MXPA06014888A - Method of modulating cellular activity involving sphingosine kinase and agents for same, and sphingosine kinase variants. - Google Patents

Abstract

The present invention relates generally to a method of modulating cellular activity and to agents for use therein. More particularly, the present invention provides a method of modulating cellular activity by modulating intracellular translocation of sphingosine kinase to the cell membrane. In a related aspect, the present invention provides a method of modulating sphingosine kinase mediated signalling via modulation of its intracellular translocation and agents for use therein. The present invention still further extends to sphingosine kinase variants and to functional derivatives, homologues and analogues thereof, exhibiting ablated or reduced capacity to undergo translocation. The method and molecules of the present invention are useful, inter alia, in the treatment and/or prophylaxis of conditions characterised by aberrant, unwanted or otherwise inappropriate cellular functional activity and/or aberrant, unwanted or otherwise inappropriate sphingosine kinase mediated signalling. The present invention is further directed to methods for identifying and/or designing agents capable of modulating sphingosine kinase intracellular translocation.

Description

POROUS TABLETS AS CARRIERS FOR LIQUID FORMULATIONS Field of the invention The present invention relates to a new tablet product that can be loaded in an easy, flexible and reproducible manner with a relatively high amount of a pharmaceutically acceptable liquid formulation for example carrying a active substance therapeutic, prophylactic and / or diagnostically. The new tablet product can be produced in large-scale batches and stored until use and each batch or sub-batch can be loaded with the same liquid formulations and / or pharmaceutically acceptable active substances or different ones. The invention also provides tablets that have been loaded with such a liquid formulation as well as a method for the preparation thereof. The invention provides a means for obtaining tablets comprising an active substance together with a suitable and relatively high amount of a liquid having influence on the accessibility of the active substance for example, which is to be released and / or absorbed during oral administration . BACKGROUND OF THE INVENTION Many substances of a drug have, and it is expected that many of the drug substances of the future will have, undesirable properties especially with regard to ref.178386 example, to the solubility in water and oral bioavailability. Therefore, novel technologies, which make it possible especially for the therapeutic active substances and / or prophylactically to be delivered to the body in a relatively easy manner and at the same time make it possible to obtain the desired prophylactic and / or therapeutic response, are highly necessary In the pharmaceutical area it is common to prepare pharmaceutical compositions comprising one or more active substances and various excipients. One reason for preparing such pharmaceutical compositions is to manipulate the availability of the active compound after ingestion of the pharmaceutical composition. For the preparation of the pharmaceutical composition for oral administration, the active substances are frequently incorporated in an agglomerated preparation to provide the active compounds in a form that can be tableted or filled into capsules. In addition to providing the active substance in a form that can be compressed into tablets, the agglomerates can also be designed to ensure a desired availability of the active compound after ingestion of a pharmaceutical composition containing the granulate. The improvement of the oral bioavailability of poorly water soluble drugs as well as the provision of a fairly soluble drug in water in a sustained release form remains one of the most challenging aspects of drug development and further development of the techniques of agglomeration can provide valuable tools for these aspects. A commonly used technique for granulation is a wet granulation, wherein a mixture of the powders including the active compound is mixed with a liquid, usually an aqueous liquid, under mechanical influence for the preparation of the granules. Usually the granules prepared by wet granulation are dried before use. Melt agglomeration and controlled agglomeration are techniques for the agglomeration of an active compound, effected essentially by melting a pharmaceutically acceptable carrier such as an oil or an oil-like material, dissolving or dispersing one or more active compounds in the molten vehicle and the deposition of the mixture thus prepared on a particulate material, the filler, and subsequently the particles adhere to each other and form the agglomerates. In WO 03/004001 (by the present inventors) the novel technique of controlled agglomeration is described by which it is possible to charge a particulate material with a relatively high amount of an oil or an oil-like material. The technique is based on a process involving the spraying of a carrier composition containing the oil or the oil-like material on a particulate material. The process conditions make it possible for the particulate material to be charged with a relatively high amount of the oil or oil-like material. Usually, the process involves heating the carrier composition and maintaining the temperature of the carrier composition during the application. When the application is made by spraying, a strict control of the temperature of the spray equipment is a requirement to avoid problems that refer to the formation of clots in the spray nozzle, etc. DETAILED DESCRIPTION OF THE INVENTION The present inventors have now found a much simpler solution. They have found that it is possible to prepare a tablet containing only pharmaceutically acceptable, inert excipients (although in some cases it may also be appropriate to incorporate an active substance therein), and when the tablet is subjected to a pharmaceutically acceptable liquid formulation containing For example, the active substance, the tablet due to its porosity will suck the liquid formulation towards the tablet. More surprisingly this charge of an inert tablet is carried out within a relatively short period of time and is reproducible, i.e. the same amount of the liquid formulation is sorbed when the same type and size of the tablet and the liquid formulation are used (see examples here). In the best understanding of the inventors, inert tablets with the properties mentioned above have not been previously recognized or used in the pharmaceutical field to load the tablets with liquids containing, for example, an active substance. WO 00/38655 (Alza Corporation) describes a dosage form comprising porous particles. The dosage form can be in the form of tablets that are prepared by mixing the porous particles with a liquid carrier such as propylene glycol. However, in contrast to the present invention, this document does not disclose inert tablets having the ability to sorb a liquid active substance or a lipophilic medium containing one or more active substances in a reproducible manner and leading to a high charge of the liquid. liquid. EP-A-0 001 247 relates to preparations of nifedipine for oral administration in the form of a solution of nifedipine in a polyethylene glycol carried on a porous pharmaceutically acceptable carrier or a non-crystalline dispersion of nifedipine in polyvinylpyrrolidone. Ineligible, inert tablets are not described. US 6,399,591 (Yung-Shin Pharmaceutical Ind. Co. Ltd.) refers to crude tablets that include an absorbent, a disintegrant, a lubricant, and a diluent or a binder, or a mixture of a diluent and a binder. An active ingredient in the liquid form is introduced into the crude tablet to produce a pharmaceutical composition. However, the examples show that only a charge of about 13% w / w can be obtained. The tablets provided by the present invention can be loaded with any type of active substance as well as they can be designed for any type of release of the active substance. The loading of the inert tablets depends on the type and nature of the pharmaceutically acceptable excipients that are contained in the tablet. The critical parameter, however, is not only the properties of the pharmaceutically acceptable excipients contained in the tablet, but also the properties of the tablet itself. For this purpose, the most critical properties are the ability of the tablet to (i) suck a pharmaceutically acceptable liquid formulation in a sufficient amount, (ii) maintain the amount sorbed during storage without any transpiration of the liquid formulation from the surface of the tablet, and (iii) releasing the active substance once the tablet is subjected to an in vitro dissolution test and / or that is administered orally to a subject such as an animal, including a human being. To meet these requirements, the present inventors have identified that the critical property of the tablets to be loaded is the porosity of the tablets. Accordingly, in one aspect, the present invention relates to a chargeable tablet having a porosity of 30% w / w or greater, as a pharmaceutical carrier composition for a pharmaceutically acceptable liquid formulation. The normal tablets used within the pharmaceutical field have a porosity that is much lower. One of the reasons for avoiding very porous tablets is that such tablets do not have a sufficient robustness to make possible the normal handling of the tablets during packaging and storage, ie they are rejected because they do not meet the requirements of the pharmacopoeia with respect to the hardness and friability. The porosity is defined as the volumetric relationship between the voids in the tablet and the total volume of the tablet according to equation 1 in the examples here.

