US008383155B2

(12) United States Patent (10) Patent No.: US 8,383,155 B2 Bar-Shalom et al. (45) Date of Patent: Feb. 26, 2013

(54) SWELLABLE DOSAGE FORM COMPRISING FOREIGN PATENT DOCUMENTS GELLAN GUMI EP O272220 6, 1993 EP 1371 360 B1 12/2003 JP 11-187827 7, 1999 (75) Inventors: Daniel Bar-Shalom, Kokkedal (DK); JP 2004-97114 4/2004 Lillian Slot, Virum (DK); Gina Fischer, WO WO92f1 1084 7, 1992 Vaerlose (DK); Pernille Hoyrup WO WO97/38679 A2 10, 1997 Hemmingsen, Bagsvaerd (DK) WO WO 98.23292 A1 6, 1998 WO WO99/62498 A1 12/1999 WO WOO1,76610 10, 2001 (73) Assignee: Egalet A/S, Vaerlose (DK) WO WOO2,46571 A2 6, 2002 WO WO O2/49571 A2 6, 2002 (*) Notice: Subject to any disclaimer, the term of this WO WO 03/043638 A1 5, 2003 patent is extended or adjusted under 35 WO WO 2004/096906 11, 2004 WO WO 2004/096906 A1 11, 2004 U.S.C. 154(b) by 0 days. WO WO 2005/007074 1, 2005 (21) Appl. No.: 13/212,679 WO WO 2005/007074 A 1, 2005 OTHER PUBLICATIONS (22) Filed: Aug. 18, 2011 JECFA, “Gellan Gum.” FNP 52 Addendum 4 (1996). (65) Prior Publication Data JECFA, “Talc.” FNP 52 Addendum 1 (1992). Alterna LLC, “ElixSure, Allergy Formula', description and label US 2012/OO39969 A1 Feb. 16, 2012 directions, online (Feb. 6, 2007). Hagerström, H., “Polymer gels as pharmaceutical dosage forms'. comprehensive Summaries of Uppsala dissertations from the faculty Related U.S. Application Data of pharmacy, vol. 293 Uppsala (2003). Lin, “Gellan Gum', U.S. Food and Drug Administration, www. (62) Division of application No. 1 1/596,123, filed as inchem.org, online (Jan. 17, 2005). application No. PCT/DK2005/000317 on May 11, Miyazaki, S., et al., “In situ-gelling gellan formulations as vehicles 2005. for oral drug delivery”. J. Control Release, vol. 60, pp. 287-295 (1999). (30) Foreign Application Priority Data Rowe, Raymond C. et al., “Handbook of Pharmaceutical Excipients'. Pharmaceutical Press, Fourth Edition, 2003, pp. 257 May 11, 2004 (DK) ...... 2004 OO755 258. “Gellan Gum Wins IFT's Food Technology Industrial Achievement (51) Int. Cl. Award.” Food Technology, Institute of Food Technologists, vol. 47. A6 IK 8/02 (2006.01) No. 9, Sep. 1, 1993, pp. 94-96. A6 IK9/48 (2006.01) Monsanto, “Kelcogel Gellan Gum.” Kelcogel, 1998. A6 IK3I/546 (2006.01) (Continued) A6 IK3I/44 (2006.01) A 6LX3L/295 (2006.01) A 6LX3L/75 (2006.01) Primary Examiner – Walter Webb A6 IK 8/00 (2006.01) (74) Attorney, Agent, or Firm — Foley & Lardner LLP A6 IK3I/67 (2006.01) A6 IK9/00 (2006.01) (57) ABSTRACT A6 IK3I/92 (2006.01) A61O I/00 (2006.01) A novel dosage form. The dosage form is presented in par A61O II/00 (2006.01) ticulate form and before oral ingestion the particulate mate A6IP 43/00 (2006.01) rial is subjected to an aqueous medium, whereby it is con A6IP 29/00 (2006.01) Verted to a semi-solid form by Swelling or gelling of one or (52) U.S. Cl...... 424/485; 426/573 more of the components, especially of a gellan gum, of the (58) Field of Classification Search ...... 424/484 particulate matter. The invention also relates to a vehicle for See application file for complete search history. oral administration of one or more active Substances, the vehicle comprising a gellan gum arranged in a configuration (56) References Cited allowing optimal water diffusion so that upon addition of a predetermined amount of an aqueous medium, without the U.S. PATENT DOCUMENTS necessity of applying shear forces or other mixing forces, 4,590,075 A 5, 1986 Wei et al. within a time period of 5 minutes or less swells and/or gels 4,824,681 A 4, 1989 Schobel et al. and the texture of the swelled vehicle being similar to that of 4,882,169 A 11, 1989 Ventouras a soft pudding and having a viscosity of at least about 10,000 4,994.260 A 2f1991 Kallstrand et al. 5,126,151 A 6, 1992 Boder et al. cps as measured by a Brookfield Viscometer with a #4 LV 6,102.254. A 8, 2000 ROSS spindle at 6 rpm and at 20-25°C. In one embodiment of the 6,395,298 B1 5/2002 Flanagan et al. invention, the particulate matter can be molded into a desired 6,488.962 B1 12/2002 Berner et al. shape or pressed onto a dispensing unit such as a spoon. 6,709,678 B2 3, 2004 Gruber 2003/0232082 A1 12, 2003 Li et al. 2004/O247675 A1 12, 2004 Gruber et al. 22 Claims, 10 Drawing Sheets US 8,383,155 B2 Page 2

OTHER PUBLICATIONS Office Action issued on Nov. 24, 2010 by the Examiner in U.S. Appl. Bar-Shalom et al., “Opportunities and obstacles in Pediatric Oral No. 1 1/596,123 (US 2008/02991.99). Controlled Release Dosage Forms.” Parvulet Poster, Online, Oct. 28. Office Action issued on Aug. 17, 2010 by the Examiner in U.S. Appl. 2004. No. 1 1/596,123 (US 2008/02991.99). Office Action issued on May 11, 2011 by the Examiner in U.S. Appl. Office Action issued on Oct. 17, 2011 by the Examiner in U.S. Appl. No. 1 1/596,123 (US 2008/02991.99). No. 1 1/596,123 (US 2008/02991.99). U.S. Patent Feb. 26, 2013 Sheet 1 of 10 US 8,383,155 B2 U.S. Patent Feb. 26, 2013 Sheet 2 of 10 US 8,383,155 B2

Dissolution of 200 mg Paracetamol parvulet

-- 61%. Coated Paracetamol -s-200 mg Paracetamol parvulet -a-200 mg Paracetamol. parvulet e -X-200 mg Paracetamol parvulet -- 200 mg Paracetamol parvulet -e-200 mg Paracetamol parvulet |- O 5 1 O 15 20 25 30 35 4O 45 5O 55 time min

Fig. 2 U.S. Patent Feb. 26, 2013 Sheet 3 of 10 US 8,383,155 B2

Figure 3 U.S. Patent Feb. 26, 2013 Sheet 4 of 10 US 8,383,155 B2

Figure 4 U.S. Patent Feb. 26, 2013 Sheet 5 of 10 US 8,383,155 B2

Figure 5 U.S. Patent Feb. 26, 2013 Sheet 6 of 10 US 8,383,155 B2

Figure 6 U.S. Patent Feb. 26, 2013 Sheet 7 of 10 US 8,383,155 B2

Figure 7 U.S. Patent Feb. 26, 2013 Sheet 8 of 10 US 8,383,155 B2

Figure 8 U.S. Patent Feb. 26, 2013 Sheet 9 of 10 US 8,383,155 B2

-- Wesse 1 w-r- Wessel 2 |-- Wessel 3 reham vesse 4 mer Wesses wam Vesses

O y- - mym wn -M -- O 1. 2O 30 4. 50 s 70 Time ?min) -

Fig. 9 U.S. Patent Feb. 26, 2013 Sheet 10 of 10 US 8,383,155 B2 CL (O) () | \Ll (1a) - N3-27 (1b) CIT O) (2) -- Ssey (2e) OL (O) (c) / N321 Fig. 10 US 8,383,155 B2 1. 2 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 The present application relates to a novel dosage form. The powder on syrup or pudding or applesauce or similar and then dosage form is presented in particulate form and before oral administered. This approach has limitations. The carrier ingestion the particulate material is subjected to an aqueous (syrup, pudding, applesauce) is not a well defined entity and medium, whereby it is converted to a semi-solid form by different carriers might interact differently with the multi Swelling or gelling of one or more of the components, espe 10 particles and/or drug and thereby compromise the treatment. cially of a gellan gum, of the particulate matter. The invention Also, children might object to the grittiness in the material. also relates to a vehicle for oral administration of one or more Syrups do not necessarily resemble types of food or bever active Substances, the vehicle comprising a gellan gum ages that children are used to consume. arranged in a configuration allowing optimal water diffusion Alternatively the powder can be formulated into efferves so that upon addition of a predetermined amount of an aque 15 cent granules or tablets. These granules or tablets are intended ous medium, without the necessity of applying shear forces or to be dissolved in an aqueous liquid requiring the provision of other mixing forces, within a time period of 5 minutes or less a glass of liquid and a waiting period Sufficient to allow the swells and/or gels and the texture of the swelled vehicle being tablet to completely dissolve and the resulting Volume might similar to that of a soft pudding and having a viscosity of at be considerable. Often, these dosage forms leave an objec least about 10,000 cps as measured by a Brookfield Viscom tionable deposit in the glass, which may represent a non eter with a #4 LV spindle at 6 rpm and at 20-25°C. ingested part of the drug. Effervescent formulations are, in In one embodiment of the invention, the particulate matter general more appropriate for adults although some commer can be molded into a desired shape or pressed onto a dispens cial vitamin preparations for children use this approach. ing unit Such as a spoon. Another category is the fast-melting tablets meant to be put 25 on the tongue and disintegrate upon contact with Saliva. The BACKGROUND OF THE INVENTION might be effervescent or non-effervescent. Yet another solu tion is to dispense the multi-particles in lozenges, chewable A recurring problem in the treatment of patients, in par tablets and chewing gum. ticular children and the elderly, is their inability or unwilling One example of these approaches was described in ness to Swallow solid oral dosage forms such as tablets or 30 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 35 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 patients If an orally administered drug has such a taste that is 40 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, Kallstrand, et al., U.S. Pat. No. 4,994.260 relates to a phar Suspension or other liquid dosage forms. Unfortunately, in maceutical mixture. The mixture is used for the controlled many cases the native taste of the drug is unpleasant and not 45 release of a Substance. According to Kallstrand et al., a liquid amenable to taste-masking by the addition of Sweeteners of dosage form is produced using either a dry powder or micro flavours. Also, many drugs have such pharmacokinetic capsules, 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 50 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, 55 lycol. each particle containing a fraction of the total dosage. The Boder et al., U.S. Pat. No. 5,126,151 relates to an encap monolithical units are often unacceptable to people having sulation mixture. Boder et al. refers to the construction of the swallowing problems described above. The multi-par gums and candies in oral dosage forms. According to Boderet ticles must be further processed into finished dosage forms al., microcapsules are produced including a core material Such as tablets and capsules with the same limitation as the 60 which can be selected from a wide variety of materials includ monolithical units or other forms specifically designed for ing Sweeteners, medicaments, drugs, flavoring agents and the children and/or adults unable to swallow oral solid dosage like. These materials can be used, either singularly or in forms. Finally, some substances are administered in Such high combination, in either a single or multiple part delivery sys doses that the resulting tablets or capsules are either very tems. That is, one or more of these materials may be present large or that many tablets or capsules must be administered 65 within one coating matrix or maybe separately coated by the simultaneously, in either case, causing discomfort. The multi matrix and employed alone or in combination in the final particles may be presented as a powder. This powder might product. The resulting formulations are said to be able to US 8,383,155 B2 3 4 provide a masking of unpleasant tasting drugs such as potas and having a viscosity of at least about 10,000 cps as mea sium chloride and the like, making consumption of the drug sured by a Brookfield Viscometer with a #4 LV spindle at 6 more appealing to the public. The dosage forms may be rpm and at 20-25°C. prepared in chewable tablet form. Dispersing, wetting/hydrating, dissolving gelling agents in Schobel et al., U.S. Pat. No. 4,824,681, and Wei et al., U.S. water to form colloidal dispersions is a notoriously difficult Pat. No. 4,590,075. Encapsulated Sweeteners have also been procedure A discussion of the general properties of colloidal used to provide an extended release of Sweetening in, for dispersions and their preparation can be foundin: Remington; example, chewing gum, see for example European patent The Science and Practice of Pharmacy, 20" Edition, A. R. application EPO 87-810747 to Schobel et al. and in bakery Gennaro et al editors, published in 2000 by Lippincott Will 10 iams and Wilkins (Chapter 21). Diverse techniques are products such as disclosed in WO91-US9434 filed Dec. 17, involved, among them stirring, shaking, heating/cooling, 1991 to Redding et al. slow and gradual addition of the gelling agent to the liquid, et Further, in WO 01/76610 Simeketal describe a pharma cetera. This explains why the in the directions of use of the so ceutical composition containing calcium or mixture of cal called “Instant Puddings” or “Instant Creams' or “Instant cium and vitamin D or mixture of calcium and magnesium 15 Sauces instructions such as “add the powder slowly to the and adjuvants, presented in the form of soluble powder, which boiling water or “stir vigorously” or “let it stand for 30 by addition of liquids and mechanical mixing, forms a gelati minutes' are often found. nous Suspension resembling a pudding. In another aspect, the invention relates to a pharmaceutical U.S. Pat. No. 6,709,678 discloses an oral pharmaceutical composition for oral administration comprising one or more composition to be dispersed in an aqueous carrier prior to active Substances and a gellan gum arranged in a configura administration comprising a multiplicity of particles consist tion allowing optimal water diffusion so that upon addition of ing of a drug core individually coated with one or more layers a predetermined amount of an aqueous medium, without the with a hydratable polymer. The preferred hydratable poly necessity of applying shear forces or other mixing forces, mers are preferably alginates, carboxymethylcellulose, within a time period of 5 minutes or less, the composition hydroxypropylmethylcellulose and polyvinylpyrrolidone. 25 swells and/or gels and the texture of the swelled composition The coating is applied by conventional coating methods with being similar to that of a soft pudding and having a viscosity a powder mixture in a spheronizer or by spraying on a solu of at least about 10,000 cps as measured by a Brookfield tion or Suspension of the coating materials to the core. The Viscometer with a #4 LV spindle at 6 rpm and at 20-25°C. aim of the hydrated formulation is to obtain a formulation in In a still further aspect, the invention relates to a dispensing a single, slippery, non disintegrating mouldable coherent vis 30 unit comprising a pharmaceutical composition for oral cous plastic mass, which does not adhere to the mucosa. administration comprising one or more active Substances and WO2004/096906 A1 discloses a thickenable composition a gellan gum arranged in a configuration allowing optimal in water-containing liquid form which upon adition of further water diffusion so that upon addition of a predetermined water increases in Viscosity. The composition comprises dif amount of an aqueous medium, without the necessity of ferent anionic polymers such as Xanthan together with algi 35 applying shear forces or other mixing forces, within a time nate, carboxymethylcellulose, carrageenan, an acrylate poly period of 5 minutes or less, the composition Swells and/or gels mer or pectin. and the texture of the swelled composition being similar to WO 2005/007074 A2 published on 27 Jan. 2005 discloses that of a soft pudding and having a viscosity of at least about a gellan gum based oral controlled release dosage form for 10,000 cps as measured by a Brookfield Viscometer with a #4 gastric retention. The formulation is Swallowed in a non 40 LV spindle at 6 rpm and at 20-25°C. hydrated form such as a tablet and it is expected that the The pharmaceutical composition and the dispensing unit formulation when reaching the aqueous environment of the according to the invention are intended to be contacted with a stomach would form a strong gel. small amount of water before administration and the water The present invention proposes an improvement over the induces the Swelling of the gellan gum, which makes the art by providing a Substantially water free dosage form, con 45 composition easy to ingest and at the same time provides an taining particulate material Such as, e.g., particulate units, that acceptable mouth-feel. is/are designed for the purpose of masking the taste of drug In the context of the present invention relatively small Substance(s) and/or to provide controlled release of a drug Volumes are contemplated for the ready-to-administer unit Substance or drug Substances. In turn the particulate material (meaning after exposure to water), typically in the range of 1 may be coated and/or mixed with components that, upon 50 to 100 mL, in particular 1 to 20 mL. Stirring/shaking or any exposure to water will Swell into a soft pudding-like, mousse type of mixing would be difficult and often result in loss of like or Souffle-like semisolid mass that has a sensory-accept material thus compromising the accuracy of dosing. There able mouth-feel) and taste as determined and judged by a fore it is desirable to have a composition, which, upon expo professional taste panel. Further, the invention provides a sure to water, will swell without shaking. It was found that if vehicle to be combined prior to administration with particu 55 steps are taken to ensure rapid diffusion of water into the bulk, late matter Such as microencapsulated drugs. then the desired result is achieved. The steps include: (1) Addition of very soluble Substances such as soluble Sugars. SUMMARY OF THE INVENTION (2) Using gelling agents presenting as fine powders (3) Granulating the ingredients with Small amounts of binding In one aspect, the invention relates to a vehicle for oral 60 Solutions and (4) Packing the granulate (if desired) loosely. administration of one or more active Substances, the vehicle Other possible techniques are forming the components, comprising agellangum arranged in a configuration allowing typically either the gelling agents and/or the Sugars into optimal water diffusion so that upon addition of a predeter threads which can be subsequently formed into non-woven mined amount of an aqueous medium, without the necessity tissues or forming the gelling agents into films where readily of applying shear forces or other mixing forces, within a time 65 soluble substance are embedded to ensure channel of diffu period of 5 minutes or less swells and/or gels and the texture sion for the water. The last mentioned techniques might, in of the swelled vehicle being similar to that of a soft pudding turn, be combined with granulated matter. US 8,383,155 B2 5 6 In accordance with the present invention, a pharmaceutical preparation in order to intake the composition is easy and unit dosage form is provided that is dispensed as a solid, but convenient for the patient and do not require specific equip which upon contact with a measured amount of water and ment. without application of a shear force such as mixing quickly As it will appear from the description herein, the ready-to Swells to provide a semi-solid mass that easily can be orally use composition is intended to adhere to the dispensing unit ingested by a patient, in particular patients with Swallowing Such as e.g. a spoon. Furthermore, it is advantageous that the difficulties. ready-to-use composition does not fall off the dispensing unit The unit dosage form includes a plurality of particles or a and accordingly, the vehicle and/or the pharmaceutical com plurality of units. In the following the drug-containing par position must have a certain viscosity as mentioned above. In 10 specific embodiments, a vehicle and/or composition of the ticle or unit is commonly denoted "drug-containing micro invention has a viscosity in a range from about 10,000 to particle'. The drug-containing micro-particle carries at least about 99,000 cps. The viscosity can be measured using a one therapeutically, prophylactically and/or diagnostically Brookfield Viscometer with a #4 LV spindle at 6 RPM and at active Substance and, optionally, components providing taste 20-25 degrees C., or equivalent. Viscosity decreases slightly masking and/or controlled release functionality. Further, the 15 with increasing temperature. dosage form contains one or more substances that are able to The inventive formulations may also have a Brookfield swell upon contact with water. Yet further the dosage form viscosity within the range of about 10,000 cps to about 99,000 may contain taste modifiers such as Sweeteners, flavors, pre cps at room temperature. Below about 20,000 cps, formula serving Substances, texture modifiers, color modifiers and tions tend to spill but formulations less viscous might be other additives such as binders. Importantly, the dosage form appropriate in some instances, such as reclining patients. according to the invention has properties that are acceptable Formulations exhibit desirable spill-resistant properties at a to the patient from a sensory aspect, i.e. wheningested, it does viscosity greater than about 20,000 cps. not have an unpleasant mouth-feel and/or a bad taste or odor. The ready-to-use compositions are non-Newtonian and These properties are tested by a professional taste panel con time independent fluids. Non-Newtonian refers to a fluid sisting of at least 6 persons that have been specifically 25 whose behavior departs from that of an ideal Newtonian fluid. selected due to their tasting ability as well as to children age These fluids have different viscosities at different shear rates 5-6 years to evaluate whether the children would have any and fall under two groups: time independent and time depen objections to a repetitive placebo dosage according to the dent. In contrast, for a Newtonian fluid the rate of shear in the present invention. fluid under isothermal conditions is proportional to the cor The drug-containing micro-particles can be prepared fol 30 responding stress at the point under consideration. (McGraw Hill Encyclopedia of Science & Technology, 6

