57 in the form of a granu Sodium Sulfate; dihydrogen Sodium phosphate, monohydro late. gen sodium phosphate, disodium hydrogen phosphate, and 84. A vehicle according to claim 57 further comprising one mixtures thereof, and multivalent metal cations. or more active Substances. 72. A vehicle according to claim 71, wherein the salt is 85. A vehicle according to claim 84, wherein an active calcium Sulfate or sodium chloride. substance is present in admixture with the vehicle. 73. A vehicle according to claim 57, wherein the hydro 86. A vehicle according to claim 82, wherein an active philic agent is an organic acid selected from the group con Substance is present in the granulate. sisting of benzoic acid, Succinic acid, citric acid and adipic 87. A vehicle according to claim 84, wherein the active acid and other pharmaceutically approved organic acids. Substance is present in a coated and/or microencapsulated 74. A vehicle according to claim 57 further comprising one form or embedded in a matrix. or more additives selected from the group consisting of Sur factants, coloring agents, Sweetening agents, taste-masking 88. A vehicle according to claim 84, wherein the active agents, antioxidants, polysaccharides, Sugars, Wetting agents, substance is present in a form that allows for controlled UV-absorbers, Suspending agents, stabilizers, solubilizers, release of the active substance. preservatives, processing aids, pH controlling agents, plasti 89. A vehicle according to claim 57, wherein the vehicle cizers, odor masking agents, nutrients, flavouring agents, fla passes the drop down test: in a test spoon 0.5 g-0.7 g test Vour masking agents, emulsifiers, thickening agents, dispers material is accurately weighed; 3 ml-5 ml tapped water is ing agents, crystal grow inhibitors, crystallization promoters, added; wait /2 min, turn the spoon around, and if the test chelating agents, buffers, bases, and antimicrobials, and mix material does not drop down (fall off the spoon) within2 min, tures thereof. the material has passed the test. 75. A vehicle according to claim 57 further comprising 90. A pharmaceutical composition for oral administration glycerol. comprising one or more active Substances and a vehicle com 76. A vehicle according to claim 57 comprising a pH prising a gellan gum, or mixture of gellan gums, arranged in adjusting agent selected from the group consisting of any a configuration allowing optimal water diffusion so that upon material which is Suitable to adjust the pH of an aqueous gel addition of a predetermined amount of an aqueous medium, Such as, e.g., sodium bicarbonate, sodium phosphate, sodium without the necessity of applying shear forces or other mixing hydroxide, ammonium hydroxide, Sodium stannate, trietha forces, within a time period of 5 minutes or less, the compo nolamine, citric acid, hydrochloric acid, Sodium citrate, and sition Swells and/or gels; combinations thereof. wherein the gellangum is acylated within a degree of up to 77. A vehicle according to claim 76, wherein the pH adjust 4 per every two repeats of the glucose-rhamnose-glu ing agent is present in an amount So as to adjust the pH of the cose-glucoronic acid unit of the polymer, and the vehicle gel formed upon addition of an aqueous medium to about 4.5 further comprises a hydrophilic agent selected from the to about 11, preferably from about 5 to about 9, and more group consisting of electrolytes, organic acids and preferably from about 5 to about 8. osmotic agents, and mixtures thereof, that improves 78. A vehicle according to claim 76, wherein the pH adjust Swelling of the gellan gum; and ing agent is present in an amount of from about 0.01% to the texture of the swelled composition being similar to that about 15% w/w such as, e.g., from about 0.05% to about 5% of a soft pudding and having a viscosity of at least about wfw. 10,000 cps as measured by a BrookfieldViscometer with 79. A vehicle according to claim 57 comprising a wetting a #4 LV spindle at 6 rpm and at 20-25°C.; the Viscom agent selected from the group consisting of pharmaceutically eter spindle is centered in the test sample container, the acceptable anionic Surfactants, cationic Surfactants, amphot spindle is properly immersed to the mid-point of the eric (amphipathic/amphophilic) Surfactants, and non-ionic shafts narrow portion; test method: Into a 500 ml beaker surfactants including poloxamer, PEG, and PEO; alkane 22-88 g test material is accurately weighed, 500 ml metal sulfates, wherein the alkyl group is from 1 to 14 carbon tapped water is added, mix until all the material is dis atoms, such as Sodium methyl Sulfate, sodium lauryl Sulfate persed/dissolved, and after about 5 min the viscosity and and the like as well as dioctyl sodium sulfo Succinate. the temperature are measured. US 2008/0299.199 A1 Dec. 4, 2008