Tablets that can be loaded In the present context, the term "inert tablet" is used to denote a tablet that only contains ingredients that are normally considered inert with respect to the therapeutic effect. More specifically, such tablet contains pharmaceutically acceptable excipients selected from the group consisting of fillers, diluents, binders, lubricants, antifriction agents, etc. Additives such as, for example, pH adjusting agents, buffering agents, enhancers, wetting agents, solubilizing agents, surfactants, antioxidants, etc. The term "chargeable tablet", used in the present context, denotes an "inert tablet" as defined above, but which also has a porosity of at least about 30% v / v to enable adequate loading with a liquid. However, in some cases it may be of interest to include an active substance in such a tablet and, consequently, the term "tablet that can be loaded" also includes such cases. In a preferred embodiment, the tablets are "inert and chargeable", ie, without any content of the active substance before loading. However, as shown in the examples herein, the present inventors have found that it is possible to charge the tablets having a high porosity with a pharmaceutically acceptable liquid, preferably containing one or more therapeutic active substances, prophylactically and / or diagnostically ( in the following abbreviated as "active substance"). The loaded tablets are robust enough to withstand the normal handling of the tablets during further processing (eg coating), packing, storage etc., i.e., they meet the requirements of the pharmacopoeia with respect to hardness and the friability. In a specific embodiment, a tablet that can be charged according to the invention leads - when tested as described herein - to a loading of the tablet with at least 20% w / w such as, for example, at least 25% at least 30% w / w of the corn oil (based on the total weight of the solid dosage form during loading). Such proof ensures that the tablet has the ability to sorb a liquid formulation that is suitable for use in the preparation of the tablets. As mentioned above, the tablets that can be loaded according to the invention are sufficiently robust to withstand the normal handling of the tablets, i.e. they have a hardness of 20 N or greater such as, for example, about 25 N or greater, approximately 30 N or greater, approximately 35 N or greater, approximately 40 N or greater, approximately 45 N or greater or approximately 50 N or greater. In addition, the tablets according to the invention have a friability of about 5% or less such as, for example, about 4% or less, about 3% or less, about 2% or less such as about 1% or less. As mentioned above, tablets that can be loaded according to the invention comprise one or more pharmaceutically acceptable excipients. However, it is important that at least one pharmaceutically acceptable excipient has the exact properties with respect to the provision of a tablet with a porosity of 30% v / v greater and that this excipient is present in a sufficient amount so that the tablet obtained also have the desired porosity. Such pharmaceutically acceptable excipients are denoted in some instances herein as "porosity, pharmaceutically acceptable excipients". For this purpose, the present inventors have found that if the pharmaceutically acceptable excipient is manufactured in tablets together with at most 50% w / w of the lactose or other pharmaceutically acceptable excipients used for direct compression such as, for example, Emcompress, and the tablets obtained have a porosity of 30% by volume or greater, then the pharmaceutically acceptable excipient is suitable for use in the present context. The quality of the lactose is for direct compression. In tablets that can be loaded, the sum of the pharmaceutically acceptable excipients having the aforementioned property (ie satisfying the aforementioned test) corresponds to at least 50% w / w such as, for example at least 55% p / p, at least 60% p / p, at least 65% p / p, at least 70% p / p, at least 80%, p / p, at least 90% p / p, at least 95% p / p at least 98% w / w such as for example 100% w / w of the total weight of the tablet. In preferred aspects, one or more excipients that provide porosity are present at a concentration of about 50% w / w greater such as, for example, about 60% w / w greater such as, for example, about 70% w / w. greater, approximately 80% w / w greater, approximately 90% w / w greater or approximately 95% w / w greater in the tablet. In addition, it is contemplated that the specific surface area (BET surface area) of the excipient providing the porosity should be relatively large such as, for example, at least 50 m2 / g when measured by gas adsorption. The following is a list of pharmaceutically acceptable excipients having the appropriate properties that make possible the provision of a tablet that can be loaded according to the invention. The individual pharmaceutically acceptable excipients may be used alone or in combination provided that the overall objective is obtained with respect to porosity. For this purpose, it should be noted that tablets are compressed into tablets by the use of a certain compressive force. However, the compression force can not be so low that the requirements are compromised with respect to the hardness and friability of the tablets, that is, these requirements ensure that the tablets are sufficiently robust. Suitable pharmaceutically acceptable excipients, which can be used to obtain the tablets having a porosity of 30% v / v or greater, are selected from the group consisting of metal oxides, metal silicates, metal carbonates, metal phosphates, metal sulfates, alcohols of sugar, sugars and cellulose and cellulose derivatives. The metal is typically selected from the group consisting of sodium, potassium, magnesium, calcium, zinc, aluminum, titanium and silicon. A metal oxide suitable for use according to the invention can be selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, aluminum oxide, titanium dioxide including Tronox A-HP-328 and Tronox A -HP-100, silicon dioxides including Aerosil, Cab-O-Sil, Syloid, Aeroperl, Sunsil (silicon beads), Zeofree, Sipernat, and mixtures thereof. In a specific embodiment, the metal oxide is a titanium dioxide or a silicon dioxide or mixtures thereof. The silicates can be divided into the following groups: • Smectite type swelling clays, for example bentonite, "veegum", laponite. • Hydrated aluminum silicates or alkaline earth substances. Neusilin belongs to this group and is based on synthetic polymerization (magnesium and aluminum metasilicate). • Silicon dioxides are subdivided into porous and non-porous silicas. 0 Nonporous colloidal silicas for example Aerosil (fumed silicas). ° Porous silicate gels for example Syloid, Porasil, Lichrosorp. ° Others eg Zeopharm S170, Zeopharm 6000, Aeroperl 300. Accordingly, a tablet that can be charged in accordance with the present invention can contain a metal oxide which is a non-porous silicate including fuming silicas of the Aerosil type, and / or a porous silicate including for example Syloid, Porasil and Lichrosorp. In other embodiments, the pharmaceutically acceptable excipient for use in accordance with the invention is a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, calcium silicate including synthetic calcium silicate such as, for example, example-, Hubersorp, zinc silicate, aluminum silicate, sodium aluminosilicate such as, for example, Zeolex, magnesium aluminum silicate, aluminum magnesium metasilicate, aluminum metasilicate, Neusilin SG2 and Neusilin US2 and mixtures thereof . The metal silicate can also be a swelling clay of the smectite type selected from the group consisting of bentonite, "veegum" and laponite, and / or the metal silicate is selected from the alkaline earth metal silicates and aluminum silicates included. the aluminum and magnesium metasilicate. In a specific embodiment, the metal silicate is Neusilin. As mentioned above, a suitable pharmaceutically acceptable excipient can be a metal carbonate such as a carbonate selected from the group consisting of sodium carbonate, sodium acid carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, carbonate of magnesium, zinc carbonate and aluminum carbonate, and mixtures thereof. Another metal salt suitable for use according to the invention are the metal phosphates selected from the group consisting of sodium phosphate, disodium acid phosphate, sodium diacid phosphate, potassium phosphate, dipotassium acid phosphate, potassium dihydrogen phosphate, calcium phosphate, magnesium phosphate, zinc phosphate and aluminum phosphate. More specifically, the pharmaceutically acceptable excipient may be a calcium phosphate selected from the group consisting of dibasic anhydrous calcium phosphate, calcium phosphate dibasic dihydrate, and tribasic calcium phosphate. Dibasic anhydrous calcium phosphate is typically selected from the group consisting of A-Tab, calcium monoacid phosphate, calcium orthophosphate, Di-Cafos AN, dicalcium orthophosphate, E341, anhydrous Emcompress, Fujicalin, calcium salt of phosphoric acid ( 1: 1), and secondary calcium phosphate, and mixtures thereof. The calcium phosphate dihydrate dihydrate can be selected from the group consisting of Caphos, calcium acid orthophosphate dihydrate, monohydric calcium phosphate dihydrate, Calipharm, Calstar, Di-Cafos, dicalcium orthophosphate, DI- , Emcompress, phosphoric acid, salt of calcium (1: 1) dihydrate, secondary calcium phosphate, Fujiclin SG.

Examples of tribasic calcium phosphates are for example hydroxyapatite, phosphoric acid, calcium salt (2: 3), precipitated calcium phosphate, tertiary calcium phosphate, Tri-Cafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI- . Other suitable metal salts are metal sulfates such as, for example, sodium sulfate, sodium acid sulfate, potassium sulfate, potassium acid sulfate, calcium sulfate, magnesium sulfate, zinc sulfate and / or aluminum sulfate. Examples of suitable calcium sulfates are for example anhydrous calcium sulfate including anhydrite, anhydrous gypsum, lime anhydrous sulfate, Destab, Drierte, E516, karstenite, muriacite, and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, calcium sulfate, natural calcium sulfate, precipitated calcium sulfate, satinite, fibrous gypsum, selenite, alba and Terra Alba USG. In other embodiments, the pharmaceutically acceptable excipient may be a sugar alcohol selected from the group consisting of sorbitol (such as, for example, Sorbogem, SPI Pharma), xylitol, mannitol (such as, for example, Mannogem, SPI. Pharma), maltitol, inositol, mannitol (for example Pealitol SP 100) and / or may be a sugar selected from the group consists of mono-, di- or polysaccharides which includes sucrose, glucose, fructose, sorbose, xylose, lactose, dextran, dextran derivatives, cyclodextrins. Cellulose and cellulose derivatives are also suitable pharmaceutically acceptable excipients for the purpose of obtaining tablets having a porosity of 30% v / v or greater. Examples include cellulose, microcrystalline cellulose, Celphere, cellulose derivatives including porous cellulose beads: cellulose acetate Celluflow TA-25 and cellulose Celluflow C-25, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, ethylcellulose, carboxymethylcellulose sodium, hydroxyethyl cellulose, etc. Other pharmaceutically acceptable excipients for use in a tablet that can be charged according to the invention The tablet that can be loaded can of course also contain other pharmaceutically acceptable excipients such as those normally employed in the manufacture of the tablets. In the present context, the terms "pharmaceutically acceptable excipient" are meant to denote some material, which is inert in the sense that it substantially has no therapeutic and / or prophylactic effect per se. Such excipient may be added for the purpose of making it possible to obtain a pharmaceutical, cosmetic and / or food composition having acceptable technical properties. Examples of excipients suitable for use in a tablet that can be charged according to the invention include fillers, diluents, disintegrants, binders, lubricants, etc. or a mixture of them. When the composition or solid dosage form according to the invention can be used for different purposes, the choice of excipients is normally made by taking such different uses into consideration. Other pharmaceutically acceptable excipients for suitable use are for example acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and / or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents, etc. Examples of suitable fillers, diluents and / or binders include lactose (for example spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floc®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (substituted at a low level), hydroxypropyl methylcellulose (HPMC) (for example Methocel E, F and K) , Metolose SH of Shin-Etsu, Ltd, such as, for example, the 4,000 cps' grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps of Methocel K; and grades 4,000, 15,000, 39,000 and 100,000 of Metolose 90 SH), methyl cellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and others. derivatives of cellulose, sucrose, agarose, sorbitol, mannitol, dextrins, malxtrins, modified starches or starches (including potato starch, corn starch and rice starch), calcium phosphate (eg basic calcium phosphate, calcium acid phosphate, hydrated dicalcium phosphate), calcium sulfate, calcium carbonate, sodium alginate, collagen , etc. Specific examples of the diluents are for example calcium carbonate, dibasic calcium sulfate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch. , pregelatinized starch, sucrose, sugar, etc. Specific examples of the disintegrants are for example alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®), etc. Specific examples of binders are for example acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch. , etc. Antifriction agents and lubricants can also be included in the tablet. Examples include stearic acid, magnesium stearate, calcium stearate or other metal stearate, talc, waxes and glycerides, light mineral oils, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, stearyl fumarate and sodium , polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate, etc. Other excipients that can be included in a chargeable tablet of the invention are for example flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizing agents, antioxidants, wetting agents, agents for moisture adjustment, surface active agents, suspending agents, absorption enhancing agents, agents for modified release, etc. Other additives in a composition or a solid dosage form according to the invention may be antioxidants similar to, for example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehyde sulphoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. The carrier composition may also contain, for example, stabilizing agents. The concentration of an antioxidant and / or a stabilizing agent in the carrier composition is usually from about 0.1% w / w to about 5% w / w. A solid composition or dosage form according to the invention may also include one or more surfactants or substances having surface active properties. It is contemplated that such substances are involved in the wetting of the slightly soluble active substance and therefore contribute to the improved solubility characteristics of the active substance. Examples of surfactants are provided below. Suitable excipients for use in a tablet according to the invention are surfactants such as, for example, amphiphilic surfactants such as those described in WO 00/50007 in the name of Lipocine, Inc.