CH2OH COOH CH2OH 1- O O O O O O O OH O OH CH

HO O H OH OH HO OH Low Acyl form

Comparison of Physical Properties of High Acyl and Low 25 hard, non-elastic brittle gels. An important feature is the irre Acyl Gellan Gum Vasible gelling properties where gellan gum may form an irrevasible film after dehydration, which will prevent gelling on rehydration. A gel sol transition occurs at about 50° C. Kelcogel LT100 Kelcogel F dependent on concentration. Thermoreversible gels form on (High Acyl) (Low acyl) 30 cooling in the presence of cations even at low (0.1% w/w) to very low (0.005% w/w) concentrations. Molecular Weight 1-2 x 106 Daltons 2-3 x 105 Daltons Solubility Hot water Hot or cold water Gellan is unique in that it forms gels with allions, including Set temperature 70-80° C. 30°-50 hydrogen. Gellan is compatible with a number of other gums Thermo reversibility Thermo-reversible Heat stable (Xanthan, locust bean), starches and gelatin to manipulate the 35 type of gel, elasticity and stability. Gellan may be combined The molecular structure of gellan gum is straight chain in mixtures producing synergistic properties which mixtures based on repeating glucose, rhamose and glucuronic acid may also include natural seaweeds, natural seed gums, natu units. In its native or high acyl form, two acyl Substituents— ral plant exudates, natural fruit extracts, bio-synthetic gums, acetate and glycerate—are present. Both substituents are a bio-synthetic processed starch or cellulosic materials. More located on the same glucose residue, and on average, there is specifically, the mixture may include alginates, agar gum, one glycerate per repeat and one acetate per every two guar gum, locust bean gum (carob), carrageenan, tara gum, repeats. In low acylgellan gum, the acyl groups are removed gum arabic, ghatti gum, Khaya grandifolia gum, tragacanth completely. The acyl groups have a profound influence on gel gum, karaya gum, pectin, arabian (araban), Xanthan, starch, characteristics. The high acyl form produces soft, elastic, as konjak mannan, galactomannan, funoran. non-brittle gels, whereas the low acyl form produces firm, Another preferred Swelling and Swelling improving agent non-elastics, and brittle gels. The acylated form is shown is konjak. Konjak contains 50%-60% glucomannan, 20-30% below. starch, 2-5% fiber, 5-10% crude protein, 3-5% soluble sugars

Gellangum forms a coaxial triangular 3-fold double helix 65 (monosaccharide and oligosaccharide) and 3-5% ash (miner (pitch 56.4 A) from two left-handed chains coiled around als). Chemical Structure of Konjac Glucomannan (KGM) is each other with the acetate residues on the periphery and shown below. The molecular weight of KGM varied from US 8,383,155 B2 11 12 1,000,000 to 2,000,000 daltons according to konjac species or which may be formed by addition or by condensation poly variety, processing method and storage time of the raw mate merization, the components of which may comprise hydro rial. philic and hydrophobic monomers. Preferred polymers for In a preferred embodiment, the gellan gum has a mean use at the water-swellable hydrophilic polymers include particle size within 25 mesh to 300 mesh in order to allow a 5 PEO, PEG, PVP HPMC and polyacrylic acid. suitable distribution of water into the vehicle. By “osmotically effective solutes' is meant any water Furthermore, in a specific embodiment, the gellan gum is acylated within a degree of 0 to 4 per every two repeats of the soluble compound that is commonly referred to in the phar glucose-rhamnose-glucose-glucuronic acid unit of the poly maceutical arts as an “osmogen' or an "oSmagent'. Typically mer. The vehicle or composition may contain a mixture of 10 classes of Suitable osmogens are water-soluble organic acids, gellan gums having different degrees of acylation and/or dif salts and Sugars that are capable of imbibing water to thereby ferent mean particle sizes. affect an osmotic pressure gradient across the barrier of the In a specific embodiment, the gellan gum has a degree of Surrounding matrix. Typical useful osmogens include mag acylation of one glycerate per repeat and one acetate per every nesium sulfate, magnesium chloride, calcium chloride, two repeats. 15 As mentioned above, the presence of gellan gum in a Sodium chloride, lithium chloride, potassium Sulfate, sodium vehicle or a composition according to the invention may lead carbonate, Sodium sulfite, lithium Sulfate, potassium chlo to a porous hydrogel when contacted with water Such as, e.g., ride, Sodium sulfate, mannitol, Xylitol, urea, Sorbitol, inositol, a micro-porous hydrogel havingapore size of at the most 4A raffinose, Sucrose, glucose, fructose, lactose, inulin, instant or a macro-porous hydrogel having a pore size of from about 20 Sugar, citric acid, Succinic acid, tartaric acid, and mixtures 4 to about 15 A. thereof. Particularly preferred osmogens are glucose, lactose, Konjak: Sucrose, mannitol, Xylitol and sodium chloride.

