Method for preparing composition

FIELD: pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions in the form of cellular mechanically stable, lamellar, porous, spongy or foam-like structures and to a method for their preparing from solutions and dispersions. Method involves carrying out the following stages: a) preparing a solution or homogenous dispersion liquid and compound taken among the group including one or some pharmaceutically active compounds, one or some pharmaceutically acceptable additives and their mixtures, and the following stage b) foaming solution or homogenous dispersion at reducing pressure 30-150 torrs without boiling. Invention provides stabilizing the composition.

EFFECT: improved preparing method.

38 cl, 4 ex

 

The present invention relates to a method of preparation of the compositions, preferably pharmaceutical compositions, in the form of aerated mechanically resistant, layered, porous, spongy, or prepodobnykh structures from solutions and dispersions. This method involves the following stages (a) preparation of a solution or a homogeneous dispersion of liquids and compounds, selected from the group comprising one or more pharmaceutically active compounds, one or more pharmaceutically acceptable additives and their mixtures, and the subsequent b) foaming solution or homogeneous dispersion without boiling. The invention also relates to compositions, to their further processing and to all relevant medications that can be obtained by a specified method.

In pharmaceutical technology work on the preparation of the compositions to the greatest extent due to the physico-chemical properties of pure active medicinal substance (the size and shape of particles, fluidity, compressibility, polymorphism, wettability, melting point, stability, shelf life etc) or other important supplements. On the market of pharmaceutical products is well known for many dosage forms, of which the most important are tablets and capsules. In order to stabilize very sensitive drug what s means, you want to use or introduce into the body orally or parenterally after re-hydration, the most interesting are dry solutions or dispersions (for example, suspension, emulsion).

Gradual progressive advancement of pure drug is ready for market the drug usually includes several basic operations, such as grinding, classification by particle size, wet or dry granulation, slugging, encapsulation, etc. currently, many of these processes are designed to produce large quantities of material, such as high-speed tableting. Thus the material reported the mechanical energy released during the impact, pressure or shear forces. Very often this leads to melting, decomposition of the drug substance or the loss of activity. Caused by such deposition or formation of deposits can cause the interruption of the process or even equipment failure.

In order to simplify the manufacturing process of the pharmaceutical form of the medicinal ingredient is usually mixed, combined or granularit with various pharmaceutical additives, such as lubricants, fillers, binding agents, agents for imparting mobility, dispersing agents, etc. Such add and enter to influence the properties of the final composition, but they can only partially protect against mechanical energy, or even lead to stability issues.

It is also assumed that the final composition, as well as the appropriate dosage form, have very specific properties before, during or after application. For bulk materials (powders, granules, pills, tablets, etc.) during storage requires high stability and compatibility. Dry suspension must be fully dispersible in liquids; tablets after their ingestion should disintegrants either very quickly or very slowly.

Sufficient wettability of the particles of the drug in the gastric juice and intestinal fluid is a prerequisite for good solubility and absorption. As dosed by volume, pharmaceutical powders or granules must have sufficient bulk density for tableting or encapsulating. Depending on the dose of these important glenavy properties can have a very bad effect the presence of drug or Supplement with unacceptable physical and chemical properties (for example, low melting point, low solubility, and so on).

Therefore, the route of administration of pharmaceutically active compounds or pharmaceutically acceptable the additives (additives) in Galanova composition or preparation is the most important factor, which must be controlled in order

to mask undesirable properties

to stabilize, to ensure inertness and protect critical input connection

to achieve optimum mobility and density for subsequent processing operations,

to give the required dispersibility and to ensure the manifestation of characteristics during or after administration etc.

In order to improve some of these properties, in the art there are some well-known technology, but very often their implementation not only allows you to fix all problems, and perhaps cause new because

the coating in the fluidized bed is unacceptable for substances with low melting points or for fine and light particles with very large specific surface area and a cylindrical or needle shape; powder processes (co)precipitation (for example, when drying spray) still contain significant amounts of reactive material on the surface of the particle;

drying by freezing is associated with very high costs and unacceptable for substances that are sensitive to cycles of freezing/thawing;

the operation of the spray by solidification, melting around the filling or extrusion of the melt is possible only what about in relation to the heat-resistant material.

In the application WO 96/40077 (firm Quadrant Holdings Cambridge Limited) describes a method for thin foamed glass matrices, including the stage (a) initial preparation of a mixture containing at least one glass forming matrix material and at least one solvent comprising a solvent for forming a glass matrix material, (b) evaporation of a mixture of the greater part of the solvent to obtain a concentrated solution, (C) exposure to concentrated solution at a pressure and temperature sufficient to cause boiling concentrated solution, and (d) optional removal of residual moisture.

In the application WO 98/02240 (firm Universal Preservation Technologies) described a method of protecting sensitive biologically active dispersions, suspensions, emulsions and solutions preparation of a stable foam from a liquid material that must be degidratiruth order as assist in the drying of one or more biologically active principles in liquid and assist in the preparation of easily dividend dried product that is acceptable for further technical use. Stable foam is prepared by partial removal of water to obtain a viscous liquid and subsequent processing of the reduced volume of liquid under vacuum to raise its boiling in the subsequent drying at temperatures significantly below 100°C. in Other words, viscous solutions or suspensions of biologically active materials act reduced pressure to cause foaming of these solutions or suspensions during the boil and take advantage of the additional removal of the solvent in the foaming process to obtain eventually a stable foam material with open pores and closed pores.

However, in both these links as a necessary stage of the preparation of the respective compositions are invited boiling. In addition, the first such mixtures, solutions, emulsions or dispersions should be concentrated by evaporating most of the solvent to obtain the desired for subsequent use concentrated solution (low vacuum; <30/<24 Torr). Then after getting concentrated solution of sufficient viscosity foaming (expansion of the structure) is conducted under conditions of temperature and pressure, which cause the boiling of this concentrated solution.

