US 201200399.69A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0039969 A1 Bar-Shalom et al. (43) Pub. Date: Feb. 16, 2012
(54) SWELLABLE DOSAGE FORM COMPRISING A 6LX 3L/75 (2006.01) GELLAN GUMI A6II 3/167 (2006.01) A6IR 8/00 (2006.01) (75) Inventors: Daniel Bar-Shalom, Kokkedal A61O II/00 (2006.01) (DK); Lillian Slot, Virum (DK); A6IP 43/00 (2006.01) Gina Fischer, Vaerlose (DK); A6IP 29/00 (2006.01) Pernille Hoyrup Hemmingsen, A6IR 9/00 (2006.01) Bagsvaerd (DK) A63L/92 (2006.01) (73) Assignee: EGALET A/S (52) U.S. Cl...... 424/401; 424/400; 424/451; 514/207; 514/277; 514/502: 514/570; 514/54: 514/629; (21) Appl. No.: 13/212,679 424/49 (22) Filed: Aug. 18, 2011 (57) ABSTRACT Related U.S. Application Data A novel dosage form. The dosage form is presented in par ticulate form and before oral ingestion the particulate mate (62) Division of application No. 1 1/596,123, filed on Aug. rial is subjected to an aqueous medium, whereby it is con 14, 2007, filed as application No. PCT/DK2005/ Verted to a semi-solid form by Swelling or gelling of one or 000317 on May 11, 2005. more of the components, especially of a gellan gum, of the particulate matter. The invention also relates to a vehicle for (30) Foreign Application Priority Data oral administration of one or more active Substances, the vehicle comprising a gellan gum arranged in a configuration May 11, 2004 (DK) ...... PA 2004 OO755 allowing optimal water diffusion so that upon addition of a predetermined amount of an aqueous medium, without the Publication Classification necessity of applying shear forces or other mixing forces, (51) Int. Cl. within a time period of 5 minutes or less swells and/or gels A6 IK 8/02 (2006.01) and the texture of the swelled vehicle being similar to that of A6 IK 9/48 (2006.01) a soft pudding and having a viscosity of at least about 10,000 A6 IK3I/546 (2006.01) cps as measured by a Brookfield Viscometer with a #4 LV A6 IK 3/44 (2006.01) spindle at 6 rpm and at 20-25°C. In one embodiment of the A 6LX 3L/295 (2006.01) invention, the particulate matter can be molded into a desired A61O I/00 (2006.01) shape or pressed onto a dispensing unit such as a spoon.
Patent Application Publication Feb. 16, 2012 Sheet 1 of 10 US 2012/00399.69 A1
Patent Application Publication Feb. 16, 2012 Sheet 2 of 10 US 2012/00399.69 A1
-- 61%. Coated Paracetamol -- 200 mg Paracetamol parvulet -a-200 mg Paracetamol parvulet -X-200 mg Paracetamol parvulet -- 200 mg Paracetamol parvulet -e-200 mg Paracetamol parvulet - --w
time min Patent Application Publication Feb. 16, 2012 Sheet 3 of 10 US 2012/00399.69 A1
Figure 3 Patent Application Publication Feb. 16, 2012 Sheet 4 of 10 US 2012/00399.69 A1
Figure 4 Patent Application Publication Feb. 16, 2012 Sheet 5 of 10 US 2012/00399.69 A1
Figure 5 Patent Application Publication Feb. 16, 2012 Sheet 6 of 10 US 2012/00399.69 A1
Figure 6 Patent Application Publication Feb. 16, 2012 Sheet 7 of 10 US 2012/00399.69 A1
Figure 7 Patent Application Publication Feb. 16, 2012 Sheet 8 of 10 US 2012/00399.69 A1
Figure 8 Patent Application Publication Feb. 16, 2012 Sheet 9 of 10 US 2012/00399.69 A1
0m Wessel 1 mum Wesses 2 -- Wesse 3 -ehr Wesse 4 mer Wesse 5 vessel 6
O t y t t w O 10 20 3G 40 50 60 70
w Time (min) vom- -
Fig. 9 Patent Application Publication Feb. 16, 2012 Sheet 10 of 10 US 2012/00399.69 A1
Fig. 10 US 2012/00399.69 A1 Feb. 16, 2012
SWELLABLE DOSAGE FORM COMPRISING large or that many tablets or capsules must be administered GELLAN GUMI simultaneously, in either case, causing discomfort. The multi particles may be presented as a powder. This powder might FIELD OF THE INVENTION then be formulated into tablets or capsules meant to be swal lowed whole. Those tablets and capsules as Such are inappro 0001. The present application relates to a novel dosage priate for patients with Swallowing difficulties. Patients (or form. The dosage form is presented in particulate form and they providers in the case of children) are often instructed to before oral ingestion the particulate material is subjected to open the capsules (or crush the tablets) and to sprinkle the an aqueous medium, whereby it is converted to a semi-solid powder on syrup or pudding or applesauce or similar and then form by Swelling or gelling of one or more of the components, administered. This approach has limitations. The carrier especially of a gellan gum, of the particulate matter. The (syrup, pudding, applesauce) is not a well defined entity and invention also relates to a vehicle for oral administration of different carriers might interact differently with the multi one or more active Substances, the vehicle comprising a gel particles and/or drug and thereby compromise the treatment. langum arranged in a configuration allowing optimal water Also, children might object to the grittiness in the material. diffusion so that upon addition of a predetermined amount of Syrups do not necessarily resemble types of food or bever an aqueous medium, without the necessity of applying shear ages that children are used to consume. forces or other mixing forces, within a time period of 5 0005. Alternatively the powder can be formulated into minutes or less swells and/or gels and the texture of the effervescent granules or tablets. These granules or tablets are swelled vehicle being similar to that of a soft pudding and intended to be dissolved in an aqueous liquid requiring the having a viscosity of at least about 10,000 cps as measured by provision of a glass of liquid and a waiting period sufficient to a BrookfieldViscometer with a #4 LV spindle at 6 rpm and at allow the tablet to completely dissolve and the resulting vol 20-25 o C. ume might be considerable. Often, these dosage forms leave 0002. In one embodiment of the invention, the particulate an objectionable deposit in the glass, which may represent a matter can be molded into a desired shape or pressed onto a non-ingested part of the drug. Effervescent formulations are, dispensing unit Such as a spoon. in general more appropriate for adults although some com mercial vitamin preparations for children use this approach. BACKGROUND OF THE INVENTION 0006 Another category is the fast-melting tablets meant to 0003. A recurring problem in the treatment of patients, in be put on the tongue and disintegrate upon contact with saliva. particular children and the elderly, is their inability or unwill The might be effervescent or non-effervescent. Yet another ingness to Swallow solid oral dosage forms such as tablets or Solution is to dispense the multi-particles in lozenges, chew capsules. The problem is, however, not uncommon in healthy able tablets and chewing gum. adults as well. This problem is not trivial, the inability or 0007. One example of these approaches was described in unwillingness of some people to take Solid oral dosage forms Wehling et al., U.S. Pat. No. 5,178.878, which relates to can severely compromise the patient's compliance with a certain effervescent dosage forms including microparticles. prescribed treatment protocol. Moreover, due to embarrass The effervescent dosage forms of Wehling et al. provide a ment, many patients are unwilling to tell their doctor of their significant advance over the art in that they provide an effer problem so that the doctor can consider other drugs and/or Vescent dosage form for direct oral administration. The dos alternate dosage forms. Such a lack of compliance can com age form is designed to disintegrate rapidly in the mouth promise treatment or cure. releasing its microparticles as a slurry for ingestion. The 0004 Ifan orally administered drug has such a taste that is dosage forms produced in accordance with Wehling et al. can acceptable to the patient and the pharmacokinetic character be placed in the patient's mouth and the effervescence con istics allow reasonable administration regimens, such as once tained therein will be activated by contact with the patient’s or twice daily, the drug might be formulated in a sirup, elixir, saliva. The tablet will then disintegrate in a number of sec Suspension or other liquid dosage forms. Unfortunately, in onds. However, the effervescence on the tongue may be many cases the native taste of the drug is unpleasant and not unpleasant to Some adults and to many children. amenable to taste-masking by the addition of Sweeteners of 0008 Kallstrand, et al., U.S. Pat. No. 4,994.260 relates to flavours. Also, many drugs have such pharmacokinetic a pharmaceutical mixture. The mixture is used for the con parameters that demand administration at short intervals, dis trolled release of a Substance. According to Kallstrand et al., rupting sleep and other activities. The taste and/or pharma a liquid dosage form is produced using either a dry powder or cokinetic deficiencies can be corrected by the use of various microcapsules, which are Suspended in a solution of a release coating and/or matrices and/or by modifying the crystalline controlling Substance, also referred to as a "sink. Alterna structure, etcetera. U.S. Pat. No. 6,589,955 illustrates such an tively, it is possible to encapsulate the release-controlling approach. The resulting material after micro-encapsulation or Substance, together with a drug, within an encapsulating crystallization or other strategies might be a monolithical shell. The release-controlling Substance may include, inter unit, one unit containing the whole dose, or multi-particles, alia, carbohydrates and carbohydrate-related compounds, each particle containing a fraction of the total dosage. The disaccharides, monosaccharides, glycerol, glycol, glycosides monolithical units are often unacceptable to people having of monosaccharides and Substances derived from ethyleneg the swallowing problems described above. The multi-par lycol. ticles must be further processed into finished dosage forms 0009 Boder et al., U.S. Pat. No. 5,126,151 relates to an Such as tablets and capsules with the same limitation as the encapsulation mixture. Boder et al. refers to the construction monolithical units or other forms specifically designed for of gums and candies in oral dosage forms. According to children and/or adults unable to swallow oral solid dosage Boder et al., microcapsules are produced including a core forms. Finally, some substances are administered in Such high material which can be selected from a wide variety of mate doses that the resulting tablets or capsules are either very rials including Sweeteners, medicaments, drugs, flavoring US 2012/00399.69 A1 Feb. 16, 2012
agents and the like. These materials can be used, either sin vehicle comprising a gellan gum arranged in a configuration gularly or in combination, in either a single or multiple part allowing optimal water diffusion so that upon addition of a delivery systems. That is, one or more of these materials may predetermined amount of an aqueous medium, without the be present within one coating matrix or maybe separately necessity of applying shear forces or other mixing forces, coated by the matrix and employed alone or in combination in within a time period of 5 minutes or less swells and/or gels the final product. The resulting formulations are said to be and the texture of the swelled vehicle being similar to that of able to provide a masking of unpleasant tasting drugs such as a soft pudding and having a viscosity of at least about 10,000 potassium chloride and the like, making consumption of the cps as measured by a Brookfield Viscometer with a #4 LV drug more appealing to the public. The dosage forms may be spindle at 6 rpm and at 20-25 °C. prepared in chewable tablet form. 0017 Dispersing, wetting/hydrating, dissolving gelling 0010 Schobel et al., U.S. Pat. No. 4,824,681, and Wei et agents in water to form colloidal dispersions is a notoriously al., U.S. Pat. No. 4,590,075. Encapsulated sweeteners have difficult procedure A discussion of the general properties of also been used to provide an extended release of Sweetening colloidal dispersions and their preparation can be found in: in, for example, chewing gum, see for example European Remington; The Science and Practice of Pharmacy, 20" Edi patent application EPO 87-810747 to Schobel et al. and in tion, A. R. Gennaro et al editors, published in 2000 by Lip bakery products such as disclosed in WO 91-US9434 filed pincott Williams and Wilkins (Chapter 21). Diverse tech Dec. 17, 1991 to Redding et al. niques are involved, among them stirring, shaking, heating/ 0011. Further, in WO 01/76610 Simek et al describe a cooling, slow and gradual addition of the gelling agent to the pharmaceutical composition containing calcium or mixture liquid, etcetera. This explains why the in the directions of use of calcium and vitamin D or mixture of calcium and magne of the so called “Instant Puddings” or “Instant Creams' or sium and adjuvants, presented in the form of soluble powder, “Instant Sauces instructions such as “add the powder slowly which by addition of liquids and mechanical mixing, forms a to the boiling water or “stir vigorously” or “let it stand for 30 gelatinous Suspension resembling a pudding. minutes' are often found. 0012 U.S. Pat. No. 6,709,678 discloses an oral pharma 0018. In another aspect, the invention relates to a pharma ceutical composition to be dispersed in an aqueous carrier ceutical composition for oral administration comprising one prior to administration comprising a multiplicity of particles or more active Substances and a gellan gum arranged in a consisting of a drug core individually coated with one or more configuration allowing optimal water diffusion so that upon layers with a hydratable polymer. The preferred hydratable addition of a predetermined amount of an aqueous medium, polymers are preferably alginates, carboxymethylcellulose, without the necessity of applying shear forces or other mixing hydroxypropylmethylcellulose and polyvinylpyrrolidone. forces, within a time period of 5 minutes or less, the compo The coating is applied by conventional coating methods with sition swells and/or gels and the texture of the swelled com a powder mixture in a spheronizer or by spraying on a solu position being similar to that of a soft pudding and having a tion or Suspension of the coating materials to the core. The viscosity of at least about 10,000 cps as measured by a Brook aim of the hydrated formulation is to obtain a formulation in field Viscometer with a #4 LV spindle at 6 rpm and at 20-25 a single, slippery, non disintegrating mouldable coherent vis C cous plastic mass, which does not adhere to the mucosa. 0019. In a still further aspect, the invention relates to a 0013 WO2004/096906 A1 discloses a thickenable com dispensing unit comprising a pharmaceutical composition for position in water-containing liquid form which upon adition oral administration comprising one or more active substances of further water increases in viscosity. The composition com and a gellan gum arranged in a configuration allowing opti prises different anionic polymers such as Xanthan together mal water diffusion so that upon addition of a predetermined withalginate, carboxymethylcellulose, carrageenan, an acry amount of an aqueous medium, without the necessity of late polymer or pectin. applying shear forces or other mixing forces, within a time 0014 WO 2005/007074 A2 published on 27 Jan. 2005 period of 5 minutes or less, the composition Swells and/or gels discloses a gellan gum based oral controlled release dosage and the texture of the swelled composition being similar to form for gastric retention. The formulation is swallowed in a that of a soft pudding and having a viscosity of at least about non hydrated form such as a tablet and it is expected that the formulation when reaching the aqueous environment of the 10,000 cps as measured by a Brookfield Viscometer with a #4 stomach would form a strong gel. LV spindle at 6 rpm and at 20-25 °C. 0015 The present invention proposes an improvement 0020. The pharmaceutical composition and the dispensing over the art by providing a Substantially water free dosage unit according to the invention are intended to be contacted form, containing particulate material Such as, e.g., particulate with a small amount of water before administration and the units, that is/are designed for the purpose of masking the taste water induces the Swelling of the gellan gum, which makes of drug Substance(s) and/or to provide controlled release of a the composition easy to ingest and at the same time provides drug Substance or drug Substances. In turn the particulate an acceptable mouth-feel. material may be coated and/or mixed with components that, 0021. In the context of the present invention relatively upon exposure to water will Swell into a soft pudding-like, Small Volumes are contemplated for the ready-to-administer mousse-like or souffle-like semisolid mass that has a sensory unit (meaning after exposure to water), typically in the range acceptable mouth-feel) and taste as determined and judged by of 1 to 100 mL, in particular 1 to 20 mL. Stirring/shaking or a professional taste panel. Further, the invention provides a any type of mixing would be difficult and often result in loss vehicle to be combined prior to administration with particu of material thus compromising the accuracy of dosing. There late matter Such as microencapsulated drugs. fore it is desirable to have a composition, which, upon expo sure to water, will swell without shaking. It was found that if SUMMARY OF THE INVENTION steps are taken to ensure rapid diffusion of water into the bulk, 0016. In one aspect, the invention relates to a vehicle for then the desired result is achieved. The steps include: (1) oral administration of one or more active Substances, the Addition of very soluble Substances such as soluble Sugars. US 2012/00399.69 A1 Feb. 16, 2012
(2) Using gelling agents presenting as fine powders (3) gelling agents mentioned herein may be used together with Granulating the ingredients with Small amounts of binding gellan gum as well. Furthermore, it is important that the Solutions and (4) Packing the granulate (if desired) loosely. Swelling takes place rapidly and without the necessity of 0022. Other possible techniques are forming the compo stirring, shaking or using any other mechanical means. This nents, typically either the gelling agents and/or the Sugars into characteristic of the vehicle (and the composition of the threads which can be subsequently formed into non-woven invention based on the vehicle) ensures that a pharmaceutical tissues or forming the gelling agents into films where readily composition of the invention is easily transformed into a soluble substance are embedded to ensure channel of diffu ready-to-use composition without any other means that addi sion for the water. The last mentioned techniques might, in tion of a small amount of water. Accordingly, the last-minute turn, be combined with granulated matter. preparation in order to intake the composition is easy and 0023. In accordance with the present invention, a pharma convenient for the patient and do not require specific equip ceutical unit dosage form is provided that is dispensed as a ment. Solid, but which upon contact with a measured amount of 0028. As it will appear from the description herein, the water and without application of a shear force Such as mixing ready-to-use composition is intended to adhere to the dis quickly Swells to provide a semi-solid mass that easily can be pensing unit Such as e.g. a spoon. Furthermore, it is advanta orally ingested by a patient, in particular patients with Swal geous that the ready-to-use composition does not fall off the lowing difficulties. The unit dosage form includes a plurality dispensing unit and accordingly, the vehicle and/or the phar of particles or a plurality of units. In the following the drug maceutical composition must have a certain viscosity as men containing particle or unit is commonly denoted "drug-con tioned above. In specific embodiments, a vehicle and/or com taining micro-particle'. The drug-containing micro-particle position of the invention has a viscosity in a range from about carries at least one therapeutically, prophylactically and/or 10,000 to about 99,000 cps. The viscosity can be measured diagnostically active Substance and, optionally, components using a Brookfield Viscometer with a #4 LV spindle at 6 RPM providing taste masking and/or controlled release function and at 20-25 degrees C., or equivalent. Viscosity decreases ality. Further, the dosage form contains one or more Sub slightly with increasing temperature. stances that are able to swell upon contact with water. Yet 0029. The inventive formulations may also have a Brook further the dosage form may contain taste modifiers such as field viscosity within the range of about 10,000 cps to about Sweeteners, flavors, preserving Substances, texture modifiers, 99,000 cps at room temperature. Below about 20,000 cps, color modifiers and other additives such as binders. Impor formulations tend to spill but formulations less viscous might tantly, the dosage form according to the invention has prop be appropriate in some instances, such as reclining patients. erties that are acceptable to the patient from a sensory aspect, Formulations exhibit desirable spill-resistant properties at a i.e. when ingested, it does not have an unpleasant mouth-feel viscosity greater than about 20,000 cps. and/or a bad taste or odor. These properties are tested by a 0030 The ready-to-use compositions are non-Newtonian professional taste panel consisting of at least 6 persons that and time independent fluids. Non-Newtonian refers to a fluid have been specifically selected due to their tasting ability as whose behavior departs from that of an ideal Newtonian fluid. well as to children age 5-6 years to evaluate whether the These fluids have different viscosities at different shear rates children would have any objections to a repetitive placebo and fall under two groups: time independent and time depen dosage according to the present invention. dent. In contrast, for a Newtonian fluid the rate of shear in the 0024. The drug-containing micro-particles can be pre fluid under isothermal conditions is proportional to the cor pared following any of the conventional methods used e.g. in responding stress at the point under consideration. (McGraw micro-encapsulation, in incorporation into matrices or by Hill Encyclopedia of Science & Technology, 6
