Method for preparing a composition

ES 2 269 441 T3

DESCRIPTION

Method for the preparation of a composition.

The present invention relates to a method for the preparation of compositions, preferably pharmaceutical compositions in the form of expanded structures, mechanically stable, laminar, porous, spongiform or as foams, from solutions and dispersions. This method comprises the steps of a) preparation of a homogeneous solution or dispersion of a liquid and a compound selected from the group consisting of one or more pharmaceutically active compounds, one or more pharmaceutically suitable excipients, and mixtures thereof, followed by b ) expansion of the solution or homogeneous dispersion without reaching boiling. The invention also relates to the compositions, their further processing and any corresponding dosage form obtainable by the above method.

In pharmaceutical technology, formulation work is determined in most cases, by the physicochemical properties of the pure active substance of the drug (particle size and shape, fluidity, compressibility, polymorphism, wettability, melting point, stability, expiration date, etc.), or other important additives. Many dosage forms are already well known in the pharmaceutical market, the most important of which are tablets and capsules. In order to stabilize highly sensitive drugs that are supposed to be used or applied orally or parenterally after rehydration, dry solutions or dispersions (eg, suspensions, emulsions) are also of greatest interest.

The route of processing the pure substance of the drug in the final formulation on the market normally comprises several fundamental operations such as grinding, size selection, wet or dry granulation, grinding, encapsulation, etc. Currently many of these processes are designed for the production of large quantities of material, eg. eg, high speed tabletting. With this, the mechanical energy produced by impact, pressure or shear stress is absorbed by the material. Very often this leads to melting, decomposition, or inactivation of the drug substance. In this way, deposits or encrustations can lead to the interruption of the process or even the destruction of the machines.

In order to facilitate the dosage form manufacturing process, the drug substance usually has to be mixed, combined or granulated with different pharmaceutical excipients such as lubricants, bulking agents, binders, thinners or dispersants, etc. These additives will influence the properties of the final composition, but may only partially provide protection against mechanical energy or may even induce stability problems by themselves.

The final composition as well as the corresponding dosage form is also assumed to have very specific properties, before, during or after application. For bulk materials (powders, granules, pills, tablets, etc.) high stability and compatibility during storage is required. The dry suspensions must have an exquisite dispersibility in liquids; The tablets should disintegrate well and very quickly or very slowly after they have been swallowed. Sufficient wettability of the drug particles in gastric or intestinal fluids is a prerequisite for good solubility and absorption. When dosed by volume, pharmaceutical powders or granules need to have a sufficient bulk density for tablet pressing or encapsulation. Depending on the dose, these important galenic properties can be adversely affected by having a drug substance or excipient with inadequate physicochemical properties (eg, low melting point, low solubility, etc.).

In summary, the way of incorporation of the pharmaceutically active compound or of the pharmaceutically suitable excipients in a composition or galenic formulation, is the most critical factor that has to be controlled to:

- mask undesirable properties,

- stabilize, inert and protect the critical compound incorporated,

- obtain an optimal fluidity and density, for the work to be carried out later,

- achieve the necessary dispersibility and release characteristics during or after application, etc.

In order to improve some of the mentioned properties, various techniques are already known in the art, but these are very often unable to solve all the problems, and sometimes even induce new drawbacks.

- the coating in a fluid bed is not suitable for substances with low melting points or fine and light particles with a large surface area and of cylindrical or acicular shape,

- powders from (co) precipitation processes (eg spray drying) still have significant amounts of reactive material located on the surface of the particles.

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- lyophilization is very expensive and is not suitable for substances that are sensitive to freeze-thaw cycles;

- Spray freezing, melt coating, or melt extrusion are only feasible for materials that resist temperature.

International patent application WO96 / 40077 (Quadrant Holdings Cambridge Limited) describes a method for the preparation of foamed thin glass pastes comprising the steps of a) preparation of an initial mixture comprising at least one glass paste forming material, and at least one solvent including a solvent for the glass paste forming material, b) evaporation of the bulk solvent from the mixture to obtain a syrup, (c) subjecting the syrup to a pressure and temperature sufficient to cause the syrup to boil, and (d) optionally removing residual moisture.

International patent application WO98 / 02240 (Universal Preservation Technologies) describes a method of preserving sensitive biological dispersions, suspensions, emulsions and solutions by forming stable foams from the fluid materials to be dehydrated, as an aid both for the drying of one or more biologically active substrates of the fluid, as for the preparation of an easily divisible dry product, suitable for later commercial use. Stable foams are formed by partially removing water to form a viscous liquid and subsequently subjecting the reduced liquid to a vacuum, to cause boiling during subsequent drying at temperatures substantially below 100 ° C. In other words, a reduced pressure is applied to the viscous solutions or suspensions of biologically active materials so that the solutions or suspensions form a foam during boiling, and using the foaming process in addition to the removal of the solvent the final production of a stable open-cell or closed-cell foam.