Sinnamon and others (J. Dairy Sci. 40, 1957, 1036-1045) describe the properties of the new dried whole milk, dried under high vacuum and at low temperatures, in the form of a porous, sponge-like structure. The resulting product is easily dispersed in cold water and in fresh condition after recovery has estestvennymi taste data. However, this method was developed to improve the dispersive ability of the pigment and taste properties of food products such as milk powder. The lack of the necessary conditions is the initial stage of concentration (up to 50 wt.% dry matter), which is required for the subsequent foaming process. Achieving the necessary "expanded", the honeycomb structure is possible only when bubbling nitrogen through such concentrated milk.

Schroeder (Ph. D., thesis, entitled "Entwicklung von kompakten Darreichungsformen aus sprehgetrockneten Milcherzeugnissen zur spontanen Rekonstitution", 1999) describes mainly the development of technology, the implementation of which allows you to demulsibility dairy or non-dairy foods without changing existing properties originally obtained by spray drying powdered products during recovery. However, the described method of drying under vacuum hydrated powders is carried out in conditions (50°C/37,5 Torr), which cause the boiling water entered while creating the desired cellular structure.

Thus, a task that became the basis for the creation of the present invention is the development of a new method and new compositions, the use of which allows to reduce to the minimum the above-mentioned disadvantages.

In accordance with the present invention this task allows the exit implementation of the method of preparation of the pharmaceutical composition, includes the following stages:

a) preparation of a solution or a homogeneous dispersion of liquids and compounds, selected from the group comprising one or more pharmaceutically active compounds, one or more pharmaceutically acceptable additives and their mixtures, and then

b) foaming solution or homogeneous dispersion without boiling.

It was found that the preparation of homogeneous quite viscous solutions or dispersions prior to the stage of expansion is feasible and creates some advantages in comparison with the technologies presented as prior art, including

the lack of pre-evaporating most of the solvent, which is necessary for creating the appropriate conditions for foam concentrate;

the continuity of the process that leads to high performance;

immediate (continuous process) or after a few minutes (periodic process) necessary cooperation to the development of structure during the stage of foaming;

the course of the foaming process even under pressure that is less than critical (>30 Torr at room temperature), so that the boiling of the concentrate is not an indispensable precondition;

easy foaming and solidification of highly concentrated pharmaceutically what songs inside their containing shell capsules, blister packaging, etc. due to low filling of the volume.

Examples achieved as a result of advantages and opportunities in relation to physicochemical and biopharmaceutical properties serve as protection and stabilization of pharmaceutically active compounds or pharmaceutically acceptable additives during processing and storage; increased shelf life; elimination of incompatibilities, because depending on the material used for placement of the required physico-chemical properties can be achieved regardless of the initial properties; finite morphology or the gradual transformation (i.e. improved wettability, mobility, solubility, etc.); taste masking properties; weakening side effects; increased biological availability (especially for pharmaceutically active compounds, hardened as the amorphous glass) and/or regulation of the release characteristics.

In all cases, unless otherwise stated, the following definitions serve to illustrate, specify the value and volume covered by the various concepts used to explain the entity presented in this description.

The concept of "solution" used in the present description as referring to the physical system consisting of at meradog compounds, in which all connections are mutually distributed at the molecular level and appear as a single phase.

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

The term "pharmaceutically acceptable" is used in this description as meaning that the substances applied are acceptable from the standpoint of toxicity.

The concept of "boiling" refers to the evaporation of the liquid in the case, when the pressure that the environment on the liquid, compared with the pressure, which create vapors from the liquid; under this condition, the addition of heat or reduced pressure environment in the liquid leads to the transformation of a liquid into its vapor without raising the temperature.

The concept of "glass forming matrix material" refers to pharmaceutically active compounds or pharmaceutically acceptable additives, which after curing are in the amorphous state.

The concept used to place material" refers to substances that are able to cover, to contain, to divide, to protect or to provide inertness other materials.

The concept of "expansion" means an increase in objemail surface area of the solution or homogeneous dispersion, caused by the pressure change resulting material is characterized by a coherent, layered, porous, spongy, or kicsomagolni structure.

The term "polyol" in the context of describing the present invention relates to material not included in the group of carbohydrates, such as maltodextrin.

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

The term "polymer" refers to a material which is a macromolecular (natural or synthetic) material. He may be a homopolymer (i.e. polyethylene glycol) or copolymer (i.e., polymethacrylate).

The term "lipase inhibitor" refers to compounds that can inhibit the action of lipases, such as lipases in the stomach and pancreas. For example, potent inhibitors of lipases are orlistat and lipstatin as set forth in US 4598089. Lipstatin is a natural product of microbiological origin, and orlistat is the product of hydrogenation of lipstatin. Other lipase inhibitors include compounds of the class known as anglicani. Anglicani are analogues of orlistat [Mutoh etc., J. Antibiot., 47(12): 1369-1375 (1994)]. The term "lipase inhibitor" also refers to synthetic inhibitors of lipases described, for example, in WO 99/34786 (firm Geltx Pharmaceuticals Inc.). These polymers are characterized by the fact that each of them is substituted by one or more groups, which inhibit the action of lipases. In addition, the term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" also refers to 2-oxy-4H-3,1-benzoxazin-4-ones, which are described in WO 00/40569 (firm Alizyme Therapeutics Ltd.), for example, 2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one, 6-methyl-2-tetradecenoic-4H-3,1-benzoxazin-4-one and 2-hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one. In the most preferred embodiment, the term "lipase inhibitor" refers to orlistat.

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

The proposed method does not necessarily carry out the drying and/or cooling of the composition. This method is particularly effective in the preparation of pharmaceutical compositions.

In a preferred embodiment, the solution or homogeneous dispersion of the foamed decompression.