91. A pharmaceutical composition according to claim 90, chlorides, borates, bromides, etc., and ionizable alkaline wherein the viscosity is in a range from about 10,000 to about earth organic salts such as citrates, acetates, lactates, etc. 99,000 cps. 104. A pharmaceutical composition according to claim 92. A pharmaceutical composition according to claim 90, 103, wherein the salt is selected from calcium sulfate, sodium further comprising a Swelling and/or gelling agent selected chloride, potassium sulfate, sodium carbonate, lithium chlo from hydrocolloids and hydrogelling agents such as alginic ride, tripotassium phosphate, sodium borate, potassium bro acid, sodium alginate, potassium alginate, ammonium algi mide, potassium fluoride, Sodium bicarbonate, calcium chlo nate, calcium alginate, propane-1,2-diol alginate, agar, carra ride, magnesium chloride, Sodium citrate, Sodium acetate, geenan, processed eucheuma seaweed, locust bean gum, guar calcium lactate, magnesium sulfate, alkali metal chlorides, gum, tragacanth, acacia gum, Xanthan gum, karayagum, tara Sodium fluoride, organic acids such as citric, succinic, gum, konjac, pectins, cellulose derivatives Such as: methyl fumaric, malic, maleic, glutaric, lactic and the like; alkali cellulose, hydroxypropyl cellulose, hydroxypropyl methyl metal Sulfates Such as sodium sulfate; dihydrogen sodium cellulose, ethyl methyl cellulose, carboxy methyl cellulose, phosphate, monohydrogen sodium phosphate, disodium Sodium carboxy methyl cellulose, crosslinked sodium car hydrogen phosphate, and mixtures thereof, and multivalent boxy methyl cellulose, enzymatically hydrolysed carboxy metal cations. methyl cellulose, gelatine, or mixtures thereof. 105. A pharmaceutical composition according to claim 93. A pharmaceutical composition according to claim 90, 104, wherein the salt is calcium sulfate or sodium chloride. wherein the gellan gum has a mean particle size within 25 106. A pharmaceutical composition according to claim 90, mesh to 300 mesh. wherein the hydrophilic agent is an organic acid selected from 94. A pharmaceutical composition according to claim 90, the group consisting of benzoic acid, Succinic acid, citric acid wherein the gellan gum is acylated within a degree of 0 to 4 and adipic acid and other pharmaceutically approved organic per every two repeats of the glucose-rhamnose-glucose-glu acids. curonic acid unit of the polymer. 107. A pharmaceutical composition according to claim 90, 95. A pharmaceutical composition according to claim 90, further comprising one or more additives selected from the wherein the gellan gun has a degree of acylation of one group consisting of Surfactants, coloring agents, Sweetening glycerate per repeat and one acetate per every two repeats. agents, taste-masking agents, antioxidants, polysaccharides, 96. A pharmaceutical composition according to claim 90, Sugars, wetting agents, UV-absorbers, Suspending agents, which when contacted with water—forms a micro-porous stabilizers, solubilizers, preservatives, processing aids, pH hydrogel having a pore size of at the most 4 A. controlling agents, plasticizers, odor masking agents, nutri 97. A pharmaceutical composition according to claim 90, ents, flavouring agents, flavour masking agents, emulsifiers, which when contacted with water—forms a macro-porous thickening agents, dispersing agents, crystal grow inhibitors, hydrogel having a pore size of from about 4 to about 15 A. crystallization promoters, chelating agents, buffers, bases, 98. A pharmaceutical composition according to claim 90, and antimicrobials, and mixtures thereof. wherein the hydrophilic agent is an osmotic agent selected 108. A pharmaceutical composition according to claim 90, from the group consisting of hydrophilic vinyl and acryl further comprising glycerol. polymers, poly saccharides, PEO, PEG, PPG, poly(2-hy