However, these references both propose boiling as a necessary step for the preparation of the corresponding compositions. Furthermore, said mixtures, solutions, emulsions or dispersions have to be initially concentrated by evaporation of the bulk solvent, to obtain the syrup necessary for the subsequent treatment (under vacuum; <30 / <24 Torr). Then, after having obtained a syrup of sufficient viscosity, the "foaming" (expansion of the structure) is carried out at such conditions of temperature and pressure that cause the syrup to boil.

Sinnamon et al. (J. Dairy Sci 40, 1957, 1036-1045), describe the properties of a new dry whole milk, dried under high vacuum and at low temperatures in the form of a spongiform expanded structure. The product obtained is easily dispersed in cold water and has a natural flavor when reconstituted in the fresh state. However, this method was devised to improve the dispersibility and flavor of food products such as dry milk. As a disadvantageous prerequisite, an initial concentration step (up to 50% w / w solids) is also necessary for the following foaming processes. Only when nitrogen is bubbled through such concentrated milk can the desired "blown" foam structure be achieved.

Schroeder (thesis Ph.D. entitled "Entwicklung von kompakten Darreichungsformen aus sprühgetrockneten Milcherzeugnissen zur spontanen Rekonstitution" ("Development of compact forms of administration of spray-dried dairy products, for their spontaneous reconstitution"), 1999) mainly describes the development of a technology that provides the densification of products dairy or non-dairy foods without changing the original properties of the dry powders, originally powdered, during reconstitution. However, the method described for the vacuum drying of wet powders was carried out under conditions (50 ° C / 37.5 Torr) which caused the incorporated water to boil while creating the foam structure.

The problem that constitutes the rationale for the present invention is therefore to provide a new process and new compositions to minimize the disadvantages mentioned above.

The problem is solved according to the present invention, by a method for the preparation of a pharmaceutical composition comprising the steps of:

a) preparation of a solution or a homogeneous dispersion of a liquid and a compound selected from the group consisting of one or more pharmaceutically active compounds, one or more pharmaceutically suitable excipients, and mixtures thereof, followed by

b) expansion of the solution or homogeneous dispersion without reaching boiling point.

It was surprisingly found that the preparation of sufficiently viscous homogeneous solutions or dispersions prior to the expansion step is highly feasible and creates several advantages when compared to techniques described as the state of the art, including:

- no preliminary evaporation of the bulk solvent necessary to obtain suitable conditions for expansion of the concentrate;

- continuous process conditioned to have high performance;

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- the desired support structure for the expansion step develops immediately (in the continuous process) or after a few minutes (in the batch batch process);

- expansion takes place even under less critical pressure conditions (> 30 Torr, at room temperature), so that boiling of the concentrate is not an initial prerequisite.

- highly concentrated pharmaceutical compositions can be easily expanded and solidified within their capsule, blister, etc.

Examples of the resulting advantages and possibilities with respect to the physicochemical and biopharmaceutical properties are the protection and stabilization of pharmaceutically active compounds or pharmaceutically suitable excipients, during processing and storage; the expansion of expiration; elimination of incompatibilities; Regardless of its original properties, desired physicochemical characteristics can be generated, according to the material used for the coating; the resulting morphology or the method subsequently followed (ie, increased wettability, flowability, solubility, etc.); taste masking; reduction of side effects; increased bioavailability (especially for a pharmaceutically active compound, solidified as an amorphous glass) and / or control of release characteristics.

Unless otherwise indicated, the following definitions are mentioned to illustrate and define the meaning and scope of various terms used to describe the invention herein.

The term "solution" as used herein means a physical system consisting of at least two compounds, in which all compounds are molecularly distributed, and which appears as a phase.

The term "dispersion" means a physical system consisting of at least two phases. One of these phases is the dispersion medium, in which one or more compounds (second and third phase) are uniformly distributed.

The term "pharmaceutically suitable" as used herein means that the substances employed are acceptable from a toxic point of view.

The term "boiling" refers to the evaporation of a liquid in the event that the pressure exerted by the environment on the liquid equals the pressure exerted by the vapor of the liquid; In this condition, the addition of heat or the reduction of the pressure exerted by the environment, results in the transformation of the liquid into its vapor without reaching the temperature.

The term "glass paste-forming material" refers to pharmaceutically active compounds or pharmaceutically suitable excipients, which appear in an amorphous state after solidification.

The term "coating material" refers to substances that are capable of coating, occluding, separating, protecting or inerting other materials.

The term "expansion" means that the homogeneous solution or dispersion develops a larger volume and surface area through a change in pressure, as a result of which it is characterized as a coherent, laminar, spongy or caked structure.

The term "polyol", in connection with the present invention, refers to a material from the group of carbohydrates, such as e.g. eg, maltodextrin.