In a preferred embodiment, the solution or homogeneous dispersion is prepared using a liquid pharmaceutically active compound or pharmaceutically acceptable additives. In a preferred embodiment, such a solution or dispersion prepared by adding liquid as pharmaceutically active washes the VA, and pharmaceutically acceptable additives.

When implementing the above method, the liquid used should be easily evaporated or is able to evaporate, it is possible to choose from a group comprising water (i.e. purified, deionized, distilled or sterilized water), aqueous buffer solutions or isotonic solutions (i.e. bicarbonate buffer with a pH 7,38), culture medium or the culture fluid (i.e. peptone broth), alcohols (i.e. ethanol or isopropyl alcohol), ketones (i.e. acetone), ethers (i.e. diethyl ether), liquid hydrocarbons (i.e. octane), oils (i.e. essential oils, such as chamomile oil) and synthetic materials (i.e. plasma substitutes, such as dextrans), but the list may not be limited. When implementing the method according to the present invention can also be used mixtures of the above liquids. The preferred liquid is an aqueous buffer and/or saline.

Homogeneous dispersion may be in the form of a colloid, Sol, gel, liquid crystal, emulsions, pastes, suspensions or ointments.

The solution or homogeneous dispersion can be prepared by pouring a liquid or mixture of liquids in a planetary mixer (or comparable), followed by dissolving and/or dispersing pharmaceutically active connection is the link (connection) or pharmaceutically acceptable additives (additives) in a fluid or mixture of fluids to the formation of homogeneous dispersion. In the process of mixing with the liquid or liquid mixture material (s) may be in a dry condition, to be dissolved, dispersed or melted. At the same time or after that, you can add other compounds, additives and liquids.

Alternatively, the solution or homogeneous dispersion can be prepared by loading pharmaceutically active compounds (compounds), pharmaceutically acceptable additives (additives) or their mixture in a planetary mixer (or comparable) with subsequent wetting, dissolution and/or dispersion of the material (materials) using a solvent or mixture of solvents to form a solution or a homogeneous dispersion. At the same time or after that, you can add other compounds, additives and liquids.

To improve the homogeneity of the solution or dispersion, particularly when the dry matter content is very high, the process of mixing or dispersion can be facilitated by use of a static mixer, microfluidizer, homogenizer, mixing devices, wysokosciowe efforts, ultrasound, mills for the preparation of ointments or other devices known in the art. The viscosity of a homogeneous solution or dispersion can be either low or high, provided that the mass remains Ave is suitable for filing or distribution.

The solution or dispersion is transformed into cellular structure by exposure to pressure changes, such as the creation of a vacuum or blowing in the vacuum and drying thereby, or by introduction into contact, by convection, radiation, sonification, the electromagnetic field of high frequency, dry (hot or cold) gas or with some drying substances such as organic solvents, silica gel, etc. If more, then this homogenized solution or dispersion usually upload, submit, distribute or place or on the plate, sieve, belt, roller, etc. or in the shell of a capsule, blister packaging, bottle, jar, syringe or other suitable container forms. Then almost immediately (continuous process) or after a short period of time (periodic process) adjustable pressure change leads to the formation of cellular structure. For excellence in the density of the finished, hardened material acceptable conditions of low pressure, in the range of 30 to 150 Torr. Depending on the liquid or mixture of liquids and the selected temperature foaming can be carried out by regulating the pressure conditions in such a way as not to cause boiling homogenized solution or dispersion. Depending on composities achieve the target residual solvent at the same time or after the stabilization of the cellular structure can be varied according to the pressure conditions, you can change the temperature or apply any drying method known in the art. The drying process may be internal or external, it can contribute to vibration, fluidizable or using well-known techniques of any kind, the implementation of which contributes to the removal of the liquid solvent or saturated gas phase. The above variation of the conditions of temperature and/or pressure can be done in several stages (batch) or in different zones (continuous process), which can enable the final stage of cooling.

To achieve the target shape, density and stability of the cellular structure of the liquid boiling should be avoided. The dried and optionally cooled structure is characterized by a long shelf life, it can be easily cut, crush, respectively finely ground to engineering powder, which, on the one hand, provides the opportunity to simplify subsequent processing, like for example wet or dry agglomeration, granulation (possibly from the melt), clumping, pelletizing, extrusion, fabrication crumbs, or encapsulating the process of packing of any kind, and on the other hand, the ability to demonstrate excellent ability to recover in cold or brought to the right when standing liquids or contained in the body of water, thus keeping properties and the effectiveness of any posted material pharmaceutically active compounds or pharmaceutically acceptable additives. The implementation described a new method of preparation of the pharmaceutical compositions also provides the possibility of creating a mesh sufficiently dense structure with its direct final composition or in the form of a ready to use package.

The initial process of creating and drying of the honeycomb structure can be periodic (e.g., in a vacuum drying Cabinet), or continuous (for example, a drying belt conveyor), or by using other techniques known in the art.

In a preferred embodiment, the connection stage (a) is a pharmaceutically active compound. In another preferred embodiment, the connection stage (a) is a pharmaceutically acceptable additive.

More specifically, an object of the present invention is a method for preparing a pharmaceutical composition, comprising the following stages:

a) preparing a homogeneous solution or dispersion by mixing the pharmaceutically active compound and/or pharmaceutically acceptable additives with the liquid or liquid mixture in sufficient quantity to create a homogeneous dispersion,

b)impact on the variance of the change in pressure without boiling and

C) optionally drying and/or cooling of the composition.

The above methods can also include stage a) preparation of a solution or a homogeneous dispersion by mixing the pharmaceutically active compound and/or liquid or mixture of liquids in sufficient quantity to create a solution or homogeneous dispersion, b) impact on the solution or dispersion pressure change without boiling, and C) optional drying and/or cooling of the composition.