CH2OH CH2OH CH2OH O O OH O O OH O

OH

Mannose Mannose Glucose Glucose

Some of the factors there can effect the swelling include Electrolytes pH, ionic strengths, and temperature. The behaviours of the The electrolyte’s greater hydrophilicity than the other for different hydrogels as drug carrier, is well known. The behav 40 mulation components allows it to hydrate preferentially in iour of e.g. Gellangum is quite different from that of PVP and comparison to the Surrounding polymers and the drug mol ecules. This peripheral matrix-hardening creates a control PEO, respectively. In fact, although the gel Gellan Gum with lable micro-environment within the hydrated layer, and make cations shows a very well ordered and regular structure both the formulation robust again variable ion strengths from in the Solid state and in Solution, when it is tested as a matrix added water to the matrix. it Swells up and it is rapidly dispersed, leading to a quite fast 45 The use of e.g. alkalizing agents to preserve internal dosage release of the API (active substance). form pH though the acid regions of the upper gastrointestinal As mentioned above, a vehicle or a composition according tract is well established. to the invention may further comprise an agent that improves One advantage of maintaining a constant internal pH is that Swelling of the gellan gum. Such an agent may be a hydro a very soluble drug in 0.1M HCl may be made less soluble if philic agent selected from the group consisting of electro 50 the environmental pH is above the pKa-value of the drugs. Through the application of colloidal chemistry principles, it is lytes, organic acids and osmotic agents, and mixtures thereof. possible to provide pH-control via a formulation component Osmotic Agents that is also active as a release controlling excipient within a By the term "osmotic agent' is meant any agent which hydrophilic matrix. creates a driving force for transport of water or media (aq) 55 A vehicle or composition according to the invention may from the environment of use into the matrix. Exemplary also comprise a pH-adjusting agent selected from the group osmotic agents are water swell able or water soluble. The consisting of any material which is suitable to adjust the pH of vehicle or composition according to the invention may an aqueous gel Such as, e.g., sodium bicarbonate, Sodium include water-swell able hydrophilic polymers, both ionic phosphate, Sodium hydroxide, ammonium hydroxide, Sodium stannate, triethanolamine, citric acid, hydrochloric and non-ionic, often refers to as “osmopolymers' and hydro 60 acid, Sodium citrate, and combinations thereof. Generally, if gels. Exemplary materials include hydrophilic vinyl and acryl present, the pH adjusting agent is present in an amount So as polymers, poly saccharides, PEO, PEG, PPG, poly(2-hy to adjust the pH of the gel formed upon addition of an aqueous droxyethyl methacrylate), poly(acrylic)acid, poly(meth medium to about 4.5 to about 11, preferably from about 5 to acrylic)acid, PVP, PVA, PVA/PVP copolymers, HEC, HPC, about 9, and more preferably from about 5 to about 8. A HPMC, CMC, CEC, sodium alginate, polycarbophil, gelatine 65 Suitable amount is normally in an amount of from about and Sodium starch glycolate. Other materials include hydro 0.01% to about 15% w/w such as, e.g., from about 0.05% to gels comprising interpenetrating networks of polymers, about 5% w/w. US 8,383,155 B2 13 14 Upon ingestion, gastric fluid enter into the dosage form, hydrophobic groups. Hydrophobic groups collapse in the causing the composition to hydrate and activates the pH and presence of water, thus minimizing their exposed to the water release-controlling characteristics of the excipients. molecule. A suitable electrolyte for use according to the invention is pH-Sensitive Hydro Gels a ionizable Substance that is selected from the group consist The hydrogels which exhibiting pH dependent swelling ing of monovalent, divalent, or multivalent ionizable salts. behaviour will in aqueous media of appropriate pH and ionic More specifically, the Salt is selected from inorganic salts, strengths be ionized. As a result in of the electrostatic repul including various alkali metal and/or alkaline earth metal sions, the uptake of water in the network is increased. Ionic Sulfates, chlorides, borates, bromides, etc., and ionizable hydrogels are Swollen polymer networks containing pendant alkaline earth organic salts such as citrates, acetates, lactates, 10 groups, such as carboxylic acid, which show Sudden or etc. gradual changes in their dynamic and equilibrium behaviour In specific embodiments, the salt is selected from calcium as a result of changing the external pH. In these gels, ioniza Sulfate, sodium chloride, potassium sulfate, sodium carbon tion occurs when the ph of the environment is above the pKa ate, lithium chloride, tripotassium phosphate, Sodium borate, of the ionisable group. As degree of ionization increases the potassium bromide, potassium fluoride, Sodium bicarbonate, 15 number offixed charges increases resulting in increased elec calcium chloride, magnesium chloride, Sodium citrate, trostatic repulsions between the chains. This in turn, results in Sodium acetate, calcium lactate, magnesium sulfate, alkali an increased hydrophilicity of the network, and greater Swell metal chlorides, sodium fluoride, organic acids such S citric, ing ratio. The Swelling of polyelectrolyte gels is significantly Succinic, fumaric, malic, maleic, glutaric, lactic and the like; affected by the ionic strengths of the Swelling agent. As the alkali metal Sulfates such as sodium sulfate; dihydrogen ionic strengths of the Swelling agent increases, the concen Sodium phosphate, monohydrogen Sodium phosphate, diso tration of ions within the gel must increase in order to satisfy dium hydrogen phosphate, and mixtures thereof, and multi the Donnan equilibrium. valent metal cations. Notably, the salt is calcium sulfate or A vehicle or composition according to the invention may sodium chloride. also comprise one or more pharmaceutically acceptable Organic Acids 25 excipients or additive. The present formulations may also contain organic acids to Excipients delay dissolution rate in the acid media and/or to increase the A wetting agent may be used such as one or more selected dissolution rate in buffer at pH 6.8 or to ensure drug stability from the group consisting of pharmaceutically acceptable with time and provide a substantially pH independent disso anionic Surfactants, cationic Surfactants, amphoteric (amphi lution profile. 30 pathic/amphophilic) surfactants, and non-ionic Surfactants The organic acids are chosen to cover a solubility and including poloxamer, PEG, and PEO; alkane metal sulfates, pKa-values range, in order to cover a range of pH and to help wherein the alkyl group is from 1 to 14 carbon atoms, such as controlling the release mechanism. The aim is to obtain the sodium methylsulfate, sodium lauryl sulfate and the like as same release time in both buffer 6.8 and in 0.1 M HCl. well as dioctyl sodium sulfoSuccinate. Pharmaceutically acceptable organic acids are e.g. Benzoic 35 In a specific embodiment of the invention, a vehicle or acid, Succinic acid, Citric acid and Adipic acid but can composition further comprises glycerol, cf. the examples include other pharmaceutically approved organic acids. herein. Ionic Strengths Suitable excipients and/or additives may be selected from An increase in electrostatic repulsion, by adding e.g. the group consisting of Surfactants, coloring agents, Sweeten monovalent or/and divalent metal ions (natively present or 40 ing agents, taste-masking agents, antioxidants, polysaccha introduced in the formulation) also promotes a Swelling until rides, Sugars, wetting agents, UV-absorbers, Suspending a saturation point. The driving force necessary to expand the agents, stabilizers, solubilizers, preservatives, processing material during Swelling is the electrostatic repulsion aids, pH controlling agents, plasticizers, odor masking between different ionic groups with the same charges. The agents, nutrients, flavoring agents, flavor masking agents, nature of the counter ions is thus of extremely importance for 45 emulsifiers, thickening agents, dispersing agents, crystal the degree of Swelling of Such charged gel-like systems. grow inhibitors, crystallization promoters, chelating agents, Changing the ionic content in the formulation will affect the buffers, bases, and antimicrobials, and mixtures thereof. water uptake. The nature of the ions (ion pair) has a profound In order to ensure an effective interaction of the water with effect on the characteristics of the water adsorption due to the the gellig agent or agents, the addition of a cation and/or different ability of the ion pair to dissociate. 50 sequestering agent to the mixture might be desirable and is The ion pairs will compete with the hydrogel about the generally depending on the Swelling agent or mixtures hereof. water molecules, and can thereby increase the hydration and Examples of Suitable cations and sequestering agents which decrease the solubility of the hydrogel, respectively, which may be added to cause this gelling agent to gel are well known can stabilise the gel formation. to persons skilled in the art and include Na+, Ca", K" and H", Physical and Chemical Properties of Hydrogels 55 Sodium hexametaphosphate, sodium tripolyphosphate, The cross linking ratio is one of the most important factors EDTA, citric acid, sodium citrate and other citric acid salts, that effects the swelling of hydrogels. It is defined as the ratio phosphoric acid, dicalcium phosphate and tetrasodium pyro of moles of cross linking agent to the moles of polymer phosphate. repeating units. The higher the cross linking ratio, the more An excipient for use in a dosage form according to the cross linking agent is incorporated in the hydrogel structure. 60 present invention may also include one or more other com Highly cross linked hydrogels have a tighter structure, and ponents generally known for use in food products, such as will swell less compared to the same hydrogel with lower flavourings, colorings, Sugar and/or other Sweeteners, preser cross linking ratios. Cross linking hinders the mobility of the Vatives, buffering agents, texturing agents, fats, colloids, Sus polymer chains, hence lowering the Swelling ratio. The pended solids, etc., to give the a desired texture and/or appear chemical structure of the polymer may also affect the swell 65 ance. The amounts of Such components are not critical to the ing ratio of the hydrogels. Hydrogel contains hydrophilic invention and may be adjusted according to taste and accord groups Swell to a higher degree compare to those containing ing to the flavor/texture characteristics desired of the mixture US 8,383,155 B2 15 16 of the invention. The pH of the mixture might be adjusted to the composition Swells and/or gels and the texture of the the requirements of the active Substance(s). Swelled composition being similar to that of a soft pudding Excipients Used to Change the Hydration and Diffusion of and having a viscosity of at least about 10,000 cps as mea Water Into the Matrix System sured by a Brookfield Viscometer with a #4 LV spindle at 6 While the slow swelling property is the one that also made rpm and at 20-25°C. hydrogels useful in controlled drug delivery, many applica All the details and particulars mentioned hereinbefore tions required fast Swelling (i.e. Swelling in a matter of min relating to other aspects of the invention apply mutatis mutan utes or seconds rather than hours) of dried hydrogels. dis to this aspect. Being a water soluble polysaccharide e.g. Gellan gum can The pharmaceutical composition or the dosage form of the be difficult to disperse in water due to the formation of a film 10 layer around each Gellan gum particle. This leads to the invention includes a plurality of drug-containing micro-par formation of large agglomerates (lumps), which, due to the ticles. Each micro-particle carries at least one active Sub protective film layer, are very difficult for the water molecules stance and, optionally, components providing taste masking to penetrate. and/or controlled release functionality. The micro-particles The less soluble the Gellangum is the easier the dispersion, 15 can be produced using know micro-encapsulation or by inte other factors which decrease the solubility of Gelangum will gration into a matrix or by crystallization. The particles may improve the dispersibility. be further fragmented to reduce the particle size. The pre Different formulation initiative, by e.g. incorporation of ferred embodiments are those where the particles are small so hydrophilic excipients, can change the hydration, and Swell as to be imperceptible or nearly imperceptible to the patient, ing rate: visually and/or tactilely, in particular on the tongue. The Fast Swelling is usually done by making very Small par preferred embodiments are those where the particle size is ticles of dried hydrogels. The extremely short diffusion path less than 500 micrometers and best less than 200 microme length of micro particles makes it possible to complete Swell ters. However, if the retention in the mouth of even a few ing in a matter of seconds or minutes. particles after a few minutes is not desired (because, for By creating pores that are interconnected to each other 25 example, the taste being masked leaks), the particles should throughout the hydrogel matrix. The interconnected pores not be smaller than 100 micrometers so they are not retained allow for fast absorption of water by capillary force. A simple in crevices in the pouth or between papillae on the tongue, method of making porous hydrogel includes, produce gas unless the cohesivness of the semisolid vehicle ensures that bubbles by adding sodium bicarbonate to generate carbon all particles are swallowed with the vehicle. dioxide bubbles, and generation of gas bubbles makes the 30 In another aspect of this invention, the active substances do foam rise. not require controlled release or taste masking but, because of Another approach is to separate the hydrogel particles stability problems, in particular hydrolysis they can not be from each other before contact with water. If the hydrogel formulated in water containing dosage forms; also the particles are right next to each other then they all try to swell approach may be useful if very large doses are to be admin at the same time, and weld themselves together into one large, 35 istered. Accordingly, in one aspect of the invention a dosage slow to hydrate lump. If the pectin particles are all slightly form is provided having a water content of at the most about separated from each other when they contact the water, then 5% w/w such as, e.g., at the most about 4% w/w, at the most they all have enough room to go through their initial expan about 3% w/w, at the most about 2% w/w, at the most about sion. To achieve a fast hydration, and thereby swelling for the 1% w/w or at the most about 0.5% w/w. matrix system it is preferable to added hydrophilic or/and ion 40 The dosage form may be dispensed as a granulate in bulk or pair formation excipients. further processed into discrete units. The discrete units may Hydrophilic Excipients: be capsules or cachets or Sachets filled with a measured Known excipients can be blended with the molecular or amount of granulate meant to be opened and the contents dispersed dosage form to provide a controllable water diffu poured onto a measured amount of water. However, the cap sion/drug release mechanism. 45 Sules or cachets or Sachets may be made from fast dissolving Vehicle Form materials such as water Soluble polymer films, woven or A vehicle according to the invention may have any Suitable non-woven fabrics made of water soluble materials such as form such as, e.g., in the form of a powder blend, in the form candy floss. Further, the capsules or cachets or Sachets might of granules, beads, oblates or pellets, or in the form of a be made of gelling polymers such as those described for the granulate. Any additive or excipient, if present, may be incor 50 mixture. porated e.g. in the granules etc, or it may be loosely added e.g. The discrete units may also be tablets meant to be put into after formation of a granulate. As mentioned hereinbefore, a measured amount of water. In producing the tables, atten the vehicle may be admixed with one or more active sub tion must be paid to the fact that, the more the material is stances, i.e. the active Substance may be incorporated in the compacted, the more difficult the penetration of water into the granules etc., or it may be added after formation e.g. of a 55 unit will be. Therefore, the production method for the tablets granulate. The active Substance may also be present in a must be adapted. Production methods might include low coated and/or microencapsulated form or embedded in a pressure compression, extruding, molding and calendaring. matrix, or in a form that allows for controlled release of the In a specific embodiment of interest, the discrete units may active Substance. be in the form of a disposable spoon where the granulated is Compositions 60 fastened, typically by using a hydrocolloid solution as a As mentioned above, the present invention also relates to a binder and drying. Such a unit is illustrated in FIG.1. To this pharmaceutical composition for oral administration compris end, it is extremely important that the dosage form of the ing one or more active Substances and a gellan gum arranged drug-containining micro-particles is designed so that a Suit in a configuration allowing optimal water diffusion so that able texture of the dosage form is obtained after addition of a upon addition of a predetermined amount of an aqueous 65 predetermined amount of an aqueous medium Such as water medium, without the necessity of applying shear forces or without the necessity of employing any shear force Such as other mixing forces, within a time period of 5 minutes or less, e.g. mechanical mixing or stirring. US 8,383,155 B2 17 18 The dosage form might also be formed into a tape or Release mechanisms for API incorporated in a primary laminate, with or without the help of water soluble polymer based hydrogels: films, woven or non-woven fabrics made of water soluble In development of an a delivery system, three significant materials such as candy floss. This laminate can then be cut phenomena (simplified) must be taken into account simulta into discrete portions or dispensed as such, so the user can cut neously, it to the required dose/size. Diffusion of water, drug, excipients and disentangled poly In some cases, where the purity of the water is an important merchains, factor. Such as when presence or absence of given ions might Polymer hydration and swelling, interfere with the gelling process, it might be desirable to Drug, excipient and polymer dissolution. 10 Furthermore, in a formulation containing an API, dispense the water alongside the granulate. In the case of a polymer(s), and excipients, three different kinds of interac Satchet it might be dispensed as a two compartment plastic tion may affect the release of the API: (i) the API may interact bag, one compartment containing the granulate, the other the with the polymer, (ii) the drug may interact with the excipi water. In the case of the spoon, a reservoir might be built-into ents, and (iii) the excipients may interact with the polymer(s) the handle of the spoon. 15 matrix. The rate of API release can be successfully controlled Conventional coating procedures and equipment may then by controlling these interactions. be used to coat or embed the drug-containing micro-particles, The dissolution rate is often influenced by a) composition i.e., the drug-containing beads or particles. For example, a and level of drugs and other additives within the matrix, and delayed release coating composition may be applied using a b) composition and ionic strengths of electrolytes in the dis coating pan, an airless spray technique, fluidized bed coating Solution medium. equipment, or the like. For detailed information concerning It is possible to control or/and change the release rate of the materials, equipment and processes for preparing beads, drug drug from the polymer by varying e.g. the physical-chemical particles, and delayed release dosage forms, reference may be properties of the active drug, excipients or/and the polymer made to Pharmaceutical Dosage Forms: Tablets, eds. Lieber system. Extremely simplified, by adding more soluble excipi man et al. (New York: Marcel Dekker, Inc., 1989), and to 25 ents compared to the API solubility, will to some extent Ansel et al., Pharmaceutical Dosage Forms and Drug Deliv increase the release rate of the matrix system, and opposite for ery Systems, 6' Ed. (Media, PA: Williams & Wilkins, 1995). more hydrophobic excipients the release rate will be slowed Drug Delivery (Release) From the Composition down. When e.g. adding very soluble excipients, the network Swelling-Controlled System: becomes more and more porous upon drug depletion. Con 30 sequently, the free Volume increases, and thus polymer dis Formulations consisting of hydrophilic matrixes, and from entanglement increases giving rise to higher diffusion con which the drug release is controlled by the inward flux of stants and thus faster dissolution. Solvent molecules and consequent Swelling of the polymer The physical-chemical properties of the matrix (composi matrix, are often referred to as a Swelling-controlled systems. tion) components will alter the intermolecular forces, free In these systems, the drug are initially dissolved or dispersed 35 Volume, glass transition temperature, and consequently, can in the glassy polymers. Upon contact with fluids (pre-hydra alter the transport mechanisms. tion with water or/and biological fluids), the polymer matrix In general, Solubility of drug molecule itself crucially gov begins to swell and two distinct phases can be observed in the erns the rate and extent of diffusion release in both the matrix polymer: the inner glassy phase and the Swollen rubbery system, and the delivery sites. For diffusion to occur, the first phase. The drug molecule are able to diffuse out of the out of 40 step is wetting of the drug by water, followed by its dissolu the rubbery phase of the polymer. Clearly, the drug release is tion to enable the drug molecule to be available in molecular. controlled by the velocity and position of the glass-rubbery Hence, the net release rate observed is a cumulative effect of interface. A very important phenomenon of macromolecular drug solubility (influence by its structure, molecular weight, relaxation takes place at the glass-rubbery interface, and sig pKa), polymer property (hydrophilicity/lipophilicity, nificant affects the drug release. 45 molecular weight, tortuosity), excipients (structure, molecu This is due to the fact that the matrix is exposed to continu lar weight, solubility, pKa) and the relative ratio of drug/ ous changes in its structure and thickness. The gel layer is a polymer, and excipient/polymer in the unit. hydrophilic barrier that can controls water penetration and Initial Load/Dissolution Profiles drug diffusion. It begins when the polymer becomes hydrated Various factors contribute to the overall control of drug and Swells. Here, the polymer chains are strongly entangled 50 release, such as the solubility of the drug within the bulk fluid, in a network, and the gel layer is highly resistant. However, drug load, the size of the drug molecule, and its mobility moving away from this Swelling position, the gel layer within the swollen polymeric network. becomes progressively more hydrated and, when Sufficient In the case of poorly water-soluble drugs (solubility <1 g water has accumulated, the chains disentangle and the poly drug/100 mL solution) or high initial loadings of moderately mer dissolves. 55 water soluble drugs (1 g drug/10 mL Solution), dissolved and In matrix systems, which are also diffusion-controlled, the non-dissolved drug coexist within the corn position. If the drug can be either dissolved or dispersed in throughout the total amount of drug exceeds the amount, which is soluble network of the hydrogel. under the actual conditions, it exceeds the amount Soluble There are different approaches to controlling the release under the actual conditions, the excess is considered to be rate from the matrix system. Some of the major formulation 60 non-dissolved and thus not available for diffusion. parameters, which can be varied to adjust the resulting release With decreasing drug solubility the concentration differ patterns to designing a new oral controlled release system can ence during drug release (matrix position vs. bulk fluid) include: decreases, and thus the driving force for drug diffusion out of The initial drug loading the matrix decreases. Under theses conditions a decrease of The API solubility 65 the porosity of the matrix upon drug depletion (due to an Type of matrix forming polymers increase initial drug loading) has probably a more pro Type and load of hydrophilic/hydrophobic excipients nounced effect on the resulting absolute drug release rate than US 8,383,155 B2 19 20 in the case of e.g. freely soluble drugs, and thus higher diffu The composition of the invention may be dispensed in any sion driving forces. Consequently, the critical initial drug suitable device. Preferably the device is made of a suitable loading increases with decreasing drug solubility. material Such as a plastic based material or glass or metal, The effect of the initial drug loading of the tablet on the preferable a disposable material. In order to adhere to the resulting release kinetic is more complex in the case of poorly 5 device it is preferred that the device has a concave surface. soluble drugs compared to freely water soluble drugs. Spoons or devices having similar shape and function are With decreasing drug solubility the concentration differ Suitable in the present context. ence during drug release (matrix position vs. bulk fluid) Active Substances decreases, and thus the driving force for drug diffusion out of In a specific embodiment the vehicle according to the the matrix decreases. Under these conditions, decrease of the 10 invention comprises one or more active Substances. The porosity of the matrix upon depletion (due to an increased active Substance may be present in admixture with the initial drug loading) has probably a more pronounced effect vehicle, it may be present in the granulate comprising the on the resulting drug release rate than in the case of higher Swelling and/or gelling agent, it may be present in microen drug solubility. Consequently, the critical initial drug loading capsulated form or embedded in a matrix, and/or it may be (above which the relative release rate increases) increases 15 present in a form that allows for controlled release of the with decreasing drug solubility. These phenomena are not active Substance. straightforward and have to be taken into account when “Drug substances” or “active substances' in accordance designing the new formulation. with the present invention include systematically distribut With respect to the blending of the vehicle according to the able therapeutically, prophylactically and/or diagnostically present invention it should be noticed whether any of the active Substances, vitamins, minerals, dietary Supplements, desires excipients or active drugs have a solubility consider as well as non-systemically distributable active Substances. able below that of gellangum as the Substance may decrease Therapeutically, prophylactically and/or diagnostically the hydration of the gellan gum. In Such cases the Substance active Substances may include, without limitation, antacids, should be added to a premixture of other ingredients, which analgesics, anti-inflammatories, antibiotics, laxatives, anor pre mixture or blend preferable is granulated before adding 25 exics, antihistamines, antiasthmatics, antidiuretics, antiflatu the substance with lower solubility. In cases where one of the ents, antimigraine agents, antispaspodics, sedatives, antihy ingredients is capable of Solubilizing the gellan gum, the peractives, antihypertensives, tranquilizers, decongestants, same procedure is to be used in order to prevent any solubi beta blockers and combinations thereof. Also encompassed lizing of the gellan gum which will otherwise result in by the terms “drug substances” and “active substances are decreased gelling capacity. 