The term "gum" refers to a material that consists of a mixture of polysaccharides such as xanthan.

The term "polymer" refers to a material that is a macromolecule (natural or synthetic substance). It can be a homopolymer (eg, polyethylene glycol) or a copolymer (eg, polymethacrylate).

The term "lipase inhibitor" refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example, orlistate and lipstatin as described in US Patent No. 4,598,089, are potent lipase inhibitors. Lipstatin is a natural product of microbial origin, and orlistat is the result of the hydrogenation of lipstatin. Other lipase inhibitors include a class of compounds commonly called panclycins. Panclycins are orlistate analogs (Mutoh et al., J. Antibiot., 47 (12): 1369-1375 (1994)). The term "lipase inhibitor" also refers to synthetic lipase inhibitors, for example, described in international patent application WO99 / ​​34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases. The term "lipase inhibitor" also encompasses pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" also refers to the 2-oxy-4H-3,1-benzoxacin-4-ones that have been described in the international patent application WO00 / 40569 (Alyzime Therapeutics Ltd), p. e.g. 2-decyloxy-6-methyl-4H-3,1-benzooxacin-4-one, 6-methyl-2-tetradecyloxy-4H-3,1-benzoxacin-4-one, and 2-hexadecyloxy-6-methyl -4H-3,1-benzoxacin4-one. Preferably, the term "lipase inhibitor" refers to orlistate.

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The resulting pharmaceutical composition is a solid or gel-type composition, preferably a solid composition.

Optionally, the method is continued with drying and / or freezing of the composition. This method is especially useful for the preparation of pharmaceutical compositions.

Preferably, the homogeneous solution or dispersion expands by lowering the pressure.

In a preferred version, the homogeneous solution or dispersion is prepared by means of a liquid pharmaceutically active compound or a suitable pharmaceutically excipient. Preferably the solution or dispersion is prepared by adding to the liquid both a pharmaceutically active substance and a suitable pharmaceutically excipient.

The liquid used in the above method should be easy to evaporate or vaporizable, and can be selected from the group consisting of water (i.e., purified, deionized, distilled, or sterilized water), aqueous buffer solutions, or isotonic (e.g. ., bicarbonate buffer, pH 7.38), nutrient medium or culture broth (eg, peptone broth), alcohols (eg, ethanol or isopropyl alcohol), ketones (eg. g. acetone), ethers (p. g. diethyl ether), liquid carbohydrates (eg, octane), oils (eg, essential oils such as chamomile oil), and synthetics (eg, plasma expanding agents such as eg dextrans), although they may not be limited to these. Mixtures of the liquids mentioned above may also be useful for the method of the present invention. Preferably, the liquid is an aqueous buffer and / or an isotonic solution.

The homogeneous dispersion can be in the form of a colloid, a sol, a gel, a liquid crystal, an emulsion, a paste, a suspension or an ointment.

Homogeneous solutions or dispersions can be prepared by pouring the liquid or mixture of liquids into a planetary mixer (or similar), followed by dissolution and / or dispersion of the pharmaceutically active compound (s) or excipient (s) pharmaceutically suitable (s) in the liquid or mixture of liquids until said homogeneous dispersion is prepared. While mixing with the liquid or liquid mixture, the material (s) may be in a dry, dissolved, dispersed or molten state (s). Through them or later, other compounds, excipients or liquids may be added.

Alternatively, homogeneous solutions or dispersions can be prepared by placing the pharmaceutically active compound (s), the pharmaceutically suitable excipient (s), or a mixture thereof, in a planetary mixer (or similar), followed by wetting, dissolving and / or dispersing the material (s) with the solvent or solvent mixture, until said homogeneous solution or dispersion is prepared. Through them or later, other compounds, excipients or liquids may be added.

In order to increase the homogeneity of said solution or dispersion, especially when the solids content is very high, the mixing or dispersing process can be carried out by e.g. eg, a static mixer, microfluidizer, homogenizer, kneading devices, high shear forces, ultrasound, an ointment mill or other devices already known in the art. The viscosity of said homogeneous solution or dispersion can be low or high, provided that the mass can be fed or sprayed.