Sodium alginate, potassium alginate, ammonium alginate, bound is very difficult to explain (or investigate) exactly and calcium alginate, propane-1,2-diol alginate, agar, carrag has been defined as non-bulk water. Using a simplistic eenan, processed eucheuma seaweed, locust bean gum, guar approach to polysaccharide hydration, water can be divided gum, tragacanth, acacia gum, Xanthan gum, karayagum, tara into bound water, Subcategorized as being capable of freez gum, konjac, pectins, cellulose derivatives Such as: methyl ing or not, and unbound water, Subcategorized as being cellulose, hydroxypropyl cellulose, hydroxypropyl methyl trapped or not. Unbound water freezes at the same tempera cellulose, ethyl methyl cellulose, carboxy methyl cellulose, ture as normal water (<0° C. dependent on cooling rate). Sodium carboxy methyl cellulose, crosslinked sodium car 0039. In practical experience, the effects of water on boxy methyl cellulose, enzymatically hydrolysed carboxy polysaccharide and polysaccharide on water are complex and become even more complex in the presence of other materi methyl cellulose, gelatine, or mixtures thereof. als. Such as salts. Water competes for hydrogen bonding sites 0033. However, in a particularly preferred aspect of the with intra-molecular and intermolecular hydrogen bonding, invention, the vehicle or composition according to the present certainly will determine the carbohydrate's flexibility and invention comprises a gellangum arranged in a configuration may determine the carbohydrate's preferred conformation(s). allowing optimal water diffusion in order for the formulation There is a high entropic cost (up to about 20.8 kJ mol-1 at 25° to gel and Swell within a short time and obtaining a texture C. for a totally frozen molecule) when water is bound and like a soft pudding or mousse and which is easy to disperse. this must be reclaimed, for example, by the formation of 0034. The present invention also relates to a vehicle for stronger or extra hydrogen bonds. An additional approach to oral administration of one or more active Substances, the explain the adsorption of water in hydrophilic polymers in vehicle comprising a Swelling and/or gelling agent selected general is the theory of clusters. In this approach, the poly from the group consisting of hydrocolloids, gums and cellu mers are said to provide adsorption sites rather than an lose derivatives, at least a part of the Swelling and/or gelling adsorption Surface. Certain adsorptions sites can adsorb one, agent arranged in a configuration allowing optimal water two and in some cases more water molecules before other diffusion so that upon addition of a predetermined amount of sites, less energetically attractive to new water molecules, an aqueous medium, without the necessity of applying shear adsorb their first water molecule. As the water content forces or other mixing forces, within a time period of 5 increases, the tendency for water molecules to cluster also minutes or less swells and/or gels and the texture of the increases, and thus grows in size. Swelled vehicle being similar to that of pudding and having a 0040. When the number of water molecules in a cluster viscosity of at least about 10,000 cps as measured by a Brook reaches about four, the interactive forces between the adsorp field Viscometer with a #4 LV spindle at 6 rpm and at 20-25 tion site and the water molecules are no longer large enough C. to hold the cluster, and whole clusters may move from one site 0035. In a further aspect, the invention relates to a solid to another. In anion free aqueous medium, Gellangum forms dosage form comprising an active Substance and a vehicle double helices at room temperature. The helices are only according to the invention. The Solid dosage form may be in weakly associated with each other (by van der walls attrac the form of a unit dosage form or a dosage kit comprising a tion). dispensing unit incorporating the Solid dosage form. Typi 0041) Dynamics of Swelling: cally the dispensing unit is a spoon and the solid dosage form 0042. The swelling kinetics of hydrogels can be classified may be glued to the concave part of the spoon. as diffusion controlled (Fickian) and relaxation-controlled 0036 Hydrogels—Gellan Gum (non-Fickian) Swelling. 0037. In order to swell the gel needs to absorb water and 0043 Mechanical Properties: this is associated with dimensional changes and it is neces 0044) The mechanical properties of the hydrogels are rel sary for the water molecules to gain access to the inner struc evant for the pharmaceutical application; in the present case ture of the materials. The small size of the water molecule and where it is desirable that the gel formed will not slip the the fact that the material is substantially amorphousingeneral delivery device before applied. offer good possibilities of hydrogen bonding, enabeling the 0045 Changing the degree of cross-linking by adding e.g. water molecules to penetrate, and thus Swell. The primary salt will untila Saturation point result in a stronger gel. Hence, mechanism of absorption of water and desorption of drugs there is an optimum degree of cross-linking to achieve a from hydrogels is diffusion, occurring through the space relatively strong and yet elastic hydrogel, e.g. at high ionic available between macromolecular chains. This space is often content the polysaccharides will form insoluble aggregates regarded as the "pore'. Depending on the size of these pores, which can interconnect and form a weakened gel network. hydrogels can be conveniently classified as (1) macro-porous; 0046. The plurality of drug-containing micro-particles (2) micro-porous; and (3), non-porous. The meaning of the described above may be mixed with one or more pharmaceu term "pore' can sometimes be confusing, as it is only a tically acceptable excipients or additives. A measured amount reflection of the radius of gyration of a probe molecule, which like water may be sorbed in the system. The smallest pore of such a mixture in powder form is designed to interact with (Smaller in 4A in radius) represents areas between the poly a specified amount of water to form a semisolid mass meant to mer chains where mainly bound, or inaccessible water is resemble in appearance, mouth, feel, taste, texture and color, being held. Other areas in the gels form a polymer network a form of food of daily occurrence, Such as pudding, apple (e.g. amorphous), which holds water in pores (about 10 A in sauce, custard, puree, etc. The interaction should lead to the radius) within the gel structure. Bound water directly desired semisolid mass in as short a period as possible and adsorbed to the polar groups and free water fills all available without the necessity to apply any external force like e.g. a space created by Swelling within the gel. Larger pores (larger shear force like mixing. In the case where the active Substance than about 10-15A in radius) can be cracks, voids etc, and is in the form of microencapsule, i.e. the active Substance is formed due to various treatments. The larger pores contain incorporated in Small particles that e.g. is coated by a con mainly free water present in Smaller or larger quantities trolled release or taste-masking coating, a long period would depending on the size of the pore. result in release of the active Substances trapped in the par 0038 Hydration is a general term concerning the amount ticles, thereby compromising the controlled release of the of bound water but it is poorly defined. Even what is meant by drug and/or negatively affect the taste of the composition US 2012/00399.69 A1 Feb. 16, 2012 and/or compromise the stability of the active substances. The 0048 Comparison of Physical Properties of High Acyl desirable range for the Swelling is less than 5 minutes, pref and Low Acyl Gellan Gum erably less than 3 minutes and most preferred, less than a minute. In particular for children, a period less than 30 sec onds is further preferred as the administering adult has to control the child at the same time. Suitable excipients are any Kelcogel LT100 Kelcogel F gelling agentoragents capable of forming a semisolid mass in (High Acyl) (Low acyl) a short time when in contact with waterina temperature range Molecular Weight 1-2 x 106 Daltons 2-3 x 105 Daltons from cold (ice water) to tepid (50 degrees celcius). Typically, Solubility Hot water Hot or cold water the gelling agent or agents or mixtures of gelling agents are Set temperature 70-80° C. 30°-50 selected from the group consisting hydrocolloids such as of Thermo reversibility Thermo-reversible Heat stable gellan (native, or in high acyl form or low acyl form, agar, alginate, modified alginates Such as propylene glycol algi nate, pectin, iota-carrageenan, kappa-carrageenan and furcel 0049. The molecular structure of gellan gum is straight leran, agar, processed eucheuma seaweed, locust bean gum, chain based on repeating glucose, rhamose and glucuronic guar gum, tragacanth, acacia gum, Xanthan gum, karayagum, acid units. In its native or high acyl form, two acyl Substitu tara gum, konjac, pectins, cellulose derivatives such as: ents—acetate and glycerate—are present. Both Substituents methyl cellulose, hydroxypropyl cellulose, Hydroxypropyl are located on the same glucose residue, and on average, there methyl cellulose, Ethyl methyl cellulose, Carboxy methyl is one glycerate per repeat and one acetate per every two cellulose, Sodium carboxy methyl cellulose, Crosslinked repeats. In low acylgellan gum, the acyl groups are removed sodium carboxy methyl cellulose, Enzymatically hydrolysed completely. The acyl groups have a profound influence on gel carboxy methyl cellulose, native or modified starches, gelling characteristics. The high acyl form produces soft, elastic, proteins including whey proteins and caseinates, gelatine etc. non-brittle gels, whereas the low acyl form produces firm, 0047. A preferred gelling agent is Gellan having the fol non-elastics, and brittle gels. The acylated form is shown lowing chemical structure, show in low acyl form: below.
CHOH COOH CHOH 1-0 O O O O OH O OH CH3 HO OH OH OH HO OH Low Acyl form
0050 Gellangum forms a coaxial triangular 3-fold double helix (pitch 56.4 A) from two left-handed chains coiled around each other with the acetate residues on the periphery and glyceryl groups stabilizing the interchain associations. Hydrogen-bonds are formed between the hydroxy methyl of US 2012/00399.69 A1 Feb. 16, 2012
4-linked glucosyl units of one chain and the carboxylate 0057. In a specific embodiment, the gellan gum has a group of other. There are ion-binding sites by both carboxy degree of acylation of one glycerate per repeat and one acetate late oxygenatoms and a hydroxyl group in one chain and two per every two repeats. hydroxyl groups in the other plus one strongly bound water 0.058 As mentioned above, the presence of gellan gum in molecule. Pairs of helices may form antiparallel junction a vehicle or a composition according to the invention may Zones with Ca2+. lead to a porous hydrogel when contacted with water Such as, 0051 Functionality: e.g., a micro-porous hydrogel havingapore size of at the most 0052. The functionality depends on the degree of acyla 4. A or a macro-porous hydrogel having a pore size of from tion and the ions present. If low acylated, gellan forms Soft, about 4 to about 15 A. elastic, transparent and flexible gels but once de-acylated it 0059) Konjak:
CH2OH CH2OH CH2OH
O O O OH O O OH O OH N
OH
Mannose Mannose Glucose Glucose forms hard, non-elastic brittle gels. An important feature is 0060 Some of the factors there can effect the swelling the irrevasible gelling properties where gellangum may form include pH, ionic strengths, and temperature. The behaviours an irrevasible film after dehydration, which will prevent gel of the different hydrogels as drug carrier, is well known. The ling on rehydration. A gel sol transition occurs at about 50° C. behaviour of e.g. Gellan gum is quite different from that of dependent on concentration. Thermoreversible gels form on PVP and PEO, respectively. In fact, although the gel Gellan cooling in the presence of cations even at low (0.1% w/w) to Gum with cations shows a very well ordered and regular very low (0.005% w/w) concentrations. structure both in the solid state and in solution, when it is 0053 Gellan is unique in that it forms gels with all ions, tested as a matrix it swells up and it is rapidly dispersed, including hydrogen. Gellan is compatible with a number of leading to a quite fast release of the API (active substance). other gums (Xanthan, locust bean), starches and gelatin to 0061. As mentioned above, a vehicle or a composition manipulate the type of gel, elasticity and stability. Gellan may according to the invention may further comprise an agent that be combined in mixtures producing synergistic properties improves Swelling of the gellangum. Such an agent may be a which mixtures may also include natural seaweeds, natural hydrophilic agent selected from the group consisting of elec seed gums, natural plant exudates, natural fruit extracts, bio trolytes, organic acids and osmotic agents, and mixtures synthetic gums, bio-synthetic processed starch or cellulosic thereof. materials. More specifically, the mixture may include algi nates, agar gum, guar gum, locust bean gum (carob), carrag 0062 Osmotic Agents eenan, tara gum, gum arabic, ghatti gum, Khaya grandifolia 0063. By the term “osmotic agent' is meant any agent gum, tragacanth gum, karayagum, pectin, arabian (araban). which creates a driving force for transport of water or media Xanthan, starch, konjak mannan, galactomannan, funoran. (aq.) from the environment of use into the matrix. Exemplary 0054 Another preferred swelling and swelling improving osmotic agents are water swell able or water soluble. The agent is konjak. Konjak contains 50%-60% glucomannan, vehicle or composition according to the invention may 20-30% starch, 2-5% fiber, 5-10% crude protein, 3-5% include water-swell able hydrophilic polymers, both ionic soluble Sugars (monosaccharide and oligosaccharide) and and non-ionic, often refers to as "osmopolymers' and hydro 3-5% ash (minerals). Chemical Structure of Konjac Gluco gels. Exemplary materials includehydrophilic vinyl and acryl mannan (KGM) is shown below. The molecular weight of polymers, poly saccharides, PEO, PEG, PPG, poly(2-hy KGM varied from 1,000,000 to 2,000,000 daltons according droxyethyl methacrylate), poly(acrylic)acid, poly(meth to konjac species or variety, processing method and storage acrylic)acid, PVP, PVA, PVA/PVP copolymers.HEC, HPC, time of the raw material. HPMC, CMC, CEC, sodium alginate, polycarbophil, gelatine 0055. In a preferred embodiment, the gellan gum has a and sodium starch glycolate. Other materials include hydro mean particle size within 25 mesh to 300 mesh in order to gels comprising interpenetrating networks of polymers, allow a suitable distribution of water into the vehicle. which may be formed by addition or by condensation poly 0056 Furthermore, in a specific embodiment, the gellan merization, the components of which may comprise hydro gum is acylated within a degree of 0 to 4 per every two repeats philic and hydrophobic monomers. Preferred polymers for of the glucose-rhamnose-glucose-glucuronic acid unit of the use at the water-swellable hydrophilic polymers include polymer. The vehicle or composition may contain a mixture PEO, PEG, PVP HPMC and polyacrylic acid. of gellan gums having different degrees of acylation and/or 0064. By “osmotically effective solutes' is meant any different mean particle sizes. water-soluble compound that is commonly referred to in the US 2012/00399.69 A1 Feb. 16, 2012
pharmaceutical arts as an “osmogen' oran “oSmagent'. Typi like: alkali metal Sulfates such as Sodium sulfate; dihydrogen cally classes of Suitable osmogens are water-soluble organic Sodium phosphate, monohydrogen Sodium phosphate, diso acids, salts and Sugars that are capable of imbibing water to dium hydrogen phosphate, and mixtures thereof, and multi thereby affect an osmotic pressure gradient across the barrier valent metal cations. Notably, the salt is calcium sulfate or of the Surrounding matrix. Typical useful osmogens include sodium chloride. magnesium sulfate, magnesium chloride, calcium chloride, (0073 Organic Acids Sodium chloride, lithium chloride, potassium Sulfate, sodium 0074 The present formulations may also contain organic carbonate, Sodium sulfite, lithium sulfate, potassium chlo acids to delay dissolution rate in the acid media and/or to ride, Sodium sulfate, mannitol, Xylitol, urea, Sorbitol, inositol, increase the dissolution rate in buffer at pH 6.8 or to ensure raffinose, Sucrose, glucose, fructose, lactose, inulin, instant drug stability with time and provide a substantially pH inde Sugar, citric acid, Succinic acid, tartaric acid, and mixtures pendent dissolution profile. thereof. Particularly preferred osmogens are glucose, lactose, 0075. The organic acids are chosen to cover a solubility Sucrose, mannitol, Xylitol and sodium chloride. and pKa-values range, in order to cover a range of pH and to 0065 Electrolytes help controlling the release mechanism. The aim is to obtain 0066. The electrolyte's greater hydrophilicity than the the same release time in both buffer 6.8 and in 0.1 MHC1. other formulation components allows it to hydrate preferen Pharmaceutically acceptable organic acids are e.g. Benzoic tially in comparison to the Surrounding polymers and the drug acid, Succinic acid, Citric acid and Adipic acid but can molecules. This peripheral matrix-hardening creates a con include other pharmaceutically approved organic acids. trollable micro-environment within the hydrated layer, and (0076 Ionic Strengths make the formulation robust again variable ion strengths from 0077. An increase in electrostatic repulsion, by adding e.g. added water to the matrix. monovalent or/and divalent metal ions (natively present or 0067. The use of e.g. alkalizing agents to preserve internal introduced in the formulation) also promotes a Swelling until dosage form pH though the acid regions of the upper gas a saturation point. The driving force necessary to expand the trointestinal tract is well established. material during Swelling is the electrostatic repulsion 0068. One advantage of maintaining a constant internal between different ionic groups with the same charges. The pH is that a very soluble drug in 0.1M HCl may be made less nature of the counter ions is thus of extremely importance for soluble if the environmental pH is above the pKa-value of the the degree of Swelling of Such charged gel-like systems. drugs. Through the application of colloidal chemistry prin Changing the ionic content in the formulation will affect the ciples, it is possible to provide pH-control via a formulation water uptake. The nature of the ions (ion pair) has a profound component that is also active as a release controlling excipi effect on the characteristics of the water adsorption due to the ent within a hydrophilic matrix. different ability of the ion pair to dissociate. 0069. A vehicle or composition according to the invention 0078. The ion pairs will compete with the hydrogel about may also comprise a pH-adjusting agent selected from the the water molecules, and can thereby increase the hydration group consisting of any material which is suitable to adjust and decrease the solubility of the hydrogel, respectively, the pH of an aqueous gel Such as, e.g., Sodium bicarbonate, which can stabilise the gel formation. Sodium phosphate, sodium hydroxide, ammonium hydrox (0079 Physical and Chemical Properties of Hydrogels ide, Sodium Stannate, triethanolamine, citric acid, hydrochlo 0080. The cross linking ratio is one of the most important ric acid, sodium citrate, and combinations thereof. Generally, factors that effects the swelling of hydrogels. It is defined as if present, the pH adjusting agentis present in an amount So as the ratio of moles of cross linking agent to the moles of to adjust the pH of the gel formed upon addition of an aqueous polymer repeating units. The higher the cross linking ratio, medium to about 4.5 to about 11, preferably from about 5 to the more cross linking agent is incorporated in the hydrogel about 9, and more preferably from about 5 to about 8. A structure. Highly cross linked hydrogels have a tighter struc Suitable amount is normally in an amount of from about ture, and will swell less compared to the same hydrogel with 0.01% to about 15% w/w such as, e.g., from about 0.05% to lower cross linking ratios. Cross linking hinders the mobility about 5% w/w. of the polymer chains, hence loweringhe Swelling ratio. The 0070. Upon ingestion, gastric fluid enter into the dosage chemical structure of the polymer may also affect the swell form, causing the composition to hydrate and activates the pH ing ratio of the hydrogels. Hydrogel contains hydrophilic and release-controlling characteristics of the excipients. groups Swell to a higher degree compare to those containing 0071. A suitable electrolyte for use according to the inven hydrophobic groups. Hydrophobic groups collapse in the tion is a ionizable Substance that is selected from the group presence of water, thus minimizing their exposed to the water consisting of monovalent, divalent, or multivalent ionizable molecule. salts. More specifically, the salt is selected from inorganic I0081 pH-Sensitive Hydro Gels salts, including various alkali metal and/or alkaline earth I0082. The hydrogels which exhibiting pH dependent metal Sulfates, chlorides, borates, bromides, etc., and ioniz Swelling behaviour will in aqueous media of appropriate pH able alkaline earth organic salts such as citrates, acetates, and ionic strengths be ionized. As a result in of the electro lactates, etc. static repulsions, the uptake of water in the network is 0072. In specific embodiments, the salt is selected from increased. Ionic hydrogels are Swollen polymer networks calcium sulfate, Sodium chloride, potassium Sulfate, sodium containing pendant groups, such as carboxylic acid, which carbonate, lithium chloride, tripotassium phosphate, sodium show Sudden or gradual changes in their dynamic and equi borate, potassium bromide, potassium fluoride, Sodium bicar librium behaviour as a result of changing the external pH. In bonate, calcium chloride, magnesium chloride, Sodium cit these gels, ionization occurs when the ph of the environment rate, Sodium acetate, calcium lactate, magnesium Sulfate, is above the pKa of the ionisable group. As degree of ioniza alkali metal chlorides, sodium fluoride, organic acids such S tion increases the number offixed charges increases resulting citric, succinic, fumaric, malic, maleic, glutaric, lactic and the in increased electrostatic repulsions between the chains. This US 2012/00399.69 A1 Feb. 16, 2012