Examples of suitable surfactants are: i) polyethoxylated fatty acids, such as, for example, mono- or diesters of polyethylene glycol fatty acids or mixtures thereof such as, for example, mono- or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and polyethylene glycol can be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9 PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000. ii) fatty acid esters of polyethylene glycol glycerol, ie the esters similar to those mentioned above but in the form of glyceryl esters of the individual fatty acids; iii) glycerol, propylene glycol, ethylene glycol, PEG or sorbitol esters for example with vegetable oils similar to, for example, hydrogenated castor oil, almond oil, palm kernel oil, castor oil, apricot kernel oil, olive oil , peanut oil, hydrogenated palm kernel oil and the like, iv) polyglycerized fatty acids similar to, for example, polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate, polyglycerol linoleate, v) propylene glycol fatty acid esters, such as , for example propylene glycol monolaurate, propylene glycol ricinoleate and the like, vi) mono or diglycerides similar to, for example, glyceryl monooleate, glyceryl dioleate, glyceryl mono- and / or dioleate, glyceryl caprylate, glyceryl caprate, etc .; vii) sterol and sterol derivatives; viii) polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as the PEG esters with the various molecular weights indicated above, and the various Tween® series; ix) polyethylene glycol alkyl ethers such as, for example, PEG oleyl ether and PEG lauryl ether; x) sugar esters similar to, for example, sucrose monopalmitate and sucrose monolaurate; xi) polyethylene glycol alkylphenols similar to, for example, the Triton® X or N series; xii) polyoxyethylene-polyoxypropylene block copolymers such as, for example, Pluronic® series, Synperonic® series, Emkalyx®, Lutrol®, Supronic®, etc. The generic term for these polymers is "poloxamers" and the relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231 , 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407; xiii) sorbitan fatty acid esters similar to the Span® or Ariacel® series such as, for example, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, etc .; xiv) fatty acid esters of lower alcohols similar to, for example, oleate, isopropyl myristate, isopropyl palmitate, etc .; xv) surfactants including cationic, anionic and zwitterionic surfactants such as, for example, salts of fatty acids, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates and sulfonates, etc. When a surfactant or a mixture of surfactants is present in a composition or in a solid dosage form of the invention, the concentration of the surfactant (s) is usually in a range of from about 0.1 - 80% w / w such as, for example, from about 0.1 to about 20% w / w, from about 0.1 to about 15% w / w, from about 0.5 to about 10% w / w, or alternatively, from about 0.10 up to about 80% w / w such as, for example, from about 10 to about 70% w / w, from about 20 to about 60% w / w from about 30 to about 50% w / w-Tablets loaded with a liquid Pharmaceutically Acceptable The tablets described above are designed so that they can be loaded with a pharmaceutically acceptable liquid formulation in a concentration d and about 20% w / w or greater such as, for example, about 25% w / w or greater, about 30% w / w or greater (based on the total weight of the solid dosage form during loading). Accordingly, in another aspect the invention relates to such tablets. In preferred aspects, the pharmaceutically acceptable liquid formulation is present in a concentration of about 40% w / w greater such as, for example, about 50% w / w greater or approximately 60 w / w greater (based on total weight of the solid dosage form during loading).

A critical parameter related to the loading of the liquid formulation is the viscosity of the liquid formulation. The loading can be effected in any possible way such as, for example, by placing the tablets in a suitable container containing the liquid or by spraying liquid into the tablets in a suitable apparatus such as, for example, using equipment of conventional coating such as a coating tray, a perforated container or a fluidized bed. Especially, the viscosity of the liquid is important when the liquid formulation is sprayed onto the tablets. Accordingly, in a specific embodiment, the pharmaceutically acceptable liquid formulation has a viscosity as much as about 600 mPa sec at a temperature at most about 150 ° C. In addition, the pharmaceutically acceptable liquid formulation normally has a melting point of about 0 ° C and at most about 250 ° C such as, for example, about 5 ° C or higher such as, for example, about 10 ° C or higher , approximately 15 ° C or higher, approximately 20 ° C or higher or approximately 25 ° C or higher. The melting point is not very critical because the liquid formulation can be heated or cooled in a manner related to loading the tablets with the liquid formulation.