The solution or dispersion is transformed into an expanded structure by subjecting it to a pressure change, vacuum or by blowing, and is dried thereby or by contact, convection, radiation, sonification, high frequency, dry gas (hot or cold) or with help of a desiccator such as organic solvents, silica gel, etc. In more detail, said homogenized solution or dispersion is normally pumped, dispensed, sprayed, or placed on a plate, sieve, tape, cylinder, etc., or in a capsule, blister, vial, jar, syringe, or other suitable form. . Then, almost immediately (in a continuous process) or after a short time (in a batch process) a controlled change in pressure leads to such an expanded structure. For this, low pressure conditions, between 30 and 150 Torr, are suitable to provide an excellent density of the resulting solidified material. According to the liquid or mixture of liquids used and the chosen temperature, the expansion can be carried out by adjusting the pressure conditions in such a way that said homogenized solution or dispersion does not boil. Depending on the composition used, simultaneously or after stabilization of said expanded structure, the pressure conditions can be varied, the temperature can be changed or any drying method already known in the current art can be applied, to achieve the desired level of residual solvent. Drying can be an internal or external process and can be supported by vibration, fluidization or any other kind of known technique that helps to remove the fluid, solvent or the saturated gas phase. The variation of the temperature and / or pressure conditions described above can be carried out in several steps (in a batch batch process) or in different zones (in a continuous process), where a final cooling step can be included.

To achieve the desired shape, density and stability of the expanded structure, the liquid must be prevented from boiling. The dry and optionally cooled structure has a long shelf life and can be easily cut, crushed, ground or respectively pulverized into a free-flowing powder so that, on the one hand, it provides easy processing in subsequent operations such as p. e.g. wet or dry agglomeration, granulation (melt), crushing, compressing, compacting, pilling, encapsulation or any other kind of

ES 2 269 441 T3 filling process, and on the other hand it has excellent reconstitution properties in cold or tempered liquids or body fluids, thereby maintaining the properties and efficacy of any pharmaceutically active compound or pharmaceutically appropriate excipient, which is incorporated. The new method described for the preparation of pharmaceutical compositions also provides the possibility of creating the expanded structure, sufficiently dense, directly in its formulation or in its final container, ready to be used.

The initial process for the creation and drying of said expanded structure can be in the form of batch batches (eg, in a vacuum drying oven) or continuously (eg, with a vacuum drying conveyor belt ) or with the aid of other techniques already known in the art.

In a preferred version, the compound of step a) is a pharmaceutically active compound. In another preferred version, the compound of step a) is a suitable pharmaceutically excipient.

More specifically, the present invention relates to a method of preparing a pharmaceutical composition comprising the steps of

a) Preparation of a homogeneous solution or dispersion by mixing a pharmaceutically active compound and / or a pharmaceutically suitable excipient with a liquid or mixture of liquids in an amount sufficient to create a homogeneous dispersion.

b) subjecting the dispersion to a pressure change without boiling, and

c) optionally, drying and / or cooling the composition.

The above methods may also comprise the steps of a) preparing a homogeneous solution or dispersion, mixing a pharmaceutically active compound and a liquid or liquid mixture in sufficient quantity to create a homogeneous solution or dispersion, b) subjecting the solution or dispersion at a pressure change without boiling, and c) optionally, drying and / or cooling of the composition.

The procedure described above is especially useful for the preparation of pharmaceutical compositions. The pharmaceutically active compounds suitable for this procedure cannot be limited to any special group. The method described above for the preparation of pharmaceutical compositions is basically supposed to be a powerful tool whenever physicochemical, technical, galenic or biopharmaceutical problems arise, during or after the development of pharmaceutically relevant products (e.g. drugs, drugs , vitamins, medical devices). However, lipase inhibitors are especially preferred compounds to be used in the above process, preferably orlistate.

Orlistate, a gastrointestinal lipase inhibitor, also known as orlistate, is a known compound useful for the control or prevention of obesity and hyperlipidemia. See US Patent No. 4,598,089 published July 1, 1986, which also describes processes for obtaining orlistate, and US Patent No. 6,004,996, which describes appropriate pharmaceutical compositions. Furthermore, suitable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123.

Other examples of pharmaceutically active compounds are neuraminidase inhibitors, e.g. eg, oseltamivir and insulin sensitizers, eg. eg, 5- [7- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -benzothiophene-4-methyl] 2,4-thiazolidinedione or its sodium salt. These compounds are known in the art and are described, for example, in European patent applications No.^you 96912404.9 and 99117934.2 and the international patent application WO94 / 27995, respectively.

In a preferred version of the present invention, the above solutions or dispersions further comprise a coating material or glass paste forming material. Preferably the coating material or glass paste forming material is a polyol, rubber, polymer or pharmaceutically acceptable salts thereof.

The coating material or material forming a glass paste can be the pharmaceutically active compound, highly dispersed in the crystalline state, or respectively solidified in the amorphous state, or the suitable pharmaceutically excipient, preferably a polyol, e.g. eg, a carbohydrate. The coating material or glass paste forming material may be amorphous or partially or fully crystalline.