in turn, results in an increased hydrophilicity of the network, the formation of large agglomerates (lumps), which, due to and greater Swelling ratio. The Swelling of polyelectrolyte the protective film layer, are very difficult for the water mol gels is significantly affected by the ionic strengths of the ecules to penetrate. Swelling agent. As the ionic strengths of the Swelling agent 0093. The less soluble the Gellan gum is the easier the increases, the concentration of ions within the gel must dispersion, other factors which decrease the solubility of increase in order to satisfy the Donnan equilibrium. Gelangum will improve the dispersibility. 0094. Different formulation initiative, by e.g. incorpora 0083) A vehicle or composition according to the invention tion of hydrophilic excipients, can change the hydration, and may also comprise one or more pharmaceutically acceptable Swelling rate: excipients or additive. 0.095 Fast swelling is usually done by making very small 0084 Excipients particles of dried hydrogels. The extremely short diffusion 0085. A wetting agent may be used such as one or more path length of micro particles makes it possible to complete selected from the group consisting of pharmaceutically Swelling in a matter of seconds or minutes. acceptable anionic Surfactants, cationic Surfactants, amphot 0096. By creating pores that are interconnected to each eric (amphipathic/amphophilic) Surfactants, and non-ionic other throughout the hydrogel matrix. The interconnected surfactants including poloxamer, PEG, and PEO; alkane pores allow for fast absorption of water by capillary force. A metal sulfates, wherein the alkyl group is from 1 to 14 carbon simple method of making porous hydrogel includes, produce atoms, such as Sodium methyl Sulfate, sodium lauryl Sulfate gas bubbles by adding sodium bicarbonate to generate carbon and the like as well as dioctyl sodium sulfo Succinate. dioxide bubbles, and generation of gas bubbles makes the I0086. In a specific embodiment of the invention, a vehicle foam rise. or composition further comprises glycerol, cf. the examples 0097 Another approach is to separate the hydrogel par herein. ticles from each other before contact with water. If the hydro 0087 Suitable excipients and/or additives may be selected gel particles are right next to each other then they all try to from the group consisting of Surfactants, coloring agents, Swell at the same time, and weld themselves together into one Sweetening agents, taste-masking agents, antioxidants, large, slow to hydrate lump. If the pectin particles are all polysaccharides, Sugars, wetting agents, UV-absorbers, Sus slightly separated from each other when they contact the pending agents, stabilizers, Solubilizers, preservatives, pro water, then they all have enough room to go through their cessing aids, pH controlling agents, plasticizers, odor mask initial expansion. To achieve a fast hydration, and thereby ing agents, nutrients, flavoring agents, flavor masking agents, Swelling for the matrix system it is preferable to added hydro emulsifiers, thickening agents, dispersing agents, crystal philic or/and ion pair formation excipients. grow inhibitors, crystallization promoters, chelating agents, (0098 Hydrophilic Excipients: buffers, bases, and antimicrobials, and mixtures thereof. 0099 Known excipients can be blended with the molecu 0088. In order to ensure an effective interaction of the lar or dispersed dosage form to provide a controllable water water with the gellig agent or agents, the addition of a cation diffusion/drug release mechanism. and/or sequestering agent to the mixture might be desirable 0100 Vehicle Form and is generally depending on the Swelling agent or mixtures 0101. A vehicle according to the invention may have any hereof. Examples of Suitable cations and sequestering agents Suitable form such as, e.g., in the form of a powder blend, in which may be added to cause this gelling agent to gel are well the form of granules, beads, oblates or pellets, or in the form known to persons skilled in the art and include Na+, Ca", K" of a granulate. Any additive or excipient, if present, may be and H", sodium hexametaphosphate, Sodium tripolyphos incorporated e.g. in the granules etc, or it may be loosely phate, EDTA, citric acid, sodium citrate and other citric acid added e.g. after formation of a granulate. As mentioned here salts, phosphoric acid, dicalcium phosphate and tetrasodium inbefore, the vehicle may be admixed with one or more active pyrophosphate. Substances, i.e. the active Substance may be incorporated in the granules etc., or it may be added after formation e.g. of a 0089. An excipient for use in a dosage form according to granulate. The active Substance may also be present in a the present invention may also include one or more other coated and/or microencapsulated form or embedded in a components generally known for use in food products, such matrix, or in a form that allows for controlled release of the as flavourings, colorings, Sugar and/or other Sweeteners, pre active Substance. servatives, buffering agents, texturing agents, fats, colloids, 0102 Compositions Suspended solids, etc., to give the a desired texture and/or 0103) As mentioned above, the present invention also appearance. The amounts of such components are not critical relates to a pharmaceutical composition for oral administra to the invention and may be adjusted according to taste and tion comprising one or more active Substances and a gellan according to the flavor/texture characteristics desired of the gum arranged in a configuration allowing optimal water dif mixture of the invention. The pH of the mixture might be fusion so that upon addition of a predetermined amount of an adjusted to the requirements of the active Substance(s). aqueous medium, without the necessity of applying shear 0090 Excipients Used to Change the Hydration and Dif forces or other mixing forces, within a time period of 5 fusion of Water Into the Matrix System minutes or less, the composition Swells and/or gels and the 0091. While the slow swelling property is the one that also texture of the swelled composition being similar to that of a made hydrogels useful in controlled drug delivery, many soft pudding and having a viscosity of at least about 10,000 applications required fast Swelling (i.e. Swelling in a matter of cps as measured by a Brookfield Viscometer with a #4 LV minutes or seconds rather than hours) of dried hydrogels. spindle at 6 rpm and at 20-25 °C. 0092 Being a water soluble polysaccharide e.g. Gellan 0104 All the details and particulars mentioned hereinbe gum can be difficult to disperse in water due to the formation fore relating to other aspects of the invention apply mutatis of a film layer around each Gellangum particle. This leads to mutandis to this aspect. US 2012/00399.69 A1 Feb. 16, 2012
0105. The pharmaceutical composition or the dosage form 0111. In some cases, where the purity of the water is an of the invention includes a plurality of drug-containing important factor, Such as when presence or absence of given micro-particles. Each micro-particle carries at least one ions might interfere with the gelling process, it might be active Substance and, optionally, components providing taste desirable to dispense the water alongside the granulate. In the masking and/or controlled release functionality. The micro case of a satchet it might be dispensed as a two compartment particles can be produced using know micro-encapsulation or plastic bag, one compartment containing the granulate, the by integration into a matrix or by crystallization. The particles other the water. In the case of the spoon, a reservoir might be may be further fragmented to reduce the particle size. The built-into the handle of the spoon. preferred embodiments are those where the particles are small so as to be imperceptible or nearly imperceptible to the 0112 Conventional coating procedures and equipment patient, visually and/or tactilely, in particular on the tongue. may then be used to coat or embed the drug-containing micro The preferred embodiments are those where the particle size particles, i.e., the drug-containing beads or particles. For is less than 500 micrometers and best less than 200 microme example, a delayed release coating composition may be ters. However, if the retention in the mouth of even a few applied using a coating pan, an airless spray technique, flu particles after a few minutes is not desired (because, for idized bed coating equipment, or the like. For detailed infor example, the taste being masked leaks), the particles should mation concerning materials, equipment and processes for not be smaller than 100 micrometers so they are not retained preparing beads, drug particles, and delayed release dosage in crevices in the pouth or between papillae on the tongue, forms, reference may be made to Pharmaceutical Dosage unless the cohesivness of the semisolid vehicle ensures that Forms: Tablets, eds. Lieberman et al. (New York: Marcel all particles are swallowed with the vehicle. Dekker, Inc., 1989), and to Ansel et al., Pharmaceutical Dos 0106. In another aspect of this invention, the active sub age Forms and Drug Delivery Systems, 6' Ed. (Media, PA: stances do not require controlled release or taste masking but, Williams & Wilkins, 1995). because of stability problems, in particular hydrolysis they 0113 Drug Delivery (Release) From the Composition can not be formulated in water containing dosage forms; also the approach may be useful if very large doses are to be 0114 Swelling-Controlled System: administered. Accordingly, in one aspect of the invention a 0115 Formulations consisting of hydrophilic matrixes, dosage form is provided having a water content of at the most and from which the drug release is controlled by the inward about 5% w/w such as, e.g., at the most about 4% w/w, at the flux of solvent molecules and consequent Swelling of the most about 3% w/w, at the most about 2% w/w, at the most polymer matrix, are often referred to as a Swelling-controlled about 1% w/w or at the most about 0.5% w/w. systems. In these systems, the drug are initially dissolved or 0107 The dosage form may be dispensed as a granulate in dispersed in the glassy polymers. Upon contact with fluids bulk or further processed into discrete units. The discrete (pre-hydration with water or/and biological fluids), the poly units may be capsules or cachets or Sachets filled with a mer matrix begins to Swell and two distinct phases can be measured amount of granulate meant to be opened and the observed in the polymer: the inner glassy phase and the Swol contents poured onto a measured amount of water. However, len rubbery phase. The drug molecule are able to diffuse out the capsules or cachets or Sachets may be made from fast of the out of the rubbery phase of the polymer. Clearly, the dissolving materials such as water Soluble polymer films, drug release is controlled by the velocity and position of the woven or non-woven fabrics made of water soluble materials glass-rubbery interface. A very important phenomenon of Such as candy floss. Further, the capsules or cachets or Sachets macromolecular relaxation takes place at the glass-rubbery might be made of gelling polymers such as those described interface, and significant affects the drug release. for the mixture. 0116. This is due to the fact that the matrix is exposed to 0108. The discrete units may also be tablets meant to be continuous changes in its structure and thickness. The gel put into a measured amount of water. In producing the tables, layer is a hydrophilic barrier that can controls water penetra attention must be paid to the fact that, the more the material is tion and drug diffusion. It begins when the polymer becomes compacted, the more difficult the penetration of water into the hydrated and Swells. Here, the polymer chains are strongly unit will be. Therefore, the production method for the tablets entangled in a network, and the gel layer is highly resistant. must be adapted. Production methods might include low However, moving away from this Swelling position, the gel pressure compression, extruding, molding and calendaring. layer becomes progressively more hydrated and, when Suffi 0109. In a specific embodiment of interest, the discrete cient water has accumulated, the chains disentangle and the units may be in the form of a disposable spoon where the polymer dissolves. granulated is fastened, typically by using a hydrocolloid solu 0117. In matrix systems, which are also diffusion-con tion as a binder and drying. Such a unit is illustrated in FIG.1. trolled, the drug can be either dissolved or dispersed in To this end, it is extremely important that the dosage form of throughout the network of the hydrogel. the drug-containining micro-particles is designed so that a 0118. There are different approaches to controlling the suitable texture of the dosage form is obtained after addition release rate from the matrix system. Some of the major for of a predetermined amount of an aqueous medium Such as mulation parameters, which can be varied to adjust the result water without the necessity of employing any shear force ing release patterns to designing a new oral controlled release Such as e.g. mechanical mixing or stirring. system can include: 0110. The dosage form might also be formed into a tape or 0119 The initial drug loading laminate, with or without the help of water soluble polymer films, woven or non-woven fabrics made of water soluble I0120) The API solubility materials such as candy floss. This laminate can then be cut I0121 Type of matrix forming polymers into discrete portions or dispensed as such, so the user can cut 0.122 Type and load of hydrophilic/hydrophobic excipi it to the required dose/size. ents US 2012/00399.69 A1 Feb. 16, 2012
0123 Release mechanisms for API incorporated in a pri the porosity of the matrix upon drug depletion (due to an mary based hydrogels: increase initial drug loading) has probably a more pro 0.124. In development of an a delivery system, three sig nounced effect on the resulting absolute drug release rate than nificant phenomena (simplified) must be taken into account in the case of e.g. freely soluble drugs, and thus higher diffu simultaneously, sion driving forces. Consequently, the critical initial drug 0.125. Diffusion of water, drug, excipients and disen loading increases with decreasing drug solubility. tangled polymer chains, 0.137 The effect of the initial drug loading of the tableton 0126 Polymer hydration and swelling, the resulting release kinetic is more complex in the case of 0127 Drug, excipient and polymer dissolution. poorly soluble drugs compared to freely water Soluble drugs. 0128. Furthermore, in a formulation containing an API, 0.138. With decreasing drug solubility the concentration polymer(s), and excipients, three different kinds of interac difference during drug release (matrix position vs. bulk fluid) tion may affect the release of the API: (i) the API may interact decreases, and thus the driving force for drug diffusion out of with the polymer, (ii) the drug may interact with the excipi the matrix decreases. Under these conditions, decrease of the ents, and (iii) the excipients may interact with the polymer(s) porosity of the matrix upon depletion (due to an increased matrix. The rate of API release can be successfully controlled initial drug loading) has probably a more pronounced effect by controlling these interactions. on the resulting drug release rate than in the case of higher 0129. The dissolution rate is often influenced by a) com drug solubility. Consequently, the critical initial drug loading position and level of drugs and other additives within the (above which the relative release rate increases) increases matrix, and b) composition and ionic strengths of electrolytes with decreasing drug solubility. These phenomena are not in the dissolution medium. straightforward and have to be taken into account when 0130. It is possible to control or/and change the release designing the new formulation. rate of the drug from the polymer by varying e.g. the physical 0.139. With respect to the blending of the vehicle accord chemical properties of the active drug, excipients or/and the ing to the present invention it should be noticed whether any polymer system. Extremely simplified, by adding more of the desires excipients or active drugs have a solubility soluble excipients compared to the API solubility, will to considerable below that of gellan gum as the Substance may Some extent increase the release rate of the matrix system, and decrease the hydration of the gellan gum. In Such cases the opposite for more hydrophobic excipients the release rate will substance should be added to a premixture of other ingredi be slowed down. When e.g. adding very soluble excipients, ents, which pre mixture or blend preferable is granulated the network becomes more and more porous upon drug deple before adding the substance with lower solubility. In cases tion. Consequently, the free Volume increases, and thus poly where one of the ingredients is capable of solubilizing the mer disentanglement increases giving rise to higher diffusion gellan gum, the same procedure is to be used in order to constants and thus faster dissolution. prevent any solubilizing of the gellan gum which will other 0131 The physical-chemical properties of the matrix wise result in decreased gelling capacity. (composition) components will alter the intermolecular 0140 Particle and Granular Sizes: forces, free Volume, glass transition temperature, and conse 0141 Although it is not required, it is preferred that the quently, can alter the transport mechanisms. API, gellangum, hydrogel(s), and excipients is in particulate 0.132. In general, solubility of drug molecule itself cru form. The particles should, as a general rule, be of a size. Such cially governs the rate and extent of diffusion release in both that, the matrix can hydrate Sufficiently, and equally through the matrix system, and the delivery sites. For diffusion to out the matrix. To prevent segregation, and consequently occur, the first step is wetting of the drug by water, followed inhomogen products it would be preferable to formulate with by its dissolution to enable the drug molecule to be available uniform particle sizes, with exception of PVP, wherein it can in molecular. Hence, the net release rate observed is a cumu also be an advantage to have Smaller particles. A Suitable lative effect of drug solubility (influence by its structure, granular size should be between 350-500 um. Furthermore it molecular weight, pKa), polymer property (hydrophilicity/ is an advantage to seal the material after fastened the discrete lipophilicity, molecular weight, tortuosity), excipients (struc units on a delivering device. The fastening is easily done by ture, molecular weight, solubility, pKa) and the relative ratio spraying the device with a glue to adhere the discrete unit to of drug/polymer, and excipient/polymer in the unit. the device. Such glue may be produced by mixing a volatile 0133. Initial Load/Dissolution Profiles liquid with a binder until a clear solution is achieved, and the 0134. Various factors contribute to the overall control of formulation is transferred to e.g. by use of an aerosol can to drug release, such as the solubility of the drug within the bulk the device. Such as a spoon the Volatile liquid is evaporated fluid, drug load, the size of the drug molecule, and it's mobil from the spoon in an oven, and thus the device Surface is ity within the swollen polymeric network. Sticky. 0135) In the case of poorly water-soluble drugs (solubility 0142. The layer thickness of the applied mixtures varies <1 g drug/100 mL Solution) or high initial loadings of mod greatly and depends on the processing method or the quantity erately water Soluble drugs (1 g drug / 10 mL solution), dis of additional substances. The thickness ranges from 1-100 Solved and non-dissolved drug coexist within the corn posi ..um, preferably from 10-50 um. This corresponds to a binder tion. If the total amount of drug exceeds the amount, which is application of 0.1-5 wt.%. soluble under the actual conditions, it exceeds the amount 0143. The desired dose of the formulation to be applied to soluble under the actual conditions, the excess is considered the device is weight out separately and distributed by pressing to be non-dissolved and thus not available for diffusion. the granules against the spoon with a stopper to a thin layer. 0136. With decreasing drug solubility the concentration The layer thickness will dependent on the formulation, but difference during drug release (matrix position vs. bulk fluid) preferable approximately 2 mm in height in the bottom, and decreases, and thus the driving force for drug diffusion out of sides of the spoon. The glue attaches the material to the the matrix decreases. Under theses conditions a decrease of device. When the composition is applied to the device, the US 2012/00399.69 A1 Feb. 16, 2012