The pharmaceutically acceptable liquid formulation can be water based or it can be based on an organic solvent or an oil or an oil-like material. Surprisingly, the inventors have found that a tablet that can be charged according to the invention can be immersed in water and during saturation with water (which takes only a few minutes or less) the tablet appears with a cold but dry surface, it is The water and the water-based liquid can also be used in a suitable pharmaceutically acceptable liquid formulation. However, the more general applicability is contemplated with respect to the loading of the tablets with the active substances contained in an aqueous or organic-based liquid. Such liquids include oil or materials similar to oil or pharmaceutically acceptable solvents. Such oils or oil-like materials can be selected from the group consisting of water, vegetable oils, hydrogenated vegetable oils, and animal oils. Suitable examples include apricot oil, almond oil, avocado oil, castor oil, coconut fat, cocoa butter, corn oil, cottonseed oil, grapeseed oil, jojoba oil, oil. flaxseed, corn seed oil, olive oil, palm oil, peanut oil, pepper oil, poppy seed oil, rapeseed oil, sesame oil, soybean oil, sunflower oil, oil Marian thistle seed, walnut oil, wheat germ oil, beef tallow, lard, cellulosic lye resin, whale oil and mixtures thereof. Other examples are hydrophilic oils or oil-like materials selected from the group consisting of: polyether glycols such as, for example, polyethylene glycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or may be selected from the group consisting of: xylitol, sorbitol, sodium and potassium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, fumarate of ethyl, myristic acid, citric acid, Gelucire 50/13, other types of Gelucire, such as, for example, Gelucire 44/14, etc., Gelucire 50/10, Gelucire 62/05, Sucro-ester 7, Serum ester 11, Sucrose-ester 15, maltose, mannitol and mixtures thereof. The oil or oil-like material can also be a hydrophobic oil or an oil-like material selected from the group consisting of: straight chain saturated hydrocarbons, sorbitan esters, paraffins; fats and oils such as, for example, cocoa butter, beef tallow, lard, polyether glycol esters; higher fatty acids such as, for example, stearic acid, myristic acid, palmitic acid, higher alcohols such as, for example, cetanol, stearyl alcohol, low melting waxes such as, for example, glyceryl monostearate, glyceryl monooleate , hydrogenated cellulose bleach resins, myristyl alcohol, stearyl alcohol, substituted and / or unsubstituted monoglycerides, substituted and / or unsubstituted diglycerides, substituted and / or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax , castor wax, Japanese wax, acetylate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof. Suitable polyethylene glycols generally have an average molecular weight in a range from about 400 to about 35,000 such as, for example, from about 800 to about 35,000, from about 1,000 to about 35,000 such as, for example, polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5, 000, polyethylene glycol 6,000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000, polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000. In certain situations the polyethylene glycol can be employed with a molecular weight of from about 35,000 to about 100,000. In a specific embodiment, the oil or oil-like material can be a polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, for example, from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, for example, from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 up to about 400,000 or from about 100,000 to about 300,000. The poloxamers can also be used according to the invention. Examples include Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 and other block copolymers of ethylene oxide and propylene oxide such as the Pluronic® and / or Tetronic® series. Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of from about 3,000 or greater such as, for example, from about 4,000 to about 20,000 and / or a viscosity (Brookfield) from about 200 to about 4,000 cps such as, for example, from about 250 to about 3,000 cps. Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, • 25R8 etc. Suitable block copolymers of the Tetronic® series include polymers having a molecular weight of about 8,000 or greater such as, for example, from about 9,000 to about 35,000 and / or a viscosity (Brookfield) from about 500 to about 45,000. cps such as, for example, from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances that are pastes at room temperature and at 77 ° C for substances that are solid at room temperature. In another embodiment, the oil or oil-like material may be a sorbitan ester such as, for example, sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof. In addition or alternatively, the oil or oil-like material may be a mixture of different oils or oil-like materials such as, for example, a mixture of hydrophilic and / or hydrophobic materials, or a solvent or semi-excipient. similar solid, for example to propylene glycol, polyglycolized glycerides including Gelucire 44/14, complex fats materials of vegetable origin including theobroma oil, carnauba wax, vegetable oils similar for example to almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil, olive oil, castor oil, palm kernel oil, peanut oil, rape seed oil, grapeseed oil, etc., vegetable oils hydrogenated such as, for example hydrogenated peanut oil, hydrogenated palm seed oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; Natural fat materials of animal origin include beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric, myristic, palmitic, stearic fatty alcohols; esters that include glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; interesterified, liquid semi-synthetic glycerides, including Miglycol 810/812; fatty acid amides or alcolamides including stearamide ethanol, diethanolamide of fatty coconut acids, acetic acid esters of mono and di-glycerides, citric acid esters of mono and di-glycerides, lactic acid esters of mono and diglycerides, mono and di-glycerides, polyglycerol esters of fatty acids, poly-glycerol poly-ricinoleate, propylene glycol esters of fatty acids, sorbitan monostearate, sorbitan tristearate, stearoyl and sodium lactylates, stearoyl and calcium lactylates, diacetyl tartaric acid esters of mono and di-glycerides, etc. The pharmaceutically acceptable liquid formulation may also be a dispersion including an emulsion, a microemulsion, for example a self-microemulsifying drug delivery system (SMEDDS) or a suspension. Typically, the concentration of the pharmaceutically acceptable liquid formulation in the tablet is about 5% w / w greater such as, for example, about 10% w / w greater, about 15% w / w greater, about 20% w / w. greater, approximately 25% w / w greater, approximately 30% w / w greater, approximately 35% w / w greater, approximately 40% w / w greater, approximately 45% w / w greater, approximately 50% w / w greater, approximately 60% p / p major or approximately 70% p / p major. Tablets obtained after loading a tablet that can be loaded with a pharmaceutically acceptable liquid formulation typically meet the requirements of the pharmacopoeia. Accordingly, a tablet according to the invention typically has a hardness of at least about 20 N and / or a friability at most of about 5% such as, for example, when much of about 4%, much of about 3%. , when much of approximately 2%, when much of approximately 1% or when much of approximately 0.5%. Furthermore, it is contemplated that charging the liquid in a chargeable tablet of the invention leads to a substantially homogeneous distribution of the liquid within the tablet. In addition, tablets can be designed to release the active substance substantially immediately or in a modified manner. A tablet designed for immediate release typically has a disintegration time of at most 15 minutes when tested according to Ph. Eur, while a tablet coated with a film can have a disintegration time of at most about 30 minutes. For the modified release tablets, the release of the active substance is of importance. For a flat tablet according to the invention, at least 75% of the therapeutic active substance, prophylactically and / or diagnostically is released within 30 minutes when tested in a dissolution method according to USP. As mentioned above, a preferred embodiment is a tablet loaded with one or more active substances therapeutically, prophylactically and / or diagnostically. Disintegrating formulation principle of the effervescent tablet The present inventors have found that the disintegration of the tablets loaded with the lipophilic formulation is not enhanced by adding a super hydrophilic disintegrant due to the reduced properties of swelling of the disintegrant in the lipid environment. In this case, a different disintegration principle could be applied based on an effervescent effect. The disintegration of the tablet is enhanced by the internal release of carbon dioxide. An effervescent tablet formulation is based on a combination of metal carbonates with an acid source. Metallic carbonates are such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, and sodium sesquicarbonate. Sources of acids are such as citric acid, diacid sodium citrate, disodium acid citrate, tartaric acid, malic acid, fumaric acid, sodium diacid phosphate, and sodium acid sulfite. The acid component could be excluded in the tablet formulation because the effervescent effect is obtained in-vivo when the tablet is dissolved in the acidic gastric juice and reacts with the metal carbonate. Coating The tablet can also be coated with a film coating, for example for immediate or modified release, an enteric coating, a modified release coating, a protective coating, an anti-adhesive coating, etc. Suitable coating materials are, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, phthalate and cellulose acetate, phthalate and polyvinyl acetate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, sodium carboxymethylcellulose, cellulose acetate, phthalate and cellulose acetate, gelatin, methacrylic acid copolymer, polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zema. The plasticizing agents and other ingredients can be added to the coating material. The same active substance or a different one can also be added in the coating material. Fusion Coating The hydrophobic surface of a lipid-loaded tablet according to the invention could prevent adhesion of a coating polymer applied in an aqueous or organic solvent. As an alternative, the melt coating is suitable using different lipids that can be melted, lipophilic, sprayed in a molten form and solidified on the surface of the • tablet using conventional coating equipment. Useful melt coating substances are such as polyglycolized glycerides (Gelucire 50/02, Gelucire 62/05, Gelucire 53/10), polyglyceryl palmitostearate, glyceryl behenate (Compritol 888 ATO), glyceryl stearate (Precirol WL) ), glyceryl palmitate stearate (Precirol ATO 5), polyglycolized unsaturated glycerides (Labrafil M1944). ACTIVE SUBSTANCES In the present context, a therapeutically and / or prophylactically active substance includes any biologically and / or physiologically active substance having a function on an animal such as, for example, a mammal similar to a human being. The term includes substances of the drug, hormones, genes or gene sequences, a material comprising antigens, proteins, peptides, nutrients similar to, for example, vitamins, minerals, lipids and carbohydrates and mixtures thereof. Thus, the term includes substances that have utility in the treatment and / or prevention of diseases or disorders that affect animals or humans, or in the regulation of any physiological condition of the animal or human being. The term also includes any biologically active substance which, when administered in an effective amount, has an effect on living organisms or cells. Examples of the active substances suitable for use in a tablet according to the invention are, in principle, any active substance such as, for example, freely soluble active substances in water as well as insoluble or slightly insoluble active substances. Accordingly, examples of suitable active substances for use are, for example, antibacterial, antihistamine and decongestant substances, anti-inflammatory agents, antiparasitic agents, antivirals, local anesthetics, antifungals, amoebicidal or trichomonomide agents, analgesics, antianxiety agents, agents anticoagulation, antiarthritics, antiasthmatics, antiarthritics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents, antimalarial agents, antimicrobials, antineoplastic agents, antiobesity agents, antipsychotics, antihypertensives, antitussives, agents for autoimmune disorders, anti-impotence agents, anti- Parkinsonism, anti-Alzheimer agents, antipyretics, anticholinergics, anti-ulcer anti-ulcer agents, beta-blockers, beta-2 agonists, beta agonists, blood glucose lowering agents, bronchodilators, agents with effect on the central nervous system, agents cardiovascul ares, cognitive enhancers, contraceptives, cholesterol-lowering agents, cytostatics, diuretics, germicides, H-2 blockers, hormonal agents, hypnotic agents, inotropic muscle relaxants, muscle contraction agents, physical energizers, sedatives, sympathomimetics, vasodilators, - • vasoconstrictors, tranquilizers, electrolyte supplements, vitamins, anti-irritants, stimulants, anti-hormones, drug antagonists, lipid regulation agents, uricosurics, cardiac glycosides, expectorants, purgatives, contrast materials, radiopharmaceuticals, agents for the formation of images, peptides, enzymes, growth factors, etc. Specific examples include, for example: Anti-inflammatory drugs similar to, for example, ibuprofen, indomethacin, naproxen, nalofin; Anti-Parkinsonism agents similar for example to bromocriptine, biperidine, benzhexol, benzotropin etc. Anti-depressants similar to, for example, imipramine, nortriptyline, pritiptilin, etc. Antibiotics similar to, for example, clindamycin, erythomycin, fusidic acid, gentamicin, mupirocin, ampomycin, neomycin, metronidazole, sulfametizole, bacitracin, framycetin, polymyxima B, azithromycin, etc. Antifungal agents similar to, for example, miconazole, ketoconazole, clotrimazole, amphotericin B, nystatin, mepyramine, econazole, fluconazole, flucitocin, griseofulvin, bifonazole, amorofine, mycostatin, itraconazole, terbenaflna, terconazole, tolnaftate, etc. Antimicrobial agents similar to, for example, metronidazole, tetracyclines, oxytetracyclines, penicillins, etc. Anti-emetics similar to, for example, metoclopramide, droperidol, haloperidoi, promethazine, etc. Antihistamines similar to, for example, chlorpheniramine, terfenadine, triprolidine, etc. Antimigraine agents similar to, for example, dihydroergotamine, ergotamine, pizophylline, etc.