30 the drugs and pharmaceutical active ingredients described in Particle and Granular Sizes: Mantelle U.S. Pat. No. 5,234,957 includes 18 through 21. Although it is not required, it is preferred that the API, This text is hereby incorporated by reference. gellan gum, hydro gel(s), and excipients is in particulate With respect to the individual dosages of the active to be form. The particles should, as a general rule, be of a size. Such incorporated in the novel dosage form this will follow the that, the matrix can hydrate Sufficiently, and equally through 35 general recommendations known to the skilled person and are out the matrix. To prevent segregation, and consequently generally calculated based on the body weight or body Sur inhomogen products it would be preferable to formulate with face, especially for children, and the daily dosage may natu uniform particle sizes, with exception of PVP wherein it can rally be divided in several dosages according to conventional also be an advantage to have Smaller particles. A Suitable treatment regimens for the active Substance in question. granular size should be between 350-500 um. Furthermore it 40 Depending of the actual amount, a dosage may be present in is an advantage to seal the material after fastened the discrete a single spoon or similar dosing device or in several spoons to units on a delivering device. The fastening is easily done by be ingested. Alternatively, the actual dosage can be measured spraying the device with a glue to adhere the discrete unit to based the content per Volume of a pre-prepared product simi the device. Such glue may be produced by mixing a volatile lar with dosing from bottles of mixtures generally employed liquid with a binder until a clear solution is achieved, and the 45 with liquid formulations. formulation is transferred to e.g. by use of an aerosol can to The active Substance administered may be any compound the device. Such as a spoon the Volatile liquid is evaporated that is suitable for oral drug administration; examples of the from the spoon in an oven, and thus the device Surface is various classes of active Substances that can be administered Sticky. using the present dosage forms include, but are not limited to: The layer thickness of the applied mixtures varies greatly 50 analgesic agents; anesthetic agents; antiarthritic agents; res and depends on the processing method or the quantity of piratory drugs; anticancer agents; anticholinergics; anticon additional Substances. The thickness ranges from 1-100.um, Vulsants; antidepressants; antidiabetic agents; antidiarrheals; preferably from 10-50 um. This corresponds to a binder appli antihelminthics; antihistamines; antihyperlipidemic agents; cation of 0.1-5 wt.%. antihypertensive agents; anti-infective agents such as antibi The desired dose of the formulation to be applied to the 55 otics and antiviral agents; antiinflarrimatory agents; antimi device is weight out separately and distributed by pressing the graine preparations; antinauseants; antineoplastic agents; granules against the spoon with a stopper to a thin layer. The antiparkinsonism drugs; antipruritics; antipsychotics; anti layer thickness will dependent on the formulation, but pref pyretics; antispasmodics; antitubercular agents; antiulcer erable approximately 2 mm in height in the bottom, and sides agents and other gastrointestinally active agents; antiviral of the spoon. The glue attaches the material to the device. 60 agents; anxiolytics; appetite Suppressants; attention deficit When the composition is applied to the device, the glue may disorder (ADD) and attention deficit hyperactivity disorder be in liquid form or in Solution selected from the group (ADHD) drugs; cardiovascular preparations including cal consisting of Sugar alcohols, Sugars, polyvinylpyrrolidone cium channel blockers, CNS agents, and vasodilators; beta (PVP), gums. Other binders may be employed. Normally, the blockers and antiarrhythmic agents; central nervous system binder is dissolved in a volatile solvent. As it appears from the 65 stimulants; cough and cold preparations, including deconges examples herein, an especially suitable glue or adhesive agent tants; diuretics; genetic materials; herbal remedies; hor comprises a mixture of PVP and glycerol. monolytics; hypnotics; hypoglycemic agents; immunosup US 8,383,155 B2 21 22 pressive agents; leukotriene inhibitors; mitotic inhibitors; trifluridine, Valacyclovir, Vidarabine, didanosine, stavudine, muscle relaxants; narcotic antagonists; nutritional agents, Zalcitabine, Zidovudine, amantadine, interferon alpha, ribavi Such as vitamins, essential amino acids and fatty acids; para rin and rimantadine; and miscellaneous antimicrobial agents sympatholytics; peptide drugs; psychoStimulants; sedatives; Such as chloramphenicol, spectinomycin, polymyxin B steroids; sympathomimetics; and tranquilizers. (colistin), bacitracin, nitrofurantoin, methenamine mandelate Several known drugs are substantially insoluble or only and methenamine hippurate. slightly soluble in water and accordingly difficult to formu Anti-diabetic agents. These include, by way of example, late in Solutions and Suspensions for administration to chil acetohexamide, chlorpropamide, ciglitaZone, gliclazide, dren, elderly or other subjects having difficulties in Swallow glipizide, glucagon, glyburide, miglitol, pioglitaZone, tolaza ing and Such drugs are therefore of particular interest 10 mide, tolbutamide, triampterine, and troglitaZone. according to the present invention and include, by way of Analgesics. Non-opioid analgesic agents include apaZone, example, the following: etodolac, difenpiramide, indomethacin, meclofenamate, Gastrointestinally active substances. Gastrointestinally mefenamic acid, oxaprozin, phenylbutaZone, piroXicam, and active Substances are particularly preferred drugs that can be tolmetin, opioid analgesics include alfentanil, buprenor administered using the present dosage forms. These types of 15 phine, butorphanol, codeine, drocode, fentanyl, hydroc drugs include agents for inhibiting gastric acid secretion, Such odone, hydromorphone, levorphanol, meperidine, metha as the H. Sub.2 receptor antagonists cimetidine, ranitidine, done, morphine, nalbuphine, oxycodone, oxymorphone, famotidine, and nizatidine, the H. Sup.+, K. Sup.+-ATPase pentazocine, propoxyphene, Sufentanil, and tramadol. inhibitors (also referred to as “proton pump inhibitors') ome Anti-inflammatory agents. Anti-inflammatory agents prazole and lanSoprazole, and antacids such as calcium car include the nonsteroidal anti-inflammatory agents, e.g., the bonate, aluminum hydroxide, and magnesium hydroxide. propionic acid derivatives as ketoprofen, flurbiprofen, ibu Also included within this general group are agents for treating profen, naproxen, fenoprofen, benoxaprofen, indoprofen, infection with Helicobacter pylori (H. pylori), such as met pirprofen, carprofen, oxaprozin, pranoprofen, Suprofen, ronidazole, tinidazole, amoxicillin, clarithromycin, tetracy alminoprofen, butibufen, and fenbufen, apaZone; diclofenac; cline, thiamphenicol, and bismuth compounds (e.g., bismuth 25 difenpiramide; diflunisal; etodolac; indomethacin; ketorolac, subcitrate and bismuth subsalicylate). Other gastrointesti meclofenamate: nabumetone; phenylbutaZone, piroxicam, nally active Substances administrable using the present dos Sulindac; and tolmetin. Steroidal anti-inflammatory agents age forms include, but are not limited to, pentagastrin, car include hydrocortisone, hydrocortisone-21-Monoesters benoXolone, Sulfated polysaccharides such as Sucralfate, hydrocortisone-21-acetate, hydrocortisone-21-butyrate, prostaglandins such as misoprostol, and muscarinic antago 30 hydrocortisone-21-propionate, hydrocortisone-21-valerate, nists such as pirenzepine and telenzepine. Additionally etc.), hydrocortisone-17,21-diesters (e.g., hdrocortisone-17, included are antidiarrheal agents, antiemetic agents and pro 21-diacetate, hydrocortisone-17-acetate-21-butyrate, hydro kinetic agents such as ondansetron, granisetron, metoclopra cortisone-17,21-dibutyrate, etc.), alclometaSone, dexametha mide, chlorpromazine, perphenazine, prochlorperazine, Sone, flumethasone, prednisolone, and methylprednisolone. promethazine, thiethylperazine, triflupromazine, domperi 35 Anti-convulsantagents. Suitable anti-convulsant (anti-Sei done, trimethobenzamide, cisapride, motilin, loperamide, Zure) drugs include, by way of example, aZetazolamide, car diphenoxylate, and octreotide. bamazepine, clonazepam, cloraZepate, ethoSuximide, etho Anti-microbial agents. These include: quinolone antibiot toin, felbamate, lamotrigine, mephenytoin, mephobarbital, ics Such as nalidixic acid, and particularly fluorinated qui phenytoin, phenobarbital, primidone, trimethadione, nolone antibiotics such as ciprofloxacin, clinafloxacin, 40 vigabatrin, topiramate, and the benzodiazepines. BenZodiaz enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lom epines, as is well known, are useful for a number of indica efloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, tions, including anxiety, insomnia, and nausea. sparfloxacin, and trovafloxacin, tetracycline antibiotics and CNS and respiratory stimulants. CNS and respiratory related compounds (chlortetracycline, oxytetracycline, stimulants also encompass a number of active agents. These demeclocycline, methacycline, doxycycline, minocycline, 45 stimulants include, but are not limited to, the following: Xan rolitetracycline); macrollide antibiotics such as erythromycin, thines Such as caffeine and theophylline; amphetamines Such clarithromycin, and azithromycin; streptogramin antibiotics as amphetamine, benzphetamine hydrochloride, dextroam Such as quinupristin and dalfopristin; beta-lactamantibiotics, phetamine, dextroamphetamine Sulfate, levamphetamine, including penicillins (e.g., penicillin G, penicillin VK), anti levamphetamine hydrochloride, methamphetamine, and staphylococcal penicillins (e.g., cloxacillin, dicloxacillin, 50 methamphetamine hydrochloride; and miscellaneous stimu nafcillin, and oxacillin), extended spectrum penicillins (e.g., lants such as methylphenidate, methylphenidate hydrochlo aminopenicillins such as amplicillin and amoxicillin, and the ride, modafinil, pemoline, Sibutramine, and Sibutramine antipseudomonal penicillins such as carbenicillin), and hydrochloride. cephalosporins (e.g., cefadroxil, cefepime, cephalexin, cefa Neuroleptic agents. Neuroleptic drugs include antidepres Zolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazi 55 Sant drugs, antimanic drugs, and antipsychotic agents, dime, and ceftriaxone), and carbapenems such as imipenem, wherein antidepressant drugs include (a) the tricyclic antide meropenem and aztreonam; aminoglycoside antibiotics Such pressants such as amoxapine, amitriptyline, clomipramine, as streptomycin, gentamicin, tobramycin, amikacin, and neo desipramine, doxepin, imipramine, maprotiline, nortrip mycin; glycopeptide antibiotics such as teicoplanin; Sulfona tyline, protriptyline, and trimipramine, (b) the serotonin mide antibiotics Such as Sulfacetamide, Sulfabenzamide, Sul 60 reuptake inhibitors citalopram, fluoxetine, fluvoxamine, par fadiazine, Sulfadoxine, Sulfamerazine, Sulfamethazine, oxetine, Sertraline, and Venlafaxine, (c) monoamine oxidase Sulfamethizole, and Sulfamethoxazole; anti-mycobacterials inhibitors such as phenelzine, tranylcypromine, and (-)-sel Such as isoniazid, rifampin, rifabutin, ethambutol, pyraZina egiline, and (d) other, "atypical antidepressants such as nefa mide, ethionamide, aminosalicylic, and cycloserine; sys Zodone, traZodone and Venlafaxine, and wherein antimanic temic antifungal agents such as itraconazole, ketoconazole, 65 and antipsychotic agents include (a) phenothiazines Such as fluconazole, and amphotericin B; antiviral agents such as acetophenazine, acetophenazine maleate, chlorpromazine, acyclovir, famcicylovir, ganciclovir, idoxuridine, Sorivudine, chlorpromazine hydrochloride, fluphenazine, fluphenazine US 8,383,155 B2 23 24 hydrochloride, fluiphenazine enanthate, fluiphenazine vasodilators such as nitroglycerin; and diuretic agents such as decanoate, mesoridazine, mesoridazine besylate, perphena hydrochlorothiazide, furosemide, bumetanide, ethacrynic zine, thioridazine, thioridazine hydrochloride, trifluopera acid, torsemide, azosemide, muZolimine, piretanide, and tri zine, and trifluoperazine hydrochloride, (b) thioxanthenes pamide. Such as chlorprothixene, thiothixene, and thiothixene hydro Anti-viral agents. Antiviral agents that can be delivered chloride, and (c) other heterocyclic drugs such as carbam using the present dosage forms include the antiherpes agents azepine, clozapine, droperidol, haloperidol, haloperidol acyclovir, famciclovir, foscamet, ganciclovir, idoxuridine, decanoate, loxapine Succinate, molindone, molindone hydro sorivudine, trifluridine, Valacyclovir, and vidarabine; the anti chloride, olanzapine, pimozide, quetiapine, risperidone, and retroviral agents didanosine, stavudine, Zalcitabine, and sertindole. 10 Zidovudine; and other antiviral agents such as amantadine, Hypnotic agents and sedatives include clomethiazole, ethi interferon alpha, ribavirin and rimantadine. namate, etomidate, glutethimide, meprobamate, methypry Sex steroids. The sex steroids include, first of all, progesto lon, Zolpidem, and barbiturates (e.g., amobarbital, apropbar gens such as acetoxmegnenolone, allylestrenol, anagestone bital, butabarbital, butalbital, mephobarbital, methohexital, acetate, chlormadinone acetate, cyproterone, cyproterone pentobarbital, phenobarbital, secobarbital, thiopental). 15 acetate, desogestrel, dihydrogesterone, dimethisterone, ethis Anxiolytics and tranquilizers include benzodiazepines terone (17.alpha.-ethinyltestoster-one), ethynodiol diacetate, (e.g., alprazolam, brotizolam, chlordiazepoxide, clobazam, flurogestone acetate, gestadene, hydroxyprogesterone, clonazepam, clorazepate, demoxepam, diazepam, estazolam, hydroxyprogesterone acetate, hydroxyprogesterone flumazenil, flurazepam, halazepam, lorazepam, midazolam, caproate, hydroxymethylprogesterone, hydroxymethyl nitrazepam, nordazepam, oxazepam, prazepam, quaZepam, progesterone acetate, 3-ketodesogestrel, levonorgestrel, temazepam, triazolam), buspirone, chlordiazepoxide, and lynestrenol, medrogestone, medroxyprogesterone acetate, droperidol. megestrol, megestrol acetate, melengestrol acetate, norethin Anticancer agents, including antineoplastic agents: Pacli drone, norethindrone acetate, norethisterone, norethisterone taxel, docetaxel, camptothecin and its analogues and deriva acetate, norethynodrel, norgestimate, norgestrel, norg tives (e.g., 9-aminocamptothecin, 9-nitrocamptothecin, 25 estrienone, normethisterone, and progesterone. Also included 10-hydroxy-camptothecin, irinotecan, topotecan, 20-O- within this general class are estrogens, e.g.: estradiol (i.e., .beta.-glucopyranosyl camptothecin), taxanes (baccatins, 1.3.5-estratriene-3,17.beta.-diol, or “ 17.beta.-estradiol) and cephalomannine and their derivatives), carboplatin, cisplatin, its esters, including estradiol benzoate, Valerate, cypionate, interferon-alpha. Sub.2A, interferon-alpha. Sub.2B, inter heptanoate, decanoate, acetate and diacetate; 17.alpha.-estra feron-alpha. Sub.N3 and other agents of the interferon fam 30 diol; ethinylestradiol (i.e., 17.alpha.-ethinylestradiol) and ily, levamisole, altretamine, cladribine, tretinoin, procarba esters and ethers thereof, including ethinylestradiol 3-acetate Zine, dacarbazine, gemcitabine, mitotane, asparaginase, and ethinylestradiol 3-benzoate; estriol and estriol succinate: porfimer, mesna, amifostine, mitotic inhibitors including polyestrol phosphate; estrone and its esters and derivatives, podophyllotoxin derivatives such as teniposide and etoposide including estrone acetate, estrone Sulfate, and piperazine and Vinca alkaloids Such as vinorelbine, Vincristine and Vin 35 estrone Sulfate; quinestrol; mestranol; and conjugated equine blastine. estrogens. Androgenic agents, also included within the gen Antihyperlipidemic agents. Lipid-lowering agents, or eral class of sex steroids, are drugs such as the naturally “hyperlipidemic' agents, include HMG-CoA reductase occurring androgens androsterone, androsterone acetate, inhibitors such as atorvastatin, simvastatin, pravastatin, lov androsterone propionate, androsterone benzoate, androstene astatin and cerivastatin, and other lipid-lowering agents such 40 diol, androstenediol-3-acetate, androstenediol-17-acetate, as clofibrate, fenofibrate, gemfibrozil and tacrine. androstenediol-3,17-diacetate, androstenediol-17-benzoate, Anti-hypertensive agents. These include amlodipine, androstenediol-3-acetate-17-benzoate, androstenedione, benazepril, darodipine, dilitaZem, diaZoxide, doxazosin, dehydroepiandrosterone (DHEA; also termed “prasterone'), enalapril, epoSartan, losartan, Valsartan, felodipine, Sodium dehydroepiandrosterone Sulfate, 4-dihydrotestoster fenoldopam, fosinopril, guanabenZ, guanadrel, guanethidine, 45 one (DHT; also termed “stanolone'), 5.alpha.-dihydrotest guanfacine, hydralazine, metyrosine, minoxidil, nicardipine, osterone, dromostanolone, dromostanolone propionate, eth nifedipine, nisoldipine, phenoxybenzamine, praZosin, ylestrenol, nandrolone phenpropionate, nandrolone quinapril, reserpine, and teraZosin. decanoate, nandrolone furylpropionate, nandrolone cyclo Cardiovascular preparations. Cardiovascular preparations hexanepropionate, nandrolone benzoate, nandrolone cyclo include, by way of example, angiotensin converting enzyme 50 hexanecarboxylate, Oxandrolone, Stanozolol and testoster (ACE) inhibitors such as enalapril, 1-carboxymethyl-3-1-car one; pharmaceutically acceptable esters of testosterone and boxy-3-phenyl-(1S)-propylamino-2,3,4,5-tetrahydro-1H 4-dihydrotestosterone, typically esters formed from the (3S)-1-benzazepine-2-one, amino-1-carboxy-1S-pentyl) hydroxyl group present at the C-17 position, including, but amino-2,-3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1- not limited to, the enanthate, propionate, cypionate, pheny acetic acid or 3-(1-ethoxycarbonyl-3-phenyl-(1S)- 55 lacetate, acetate, isobutyrate, buciclate, heptanoate, propylamino)-2,3,4,5-tetrahydro-2-oxo-(-3S)-benzazepine decanoate, undecanoate, caprate and isocaprate esters; and 1-acetic acid monohydrochloride; cardiac glycosides Such as pharmaceutically acceptable derivatives of testosterone Such digoxin and digitoxin; inotropes such as amrinone and mil as methyl testosterone, testolactone, oxymetholone and flu rinone; calcium channel blockers such as Verapamil, nife oxymesterone. dipine, nicardipene, felodipine, isradipine, nimodipine, 60 Muscarinic receptor agonists and antagonists. Muscarinic bepridil, amlodipine and diltiazem; beta-blockers such as receptor agonists include, by way of example: choline esters atenolol, metoprolol; pindolol, propafenone, propranolol. Such as acetylcholine, methacholine, carbachol, bethanechol esmolol, Sotalol, timolol, and acebutolol; antiarrhythmics (carbamylmethylcholine), bethanechol chloride, cholinomi Such as moricizine, ibutilide, procainamide, quinidine, dis metic natural alkaloids and synthetic analogs thereof, includ opyramide, lidocaine, phenytoin, tocainide, mexiletine, 65 ing pilocarpine, muscarine, McN-A-343, and oxotremorine. flecainide, encainide, bretylium and amiodarone; and cardio Muscarinic receptor antagonists are generally belladonna protective agents such as dexraZOxane and leucovorin; and alkaloids or semisynthetic or synthetic analogs thereof. Such US 8,383,155 B2 25 26 as atropine, Scopolamine, homatropine, homatropine methyl Abacavir, Acetazolamide; Adefovir; Albuterol; Albuterol; bromide, ipratropium, methantheline, methScopolamine and Alendronate; Almotriptan; Alosetron; Alprazolam; Amio tiotropium. darone; Amlexanox, Amlodipine; the combination Amlo Peptide drugs. Peptidyl drugs include the peptidyl hor dipine/Benazepril; Ammonium Lactate; Amphetamine (in mones activin, amylin, angiotensin, atrial natriuretic peptide cluding mixed salts); Amprenavir, Anagrelide; Anastrozole; (ANP), calcitonin, calcitonin gene-related peptide, calcitonin Argatroban; Aripiprazole; Atazanavir, Atomoxetine; AtorV N-terminal flanking peptide, ciliary neurotrophic factor astatin; the mixture Atovaquone/Proguanil; AZelastine; (CNTF), corticotropin (adrenocorticotropin hormone, Baclofen; Balsalazide; Beclomethasone; Beclomethasone; ACTH), corticotropin-releasing factor (CRF or CRH), epi Benazepril; Betamethasone; Betaxolol; Betaxolol; Bicaluta dermal growth factor (EGF), follicle-stimulating hormone 10 mide: Bisoprolol; Brimonidine; Brinzolamide: Budesonide; (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-re Buproprion; Buspirone; Busulfan; C-Urea; Calcitriol: Can leasing peptide, gonadotropin-releasing factor (GnRF or desartan; Carboplatin: Carteolol, Carvedilol; Caspofungin: GNRH), growth hormone releasing factor (GRF, GRH), Celecoxib Cerivastatin; Cetirizine; Cilostazol; Cimetidine; human chorionic gonadotropin (hCH), inhibin A, inhibin B, Ciprofloxacin, Ciprofloxacin; Cisatracurium; Citalopram; insulin, luteinizing hormone (LH), luteinizing hormone-re 15 Clopidogrel; Colesevelam; Cromolyn; Cromolyn; Cytara leasing hormone (LHRH), alpha.-melanocyte-stimulating bine; Desflurane; Desloratadine; Dexrazoxane; Dichlorphe hormone..beta.-melanocyte-stimulating hormone, gamma.- namide: Didanosine; Dorzolamide, Efavirenz; Eletriptan; melanocyte-stimulating hormone, melatonin, motilin, oxyto Emtricitabine: Enalapril; Enfluvirtide (T-20); Enoxaparin; cin (pitocin), pancreatic polypeptide, parathyroid hormone Epirubicin; Eplerenone; Ertapenem, Esmolol; Esomepra (PTH), placental lactogen, prolactin (PRL), prolactin-release Zole; Etodolac. Famciclovir, Famotidine: Felodipine; inhibiting factor (PIF), prolactin-releasing factor (PRF), Fenoldopam; Fentanyl: Fentanyl; Fexofenadine: Flucona secretin, Somatotropin (growth hormone, GH). Somatostatin Zole: Fludarabine, luocinolone; Fluoxetine; Fluticasone; Flu (SIF, growth hormone-release inhibiting factor, GIF), thy vastatin: Fluvoxamine; Formoterol; Fosinopril; Fospheny rotropin (thyroid-stimulating hormone, TSH), thyrotropin toin: Fulvestrant; Gabapentin; Gatifloxacin; Gatifloxacin: releasing factor (TRH or TRF), thyroxine, vasoactive intesti 25 Gemcitabine; Gemtuzumab; Gentamicin; Glatiramer; nal peptide (VIP), and vasopressin. Other peptidyl drugs are Glimepiride; Glipizide/Metformin; Glyburide/Metformin; the cytokines, e.g., colony stimulating factor 4, heparin bind Granisetron: Hydrocortisone, Hydroxyurea; Ibuprofen; Ibu ing neurotrophic factor (HBNF), interferon-a, interferon profen/pseudoephedrine: Imatinib. Imiquimod, Indinavir, ..alpha.-2a, interferon alpha.-2b, interferon alpha.-n3, inter Insulin glargine; Irbesartan; Irinotecan; Isotretinoin, Itra feron-beta., etc., interleukin-1, interleukin-2, interleukin-3, 30 conazole; Ketoconazole, Ketorolac, Labetalol, Lamivudine, interleukin-4, interleukin-5, interleukin-6, etc., tumor necro Lamotrigine; Lansoprazole; Leflunomide; Levalbuterol; sis factor, tumor necrosis factor-alpha., granuloycte colony Levetiracetam; Levobetaxolol; Levobunolol; Levofloxacin: stimulating factor (G-CSF), granulocyte-macrophage Levofloxacin; Linezolid; Lisinopril; Lisinopril; Lopinavir/ colony-stimulating factor (GM-CSF), macrophage colony Ritonavir, Loratadine; Losartan; Lovastatin: Mesalamine; stimulating factor, midkine (MD), and thymopoietin. Still 35 Metformin; Methazolamide; Methylphenidate; Metipra other peptidyl drugs that can be advantageously delivered nolol; Metoprolol; Midazolam; Milrinone; Minoxidil; Mir using the present systems include endorphins (e.g., dermor tazapine: Modafinil; Moexipril; Mometasone; Montelukast; phin, dynorphin, alpha.-endorphin, beta.-endorphin, Morphine; Moxifloxacin; Nabumetone; Nateglinide; Nefaz gamma.-endorphin, ..sigma.-endorphin, Leu. Sup.5en odone; Nelfinavir, Nevirapine; Nicotine; Nizatidine; Nor kephalin, Met. Sup.5enkephalin, Substance P), kinins (e.g., 40 floxacin; Norgestimate/ethinyl estradiol; Octreotide; Ofloxa bradykinin, potentiator B, bradykinin potentiator C. kallidin), cin; Olanzapine; Olmesartan; Omeprazole, Ondansetron; LHRH analogues (e.g., buserelin, deslorelin, fertirelin, gos Orlistat; Oseltamivir; Oxaprozin; Oxcarbazepine; Oxybuty erelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), nin: Oxybutynin. Oxycodone; Pantoprazole; Paricalcitol; and the coagulation factors, such as alpha. Sub. 1-antitrypsin, Paroxetine; Pegvisomant; Pemirolast; Pimecrolimus; Piogli ..alpha. Sub.2-macroglobulin, antithrombin III, factor I (fi 45 taZone; Pravastatin: Propofol; Quetiapine Fumerate; brinogen), factor II (prothrombin), factor III (tissue pro Quinapril; Rabeprazole; Ramipril; Ranitidine: Remifentanil, thrombin), factor V (proaccelerin), factor VII (proconvertin), Repaglinide; Ribavirin/Interferon alfa-2B, recombinant, factor VIII (antihemophilic globulin or AHG), factor IX Rifapentine: Risedronate; Risperidone; Ritonavir, Rocuro (Christmas factor, plasma thromboplastin component or nium; Rofecoxib; Ropivacaine; RosiglitaZone; Rosiglita PTC), factor X (Stuart-Power factor), factor XI (plasma 50 Zone: Salmeterol: Saquinavir; Sertraline: Sevelamer; Sevof thromboplastin antecedent or PTA), factor XII (Hageman lurane; Sibutramine; Sildenafil; Simvastatin; Sirolimus: factor), heparin cofactor II, kallikrein, plasmin, plasminogen, Sodium ferric gluconate complex: Sotalol; Stavudine: prekallikrein, protein C, protein S, and thrombomodulin and Sumatriptan; Tacrolimus; Tamoxifen; Temozolomide; Teno combinations thereof. fovir, Terbinafine; Testosterone; Timolol; Tolterodine; Topi Genetic material may also be delivered using the present 55 ramate; Topotecan; Tramadol; Valacyclovir, Valganciclovir, dosage forms, e.g., nucleic acids, RNA, DNA, recombinant Vaiproate; Valsartan; Venlafaxine, Verapamil: Vinorelbine; RNA, recombinant DNA, antisense RNA, antisense DNA, Voriconazole; Zafirlukast; Zanamivir; Ziprasidone; ribozymes, ribooligonucleotides, deoxyribonucleotides, Zoledronic acid; Zolmitriptan; Zonisamide. antisense ribooligonucleotides, and antisense deoxyribooli As incorporated be reference according to Mantelle U.S. gonucleotides. Representative genes include those encoding 60 Pat. No. 234,957: for vascular endothelial growth factor, fibroblast growth fac 1. Analgesic anti-inflammatory agents such as, acetami tor, Bcl-2, cystic fibrosis transmembrane regulator, nerve nophen, aspirin, salicylic acid, methyl salicylate, choline Sali growth factor, human growth factor, erythropoietin, tumor cylate, glycol salicylate, 1-menthol, camphor, mefenamic necrosis factor, and interleukin-2, as well as histocompatibil acid, fluiphenamic acid, indomethacin, diclofenac, alclofenac, ity genes such as HLA-B7. 65 ibuprofen, ketoprofen, naproxene, pranoprofen, fenoprofen, In a preferred embodiment for a paediatric product and use Sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, pro according to the invention, the active drug is selected from tizidic acid, fentiazac, tolmetin, tiaprofenic acid, bendazac, US 8,383,155 B2 27 28 bufexamac, piroxicam, phenylbutaZone, oxyphenbutaZone, 13. Coronary vasodilators such as, organic nitrates such as, clofeZone, pentazocine, mepirizole, and the like; nitroglycerine, isosorbitol dinitrate, erythritol tetranitrate, 2. Drugs having an action on the central nervous system, and pentaerythritol tetranitrate, dipyridamole, dilaZep, trapi for example sedatives, hypnotics, antianxiety agents, analge dil, trimetazidine, and the like; sics and anesthetics, such as, chloral, buprenorphine, nalox 14. Vasoconstrictors such as, dihydroergotamine, dihydro one, haloperidol, fluphenazine, pentobarbital, phenobarbital, ergotoxine, and the like; secobarbital, amobarbital, cydobarbital, codeine, lidocaine, 15.beta.