glue may be in liquid form or in Solution selected from the agents and other gastrointestinally active agents; antiviral group consisting of Sugar alcohols, Sugars, polyvinylpyrroli agents; anxiolytics; appetite Suppressants; attention deficit done (PVP), gums. Other binders may be employed. Nor disorder (ADD) and attention deficit hyperactivity disorder mally, the binder is dissolved in a volatile solvent. As it (ADHD) drugs; cardiovascular preparations including cal appears from the examples herein, an especially Suitable glue cium channel blockers, CNS agents, and vasodilators; beta or adhesive agent comprises a mixture of PVP and glycerol. blockers and antiarrhythmic agents; central nervous system 0144. The composition of the invention may be dispensed stimulants; cough and cold preparations, including deconges in any suitable device. Preferably the device is made of a tants; diuretics; genetic materials; herbal remedies; hor Suitable material Such as a plastic based material or glass or monolytics; hypnotics; hypoglycemic agents; immunosup metal, preferable a disposable material. In order to adhere to pressive agents; leukotriene inhibitors; mitotic inhibitors; the device it is preferred that the device has a concave surface. muscle relaxants; narcotic antagonists; nutritional agents, Spoons or devices having similar shape and function are Such as vitamins, essential amino acids and fatty acids; para Suitable in the present context. sympatholytics; peptide drugs; psychoStimulants; sedatives; (0145 Active Substances steroids; sympathomimetics; and tranquilizers. 0146 In a specific embodiment the vehicle according to 0150. Several known drugs are substantially insoluble or the invention comprises one or more active Substances. The only slightly soluble in water and accordingly difficult to active Substance may be present in admixture with the formulate in Solutions and Suspensions for administration to vehicle, it may be present in the granulate comprising the children, elderly or other subjects having difficulties in Swal Swelling and/or gelling agent, it may be present in microen lowing and Such drugs are therefore of particular interest capsulated form or embedded in a matrix, and/or it may be according to the present invention and include, by way of present in a form that allows for controlled release of the example, the following: active Substance. 0151 Gastrointestinally active substances. Gastrointesti 0147 “Drug substances” or “active substances” in accor nally active Substances are particularly preferred drugs that dance with the present invention include systematically dis can be administered using the present dosage forms. These tributable therapeutically, prophylactically and/or diagnosti types of drugs include agents for inhibiting gastric acid secre cally active Substances, vitamins, minerals, dietary tion, Such as the H. Sub.2 receptor antagonists cimetidine, Supplements, as well as non-systemically distributable active ranitidine, famotidine, and nizatidine, the H. Sup.+, K. Sup.+- Substances. Therapeutically, prophylactically and/or diag ATPase inhibitors (also referred to as “proton pump inhibi nostically active substances may include, without limitation, tors') omeprazole and lansoprazole, and antacids such as antacids, analgesics, anti-inflammatories, antibiotics, laxa calcium carbonate, aluminum hydroxide, and magnesium tives, anorexics, antihistamines, antiasthmatics, antidiuretics, hydroxide. Also included within this general group are agents antiflatuents, antimigraine agents, antispaspodics, sedatives, for treating infection with Helicobacter pylori (H. pylori), antihyperactives, antihypertensives, tranquilizers, deconges Such as metronidazole, tinidazole, amoxicillin, clarithromy tants, beta blockers and combinations thereof. Also encom cin, tetracycline, thiamphenicol, and bismuth compounds passed by the terms “drug substances” and “active sub (e.g., bismuth subcitrate and bismuth subsalicylate). Other stances are the drugs and pharmaceutical active ingredients gastrointestinally active Substances administrable using the described in Mantelle U.S. Pat. No. 5,234,957 includes 18 present dosage forms include, but are not limited to, penta through 21. This text is hereby incorporated by reference. gastrin, carbenoXolone, Sulfated polysaccharides such as 0148 With respect to the individual dosages of the active Sucralfate, prostaglandins such as misoprostol, and muscar to be incorporated in the novel dosage form this will follow inic antagonists such as pirenzepine and telenzepine. Addi the general recommendations knownto the skilled personand tionally included are antidiarrheal agents, antiemetic agents are generally calculated based on the body weight or body and prokinetic agents such as ondansetron, granisetron, meto Surface, especially for children, and the daily dosage may clopramide, chlorpromazine, perphenazine, prochlorpera naturally be divided in several dosages according to conven Zine, promethazine, thiethylperazine, triflupromazine, dom tional treatment regimens for the active Substance in question. peridone, trimethobenzamide, cisapride, motilin, Depending of the actual amount, a dosage may be present in loperamide, diphenoxylate, and octreotide. a single spoon or similar dosing device or in several spoons to 0152 Anti-microbial agents. These include: quinolone be ingested. Alternatively, the actual dosage can be measured antibiotics such as nalidixic acid, and particularly fluorinated based the content per Volume of a pre-prepared product simi quinolone antibiotics Such as ciprofloxacin, clinafloxacin, lar with dosing from bottles of mixtures generally employed enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lom with liquid formulations. efloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, 014.9 The active substance administered may be any com sparfloxacin, and trovafloxacin, tetracycline antibiotics and pound that is Suitable for oral drug administration; examples related compounds (chlortetracycline, Oxytetracycline, of the various classes of active Substances that can be admin demeclocycline, methacycline, doxycycline, minocycline, istered using the present dosage forms include, but are not rolitetracycline); macrollide antibiotics such as erythromycin, limited to: analgesic agents; anesthetic agents; antiarthritic clarithromycin, and azithromycin; streptogramin antibiotics agents; respiratory drugs; anticancer agents; anticholinergics; Such as quinupristin and dalfopristin; beta-lactamantibiotics, anticonvulsants; antidepressants; antidiabetic agents; antidi including penicillins (e.g., penicillin G, penicillin VK), anti arrheals; antihelminthics; antihistamines; antihyperlipidemic staphylococcal penicillins (e.g., cloxacillin, dicloxacillin, agents; antihypertensive agents; anti-infective agents such as nafcillin, and oxacillin), extended spectrum penicillins (e.g., antibiotics and antiviral agents; antiinflarrimatory agents; aminopenicillins such as amplicillin and amoxicillin, and the antimigraine preparations; antinauseants; antineoplastic antipseudomonal penicillins such as carbenicillin), and agents; antiparkinsonism drugs; antipruritics; antipsychotics; cephalosporins (e.g., cefadroxil, cefepime, cephalexin, cefa antipyretics; antispasmodics; antitubercular agents; antiulcer Zolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazi US 2012/00399.69 A1 Feb. 16, 2012 dime, and ceftriaxone), and carbapenems such as imipenem, and methamphetamine hydrochloride; and miscellaneous meropenem and aztreonam; aminoglycoside antibiotics Such stimulants such as methylphenidate, methylphenidate hydro as streptomycin, gentamicin, tobramycin, amikacin, and neo chloride, modafinil, pemoline, Sibutramine, and Sibutramine mycin; glycopeptide antibiotics such as teicoplanin; Sulfona hydrochloride. mide antibiotics Such as Sulfacetamide, Sulfabenzamide, Sul 0158 Neuroleptic agents. Neuroleptic drugs include anti fadiazine, Sulfadoxine, Sulfamerazine, Sulfamethazine, depressant drugs, antimanic drugs, and antipsychotic agents, Sulfamethizole, and Sulfamethoxazole; anti-mycobacterials wherein antidepressant drugs include (a) the tricyclic antide Such as isoniazid, rifampin, rifabutin, ethambutol, pyraZina pressants such as amoxapine, amitriptyline, clomipramine, mide, ethionamide, aminosalicylic, and cycloserine; sys desipramine, doxepin, imipramine, maprotiline, nortrip temic antifungal agents such as itraconazole, ketoconazole, tyline, protriptyline, and trimipramine, (b) the serotonin fluconazole, and amphotericin B; antiviral agents such as reuptake inhibitors citalopram, fluoxetine, fluvoxamine, par acyclovir, famcicylovir, ganciclovir, idoxuridine, Sorivudine, oxetine, Sertraline, and Venlafaxine, (c) monoamine oxidase trifluridine, Valacyclovir, Vidarabine, didanosine, stavudine, inhibitors such as phenelzine, tranylcypromine, and (-)-sel Zalcitabine, Zidovudine, amantadine, interferon alpha, ribavi egiline, and (d) other, "atypical antidepressants such as nefa rin and rimantadine; and miscellaneous antimicrobial agents Zodone, traZodone and Venlafaxine, and wherein antimanic Such as chloramphenicol, spectinomycin, polymyxin B and antipsychotic agents include (a) phenothiazines Such as (colistin), bacitracin, nitrofurantoin, methenamine mandelate acetophenazine, acetophenazine maleate, chlorpromazine, and methenamine hippurate. chlorpromazine hydrochloride, fluphenazine, fluphenazine 0153 Anti-diabetic agents. These include, by way of hydrochloride, fluiphenazine enanthate, fluphenazine example, acetohexamide, chlorpropamide, ciglitaZone, gli decanoate, mesoridazine, mesoridazine besylate, perphena clazide, glipizide, glucagon, glyburide, miglitol, pioglita zine, thioridazine, thioridazine hydrochloride, trifluopera Zone, tolaZamide, tolbutamide, triampterine, and troglita zine, and trifluoperazine hydrochloride, (b) thioxanthenes ZO. Such as chlorprothixene, thiothixene, and thiothixene hydro 0154 Analgesics. Non-opioid analgesic agents include chloride, and (c) other heterocyclic drugs such as carbam apaZone, etodolac, difenpiramide, indomethacin, meclofe azepine, clozapine, droperidol, haloperidol, haloperidol namate, mefenamic acid, Oxaprozin, phenylbutaZone, piroxi decanoate, loxapine Succinate, molindone, molindone hydro cam, and tolmetin; opioid analgesics include alfentanil, chloride, olanzapine, pimozide, quetiapine, risperidone, and buprenorphine, butorphanol, codeine, drocode, fentanyl. sertindole. hydrocodone, hydromorphone, levorphanol, meperidine, 0159) Hypnotic agents and sedatives include clomethiaz methadone, morphine, nalbuphine, oxycodone, oxymor ole, ethinamate, etomidate, glutethimide, meprobamate, met phone, pentazocine, propoxyphene, Sufentanil, and tramadol. hyprylon, Zolpidem, and barbiturates (e.g., amobarbital, 0155 Anti-inflammatory agents. Anti-inflammatory apropbarbital, butabarbital, butalbital, mephobarbital, agents include the nonsteroidal anti-inflammatory agents, methohexital, pentobarbital, phenobarbital, secobarbital, e.g., the propionic acid derivatives as ketoprofen, flurbipro thiopental). fen, ibuprofen, naproxen, fenoprofen, benoxaprofen, 0160 Anxiolytics and tranquilizers include benzodiaz indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, epines (e.g., alprazolam, brotizolam, chlordiazepoxide, clo Suprofen, alminoprofen, butibufen, and fenbufen, apaZone; bazam, clonazepam, cloraZepate, demoxepam, diazepam, diclofenac; difenpiramide; diflunisal: etodolac, indometha estazolam, flumazenil, flurazepam, halazepam, lorazepam, cin; ketorolac, meclofenamate: nabumetone; phenylbuta midazolam, nitrazepam, nordazepam, oxazepam, prazepam, Zone; piroXicam, Sulindac; and tolmetin. Steroidal anti-in quazepam, temazepam, triazolam), buspirone, chlordiazep flammatory agents include hydrocortisone, hydrocortisone oxide, and droperidol. 21-Monoesters hydrocortisone-21-acetate, hydrocortisone 0.161 Anticancer agents, including antineoplastic agents: 21-butyrate, hydrocortisone-21-propionate, hydrocortisone Paclitaxel, docetaxel, camptothecin and its analogues and 21-Valerate, etc.), hydrocortisone-17,21-diesters (e.g., derivatives (e.g., 9-aminocamptothecin, 9-nitrocamptoth hdrocortisone-17,21-diacetate, hydrocortisone-17-acetate ecin, 10-hydroxy-camptothecin, irinotecan, topotecan, 21-butyrate, hydrocortisone-17,21-dibutyrate, etc.), alclom 20-O-beta.-glucopyranosyl camptothecin), taxanes (bacc etaSone, dexamethasone, flumethasone, prednisolone, and atins, cephalomannine and their derivatives), carboplatin, cis methylprednisolone. platin, interferon-alpha. Sub.2A, interferon-alpha. Sub.2B, 0156 Anti-convulsant agents. Suitable anti-convulsant interferon-alpha...sub.N3 and other agents of the interferon (anti-seizure) drugs include, by way of example, aZetazola family, levamisole, altretamine, cladribine, tretinoin, procar mide, carbamazepine, clonazepam, cloraZepate, ethoSuxim bazine, dacarbazine, gemcitabine, mitotane, asparaginase, ide, ethotoin, felbamate, lamotrigine, mephenytoin, porfimer, mesna, amifostine, mitotic inhibitors including mephobarbital, phenytoin, phenobarbital, primidone, tri podophyllotoxin derivatives such as teniposide and etoposide methadione, vigabatrin, topiramate, and the benzodiaz and Vinca alkaloids Such as Vinorelbine, Vincristine and Vin epines. BenZodiazepines, as is well known, are useful for a blastine. number of indications, including anxiety, insomnia, and nau 0162 Antihyperlipidemic agents. Lipid-lowering agents, SCa or “hyperlipidemic agents, include HMG-CoA reductase 0157 CNS and respiratory stimulants. CNS and respira inhibitors such as atorvastatin, simvastatin, pravastatin, lov tory stimulants also encompass a number of active agents. astatin and cerivastatin, and other lipid-lowering agents such These stimulants include, but are not limited to, the follow as clofibrate, fenofibrate, gemfibrozil and tacrine. ing: Xanthines such as caffeine and theophylline; amphet 0163 Anti-hypertensive agents. These include amlo amines such as amphetamine, benzphetamine hydrochloride, dipine, benazepril, darodipine, dilitazem, diazoxide, dox dextroamphetamine, dextroamphetamine Sulfate, levamphet aZosin, enalapril, eposartan, losartan, Valsartan, felodipine, amine, levamphetamine hydrochloride, methamphetamine, fenoldopam, fosinopril, guanabenz, guanadrel, guanethidine, US 2012/00399.69 A1 Feb. 16, 2012 guanfacine, hydralazine, metyrosine, minoxidil, nicardipine, Zoate, androstenedione, dehydroepiandrosterone (DHEA: nifedipine, nisoldipine, phenoxybenzamine, praZosin, also termed “prasterone'), sodium dehydroepiandrosterone quinapril, reserpine, and teraZosin. sulfate, 4-dihydrotestosterone (DHT; also termed 0164 Cardiovascular preparations. Cardiovascular prepa 'stanolone'), 5.alpha-dihydrotestosterone, dromoStanolone, rations include, by way of example, angiotensin converting dromostanolone propionate, ethylestrenol, nandrolone phen enzyme (ACE) inhibitors such as enalapril, 1-carboxym propionate, nandrolone decanoate, nandrolone furylpropi ethyl-3-1-carboxy-3-phenyl-(1S)-propylamino-2,3,4,5-tet onate, nandrolone cyclohexanepropionate, nandrolone ben rahydro-1H-(3S)-1-benzazepine-2-one, amino-1-carboxy Zoate, nandrolone cyclohexanecarboxylate, Oxandrolone, 1S-pentyl)amino-2,-3,4,5-tetrahydro-2-oxo-3S-1H-1- stanozolol and testosterone; pharmaceutically acceptable benzazepine-1-acetic acid or 3-(1-ethoxycarbonyl-3-phenyl esters of testosterone and 4-dihydrotestosterone, typically (1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo-(-3S)- esters formed from the hydroxyl group present at the C-17 benzazepine-1-acetic acid monohydrochloride; cardiac position, including, but not limited to, the enanthate, propi glycosides such as digoxin and digitoxin; inotropes such as onate, cypionate, phenylacetate, acetate, isobutyrate, buci amrinone and milrinone; calcium channel blockers such as clate, heptanoate, decanoate, undecanoate, caprate and isoca Verapamil, nifedipine, nicardipene, felodipine, isradipine, prate esters; and pharmaceutically acceptable derivatives of nimodipine, bepridil, amlodipine and diltiazem; beta-block testosterone Such as methyl testosterone, testolactone, erS Such as atenolol, metoprolol; pindolol, propafenone, pro oxymetholone and fluoxymesterone. pranolol, esmolol, Sotalol, timolol, and acebutolol; antiar 0.167 Muscarinic receptoragonists and antagonists. Mus rhythmics such as moricizine, ibutilide, procainamide, carinic receptoragonists include, by way of example: choline quinidine, disopyramide, lidocaine, phenytoin, tocainide, esters such as acetylcholine, methacholine, carbachol, mexiletine, flecainide, encainide, bretylium and amiodarone; bethanechol (carbamylmethylcholine), bethanechol chloride, and cardioprotective agents such as dexraZoxane and leuco cholinomimetic natural alkaloids and synthetic analogs Vorin; and vasodilators such as nitroglycerin; and diuretic thereof, including pilocarpine, muscarine, McN-A-343, and agents such as hydrochlorothiazide, furosemide, bumetanide, oxotremorine. Muscarinic receptor antagonists are generally ethacrynic acid, torsemide, azosemide, muZolimine, piret belladonna alkaloids or semisynthetic or synthetic analogs anide, and tripamide. thereof. Such as atropine, Scopolamine, homatropine, homa 0.165 Anti-viral agents. Antiviral agents that can be deliv tropine methyl bromide, ipratropium, methantheline, meth ered using the present dosage forms include the antiherpes Scopolamine and tiotropium. agents acyclovir, famciclovir, foScamet, ganciclovir, idoxuri (0168 Peptide drugs. Peptidyl drugs include the peptidyl dine, sorivudine, trifluridine, Valacyclovir, and Vidarabine; hormones activin, amylin, angiotensin, atrial natriuretic pep the antiretroviral agents didanosine, stavudine, Zalcitabine, tide (ANP), calcitonin, calcitonin gene-related peptide, cal and Zidovudine; and other antiviral agents such as amanta citonin N-terminal flanking peptide, ciliary neurotrophic fac dine, interferon alpha, ribavirin and rimantadine. tor (CNTF), corticotropin (adrenocorticotropin hormone, 0166 Sex steroids. The sex steroids include, first of all, ACTH), corticotropin-releasing factor (CRF or CRH), epi progestogens such as acetoxmegnenolone, allylestrenol, dermal growth factor (EGF), follicle-stimulating hormone anagestone acetate, chlormadinone acetate, cyproterone, (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-re cyproterone acetate, desogestrel, dihydrogesterone, dime leasing peptide, gonadotropin-releasing factor (GnRF or thisterone, ethisterone (17.alpha.-ethinyltestoster-one), GNRH), growth hormone releasing factor (GRF, GRH), ethynodiol diacetate, flurogestone acetate, gestadene, human chorionic gonadotropin (hCH), inhibin A, inhibin B, hydroxyprogesterone, hydroxyprogesterone acetate, hydrox insulin, luteinizing hormone (LH), luteinizing hormone-re yprogesterone caproate, hydroxymethylprogesterone, leasing hormone (LHRH), alpha.-melanocyte-stimulating hydroxymethylprogesterone acetate, 3-ketodesogestrel, hormone, beta.-melanocyte-stimulating hormone, gamma.- levonorgestrel, lynestrenol, medrogestone, medroxyprogest melanocyte-stimulating hormone, melatonin, motilin, oxyto erone acetate, megestrol, megestrol acetate, melengestrol cin (pitocin), pancreatic polypeptide, parathyroid hormone acetate, norethindrone, norethindrone acetate, norethister (PTH), placental lactogen, prolactin (PRL), prolactin-release one, norethisterone acetate, norethynodrel, norgestimate, inhibiting factor (PIF), prolactin-releasing factor (PRF), norgestrel, norgestrienone, normethisterone, and progester secretin, Somatotropin (growth hormone, GH). Somatostatin one. Also included within this general class are estrogens, (SIF, growth hormone-release inhibiting factor, GIF), thy e.g.: estradiol (i.e., 1,3,5-estratriene-3,17.beta.