Coronary, cerebral or peripheral vasodilators similar to, for example, nifedipine, diltiazem, etc. Antianginals such as, for example, glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil, etc. Calcium channel blockers similar to, for example, verapamil, nifedipine, diltiazem, nicardipine, etc. Hormonal agents similar to for example estradiol, estrone, estriol, polyestradiol, poliestriol, dienestrol, diethylethylbestrol, progesterone, '- dihydroprogesterone, ciprosterone, danazol, testosterone, etc. Contraceptive agents similar to, for example: .etinyl estradiol, • linestrenol, ethinodiol, norethisterone, mestranol, - norgestrel, levonorgestrel, desodestrel, medroxyprogesterone, etc. Antithrombotic agents similar to, for example, heparin, warfarin, etc. Similar diuretics for example to hydrochlorothiazide, flunarizine, minoxidil, etc. Antihypertensive agents similar, for example, to propranolol, metoprolol, clonidine, pindolol, etc. Corticosteroids similar to. beclomethasone, betamethasone, betamethasone-17-valerate, betamethasone-dipropionate, clobetasol, clobetasol-17-butyrate, clobetasol-propionate, desonide, deoximetasone, dexamethasone, diflucortolone, flumethasone, flumethasone-pivalto, fluocinolone acetonide, fluocinoid, hydrocortisone, hydrocortisone-17 -butyrate, hydrocortisonebuteprate, methylprednisolone, triamcinolone acetonide, hacinonide, fluprednide acetate, alclometasone-dipropionate, fluocortolone, fluticasone-propionate, mometasone-furate, desoximetasone, diflurasone-diacetate, halquinol, clioquinol, chlorquinaldol, fluocinolone-acetonide, etc. Similar dermatological agents for example to -v-nitrofurantoin, dithranol, clioquinol, hydroxyquinoline, isotrethionine, methoxsalen, methotrexate, trethionine, trioxalen, salicylic acid, penicillamine, etc. '' Steroids similar to, for example, estradiol, progesterone, norethindrone, levonorgestrel, ethinodiol, levonorgestrol, norgestimate, gestanin, desogestrel, 3-keton-desogestrel, demegestone, prometoestrol, testosterone, spironolactone and esters thereof, etc. Nitro compounds similar to, for example, amyl nitrates, nitroglycerin and isosorbide nitrate, etc. Opioids similar to, for example, morphine, buprenorphine; oxymorphone, hydrmorphone, codeine, tramadol, etc. Prostaglandins such as, for example, a member of the PGA, PGB, PGE or PGF series such as, for example, minoprostol, dinoproston, carboprost, eneprostyl, etc. Peptides similar to, for example, growth hormone releasing factors, growth factors (eg, epidermal growth factor (EGF)), nerve growth factor (NGF) in English)), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF, etc.), somatostatin, calcitonin, insulin, vasopressin, interferons, IL-2, etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropin releasing hormone, luteinizing hormone releasing hormone (LH-RH (for its acronym in English)), corticotrophin-releasing hormone, hormone release of growth hormone (GHRH), oxytocin, erythropoietin (EPO), colony-stimulating factor (C? F) etc. Other active substances of interest s include ubiquinone (Coenzyme Q10), omega-3 fatty acids including fish oils containing such fatty acids, statins including simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, rosuvastatin, etc., fenofibrate.

Examples of interest are also prescription drugs similar to: Cardiovascular Drugs Zocor®, Lipitor®, Prevachol®, Mevalotin®, Mevacor®, Lescol®, TriCor®, Norvasc®, Cozaar and Hyzaar®, Prinivil and Prinzide®, Diovan® / Co-Diovan®, Zestril®, Vasotech®, and Vaseretic®, Lotensin® / Cibacen® and Lotrel®, Adalat®, Toprol-XL® / Seloken®, Tritace® / Delix®, Accupril® and Accuretic®, Avapro® and Avalide®, Plendil ®, Monopril®, Blopress®, Atacand®, Tenormin®, Avapro® / Aprovel®, Coreg®, Altace®, Capoten®, Plavix®, Lovenox® / Clexane®, Fraxiparine®, ReoPro®, Panaldine®, Cordarone®. Paxil / Seroxat® Central Nervous System Drugs, Zolotoft®, Prozac®, Prozac Weekly® and Sarafem®, Effexor®, Wellbutrin®, Celexa®, Remeron®, Serzone®, Zyprexa®, Risperdal®, Seroquel®, Clozaril® / Leponex®, Neurontin®, Depaktoke®, Lamictal®, Topamax®, Tegretol®, Imitrex® / Imigran®, Zomig®, Maxalt®, Ambien®, Stilnox®, Ultane® / Sevorane®, Diprivan®, BuSpar®, Xanax ®, Aricept®, Memantine®, Adderall®, Dystonia®, Botox®. Anti-infective agents. Augmentin®, Cipro® / Ciprobay®, Zithromax®, Biaxin®, Levaquin® and Floxin®, Rocephin®, Primaxin®, Ceftin® / Zinnat®, Cravit®, Zosyn® / Tazocin®, Cefzil®, Tequin®, Tortaz® / Fortum®, Combivir®, Zerit®, Valtrex®, Epivir®, Zovirax®, Crixivan®, Viracept®, Viramune®, Kaletra®, Diflucan®, Lamisil®, Sporanox®. ClaritinAllegra®, Telfast®, Zyrtec®, Flonase® / Flixonase®, Atrovent®, Nasonex®, Rhinocort®, Alesion®, Singulair®, respiratary drugs Flovent® / Flixotide®, Advair® / Seretide®, Serevent®, Pulmicort®, Ventoline®, Combivent®, Synagis®, Mucosolvan®.

Gastrointestinal Drugs Prilosec® / Losec®, Prevacid®, Gaster®, Takepron®, Zantac®, Pantozole, Nexium, Protonix®, Aciphex® / Pariet®, Pepcid®, Axid®, Zoton®, Zofran®. Cancer Drugs Taxol®, Taxotere®, Nolvadex®, Hercepti®, Ellence® / Pharmórubicin®, Lupron®, Zoladex®, Leuplin®, Casodex®, Intron A®, Peg-Intron® and Rebertron®, Rituxan®, Gemzar®, Paraplatin®, Camptosar®. Analgesic / analgesic drugs Celebrex®, Vioxx®, Enbrel®, Remicade®, Voltaren®, Mobic® Duragesic®, Ultram® and Ultrcet®. Treatments for blood disorders Procrit® / Eprex®, Epogen®, Epogin®, NeoRecormon®, Neupogen®, NovoSeven® Drugs for diabetes Glucophage®, Humulin Avandia®, Humalog®, Actos®, Amaryl®, Glucovance®, Glucophage XR®, Glucotrol XL®, Precose® / Glucobay®. Regulators of bone metabolism Fosamax®, Evista®, Miacalcin®, Actone®I, Aredia®. Agents for urinary disorders Harnal®, Prosear®, Cardura®, Flomax®, Detrol®. Premarin®, Premphase® and Prempro®, Estraderm®, Synthroid® hormones.

Immunosuppressive agents Neoral® / Sandimmun®, CellCept®, Rapamune®, Tacrolimus for example Prograf®, Medrol®. Drugs against multiple sclerosis Avonex®, Betaseron® / Betaferon®, Rebif®, Copaxone®. Biological substances Prevnar®, Engerix-B®, Infanrix®, Gamimune N®. Drugs for sexual function Viagra®. Agents for imaging Iopamiron®, Omnipaque®, Magnevist®. Xalatan®, Trusopt® and Cosopt® ophthalmic drugs. Accutane® / Roaccutan®, Cleocin® derma tological drugs. Therapies for growth failure Genotropin®, Humatrope®. Drugs against infertility Gonal-F®, Follistim (Puregon®). Drugs for Gaucher Cerezyme® disease. Drugs with obesity Xencial®. Drugs for Sandostatin® acromegaly. Contraceptives Depo-Provera®. Other interesting examples of active substances that are slightly soluble, sparingly soluble or insoluble in water are given in the following tables: Table 1 Barely soluble drug candidates Table 1 (Cont.) Table 1 (Cont.) Table 1 (Cont.) Table 2 Barely soluble drugs with low bioavailability The amount of active substance incorporated in a tablet can be selected according to the known principles of the pharmaceutical formulation. In general, the dosage of the active substance present in a tablet according to the invention depends inter alia on the substance of the specific drug, the age and condition of the patient and the disease to be treated. In a specific embodiment of the invention, the therapeutic active substance, prophylactically and / or diagnostically, is solid at room temperature. However, this is not an absolute requirement, it can also be liquid at room temperature. The active substance may also be present in the form of a dispersion of the active substance in the pharmaceutically acceptable liquid formulation, or the active substance may be present in the form of an emulsion that includes a SMEDDs (self-microemulsifier drug delivery system). ). As mentioned above, the active substance can be dispersed in the pharmaceutically acceptable liquid formulation. In a specific embodiment, the active substance is at least partially dissolved in the pharmaceutically acceptable liquid formulation and / or it is at least partially present in an amorphous form. Other cts of the invention The invention also relates to a method for the preparation of a tablet, comprising the steps of: i) preparing a chargeable tablet, as defined in any of claims 1-32, optionally comprising one or more therapeutic active substances, prophylactically and / or diagnostically, ii) loading the tablet that can be loaded, obtained from step i), with a pharmaceutically acceptable liquid formulation as defined in any of claims 33- 59, optionally comprising one or more active substances therapeutically, prophylactically and / or diagnostically for the period of time which is sufficient to saturate the tablet that can be loaded with the pharmaceutically acceptable liquid formulation. The loading of the tablet that can be loaded with the pharmaceutically acceptable liquid formulation optionally comprising one or more active substances therapeutically, prophylactically and / or diagnostically, is typically effected by spraying or the same is carried out by placing the tablet that can be loaded in a excess of the pharmaceutically acceptable liquid formulation comprising one or more active substances therapeutically, prophylactically and / or diagnostically. In the method mentioned above, the period of time in step ii) is usually at most about 60 minutes such as, for example, when much of 45 minutes or at most 30 minutes for a number of tablets that can be charged corresponds to 1 kg (and the corresponding time periods for batches having a different weight of 1 kg). The composition is further illustrated in the following non-limiting examples. EXAMPLES Example 1 Preparation of chargeable tablets and properties thereof The six tablet compositions were manufactured based on the oil absorption materials Aeroperl 300 (silicon dioxide, Degussa), Neusilin US2 (magnesium and aluminum metasilicate, Fuji Chemical Industry), Avicel (microcrystalline cellulose, FMC) and Fujicalin SG (dibasic calcium phosphate anhydrous, Fuji Chemical Industry). Composition 1 Neusilin US2 99% Magnesium stearate 1% Composition 2 Avicel PH102 99% Magnesium stearate 1% Composition 3 Aeroperl 300 80% PEG 6000 19% Magnesium stearate 1% Composition 4 Aeroperl 300 55% Avicel PH 101 44% Stearate magnesium 1% Composition 5 Avicel PH 102 99% Magnesium stearate 1% Composition 6 Fujicalin 99% Magnesium stearate 1% Magnesium stearate was combined with the remaining constituents in a Turbula mixer for 3 minutes. The tablets were compressed in a Diaf TM20 single punch tablet machine. Tablet size: shaped like a round cup to form the 9mm composite. The tablets were placed in corn oil for 24 hours. The absorption of the oil was complemented within the course of the first hour. Tablets of composition 5 were loaded with Imwitor 308, Sasol (glyceryl monocaprylate) with 10% dissolved Simvastatin. The loading with the oil was carried out at a temperature above the melting point of Imwitor 308 (mp 35 ° C) corresponding to 40 ° C.