Carbohydrate as a suitable pharmaceutically excipient can be selected from the group consisting of p. e.g. from maltodextrin, trehalose, cellobiose, glucose, fructose, maltulose, iso-maltulose, lactulose, maltose, gentobiose, lactose, isomalt, maltitol, lactitol, erythritol, palatinitol, xylitol, mannitol, sucbitol and dulcitol, dulcitol , raffinose, gentianose, plantose, verbascosa, stachyose, melezitose, dextran and also inositol, although it cannot be limited to these mentioned. In a preferred version, the carbohydrate is maltodextrin. In another preferred version, the carbohydrate is trehalose. In another preferred version, the carbohydrate is maltitol. The term "maltodextrin" preferably refers eg. For example, to Glucidex from Roquette, the term "trehalose" preferably refers to eg. eg, Trehalose from Merck, and the term maltitol preferably refers to Maltisorb from Roquette.

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Other pharmaceutically suitable excipients for use can be selected from the group of polymers, gums and their salts, such as polyethylene glycol; modified or substituted starch (eg, pregelatinized starch, hydroxyethyl starch, sodium starchonocythene succinate, inulin, etc.); modified or substituted cellulose (p. g., methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, sodium carboxymethyl cellulose, cellulose acetate phthalate, etc.); povidone; polyvinyl alcohol; acacia gum; carbomer; alginic acid; cyclodextrin; jelly; guar gum; welan gum; gellan gum; tara gum; locust bean gum; fibers (p. eg, pectin); carrageenan gum; glucomannan; polymethacrylates; Propylene Glycol Alginate; shellac; sodium alginate; xanthan and chitosan tragacanth gum, although they should not be limited to these.

Some of the mentioned materials can be completely amorphous or they can appear in a partially or completely crystalline state.

The procedure described above is also useful for the preparation of pharmaceutical compositions wherein a suitable pharmaceutically excipient is prepared according to the procedures described above. Any pharmaceutically acceptable excipient for this class of procedure can generally be selected from all the possible groups of adjuvants that help transform the pharmaceutically active compound into its final formulation, modify or optimize its efficacy, change its properties, immobilize its molecules or preserve its stability. The invention is suitable for improving desirable properties of an inert, pharmaceutically suitable excipient, as well as masking undesirable properties. Some of the preferred groups of pharmaceutically suitable excipients comprise compounds selected from solvents, solubilizers, dissolution enhancers, salt-forming agents, (volatile) salts, buffers, effervescent agents, stabilizing agents, gel-forming agents, surfactants, lipids, acids. fatty, antioxidants, synergists, chelating agents, preservatives, fillers, bulking agents, chemical supports, adsorbents, binders, disintegrators, glidants, lubricants, parting agents, flow promoters, coating agents, retarding agents, coloring agents, pigments, odor and taste adjusting / masking agents, resorption enhancer, moisture adjusting agents, flocculating agents, etc.

In particular, the invention relates to the above methods, wherein the pharmaceutically active compound is selected from the group consisting of p. For example, in molecules, drugs, vitamins, minerals, trace elements, enzymes, cells, sera, vaccines, proteins, viruses, bacteria, nucleic acids, complexes, liposomes or nanoparticles, although they cannot be limited to these mentioned.

Especially, the present invention relates to methods wherein the solution or dispersion comprises a surfactant. Surfactants in the sense of the present invention refer to pharmaceutically suitable excipients with emulsifying, stabilizing, solubilizing, wetting, anti-foaming or spraying properties. These adjuvants have an amphiphilic character and influence the interfacial tension between the different phases. The term "surfactants" encompasses anionic or co-emulsifying surfactants (ie, detergents, sulfonates, sodium lauryl sulfate, docusate sodium, sodium caseinate, fatty acid salts), cationic surfactants (ie quaternary amines, sodium chloride). cetylpyridinium), nonionic surfactants (i.e. polyoxyethylene fatty acid esters, e.g. e.g., polyoxyl 40 stearate, sucrose fatty acid esters, cetyl alcohol, fatty acid esters, cetostearyl alcohol, cholesterol, sorbitan fatty acid esters, polysorbates, poloxamer, polyethylene glycol tocopheryl succinate), and amphoteric surfactants ( i.e. phospholipids, ampholytes, proteins). In a preferred version, the surfactant is a polyoxyethylene fatty acid ester. In another preferred version the surfactant is a phospholipid. Preferably, the surfactant selected from the group consists of sodium lauryl sulfate, sodium docusate, sodium caseinate, fatty acid salts, quaternary amines, cetylpyridinium chloride, polyoxyethylene fatty acid esters, sucrose fatty acid esters, cetyl alcohol , fatty acid esters, cetostearyl alcohol, cholesterol, sorbitan fatty acid esters, polysorbates, poloxamers, polyethylene glycol tocopheryl succinate, and phospholipids.