-diol, or “ 17. rotropin (thyroid-stimulating hormone, TSH), thyrotropin beta.-estradiol) and its esters, including estradiol benzoate, releasing factor (TRH or TRF), thyroxine, vasoactive intesti Valerate, cypionate, heptanoate, decanoate, acetate and diac nal peptide (VIP),and vasopressin. Other peptidyl drugs are etate; 17.alpha.-estradiol; ethinylestradiol (i.e., 17.alpha.- the cytokines, e.g., colony stimulating factor 4, heparin bind ethinylestradiol) and esters and ethers thereof, including ethi ing neurotrophic factor (HBNF), interferon-a, interferon al nylestradiol 3-acetate and ethinylestradiol 3-benzoate; estriol pha.-2a, interferon alpha.-2b, interferon alpha.-n3, inter and estriol Succinate; polyestrol phosphate; estrone and its feron-beta., etc., interleukin-1, interleukin-2, interleukin-3, esters and derivatives, including estrone acetate, estrone Sul interleukin-4, interleukin-5, interleukin-6, etc., tumor necro fate, and piperazine estrone sulfate; quinestrol; mestranol: sis factor, tumor necrosis factor-alpha., granuloycte colony and conjugated equine estrogens. Androgenic agents, also stimulating factor (G-CSF), granulocyte-macrophage included within the general class of sex steroids, are drugs colony-stimulating factor (GM-CSF), macrophage colony Such as the naturally occurring androgens androsterone, stimulating factor, midkine (MD), and thymopoietin. Still androsterone acetate, androsterone propionate, androsterone other peptidyl drugs that can be advantageously delivered benzoate, androstenediol, androstenediol-3-acetate, andros using the present systems include endorphins (e.g., dermor tenediol-17-acetate, androstenediol-3,17-diacetate, andros phin, dynorphin, alpha.-endorphin, beta.-endorphin, tenediol-17-benzoate, androstenediol-3-acetate-17-ben gamma.-endorphin, ..sigma.-endorphin, Leu. Sup.5en US 2012/00399.69 A1 Feb. 16, 2012 kephalin, Met. Sup.5enkephalin, Substance P), kinins (e.g., rinone; Minoxidil; Mirtazapine: Modafinil; Moexipril; bradykinin, potentiator B, bradykinin potentiator C. kallidin), Mometasone; Montelukast; Morphine; Moxifloxacin; Nabu LHRH analogues (e.g., buserelin, deslorelin, fertirelin, gos metone; Nateglinide; Nefazodone; Nelfinavir. Nevirapine; erelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), Nicotine; Nizatidine; Norfloxacin; Norgestimate/ethinyl and the coagulation factors, such as alpha. Sub. 1-antitrypsin, estradiol; Octreotide; Ofloxacin; Olanzapine; Olmesartan; ..alpha. Sub.2-macroglobulin, antithrombin III, factor I (fi Omeprazole; Ondansetron; Orlistat; Oseltamivir; Oxaprozin; brinogen), factor II (prothrombin), factor III (tissue pro Oxcarbazepine; Oxybutynin. Oxybutynin. Oxycodone; Pan thrombin), factor V (proaccelerin), factor VII (proconvertin), toprazole; Paricalcitol; Paroxetine; Pegvisomant; Pemirolast; factor VIII (antihemophilic globulin or AHG), factor IX Pimecrolimus: Pioglitazone: Pravastatin: Propofol; Quetiap (Christmas factor, plasma thromboplastin component or ine Fumerate; Quinapril; Rabeprazole; Ramipril; Ranitidine: PTC), factor X (Stuart-Power factor), factor XI (plasma Remifentanil, Repaglinide; Ribavirin/Interferon alfa-2B, thromboplastin antecedent or PTA), factor XII (Hageman recombinant, Rifapentine; Risedronate; Risperidone; factor), heparin cofactor II, kallikrein, plasmin, plasminogen, Ritonavir; Rocuronium; Rofecoxib; Ropivacaine; Rosiglita prekallikrein, protein C, protein S, and thrombomodulin and Zone; RosiglitaZone; Salmeterol, Saquinavir, Sertraline; combinations thereof. Sevelamer; Sevoflurane; Sibutramine; Sildenafil; Simvasta 0169 Genetic material may also be delivered using the tin; Sirolimus; Sodium ferric gluconate complex: Sotalol; present dosage forms, e.g., nucleic acids, RNA, DNA, recom Stavudine: Sumatriptan; Tacrolimus; Tamoxifen: Temozolo binant RNA, recombinant DNA, antisense RNA, antisense mide; Tenofovir, Terbinafine; Testosterone; Timolol;Toltero DNA, ribozymes, ribooligonucleotides, deoxyribonucle dine; Topiramate; Topotecan; Tramadol; Valacyclovir; Val otides, antisense ribooligonucleotides, and antisense deox ganciclovir, Vaiproate; Valsartan; Venlafaxine, Verapamil; yribooligonucleotides. Representative genes include those Vinorelbine; Voriconazole; Zafirlukast; Zanamivir; Ziprasi encoding for vascular endothelial growth factor, fibroblast done; Zoledronic acid; Zolmitriptan; Zonisamide. growth factor, Bcl-2, cystic fibrosis transmembrane regulator, 0171 As incorporated be reference according to Mantelle nerve growth factor, human growth factor, erythropoietin, U.S. Pat. No. 234,957: tumor necrosis factor, and interleukin-2, as well as histocom 0172 1. Analgesic anti-inflammatory agents such as, patibility genes such as HLA-B7. acetaminophen, aspirin, Salicylic acid, methyl salicylate, cho 0170 In a preferred embodiment for a paediatric product line Salicylate, glycol salicylate, 1-menthol, camphor, mefe and use according to the invention, the active drug is selected namic acid, fluiphenamic acid, indomethacin, diclofenac, from Abacavir; Acetazolamide: Adefovir; Albuterol: alclofenac, ibuprofen, ketoprofen, naproxene, pranoprofen, Albuterol; Alendronate; Almotriptan; Alosetron: Alpra fenoprofen, Sulindac, fenbufen, clidanac, flurbiprofen, Zolam; Amiodarone; Amlexanox: Amlodipine; the combina indoprofen, protizidic acid, fentiazac, tolmetin, tiaprofenic tion Amlodipine/Benazepril; Ammonium Lactate; Amphet acid, bendazac, bufexamac, piroxicam, phenylbutaZone, amine (including mixed salts); Amprenavir, Anagrelide; oxyphenbutaZone, clofeZone, pentazocine, mepirizole, and AnastroZole; Argatroban; Aripiprazole; Atazanavir, Atomox the like: etine; Atorvastatin; the mixture Atovaquone/Proguanil; 0173 2. Drugs having an action on the central nervous Azelastine; Baclofen; Balsalazide. Beclomethasone; system, for example sedatives, hypnotics, antianxiety agents, Beclomethasone; Benazepril; Betamethasone; Betaxolol; analgesics and anesthetics, such as, chloral, buprenorphine, Betaxolol; Bicalutamide; Bisoprolol; Brimonidine: Brinzola naloxone, haloperidol, fluiphenazine, pentobarbital, phe mide: Budesonide; Buproprion; Buspirone; Busulfan; nobarbital, secobarbital, amobarbital, cydobarbital, codeine, C-Urea; Calcitriol: Candesartan; Carboplatin: Carteolol, lidocaine, tetracaine, dyclonine, dibucaine, cocaine, Carvedilol; Caspofungin: Celecoxib; Cerivastatin: Cetiriz procaine, mepivacaine, bupivacaine, etidocaine, prilocaine, ine: Cilostazol; Cimetidine: Ciprofloxacin: Ciprofloxacin: benzocaine, fentanyl. nicotine, and the like; Cisatracurium; Citalopram; Clopidogrel; Colesevelam: Cro 0.174 3. Antihistaminics or antiallergic agents such as, molyn; Cromolyn; Cytarabine; Desflurane. Desloratadine: diphenhydramine, dimenhydrinate, perphenazine, triproli Dexrazoxane; Dichlorphenamide; Didanosine; Dorzola dine, pyrilamine, chlorcyclizine, promethazine, carbinoxam mide, Efavirenz: Eletriptan; Emtricitabine: Enalapril; Enfu ine, tripelennamine, brompheniramine, hydroxy Zine, cycliz virtide (T-20); Enoxaparin: Epirubicin; Eplerenone; Ertap ine, meclizine, clorprenaline, terfenadine, chlorpheniramine, enem, Esmolol; Esomeprazole; Etodolac. Famciclovir; and the like; Famotidine: Felodipine: Fenoldopam; Fentanyl: Fentanyl: 0.175. 4. Acetonide anti-inflammatory agents, such as Fexofenadine: Fluconazole; Fludarabine, luocinolone; Flu hydrocortisone, cortisone, dexamethasone, fluocinolone, tri oxetine: Fluticasone; Fluvastatin: Fluvoxamine; Formoterol; amcinolone, medrysone, prednisolone, flurandrenolide, Fosinopril; Fosphenytoin: Fulvestrant; Gabapentin; Gati prednisone, halcinonide, methylprednisolone, fludrocorti floxacin; Gatifloxacin; Gemcitabine; Gemtuzumab; Gen Sone, corticosterone, paramethasone, betamethasone, ibu tamicin; Glatiramer; Glimepiride; Glipizide/Metformin; prophen, naproxen, fenoprofen, fenbufen, flurbiprofen, Glyburide/Metformin: Granisetron; Hydrocortisone, indoprofen, ketoprofen, Suprofen, indomethacin, piroxicam, Hydroxyurea; Ibuprofen; Ibuprofen/pseudoephedrine: Ima aspirin, Salicylic acid, diflunisal, methyl salicylate, phenylb tinib. Imiquimod; Indinavir, Insulin glargine; Irbesartan; utaZone, Sulindac, mefenamic acid, meclofenamate Sodium, Irinotecan; Isotretinoin, Itraconazole; Ketoconazole, Ketoro tolimetin, and the like: lac; Labetalol; Lamivudine, Lamotrigine; Lansoprazole; 0176 5. Steroids such as, androgenic steriods, such as, Leflunomide; Levalbuterol; Levetiracetam; Levobetaxolol; testosterone, methyltestosterone, fluoxymesterone, estrogens Levobunolol; Levofloxacin; Levofloxacin; Linezolid; Lisino Such as, conjugated estrogens, esterified estrogens, estropi pril; Lisinopril; Lopinavir/Ritonavir, Loratadine; Losartan; pate, 17-beta. estradiol, 17-beta. estradiol Valerate, equilin, Lovastatin; Mesalamine; Metformin; Methazolamide; Meth mestranol, estrone, estriol, 17-beta. ethinyl estradiol, dieth ylphenidate; Metipranolol; Metoprolol:Midazolam; Mil ylstilbestrol, progestational agents, such as, progesterone, US 2012/00399.69 A1 Feb. 16, 2012
19-norprogesterone, norethindrone, norethindrone acetate, dol, bromperidol, loxapine, and molindone, as well as, those melengestrol, chlormadinone, ethisterone, medroxyprogest agents used at lower doses in the treatment of nausea, Vom erone acetate, hydroxyprogesterone caproate, ethynodiol iting, and the like; diacetate, norethynodrel, 17-.alpha. hydroxyprogesterone, 0.192 21. Muscle relaxants such as, tolperisone, baclofen, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, dantrolene Sodium, cyclobenzaprine; 22. Drugs for Parkin demegestone, promegestone, megestrol acetate, and the like; son's disease, spasticity, and acute muscle spasms such as 0177 6. Respiratory agents such as, theophilline and levodopa, carbidopa, amantadine, apomorphine, bromocrip .beta. Sub.2-adrenergic agonists, such as, albuterol, terbuta tine, selegiline (deprenyl), trihexyphenidyl hydrochloride, line, metaproterenol, ritodrine, carbuterol, fenoterol, quinter benztropine mesylate, procyclidine hydrochloride, baclofen, enol, rimiterol, Solmefamol, Soterenol, tetroquinol, and the diazepam, dantrolene, and the like; like: 0193 23. Respiratory agents such as, codeine, ephedrine, 0.178 7. Sympathomimetics such as, dopamine, norepi isoproterenol, dextromethorphan, orciprenaline, ipratropium nephrine, phenylpropanolamine, phenylephrine, pseu bromide, cromglycic acid, and the like; doephedrine, amphetamine, propylhexedrine, arecoline, and 0194 24 Non-steroidal hormones or antihormones such the like: as, corticotropin, oxytocin, vasopressin, salivary hormone, 0179 8. local anesthetics such as, benzocaine, procaine, thyroid hormone, adrenal hormone, kallikrein, insulin, oxen dibucaine, lidocaine, and the like; dolone, and the like; 0180 9. Antimicrobial agents including antibacterial 0.195. 25. Vitamins such as, vitamins A, B, C, D, E and K agents, antifungal agents, antimycotic agents and antiviral and derivatives thereof, calciferols, mecobalamin, and the agents; tetracyclines Such as, oxytetracycline, penicillins, like for dermatologically use: Such as, amplicillin, cephalosporins such as, cefalotin, ami 0196. 26. Antitumor agents such as, 5-fluorouracil and noglycosides, such as, kanamycin, macrollides such as, eryth derivatives thereof, krestin, picibanil, ancitabine, cytarabine, romycin, chloramphenicol, iodides, nitrofrantoin, nystatin, and the like; amphotericin, fradiomycin, Sulfonamides, purrolnitrin, clot 0.197 27. Enzymes such as, lysozyme, urokinaze, and the rimazole, miconazole chloramphenicol, Sulfacetamide, Sul like: famethazine, Sulfadiazine, Sulfamerazine, Sulfamethizole and 0198 28. Herb medicines or crude extracts such as, gly Sulfisoxazole; antivirals, including idoxuridine; clarithromy cyrrhiza, aloe, Sikon (Lithospermi Radix), and the like: cin; and other anti-infectives including nitrofuraZone, and the 0199. 29. Miotics such as pilocarpine, and the like; lo 30. like: Cholinergic agonists such as, choline, acetylcholine, metha 0181 10. Antihypertensive agents such as, clonidine, choline, carbachol, bethanechol, pilocarpine, muscarine, alpha.-methyldopa, reserpine, Syrosingopine, rescinnamine, arecoline, and the like; cinnarizine, hydrazine, praZosin, and the like; 0200 31. Antimuscarinic or muscarinic cholinergic 0182 11. Antihypertensive diuretics such as, chlorothiaz blocking agents such as, atropine, Scopolamine, homatro ide, hydrochlorothrazide, bendoflumethazide, trichlormethi pine, methScopolamine, homatropine methylbromide, meth azide, furosemide, tripamide, methylclothiazide, penfluzide, antheline, cyclopentolate, tropicamide, propantheline, hydrothiazide, Spironolactone, metolaZone, and the like; anisotropine, dicyclomine, eucatropine, and the like; 0183) 12. Cardiotonics such as, digitalis, ubidecarenone, 0201 32. Mydriatics such as, atropine, cyclopentolate, dopamine, and the like; homatropine, Scopolamine, tropicamide, eucatropine, 0184 13. Coronary vasodilators such as, organic nitrates hydroxyamphetamine, and the like; 33. Psychic energizers Such as, nitroglycerine, isosorbitol dinitrate, erythritol tet Such as 3-(2-aminopropy)indole, 3-(2-aminobutyl)indole, ranitrate, and pentaerythritol tetranitrate, dipyridamole, and the like; dilaZep, trapidil, trimetazidine, and the like; 0202 34. Humoral agents such as, the prostaglandins, 0185. 14. Vasoconstrictors such as, dihydroergotamine, natural and synthetic, for example PGE. Sub.1, PGE. Sub.2. dihydroergotoxine, and the like; alpha., and PGF.Sub.2.alpha., and the PGE. Sub.1 analog 0186 15...beta.-blockers or antiarrhythmic agents such as, misoprostol. timolol pindolol, propranolol, and the like; 0203 35. Antispasmodics such as, atropine, methanthe 0187. 16. Calcium antagonists and other circulatory organ line, papaverine, cinnamedrine, methScopolamine, and the agents, such as, aptopril, diltiazem, nifedipine, nicardipine, like: Verapamil, bencyclane, ifenprodil tartarate, molsidomine, 0204 36. Antidepressant drugs such as, isocarboxazid, clonidine, prazosin, and the like; phenelZine, tranylcypromine, imipramine, amitriptyline, 0188 17. Anti-convulstants such as, nitrazepam, mep trimipramine, doxepin, desipramine, nortriptyline, protrip robamate, phenytoin, and the like; tyline, amoxapine, maprotiline, traZodone, and the like; 0189 18. Agents for dizziness such as, isoprenaline, beta 0205 37. Anti-diabetics such as, insulin, and anticancer histine, Scopolamine, and the like; drugs such as, tamoxifen, methotrexate, and the like; 0190. 19. Tranquilizers such as, reserprine, chlorprom 0206 38. Anorectic drugs such as, dextroamphetamine, azine, and antianxiety benzodiazepines such as, alprazolam, methamphetamine, phenylpropanolamine, fenfluramine, chlordiazepoxide, cloraZeptate, halazepam, oxazepam, diethylpropion, mazindol, phentermine, and the like; prazepam, clonazepam, flurazepam, triazolam, lorazepam, 0207 39. Anti-allergenics such as, antazoline, methapy diazepam, and the like; rilene, chlorpheniramine, pyrilamine, pheniramine, and the 0191 20. Antipsychotics such as, phenothiazines includ like: ing thiopropazate, chlorpromazine, triflupromazine, 0208 40. Decongestants such as, phenylephrine, ephe mesoridazine, piperracetazine, thioridazine, acetophenazine, drine, naphazoline, tetrahydrozoline, and the like; fluiphenazine, perphenazine, trifluoperazine, and other major 0209 41. Antipyretics such as, aspirin, salicylamide, and tranquilizers such as, chlorprathixene, thiothixene, haloperi the like: US 2012/00399.69 A1 Feb. 16, 2012
0210 42. Antimigrane agents such as, dihydroergotamine, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefradine, Cilasta pizotyline, and the like; tin, Faropenem, Flomoxef. Imipenem, Latamoxef, Loracar 02.11 43. Anti-malarials such as, the 4-aminoquinolines, bef, Meropenem, Panipenem, alphaaminoquinolines, chloroquine, pyrimethamine, and the 0228. Chloramphenicols like: 0229 AZidamfenicol, Chloramphenicol, Florfenicol, 0212 44. Anti-ulcerative agents such as, misoprostol, Thiamphenicol, Avoparcin, Ramoplanin, Teicoplanin, Van omeprazole, enprostil, and the like; comycin, 0213 45. Peptides such as, growth releasing factor, and 0230 Lincosamides the like: 0231 Clindamycin, Lincomycin, Pirlimycin, 0232 Macrollides 0214. 46. Anti-estrogen or anti-hormone agents such as, 0233. Azithromycin, Clarithromycin, Dirithromycin, tamoxifen or human chorionic gonadotropin, and the like; Erythromycin, Flurithromycin, Josamycin, Kitasamycin, 0215 47. Antiulcer agents such as, allantoin, aldioxa, Midecamycin, Oleandomycin, Pristinamycin, Quinupristin/ alcloxa, N-methylscopolamine methylsuflate, and the like: Dalfopristin, Rokitamycin, Roxithromycin, Spiramycin, 0216) 48. Antidiabetics, and the like. Tilmicosin, Troleandomycin, Tylosin, Virginiamycin, 0217. The drugs mentioned above can be used in combi 0234 Penicillins nation as required. Moreover, the above drugs may be used 0235. The beta-lactamase inhibitors clavulanic acid, sul either in the free form or, if capable of forming salts, in the bactam, and taZobactam are used to extend the antimicrobial form of a salt with a suitable acid or base. If the drugs have a range of certain beta-lactam antibiotics. Amoxicillin, Ampi carboxyl group, their esters can be employed. cillin, Aspoxicillin, AZidocillin, AZlocillin, Bacampicillin, 0218. The acid mentioned above may be an organic acid, Benethamine Penicillin, BenZathine Benzylpenicillin, Ben for example, methanesulfonic acid, lactic acid, tartaric acid, Zathine Phenoxymethylpenicillin, Benzylpenicillin, Carbeni fumaric acid, maleic acid, acetic acid, oran inorganic acid, for cillin, Carfecillin, Carindacillin, Ciclacillin, Clavulanic Acid, example, hydrochloric acid, hydrobromic acid, phosphoric Clemizole Penicillin, Clometocillin, Cloxacillin, Dicloxacil acid or Sulfuric acid. The base may be an organic base, for lin, Flucloxacillin, Mecillinam, Metampicillin, Meticillin, example, ammonia, triethylamine, or an inorganic base, for Mezlocillin, Nafcillin, Oxacillin, Penethamate, Pheneticillin, example, sodium hydroxide or potassium hydroxide. The Phenoxymethylpenicillin, Piperacillin, Pivampicillin, Piv esters mentioned above may be alkyl esters, aryl esters, mecillinam, Procaine Penicillin Procaine Benzylpenicillin, aralkyl esters, and the like. Propicillin, Sulbactam, Sulbenicillin, Sultamicillin, Tazobac 0219. In one embodiment of the invention, the active sub tam, Temocillin, Ticarcillin, stance is selected from the following: 0236 Quinolones 0220 Antibacterials Including Metronidazole 0237 Acrosoxacin Rosoxacin, Alatrofloxacin, Balof 0221 Although antibiotics and other antibacterials are a loxacin, Cinoxacin, Ciprofloxacin, Clinafloxacin, Danof very diverse class of compounds they are often classified and loxacin, Difloxacin, Enoxacin, Enrofloxacin, Fleroxacin, discussed in groups. They may be classified according to their Flumequine, GatifloxacinCemifloxacin, Grepafloxacin, mode of action or spectrum of antimicrobial activity, but Levofloxacin, Lomefloxacin, Marbofloxacin, Moxifloxacin, generally those with similar chemical structures are grouped Nadifloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Orbi together. floxacin, Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piro midic Acid, Prulifloxacin, Rufloxacin, Sarafloxacin, Spar 0222 Aminoglycosides floxacin, Temafloxacin, ToSufloxacin, Trovafloxacin, 0223) Amikacin, Apramycin, Arbekacin, Astromicin, 0238 Sulfonamides and Diaminopyrimidines Bekanamycin, Dibekacin, Dihydrostreptomycin, Framyce 0239 Baquiloprim, Brodimoprim, Calcium Sulfaloxate, tin, Gentamicin, Isepamicin, Kanamycin, Micronomicin, Co-tetroxazine, Co-trifamole, Co-trimazine, Co-trimox Neomycin, Netilmicin, Sisomicin, Streptomycin, Tobramy azole, FormosulfathiazoleMafenide, Ormetoprim, Phthalyl C1. sulfathiazole. Succinylsulfathiazole, Sulfabenzamide, Sulfa 0224 Antimycobacterials Drug Groups: Antimycobacte clozine, Sulfachrysoidine, Sulfadicramide, Sulfadoxine, rials Sulfamerazine, Sulfamethylthiazole, Sulfametopyrazine, 0225. Aminosalicylic Acid, Capreomycin, Clofazimine, Sulfametrole, Sulfamonomethoxine, Sulfaquinoxaline, Sul Cycloserine, Dapsone, Ethambutol, Ethionamide, Isoniazid, fasuccinamide, Sulfatroxazole, Sulfacetamide, Sulfachlorpy Methaniazide, Morinamide, Protionamide, Pyrazinamide, ridazine, Sulfadiazine, Sulfadiazine Silver, Sulfadimethox Rifabutin, Rifampicin, Rifamycin, Rifapentine, Rifaximin, ine, Sulfadimidine, Sulfafurazole, Sulfaguanidine, Thioacetazone. Sulfamethizole, Sulfamethoxazole, Sulfamethoxypy 0226 Cephalosporins and Related Beta Lactams ridazine, Sulfamoxole, Sulfanilamide, Sulfapyridine, Sulfi 0227 Drug Groups: Cephalosporins, related Beta Lac somidine, Sulfathiazole, Sulfacarbamide, Tetroxoprim, Tri tams or cephem antibiotics Aztreonam, Betamipron, Biap methoprim, enem, Carumonam, Cefaclor, Cefadroxil, Cefalexin, Cefalo 0240 Tetracyclines nium, Cefaloridine, Cefalotin, Cefamandole, Cefazolin, 0241 Chlortetracycline, Demeclocycline, Doxycycline, Cefapirin, Cefatrizine, Cefcapene, Cefdinir, Cefditoren, Lymecycline, Meclocycline, Methacycline, Minocycline, Cefepime, Cefetamet, Cefixime, Cefluprenam, Cef Oxytetracycline, Rolitetracycline, Tetracycline, menoxime, Cefnmetazole, Cefninox, Cefodizime, Cefonicid, 0242 Miscellaneous Antibacterials CefoperaZone, Ceforanide, Cefoselis, Cefotaxime, 0243 Acediasulfone, Arsanilic Acid, Avilamycin, Baci Cefotetan, Cefotiam, Cefoxitin, Cefozopran, Ce?piramide, tracin, Bambermycin, Carbadox, Chlorquinaldol, Clio Cefpirome, Cefpodoxime, Cefprozil, Cefauinome, Cefsulo quinol, Clofoctol, Colistin, Daptomycin, Evernimicin, Fos din, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftiofur, fomycin, Furaltadone, Fusafungine, Fusidic Acid, US 2012/00399.69 A1 Feb. 16, 2012