droxyethyl methacrylate), poly(acrylic)acid, poly(meth 109. A pharmaceutical composition according to claim 90, acrylic)acid, PVP, PVA, PVA/PVP copolymers, HEC, HPC, comprising a pH-adjusting agent selected from the group HPMC, CMC, CEC, sodium alginate, polycarbophil, gelatine consisting of any material which is suitable to adjust the pH of and sodium starch glycolate, and mixtures thereof. an aqueous gel Such as, e.g., sodium bicarbonate, Sodium 99. A pharmaceutical composition according to claim 90, phosphate, Sodium hydroxide, ammonium hydroxide, wherein the hydrophilic agent is an osmotic agent selected Sodium stannate, triethanolamine, citric acid, hydrochloric from the group consisting of PEO, PEG, PVP. HPMC and acid, sodium citrate, and combinations thereof. polyacrylic acid, and mixtures thereof. 110. A pharmaceutical composition according to claim 100. A pharmaceutical composition according to claim 90, 109, wherein the pH adjusting agent is present in an amount wherein the hydrophilic agent is an osmotic agent selected So as to adjust the pH of the gel formed upon addition of an from the group consisting of magnesium sulfate, magnesium aqueous medium to about 4.5 to about 11, preferably from chloride, calcium chloride, sodium chloride, lithium chlo about 5 to about 9, and more preferably from about 5 to about ride, potassium Sulfate, sodium carbonate, Sodium Sulfite, 8. lithium sulfate, potassium chloride, Sodium sulfate, mannitol, 111. A pharmaceutical composition according to claim Xylitol, urea, Sorbitol, inositol, raffinose, Sucrose, glucose, 109, wherein the pH adjusting agent is present in an amount fructose, lactose, inulin, instant Sugar, citric acid, Succinic of from about 0.01% to about 15% w/w such as, e.g., from acid, tartaric acid, and mixtures thereof. about 0.05% to about 5% w/w. 101. A pharmaceutical composition according to claim 90, 112. A pharmaceutical composition according to claim 90. wherein the hydrophilic agent is an osmotic agent selected comprising a wetting agent selected from the group consist from the group consisting of glucose, lactose, Sucrose, man ing of pharmaceutically acceptable anionic Surfactants, cat nitol, xylitol and sodium chloride, and mixtures thereof. ionic Surfactants, amphoteric (amphipathic/amphophilic) 102. A pharmaceutical composition according to claim 90, Surfactants, and non-ionic Surfactants including poloxamer, wherein the hydrophilic agent is an electrolyte is a ionizable PEG, and PEO; alkane metal sulfates, wherein the alkyl group Substance that is selected from the group consisting of is from 1 to 14 carbon atoms, such as Sodium methylsulfate, monovalent, divalent, or multivalent ionizable salts. sodium lauryl sulfate and the like as well as dioctyl sodium 103. A pharmaceutical composition according to claim SulfoSuccinate. 102, wherein the salt is selected from inorganic salts, includ 113. A pharmaceutical composition according to claim 90, ing various alkali metal and/or alkaline earth metal Sulfates, in the form of a powder blend. US 2008/0299.199 A1 Dec. 4, 2008 34

114. A pharmaceutical composition according to claim 90. osmotic agents, and mixtures thereof, that improves wherein at least one of the additives selected from the group Swelling of the gellan gum; and consisting of Surfactants, coloring agents, Sweetening agents, the texture of the swelled composition being similar to that taste-masking agents, antioxidants, polysaccharides, Sugars, of a soft pudding and having a viscosity of at least about wetting agents, UV-absorbers, Suspending agents, stabilizers, 10,000 cps as measured by a BrookfieldViscometer with solubilizers, preservatives, processing aids, pH controlling a #4 LV spindle at 6 rpm and at 20-25°C.; the Viscom agents, plasticizers, odor masking agents, nutrients, flavour eter spindle is centered in the test sample container, the ing agents, flavour masking agents, emulsifiers, thickening spindle is properly immersed to the mid-point of the agents, dispersing agents, crystal grow inhibitors, crystalliza shafts narrow portion; test method: Into a 500 ml beaker tion promoters, chelating agents, buffers, bases, and antimi 22-88 g test material is accurately weighed, 500 ml crobials, and mixtures thereof, and/or the hydrophilic agent tapped water is added, mix until all the material is dis and/or the Swelling and/or gelling agent is added to a granu persed/dissolved, and after about 5 min the viscosity and late material. the temperature are measured. 