The above method is especially suitable for the preparation of pharmaceutical compositions. A list of acceptable for carrying out the method of pharmaceutically active compounds is not limited to any specific group. It is assumed that the above method of preparation of pharmaceutical compositions is essentially a powerful tool for solving physical-chemical, herbal or pharmaceutical problems that can occur any time during or after the creation of the relevant pharmaceutical products (i.e. medicines, drugs, vitamins, devices for medical purposes). However, particularly preferred compounds intended for use when carrying out the above method, are inhibitors of lipases, preferably orlistat.

Orlistat, also known as inhibitor of the action of gastrointestinal lipases, is a known compound that can be used to fight or prevent obesity and hyperlipidemia (see U.S. patent No. 4598089, issued July 1, 1986, which also describes how to get orlistat, and U.S. patent No. 6004996, which describes the corresponding pharmaceutical compositions). Other acceptable pharmaceutical compositions are described, for example, in WO 00/09122 and WO 00/09123.

Other examples of pharmaceutically active compounds are neuraminidase inhibitors such as oseltamivir and insulin sensitizing substances, in particular 5-[7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzothiophen-4-methyl]-2,4-thiazolidinedione or its sodium salt. These connections in the art are known and described, for example, in European patent applications No. 96912404.9 and 99117934.2 and in WO 94/27995.

In a preferred embodiment of the present invention the above-mentioned solution or dispersion further includes containing the filling or forming a glass matrix material. Preferred containing the filling or forming a glass matrix material is a polyol, gum, polymer or its pharmaceutically acceptable salt.

Containing the filling or forming a glass matrix material may be farmaci is automatically active connection highly dispersed in the crystalline form, respectively solidified in an amorphous state or a pharmaceutically acceptable additive, preferably a polyol, such as a carbohydrate. Containing the filling or forming a glass matrix material may be amorphous or partially or fully crystalline.

Carbohydrate as pharmaceutically acceptable additives may be selected from the group including, for example, maltodextrin, trehalose, cellobiose, glucose, fructose, maltose, isomaltulose, lactulose, maltose, gentiobiose, lactose, isomaltose, ▫ maltitol, lactic, aritra, platinet, xylitol, mannitol, sorbitol, dulcet and ribitol, sucrose, raffinose, gentians, planteose, verbascose, stachyose, melezitose, dextran and additionally Inositol, but their list may not be limited. In a preferred embodiment, the carbohydrate is a maltodextrin. In another preferred embodiment, the carbohydrate is a trehalose. In another preferred embodiment, the carbohydrate is a ▫ maltitol. In a preferred embodiment, the term "maltodextrin" refers, for example, to the product Glucidex Roquette, the preferred meaning of "trehalose" is, for example, the product Trehalose Merck, and the preferred meaning of " ▫ maltitol is, for example, the product Maltisorb Roquette.

Other pharmaceutically acceptable the e for use of the additive can be selected from the group of polymers, gums and their salts, such as polyethylene glycol; modified and substituted starches (e.g., starch, swelling in cold water, gidroxiatilkrahmal, nationalassociate starch, inulin, etc.); modified and substituted cellulose (for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, acetic ether and phthalic acid cellulose, etc.); povidone (polyvinylpyrrolidone); polyvinyl alcohol; resin of acacia; carbomer; alginic acid; cyclodextrins; gelatin; guerova gum; Kelcogel® (polysaccharide obtained by fermentation); Kelco-Crete® (polysaccharide obtained by fermentation); gum of cesalpinia barbed; carob bean gum; fiber (i.e. pectin); karragenana gum; glucomannan; polymethacrylates; propilenglikolstearat; shellac; sodium alginate; tragacanth gum, xanthan gum and chitosan, but the list may not be limited.

Some of these materials can be fully amorphous or may also be partially or fully contained in the crystalline state.

The above method can also be applied in the preparation of pharmaceutical compositions, which is contained in pharmaceutically acceptable additive preparing is in accordance with the above-described method. Any additive that is pharmaceutically acceptable for implementing the method of this kind, in General you can choose from all possible groups adjuvants that promote transformation of pharmaceutically active compounds in containing the finished composition, modify or optimize its effectiveness, change its properties, immobilizer its molecules or maintain its stability. The invention can be applied to improve the required properties of the inert pharmaceutically acceptable additives, as well as for masking undesirable properties. Some of pharmaceutically acceptable additives preferred groups include compounds selected from solvents, solubilization, substances contributing to the dissolution of salt-forming agents, salts (volatile), buffers, agents that cause foaming, stabilizing agents, gelatinizing agents that lower the surface tension of the substances, lipids, fatty acids, antioxidants, synergists, chelating agents, preservatives, fillers, dry diluents, carriers, adsorbents, binders, chemicals, giving friability, substances, giving the ability to glide, lubricating substances, substances that promote division, agents, giving mobility, substances for coating, retardery agents (retarding agents), the dye is, pigments, regulation means smell and taste masking additives, substances that promote absorption, the means of humidity control, flocculants, etc.

Specifically, the object of the invention is the above methods in which the pharmaceutically active compound selected from the group including, for example, molecules, drugs, vitamins, mineral substances, trace elements, enzymes, cells, serum, vaccines, proteins, viruses, bacteria, nucleic acids, complex compounds, liposomes and nanoparticles, but the list may not be limited.