Gramicidin, Halquinol, Methenamine, LineZolid, Magainins, and vitamin K. Also included within the term vitamin are the Mandelic Acid, Mupirocin, Nifuroxazide, Nifurtoinol, coenzymes thereof. Coenzymes are specific chemical forms Nifurzide, Nisin, Nitrofurantoin, Nitrofurazone, Nitroxoline, of vitamins. Coenzymes include thiamine pyrophosphates Novobiocin, Polymyxin B. Spectinomycin, Sulfamazone, (TPP), flavin mononucleotide (FMM), flavin adenine Taurolidine, Telithromycin, Terizidone. Thenoic Acid, Thios dinucleotive (FAD), Nicotinamide adenine dinucleotide trepton, Tiamulin, Trospectomycin, Tyrothricin, Valnemulin, (NAD), Nicotinamide adenine dinucleotide phosphate Xibornol, (NADP) Coenzyme A (CoA) pyridoxal phosphate, biocytin, 0244 Anthelmintics tetrahydrofolic acid, coenzyme B.Sub.12, lipoyllysine, 0245 Albendazole, Diethylcarbamazine, Ivermectin, 11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term Levamisole, Mebendazole, Niclosamide, Oxamniquine, Pip Vitamin(s) also includes choline, carnitine, and alpha, beta, erazine, Praziquantel, Pyrantel. Thiabendazole. and gamma carotenes. 0246 Antimalarial Drugs 0265. As used in this disclosure, the term “mineral refers 0247 4-methanolduinoline derivatives such as the cin to inorganic Substances, metals, and the like required in the chona alkaloids and mefloquine. The 4-aminoquinolines, human diet. Thus, the term “mineral as used herein includes, Such as chloroquine, hydroxychloroquine, and amodiaquine. without limitation, calcium, iron, Zinc, Selenium, copper, The 8-aminoquinolines such as primaquine and tafenoquine. iodine, magnesium, phosphorus, chromium and the like, and The big uanides, such as proguanil and chlorproguanil. The mixtures thereof. diaminopyrimidines such as pyrimethamine. The dichlo 0266 The term "dietary supplement’ as used herein robenzylidine lumefantrine. The hydroxynaphthoduinones, means a Substance, which has an appreciable nutritional Such as atovaquone. The 9-phenanthrenemethanols such as effect when administered in Small amounts. Dietary Supple halofantrine. The sesquiterpene lactones such as artemisinin ments include, without limitation, such ingredients as bee and its derivatives. The sulfonamides sulfadoxine and sul pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish fametopyrazine. The tetracyclines, such as doxycycline and oils, amino acids, proteins and mixtures thereof. As will be tetracycline. The lincosamide, clindamycin. The Sulfones appreciated, dietary Supplements may incorporate vitamins Such as dapsone. and minerals. 0248 Antiprotozoals 0267 In general, the amount of the active substance incor 0249. The antimony compounds including meglumine porated in the dosage form according to the invention may be antimonate and Sodium Stibogluconate, the aromatic dia selected according to known principles of pharmacy. An midines including pentamidine, the arsenicals including the effective amount of pharmaceutical ingredient is specifically pentavalent compounds acetarsol and tryparsamide, and contemplated. By the term effective amount, it is understood melarsoprol which is trivalent, the dichloroacetamides that, with respect to for example pharmaceuticals, a therapeu including diloxanide, the halogenated hydroxyquinolines tically, prophylactically and/or diagnostically effective including diiodohydroxyquinoline, the nitrofurans including amount is contemplated. An effective amount is the amount or furazolidone, nifuratel, and nifurtimox, and the 5-nitroimida quantity of a drug Substance, which is sufficient to elicit the Zoles including metronidazole, nimorazole, ornidazole, sec required or desired therapeutic response, or in other words, nidazole, and tinidazole. Other drugs include atovaquone, the amount, which is sufficient to elicit an appreciable bio benZnidazole, dehydroemetine, eflornithine, mepacrine, and logical response when administered to a patient. As used Suramin. herein the term “effective amount’ means an amount at least (0250 Antivirals about 10% of the United States Recommended Daily Allow 0251 Anti-asthma Drug Groups ance (“RDA) of that particular ingredient for a patient. For 0252 Antimuscarinics and Beta agonists. example, if an intended ingredient is vitamin C, then an 0253 Such as the quaternary ammonium compounds ipra effective amount of vitamin C would include an amount of tropium bromide and oxitropium bromide, Salmeterol, vitamin C sufficient to provide 10% or more of the RDA. Albuterol, Bitolterol, Isoetharine, Metaproterenol, Pir Typically, where the tablet includes a mineral or vitamin, it buterol, Terbutaline, Isoproterenol, Ephedrine, Epinephrine will incorporate higher amounts, preferably about 100% or Salbutamol. more of the applicable RDA. The amount of active agent used 0254 Corticosteroids. can vary widely from a few milligrams to 100,000 milligrams 0255. Beclomethasone dipropionate, Budesonide Turbu O. O. haler, Flunisolide, Fluticasone, Triamcinolone acetonide. 0256 Leukotriene Inhibitors and Antagonists. Preparation of a Pharmaceutical Composition 0257 Zafirlukast, Montelukast. 0268 A pharmaceutical composition according to the 0258 Mast Cell Stabilisers. invention may be prepared by blending of at least: 0259 Sodium cromoglicate and Nedocromil sodium. 0269. 1) One or more active substances as particulate mat 0260 Xanthines. ter. Either as pure material (crystals or amorphous, in powder 0261 Theophylline and its derivatives. form) or encapsulated by a coat or trapped in a matrix or 0262 Antifungals bound to an ion-exchange resin. 0263 Flucytosine, Griseofulvin, Ketoconazole, Micona 0270. 2) One or more swelling/gelling materials Zole. 0271 and, optionally: 0264. As used herein, the term vitamin refers to trace 0272 3) Sweetening agents organic Substances that are required in the diet. For the pur (0273 4) Flavours poses of the present invention, the term vitamin(s) include, (0274 5) Colorants without limitation, thiamine, riboflavin, nicotinic acid, pan 0275. In one embodiment it is possible to use the gelling tothenic acid, pyrdoxine, biotin, folic acid, vitamin B. Sub.12, agent in Solution as a binder in granulating and as a glue for lipoic acid, ascorbic acid, vitamin A, vitamin D. Vitamin E giving the formulation the desired shape, however once the US 2012/00399.69 A1 Feb. 16, 2012
gelling agent has beenhydrated, the gelling properties may be 0284 FIG.3 shows the stomach recorded by in vivo ultra reduced, accordingly sometimes the gelling agent used in Sonic measures after ingestion of water and before ingestion Solution as a binder is identical with the bulk gelling agent of the formulation according to Example 19. (example Kelcogel(R) LT100), sometimes it is a different 0285 FIG. 4 shows the subsequent ultrasonic pictures just grade of the same gelling agent (Kelcogel(R) LT 100 bulk, after ingestion of the formulation according to Example 19. Kelcogel(R) F as binder) and sometimes a different binder 0286 FIG. 5 shows the complete dispersion of the formu altogether (Kelcogel(R) LT100 as bulk, Keltrol as binder). The lation according to Example 19 and as shown in FIG. 4. desired shape mentioned could be, for example, granulating (0287 FIG. 6 shows the dissolution at low pH of the for the mixture of active substances, gelling agent, Sweetenerand mulation according to Example 24 demonstrating disintegra flavour and Subsequently moulding and gluing the granules to tion into material with individual flakes varying in size from the concave surface of a spoon, preferable in a relative thin approximately 1 to 5 mm. layor of 0.5 to 5 mm thick. This strategy contributes to that the 0288 FIG. 7 demonstrates the dissolution similar to FIG. powder/particulate material obtained as the novel dosage 6 in a media at pH 4.8 demonstrating complete disintegration form can be converted into a pudding-like mass without appli of the material cation of any shear force and within the desired time period. 0289 FIG. 8 demonstrates the dissolution similar to FIG. This feature is very advantageous in that it is possible to use 6 in a media at pH 6.8 demonstrating complete disintegration the novel dosage form also for very Small amounts of active of the material into very small and fluffy material represent substances as there is no risk that active substance will be lost ing the non soluble material of the formulation. e.g. on a spoon or stirrer during stirring or mechanical mixing. 0290 FIG. 9 shows the dissolution of the formulation In other words, the dose form presents the active substance in according to Example 24 resulting in a fast dissolution rate of a form that ensures the right dose to be ingested. To the best of the paracetamol at different pH values. Similar effect is also the inventors knowledge this is the first comparable semi obtained with simulated gastric fluid. liquid alternative in this respect to a tablet or capsule dosage 0291 FIG. 10 shows 3 different spoons for use as delivery form. devices according to the present invention. All spoons are 0276 More specifically, the invention relates to a method prepared in order to be able to be left on a table or similar for preparing a pharmaceutical composition according to the place without tilting and at the same time easy to pick up invention, the method comprising blending the dry compo providing an easy handling during administration. The means nents to a homogeneous mixture and optionally granulating for preventing the spoons for tilting when left is self-explana the mixture with a binder. tory from the drawings in that either the shaft is bend or more 0277. In a specific embodiment, the invention relates to a times and or the “floor of the spoon is flattened. The latter A method for preparing a pharmaceutical composition may further be provided with an ordinary concave inner lin according to the invention comprising one or more excipients ing of the spoon to avoid material to be left on the spoon after and/or active ingredients which have a solubility substantial application to the mouth. lower than the solubility of the gellan gum, wherein the method comprises MATERIALS AND METHODS 0278 i) granulating a first blend comprising gellan gum but essentially not containing the one or more excipients 0292. Several of the below Examples have been produced and/or active ingredients which have a solubility substantial without an active ingredient and used for demonstrating dif lower than the solubility of the gellan gum, ferent compositions to which an active can be added (i.e. they 0279 ii) adding the one or more excipients and/or active are vehicles). Several of these formulations have been used ingredients which have a solubility substantial lower than the for consumer testing. The term Parvulet as used herein rep solubility of the gellan gum to the granulated first blend. resents any formulation according to the invention and is a 0280. In a subsequent step, the one or more excipients trademark for the products. and/or active ingredients which have a solubility substantial 0293. The following materials have been employed: lower than the solubility of the gellan gum is added to the 0294 Absolute alcohol 99.9%, De danske spritfabrikker, granulated first blend as a blend or granulate with additional pharmaceutical grade excipients. 0295 Aerosil, Unikem, pharmaceutical grade 0281. The foregoing will be better understood with refer 0296 Caramel flavour, Frutarom ence to the following examples which detail certain proce 0297 CefuximeAxetil, Stragen Nordic dures for manufacture of tablets in accordance to the present 0298 Chocolate flavour, Kiranto food invention. All references made to these examples are for the 0299 Ferrous fumarate coated, Ferrosan, pharmaceutical purposes of illustration. They are not to be considered limit grade ing as to the scope and nature of the present invention. 0300 Gellan, Kelcogel LT100, CpKelco ApS, pharma ceutical grade FIGURES 0301 Gellan, Kelcogel F. CpKelco ApS, pharmaceutical 0282 FIG. 1 shows a (A) spoon with the dryg composition grade adhering to it and covered with a "peel off film which in (B) 0302 Glycerol, Uniqema, pharmaceutical grade is remove and water (C) is added whereupongelling (D) takes 0303 Ibuprofen Coated, Nycomed DK, pharmaceutical place with expansion of the material which do no not slip the grade spoon (E) when this is tipped the other way round. 0304 Instant Sugar, Danisco Oy, pharmaceutical grade 0283 FIG. 2 shows the dissolution curve according to the 0305 Inulin instant, Fibruline formulation of Example 17 of a Paracetamol dosage unit in 0306 Ispaghulae Husks, Vi-siblin, Pfizer simulated gastric fluid demonstrating a very fast release of at (0307 Maize Starch Ultrasprese HV. National Starch & least 96% within 5 minutes. Chemical US 2012/00399.69 A1 Feb. 16, 2012
0308 Medium Chain Triglyceride EP (Labrafiac cc), Gat tefossé SAS, pharmaceutical grade 0309 PVP (plastdone R. K-25, ISP (Switzerland) AG 0310 Pyridoxine Coated, Ferrosan, pharmaceutical grade % Wiw 9. 0311 Sodium Citrate, Unikem, pharmaceutical grade Blend 1: 0312 Sodium hydrogen carbonate, Unikem, pharmaceu tical grade Explotab 46.3 0.97 Instant Sugar 46.32 0.97 0313 Sodium starch glycolate, Explotab, JRS Pharma Aerosil O.53 O.O11 0314 Strawberry flavour, Kiranto food Vaniia flavor 4.6 O.096 0315 Tutti-frutti flavour, Frutarom Glycerol 2.3 (binder) O.048 0316 Vanilla flavour, Keranto food AIS Blend 2: 0317 Xanthan gum, Keltrol CpKeico ApS, pharmaceuti Blend 1 60 2.1 cal grade Coated Cefuxime 40 1.4 0318 Xylitol, Danisco Sweeteners LtD The ingredients (1-4) of Blend 1 are mixed/2 min (depending on the amount of powder) in 0319 Coat: a mortar, transferred to a Philips Food processor, Electronic type HR 2377 D, ingredient 5 0320 Eudragite EPO, Rohm 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 0321 Lauryl Sulphate, Sigma of powder). 0322. Altalc 500V. Luzenac America 0323 Eudragit NE30D, Rohm 0343. In this example, Explotab is used as a gelling agent 0324 Granulation Performed by hand mixing until that is granulated with glycerol. homogenous slightly sticky relative Small particles are 0344) The granules are divided into 570 mg/dose. The present Suitable equipment includes High Shear mixer such dose is weight out into a medical spoon and moulded by as in a Zanchetta Roto P100—100 liter capacity or a MTI gently pressing the granules against the spoon with a mortar mixer. pistil to a thin layer about 1-3 mm in high in the bottom of the 0325 Drop Down Test spoon. The water is evaporated at ambient temperature. 0326. The drop down test apparatus is a medical plastic (0345 Drop Down Test: spoon obtained from Nomeco (DBI Plastic type 1 15022) with 0346. To the above dosage form, 4 ml tapped water is markings for 2/2 and 5 ml liquid) see FIG. 1, e.g. drawing E. added. After about/2 min the liquid is absorbed. The spoon is 0327 Test Method turned around and held upside down for 2 min. The test 0328. In a test spoon 0.5g-0.7 g test material is accurately material did not fall out and passed the test. weighed. 3 ml-5 ml tapped water is added. Wait /2 min, turn the spoon around, and if the test material does not drop down EXAMPLE 2 (fall off the spoon) within 2 min, the material has passed the A Composition According to the Invention Contain teSt. ing 250 mg Coated Cefuxime in the Dosage Unit 0329 Viscosity Test 0330 Apparatus: 0347 A composition that has a shape as outlined in FIG. 1 0331 Brookfield Viscometer Model LVF, Serie 56779 containing CefuXime as active Substance, was prepared as 0332 Spindel No. #4 diameter 3.2 mm, length 33.96 mm follows (given as % w/w): 0333 Beaker 500 ml low form (approximately 90 mm internal diameter) 0334 Termometer 0335 Parameter: % Wiw 9. 0336 Speed: 6 rpm Blend 1: 0337 Spindle: The Viscometer spindle is centered in the Explotab 46.3 O.87 test sample container. The spindle is properly immersed to the Instant Sugar 46.3? O.87 mid-point of the shafts narrow portion. Aerosil O.53 O.OO94 0338 Test Method Vaniia flavour 4.6 O.O86 0339 Into a 500 ml beaker 22-88 g test material is accu Glycerol 2.35 O.043 rately weighed, 500 ml tapped water is added. Mix untill all Blend 2: the material is dispersed/dissolved, and after about 5 min the Blend 1 S3.6 1.87 Viscosity and the temperature are measured. Coated Cefuxime 35.7 1.25 (0340 Sensory Test Vi-siblin 10.7 O.38 0341 Tapped water is added to the formulation and when 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 all the liquid is absorbed (visually confirmed), the test can added and mixed for about /2 min (depending on the amount of powder) at speed 4. The start. Taste the formulation and rank the taste from 1-10, ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount where 10 is the most pleasant taste. of powder). 0348. The granules are divided into 700 mg/dose. The EXAMPLE1 dose is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortar A Composition According to the Invention Contain pistil to a thin layer about 1-3 mm in high in the bottom of the ing 250 mg Coated Cefuxime Dosage Unit spoon. The water is evaporated at ambient temperature. 0342. A composition that has a shape as outlined in FIG. 1 (0349 Drop Down Test: containing cefuXime as active substance was prepared as 0350. To the above dosage form 4 ml tapped water is follows: added. After about/2 min the liquid is absorbed. The spoon is US 2012/00399.69 A1 Feb. 16, 2012 20 turned around and held upside down for 2 min. The test material did not fall out and passed the test. -continued % Wiw 9. EXAMPLE 3 Blend 3: A Composition According to the Invention Contain Blend 2 71.4 2.50 Kelcogel F 14.32 O.S ing 250 mg Coated Cefuxime Dosage Unit Water 14.33 O.S 0351 A composition that has a shape as outlined in FIG. 1 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 containing cefuXime as active substance was prepared as the amount of powder). follows% w/w: 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 1/2 min (depending on the amount of powder) and forming the granules, 0356. The granules are divided to 700 mg/dose. The dose % Wiw 9. is weight out into a medical spoon and moulded by gently Blend 1: pressing the granules against the spoon with a mortarpistil to a thin layer about 1-3 mm in high in the bottom of the spoon. Kelcogel LT100 23.1 O.S2 The water is evaporated at ambient temperature. Xylitol 69.12 1.55 Aerosil O.53 O.O11 0357 Drop Down Test: Vaniiia flavour 54 O112 Glycerol 2.35 0358 To the above dosage form 3 ml tapped water is Blend 2: added. After about/2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test Blend 1 64.3 2.25 Coated Cefuxime 35.7 1.24 material did not fall out and pass the test. 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 EXAMPLE 5 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 ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount A Composition According to the Invention Contain of powder). ing 150 mg Coated Ferro Fumarate in the Dosage 0352. The granules are divided to 700 mg/dose. The dose Unit is weight out into a medical spoon and moulded by gently 0359 A composition that has a shape as outlined in FIG. 1 pressing the granules against the spoon with a mortarpistil to containing coated Ferro fumarate as active Substance was a thin layer about 1-3 mm in high in the bottom of the spoon. prepared as follows: The water is evaporated at ambient temperature. 0353 Drop Down Test:
0354) To the above dosage form 4 ml tapped water is % Wiw 9. added. After about/2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test Blend 1: material did 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 Blend 2:
Blend 1 75 1875 A Composition According to the Invention Contain Ferro fumarate 25 O.625 ing 150 mg Coated Pyridoxine in the Dosage Unit Blend 3: Blend 2 71.4 2.50 0355. A composition that has a shape as outlined in FIG. 1 Kelcogel F 14.32 O.S containing coated pyridoxine as active Substance was pre Water 14.3 O.S pared as follows: The ingredients (1-3) of Blend1 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). 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. Blend 1: 0360. The granules are divided into 700 mg/dose. The dose is weight out into a medical spoon and moulded by Kelcogel LT100 501 O.938 Xylitol 47.52 O.89 gently pressing the granules against the spoon with a mortar Vaniiia flavour 2.53 O.O47 pistil to a thin layer about 1-3 mm in high in the bottom of the Blend 2: spoon. The water is evaporated at ambient temperature. Blend 1 75 1875 0361 Drop Down Test: Pyridoxine coated 25 O.625 0362. To the above dosage form 3 ml tapped water is added. After about/2 min the liquid is absorbed. The spoon is US 2012/00399.69 A1 Feb. 16, 2012 21 turned around and held upside down for 2 min. The test material did not fall out and pass the test. -continued
EXAMPLE 6 % ww 9. Blend 3: A Composition According to the Invention Contain ing 125 mg Coated Ibuprofen in the Dosage Unit Blend 2 742 2.59 Kelcogel F 12.92 O.45 0363 A composition that has a shape as outlined in FIG. 1 Water 12.93 O.45 containing coated ibuprofen as active Substance was prepared The ingredients of Blend 1 are mixed/2 min (depending on the amount of powder) in a as follows: 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 and mixed for about/2 min (depending on the amount of powder).