More specifically, the method described above refers to solutions and dispersions containing from 3 to 99.99% w / w of solvent (s) and 0.01 to 97% w / w of pharmaceutically active compound (s) (s). ) or 0.01 to 97% w / w of pharmaceutically suitable excipient (s). The invention also relates to a method as described above, wherein the solution or dispersion contains from 3 to 98.98% w / w of solvent (s), 0.01 to 96.99% w / w of pharmaceutically active compound (s) and 0.01 to 96.99% w / w of pharmaceutically suitable excipient (s). Furthermore, the solutions or dispersions described above may contain from 3 to 99.98% w / w of solvent, 0.01 to 96.99% w / w of pharmaceutically active compound, and 0.01 to 96.99% w / p of a polyol. More preferably, the solutions or dispersions described above can be prepared from 3 to 99.97% w / w of solvent, 0.01 to 96.98% w / w of pharmaceutically active compound, 0.01 to 96.98 % w / w of polyol, and 0.01 to 96.98% w / w of a surfactant. Furthermore, the invention relates to the above methods, wherein the solution or dispersion contains from 3 to 99.98% w / w of solvent, 0.01 to 96.99 w / w of pharmaceutically suitable excipient and 0, 01 to 96.99% w / w of a polyol, and to methods where the solution or dispersion contains from 3 to 99.98% w / w of water or water / ethanol mixtures, 0.01 to 96.99% w / w of phospholipid and 0.01 to 96.99% w / w of maltodextrin. The invention also relates to the above methods, wherein the solution or dispersion comprises from 3 to 99.98% w / w of solvent, 0.01 to 96.99% w / w of pharmaceutically active compound and 0, 01 to 96.99% w / w of a pharmaceutically suitable excipient. Furthermore, the invention relates to the above methods, wherein the solution or dispersion contains from 5 to 95% w / w of water or a mixture of water / ethanol, 1 to 91% of orlistate, 3.9 to 93 , 9% maltodextrin and 0.1 to 90.1% w / w of one or more pharmaceutically acceptable excipients as described above. An especially preferred version of the present invention refers to a method in which the solution or dispersion is obtained from 5 to 95% w / w of solvent, preferably water or water / ethanol mixtures, 1 to 91% w / p orlistate, 3.9 to 93.9% w / w maltodextrin and 0.1 to 90.1%

ES 2 269 441 T3 w / w of a polyoxyethylene fatty acid ester. Another preferred version of the present invention refers to the above methods where the solution or dispersion contains from 5 to 95% w / w of water or water / ethanol mixtures, 1 to 91% w / w of orlistate, 1 at 91% w / w of lipids, preferably trimyristin, 2.9 to 92.9% w / w of maltodextrin and 0.1 to 90.1% w / w of a polyoxyethylene fatty acid ester. Furthermore, the invention relates to the above methods, wherein the solution or dispersion contains from 3 to 99.98% w / w of isopropyl alcohol, 0.01 to 96.99 w / w of oseltamivir, and 0.01 at 96.99% w / w polymethacrylate.

Particularly, the above method relates to the preparation of compositions, the solution or dispersion is prepared by pouring the solvent or mixture of solvents into a mixer, e.g. eg, a planetary mixer or other suitable mixing device known in the art, optionally adding a surfactant or other suitable excipients and distributing them into the solvent or solvent mixture. After homogeneously dispersing, the pharmaceutically active compound (s) or the pharmaceutically suitable excipient (s), within the fluid, the final solution or dispersion is obtained by optional addition of a polyol or other suitable excipients, stepwise, and by stirring, mixing, scraping or kneading, continuously. Depending on the viscosity, the deglomerization of the particles can be optimized using e.g. eg, a homogenizer or ointment mill. The intrinsic size of the particles can be controlled by laser diffraction or with a "fineness gauge" (metal block with a graduated groove and a scraper). The sequence of the process steps is variable and can be changed if appropriate. The viscosity of the solutions or dispersions can be increased or decreased by adding one or more pharmaceutically suitable excipients.

In a preferred version of the present invention, expansion can be effected within a temperature range of 20 to 35 ° and a pressure reduction of 30 to 150 Torr, preferably 30 to 45 Torr. This can be improved by spraying the solution or homogeneous dispersion on plates or more preferably on sieves, screens or nets and placing them in a vacuum drying oven (or other suitable device already known in the art) which is tempered in the range of 20 at 35 ° C. With respect to the chosen temperature, reducing the pressure in the range of 30 to 150 or more preferably 30 to 45 Torr creates the desired expanded, dense structure without boiling. Of course, depending on the solvent used, or mixture of solvents, the temperature and pressure conditions can be varied with the condition that the evaporated liquid does not boil during the expansion step. According to the present invention, an optional drying and / or cooling step can be carried out in parallel or after the solidification of the expanded structure, by varying the temperature and / or pressure conditions.