The object of the present invention are mainly the ways in which the solution or dispersion comprises lowering the surface tension of the substance. In the context of describing the present invention reduce the surface tension of the substances classified as pharmaceutically acceptable additives with emulsifying, stabilizing, solubilizers, wetting, defoaming, or facilitate the distribution of properties. These adjuvant have amphiphilic character and influence of interfacial tension at the boundary between different phases. The concept of "lowering the surface tension of the substances" covers anionic lowering the surface tension of the substances or simulatory (i.e. surfactants, sulfonates, laurilsulfate sodium, the docusinate sodium, sodium casein, salts of fatty acids), cationic lowering the surface tension of the substance (i.e. Quaternary amines, cetylpyridinium), nonionic lowering the surface tension of the substance (i.e. polyoxyethylene esters of fatty acids, for example the product Polyoxyl 40 stearate, esters of sucrose and fatty acids, cetyl alcohol, fatty acid esters, cetosteatil alcohol, cholesterol, sorbitane esters of fatty acids, Polysorbate, poloxamer, tocopherolacetate) and amphoteric lowering the surface tension of the substance (i.e. phospholipids, ampholytes, proteins). In a preferred embodiment, lowering the surface tension of the substance is polyoxyethylene ether fatty acids. In another preferred embodiment, lowering the surface tension of a substance is a phospholipid. Preferred lowering the surface tension of a substance chosen from the group comprising sodium lauryl sulfate, sodium docusinate, sodium casein, salts of fatty acids, Quaternary amines, cetylpyridinium, polyoxyethylene esters of fatty acids, esters of sucrose and fatty acids, cetyl alcohol, fatty acid esters, cetosteatil alcohol, cholesterol, sorbitane esters of fatty acids, Polysorbate, poloxamer, tocopherylacetate and postlip is water.

More specifically, the above method applies to solutions and dispersions comprising from 3 to 99.99 wt.% solvent (solvent) and from 0.01 to 97 wt.% pharmaceutically active compounds (compounds) or from 0.01 to 97 wt.% pharmaceutically acceptable additives (additives). The object of the invention is also the above method, in which the solution or dispersion comprises from 3 to of 99.98 wt.% diluent (s), from 0.01 to 96,99 wt.% pharmaceutically active compounds (compounds) and from 0.01 to 96,99 wt.% pharmaceutically acceptable additives (additives). Moreover, the above solution or dispersion may contain from 3 to of 99.98 wt.% solvent, 0.01 to 96,99 wt.% pharmaceutically active compound and from 0.01 to 96,99 wt.% polyol. In a more preferred variant of the above solutions or dispersions can be prepared using from 3 to of 99.97 wt.% solvent, 0.01 to 96,98 wt.% pharmaceutically active compounds from 0.01 to 96,98 wt.% polyol and from 0.01 to 96,98 wt.% lowering the surface tension of the substance. Moreover, the object of the invention is the above methods in which the dispersion comprises a solution or dispersion comprises from 3 to of 99.98 wt.% solvent, 0.01 to 96,99 wt.% pharmaceutically acceptable additives and from 0.01 to 96,99 wt.% polyol, and the ways in which the solution or dispersion comprises from 3 to of 99.98 the AC.% water or mixtures of water/ethanol, from 0.01 to 96,99 wt.% phospholipid and from 0.01 to 96,99 wt.% maltodextrin. The object of the invention are also described ways in which the solution or dispersion comprises from 3 to of 99.98 wt.% solvent, 0.01 to 96,99 wt.% pharmaceutically active compound and from 0.01 to 96,99 wt.% pharmaceutically acceptable additives.

In addition, the object of the invention is the above methods in which the solution or dispersion comprises from 5 to 95 wt.% water or a mixture of water/ethanol, from 1 to 91% of orlistat, from 3.9 to 93.9% maltodextrin and from 0.1 to 90.1 wt.% one or more pharmaceutically acceptable additives, as they are presented above. In a particularly preferred embodiment of the present invention, its object is the way in which the solution or dispersion is prepared using from 5 to 95 wt.% solvent, preferably water or mixtures of water/ethanol, 1 to 91 wt.% orlistat, from 3.9 to 93.9 wt.% maltodextrin and from 0.1 to 90.1 wt.% polyoxyethylene ether fatty acids. In yet another preferred embodiment of the present invention it is above methods in which the solution or dispersion comprises from 5 to 95 wt.% water or mixtures of water/ethanol, 1 to 91 wt.% orlistat, from 1 to 91 wt.% lipids, preferably trimyristin, from 2.9 to 92,9 wt.% maltodextrin and from 0.1 to 90.1 wt.% polyoxyethylene what about the ether fatty acids. Moreover, the object of the invention is the above methods in which the solution or dispersion comprises from 3 to of 99.98 wt.% isopropyl alcohol, from 0.01 to 96,99 wt.% oseltamivir and from 0.01 to 96,99 wt.% polymethacrylate.

The above method is applicable mainly in the preparation of compositions; the solution or dispersion is prepared by pouring the solvent or solvent mixture in a mixer such as a planetary mixer or other suitable mixing device known in the art, optional addition of lowering the surface tension of the substances or other acceptable additives and their distribution in the solvent or solvent mixture. After a homogeneous dispersion in a liquid pharmaceutically active compounds (compounds) or pharmaceutically acceptable additives (additives) of the final solution or dispersion complement optional phased by adding a polyol or other acceptable additives and continuous mixing, mixing, applying scraping or mixed. Depending on the viscosity of desagglomeration particles can be optimized using, for example, a homogenizer or mill for the preparation of ointments. Inherent in the particle size can be controlled by diffraction of a laser beam or an instrument for determining the degree of grinding (metal BL is to graduated with a groove and a scraper). The sequence of process steps can, if it is acceptable to vary or change. The viscosity of solutions or dispersions can be increased or decreased by adding one or more pharmaceutically acceptable additives.

In a preferred embodiment of the present invention, the foaming can be carried out in the temperature interval from 20 to 35°and under reduced pressure of 30 to 150 Torr, more preferably from 30 to 45 Torr. This can be achieved by the distribution of the solution or homogeneous dispersion on the plates, or more preferably on the sieves, screens or grids and place them in a vacuum drying Cabinet (or other suitable device known in the art), which keep the temperature in the range from 20 to 35°C. regarding the choice of the temperature, a lower pressure before the interval from 30 to 150 and more preferably from 30 to 45 Torr leads to the establishment of the cellular structure of the target density without boiling. Depending, of course, on the solvent or solvent mixture to conditions of temperature and pressure can be varied, suggesting that during the stage of foaming evaporating the liquid does not boil. In accordance with the present invention in parallel or after hardening of the honeycomb structure by varying conditions of temperature and/reavley you can make an optional stage of drying and/or cooling.