% Wiw 9. 0368. The granules are divided into 700 mg/dose. The dose is weight out into a medical spoon and moulded by Blend 1: gently pressing the granules against the spoon with a mortar Kelcogel LT100 52.6 O.87 pistil to a thin layer about 1-3 mm in high in the bottom of the Xylitol 47.42 0.79 Spoon. Blend 2: 0369 Drop Down Test: Blend 1 64.1 1.66 0370. To the above dosage form 3 ml tapped water is Ibuprofen 20.9 O.S4 added. After about/2 min the liquid is absorbed. The spoon is Vaniiia flavour 15 O.39 turned around and held upside down for 2 min. The test Blend 3: material did not fall out and pass the test. Blend 2 742 2.59 Kelcogel F 12.92 O.45 EXAMPLE 8 Water 12.93 O.45 A Composition According to the Invention Contain 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 ing 125 mg Coated Ibuprofen in the Dosage Unit the amount of powder). The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend 0371. A composition that has a shape as outlined in FIG. 1 and mixed for about/2 min (depending on the amount of powder). containing coated ibuprofen as active Substance was prepared 0364 The granules are divided to 700 mg/dose. The dose as follows: is weight out into a medical spoon and moulded by gently 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 % ww 9. to a sphere or stripe. The water is evaporated in an oven at 70° Blend 1: C. to constant temperature. Kelcogel LT100 52.6 0365 Drop Down Test: Xylitol 47.42 0366. To the above dosage form 3 ml tapped water is Blend 2: added. After about/2 min the liquid is absorbed. The spoon is Blend 1 71 1.83 turned around and held upside down for 2 min. The test Ibuprofen coated 23.2 O.6 material did not fall out and pass the test. Caramel flavour 5.8 O.15 Blend 3: EXAMPLE 7 Blend 2 742 2.59 A Composition According to the Invention Contain Kelcogel F 12.92 O.45 ing 125 mg Coated Ibuprofen in the Dosage Unit Water 12.93 O.45 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 0367. A composition that has a shape as outlined in FIG. 1 the amount of powder). containing coated ibuprofen dosage as active Substance was The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend prepared as follows: and mixed for about/2 min (depending on the amount of powder). 0372. The granules are divided into 700 mg/dose. The dose is weight out into a medical spoon and moulded by gently pressing the granules against the spoon with a mortar % Wiw 9. pistil to a thin layer about 1-3 mm in high in the bottom of the Blend 1: spoon. The water is evaporated at ambient temperature to a Kelcogel LT100 52.6 O.9S final amount of approximately 575 mg/dose Xylitol 47.42 O.86 0373 Drop Down Test: Blend 2: 0374. To the above dosage form 3 ml tapped water is Blend 1 69.7 1.81 added. After about/2 min the liquid is absorbed. The spoon is Ibuprofen coated 22.7 O.S8 turned around and held upside down for 2 min. The test Tutti-frutti flavour 7.6 O.20 material did not fall out and pass the test. The average absorp tion rate of water by the dosage per second measured in gram US 2012/00399.69 A1 Feb. 16, 2012 22 water absorb per gram dosageper second is 3 g/0.575 g/30sec corresponding to a water absorption rate of 0.1739 g/g/s -continued
% ww 9. EXAMPLE 9 Blend 2: A Composition According to the Invention Contain Blend 1 94.0 3.0 ing 125 mg Coated Ferro Fumarate in the Dosage Strawberry flavour 6.O O.2 Unit Blend 3: 0375. A composition that has a shape as outlined in FIG. 1 Blend 2 91.4 3.2O containing coated ferro fumarate dosage as active Substance Sodium citrate 122 O.042 was prepared as follows: Water 8.43 O.294 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). The ingredients (2-3) from blend 3 are mixed/2 min and ingredient 1 is added to the blend % Wiw 9. and mixed for about/2 min (depending on the amount of powder). Blend 1: 0381. The granules are divided into 550 mg/dose. The Kelcogel LT100 52.6 O.91 dose is weight out into a medical spoon and moulded by Xylitol 47.42 O.83 gently pressing the granules against the spoon with a mortar Blend 2: pistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature to a Blend 1 67.2 1.74 final amount of approximately 502 mg/dose. Ferro fumerate coated 21.9 O.S6 Chocolate flavour 10.9 O.29 (0382 Drop Down Test: Blend 3: 0383 To the above dosage form 3.5 ml tapped water is Blend 2 74.21 2.59 added. After about/2 min the liquid is absorbed. The spoon is Kelcogel F 12.92 O.45 turned around and held upside down for 2 min. The test Water 12.9 O.45 material did not fall out and pass the test. 0384 The average absorption rate of water by the dosage 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 per second mesured in gram water absorb per gram dosage the amount of powder). per second is 3.5 g/0.502 g/120 sec corresponding to a water 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). absorption rate of 0.0581 g/g/s
0376. The granules are divided into 700 mg/dose. The EXAMPLE 11 dose is weight out into a medical spoon and moulded By gently pressing the granules against the spoon with a mortar A Placebo Composition According to the Invention pistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature to a 0385. A composition that has a shape as outlined in FIG. 1 final amount of approximately 575 mg/dose. was prepared as follows: 0377 Drop Down Test: 0378. To the above dosage form 3 ml tapped water is added. After about/2 min the liquid is absorbed. The spoon is % Wiw 9. turned around and held upside down for 2 min. The test material did not fall out and pass the test. Blend 1: 0379 The average absorption rate of water by the dosage Kelcogel LT100 251 O.65 per second mesured in gram water absorb per gram dosage Xylitol 752 1.94 per second is 3 g/0.575 g/120 sec corresponding to a water Blend 2: absorption rate of 0.0435 g/g/s Blend 1 80.3 2.59 Inulin 13.1 O42 EXAMPLE 10 Caramel flavour 6.6 O.21 Blend 3:
A Placebo Composition According to the Invention Blend 2 92 3.22 Water 8 O.28 0380 A composition that has a shape as outlined in FIG. 1 The ingredients of Blend 1 are mixed "/2 min (depending on the amount of powder) in a was prepared as follows: mortar. The ingredients from blend 2 are mixed in a mortar for about/2 min (depending on the amount of powder). Blend 3 is mixed for about /2 min (depending on the amount of powder). 0386 The granules are divided into 550 mg/dose. The % Wiw 9. dose is weight out into a medical spoon and moulded by Blend 1: gently pressing the granules against the spoon with a mortar Kelcogel LT100 22.5 0.675 pistil to a thin layer about 1-3 mm in high in the bottom of the Xylitol 67.52 2.025 spoon. The water is evaporated at ambient temperature to a Ultrasperse HV 10.03 O.3 final dosage of 506 mg. (0387 Drop Down Test: US 2012/00399.69 A1 Feb. 16, 2012
0388 To the above dosage form 3.5 ml tapped water is added. After about/2 min the liquid is absorbed. The spoon is -continued turned around and held upside down for 2 min. The test material did not fall out and pass the test. % Wiw 9. 0389. The average absorption rate of water by the dosage Blend 3: per second measured in gram water absorb per gram dosage per second is 3.5 g/0.506 g/120 sec corresponding to a water Blend 2 60 O.64 Microencapsulated Cefuxime 40 O.42 absorption rate of 0.0576 g/g/s Blend 4: EXAMPLE 12 Kelcogel LT100 501 O.98 Xylitol 502 O.98 A Placebo Composition According to the Invention Blend 5 0390. A composition that has a shape as outlined in FIG. 1 Blend 4 56.1 1.96 was prepared as follows: 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. 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 501 1.2 Xylitol 502 1.2 0395. The granules are divided to 600 mg/dose. The dose Blend 2: is weight out into a medical spoon and moulded by pressing Blend 1 8O 2.4 the granules against the spoon with a stopper to a thin layer Keltrol 2O O6 about 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 0396 Drop Down Test: Caramel flavour 14.32 O.S 0397 To the above dosage form 4 ml tapped water (temp. Water 14.33 O.S 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 for 2 min. The test material did not fall out and pass the test. 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). EXAMPLE 1.4 0391 The granules are divided into 500 mg/dose. The dose is weight out into a medical spoon and moulded by A Composition According to the Invention Contain gently pressing the granules against the spoon with a mortar ing 120 mg Coated Cefuxime in the Dosage Unit pistil to a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature to a 0398. A composition in percentage having a shape as out final dosage of 429 mg lined in FIG. 1 containing cefuXime as active substance was 0392 Drop Down Test: prepared as follow: 0393 To the above dosage form 3 ml tapped water is added. After about/2 min the liquid is absorbed. The spoon is turned around and held upside down for 2 min. The test % Wiw 9. material did not fall out and pass the test. Blend 1: EXAMPLE 13 Kelcogel LT100 40 1.195 Xylitol 40 1.195 A Composition According to the Invention Contain Ketrol 2O O.6O ing 120 mg Coated Cefuxime in the Dosage Unit Blend 2: 0394. A composition in percentage having a shape as out Sodium citrate 251 O.128 Dem. water 733 0.372 lined in FIG. 1 containing cefuXime as active substance was Keltrol 22 O.O11 prepared as follow: Blend 3
Blend 1 85.4 2.99 Blend 2 14.6 O.S1 % ww 9. The ingredients Blend 1 are mixed in a Braun electronic mixer type 4202 for about 1 min. Blend 1: 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, Sodium citrate 251 0.157 Dem. Water 752 O.470 0399. The granules are divided to 600 mg/dose. The dose Blend 2: is weight out into a medical spoon and moulded by pressing Blend 1 98.04 O. 627 the granules against the spoon with a stopper to a thin layer Keltrol 1962 O.O13 about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature. US 2012/00399.69 A1 Feb. 16, 2012 24
(0400 Drop Down Test: -continued 04.01 To the dosage form 4 ml tapped water (temp. between 15-20°C.) is added. After about 15 sec the liquid is Blend 2: absorbed. The spoon is turned around and held upside down Blend 1 50 for 2 min. The test material did not fall out and pass the test. Sodium citrate 11 0402 Viscosity Test: PEG 200 39 0403. Transfer 43.75 g test materials Accurately weighed Blend 3: into a 500 ml beaker, and disperse/dissolve with 500 ml Kelcogel LT100 42.86 tapped water. Xylitol 42.86 04.04 The viscosity is measured to 60500 cps. Keltrol 1428 Blend 4
EXAMPLE 1.5 Blend 2 8O.SO A Composition According to the Invention Contain Blend 3 19.50 ing 50 mg Coated Paracetamol in the Dosage Unit Blend 5 Blend 4 90.00 0405. A composition in percentage having a shape as out Microencapsulated paracetamol 1O.OO lined in FIG. 1 containing paracetamol as active Substance (61% pure paracetamol) was prepared as follow: Blen : Sodium citrate is dissolved dem. water. Blen 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 Blend 1 scraper or a card until all is blend. Blend 5: The ingredient from blend 5 is mixed in a mortar with a scraper Sodium citrate 25 or a card until homogeneous blend is obtained. Dem. water 75 Blend 6: Blend 2: PVP (kollidon 25k) 9.52 Kelcogel LT100 50 Ethanol 99.9% 85.72 Xylitol 50 Glycerol 4.76 Blend 3: Blend 6: PVP (kollidon 25k) is dissolved in Ethanol 99.9%, when Blend 2 75 dissolved Glycerol is added and blend. Keltrol 12.5 Blend 6 is poured in a 50 ml spray flask with a nozzle. Apple fruit 12.5 Blend 4: 0410 Prepared spoon: The concave side of the spoons are Blend 3 74.22 sprayed twice with blend 4. The EtOH is evaporated in an Blend 1 12.13 oven at 45° C. for one hour. Microencapsulated paracetamol 13.65 (61% pure paracetamol) 0411. The blend 5 is divided to 820 mg/dose. The dose is Blend 1: Sodium citrate is dissolved in dem, water, weight out into a prepared medical spoon and moulded by Blend 2: The ingredient from blend 2 is mixed in a mortar with a scraper or a card until all pressing the granules against the spoon with a stopperto a thin is blend. Blend 3: The ingredient from blend 3 is mixed in a mortar with a scraper or a card until all layer about 1-3 mm in high in the bottom of the spoon. The is blend. The ingredient from blend4 is mixedinamortar with a scraperor a card untilahomogeneous water is evaporated at ambient temperature. blend is obtained. 0412 Drop Down Test: 0406. The blend 4 is divided to 600 mg/dose. The dose is 0413 To the above dosage form 4 ml tapped water (temp. weight out into a medical spoon and molded by pressing the between 15-20°C.) is added. After about 15 sec the liquid is granules against the spoon with a stopper to a thin layer about absorbed. The spoon is turned around and held upside down 1-3 mm in high in the bottom of the spoon. The water is for 2 min. The test material did not fall out and pass the test. evaporated at ambient temperature. 04.07 Drop Down Test: EXAMPLE 17 0408. To the above dosage form 4 ml tapped water (temp. A Composition According to the Invention Contain between 15-20°C.) is added. After about 15 sec the liquid is ing 200 mg Coated Paracetamol in the Dosage Unit absorbed. The spoon is turned around and held upside down for 2 min. The test material did not fall out and pass the test. 0414. A composition in percentage having a shape as out lined in FIG. 1 containing paracetamol as active Substance EXAMPLE 16 was prepared as follow: A Composition According to the Invention Contain ing 50 mg Coated Paracetamol in the Dosage Unit Blend 1: 04.09. A composition in percentage having a shape as out Gellan gum (Kelcogel LT100) SO.OO lined in FIG. 1 containing paracetamol as active Substance Xylitol SO.OO was prepared as follow: Blend 2: Blend 1 37.5 Microencapsulated paracetamol 52 Blend 1: (61% pure paracetamol) Glycerin 1O.S Sodium citrate 25 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 2012/00399.69 A1 Feb. 16, 2012
-continued -continued Blend 3: Sodium Hydrogen Carbonate 2.9 Povidone (kollidon 25k) 9.52 Strawberry flavour 5.8 Ethanol 99.9% 85.72 Blend 1: Sodium citrate is dissolved Dem. water. Glycerol 4.76 Blend 2: The ingredients from blend are mixed in a mortar with a pestle, Blend 3: Povidone (kollidon 25k) is dissolved Ethanol 99.9% and then scraping as needed until homogeneous blend. Glycerol is added and dissolved. Blend 3: The ingredients from blend are mixed in a mortar with a pestle, Blend 4 is poured in a 50 ml spray flask with nozzle. scraping as needed until homogeneous blend. Blend 4: 0415 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 Blend 4: Povidone (kollidon 25k) is dissolved Ethanol 99.9% and then 0416) The blend 2 is divided to 630 mg/dose. The dose is Glycerol is added and dissolved. weight out into a prepared medical spoon and moulded by Blend 4 is poured in a 50 ml spray flask with nozzle. pressing the granules against the spoon with a stopperto a thin layer about 1-3 mm in high in the bottom of the spoon. The water is evaporated at ambient temperature. 0429 Prepared spoon: The concave side of the spoons are 0417. Drop Down Test: sprayed twice with blend 4. The EtOH is evaporated in an 0418. 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 0430. The blend 3 is divided to 880 mg/dose. The dose is absorbed. The spoon is turned around and held upside down weight out into a prepared medical spoon and moulded by for 2 min. The test material did not fall out and pass the test. pressing the granules against the spoon with a stopperto a thin 0419 Dissolution layer about 1-3 mm in high in the bottom of the spoon. The 0420 Material and Methods water is evaporated at ambient temperature. 0421. Simulated gastric Fluid: For 1 L: 0.1 H HCl 0431 Drop Down Test: 0422 Dissolution system consists of online system model 0432 To the above dosage form 4 ml tapped water (temp. SOTAX AT7 and UV detector Model PE lambda 2 using between 15-20°C.) is added. After about 15 sec the liquid is Disslab version 1.1. absorbed. The spoon is turned around and held upside down 0423. The dissolutions curve was obtain with Temp 37 for 2 min. The test material did not fall out and pass the test. C. Speed 120 rpm, 280 nm and a factor of 108 over a period of 1 h. EXAMPLE19 0424 Results and Discussion A Placebo Composition According to the Invention 0425 FIG. 2 illustrates the dissolutions profile of a Parac etamol dosage unit in simulated gastric fluid. After 5 min at 0433. A composition that has a shape as outlined in FIG. 1 least 96% of the Paracetamol is released. was prepared as follows (given as % w/w): 0426. The curve with the dot-line is pure coated paraceta mol used in the dosage form; After 5 min at least 96% of the Paracetamol is released. 0427 Comparing pure coated paracetamol and the Parac Blend 1: etamol dosage unit no differences between the release profiles Sodium citrate 25 a Sel. Demineralized water 75 Blend 2: EXAMPLE 1.8 Kelcogel LT100 50 A Composition According to the Invention Contain Xylitol 50 ing 250 mg Coated Paracetamol in the Dosage Unit Blend 3: 0428. A composition in percentage having a shape as out Blend 1 11.2 Blend 2 8O lined in FIG. 1 containing paracetamol as active Substance Sodium hydrogen carbonates 3 was prepared as follow: Strawberry flavoribanana flavor 5.8
Blend 1: Sodium citrate is dissolved dem. Water, Blend 2: The ingredients from blendare mixed in a mortar with a pestle, scraping as needed until homogeneous blend. Blend 1: Blend 3: The ingredients from blendare mixed in a mortar with a pestle, scraping as needed until homogeneous blend. Sodium citrate 25 Demineralized water 75 0434. The blend 3 is divided into 250 mg/dose. The dose is Blend 2, weight out into a medical spoon and molded by gently press ing the granules against the spoon with a mortarpistil to a thin Gellan gum (Kelcogel LT100) SO.OO Xylitol SO.OO layer about 1-3 mm in high in the bottom of the spoon. The Blend 3: water is evaporated at ambient temperature. 0435 Drop Down Test: Blend 1 42.7 Blend 2 9.8 0436 To the above dosage form 3 ml tapped water is Microencapsulated paracetamol 38.7 added. After about/2 min the liquid is absorbed. The spoon is (61% pure paracetamol) turned around and held upside down for 2 min. The test material did not fall out and pass the test. US 2012/00399.69 A1 Feb. 16, 2012 26