A drying process can be an internal or external process and the drying temperature can be higher or lower than the expansion temperature. The drying pressure can be higher or lower than the expansion pressure. Drying can be done under vacuum, by heating, sublimation, vibration, fluidization, radiation, contact, convection, sonification, high frequency, dry gas (hot or cold) or with the help of some desiccants (i.e. organic solvents, silica gel) , or any other kind of well known technique that aids in the removal of the fluid, solvent or the saturated gas phase. In accordance with the present invention, after expansion and optional drying of the structure, an additional cooling step may be applied. The cooling temperature can be higher or lower than 0 ° C and lower than the drying temperature. The cooling process can be an internal or external process. Of course, the expansion, optional drying and / or cooling of the structure is carried out in several steps (in a batch process) or in different zones (in a continuous process). A continuous process can be carried out with a continuous vacuum drying belt, a vacuum drying cylinder or other suitable devices already known in the art.

The present invention also relates to the compositions obtainable by the above methods.

The compositions obtainable according to the present invention can be characterized by analysis, volume, density (preferably the bulk density of the crushed material), particle size distribution, surface measurement, relative humidity, level of residual solvent, content of solids, wettability, solubility, stability, disintegration time, release characteristics, X-ray diffraction, dynamic vapor absorption, microcalorimetry, thermogravimetry, differential scanning calorimetry, etc. Preferably, the expanded, immediately dried and ground compositions obtainable by the present invention are characterized by a residual solvent level between 0.1 and 99.9%, preferably between 1 and 10%, and more preferably between 2 and 5%. % w / w. The bulk density (per pour) is 0.1 to 0.9, preferably 0.2 to 0.8 and more preferably 0.3 to 0.6 g / cm³. The particle size distribution of these compositions, expressed as "d 'value (63.2%)", can be between 50 and 600, preferably between 200 and 400 pm.

Especially, the present invention relates to a pharmaceutical composition, containing from 0.2 to 10% w / w of waste water or water / ethanol mixtures, 1 to 96% w / w of orlistate, 3.7 to 98, 7% w / w of maltodextrin or maltitol and 0.1 to 95.1% w / w of one or more pharmaceutically acceptable excipients as described above, e.g. eg, a polyoxyethylene fatty acid ester. Furthermore, the present invention relates to a pharmaceutical composition containing from 0.2 to 10% w / w of residual isopropyl alcohol, 1 to 98.8% w / w of oseltamivir, and 1 to 98.8% w / w made of polymethacrylate.

The above compositions are characterized by a residual solvent level between 0.1 and 99.9% w / w, preferably between 0.2 and 10% w / w and more preferably between 1 and 5% w / w. The apparent density (per pour) is between 0.1 and 0.9, preferably between 0.2 and 0.8 and more preferably between 0.3 and 0.6 g / cm³. The size distribution of

ES 2 269 441 T3 particles of these compositions can be expressed as "d 'value (63.2%)" between 50 and 600, preferably between 200 and 400 pm.

Compositions obtainable according to the above methods can be blown, cut-crushed, sieved, ground, crumbled, pulverized or ground into a (free-flowing) powder. The powder can be mixed, blended, blended, granulated, compressed into tablets or processed with one or more pharmaceutically active compounds or pharmaceutically suitable excipients. The compositions can be processed into a fine powder, aerosol, powder, granule, pill, tablet, dragee, capsule, dry solution, dry syrup, dry emulsion, dry suspension, or others already known in the art.

Compositions obtainable according to the invention can be prepared directly in their final formulation and dosage form, respectively, and preferably directly in their packaging. The dosage form can be selected from the group consisting of a xerogel, a tablet or a capsule, although they cannot be limited to these. The dosage form can also be prepared directly in its container. The package can be selected from the group consisting of a blister, vial, jar, sachet or syringe, although they cannot be limited to these. The final product corresponding to the methods of the present invention can be a drug, medicine, vitamin, instant drink or medical device, although it cannot be limited to these mentioned.

Orlistate is preferably administered orally at 60 to 720 mg per day, in divided doses two or three times per day. Administration of 120 to 360 mg, more preferably 120 to 180 mg per day, of a lipase inhibitor, to a subject, preferably in doses divided into two or particularly three times per day, is preferred. The subject is preferably an obese or overweight human, that is, a human with a body mass index of 25 or greater. It is generally preferred that the lipase inhibitor is administered after approximately one to two hours after ingestion of a meal containing fat. Generally, for administration of a lipase inhibitor as defined above, it is preferred that the treatment is administered to a human who has a strong family history of functional dyspepsia and has a body mass index of 25 or greater.

Furthermore, the invention relates to the use of compositions defined below for the preparation of drugs, medicaments, vitamins, medical devices, etc. useful for the treatment and prevention of diseases as mentioned above.