115. A pharmaceutical composition according to claim 90, 126. A dispensing unit according to claim 125 in unit wherein the active Substance is present in a coated and/or dosage form. microencapsulated form or embedded in a matrix. 127. A dispensing unit according to claim 125, wherein the 116. A pharmaceutical composition according to claim 90. pharmaceutical composition is adhered or glued to a surface wherein the active substance is present in a form that allows of the dispensing unit. for controlled release of the active substance. 128. A dispensing unit according to claim 125 having a 117. A pharmaceutical composition according to claim 90, concave Surface. wherein the active substance is in admixture with the vehicle. 129. A dispensing unit according to claim 125 in the form 118. A pharmaceutical composition according to claim 90, of a spoon. wherein the active substance and the vehicle is in the form of 130. A dispensing unit according to claim 129 in which the granules, beads, oblates or pellets. pharmaceutical composition is adhered or glued to the con 119. A pharmaceutical composition according to claim 90, cave part of the spoon. wherein the active substance and the vehicle is in the form of 131. A dispensing unit according to any of claims 127 or a granulate. 130, wherein the glue comprises one or more components in 120. A pharmaceutical composition according to claim 90, liquid form or in solution selected from the group consisting which passes the drop down test: in a test spoon 0.5g-0.7g of sugar alcohols, Sugars, polyvinylpyrrolidone (PVP), gums. test material is accurately weighed; 3 ml-5 ml tapped water is 132. A dispensing unit according to any of claims 127 or added; wait 2 min, turn the spoon around, and if the test 130, wherein the glue comprises a mixture of PVP and glyc material does not drop down (fall off the spoon) within2 min, erol. the material has passed the test. 133. A method for preparing a pharmaceutical composition 121. A pharmaceutical composition according to claim 90. according to claim 90, the method comprising blending the in the form of a solid dosage form. dry components and optionally granulating the mixture with 122. A pharmaceutical composition according to claim 121 a binder. in the form of a unit dosage form. 134. A method according to claim 133, wherein the phar 123. A pharmaceutical composition according to claim 121 maceutical composition further comprises one or more in the form of a dosage kit comprising a dispensing unit excipients and/or active ingredients which have a solubility incorporating the Solid dosage form. substantial lower than the solubility of the gellangum. 124. A pharmaceutical composition according to claim 135. A method according to claim 134 comprising 123, wherein the dispensing unit is a spoon. i) granulating a first blend comprising gellan gum but 125. A dispensing unit comprising a pharmaceutical com essentially not containing the one or more excipients position for oral administration comprising one or more and/or active ingredients which have a solubility sub active Substances and a gellan gum, or mixture of gellan stantial lower than the Solubility of the gellan gum, gums, arranged in a configuration allowing optimal water ii) adding the one or more excipients and/or active ingre diffusion so that upon addition of a predetermined amount of dients which have a solubility substantial lower than the an aqueous medium, without the necessity of applying shear solubility of the gellangum to the granulated first blend. forces or other mixing forces, within a time period of 5 136. A method according to claim 135 wherein the one or minutes or less, the composition Swells and/or gels; more excipients and/or active ingredients which have a solu wherein the gellangum is acylated within a degree of up to bility substantial lower than the solubility of the gellangum is 4 per every two repeats of the glucose-rhamnose-glu added to the granulated first blend as a blend or granulate with cose-glucoronic acid unit of the polymer, and the vehicle additional excipients. further comprises a hydrophilic agent selected from the group consisting of electrolytes, organic acids and