Composition 1 Table 1. Oil absorption capacity of the tablets containing Neusilin US2. (composition 1) The hardness of the tablet was determined by the hardness tester of the Schleuninger 8M tablet.

Table 2. Hardness of the tablet before and after loading with the oil (composition 1) The disintegration time varied exceeding 24 hours before and after loading with the oil. The disintegration time was reduced to less than 15 minutes by the addition of Ac-di-sol at a concentration of 1% (before loading) and reduced to 5 hours after loading the oil. Ac-di-sol (croscarmellose sodium, FMC) is a superdisintegrant that does not affect the oil absorption capacity of Neusilin. The porosity of the tablets before loading is calculated based on the density of the tablet pt and the "true density" ps of the ingredients. The e porosity of the tablet is calculated according to equation 1.

"Equation 1.

The density of the tablet is based on the ratio between the weight and volume of the tablet. The "true density" of the ingredients is based on the pycnometric density of the gas determined in helium using Micromeritics Accupyc 1330. The maximum load capacity of corn oil based on weight is calculated according to equation 2. load capacity% p / p = 100 Equation 2 The density of corn oil, pi = 0.92 g / cm3.

Table 3. Use of oil loading capacity (composition 1). Composition 2 Table 4. Oil absorption capacity of the tablets with Avicel (composition 2). The hardness of the tablet is determined by the hardness tester of the Schleuninger 8M tablets.

Table 5. Hardness of the tablet before and after loading with the oil (composition 2).

Table 6. Use of oil loading capacity (composition 2). Composition 3 Table 7. Oil absorption capacity of the tablets with Aeroperl / PEG 6000 (composition 3). The hardness of the tablet is determined by the hardness tester of the Schleuninger 8M tablets.

Table 8. Hardness of the tablet before and after loading with the oil (composition 3).

Table 9. Use of oil loading capacity (composition 3) Composition 4 Table 10. Absorption capacity of the oil of the tablets with Aeroperl / Avicel (composition 4).

Table 11. Hardness of the tablet before and after loading with oil (composition 4).

Table 12. Disintegration time of the tablet before and after loading with oil (composition 4). Compared with composition 3, the tabletting properties and the hardness of the tablet were improved by the addition of Avicel PH101 instead of PEG 6000. Composition 5 Table 13. Absorption capacity of the oil of the tablets with Avicel loaded with a 10% solution of Simvastatin in Imwitor 308. (composition 5) Table 14. Hardness of the tablet before and after loading with a 10% solution of Simvastatin in Imwitor 308. (composition 5) Table 15. Disintegration time of the tablet before and after loading with oil (composition 5). Composition 6 Table 17. Oil absorption capacity of the tablets with Fujicalin loaded with corn oil (composition 6).

Table 18. Hardness of the tablet before and after loading with corn oil (composition 6).

Table 19. Disintegration time of the tablet before and after loading with corn oil (composition 6). Conclusion Porous tablets can be used as carriers for oily formulations such as oils, emulsions, microemulsions and semi-solids mixed at elevated temperature including drug substances as in the liquid form or dissolved or dispersed in a liquid carrier. The oils can be applied to the tablets by conventional coating techniques (cylinders, perforated containers or a fluidized bed). The oil feed speed must be adjusted to balance the speed of absorption of the oil in the cores of the tablets.

The absorption capacity of the oil is determined by the porosity of the tablet core. The oil is filling the voids of the tablets close to saturation. Any material that provides tablets with porosities in the range of 30-90% is applicable. Other materials mentioned above can be applied as a core material of the tablet, such as calcium carbonate, magnesium oxide, preferably spray dried materials with a satisfactory flowability and a high specific surface area. The disintegration time of the tablets could be adjusted by the addition of conventional tablet disintegrants and used in the formulation of the immediate release tablets as well as tablets with a controlled release matrix. Examples of porous tablets loaded with active substances (APIs) Example 2 Specification of the core tablets Neusilin US2 93 mg Magnesium stearate 1 mg Average tablet hardness: 52 N Tablet diameter: 8 mm (with composite cup shape) The tablets were compressed on a Diaf TM20 single punch tablet machine.

Specification of the loaded tablet (1 mg of tacrolimus) Tacrolimus in a concentration of 0.95% is dissolved in polyethylene glycol 400 and sprayed on a Neusilin US2 core tablet at room temperature in a coating container. The composition of the charged 1 mg tablet is shown in Table 1 corresponding to a weight of the 200 mg loaded tablet corresponding to a vehicle load of 53% w / w. Average hardness of the tablet: 52 N.

Table 20. Composition of a 1 mg tablet loaded with a solution of Tacrolimus in PEG 400. Example 3 Specification of the core tablets Neusilin US2 198 mg Magnesium stearate 2 mg Average tablet hardness: 42 N Tablet diameter: 10 mm (with composite cup shape) The tablets were compressed on a Diaf TM20 single punch tablet machine. Specification of the loaded tablet (atorvastatin 20 mg) Atorvastatin at a concentration of 10% is dissolved in Imwitor 308 (glyceryl monocaprylate) melted at 40 ° C and sprayed on the Neusilin US2 core tablet at 35 ° C in a coating vessel. The coated tablets are cooled in a refrigerator after charging to solidify the vehicle. The composition of the charged 20 mg tablet is shown in Table 2 corresponding to a weight of the charged tablet of 400 mg corresponding to a vehicle load of 50% w / w. Average hardness of the tablet: 48 N Table 21. Composition of a 20 mg tablet loaded with a solution of atorvastatin in glyceryl monocaprylate. EXAMPLE 4 Specification of the core tablets Neusilin US2 351 mg Magnesium stearate 2 mg Average tablet hardness: 60 N Tablet form: Oblong tablet 9 x 19 mm The tablets were compressed on a tabletting machine - single punch Diaf TM20 Specification of the loading tablet (145 mg fenofibrate) The fenofibrate in a concentration of 35% is dissolved in a molten mixture of polyethylene glycol 6000 and Poloxamer 188 (70: 30) at a temperature of 80 ° C and sprayed on the Neusilin US2 core tablet heated in a coating vessel to a temperature of 70 ° C. The tablets are cooled in the coating vessel after charging at a temperature below the melting point (60 ° C) of PEG and the poloxamer. The composition of the charged 145 mg tablet is shown in Table 3 corresponding to a weight of the charged tablet of 767 mg corresponding to a vehicle load of 54% w / w. Average hardness of the tablet: 57 N Table 22. Composition of a 145 mg tablet loaded with a solution of fenofibrate in a molten mixture of PEG 6000 and Poloxamer 188 (70:30).

EXAMPLE 5 Specification of the core tablets Neusilin US2 84 mg Magnesium stearate 1 mg Average tablet hardness: 42 N Tablet diameter: 7 mm (composite cup-shaped) The tablets were compressed on a single tabletting machine Diaf TM20 punch. Specification of the loaded tablet (10 mg of simvastatin) Simvastatin at a concentration of 10% is dissolved in Viscoleo (MTC) on the Neusilin US2 core in a coating container. The composition of the charged 10 mg tablet is shown in Table 4 which corresponds to a loaded tablet weight of 185 mg corresponding to a vehicle load of 54% w / w.

Table 23. Composition of a 10 mg tablet loaded with a simvastatin solution in Viscoleo.

Example 6 Loading tablets Neusilin with Viscoleo (medium chain glyceride) Process tableting tablets Neusilin were compressed on a tabletting machine of a single punch Diaf TM20: Tablet Properties before the Diameter charging tablet: 9 mm Tablet shape: composite cup Tablet weight: 134 mg Tablet weight variation, Sre ?: 1-6% Tablet hardness: 51 N (determined on a Schleuniger M8 hardness tester) Loading process (loading process) The 50 g tablets were loaded with Viscoleo in a Phast FB 100 laboratory scale fluidized bed using a top spray coating module.