-blockers orantiarrhythmic agents such as, timolol tetracaine, dyclonine, dibucaine, cocaine, procaine, mepiv pindolol, propranolol, and the like; acaine, bupivacaine, etidocaine, prilocaine, benzocaine, fen 16. Calcium antagonists and other circulatory organ tanyl, nicotine, and the like; 10 3. Antihistaminics or antiallergic agents such as, diphen agents, such as, aptopril, diltiazem, nifedipine, nicardipine, hydramine, dimenhydrinate, perphenazine, triprolidine, Verapamil, bencyclane, ifenprodil tartarate, molsidomine, pyrilamine, chlorcyclizine, promethazine, carbinoxamine, clonidine, prazosin, and the like; tripelennamine, brompheniramine, hydroxyzine, cyclizine, 17. Anti-convulstants such as, nitrazepam, meprobamate, meclizine, clorprenaline, terfenadine, chlorpheniramine, and 15 phenytoin, and the like; the like: 18. Agents for dizziness such as, isoprenaline, betahistine, 4. Acetonide anti-inflammatory agents, such as hydrocor Scopolamine, and the like; tisone, cortisone, dexamethasone, fluocinolone, triamcino 19. Tranquilizers such as, reserprine, chlorpromazine, and lone, medrysone, prednisolone, flurandrenolide, prednisone, antianxiety benzodiazepines Such as, alprazolam, chlordiaz halcinonide, methylprednisolone, fludrocortisone, corticos epoxide, cloraZeptate, halazepam, oxazepam, prazepam, terone, paramethasone, betamethasone, ibuprophen, clonazepam, flurazepam, triazolam, lorazepam, diazepam, naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen, and the like; ketoprofen, Suprofen, indomethacin, piroXicam, aspirin, Sali 20. Antipsychotics Such as, phenothiazines including thio cylic acid, diflunisal, methyl salicylate, phenylbutaZone, propazate, chlorpromazine, triflupromazine, mesoridazine, Sulindac, mefenamic acid, meclofenamate Sodium, tolmetin, 25 piperracetazine, thioridazine, acetophenazine, fluiphenazine, and the like; perphenazine, trifluoperazine, and other major tranquilizers 5. Steroids such as, androgenic steriods. Such as, testoster Such as, chlorprathixene, thiothixene, haloperidol, bromperi one, methyltestosterone, fluoxymesterone, estrogens such as, dol, loxapine, and molindone, as well as, those agents used at conjugated estrogens, esterified estrogens, estropipate, lowerdoses in the treatment of nausea, vomiting, and the like; 17-beta. estradiol, 17-beta. estradiol Valerate, equilin, 30 21. Muscle relaxants such as, tolperisone, baclofen, dant mestranol, estrone, estriol, 17-beta. ethinyl estradiol, dieth ylstilbestrol, progestational agents, such as, progesterone, rolene sodium, cyclobenzaprine; 19-norprogesterone, norethindrone, norethindrone acetate, 22. Drugs for Parkinson's disease, spasticity, and acute melengestrol, chlormadinone, ethisterone, medroxyprogest muscle spasms such as levodopa, carbidopa, amantadine, erone acetate, hydroxyprogesterone caproate, ethynodiol 35 apomorphine, bromocriptine, selegiline (deprenyl), trihex diacetate, norethynodrel, 17-.alpha. hydroxyprogesterone, yphenidyl hydrochloride, benztropine mesylate, procyclidine dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, hydrochloride, baclofen, diazepam, dantrolene, and the like; demegestone, promegestone, megestrol acetate, and the like; 23. Respiratory agents such as, codeine, ephedrine, isopro 6. Respiratory agents such as, theophilline and beta terenol, dextromethorphan, orciprenaline, ipratropium bro ... Sub.2-adrenergic agonists, such as, albuterol, terbutaline, 40 mide, cromglycic acid, and the like; metaproterenol, ritodrine, carbuterol, fenoterol, quinterenol, 24 Non-steroidal hormones or antihormones such as, cor rimiterol, Solmefamol, Soterenol, tetroquinol, and the like; ticotropin, oxytocin, Vasopressin, salivary hormone, thyroid 7. Sympathomimetics such as, dopamine, norepinephrine, hormone, adrenal hormone, kallikrein, insulin, Oxendolone, phenylpropanolamine, phenylephrine, pseudoephedrine, and the like; amphetamine, propylhexedrine, arecoline, and the like; 45 25. Vitamins such as, vitamins A, B, C, D, E and K and 8. local anesthetics Such as, benzocaine, procaine, derivatives thereof, calciferols, mecobalamin, and the like for dibucaine, lidocaine, and the like; dermatologically use: 9. Antimicrobial agents including antibacterial agents, 26. Antitumor agents such as, 5-fluorouracil and deriva antifungal agents, antimycotic agents and antiviral agents; tives thereof, krestin, picibanil, ancitabine, cytarabine, and tetracyclines such as, oxytetracycline, penicillins, such as, 50 the like: ampicillin, cephalosporins such as, cefalotin, aminoglyco 27. Enzymes such as, lysozyme, urokinaze, and the like; sides, such as, kanamycin, macrollides such as, erythromycin, 28. Herb medicines or crude extracts Such as, glycyrrhiza, chloramphenicol, iodides, nitrofrantoin, nystatin, amphoteri aloe, Sikon (Lithospermi Radix), and the like: cin, fradiomycin, Sulfonamides, purrolnitrin, clotrimazole, 29. Miotics such as pilocarpine, and the like; lo 30. Cho miconazole chloramphenicol, Sulfacetamide, SulfamethaZ 55 linergic agonists such as, choline, acetylcholine, methacho ine, Sulfadiazine, Sulfamerazine, Sulfamethizole and Sulfisox line, carbachol, bethanechol, pilocarpine, muscarine, azole; antivirals, including idoxuridine, clarithromycin; and arecoline, and the like; other anti-infectives including nitrofuraZone, and the like; 31. Antimuscarinic or muscarinic cholinergic blocking 10. Antihypertensive agents such as, clonidine, alpha.-me agents such as, atropine, Scopolamine, homatropine, meth thyldopa, reserpine, Syrosingopine, rescinnamine, cinnariz 60 Scopolamine, homatropine methylbromide, methantheline, ine, hydrazine, prazosin, and the like; cyclopentolate, tropicamide, propantheline, anisotropine, 11. Antihypertensive diuretics such as, chlorothiazide, dicyclomine, eucatropine, and the like; hydrochlorothrazide, bendoflumethazide, trichlormethiaz 32. Mydriatics such as, atropine, cyclopentolate, homatro ide, furosemide, tripamide, methylclothiazide, penfluzide, pine, Scopolamine, tropicamide, eucatropine, hydroxyam hydrothiazide, Spironolactone, metolaZone, and the like; 65 phetamine, and the like; 12. Cardiotonics such as, digitalis, ubidecarenone, dopam 33. Psychic energizers such as 3-(2-aminopropy)indole, ine, and the like; 3-(2-aminobutyl)indole, and the like: US 8,383,155 B2 29 30 34. Humoral agents such as, the prostaglandins, natural and Cephalosporins and Related Beta Lactams synthetic, for example PGE. Sub.1, PGE. Sub.2.alpha., and Drug Groups: Cephalosporins, related Beta Lactams or PGF sub.2.alpha., and the PGE. Sub.1 analog misoprostol. cephem antibiotics Aztreonam, Betamipron, Biapenem, 35. Antispasmodics such as, atropine, methantheline, Carumonam, Cefaclor, Cefadroxil, Cefalexin, Cefalonium, papaverine, cinnamedrine, methScopolamine, and the like; Cefaloridine, Cefalotin, Cefamandole, Cefazolin, Cefapirin, 36. Antidepressant drugs such as, isocarboxazid, Cefatrizine, Cefcapene, Cefdinir, Cefditoren, Cefepime, phenelZine, tranylcypromine, imipramine, amitriptyline, Cefetamet, Cefixime, Cefluprenam, Cefnmenoxime, Cefneta trimipramine, doxepin, desipramine, nortriptyline, protrip Zole, Cefninox, Cefodizime, Cefonicid, CefoperaZone, tyline, amoxapine, maprotiline, traZodone, and the like; Ceforanide, Cefoselis, Cefotaxime, Cefotetan, Cefotiam, 37. Anti-diabetics such as, insulin, and anticancer drugs 10 Cefoxitin, Cefozopran, Ce?piramide, Ce?pirome, Ce?po Such as, tamoxifen, methotrexate, and the like; doxime, Cefprozil, Cefauinome, Cefsulodin, Ceftazidime, 38. Anorectic drugs such as, dextroamphetamine, metham Cefiteram, Ceftezole, Ceftibuten, Ceftiofur, Ceftizoxime, phetamine, phenylpropanolamine, fenfluramine, diethylpro Ceftriaxone, Cefuroxime, Cefradine, Cilastatin, Faropenem, pion, mazindol, phentermine, and the like; Flomoxef. Imipenem, Latamoxef, Loracarbef, Meropenem, 39. Anti-allergenics Such as, antazoline, methapyrilene, 15 Panipenem, chlorpheniramine, pyrilamine, pheniramine, and the like; Chloramphenicols 40. Decongestants such as, phenylephrine, ephedrine, nap AZidamfenicol, Chloramphenicol, Florfenicol. Thiam hazoline, tetrahydrozoline, and the like: phenicol, Avoparcin, Ramoplanin, Teicoplanin, Vancomycin, 41. Antipyretics Such as, aspirin, Salicylamide, and the like; Lincosamides 42. Antimigrane agents such as, dihydroergotamine, pizo Clindamycin, Lincomycin, Pirlimycin, tyline, and the like: Macrollides 43. Anti-malarials such as, the 4-aminoquinolines, Azithromycin, Clarithromycin, Dirithromycin, Erythro alphaaminoquinolines, chloroquine, pyrimethamine, and the mycin, Flurithromycin, Josamycin, Kitasamycin, Mideca like: 25 mycin, Oleandomycin, Pristinamycin, Quinupristin/Dalfo 44. Anti-ulcerative agents such as, misoprostol, omepra pristin, Rokitamycin, Roxithromycin, Spiramycin, Zole, enprostil, and the like; Tilmicosin, Troleandomycin, Tylosin, Virginiamycin, 45. Peptides such as, growth releasing factor, and the like; Penicillins 46. Anti-estrogen or anti-hormone agents such as, tamox The beta-lactamase inhibitors clavulanic acid, Sulbactam, ifen or human chorionic gonadotropin, and the like; 30 and taZobactam are used to extend the antimicrobial range of 47. Antiulcer agents such as, allantoin, aldioxa, alcloxa, certain beta-lactam antibiotics. Amoxicillin, Ampicillin, N-methylscopolamine methylsuflate, and the like: Aspoxicillin, Azidocillin, AZlocillin, Bacampicillin, Beneth 48. Antidiabetics, and the like. amine Penicillin, Benzathine Benzylpenicillin, Benzathine The drugs mentioned above can be used in combination as Phenoxymethylpenicillin, Benzylpenicillin, Carbenicillin, required. Moreover, the above drugs may be used either in the 35 Carfecillin, Carindacillin, Ciclacillin, Clavulanic Acid, free form or, if capable of forming salts, in the form of a salt Clemizole Penicillin, Clometocillin, Cloxacillin, Dicloxacil with a suitable acid or base. If the drugs have a carboxyl lin, Flucloxacillin, Mecillinam, Metampicillin, Meticillin, group, their esters can be employed. Mezlocillin, Nafcillin, Oxacillin, Penethamate, Pheneticillin, The acid mentioned above may be an organic acid, for Phenoxymethylpenicillin, Piperacillin, Pivampicillin, Piv example, methanesulfonic acid, lactic acid, tartaric acid, 40 mecillinam, Procaine Penicillin Procaine Benzylpenicillin, fumaric acid, maleic acid, acetic acid, oran inorganic acid, for Propicillin, Sulbactam, Sulbenicillin, Sultamicillin, Tazobac example, hydrochloric acid, hydrobromic acid, phosphoric tam, Temocillin, Ticarcillin, acid or Sulfuric acid. The base may be an organic base, for Quinolones example, ammonia, triethylamine, or an inorganic base, for Acrosoxacin Rosoxacin, Alatrofloxacin, Balofloxacin, example, sodium hydroxide or potassium hydroxide. The 45 Cinoxacin, Ciprofloxacin, Clinafloxacin, Danofloxacin, esters mentioned above may be alkyl esters, aryl esters, Difloxacin, Enoxacin, Enrofloxacin, Fleroxacin, Flume aralkyl esters, and the like. quine, GatifloxacinCemifloxacin, Grepafloxacin, Levofloxa In one embodiment of the invention, the active substance is cin, Lomefloxacin, Marbofloxacin, Moxifloxacin, Nadifloxa selected from the following: cin, Nalidixic Acid, Norfloxacin, Ofloxacin, Orbifloxacin, Antibacterials Including Metronidazole 50 Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piromidic Acid, Although antibiotics and other antibacterials are a very Prulifloxacin, Rufloxacin, Sarafloxacin, Sparfloxacin, Tema diverse class of compounds they are often classified and dis floxacin, ToSufloxacin, Trovafloxacin, cussed in groups. They may be classified according to their Sulfonamides and Diaminopyrimidines mode of action or spectrum of antimicrobial activity, but Baquiloprim, Brodimoprim, Calcium Sulfaloxate, generally those with similar chemical structures are grouped 55 Co-tetroxazine, Co-trifamole, Co-trimazine, Co-trimox together. azole, FormosulfathiazoleMafenide, Ormetoprim, Phthalyl Aminoglycosides sulfathiazole. Succinylsulfathiazole, Sulfabenzamide, Sulfa Amikacin, Apramycin, Arbekacin, Astromicin, Bekana clozine, Sulfachrysoidine, Sulfadicramide, Sulfadoxine, mycin, Dibekacin, Dihydrostreptomycin, Framycetin, Gen Sulfamerazine, Sulfamethylthiazole, Sulfametopyrazine, tamicin, Isepamicin, Kanamycin, Micronomicin, Neomycin, 60 Sulfametrole, Sulfamonomethoxine, Sulfaquinoxaline, Sul Netilmicin, Sisomicin, Streptomycin, Tobramycin. fasuccinamide, Sulfatroxazole, Sulfacetamide, Sulfachlorpy Antimycobacterials Drug Groups: Antimycobacterials ridazine, Sulfadiazine, Sulfadiazine Silver, Sulfadimethox Aminosalicylic Acid, Capreomycin, Clofazimine, Cyclos ine, Sulfadimidine, Sulfafurazole, Sulfaguanidine, erine, Dapsone, Ethambutol, Ethionamide, Isoniazid, Meth Sulfamethizole, Sulfamethoxazole, Sulfamethoxypy aniazide, Morinamide, Protionamide, Pyrazinamide, Rifabu 65 ridazine, Sulfamoxole, Sulfanilamide, Sulfapyridine, Sulfi tin, Rifampicin, Rifamycin, Rifapentine, Rifaximin, somidine, Sulfathiazole, Sulfacarbamide, Tetroxoprim, Tri Thioacetazone. methoprim, US 8,383,155 B2 31 32 Tetracyclines present invention, the term vitamin(s) include, without limi Chlortetracycline, Demeclocycline, Doxycycline, Lyme tation, thiamine, riboflavin, nicotinic acid, pantothenic acid, cycline, Meclocycline, Methacycline, Minocycline, Oxytet pyrdoxine, biotin, folic acid, Vitamin B.Sub.12, lipoic acid, racycline, Rolitetracycline, Tetracycline, ascorbic acid, VitaminA, Vitamin D. Vitamin E and vitamin K. Miscellaneous Antibacterials Also included within the term vitamin are the coenzymes Acediasulfone, Arsanilic Acid, Avilamycin, Bacitracin, thereof. Coenzymes are specific chemical forms of vitamins. Bambermycin, Carbadox, Chlorquinaldol, Clioquinol, Clo Coenzymes include thiamine pyrophosphates (TPP), flavin foctol, Colistin, Daptomycin, Evernimicin, Fosfomycin, mononucleotide (FMM), flavin adenine dinucleotive (FAD), Furaltadone, Fusafungine, Fusidic Acid, Gramicidin, Nicotinamide adenine dinucleotide (NAD), Nicotinamide Halduinol, Methenamine, Linezolid, Magainins, Mandelic 10 adenine dinucleotide phosphate (NADP) Coenzyme A (CoA) Acid, Mupirocin, Nifuroxazide, Nifurtoinol, Nifurzide, pyridoxal phosphate, biocytin, tetrahydrofolic acid, coen Nisin, Nitrofurantoin, Nitrofurazone, Nitroxoline, Novobio Zyme B.Sub.12, lipoyllysine, 11-cis-retinal, and 1,25-dihy cin, Polymyxin B. Spectinomycin, Sulfamazone, Tauroli droxycholecalciferol. The term vitamin(s) also includes cho dine, Telithromycin, Terizidone. Thenoic Acid, Thiostrepton, line, carnitine, and alpha, beta, and gamma carotenes. Tiamulin, Trospectomycin, Tyrothricin, Valnemulin, 15 As used in this disclosure, the term “mineral' refers to Xibornol, inorganic Substances, metals, and the like required in the Anthelmintics human diet. Thus, the term “mineral as used herein includes, Albendazole, Diethylcarbamazine, Ivermectin, Levami without limitation, calcium, iron, Zinc, Selenium, copper, sole, Mebendazole, Niclosamide, Oxamniquine, Piperazine, iodine, magnesium, phosphorus, chromium and the like, and Praziquantel, Pyrantel. Thiabendazole. mixtures thereof. Antimalarial Drugs The term "dietary supplement’ as used herein means a 4-methanolduinoline derivatives such as the cinchona Substance, which has an appreciable nutritional effect when alkaloids and mefloquine. The 4-aminoquinolines, such as administered in Small amounts. Dietary Supplements include, chloroquine, hydroxychloroquine, and amodiaquine. The without limitation, such ingredients as bee pollen, bran, 8-aminoquinolines such as primaquine and tafenoquine. The 25 wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino big uanides, such as proguanil and chlorproguanil. The acids, proteins and mixtures thereof. As will be appreciated, diaminopyrimidines such as pyrimethamine. The dichlo dietary Supplements may incorporate vitamins and minerals. robenzylidine lumefantrine. The hydroxynaphthoduinones, In general, the amount of the active Substance incorporated Such as atovaquone. The 9-phenanthrenemethanols such as in the dosage form according to the invention may be selected halofantrine. The sesquiterpene lactones such as artemisinin 30 according to known principles of pharmacy. An effective and its derivatives. The sulfonamides sulfadoxine and sul amount of pharmaceutical ingredient is specifically contem fametopyrazine. The tetracyclines, such as doxycycline and plated. By the term effective amount, it is understood that, tetracycline. The lincosamide, clindamycin. The Sulfones with respect to for example pharmaceuticals, a therapeuti Such as dapsone. cally, prophylactically and/or diagnostically effective amount Antiprotozoals 35 is contemplated. An effective amount is the amount or quan The antimony compounds including meglumine anti tity of a drug substance, which is sufficient to elicit the monate and Sodium Stibogluconate, the aromatic diamidines required or desired therapeutic response, or in other words, including pentamidine, the arsenicals including the pentava the amount, which is sufficient to elicit an appreciable bio lent compounds acetarSol and tryparsamide, and melarsoprol logical response when administered to a patient. As used which is trivalent, the dichloroacetamides including dilox 40 herein the term “effective amount’ means an amount at least anide, the halogenated hydroxyquinolines including about 10% of the United States Recommended Daily Allow diiodohydroxyquinoline, the nitrofurans including furazoli ance (“RDA) of that particular ingredient for a patient. For done, nifuratel, and nifurtimox, and the 5-nitroimidazoles example, if an intended ingredient is vitamin C, then an including metronidazole, nimorazole, ornidazole, secnida effective amount of vitamin C would include an amount of Zole, and tinidazole. Other drugs include atovaquone, ben 45 vitamin C sufficient to provide 10% or more of the RDA. Znidazole, dehydroemetine, eflornithine, mepacrine, and Typically, where the tablet includes a mineral or vitamin, it Suramin. will incorporate higher amounts, preferably about 100% or Antivirals more of the applicable RDA. The amount of active agent used Anti-asthma Drug Groups can vary widely from a few milligrams to 100,000 milligrams Antimuscarinics and Beta agonists. 50 O. O. Such as the quaternary ammonium compounds ipratropium Preparation of a Pharmaceutical Composition bromide and oxitropium bromide, Salmeterol, Albuterol, A pharmaceutical composition according to the invention Bitolterol, Isoetharine, Metaproterenol, Pirbuterol, Terbuta may be prepared by blending of at least: line, Isoproterenol, Ephedrine, Epinephrine Salbutamol. 1) One or more active substances as particulate matter. Corticosteroids. 55 Either as pure material (crystals or amorphous, in powder Beclomethasone dipropionate, Budesonide Turbuhaler, form) or encapsulated by a coat or trapped in a matrix or Flunisolide, Fluticasone, Triamcinolone acetonide. bound to an ion-exchange resin. Leukotriene Inhibitors and Antagonists. 2) One or more Swelling/gelling materials Zafirlukast, Montelukast. and, optionally: Mast Cell Stabilisers. 60 3) Sweetening agents Sodium cromoglicate and Nedocromil Sodium. 4) Flavours Xanthines. 5) Colorants Theophylline and its derivatives. In one embodiment it is possible to use the gelling agent in Antifungals Solution as a binder in granulating and as a glue for giving the Flucytosine, Griseofulvin, Ketoconazole, Miconazole. 65 formulation the desired shape, however once the gelling agent As used herein, the term vitamin refers to trace organic has been hydrated, the gelling properties may be reduced, substances that are required in the diet. For the purposes of the accordingly sometimes the gelling agent used in solution as a US 8,383,155 B2 33 34 binder is identical with the bulk gelling agent (example FIG. 5 shows the complete dispersion of the formulation Kelcogel(R) LT100), sometimes it is a different grade of the according to Example 19 and as shown in FIG. 4. same gelling agent (Kelcogel(R) LT 100 bulk, Kelcogel(R) Fas FIG. 6 shows the dissolution at low pH of the formulation binder) and sometimes a different binder altogether (Kelco according to Example 24 demonstrating disintegration into gel(R) LT 100 as bulk, Keltrol as binder). The desired shape material with individual flakes varying in size from approxi mentioned could be, for example, granulating the mixture of mately 1 to 5 mm. active Substances, gelling agent, Sweetener and flavour and FIG. 7 demonstrates the dissolution similar to FIG. 6 in a Subsequently moulding and gluing the granules to the con media at pH 4.8 demonstrating complete disintegration of the cave surface of a spoon, preferable in a relative thin layor of material 0.5 to 5 mm thick. This strategy contributes to that the pow 10 FIG. 8 demonstrates the dissolution similar to FIG. 6 in a der/particulate material obtained as the novel dosage form media at pH 6.8 demonstrating complete disintegration of the can be converted into a pudding-like mass without applica material into very small and fluffy material representing the tion of any shear force and within the desired time period. non soluble material of the formulation. This feature is very advantageous in that it is possible to use FIG. 9 shows the dissolution of the formulation according the novel dosage form also for very Small amounts of active 15 to Example 24 resulting in a fast dissolution rate of the parac substances as there is no risk that active substance will be lost etamol at different pH values. Similar effect is also obtained e.g. on a spoon or stirrer during stirring or mechanical mixing. with simulated gastric fluid. In other words, the dose form presents the active substance in FIG. 10 shows 3 different spoons for use as delivery a form that ensures the right dose to be ingested. To the best of devices according to the present invention. All spoons are the inventors knowledge this is the first comparable semi prepared in order to be able to be left on a table or similar liquid alternative in this respect to a tablet or capsule dosage place without tilting and at the same time easy to pick up form. providing an easy handling during administration. The means More specifically, the invention relates to a method for for preventing the spoons for tilting when left is self-explana preparing a pharmaceutical composition according to the tory from the drawings in that either the shaft is bend or more invention, the method comprising blending the dry compo 25 times and or the “floor of the spoon is flattened. The latter nents to a homogeneous mixture and optionally granulating may further be provided with an ordinary concave inner lin the mixture with a binder. ing of the spoon to avoid material to be left on the spoon after In a specific embodiment, the invention relates to a A application to the mouth. method for preparing a pharmaceutical composition accord ing to the invention comprising one or more excipients and/or 30 MATERIALS AND METHODS active ingredients which have a solubility substantial lower than the solubility of the gellan gum, wherein the method Several of the below Examples have been produced with comprises out an active ingredient and used for demonstrating different i) granulating a first blend comprising gellan gum but compositions to which an active can be added (i.e. they are essentially not containing the one or more excipients and/or 35 vehicles). Several of these formulations have been used for active ingredients which have a solubility substantial lower consumer testing. The term Parvuletas used herein represents than the solubility of the gellan gum, any formulation according to the invention and is a trademark ii) adding the one or more excipients and/or active ingre for the products. dients which have a solubility substantial lower than the solu The following materials have been employed: bility of the gellan gum to the granulated first blend. 40 Absolute alcohol 99.9%, De danske spritfabrikker, phar In a Subsequent step, the one or more excipients and/or maceutical grade active ingredients which have a solubility substantial lower Aerosil, Unikem, pharmaceutical grade than the solubility of the gellangum is added to the granulated Caramel flavour, Frutarom first blend as a blend or granulate with additional excipients. CefuximeAxetil, Stragen Nordic The foregoing will be better understood with reference to 45 Chocolate flavour, Kiranto food the following examples which detail certain procedures for Ferrous fumarate coated, Ferrosan, pharmaceutical grade manufacture of tablets in accordance to the present invention. Gellan, Kelcogel LT 100, CpKelco ApS, pharmaceutical All references made to these examples are for the purposes of grade illustration. They are not to be considered limiting as to the Gellan, Kelcogel F. CpKelco ApS, pharmaceutical grade Scope and nature of the present invention. 50 Glycerol, Uniqema, pharmaceutical grade Ibuprofen Coated, Nycomed DK, pharmaceutical grade FIGURES Instant Sugar, Danisco Oy, pharmaceutical grade Inulin instant, Fibruline FIG. 1 shows a (A) spoon with the dryg composition adher Ispaghulae Husks, Vi-siblin, Pfizer ing to it and covered with a "peel off film which in (B) is 55 Maize Starch Ultrasprese HV. National Starch & Chemical remove and water (C) is added where upon gelling (D) takes Medium Chain Triglyceride EP (Labrafac cc), Gattefossé place with expansion of the material which do no not slip the SAS, pharmaceutical grade spoon (E) when this is tipped the other way round. PVP (plastdoneR) K-25, ISP (Switzerland) AG FIG. 2 shows the dissolution curve according to the formu Pyridoxine Coated, Ferrosan, pharmaceutical grade lation of Example 17 of a Paracetamol dosage unit in simu 60 Sodium Citrate, Unikem, pharmaceutical grade lated gastric fluid demonstrating a very fast release of at least Sodium hydrogen carbonate, Unikem, pharmaceutical 96% within 5 minutes. grade FIG. 3 shows the stomach recorded by in vivo ultrasonic Sodium starch glycolate, Explotab, JRS Pharma measures after ingestion of water and before ingestion of the Strawberry flavour, Kiranto food formulation according to Example 19. 65 Tutti-frutti flavour, Frutarom FIG. 4 shows the subsequent ultrasonic pictures just after Vanilla flavour, Keranto food AIS ingestion of the formulation according to Example 19. Xanthan gum, Keltrol CpKeico ApS, pharmaceutical grade US 8,383,155 B2 35 36 Xylitol, Danisco Sweeteners LtD -continued Coat: Eudragite EPO, Rohm % Wiw 9. Lauryl Sulphate, Sigma Blend 2: Altalc 500V. Luzenac America Blend 1 60 2.1 Eudragit NE30D, Rohm Coated Cefuxime 40 1.4 Granulation Performed by hand mixing until homogenous The ingredients (1-4) of Blend 1 are mixed/2 min (depending on the amount of powder) in a mortar, transferred to a Philips Food processor, Electronic type HR 2377 D, ingredient 5 slightly sticky relative small particles are present Suitable is added and mixed for about/2 min (depending on the amount of powder) at speed 4. The equipment includes High Shear mixer Such as in a Zanchetta 10 ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount Roto P100–100 liter capacity or a MTI mixer. of powder). Drop Down Test In this example, Explotab is used as a gelling agent that is The drop down test apparatus is a medical plastic spoon granulated with glycerol. obtained from Nomeco (DBI Plastic type 115022) with mark 15 The granules are divided into 570 mg/dose. The dose is ings for 2/2 and 5 ml liquid) see FIG. 1, e.g. drawing E. weight out into a medical spoon and moulded by gently Test Method pressing the granules against the spoon with a mortarpistil to In a test spoon 0.5 g-0.7 g test material is accurately a thin layer about 1-3 mm in high in the bottom of the spoon. weighed. 3 ml-5 ml tapped water is added. Wait /2 min, turn The water is evaporated at ambient temperature. the spoon around, and if the test material does not drop down (fall off the spoon) within 2 min, the material has passed the Drop Down Test: teSt. To the above dosage form, 4 ml tapped water is added. Viscosity Test After about /2 min the liquid is absorbed. The spoon is turned Apparatus: around and held upside down for 2 min. The test material did 25 Brookfield Viscometer Model LVF, Serie 56779 not fall out and passed the test. Spindel No. #4 diameter 3.2 mm, length 33.96 mm Beaker 500 ml low form (approximately 90 mm internal Example 2 diameter) Termometer 30 A Composition According to the Invention Parameter: Containing 250 mg Coated Cefuxime in the Dosage Speed: 6 rpm Unit Spindle: The Viscometer spindle is centered in the test sample container. The spindle is properly immersed to the 35 A composition that has a shape as outlined in FIG. 1 con mid-point of the shafts narrow portion. taining CefuXime as active Substance, was prepared as fol Test Method lows (given as % w/w): Into a 500 ml beaker 22-88 g test material is accurately weighed, 500 ml tapped water is added. Mix untill all the material is dispersed/dissolved, and after about 5 min the 40 Viscosity and the temperature are measured. % Wiw 9. Sensory Test Blend 1: Tapped water is added to the formulation and when all the Explotab 46.3 O.87 Instant Sugar 46.3? O.87 liquid is absorbed (visually confirmed), the test can start. 45 Aerosil 0.53 O.OO94 Taste the formulation and rank the taste from 1-10, where 10 Vaniia flavour 4.6 O.O86 is the most pleasant taste. Glycerol 2.35 O.043 Blend 2:

Example 1 Blend 1 S3.6 1.87 50 Coated Cefuxime 35.7 1.25 Vi-siblin 10.7 O.38 A Composition According to the Invention The ingredients (1-4) of Blend 1 are mixed/2 min (depending on the amount of powder) in Containing 250 mg Coated Cefuxime Dosage Unit a mortar transferred to a Philips Food processor Electronic type HR 2377 D, ingredient 5 is added and mixed for about /2 min (depending 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 A composition that has a shape as outlined in FIG. 1 con 55 of powder). taining cefuXime as active Substance was prepared as follows: 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 mortarpistil to % Wiw 9. 60 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 0.97 Drop Down Test: Instant Sugar 46.32 0.97 Aerosil 0.53 O.O11 To the above dosage form 4 ml tapped water is added. After Vaniia flavor 4.6 O.096 65 about /2 min the liquid is absorbed. The spoon is turned Glycerol 2.3 (binder) O.048 around and held upside down for 2 min. The test material did not fall out and passed the test. US 8,383,155 B2 37 Example 3 -continued

% Wiw 9. A Composition According to the Invention Containing 250 mg Coated Cefuxime Dosage Unit Blend 3: Blend 2 71.4 2.50 Kelcogel F 14.32 O.S A composition that has a shape as outlined in FIG. 1 con Water 14.33 O.S taining cefuXime as active Substance was prepared as follows % w/w: The ingredients (1-3) of Blend 1 are mixed/2 min (depending on the amount of powder) in a mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on 10 the amount of powder). The ingredients (2-3 (binding solution) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/3 min (depending on the amount of powder) and forming the granules, % Wiw 9. The granules are divided to 700 mg/dose. The dose is Blend 1: 15 weight out into a medical spoon and moulded by gently 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 0.53 O.O11 Drop Down Test: Vaniiia flavour 54 O112 Glycerol 2.35 To the above dosage form 3 ml tapped water is added. After Blend 2: about /2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test material did Blend 1 64.3 2.25 not fall out and pass the test. 25 Coated Cefuxime 35.7 1.24 Example 5 The ingredients (1-4) of Blend 1 are mixed/2 min (depending on the amount of powder) in a mortar transferred to a Philips Food processor Electronic type HR 2377 D, ingredient 5 is added and mixed for about/2 min (The granules are made by adding in thise case glycerol to the dry mixed powder, i.e. Kelcogel LT100 is pre-swelled in glycerol) at speed 4. The A Composition According to the Invention ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount 30 of powder). Containing 150 mg Coated Ferro Fumarate in the Dosage Unit The granules are divided to 700 mg/dose. The dose is weight out into a medical spoon and moulded by gently A composition that has a shape as outlined in FIG. 1 con pressing the granules against the spoon with a mortarpistil to 35 taining coated Ferro fumarate as active Substance was pre a thin layer about 1-3 mm in high in the bottom of the spoon. pared as follows: The water is evaporated at ambient temperature. Drop Down Test: To the above dosage form 4 ml tapped water is added. After % Wiw 9. about /2 min the liquid is absorbed. The spoon is turned 40 around and held upside down for 2 min. The test material did Blend 1: not fall out and passed the test. Kelcogel LT100 501 O.938 Xylitol 47.52 O.89 Vaniia flavour 2.53 O.O47 Example 4 45 Blend 2:

Blend 1 75 1875 A Composition According to the Invention Ferro fumarate 25 O.625 Containing 150 mg Coated Pyridoxine in the Dosage Blend 3: Unit 50 Blend 2 71.4 2.50 Kelcogel F 14.32 O.S Water 14.33 O.S A composition that has a shape as outlined in FIG. 1 con The ingredients (1-3) of Blend1 are mixed/2 min (depending on the amount of powder) in taining coated pyridoxine as active Substance was prepared as a mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on follows: the amount of powder). 55 The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). The granules are divided into 700 mg/dose. The dose is % Wiw 9. weight out into a medical spoon and moulded by gently Blend 1: pressing the granules against the spoon with a mortarpistil to 60 a thin layer about 1-3 mm in high in the bottom of the spoon. Kelcogel LT100 501 O.938 Xylitol 47.52 O.89 The water is evaporated at ambient temperature. Vaniiia flavour 2.53 O.O47 Drop Down Test: Blend 2: To the above dosage form 3 ml tapped water is added. After Blend 1 75 1875 65 about /2 min the liquid is absorbed. The spoon is turned Pyridoxine coated 25 O.625 around and held upside down for 2 min. The test material did not fall out and pass the test. US 8,383,155 B2 39 Example 6 -continued

% ww 9. A Composition According to the Invention Containing 125 mg Coated Ibuprofen in the Dosage Blend 3: Unit Blend 2 74.21 2.59 Kelcogel F 12.92 O.45 A composition that has a shape as outlined in FIG. 1 con Water 12.93 O.45 taining coated ibuprofen as active Substance was prepared as The ingredients of Blend 1 are mixed/2 min (depending on the amount of powder) in a follows: mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on 10 the amount of powder). The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). The granules are divided into 700 mg/dose. The dose is % Wiw 9. weight out into a medical spoon and moulded by gently Blend 1: 15 pressing the granules against the spoon with a mortarpistil to Kelcogel LT100 52.6 O.87 a thin layer about 1-3 mm in high in the bottom of the spoon. Xylitol 47.42 0.79 Drop Down Test: Blend 2: To the above dosage form 3 ml tapped water is added. After Blend 1 64.1 1.66 about /2 min the liquid is absorbed. The spoon is turned Ibuprofen 20.9 O.S4 around and held upside down for 2 min. The test material did Vaniiia flavour 15 O.39 not fall out and pass the test. Blend 3:

Blend 2 742 2.59 Example 8 Kelcogel F 12.92 O.45 25 Water 12.93 O.45 A Composition According to the Invention The ingredients of Blend 1 are mixed/2 min (depending on the amount of powder) in a Containing 125 mg Coated Ibuprofen in the Dosage mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). Unit The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder). 30 A composition that has a shape as outlined in FIG. 1 con The granules are divided to 700 mg/dose. The dose is taining coated ibuprofen as active Substance was prepared as weight out into a medical spoon and moulded by gently follows: pressing the granules against the spoon with a mortarpistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature, or moulded 35 to a sphere or stripe. The water is evaporated in an oven at 70° % ww 9. C. to constant temperature. Blend 1: Drop Down Test: Kelcogel LT100 52.6 To the above dosage form 3 ml tapped water is added. After 40 Xylitol 47.42 about /2 min the liquid is absorbed. The spoon is turned Blend 2: around and held upside down for 2 min. The test material did Blend 1 71 1.83 not fall out and pass the test. Ibuprofen coated 23.2 O.6 Caramel flavour 5.8 O.15 Blend 3: Example 7 45 Blend 2 74.21 2.59 Kelcogel F 12.92 O.45 A Composition According to the Invention Water 12.9 O.45 Containing 125 mg Coated Ibuprofen in the Dosage The ingredients of Blend 1 are mixed "/2 min (depending on the amount of powder) in a Unit 50 mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend A composition that has a shape as outlined in FIG. 1 con and mixed for about/2 min (depending on the amount of powder). taining coated ibuprofen dosage as active Substance was pre The granules are divided into 700 mg/dose. The dose is pared as follows: weight out into a medical spoon and moulded by gently 55 pressing the granules against the spoon with a mortarpistil 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 final % Wiw 9. amount of approximately 575 mg/dose Blend 1: 60 Drop Down Test: Kelcogel LT100 52.6 O.9S To the above dosage form 3 ml tapped water is added. After Xylitol 47.42 O.86 about /2 min the liquid is absorbed. The spoon is turned Blend 2: around and held upside down for 2 min. The test material did Blend 1 69.7 1.81 not fall out and pass the test. The average absorption rate of Ibuprofen coated 22.7 O.S8 65 water by the dosage per second measured in gram water Tutti-frutti flavour 7.6 O.20 absorb per gram dosage per second is 3 g/0.575 g/30 sec corresponding to a water absorption rate of 0.1739 g/g/s US 8,383,155 B2 41 Example 9 -continued A Composition According to the Invention % ww 9. Containing 125 mg Coated Ferro Fumarate in the Blend 3: Dosage Unit Blend 2 91.4 3.2O Sodium citrate 122 O.042 A composition that has a shape as outlined in FIG. 1 con Water 8.43 O.294 taining coated ferro fumarate dosage as active Substance was The ingredients of Blend 1 are mixed/2 min (depending on the amount of powder) in a prepared as follows: mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on 10 the amount of powder). The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about/2 min (depending on the amount of powder).