The drying process can be performed as an internal or external process, and the drying temperature may be higher or lower than the temperature of the foaming. Pressure drying can be higher or lower pressure foaming. The drying process can be facilitated by creation of a vacuum, heating, sublimation, vibration, fluidizable, radiation, introduction to contact, by convection, ultrasound, electromagnetic field of high frequency, dry (hot or cold) gas or with some drying substances (i.e., organic solvents, silica gel and so on), using well-known techniques of any kind, the implementation of which contributes to the removal of the liquid solvent or saturated gas phase. In accordance with the present invention after foaming and optional drying patterns you can implement an additional stage of cooling. The cooling temperature may be above or below 0°and below the drying temperature. The drying process can be performed as an internal or external process. The process of foaming, an optional drying and/or cooling patterns hold, of course, in several stages (batch) or in different zones (continuous process). A continuous process can be performed using vacuum drying belt conveyor, drying vakuumnaya or other suitable devices, known in this technical field.

The object of the present invention are also compositions which can be prepared by the above methods.

Compositions which can be prepared according to the present invention, can be characterized by quantitative analysis, volume, density (preferably by bulk density of crushed material), the distribution of particle size, surface properties, relative humidity, residual solvent content, dry matter content, wettability, solubility, stability, time of disintegration, release characteristics, x-ray diffraction, dynamic vapor sorption, microcalorimetry, thermogravimetric, differential scanning calorimetry, etc. In a preferred embodiment, foam, quickly dried and powdered composition which can be prepared according to the present invention, are characterized by a residual solvent content in between 0.1 and 99.9%, more preferably between 1 and 10%, and most preferably within 2 and 5 wt.%. Volumetric (bulk) density is between 0.1 and 0.9, more preferably in the range of 0.2 and 0.8, and most preferably in the range of 0.3 and 0.6 g/cm3. In these compositions the distribution of particle size, expressed as VI is e values d’ (63,2%)", may be in the range of 50 to 600, more preferably in the range of 200 and 400 ám.

The object of the present invention mainly is a pharmaceutical composition, comprising from 0.2 to 10 wt.% residual water or a mixture of water/ethanol, 1 to 96 wt.% orlistat, from 3.7 to 98,7% by weight maltodextrine or maldita and from 0.1 to 95,1 wt.% one or more pharmaceutically acceptable additives, as they are presented above, for example polyoxyethylene ether fatty acids. Moreover, the object of the present invention is a pharmaceutical composition, comprising from 0.2 to 10 wt.% residual isopropyl alcohol, from 1 to 98,8% by weight oseltamivir and from 1 to 98,8% by weight polymethacrylate.

The above compositions are characterized by a residual solvent content between 0.1 and 99.9 wt.%, more preferably in the range of 0.2 and 10 wt.% and most preferably between 1 and 5 wt.%. Volumetric (bulk) density is between 0.1 and 0.9, more preferably in the range of 0.2 and 0.8, and most preferably in the range of 0.3 and 0.6 g/cm3. The distribution of particles in these compositions, which can be expressed in the form of values d' (63,2%)"may be in the range of 50 to 600, more preferably in the range of 200 and 400 ám.

Compositions which can be prepared in accordance with the above-described method, it is possible RA is to Rosati, grind the cutting, to sift, to grind in the mill, cut into small pieces, turn or finely grind in (engineering) powder. This powder can be mixed, merge, combine, pellet, tablet or processed together with one or more pharmaceutically active compounds or pharmaceutically acceptable additives. These compositions can be processed in the dust, aerosol product, powder, granules, pills, tablets, coated tablets, capsules, dry mortar, dry concentrate, dry emulsion, dry suspension or other preparative forms known in the art.

Compositions which can be prepared in accordance with the invention, can be prepared directly in the form of their respective finished formulations or dosage forms, and more preferably directly in the package for them. Dosage form can be selected from the group comprising a xerogel, tablet and capsule, but the list does not end there. Dosage form can also be prepared directly in a package for her. Packing can be selected from the group including blister packaging, bottle, jar, sachet and a syringe, but the list does not end there. The final product prepared in accordance with the methods of the present invention, can be a drug which means, drug, vitamin, drink from water soluble drug or device for medical purposes, but the list is not limited to this only.

In a preferred embodiment, the orlistat is administered orally at a daily dose of from 60 to 720 mg in the form of fractional doses for receiving two to three times a day. More preferably, when the subject of daily injected from 120 to 360 mg, most preferably 120 to 180 mg of a lipase inhibitor, preferably in the form of fractional doses for daily intake of two or predominantly three times. A preferred subject is a person suffering from obesity or overweight, i.e. people with a body mass index of 25 or higher. Usually in a preferred embodiment, the lipase inhibitor is administered for from about one to two hours after a meal containing fat. Usually for the introduction of a lipase inhibitor, as it is presented above, in the preferred embodiment, such a therapeutic agent is administered to humans, which is characterized by a pronounced hereditary functional dyspepsia and body mass index of 25 or higher.

Moreover, the object of the invention is the use of the following compositions in the preparation of medicines, drugs, vitamins, devices for medical purposes, etc. that can be used DL the treatment and prophylaxis of the aforementioned diseases.

The invention is further illustrated in detail by the following examples.

EXAMPLES

Example 1

A) Dispersion

This example describes a composition in accordance with the invention as pharmaceutically active compounds containing orlistat. The amount of solvent required to prepare a homogeneous dispersion, expressed in percent by weight of dry substance (wt.%). The initial solvent content in the raw materials in the calculation did not take. This song used to improve the flowability, wettability, dispersive ability of the pigment, the efficiency and stability of the pharmaceutically active compounds. In addition, there was the possibility of a simple further processing into powder in the form respectively of capsules or tablets (decreasing the amount of maltodextrin to 80%, and mixing the obtained powder with 3% polyethylene glycol).