Atomization airflow: 1 m3 per hour Fluidisation air flow: 40 m3 per hour Liquid feed rate: 2.5 g min Coating time to saturation of the tablets: min Weight increase: 67.5 g of Viscoleo. Properties of the tablet after loading Weight of the tablet: 305 mg (56% w / w load) Tablet hardness: 51 N Tablet weight variation, Sre ?: 5.1% Conclusion Conventional coating equipment as A fluidized bed is feasible for loading a liquid formulation onto the porous tablets within a short processing time. The tablets rapidly absorb the liquid applied by spraying on the surface of the tablet. The hardness of the tablet is not affected by the load with the liquid. The variation in weight is increased from 1.6% to 5.2% while still being within the acceptable limits related to the variation of the dose when an active substance is incorporated. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (63)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A chargeable tablet, characterized in that it has a porosity of 30% v / v or greater, for use as a pharmaceutical carrier composition for a pharmaceutically acceptable liquid formulation, wherein the tablet has a hardness of 20 N or greater.
2. 2. A chargeable tablet according to claim 1, characterized in that it comprises one or more pharmaceutically acceptable excipients providing porosity, which - when manufactured in tablets together with at most 50% w / w lactose - they provide a tablet that has a porosity of 30% by volume or greater.
3. 3. A tablet that can be loaded, according to claim 2, characterized in that one or more excipients that provide porosity are present in a concentration of approximately 50% w / w or higher in the tablet.
4. 4. A chargeable tablet according to claim 3, characterized in that one or more excipients providing porosity, which provide a tablet having a porosity of 30% by volume or greater, are present in a concentration of about 60. % w / w greater such as, for example, approximately 70% w / w greater, approximately 80% w / w greater, approximately 90% w / w greater or approximately 95% w / w greater in the tablet.
5. 5. A chargeable tablet according to any of claims 2-4, characterized in that one or more porosity-providing excipients, which provide a tablet having a porosity of 30% by volume or greater, have a surface area specific (BET surface area) of at least 50 m2 / g when measured by gaseous adsorption.
6. 6. A tablet that can be loaded, according to any of the preceding claims, characterized in that when tested as described herein, it leads to a loading of the tablet with at least 20% w / w such as, for example, less 25% w / w at least 30% w / w corn oil (based on the total weight of the solid dosage form during loading).
7. A chargeable tablet, according to any of the preceding claims, characterized in that the tablet has a hardness of 25 N or greater, such as about 30 N or greater, about 35 N or greater, about 40 N or more , approximately 45 N or greater or approximately 50 N or greater.
8. 8. A chargeable tablet according to any of the preceding claims, characterized in that it has a friability of about 5% or less, such as, for example, about 4% or less, about 3% or less, about 2%. % or less such as about 1% or less.
9. 9. A chargeable tablet according to any of claims 2-8, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of metal oxides, metal silicates, metal carbonates, metal phosphates, metal sulphates, alcohols of sugar, sugars and cellulose and cellulose derivatives.
10. 10. A tablet that can be charged, according to claim 9, characterized in that the metal is selected from the group consisting of sodium, potassium, magnesium, calcium, zinc, aluminum, titanium and silicon.
11. 11. A tablet that can be charged, according to claims 9 or 10, characterized in that the pharmaceutically acceptable excipient is a metal oxide selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, aluminum oxide, titanium dioxide including Tronox A-HP-328 and Tronox A-HP-100, silicon dioxide including Aerosil, Cab-O-Sil, Syloid, Aeroperl, Aeroperl 300, Sunsil (silicon beads), Zeofree, Sipernat, Zeopharm S170 , Zeopharm 6000 and mixtures thereof.
12. 12. A tablet that can be charged, according to claim 11, characterized in that the metal oxide is a titanium dioxide or a silicon dioxide or mixtures thereof.
13. 13. A tablet that can be loaded, according to claims 11 or 12, characterized in that the metal oxide is a non-porous silicate that includes fuming silicas of the Aerosil type.
14. 14. A tablet that can be charged, according to claims 11 or 12, characterized in that the metal oxide is a porous silicate including for example Syloid, Porasil and Lichrosorp.
15. 15. A tablet that can be loaded according to any of claims 2-14, characterized in that the pharmaceutically acceptable excipient is a metal silicate selected from the group consisting of sodium silicate, potassium silicate, magnesium silicate, silicate calcium including synthetic calcium silicate, such as, for example, Hubersorp, zinc silicate, aluminum silicate, sodium aluminosilicate such as, for example, Zeolex, magnesium aluminum silicate, aluminum magnesium metasilicate, aluminum metasilicate , Neusilin SG2, Neusilin US2, and mixtures thereof.
16. 16. A tablet that can be loaded according to any of claims 2-15, characterized in that the metal silicate is a swelling clay of the smectite type, selected from the group consisting of bentonite, "veegum" and laponite. .
17. 17. A tablet that can be charged according to any of claims 2-16, characterized in that the metal silicate is selected from the alkaline earth metal silicates and aluminum silicates including aluminum magnesium metasilicate.
18. 18. A tablet that can be charged according to any of claims 15-17, characterized in that the metal silicate is Neusilin.
19. A tablet that can be charged according to any of claims 2-18, characterized in that the pharmaceutically acceptable excipient is a metal carbonate selected from the group consisting of sodium carbonate, sodium acid carbonate, potassium carbonate, acid carbonate of potassium, calcium carbonate, magnesium carbonate, zinc carbonate and aluminum carbonate, and mixtures thereof.
20. 20. A tablet that can be charged according to any of claims 2-19, characterized in that the pharmaceutically acceptable excipient is a metal phosphate selected from the group consisting of sodium phosphate, disodium acid phosphate, sodium diacid phosphate, phosphate of potassium, dipotassium acid phosphate, potassium diacid phosphate, calcium phosphate, magnesium phosphate, zinc phosphate and aluminum phosphate.
21. 21. A tablet that can be loaded according to claim 20, characterized in that the pharmaceutically acceptable excipient is a calcium phosphate selected from the group consisting of anhydrous dibasic calcium phosphate, calcium dibasic phosphate dihydrate, and tribasic calcium phosphate.
22. 22. A tablet that can be charged according to claim 21, characterized in that the anhydrous dibasic calcium phosphate is selected from the group consisting of A-Tab, calcium monoacid phosphate, calcium orthophosphate, Di-Cafos AN, orthophosphate dicalcium, E341, Anhydrous Emcompress, Fujicalin, calcium salt phosphoric acid (1: 1) and secondary calcium phosphate, and mixtures thereof.
23. 23. A tablet that can be charged according to claim 21, characterized in that the calcium phosphate dibasic dihydrate is selected from the group consisting of Caphos, calcium acid orthophosphate dihydrate, calcium monoacid phosphate dihydrate, Calipharm, Calstar, Di- Cafos, dicalcium orthophosphate, DI- , Emcompress, phosphoric acid calcium salt (1: 1) dihydrate, Fujiclin SG.
24. 24. A tablet that can be charged according to claim 21, characterized in that the tribasic calcium phosphate is selected from the group consisting of hydroxyapatite, phosphoric acid calcium salt (2: 3), precipitated calcium phosphate, tertiary calcium phosphate, Tri-Cafos, tricalcium diorthophosphate, tricalcium orthophosphate, tricalcium phosphate, TRI-CAL, WG, TRI- .
25. 25. A tablet that can be charged according to any of claims 2-24, characterized in that the pharmaceutically acceptable excipient is a metal sulfate selected from the group consisting of sodium sulfate, sodium acid sulfate, potassium sulfate, acid sulfate of potassium, calcium sulfate, magnesium sulfate, zinc sulfate and aluminum sulfate.
26. 26. A tablet that can be charged according to claim 25, characterized in that the metal sulfate is calcium sulfate such as anhydrous calcium sulfate including anhydrite, anhydrous gypsum, anhydrous lime sulfate, Destab, Drierfe, E516, aratenite, muriazite , and Snow White or calcium sulfate dihydrate including alabaster, Cal-Tab, Compactrol, Destab, E516, gypsum, light spar, calcium sulfate, natural calcium sulfate, precipitated calcium sulfate, satinite, fibrous gypsum, selenite, alba and Terra Alba USG.
27. 27. A tablet that can be loaded according to any of claims 2-26, characterized in that the pharmaceutically acceptable excipient is a sugar alcohol selected from the group consisting of sorbitol (such as, for example, Sorbogem, SPI Pharma), xylitol, mannitol (such as, for example, Mannogem, SPI Pharma, Pearlitol SP100), maltitol, inositol.
28. 28. A tablet that can be loaded according to any of claims 2-27, characterized in that the pharmaceutically acceptable excipient is a sugar selected from the group consisting of mono-, di- or polysaccharides.
29. 29. A tablet that can be charged according to claim 28, characterized in that the sugar is selected from the group consisting of sucrose, glucose, fructose, sorbose, xylose, lactose, dextran, dextran derivatives, cyclodextrins.
30. 30. A tablet that can be loaded according to any of claims 2-29, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of cellulose, Celphere microcrystalline cellulose, cellulose derivatives including porous cellulose beads.; cellulose acetate Celluflow TA-25 and cellulose Celluflow C-25, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, etc.
31. 31. A tablet that can be loaded according to any of the preceding claims, characterized in that it is therapeutically inert.
32. 32. A tablet that can be charged according to claim 31, characterized in that it consists of one or more pharmaceutically acceptable, inert excipients.
33. 33. A tablet according to any of claims 1-32, characterized in that it is loaded with a pharmaceutically acceptable liquid formulation in a concentration of about 20% w / w greater such as, for example, about 25% w / w greater or about 30% w / w greater (based on the total weight of the solid dosage form during loading).
34. 34. A tablet according to claim 33, characterized in that the pharmaceutically acceptable liquid formulation is present in a concentration of about 40% w / w greater, such as, for example, about 50% w / w greater or approximately 60% p / po greater (based on the total weight of the solid dosage form during loading).
35. 35. A tablet according to claim 33 or 34, characterized in that the pharmaceutically acceptable liquid formulation has a viscosity as much as 600 mPa at a temperature of at most approximately 150 ° C.
36. 36. A tablet according to any of claims 33-35, characterized in that the pharmaceutically acceptable liquid formulation has a melting point of at least about 0 2C and at most about 250 2C.