The invention will now be illustrated in detail, by means of the following examples:

Examples Example 1

A) Dispersion

This example describes a composition according to the invention, which includes orlistate as a pharmaceutically active compound. The amount of solvent necessary for the preparation of the homogeneous dispersion is expressed as percent of dry mass (w / w). The original solvent content of the raw materials is not taken into consideration. This composition has been used to increase the flowability, wettability, dispersibility, efficacy and stability of the pharmaceutically active compound. Furthermore, it is possible to carry out an easy subsequent processing in the form of a powder or respectively in capsules or tablets (reducing the amount of maltodextrin to 80% and mixing the resulting powder with 3% polyethylene glycol).

Orlistate 10.0% w / w

Trimyristin 5.0% w / w

Polyoxyl 40 stearate 2.0% w / w

Maltodextrin 83.0% w / w

Water 22.5% w / w

B) Expansion

Using a syringe, 100 g of a homogeneous dispersion was sprayed onto a sieve (mesh size 0.5 mm) in several strokes. The sieve was placed in a vacuum drying oven (Heraeus VT 5050 EK) tempered at 25 ° C. The chamber pressure was lowered to 30 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG DPI 700). After 5 minutes, the expansion of the structure was terminated.

C) Drying

By measuring the temperature of the dough and the chamber (AOiP PJN 5210), these conditions were set for approximately 30 minutes. Then, maintaining the same pressure conditions, the temperature of the chamber was raised to 50 ° C. The process was stopped after a total of 90 minutes, when the temperature

ES 2 269 441 T3 of the mass reached the desired limit of 35 ° C. The residual solvent content can be adjusted according to the amount required for further processing.

Example 2

A) Dispersion

This example describes a composition according to the invention including oseltamivir as a pharmaceutically active compound. The amount of solvent necessary for the preparation of the homogeneous dispersion is expressed as percent of dry mass (w / w). The original solvent content of the raw materials was not taken into consideration. This composition was used to mask taste, to improve stability and shelf life, to reduce side effects and to prevent incompatibilities:

Oseltamivir 10.0% w / w

Polymethacrylate 90.0% w / w

Isopropyl alcohol 80.0% w / w

B) Expansion

100 g of homogeneous dispersion were sprayed onto a plate in several strokes. The plate was placed in a vacuum drying oven (Heraeus VT 5050 EK). At room temperature in the chamber the pressure was lowered to 45 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG DPI 700). After 5 minutes the expansion of the structure was finished.

C) Drying

Maintaining the same conditions of temperature and pressure, the expanded structure was completely dried in 180 minutes.

Example 3

A) Dispersion

This example describes a composition according to the invention, which includes a phospholipid as a suitable pharmaceutically excipient. The amount of solvent necessary to prepare the homogeneous dispersion is expressed as percent dry mass (w / w). The original solvent content of the raw materials was not taken into consideration. This composition was used to prevent stability and incompatibility problems.

Lecithin 30.0% w / w

Maltodextrin 70.0% w / w

Water 40.0% w / w

B) Expansion

100 g of the homogeneous dispersion was sprayed onto a sieve (mesh size 0.5 mm) in several strokes. The screen was placed in a vacuum drying oven (Heraeus VT 5050 EK). At room temperature, the chamber pressure was lowered to 30 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG DPI 700). After 5 minutes, the expansion of the structure was finished.

C) Drying

By measuring the temperature of the dough and the chamber (AOiP PJN 5210) these conditions were set for approximately 30 minutes. Then, maintaining the same pressure conditions, the temperature of the chamber was raised to 35 ° C. The process was stopped after a total of 120 minutes.

Example 4

Directly prepared dosage form

A) Dispersion

This example describes a placebo composition and respectively the direct preparation of its final dosage form according to the invention, including maltodextrin and hydroxypropylmethyl cellulose as pharmaceutically suitable excipients. The amount of solvent required for the preparation of the homogeneous dispersion

ES 2 269 441 T3 is expressed as percent dry mass (w / w). The original solvent content of the raw materials was not taken into consideration. This composition was used to demonstrate the ease of manufacture, stability and uniformity of weight of dosage forms prepared directly in a blister pack:

Maltodextrin 20.0% w / w

Hydroxypropylmethylcellulose 20.0% w / w

Water 60.0% w / w

B) Expansion g of a homogeneous dispersion (dose: 325 mg dry mass) were poured into the trays of PVC blister packs for tablets. After covering with a sieve (mesh size 0.5 mm), the blister packs were placed in a vacuum drying oven (Heraeus VT 5050 EK). At room temperature, the chamber pressure was lowered to 75 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG DPI 700). After 15 minutes the extension of the structure was finished.

C) Drying

By measuring the dough and chamber temperature (AOiP PJN 5210), the chamber temperature was then increased to 50 ° C for about 120 minutes.

The dry, easily dried foam tablets peeled easily from the upturned blister pack, exhibited a smooth surface, good physical stability and respectively low friability, and satisfactory weight uniformity (n = 10; mv = 323.7 mg; sd = ± 2.6%).