Orlistat10.0 wt%
Trimyristin5.0 wt.%
Product Polyoxyl 40 stearate2.0 wt.%
Maltodextrin83,0 wt.%
Water22.5 wt.%

B) Foaming

With the help of syringe 100 g of a homogeneous dispersion in tracks distributed on the sieve (mesh size 0.5 mm). The sieve on which emali in a vacuum drying oven (Heraeus VT 5050 EC), in which was set a temperature of 25°C. the chamber Pressure was reduced to 30 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG 700 DPI). After 5 min, the foam structure was completed.

C) Drying

Thanks to the determination of mass and temperature in the chamber (AOiP PJN 5210) these conditions are maintained for about 30 minutes Then, while maintaining the same pressure conditions, the temperature in the chamber was increased to 50°C. after a total of 90 min, the process was stopped, after which the temperature of the mass reached the target limit, 35°C. the Final solvent content can be adjusted according to the desired level for further processing.

Example 2

A) Dispersion

This example describes a composition in accordance with the invention as pharmaceutically active compounds including oseltamivir. The amount of solvent required to prepare a homogeneous dispersion, expressed in percent by weight of dry substance (wt.%). The initial solvent content in the raw materials in the calculation did not take. This song was used with the purpose of masking of taste, to improve stability and increase shelf life, to reduce side effects and to avoid incompatibilities.

Oseltamivir10.0 wt.%
On methacrylat to 90.0 wt.%
Isopropyl alcohol80,0 wt.%

B) Foaming

100 g of a homogeneous dispersion in tracks distributed on the plate. The plate was placed in a vacuum drying oven (Heraeus VT 5050 EC). At room temperature the pressure in the chamber was lowered to 45 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG 700 DPI). After 5 min, the foam structure was completed.

C) Drying

Maintaining the same conditions of temperature and pressure, a honeycomb structure was dried in total, over 180 minutes

Example 3

A) Dispersion

This example describes a composition in accordance with the invention as a pharmaceutically acceptable additive comprising a phospholipid. The amount of solvent required to prepare a homogeneous dispersion, expressed in percent by weight of dry substance (wt.%). The initial solvent content in the raw materials in the calculation did not take. This song used to avoid problems of stability and incompatibility.

Lecithin30.0 wt.%
Maltodextrin70,0 wt.%
Water40.0 wt.%

B) Foaming

100 g of a homogeneous dispersion in tracks distributed on the sieve (mesh size 0.5 mm). the ito was placed in a vacuum drying oven (Heraeus VT 5050 EC). At room temperature the pressure in the chamber was lowered to 30 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG 700 DPI). After 5 min, the foam structure was completed.

C) Drying

Thanks to the determination of mass and temperature in the chamber (AOiP PJN 5210) these conditions are maintained for about 30 minutes Then, while maintaining the same pressure conditions, the temperature in the chamber was increased to 35°C. after a total of 120 min, the process stopped.

Example 4: direct the preparation of dosage forms

A) Dispersion

In the example described, respectively, direct the preparation of compositions placebo in its finished dosage form in accordance with the invention, comprising maltodextrin and as pharmaceutically acceptable additives hypromellose. The amount of solvent required to prepare a homogeneous dispersion, expressed in percent by weight of dry substance (wt.%). The initial solvent content in the raw materials in the calculation did not take. This song was used with the purpose to illustrate the adaptability, stability and homogeneity of the mass by direct preparation of dosage forms in the form of a blister pack.

Maltodextrin20.0 wt.%
The hypromellose 20.0 wt.%
Waterby 60.0 wt.%

B) Foaming

50 g of a homogeneous dispersion was poured into the cavity PVC blister packaging for tablets (dose: 325 mg, calculated on the dry mass). After covering sieve (mesh size 0.5 mm) these blister packs were placed in a vacuum drying oven (Heraeus VT 5050 EC). At room temperature the pressure in the chamber was lowered to 75 Torr (Leybold Heraeus TRIVAC D8B; COMAT AG 700 DPI). After 15 min, the foam structure was completed.

C) Drying

Conditions in the chamber supported by the definition of mass and temperature (AOiP PJN 5210), then the temperature was raised to 50°and when it has stood for about 120 minutes

Quickly dried honeycomb tablets easily fell out of the inverted blister packaging, showed a smooth surface, good physical stability with low friability and satisfactory uniformity of weight (n=10; mv=323,7 mg; sd=±2,6%).

1. Method of preparation of a pharmaceutical composition, comprising the following stages:

a) preparation of a solution or a homogeneous dispersion of liquids and compounds, selected from the group comprising one or more pharmaceutically active compounds, one or more pharmaceutically acceptable additives and their mixtures, and then

b) spineuniverse or homogeneous dispersion by lowering the pressure to a level within about 30 150 Torr under the condition that the solution or homogeneous dispersion do not boil.

2. The method according to claim 1, after which carry out the drying and/or cooling of the composition.

3. The method according to any of claim 1 or 2, wherein a solution or a homogeneous dispersion of the foamed decompression.

4. The method according to claim 3, in which the pressure is in the range of 30 to 150 Torr.

5. The method according to any one of claims 1 to 4, in which the compound from step (a) is a pharmaceutically active compound.

6. The method according to any one of claims 1 to 5, in which the pharmaceutically active compound is a lipase inhibitor.

7. The method according to claim 6, in which the lipase inhibitor is a orlistat.

8. The method according to claim 5, in which the pharmaceutically active compound is a oseltamivir or 5-[7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzothiophen-4-methyl]-2,4-thiazolidinedione or its salt.