37. 37. A tablet according to claim 36, characterized in that the pharmaceutically acceptable liquid formulation has a melting point of about 5 SC or greater such as, for example, about 10 2C or greater, about 15 SC or greater, about 20 2C or greater or approximately 25 2C or greater.
38. 38. A tablet according to any of claims 33-38, characterized in that the pharmaceutically acceptable liquid formulation comprises an oil or an oil-like material.
39. 39. A tablet according to any of claims 33-37, characterized in that the pharmaceutically acceptable liquid formulation comprises a pharmaceutically acceptable solvent.
40. 40. A tablet according to claim 38, characterized in that the oil or oil-like material is selected from the group consisting of water, vegetable oils, hydrogenated vegetable oils, and animal oils.
41. 41. A tablet according to claim 40, characterized in that the oil or oil-like material is selected from the group consisting of apricot oil, almond oil, avocado oil, castor oil, coconut fat, shortening cocoa, corn oil, cottonseed oil, grapeseed oil, jojoba oil, flax seed oil, corn seed oil, olive oil, palm oil, peanut oil, pepper oil , poppy seed oil, rape seed oil, sesame oil, soybean oil, sunflower oil, milk thistle seed oil, walnut oil, wheat germ oil, bovine sebum, butter pig, cellulosic lye resin, whale oil, and mixtures thereof.
42. 42. A tablet according to claim 40, characterized in that the oil or oil-like material is an oil or an oil-like material, hydrophilic, selected from the group consisting of: polyether glycols such as, for example, polyethylene glycols , polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or may be selected from the group consisting of: xylitol, sorbitol, sodium and potassium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinone monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Gelucire 50/13, other types of Gelucire , such as, for example, Gelucire 44/14, etc., Gelucire 50/10, Gelucire 62/05, Sucrose-ester 7, Sucrose-ester 11, Sucrose-ester 15, maltose, mannitol and mixtures thereof.
43. 43. A tablet according to claim 40, characterized in that the oil or oil-like material is an oil or an oil-like, hydrophobic material, selected from the group consisting of: straight-chain saturated hydrocarbons, esters of sorbitan, paraffin; fats and oils such as, for example, cocoa butter, beef tallow, lard, polyether glycol esters; higher fatty acids such as, for example, stearic acid, myristic acid, palmitic acid, higher alcohols such as, for example, 'cetanol, stearyl alcohol, low-melting waxes such as, for example, glyceryl monostearate, monooleate glyceryl, resins of hydrogenated cellulose liquors, myristyl alcohol, stearyl alcohol, substituted and / or unsubstituted monoglycerides, substituted and / or unsubstituted diglycerides, substituted and / or unsubstituted triglycerides, yellow beeswax, white beeswax, waxes carnauba, castor wax, wax from Japan, acetylate monoglycerides; NVP polymers, PVP polymers, acrylic polymers, or a mixture thereof.
44. 44. A tablet according to claim 40, characterized in that the oil or oil-like material is a polyethylene glycol having an average molecular weight in a range from about 400 to about 35,000 such as, for example, from about 800 to about 35,000, from about 1,000 to about 35,000 such as, for example, polyethylene glycol 1,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6,000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000, polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000. In certain situations the polyethylene glycol can be employed with a molecular weight of from about 35,000 to about 100,000.
45. 45. A tablet according to claim 40, characterized in that the oil or oil-like material is a polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, for example, from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, for example, from about 100,000 to about 1,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000 or from about 100,000 to about 300,000.
46. 46. A tablet according to claim 40, characterized in that the oil or the oil-like material is a poloxamer such as, for example, Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other copolymers of oxide blocks. ethylene and propylene oxide such as the Pluronic® and / or Tetronic® series. Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of from about 3,000 or greater such as, for example, from about 4,000 to about 20,000 and / or a viscosity (Brookfield) from about 200 to about 4,000 cps such as, for example, from about 250 to about 3,000 cps. Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8, etc. Suitable block copolymers of the Tetronic® series include polymers having a molecular weight of about 8,000 or greater such as, for example, from about 9,000 to about 35,000 and / or a viscosity (Brookfield) from about 500 to about 45,000 cps. such as, for example, from about 600 to about 40,000. The viscosities given above are determined at 60 ° C for substances that are pastes at room temperature and at 77 ° C for substances that are solid at room temperature.
47. 47. A tablet according to claim 40, characterized in that the oil or the oil-like material is a sorbitan ester such as, for example, sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, monostearate of sorbitan, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.
48. 48. A tablet according to claim 40, characterized in that the oil or the oil-like material is a mixture of oils or similar oil-like materials, such as, for example, a mixture of hydrophobic and / or hydrophilic materials. .
49. 49. A tablet according to claim 40, characterized in that the oil or the oil-like material is a solvent or a similar semi-solid excipient, for example to propylene glycol, polyglycolized glycerides including Gelucire 44/14, complex fat materials of vegetable origin including theobroma oil, carnauba wax, vegetable oils similar to, for example, almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soybean oil, olive oil, olive oil, castor oil, palm kernel oil, peanut oil, rape seed oil, grape seed oil, etc., hydrogenated vegetable oils such as, for example, hydrogenated peanut oil, hydrogenated palm kernel oil, hydrogenated cottonseed, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated coconut oil; Natural fat materials of animal origin include beeswax, lanolin, fatty alcohols including cetyl, stearyl, lauric, myristic, palmitic, stearic fatty alcohols; esters that include glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; interesterified, liquid semi-synthetic glycerides, including Miglycol 810/812; fatty acid amides or alcolamides including stearamide ethanol, diethanolamide of fatty coconut acids, acetic acid esters of mono and di-glycerides, citric acid esters of mono and di-glycerides, lactic acid esters of mono and diglycerides, mono and diglycerides, polyglycerol esters of fatty acids, polyglycerol poly ricinoleate, propylene glycol esters of fatty acids, sorbitan monostearate, sorbitan tristearate, stearoyl and sodium lactylates, stearoyl and calcium lactylates, diacetyl tartaric acid esters of mono and di -glycerides, etc.
50. 50. A tablet according to any of claims 33-49, characterized in that the pharmaceutically acceptable liquid formulation is a dispersion that includes an emulsion, a microemulsion for example a self-microemulsifying drug delivery system (SMEDDS) or a suspension.
51. 51. A tablet according to any of claims 33-50, characterized in that the concentration of the pharmaceutically acceptable liquid formulation in the tablet is about 5% w / w greater such as, for example, about 10% w / w higher , approximately 15% w / w greater, approximately 20% w / w greater, approximately 25% w / w greater, approximately 30% w / w greater, approximately 35% w / w greater, approximately 40% w / w greater, approximately 45% p / p major, approximately 50% p / p major, approximately 60% p / p major or approximately 70% p / p major.
52. 52. A tablet according to any of claims 33-51, characterized in that it also comprises one or more therapeutic active substances, prophylactically and / or diagnostically.
53. 53. A tablet according to claim 52, characterized in that the active substance is dispersed in the pharmaceutically acceptable liquid formulation.
54. 54. A tablet according to claim 52, characterized in that the active substance is at least partially dissolved in the pharmaceutically acceptable liquid formulation.
55. 55. A tablet according to claim 52, characterized in that the active substance is present at least partially in an amorphous form.
56. 56. A tablet according to any of claims 33-55, characterized in that it has a hardness of at least about 25 N.
57. 57. A tablet according to any of claims 33-56, characterized in that it is in the form of tablets which have a friability when very much of about 5% such as, for example, when much of about 4%, when much of about 3%, when much of about 2%, when much of about 1% or when much of about 0.5% .
58. 58. A tablet according to any of claims 33-57, characterized in that it has a disintegration time at most of 15 minutes when tested according to Ph.Eur.
59. 59. A tablet according to any of claims 52-58, characterized in that at least 75% of the therapeutic active, prophylactically and / or diagnostically is released within the course of 30 minutes when tested in a method of dissolution according to with USP.
60. 60. A method for the preparation of a tablet, characterized in that it comprises the steps of: i) preparing a tablet that can be loaded according to any of claims 1-32 optionally comprising one or more therapeutic, prophylactic active substances and / or diagnostically, ii) the loading of the tablet that can be loaded, obtained from step i), with a pharmaceutically acceptable liquid formulation according to any of claims 33-59 optionally comprising one or more active substances therapeutically, prophylactically and / or diagnostically for the period of time which is sufficient to saturate the tablet that can be loaded with the pharmaceutically acceptable liquid formulation.
61. 61. A method according to claim 60, characterized in that the loading of the tablet that can be loaded with the pharmaceutically acceptable liquid formulation optionally comprising one or more therapeutic substances, prophylactically and / or diagnostically, is effected by spraying.
62. 62. A method in accordance with the claim 60, characterized in that the loading of the tablet that can be loaded with the pharmaceutically acceptable liquid formulation optionally comprising one or more active substances therapeutically, prophylactically and / or diagnostically, is effected by the placement of the tablet that can be loaded in an excess of the liquid pharmaceutically acceptable formulation optionally comprising one or more active substances therapeutically, prophylactically and / or diagnostically.
63. 63. A tablet according to any of claims 60-62, characterized in that the period of time in step ii) is at most about 60 minutes such as, for example, at most about 45 minutes or at most about 30 minutes for a number of tablets that can be loaded, which corresponds to 1 kg.