% Wiw 9. The granules are divided into 550 mg/dose. The dose is weight out into a medical spoon and moulded by gently Blend 1: 15 pressing the granules against the spoon with a mortarpistil to Kelcogel LT100 52.6 O.91 a thin layer about 1-3 mm in high in the bottom of the spoon. Xylitol 47.42 O.83 The water is evaporated at ambient temperature to a final Blend 2: amount of approximately 502 mg/dose. Blend 1 67.2 1.74 Drop Down Test: Ferro fumerate coated 21.9 O.S6 To the above dosage form 3.5 ml tapped water is added. Chocolate flavour 10.9 O.29 After about /2 min the liquid is absorbed. The spoon is turned Blend 3: around and held upside down for 2 min. The test material did Blend 2 742 2.59 not fall out and pass the test. Kelcogel F 12.92 O.45 25 The average absorption rate of water by the dosage per Water 12.93 O.45 second mesured in gram water absorb per gram dosage per The ingredients of Blend 1 are mixed/2 min (depending on the amount of powder) in a second is 3.5 g/0.502 g/120 sec corresponding to a water mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). absorption rate of 0.0581 g/g/s The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about /2 min (depending on the amount of powder). 30 Example 11 The granules are divided into 700 mg/dose. The dose is weight out into a medical spoon and moulded By gently A Placebo Composition According to the Invention pressing the granules against the spoon with a mortarpistil to a thin layer about 1-3 mm in high in the bottom of the spoon. A composition that has a shape as outlined in FIG. 1 was The water is evaporated at ambient temperature to a final 35 prepared as follows: amount of approximately 575 mg/dose. Drop Down Test: To the above dosage form 3 ml tapped water is added. After % Wiw 9. about /2 min the liquid is absorbed. The spoon is turned 40 around and held upside down for 2 min. The test material did Blend 1: not fall out and pass the test. Kelcogel LT100 251 O.65 The average absorption rate of water by the dosage per Xylitol 752 1.94 second mesured in gram water absorb per gram dosage per Blend 2: second is 3 g/0.575 g/120 sec corresponding to a water 45 Blend 1 80.3 2.59 absorption rate of 0.0435 g/g/s Inulin 13.1 O42 Caramel flavour 6.6 O.21 Blend 3: Example 10 Blend 2 92 3.22 50 Water 8 O.28 A Placebo Composition According to the Invention The ingredients of Blend 1 are mixed "/2 min (depending on the amount of powder) in a mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). A composition that has a shape as outlined in FIG. 1 was Blend 3 is mixed for about /2 min (depending on the amount of powder). prepared as follows: 55 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 mortarpistil to % Wiw 9. a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature to a final Blend 1: 60 dosage of 506 mg. Kelcogel LT100 22.5 0.675 Drop Down Test: Xylitol 67.52 2.025 To the above dosage form 3.5 ml tapped water is added. Ultrasperse HV 10.03 O.3 After about /2 min the liquid is absorbed. The spoon is turned Blend 2: around and held upside down for 2 min. The test material did Blend 1 94.0 3.0 65 not fall out and pass the test. Strawberry flavour 6.O O.2 The average absorption rate of water by the dosage per second measured in gram water absorb per gram dosage per US 8,383,155 B2 43 second is 3.5 g/0.506 g/120 sec corresponding to a water -continued absorption rate of 0.0576 g/g/s % Wiw 9. Example 12 Blend 4: Kelcogel LT100 5O1 O.98 A Placebo Composition According to the Invention Xylitol 502 O.98 Blend 5

A composition that has a shape as outlined in FIG. 1 was Blend 4 56.1 1.96 prepared as follows: 10 Blend 3 30.3 1.06 Ketrol 9.1 O.32 Apple fruit 4.5 O16 Blend1: the ingredient1 is dissolved in ingredient 2. % Wiw 9. Blend 2: the ingredient 2 is dissolved in ingredient 1. 15 The ingredient from blend 3 is mixed in a mortar with a scraper or a card until all is blend. Blend 1: The ingredient from blend 4 is mixed in a mortar with a scraper or a card until all is blend. Kelcogel LT100 5O1 1.2 Xylitol 502 1.2 The granules are divided to 600 mg/dose. The dose is Blend 2: weight out into a medical spoon and moulded by pressing the Blend 1 8O 2.4 granules against the spoon with a stopper to a thin layer about Keltrol 2O O6 1-3 mm in high in the bottom of the spoon. The water is Blend 3: evaporated at ambient temperature. Blend 2 71.4 3.0 Drop Down Test: Caramel flavour 14.32 O.S To the above dosage form 4 ml tapped water (temp. Water 14.33 O.S 25 between 15-20°C.) is added. After about 15 sec the liquid is The ingredients (1-2) of Blend 1 are mixed/2 min (depending on the amount of powder) in absorbed. The spoon is turned around and held upside down a mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). for 2 min. The test material did not fall out and pass the test. The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend and mixed for about /2 min (depending on the amount of powder). Example 14 The granules are divided into 500 mg/dose. The dose is 30 weight out into a medical spoon and moulded by gently A Composition According to the Invention pressing the granules against the spoon with a mortarpistil to Containing 120 mg Coated Cefuxime in the Dosage a thin layer about 1-3 mm in high in the bottom of the spoon. Unit The water is evaporated at ambient temperature to a final dosage of 429 mg 35 A composition in percentage having a shape as outlined in Drop Down Test: FIG. 1 containing cefuXime as active substance was prepared To the above dosage form 3 ml tapped water is added. After as follow: about /2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test material did 40 not fall out and pass the test. % Wiw 9. Example 13 Blend 1: Kelcogel LT100 40 1.195 45 Xylitol 40 1.195 A Composition According to the Invention Ketrol 2O O.6O Containing 120 mg Coated Cefuxime in the Dosage Blend 2: Unit Sodium citrate 251 O.128 Dem. water 733 0.372 A composition in percentage having a shape as outlined in 50 Keltrol 22 O.O11 FIG. 1 containing cefuXime as active substance was prepared Blend 3 as follow: Blend 1 85.4 2.99 Blend 2 14.6 O.S1 The ingredients Blend 1 are mixed in a Braun electronic mixer type 4202 for about 1 min. 55 % ww 9. The ingredients (1-2) blend 2 are dissolved in ingredient 3. Blend 3 is mixed to granueles in a Braun electronic mixer type 4202 with a dough shaft, Blend 1: The granules are divided to 600 mg/dose. The dose is Sodium citrate 251 0.157 weight out into a medical spoon and moulded by pressing the Dem. Water 752 O.470 60 granules against the spoon with a stopper to a thin layer about Blend 2: 1-3 mm in high in the bottom of the spoon. The water is Blend 1 98.04 O. 627 evaporated at ambient temperature. Keltrol 1962 O.O13 Drop Down Test: Blend 3: To the dosage form 4 ml tapped water (temp. between Blend 2 60 O.64 65 15-20°C.) is added. After about 15 sec the liquid is absorbed. Microencapsulated Cefuxime 40 O42 The spoon is turned around and held upside down for 2 min. The test material did not fall out and pass the test. US 8,383,155 B2 45 Viscosity Test: -continued Transfer 43.75 g test materials Accurately weighed into a 500 ml beaker, and disperse/dissolve with 500 ml tapped Blend 2: Water. Blend 1 50 The viscosity is measured to 60500 cps. Sodium citrate 11 PEG 200 39 Blend 3: Example 15 Kelcogel LT100 42.86 Xylitol 42.86 A Composition According to the Invention 10 Keltrol 1428 Containing 50 mg Coated Paracetamol in the Dosage Blend 4 Unit Blend 2 8O.SO Blend 3 19.50 A composition in percentage having a shape as outlined in Blend 5 FIG. 1 containing paracetamol as active Substance was pre 15 Blend 4 90.00 pared as follow: Microencapsulated paracetamol 1O.OO (61% pure paracetamol) Blen : Sodium citrate is dissolved dem. water. Blend 2: The ingredient is mixed. Blend 3: the ingredient is mixed in a mortar with a scraper or a card until all is blend. The ingredient from blend 4 is mixed in a mortar with a Sodium citrate 25 scraper or a card until all is blend. Dem. water 75 Blend 5: The ingredient from blend 5 is mixed in a mortar with a scraper Blend 2: or a card until homogeneous blend is obtained. Blend 6: Kelcogel LT100 50 Xylitol 50 25 PVP (kollidon 25k) 9.52 Blend 3: Ethanol 99.9% 85.72 Glycerol 4.76 Blend 2 75 Blend 6: PVP (kollidon 25k) is dissolved in Ethanol 99.9%, when Keltrol 12.5 dissolved Glycerol is added and blend. Apple fruit 12.5 Blend 6 is poured in a 50 ml spray flask with a nozzle. Blend 4: 30 Blend 3 74.22 Prepared spoon: The concave side of the spoons are Blend 1 12.13 Microencapsulated paracetamol 13.65 (61% pure paracetamol) sprayed twice with blend 4. The EtOH is evaporated in an oven at 45° C. for one hour. Blend 1: Sodium citrate is dissolved in dem, water, 35 The blend 5 is divided to 820 mg/dose. The dose is weight Blend 2: The ingredient from blend 2 is mixed in a mortar with a scraper or a card until all is blend. out into a prepared medical spoon and moulded by pressing Blend 3: The ingredient from blend 3 is mixed in a mortar with a scraper or a card until all the granules against the spoon with a stopper to a thin layer is blend. The ingredient from blend4 is mixedinamortar with a scraperor a card untilahomogeneous about 1-3 mm in high in the bottom of the spoon. The water is blend is obtained. evaporated at ambient temperature. The blend 4 is divided to 600 mg/dose. The dose is weight 40 Drop Down Test: out into a medical spoon and molded by pressing the granules To the above dosage form 4 ml tapped water (temp. against the spoon with a stopper to a thin layer about 1-3 mm between 15-20°C.) is added. After about 15 sec the liquid is in high in the bottom of the spoon. The water is evaporated at absorbed. The spoon is turned around and held upside down ambient temperature. for 2 min. The test material did not fall out and pass the test. Drop Down Test: 45 Example 17 To the above dosage form 4 ml tapped water (temp. between 15-20°C.) is added. After about 15 sec the liquid is A Composition According to the Invention absorbed. The spoon is turned around and held upside down Containing 200 mg Coated Paracetamol in the for 2 min. The test material did not fall out and pass the test. 50 Dosage Unit Example 16 A composition in percentage having a shape as outlined in FIG. 1 containing paracetamol as active Substance was pre A Composition According to the Invention pared as follow: Containing 50 mg Coated Paracetamol in the Dosage 55 Unit Blend 1: A composition in percentage having a shape as outlined in Gellan gum (Kelcogel LT100) SO.OO FIG. 1 containing paracetamol as active Substance was pre Xylitol SO.OO pared as follow: 60 Blend 2:

Blend 1 37.5 Microencapsulated paracetamol 52 Blend 1: (61% pure paracetamol) Glycerin 1O.S Sodium citrate 25 65 Blend 2: The ingredients from blend 1 are mixed in a mortar with a pestle, Dem. water 75 scraping as needed until homogeneous blend. US 8,383,155 B2

-continued -continued Blend 3: Microencapsulated paracetamol 38.7 (61% pure paracetamol) Povidone (kollidon 25k) 9.52 Sodium Hydrogen Carbonate 2.9 Ethanol 99.9% 85.72 Strawberry flavour 5.8 Glycerol 4.76 Blend 1: Sodium citrate is dissolved Dem. water. Blend 3: Povidone (kollidon 25k) is dissolved Ethanol 99.9% and then Blend 2: The ingredients from blend are mixed in a mortar with a pestle, Glycerol is added and dissolved. scraping as needed until homogeneous blend. Blend 4 is poured in a 50 ml spray flask with nozzle. Blend 3: The ingredients from blend are mixed in a mortar with a pestle, scraping as needed until homogeneous blend. 10 Blend 4: Prepared spoon: The concave side of the spoons are Povidone (kollidon 25k) 9.52 sprayed twice with blend 4. The EtOH is evaporated in an Ethanol 99.9% 85.72 oven at 45° C. for one hour. Glycerol 4.76 The blend 2 is divided to 630 mg/dose. The dose is weight Blend 4: Povidone (kollidon 25k) is dissolved Ethanol 99.9% and then out into a prepared medical spoon and moulded by pressing 15 Glycerol is added and dissolved. the granules against the spoon with a stopper to a thin layer Blend 4 is poured in a 50 ml spray flask with nozzle. about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature. Prepared spoon: The concave side of the spoons are Drop Down Test: sprayed twice with blend 4. The EtOH is evaporated in an To the above dosage form 4 ml tapped water (temp. oven at 45° C. for one hour. between 15-20°C.) is added. After about 15 sec the liquid is The blend 3 is divided to 880 mg/dose. The dose is weight absorbed. The spoon is turned around and held upside down out into a prepared medical spoon and moulded by pressing for 2 min. The test material did not fall out and pass the test. the granules against the spoon with a stopper to a thin layer Dissolution about 1-3 mm in high in the bottom of the spoon. The water is 25 Material and Methods evaporated at ambient temperature. Drop Down Test: Simulated gastric Fluid. For 1 L: 0.1 HHC1 To the above dosage form 4 ml tapped water (temp. Dissolution system consists of online system model between 15-20°C.) is added. After about 15 sec the liquid is SOTAX AT7 and UV detector Model PE lambda 2 using absorbed. The spoon is turned around and held upside down Disslab version 1.1. 30 for 2 min. The test material did not fall out and pass the test. The dissolutions curve was obtain with Temp37°C., Speed 120 rpm, 280 nm and a factor of 108 over a period of 1 h. Example 19 Results and Discussion FIG. 2 illustrates the dissolutions profile of a Paracetamol dosage unit in simulated gastric fluid. After 5 minat least 96% 35 A Placebo Composition According to the Invention of the Paracetamol is released. The curve with the dot-line is pure coated paracetamol used A composition that has a shape as outlined in FIG. 1 was in the dosage form; After 5 min at least 96% of the Paraceta prepared as follows (given as % w/w): mol is released. Comparing pure coated paracetamol and the Paracetamol 40 dosage unit no differences between the release profiles are Blend 1: See. Sodium citrate 25 Demineralized water 75 Example 18 45 Blend 2: Kelcogel LT100 50 A Composition According to the Invention Xylitol 50 Containing 250 mg Coated Paracetamol in the Blend 3: Dosage Unit Blend 1 11.2 50 Blend 2 8O A composition in percentage having a shape as outlined in Sodium hydrogen carbonates 3 FIG. 1 containing paracetamol as active Substance was pre Strawberry flavoribanana flavor 5.8 pared as follow: Blend 1: Sodium citrate is dissolved dem. Water, Blend 2: The ingredients from blendare mixed in a mortar with a pestle, scraping as needed 55 until homogeneous blend. Blend 3: The ingredients from blendare mixed in a mortar with a pestle, scraping as needed until homogeneous blend. Blend 1: The blend 3 is divided into 250 mg/dose. The dose is Sodium citrate 25 weight out into a medical spoon and molded by gently press Demineralized water 75 60 ing the granules against the spoon with a mortarpistil to a thin Blend 2, layer about 1-3 mm in high in the bottom of the spoon. The Gellan gum (Kelcogel LT100) SO.OO water is evaporated at ambient temperature. Xylitol SO.OO Drop Down Test: Blend 3: To the above dosage form 3 ml tapped water is added. After Blend 1 42.7 65 about /2 min the liquid is absorbed. The spoon is turned Blend 2 9.8 around and held upside down for 2 min. The test material did not fall out and pass the test. US 8,383,155 B2 49 50 In-vivo Ultra Sound Scanning Test Drop Down Test: In vivo properties of the above placebo formulations were To the above dosage form 3 ml tapped water is added. After determined in a subject who had fasted for 8-12 hours prior to about /2 min the liquid is absorbed. The spoon is turned ingesting 250 mL of water and 5 min after havingingested the around and held upside down for 2 min. The test material did prepared dosages form. Ultrasound imaging was performed 5 not fall out and pass the test. in sitting position throughout the procedure. B-mode ultrasound imaging of the gastrointestinal tract Example 21 was done with a LOGIO (4-10 MHz) linear transducer (Lin ear 10L H40412LG) coupled to a LOGIQ 9 Ultrasound A Placebo Composition for Use According to the instrument with software version R3.0.11 abdominal pro 10 Invention gram (8 MHz). Images were videotaped before ingestion of water and immediately prior to ingestion of the dosage form A composition that has a shape as outlined in FIG. 1 was (time 0) and at five minutes intervals thereafter. prepared as follows (given as % w/w): FIG. 3 demonstrates that the ingested water appeared “black” in the ultrasonic image. FIG. 4 demonstrates that the 15 ingested dosages form appeared “white' in the ultrasonic image. Blend 1: Shortly after ingestion of the water the stomach lumen Kelcogel LT100 50 became Sonolucent and non-echogenic and thus appeared Xylitol 50 “black” in the ultrasonic image and after ingestion of the Blend 2: dosage form the stomach lumen became Sonolucent and Blend 1 83.3 echogenic and thus appeared “white' in the ultrasonic image. Medium Chain Triglyceride EP S.6 As seen from the picture FIG. 5 the dosage form is spread (Labrafiac cc) through out the stomach, which indicate that the dosage form Povidone (kollidon 25k) S.6 is totally disintegrated when reaching the stomach. 25 Vanilla flavour S.6 Blend 1: The ingredients from blend are mixed in a mortar with a pestle, scraping as needed until homogeneous blend. Example 20 Blend 2: blend 1 is mixed with Medium Chain Triglyceride EP (Labrafiac cc) in a mortar with a pestle, scraping as needed until A Placebo Composition for Use According to the homogeneous blend and Povidone (kollidon 25k) is added mixed to a 30 homogeneous blend, Vanilla flavour is added to the mixture and blend to Invention a homogeneous mass. Blend 3: A composition that has a shape as outlined in FIG. 1 was prepared as follows (given as % w/w): Povidone (kollidon 25k) 9.52 Ethanol 99.9% 85.72 35 Glycerol 4.76 Blend 3: Povidone (kollidon 25k) is dissolved in Ethanol 99.9% and Glycerol is added to the mixture and dissolved. Blend 1: Blend 4 is poured in a 50 ml spray flask with nozzle. Kelcogel LT100 50 Xylitol 50 Prepared spoon: The concave side of the spoons are Blend 2: 40 sprayed twice with blend 3. The EtOH is evaporated in an Blend 1 92.4 oven at 45° C. for one hour. Povidone (kollidon 25k) O.S Strawberry flavoribanana?vanilla flavor 7.1 The granules are divided to 250 mg/dose. The dose is Blend 3: weight out into a prepared medical spoon and moulded by 45 pressing the granules against the spoon with a stopperto a thin Blend 1 93.8 Ethanol 99.9% 6.2 layer about 1-3 mm in high in the bottom of the spoon. The Blend 1: Kelcogel LT100 and Xylitol are mixed in a mortar with a pestle, water is evaporated at ambient temperature. scraping as needed until homogeneous blend. Drop Down Test: Blend 2: The ingredients from blend 2 are mixed in a mortar with a pestle, To the above dosage form 3 ml tapped water is added. After scraping as needed until homogeneous blend. Blend 3: The ingredients from blend 3 are mixed in a mortar with a pestle, 50 about /2 min the liquid is absorbed. The spoon is turned scraping as needed until homogeneous blend. around and held upside down for 2 min. The test material did Blend 4: not fall out and pass the test. Povidone (kollidon 25k) 9.52 Ethanol 99.9% 85.72 Example 22 Glycerol 4.76 55 Blend 4: Povidone is dissolved in Ethanol and then Glycerol is added Oral Hygiene Composition for use Directly in the and dissolved. Mouth Cavity With or Without Prehydration Blend 4 is poured in a 50 ml spray flask with nozzle. A composition in percentage having a shape as outlined in Prepared spoon: The concave side of the spoons are 60 FIG. 1 was prepared as follow: sprayed twice with blend 4. The EtOH is evaporated in an oven at 45° C. for one hour. The granules are divided to 300 mg/dose. The dose is weight out into a prepared medical spoon and moulded by Blend 1: pressing the granules against the spoon with a stopperto a thin 65 Xylitol 86.6 layer about 1-3 mm in high in the bottom of the spoon. The Glycerol 13.4 water is evaporated at ambient temperature. US 8,383,155 B2 52 -continued Example 24 Blend 2: A Composition According to the Invention Blend 1 S3.6 Containing 250 mg Paracetamol Kelcogel LT100 46.4 Blend 1: Xylitol is mixed with glycerolin a Braun electronic kitchen mixer at level 4, for 2 A composition that has a shape as outlined in FIG. 1 was find 2: The ingredient from blend 2 is mixed in the Braun Electronic kitchen mixer until all prepared as follows: is blend. Sieved through a sieve mesh. The two blends are mixed and pressed into plates with a 10 thickness of approximately 2 mm and cut into pieces of 1x2 % Wiw 9. cm. The flakes are dried in an oven (Electrolux) at 45° C. for /2 h. Blend 1: The flakes are placed in the oral cavity where the formula Kelcogel LT100 50 18.78 tion will be hydrated by the saliva and any local active 15 Xylitol 50 18.78 released or the formulation can be added conventional toot Blend 2: paste components and dried on tooth brushes or on other Vanilla Flavour 92.2 2.25 devices for mechanical cleaning within the oral cavity. PVPK2 7.8 O.19 end 3:

Example 23 Blend 1 42.8 6.24 Blend 2 2.76 O4O2 A Placebo Composition According to the Invention Glycero 3.42 O499 Paracetamol 40.6 S.92 Glycero 1O.S 1.53 A composition that has a shape as outlined in FIG. 1 was Blend 4: prepared as follows: 25 PVPK25 9.5 4.OO Glycero 4.8 2.00 Ethanol 99.9% 85.7 36.O1 % Wiw 9. Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is 30 formed. Blend 1 Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under mixing to form a homogeneous blend, Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or Kelcogel LT100 50 18.78 mixing card. Glycerol is added stepwise under continuous slow mixing and a uniform Xylitol 50 18.78 granulate is formed. Paracetamol is added under continuous slow mixing and the final part of Glycerol is added to form a uniform granulate, Blend 2 Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. The 35 Glycerol is added and stirred until a clear mixture is obtained. Blend4 is poured into a 50 ml Vanilla Flavour 92.2 2.25 spray flask with nozzle, PVP K25 7.8 O.19 end 3 Medical spoon preparation: The concave side of a medical spoon is sprayed twice with Blend 4 (approximately 60 mg) Blend 1 88.89 37.56 Blend 2 5.78 2.44 and placed in an oven at 45° C. for 30 minutes. Glycerol 5.33 2.25 40 616;t20 mg/dose is weight into a prepared medicine spoon Blend 4 and distributed by pressing the granules against the spoon PVP K25 9.5 4.OO with a stopper. The final layer of granules lay in the bottom of Glycerol 4.8 2.00 the spoon and is approximately 2 mm in height. topspray Ethanol 99.9% 85.7 36.O1 Drop Down Test: 45 Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is To the above dosage form 5 ml tapped water is added. After formed. about 30 seconds the liquid is absorbed. The spoon is turned Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under mixing to form a homogeneous blend, around and held upside down for 2 min. The test material did Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or mixing card. The Glycerol is added stepwise under continuous slow mixing and a uniform not fall out and pass the test. granulate is formed. Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. The 50 Glycerol is added and stirred until a clear mixture is obtained. Blend 4 is poured into a 50 ml Example 25 spray flask with nozzle, Medical spoon preparation: The concave side of a medical A Composition According to the Invention spoon is sprayed twice with Blend 4 (approximately 60 mg) Containing 415 mg Coated Paracetamol and placed in an oven at 45° C. for 30 minutes. 55 (Corresponding to 250 mg Paracetamol) 335-17.5 mg/dose of Blend 3 is weight into a prepared medicine spoon and distributed by pressing the granules against the spoon with a stopper. The final layer of granules A composition that has a shape as outlined in FIG. 1 was lay in the bottom of the spoon and is approximately 2 mm in prepared as follows: height. The spoon is sprayed twice with blend 4 (approxi 60 mately 60 mg) and placed in an oven at 45° C. for 30 minutes, evaporating the ethanol. % Wiw 9. Drop Down Test: To the above dosage form 5 M1 tapped water is added. After Blend 1: about 30 seconds the liquid is absorbed. The spoon is turned 65 Kelcogel LT100 50 18.78 around and held upside down for 2 min. The test material did Xylitol 50 18.78 not fall out and pass the test. US 8,383,155 B2 54 -continued After cell diagnostics, replace Diluent buffer from the Standard vessel with 250 ml of standard solution (0.2 mg % Wiw 9. paracetamol/ml). Blend 2

Vanilla Flavour 92.2 2.25 PVPK25 7.8 O.19 Analytical principle Online UW end 3: API Paracetamol Method USP2 (paddle) Blend 1 33.2 1O.S Degassing Vacuum filtration at 41° C. Blend 2 2.15 O.678 10 Temperature 37°C. O.S. C. Glycerol 2.66 O840 Volume 900 + 0.2% (895 ml + 4 ml) Coated Paracetamol 57.1 18.06 Detection 280 nm. Glycerol 4.81 1.52 Rotation speed 50 rpm Blend 4: Filters 0.7 Full Flow Filter Detection frequency every 5 min. in 60 minutes PVPK25 9.5 4.OO 15 Glycerol 4.8 2.OO Ethanol 99.9% 85.7 36.01 Sample Preparation: Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is Carefully remove the shaft from the spoon using a pair of formed. Scissors. Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under mixing to form a homogeneous blend, Place sinker on outer bottom of the spoon unit. Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or mixing card. Glycerol is added stepwise under continuous slow mixing and a uniform Add 4 ml of tapped water (room temperature) to the test granulate is formed. Coated Paracetamol is added under continuous slow mixing and the unit. final part of Glycerol is added to form a uniform granulate, Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. The Results: Glycerol is added and stirred until a clear mixture is obtained. Blend4 is poured into a 50 ml spray flask with nozzle, TABLE 1 Medical spoon preparation: The concave side of a medical 25 spoon is sprayed twice with Blend 4 (approximately 60 mg) Release Time and 90 dissolved material as a function of pH. and placed in an oven at 45° C. for 30 minutes. Release time where less 720-20 mg/dose is weight into a prepared medicine spoon than 0.5% increase from and distributed by pressing the granules against the spoon last measurement with a stopper. The final layer of granules lay in the bottom of 30 Solution pH (A-0.5% absolute) % Dissolved, 60 min. the spoon and is approximately 2 mm in height. O.1NHCI 1 35 93.9 50 90.4 Drop Down Test: O.OSM 4.5 15 90.8 To the above dosage form 5 M1 tapped water is added. After Phosphate 10 90.8 about 30 seconds the liquid is absorbed. The spoon is turned 35 O.OSM 6.8 15 85.4 around and held upside down for 2 min. The test material did Phosphate 10 86.8 not fall out and pass the test. Dissolution Testing: Conclusions: For dissolution spoons prepared as described above was The results demonstrate a fast dissolution rate of the parac places in a dissolution medium after removal of the handle 40 etamol from the test product. However, at low pH the release and aided by a sinker glued to the outer concave bottom is relatively slower compared to pH 4.5 and 6.8. Note that the whereby the spoons were located in the bottom of each of the gellangum does not dissolve once gelled hence all dissolution dissolution vessels comprising 900 ml medium and equipped vessels contain a high amount of non-dissolving Substances. with a paddle rotating at 50 rpm. Besides the pH difference of the media the difference in ionic Media: 45 composition should be noted as this possibly could affect 0.1 NHCl-pH 1 (test media 1): Vessel 5 and 6 drug release. Furthermore, it is noted that drug release is Ad 1000 ml of purified water into a 5000 ml blue cap flask. approx. 91-94%at pH 1 and 4.5 and 85-87% at pH 6.8. As this Add carefully 25.5 ml 37 w/w% HCl into the 5000 ml blue test was done on n=2 it is not possible to conclude if this is cap flask. significant and it could be related to the specific coating of the Add purified water until 3000 ml is reached. 50 paracetamol. Measure the pH of the solution During dissolution it is seen that the formulation disinte 0.05M Phosphate solution pH 4.5 (test media 2): Vesses13 grates in all 3 media as illustrated in the photographs pre and 4 sented in FIGS. 6, 7, and 8 with fine homogeneous material Add 750 ml of a 0.2M KH2PO4 solution (prepare accord most prominent in buffer solution pH 6.8 (FIG. 8). Slightly ing to QCF026) in to a 5000 ml blue cap flask. 55 bigger, however still homogeneous fluffy flakes of material Add 2250 ml Elix water. are seen at pH 4.8 (FIG. 7). At low pH, the formulation still Measure the pH of the solution. The pH changed to 4.8 completely disintegrates into more inhomogeneous material after addition of sample. with individual flakes varying in size from approximately 1 to 0.05M Phosphate standard solution pH 6.8 (test media 3) 5 mm (FIG. 6). Vessel 1 and 2 60 The dissolution result appears from FIG. 9 Dissolution Procedure: A similar result has been obtained with the following Place 895 g of degassed dissolution medium in vessel 1 to media: 6. Simulated Gastric Fluid, (0.072M cation) modified SGF Vessel 1 and 2: Phosphate buffer pH 6.8. USP as without enzymes and with 2.1 x cations in 6 vessels: Vessel 3 and 4: Phosphate solution pH 4.5. 65 Add 5000 ml of purified water into a 25L plastic container. Vessel 5 and 6:0.1 NHC1. Add carefully 70 ml 37 w/w % HCl in to the plastic con Place 200 ml of Diluent buffer in the Standard vessel. tainer. US 8,383,155 B2 55 56 Weigh 42.07 g.0.1 g NaCl and add it to the plastic con and increases the range of water resulting necessary for tainer. obtaining a sufficient gelling as the 50%/50% mixture is less Dissolve the salt and add purified water until 10000 ml is sensitive to the amount of water added than the mixture com reached. prising 20% Xylitol. Clearly the less gellan gum present, the Measure the pH of the solution. less water shall be added to avoid inconvenient presence of excess water in the formulation. Example 26 TABLE 2 A Composition According to the Invention Containing 200 mg Coated Ibuprofen 10 A. B C D E (blind) Gellan 1OO 8O 50 2O O A composition that has a shape as outlined in FIG. 1 was Gum 96 Xylitol % O 2O 50 8O 1OO prepared as follows: Water 3, 4, 5 ml 4 and 5 ml 4 and 5 ml 3 ml 3 ml added to 15 spoon(s) Gelling Insufficient Sufficient Sufficient Good No gelling % Wiw 9. quality gelling for gelling gelling gelling, and all 3 spoons with 5 ml with 4 ml however Blend 1: time as dry only. as well as (XCESS granule Gelling 5 ml water water Kelcogel LT100 50 18.72 is still time added and present Xylitol 50 1876 present in between completed Blend 2: the spoons 10-12 sec. within 10 after 30 Seconds. Vanilla Flavour 92.2 2.24 Seconds. PVP K2 7.8 O.19 end 3: 25 Blend 1 50.7 5.67 The invention claimed is: Blend 2 3.29 O.33 1. A solid dosage form for oral administration comprising Glycerol 6.OO O60 one or more active substances blended with a swellable Coated Ibuprofen 40.O 4.OO Blend 4: vehicle comprising 20-80% by weight of a swellable gellan 30 gum, or Swellable mixture of gellan gums, arranged in a PVP K25 9.5 4.OO configuration allowing optimal water diffusion so that upon Glycerol 4.8 2.00 addition of a predetermined amount of an aqueous medium, Ethanol 99.9% 85.7 36.O1 without the necessity of applying shear forces or other mixing Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is forces, within a time period of 5 minutes or less, the compo formed. 35 Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under sition Swells and/or gels; mixing to form a homogeneous blend, wherein the gellangum is acylated within a degree of up to Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or mixing card. Glycerol is added stepwise under continuous slow mixing and a uniform 4 per every two repeats of the glucose-rhamnose-glu granulate is formed. Ibuprofen is added stepwise under continuous slow mixing, Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. cose-glucoronic acid unit of the polymer, and Glycerol is added and stirred until a clear mixture is obtained. Blend 4 is poured into a 50 ml the swellable vehicle further comprises a hydrophilic agent spray flask with nozzle, 40 Selected from the group consisting of electrolytes, Medical spoon preparation: The concave side of a medical organic acids and osmotic agents, and mixtures thereof, spoon is sprayed twice with Blend 4 (approximately 60 mg) that improves Swelling of the gellan gum, and and placed in an oven at 45° C. for 30 minutes. the texture of the swelled composition being similar to that 500+20 mg/dose is weight into a prepared medicine spoon of a soft pudding and having a viscosity of at least about and distributed by pressing the granules against the spoon 45 10,000 cps as measured by a BrookfieldViscometer with with a stopper. The final layer of granules lay in the bottom of a #4 LV spindle at 6 rpm and at 20-25° C. by a test the spoon and is approximately 2 mm in height. The spoon is method wherein 22-88 g test material is accurately sprayed twice with blend 4 (approximately 60mg) and placed weighed and placed in a 500 ml beaker, 500 ml tap water in an oven at 45° C. for 30 minutes, evaporating the ethanol. is added, the contents are mixed until all the test material Drop Down Test: 50 is dispersed/dissolved, and after about 5 minutes the To the above dosage form 5 M1 tapped water is added. After viscosity and temperature are measured by centering the about 30 seconds the liquid is absorbed. The spoon is turned Viscometer spindle in the test sample container and around and held upside down for 2 min. The test material did immersing the spindle to the mid-point of the shaft’s not fall out and pass the test. narrow portion. 55 2. A Solid dosage form according to claim 1, in the form of Example 27 a unit dosage form. 3. A Solid dosage form according to claim 2, in the form of Guideline Regarding Effective Ratio Between Gellan granulates contained in a capsule, cachet or Sachet. Gum Granulated with Xylitol with Respect to 4. A Solid dosage form according to claim 2, in the form of Gelling Time and Amount of Water Necessary for 60 a tablet. Obtaining an Efficient Gel (300 mg of Mixture) 5. A solid dosage form according to claim 4, wherein the tablet is produced by low-pressure compression, extruding, Xylitol enables waterpenetration in the granula and secure molding or calendaring. a fast and efficient hydration of the gum. Binder used is 6. A Solid dosage form according to claim 2, in the form of glycerol 7.0% weight of total formulation. Granulating pro 65 a tape or laminate. cedure identical with placebo formulation of Example 23. As 7. A solid dosage form according to claim 2, provided in a appears from the Table 2 Xylitol decreases the gelling time dispensing unit incorporating the solid dosage form. US 8,383,155 B2 57 58 8. A solid dosage form according to claim 7, wherein the 16. A dispensing unit according to claim 12, in the form of dispensing unit is a spoon. a Spoon. 9. A dispensing unit for oral administration comprising a 17. A dispensing unit according to claim 13, in the form of Solid dosage form according to claim 1. a Spoon. 10. A dispensing unit according to claim 9, in unit dosage 18. A kit comprising a solid dosage form according to form. claim 2, and instructions to combine the solid dosage form 11. A dispensing unit according to claim 9, wherein one or with a measured amount of water prior to administration. more active substances and the Swellable vehicle are adhered 19. A kit comprising a solid dosage form according to or glued to a Surface of the dispensing unit. claim3, and instructions to put the granulates into a measured 12. A dispensing unit according to claim 11, wherein the 10 amount of water prior to administration. one or more active substances and the Swellable vehicle are 20. A kit comprising a solid dosage form according to glued to a surface of the dispensing unit with a glue that claim 4, and instructions to put the tablet into a measured comprises one or more components in liquid form or in solu amount of water prior to administration. tion selected from the group consisting of Sugar alcohols, 21. A kit comprising a solid dosage form according to Sugars, polyvinylpyrrolidone (PVP), and gums. 15 claim 7, and instructions to add a measured amount of water 13. A dispensing unit according to claim 12, wherein the to the dispensing unit prior to administration. glue comprises a mixture of PVP and glycerol. 22. A kit comprising a solid dosage form according to 14. A dispensing unit according to claim 9, having a con claim 8, and instructions to add a measured amount of water cave Surface. to the spoon prior to administration. 15. A dispensing unit according to claim 9 in the form of a 20 Spoon. k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,383,155 B2 Page 1 of 1 APPLICATIONNO. : 13/212679 DATED : February 26, 2013 INVENTOR(S) : Daniel Bar-Shalom et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title Page of the Patent: Please change the assignee information, (item 73) from: “EGALET A/S, Vaerlose (DK) to:-- EGALET LTD., London (GB) --.

Signed and Sealed this Seventeenth Day of September, 2013

Teresa Stanek Rea Deputy Director of the United States Patent and Trademark Office