0437. In-vivo Ultra Sound Scanning Test layer about 1-3 mm in high in the bottom of the spoon. The 0438. In vivo properties of the above placebo formulations water is evaporated at ambient temperature. were determined in a subject who had fasted for 8-12 hours 0445 Drop Down Test: prior to ingesting 250 mL of water and 5 min after having 0446. To the above dosage form 3 ml tapped water is ingested the prepared dosages form. Ultrasound imaging was added. After about/2 min the liquid is absorbed. The spoon is performed in sitting position throughout the procedure. turned around and held upside down for 2 min. The test 0439 B-mode ultrasound imaging of the gastrointestinal material did not fall out and pass the test. tract was done with a LOGIC (4-10 MHz) linear transducer (Linear 10 L H40412LG) coupled to a LOGIQ 9 Ultrasound EXAMPLE 21 instrument with software version R3.0.11 abdominal pro gram (8 MHz). Images were videotaped before ingestion of A Placebo Composition for Use According to the water and immediately prior to ingestion of the dosage form Invention (time 0) and at five minutes intervals thereafter. 0447. A composition that has a shape as outlined in FIG. 1 0440 FIG. 3 demonstrates that the ingested water was prepared as follows (given as % w/w): appeared “black” in the ultrasonic image. FIG. 4 demon strates that the ingested dosages form appeared “white' in the ultrasonic image. Blend 1: 0441 Shortly after ingestion of the water the stomach Kelcogel LT100 50 lumen became Sonolucent and non-echogenic and thus Xylitol 50 appeared “black” in the ultrasonic image and after ingestion Blend 2: of the dosage form the stomach lumen became Sonolucent Blend 1 83.3 and echogenic and thus appeared “white' in the ultrasonic Medium Chain Triglyceride EP S.6 image. As seen from the picture FIG. 5 the dosage form is (Labrafiac cc) Povidone (kollidon 25k) S.6 spread through out the stomach, which indicate that the dos Vanilla flavour S.6 age form is totally disintegrated when reaching the stomach. 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 homogeneous blend, Vanilla flavour is added to the mixture and blend to Invention a homogeneous mass. 0442. A composition that has a shape as outlined in FIG. 1 Blend 3: was prepared as follows (given as % w/w): Povidone (kollidon 25k) 9.52 Ethanol 99.9% 85.72 Glycerol 4.76 Blend 3: Povidone (kollidon 25k) is dissolved in Ethanol 99.9% and Blend 1: Glycerol is added to the mixture and dissolved. Blend 4 is poured in a 50 ml spray flask with nozzle. Kelcogel LT100 50 Xylitol 50 Blend 2: 0448 Prepared spoon: The concave side of the spoons are 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 0449 The granules are divided to 250 mg/dose. The dose Blend 3: is weight out into a prepared medical spoon and moulded by pressing the granules against the spoon with a stopperto a thin Blend 1 93.8 layer about 1-3 mm in high in the bottom of the spoon. The Ethanol 99.9% 6.2 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. 0450 Drop Down Test: Blend 2: The ingredients from blend 2 are mixed in a mortar with a pestle, 0451. To the above dosage form 3 ml tapped water is scraping as needed until homogeneous blend. added. After about/2 min the liquid is absorbed. The spoon is Blend 3: The ingredients from blend 3 are mixed in a mortar with a pestle, scraping as needed until homogeneous blend. turned around and held upside down for 2 min. The test Blend 4: material did not fall out and pass the test. Povidone (kollidon 25k) 9.52 EXAMPLE 22 Ethanol 99.9% 85.72 Glycerol 4.76 Oral Hygiene Composition for use Directly in the Blend 4: Povidone is dissolved in Ethanol and then Glycerol is added and dissolved. Mouth Cavity With or Without Prehydration Blend 4 is poured in a 50 ml spray flask with nozzle. 0452. A composition in percentage having a shape as out lined in FIG. 1 was prepared as follow: 0443 Prepared spoon: The concave side of the spoons are sprayed twice with blend 4. The EtOH is evaporated in an oven at 45° C. for one hour. Blend 1: 0444 The granules are divided to 300 mg/dose. The dose Xylitol 86.6 is weight out into a prepared medical spoon and moulded by Glycerol 13.4 pressing the granules against the spoon with a stopperto a thin US 2012/00399.69 A1 Feb. 16, 2012 27
-continued spoon is turned around and held upside down for 2 min. The test material did not fall out and pass the test. Blend 2: EXAMPLE 24 Blend 1 S3.6 Kelcogel LT100 46.4 A Composition According to the Invention Contain ing 250 mg Paracetamol Blend 1: Xylitol is mixed with glycerolin a Braun electronic kitchen mixer at level 4, for 2 ill, Blend 2: The ingredient from blend 2 is mixed in the Braun Electronic kitchen mixer until all 0460 A composition that has a shape as outlined in FIG. 1 is blend. Sieved through a sieve mesh. was prepared as follows: 0453 The two blends are mixed and pressed into plates with a thickness of approximately 2 mm and cut into pieces of % Wiw 9. 1x2 cm. The flakes are dried in an oven (Electrolux) at 45° C. for /2 h. Blend 1: 0454. The flakes are placed in the oral cavity where the Kelcogel LT100 50 18.78 formulation will be hydrated by the saliva and any local active 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 Glycero 3.42 O499 A Placebo Composition According to the Invention Paracetamol 40.6 S.92 Glycero 1O.S 1.53 0455. A composition that has a shape as outlined in FIG. 1 Blend 4: was prepared as follows: 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 Blend 1 formed. Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under mixing to form a homogeneous blend, Kelcogel LT100 50 18.78 Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or Xylitol 50 18.78 mixing card. Glycerol is added stepwise under continuous slow mixing and a uniform Blend 2 granulate is formed. Paracetamol is added under continuous slow mixing and the 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 Vanilla Flavour 92.2 2.25 Glycerol is added and stirred until a clear mixture is obtained. Blend4 is poured into a 50 ml PVP K25 7.8 O.19 spray flask with nozzle, end 3 0461) Medical spoon preparation: The concave side of a Blend 1 88.89 37.56 Blend 2 5.78 2.44 medical spoon is sprayed twice with Blend 4 (approximately Glycerol 5.33 2.25 Blend 4 60 mg) and placed in an oven at 45° C. for 30 minutes. 0462 616+20 mg/dose is weight into a prepared medicine PVP K25 9.5 4.OO spoon and distributed by pressing the granules against the Glycerol 4.8 2.00 spoon with a stopper. The final layer of granules lay in the Ethanol 99.9% 85.7 36.O1 bottom of the spoon and is approximately 2 mm in height. Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is topspray formed. Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under 0463 Drop Down Test: mixing to form a homogeneous blend, Blend 3: Blend 1 is volumetrically mixed stepwise into Blend 2 with a dough scraper or 0464) To the above dosage form 5 ml tapped water is mixing card. The Glycerol is added stepwise under continuous slow mixing and a uniform added. After about 30 seconds the liquid is absorbed. The granulate is formed. Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. The spoon is turned around and held upside down for 2 min. The Glycerol is added and stirred until a clear mixture is obtained. Blend 4 is poured into a 50 ml test material did not fall out and pass the test. spray flask with nozzle, EXAMPLE 25 0456 Medical spoon preparation: The concave side of a medical spoon is sprayed twice with Blend 4 (approximately A Composition According to the Invention Contain 60 mg) and placed in an oven at 45° C. for 30 minutes. ing 415 mg Coated Paracetamol (Corresponding to 0457. 335+17.5 mg/dose of Blend 3 is weight into a pre 250 mg Paracetamol) pared medicine spoon and distributed by pressing the gran 0465. A composition that has a shape as outlined in FIG. 1 ules against the spoon with a stopper. The final layer of was prepared as follows: granules lay in the bottom of the spoon and is approximately 2 mm in height. The spoon is sprayed twice with blend 4 (approximately 60 mg) and placed in an oven at 45° C. for 30 % Wiw 9. minutes, evaporating the ethanol. Blend 1: 0458 Drop Down Test: Kelcogel LT100 50 18.78 0459. To the above dosage form 5 M1 tapped water is Xylitol 50 18.78 added. After about 30 seconds the liquid is absorbed. The US 2012/00399.69 A1 Feb. 16, 2012 28
-continued 0486 Vessel 3 and 4: Phosphate solution pH 4.5. 0487 Vessel 5 and 6:0.1 NHC1. % Wiw 9. 0488 Place 200 ml of Diluent buffer in the Standard ves Blend 2: sel.
Vanilla Flavour 92.2 2.25 0489. After cell diagnostics, replace Diluent buffer from PVPK25 7.8 O.19 the Standard vessel with 250 ml of standard solution (0.2 mg end 3: paracetamol/ml).
Blend 1 33.2 1O.S Blend 2 2.15 O.678 Glycerol 2.66 O840 Analytical principle Online UW Coated Paracetamol 57.1 18.06 API Paracetamol Glycerol 4.81 1.52 Method USP2 (paddle) Blend 4: Degassing Vacuum filtration at 41° C. Temperature 37°C. O.S. C. PVPK25 9.5 4.OO Volume 900 + 0.2% (895 ml + 4 ml) Glycerol 4.8 2.OO Detection 280 nm. Ethanol 99.9% 85.7 36.01 Rotation speed 50 rpm Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is Filters 0.7 Full Flow Filter formed. Detection frequency every 5 min. in 60 minutes 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 mixing card. Glycerol is added stepwise under continuous slow mixing and a uniform 0490 Sample Preparation: granulate is formed. Coated Paracetamol is added under continuous slow mixing and the final part of Glycerol is added to form a uniform granulate, 0491 Carefully remove the shaft from the spoon using a Blend 4: Ethanol and PWPK25 is mixed and stirred until a clear mixture is obtained. The Glycerol is added and stirred until a clear mixture is obtained. Blend4 is poured into a 50 ml pair of Scissors. spray flask with nozzle, 0492 Place sinker on outer bottom of the spoon unit. 0466 Medical spoon preparation: The concave side of a 0493 Add 4 ml of tapped water (room temperature) to the medical spoon is sprayed twice with Blend 4 (approximately test unit. 60 mg) and placed in an oven at 45° C. for 30 minutes. 0494 Results: 0467 720+20 mg/dose is weight into a prepared medicine spoon and distributed by pressing the granules against the TABLE 1 spoon with a stopper. The final layer of granules lay in the bottom of the spoon and is approximately 2 mm in height. Release Time and 90 dissolved material as a function of pH. 0468 Drop Down Test: Release time where less 0469 To the above dosage form 5 M1 tapped water is than 0.5% increase from added. After about 30 seconds the liquid is absorbed. The last measurement spoon is turned around and held upside down for 2 min. The Solution pH (A-0.5% absolute) % Dissolved, 60 min. test material did not fall out and pass the test. O.1NHCI 1 35 93.9 0470 Dissolution Testing: 50 90.4 0471. For dissolution spoons prepared as described above O.OSM 4.5 15 90.8 Phosphate 10 90.8 was places in a dissolution medium after removal of the O.OSM 6.8 15 85.4 handle and aided by a sinker glued to the outer concave Phosphate 10 86.8 bottom whereby the spoons were located in the bottom of each of the dissolution vessels comprising 900 ml medium and equipped with a paddle rotating at 50 rpm. 0495 Conclusions: The results demonstrate a fast disso 0472 Media: lution rate of the paracetamol from the test product. However, 0473 0.1 NHCl-pH 1 (test media 1.): Vessel 5 and 6 at low pH the release is relatively slower compared to pH 4.5 0474 Ad 1000 ml of purified water in to a 5000 ml blue and 6.8. Note that the gellan gum does not dissolve once cap flask. gelled hence all dissolution vessels contain a high amount of 0475 Add carefully 25.5 ml 37 w/w % HC1 in to the 5000 non-dissolving substances. Besides the pH difference of the ml blue cap flask. media the difference in ionic composition should be noted as 0476. Add purified water until 3000 ml is reached. this possibly could affect drug release. Furthermore, it is 0477. Measure the pH of the solution noted that drug release is approx. 91-94% at pH 1 and 4.5 and 0478 0.05M Phosphate solution pH 4.5 (test media 2): 85-87% at pH 6.8. As this test was done on n=2 it is not Vessesl 3 and 4 possible to conclude if this is significant and it could be 0479. Add 750 ml of a 0.2 M KH2PO4 solution (prepare related to the specific coating of the paracetamol. according to QCF026) in to a 5000 ml blue cap flask. 0496 During dissolution it is seen that the formulation 0480. Add 2250 ml Elix water. disintegrates in all 3 media as illustrated in the photographs 0481 Measure the pH of the solution. The pH changed to presented in FIGS. 6, 7, and 8 with fine homogeneous mate 4.8 after addition of sample. rial most prominent in buffer solution pH 6.8 (FIG. 8). 0482 0.05M Phosphate standard solution pH 6.8 (test Slightly bigger, however still homogeneous fluffy flakes of media 3) Vessel 1 and 2 material are seen at pH 4.8 (FIG. 7). At low pH, the formula 0483 Dissolution Procedure: tion still completely disintegrates into more inhomogeneous 0484 Place 895 g of degassed dissolution medium inves material with individual flakes varying in size from approxi sel 1 to 6. mately 1 to 5 mm (FIG. 6). 0485 Vessel 1 and 2: Phosphate buffer pH 6.8. 0497. The dissolution result appears from FIG.9 US 2012/00399.69 A1 Feb. 16, 2012 29
0498. A similar result has been obtained with the follow spoon is turned around and held upside down for 2 min. The ing media: test material did not fall out and pass the test. 0499 Simulated Gastric Fluid, (0.072M cation) modi fied SGF USP as without enzymes and with 2.1 x cations in EXAMPLE 27 6 vessels: Guideline Regarding Effective Ratio Between Gellan (0500 Add 5000 ml of purified water into a 25L plastic Gum Granulated with Xylitol with Respect to Gel container. ling Time and Amount of Water Necessary for (0501. Add carefully 70 ml 37 w/w %, HCl in to the Obtaining an Efficient Gel (300 mg of Mixture) plastic container. 0510 Xylitol enables water penetration in the granula and (0502. Weigh 42.07 gi-0.1 g NaCl and addit to the plastic secure a fast and efficient hydration of the gum. Binder used container. is glycerol 7.0% weight of total formulation. Granulating 0503 Dissolve the salt and add purified water until procedure identical with placebo formulation of Example 23. 10000 ml is reached. As appears from the Table 2Xylitol decreases the gelling time and increases the range of water resulting necessary for (0504 Measure the pH of the solution. obtaining a sufficient gelling as the 50%/50% mixture is less sensitive to the amount of water added than the mixture com EXAMPLE 26 prising 20% Xylitol. Clearly the less gellan gum present, the less water shall be added to avoid inconvenient presence of A Composition According to the Invention Contain excess water in the formulation. ing 200 mg Coated Ibuprofen TABLE 2 0505. A composition that has a shape as outlined in FIG. 1 was prepared as follows: A. B C D E (blind) Gellan 1OO 8O 50 2O O Gum 96 Xylitol % O 2O 50 8O 1OO % Wiw 9. Water 3, 4, 5 ml 4 and 5 ml 4 and 5 ml 3 ml 3 ml added to Blend 1: spoon(s) Gelling Insufficient Sufficient Sufficient Good No gelling Kelcogel LT100 50 18.72 quality gelling for gelling gelling gelling, Xylitol 50 1876 and all 3 spoons with 5 ml with 4 ml however Blend 2: time as dry only. as well as (XCESS granule Gelling 5 ml water water Vanilla Flavour 92.2 2.24 is still time added and present PVP K2 7.8 O.19 present in between completed end 3: the spoons 10-12 sec. within 10 after 30 Seconds. Blend 1 50.7 5.67 Seconds. Blend 2 3.29 O.33 Glycerol 6.OO O60 Coated Ibuprofen 40.O 4.OO 1-58. (canceled) Blend 4: 59. A solid dosage form for oral administration comprising PVP K25 9.5 4.OO one or more active Substances, the Solid dosage form com Glycerol 4.8 2.00 prising a Swellable vehicle comprising a Swellable gellan Ethanol 99.9% 85.7 36.O1 gum, or Swellable mixture of gellan gums, arranged in a Blend 1: Kelcogel LT100 and Xylitol is mixed in a mortar until a homogeneous blend is configuration allowing optimal water diffusion so that upon formed. addition of a predetermined amount of an aqueous medium, Blend 2: The vanilla flavour is grinded in a mortar and the PVPK25 is added stepwise under mixing to form a homogeneous blend, without the necessity of applying shear forces or other mixing 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 forces, within a time period of 5 minutes or less, the compo 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. sition Swells and/or gels; Glycerol is added and stirred until a clear mixture is obtained. Blend 4 is poured into a 50 ml wherein the gellangum is acylated within a degree of up to spray flask with nozzle, 4 per every two repeats of the glucose-rhamnose-glu cose-glucoronic acid unit of the polymer, and the 0506 Medical spoon preparation: The concave side of a Swellable vehicle further comprises a hydrophilic agent medical spoon is sprayed twice with Blend 4 (approximately Selected from the group consisting of electrolytes, 60 mg) and placed in an oven at 45° C. for 30 minutes. organic acids and osmotic agents, and mixtures thereof, 0507 500+20 mg/dose is weight into a prepared medicine that improves Swelling of the gellan gum, and spoon and distributed by pressing the granules against the the texture of the swelled composition being similar to that spoon with a stopper. The final layer of granules lay in the of a soft pudding and having a viscosity of at least about bottom of the spoon and is approximately 2 mm in height. The 10,000 cps as measured by a BrookfieldViscometer with spoon is sprayed twice with blend 4 (approximately 60 mg) a #4 LV spindle at 6 rpm and at 20-25°C.; the Viscom and placed in an oven at 45° C. for 30 minutes, evaporating the eter spindle is centered in the test sample container, the ethanol. spindle is properly immersed to the mid-point of the 0508 Drop Down Test: shafts narrow portion; test method: Into a 500 ml beaker 0509. To the above dosage form 5 M1 tapped water is 22-88 g test material is accurately weighed, 500 ml added. After about 30 seconds the liquid is absorbed. The tapped water is added, mix until all the material is dis US 2012/00399.69 A1 Feb. 16, 2012 30
persed/dissolved, and after about 5 min the viscosity and tapped water is added, mix until all the material is dis the temperature are measured. persed/dissolved, and after about 5 min the viscosity and 60. A solid dosage form according to claim 59, in the form the temperature are measured. of a unit dosage form. 68. A dispensing unit according to claim 67, in unit dosage 61. A solid dosage form according to claim 60, in the form form. of granulates contained in a capsule, cachet or Sachet. 69. A dispensing unit according to claim 67, wherein one or more active substances and the swellable vehicle are adhered 62. A solid dosage form according to claim 60, in the form or glued to a surface of the dispensing unit. of a tablet. 70. A dispensing unit according to claim 69, wherein the 63. A solid dosage form according to claim 62, wherein the one or more active substances and the Swellable vehicle are tablet is produced by low-pressure compression, extruding, glued to a surface of the dispensing unit with a glue that molding or calendaring. comprises one or more components in liquid form or in solu 64. A Solid dosage form according to claim 60, in the form tion selected from the group consisting of Sugar alcohols, of a tape or laminate. Sugars, polyvinylpyrrolidone (PVP), and gums. 65. A solid dosage form according to claim 60, provided in 71. A dispensing unit according to claim 70, wherein the a dispensing unit incorporating the Solid dosage form. glue comprises a mixture of PVP and glycerol. 66. A solid dosage form according to claim 65, wherein the 72. A dispensing unit according to claim 67, having a dispensing unit is a spoon. concave Surface. 67. A dispensing unit for oral administration comprising 73. A dispensing unit according to claim 67 in the form of one or more active Substances, a Swellable vehicle comprising a Spoon. a Swellable gellan gum, or Swellable mixture of gellan gums, 74. A dispensing unit according to claim 70, in the form of arranged in a configuration allowing optimal water diffusion a Spoon. so that upon addition of a predetermined amount of an aque 75. A dispensing unit according to claim 71, in the form of ous medium, without the necessity of applying shear forces or a Spoon. other mixing forces, within a time period of 5 minutes or less, 76. A kit comprising a solid dosage form according to the composition Swells and/or gels; claim 60, and instructions to combine the Solid dosage form wherein the gellangum is acylated within a degree of up to with a measured amount of water prior to administration. 4 per every two repeats of the glucose-rhamnose-glu 77. A kit comprising a solid dosage form according to cose-glucoronic acid unit of the polymer, and the vehicle claim 61, and instructions to put the granulates into a mea further comprises a hydrophilic agent selected from the sured amount of water prior to administration. group consisting of electrolytes, organic acids and 78. A kit comprising a solid dosage form according to osmotic agents, and mixtures thereof, that improves claim 62, and instructions to put the tablet into a measured Swelling of the gellan gum; and amount of water prior to administration. the texture of the swelled composition being similar to that 79. A kit comprising a solid dosage form according to of a Soft pudding and having a viscosity of at least about claim 65, and instructions to add a measured amount of water 10,000 cps as measured by a BrookfieldViscometer with to the dispensing unit prior to administration. a #4 LV spindle at 6 rpm and at 20-25°C.; the Viscom 80. A kit comprising a solid dosage form according to eter spindle is centered in the test sample container, the claim 66, and instructions to add a measured amount of water spindle is properly immersed to the mid-point of the to the spoon prior to administration. shafts narrow portion; test method: Into a 500 ml beaker 22-88 g test material is accurately weighed, 500 ml c c c c c