9. The method according to any one of claims 1 to 8, in which the solution or dispersion comprises containing the filling or forming a glass matrix material.

10. The method according to claim 9, which contains the filling or forming a glass matrix material is a pharmaceutically acceptable additive.

11. The method according to claim 10, which contains the filling or forming a glass matrix material is a polyol, gum, polymer or its pharmaceutically acceptable salt./p>

12. The method according to claim 11, in which the polyol is a carbohydrate.

13. The method according to item 12, in which the carbohydrate is selected from the group comprising maltodextrin, trehalose, cellobiose, glucose, fructose, maltose, isomaltulose, lactulose, maltose, gentiobiose, lactose, isomaltose, ▫ maltitol, lactic, aritra, platinet, xylitol, mannitol, sorbitol, dulcet and ribitol, trehalose, sucrose, raffinose, gentians, planteose, verbascose, stachyose, melezitose, acid and Inositol.

14. The method according to item 12, in which the carbohydrate is a maltodextrin.

15. The method according to item 12, in which the carbohydrate is a ▫ maltitol.

16. The method according to item 12, in which the carbohydrate is a trehalose.

17. The method according to claim 11, in which the gum, polymer or its pharmaceutically acceptable salt selected from the group including polyethylene glycol, modified and substituted starches, modified and substituted cellulose, povidone, polyvinyl alcohol resin of acacia, carbomer, alginic acid, cyclodextrins, gelatine, harowuiu gum, Kelcogel® (polysaccharide obtained by fermentation), Kelco-Crete® (polysaccharide obtained by fermentation), gum of cesalpinia barbed, carob bean gum, fiber, carragenine gum, glucomannan, polymethacrylates, propilenglikolstearat, shellac, sodium alginate, tragacanth gum, chitosan and xanthan Cam is d'.

18. The method according to 17, in which the modified or substituted starch is a starch, swelling in cold water, gidroxiatilkrahmal or nationalassociate starch.

19. The method according to 17, in which the modified or substituted cellulose is a methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose, sodium carboxymethyl cellulose or ester of acetic acid and phthalic acid cellulose.

20. The method according to any one of claims 1 to 19, in which the solution or dispersion comprises lowering the surface tension of the substance.

21. The method according to claim 20, in which lowering the surface tension of a substance chosen from the group comprising anionic lowering the surface tension of the substances, simulatory, cationic lowering the surface tension of the substances, nonionic lowering the surface tension of the substances and amphoteric lowering the surface tension of the substance.

22. The method according to claim 20 or 21, which lowers the surface tension of a substance chosen from the group comprising sodium lauryl sulfate, sodium docusinate, sodium casein, salts of fatty acids, Quaternary amines, cetylpyridinium, polyoxyethylene esters of fatty acids, esters of sucrose and fatty acids, cetyl with the IRT, esters of fatty acids, cetosteatil alcohol, cholesterol, sorbitane esters of fatty acids, Polysorbate, poloxamer, tocopherylacetate and phospholipids.

23. The method according to any one of claims 1 to 22, in which the solution or dispersion is prepared using 5 to 95 wt.% water or a mixture of water/ethanol, 1 - 91% of orlistat, 3,9 - 93,9 wt.% maltodextrin and 0.1 - 90,1 wt.% one or more pharmaceutically acceptable additives.

24. The method according to any one of claims 1 to 22, in which the solution or dispersion is prepared using 5 to 95 wt.% water or a mixture of water/ethanol, 1 - 91% of orlistat, 3,9 - 93,9 wt.% maltodextrin and 0.1 - 90,1 wt.% polyoxyethylene ether fatty acids.

25. The method according to any one of claims 1 to 22, in which the solution or dispersion is prepared using 5 to 95 wt.% water or a mixture of water/ethanol, 1 - 91 wt.% orlistat, 1 - 91 wt.% trimyristin, 2,9 - of 92.9 wt.% maltodextrin and 0.1 - 90,1 wt.% polyoxyethylene ether fatty acids.

26. The method according to any one of claims 1 to 22, in which the solution or dispersion is prepared using 3 - of 99.98 wt.% isopropyl alcohol, 0.01 to 96,99 wt.% oseltamivir and 0.01 - 96,99 wt.% polymethacrylate.

27. The method according to any one of claims 1 to 26, in which the residual solvent content in the pharmaceutical composition is in the range of 0.1 - 10 wt.%.

28. The method according to any one of claims 1 to 26, in which three-dimensional (bulk) density of the pharmaceutical companies the positions is within 0.1 - 0.9 g/cm3.

29. The method according to any one of claims 1 to 26, in which the distribution of particles in the pharmaceutical composition is in the range of 50 to 600 μm.

30. The method according to any one of claims 1 to 29, in which the composition is prepared directly in the final dosage form.

31. The method according to any one of claims 1 to 30, in which the composition is prepared directly in the packaging.

32. The song, which can be prepared according to the method according to any one of claims 1 to 31.

33. The composition obtained by the method according to claim 1, comprising 0.2 to 10 wt.% residual water or a mixture of water/ethanol, 1 - 96 wt.% orlistat, 3,7 - by 98.7 wt.% maltodextrin and 0.1 - 95,1 wt.% one or more pharmaceutically acceptable additives.

34. The composition according to p, including polyoxyethylene ether fatty acids.

35. The composition obtained by the method according to claim 1, comprising 0.2 to 10 wt.% residual isopropyl alcohol, 1 - 98,8 wt.% oseltamivir and 1 is 98.8 wt.% polymethacrylate.

36. Composition according to any one of p-35, three-dimensional (bulk) density of which is between 0.1 - 0.9 g/cm3.

37. Composition according to any one of p-35, in which the distribution of particle size is in the range of 50 to 600 μm.

38. Composition according to any one of p-35, in which the residual solvent content is in the range of 0.1 - 10 wt.%.



 

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