Melt-covered pharmaceutical composition with fast release

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a pharmaceutical composition, namely to a method of manufacturing a solid, coated pharmaceutical composition by the method of applying a coating by melt.

EFFECT: method is adapted to the provision of the solid, coated pharmaceutical composition, possessing fast release, by means of covering by melt.

6 ex, 8 tbl, 13 cl

 

The present invention relates to a method for producing a solid, coated pharmaceutical composition by means of a coating method from the melt. The process is adapted to ensure a solid, coated pharmaceutical composition by coating from the melt, which has a quick release.

Many pharmaceutically active substances have a bitter and/or unpleasant taste, and ensuring a solid, oral compositions such active ingredients, it is advisable to provide a solid, oral pharmaceutical composition with a coating to mask the bitter and/or unpleasant taste of the active ingredient (taste masking). A typical example of such active ingredient is acetaminophen, but are well known and other active substances that have this problem.

In the existing level of technology processes for coating solid pharmaceutical compositions, which have an unpleasant or bitter taste, are well known. In such a process of coating a solid pharmaceutical composition provides a layer that covers the unpleasant taste the core of pharmaceutically active ingredient. This layer masks the unpleasant taste of the core of the pharmaceutical composition in the mouth and dissolves in the gastro-intestinal tract. Such layers are usually referring�Xia taste masking layers or taste masking coating.

Early examples of coating methods to provide such a masking layer of taste are sugar coatings that provide sugar layer which covers the unpleasant taste of the core of the pharmaceutical composition. In later times became available to other coating methods. Today, probably the most common method provides a solution for coating or slurry covering the polymer in an organic or preferably aqueous solvent. This solution for coating or slurry was applied onto unpleasant taste the core of the pharmaceutical composition and the solvent is evaporated, so that the taste masking polymer and optional additives remain in the taste masking layer. However, this process has the disadvantage that consumed quite a lot of energy to evaporate the solvent from the coating composition. It usually is simple and can be done at low temperatures when the solvent is an organic solvent, however, great care must be taken to ensure that as little organic solvent remained in the coating for safety reasons. Covering compositions are water-based are not problematic from the point of view of the residual solvent of the coating since water is not a problem � pharmaceutical compositions however, many active ingredients are sensitive to water, and, in addition, the removal of water from taste masking layer after the coating layer is energy and time consuming. Despite these challenges, today water coating methods are the most common, because the apparent lack of alternatives.

Alternative coating technique is a method for coating from the melt. This method has also been known for a long time, and instead of the coating solution or suspension in which the components of the coating layer are dissolved or suspended in an organic or aqueous solvent in the coating process from the melt, the melt is obtained at the temperature at which taste masking compound is in a molten phase. As plastic taste masking substance is used mainly lipophilic compounds such as lipids, triglycerides, partial glycerides, waxes, esters of glycerides of fatty alcohols, etc., the Melt contains optional additives taste masking layer, either in the form of suspension or solution. The melt is then sprayed on the core pharmaceutical compositions that contain unpleasant or bitter-tasting pharmaceutically active ingredient.

This method is advantageous because it does not participate solvent�, which later must be removed or which may react with components of the nucleus of the pharmaceutical composition. However, dealing taste masking layer by a coating applied by spraying on the core of the pharmaceutical composition with the melt mainly masking the taste of lipophilic compounds, this leads to pharmaceutical compositions in which the release of active ingredient from the core of the pharmaceutical composition is significantly slowed. This is described in several scientific articles, for example,

- Barthelemy, P.; Laforet, J. P.; Farah, N.; Joachim, J.: Compritol 888 ATO: an innovative hot-melt coating agent for prolonged-release drug formulations, Eur J Pharm. Biopharm. 47, 1 (1999), 87-90,

- Sinchaipanid, N.; Junyaprasert, V.; Mitrevej, A.; Application of hot-melt coating for controlled release of propanol hydrochloride pellets, Powder Technol. 141 (2004), 203-209 and

- Joachim, J.; Prinderre, P.; Farah, N.; A Hot Melt Coating Agent for Controlled-Release Theophylline Dosage Forms, Pharm. Man. Rev. (1996), 24-28.

Because of these inherent problems with the use of the method of coating of a molten taste masking layers, this process is considered as not suitable for obtaining fast dissolving pharmaceutical compositions. The process was used to obtain a pharmaceutical sustained release compositions, such as, for example, described in EP 1479383 and articles mentioned above.

In WO 2005/063203 revealed that it is difficult to provide covered melt pharmaceutical composition which quickly releases and�active ingredient and where the coating completely covers the core with the active ingredient. Thus, this document discloses a method of coating a melt, in which molten taste masking material is not sprayed on the core with the active ingredient. Preferred taste masking compound is mixed with the core, and then melted. The document suggests using taste masking material such as xylitol having a high HLB index, i.e. which are hydrophilic. The opportunity to affect the integrity of the taste masking layer is not disclosed in WO 2005/063203.

WO 2004/103350 discloses sustained release compositions of the active ingredient beraprost sodium, which includes a layer of sustained release and taste masking layer. In this document, is not disclosed as applied to a taste masking layer, and therefore the document relates to compositions and controlled release, this document does not describe the manipulation of taste masking layer, leading to an increased release of the active ingredient.

EP 0841062 discloses variants of the method of coating the melt, in which granules are produced by granulation of the melt. Then these granules covered with a layer of talc and, optionally, ethylcellulose, and the pellets are melted again. In this way the view layer containing talc and ethylcellulose is formed on the surface of granules that provides some camouflage in�USA in combination with only a small effect of the release. The process described in EP 0841062, not a "classical" method for coating from the melt, in which masking the taste of the compound is melted and then sprayed on the core of the pharmaceutical composition. The process according to EP 0841062 does not exclude that the pharmaceutically active ingredient is present in the most distant from the core layer of the pharmaceutical composition, as it does not provide a layer mask flavor compounds around the core with the active ingredient. In addition, the process described in EP 0841062, is limited to the nuclei, which can be melted and, therefore, to pharmaceutically active ingredients can be used in such preparations. In addition, it is not possible to carry out this process in a standard commercially available enrobing machines.

There is a need in the prior art for the process of providing pharmaceutical compositions with a taste masking layer which, as a rule, are applicable to all pharmaceutical compositions and which provide pharmaceutical compositions in which the release of active ingredient is not significantly slowed, which is safe and economical and avoids the problems of existing methods of the prior art. There is also a need in the pharmaceutical industry�such compositions, obtained in this way.

The inventors have now found that the process of obtaining a solid, coated pharmaceutical composition includes:

(i) providing a core, which contains one or more pharmaceutically active ingredients and optionally one or more pharmaceutically acceptable excipients,

(ii) coating the core, applied by spraying at least one covering composition at least one compound, masking the taste, having a melting point at least 40°C and a HLB value of 10 or less, where at least one covering composition includes a taste masking compound having a temperature of at least 40°C, where it is sprayed on the core so that the taste masking compound is in a molten phase, whereby taste masking layer provided on the core,

characterized in that the core coated by spraying at least one coating composition comprising at least one of the released compound, which is defined as a compound in the gastrointestinal tract is the cause of destruction or decay of taste masking layer or improves the permeability of the taste masking layer one or more pharmaceutically active ingredients that alleviate these problems

The present invention also provides a solid, coated pharmaceutical composition obtained in accordance with such process.

The method of the present invention is a method for coating from the melt, in which the melt is sprayed directly on the core of the pharmaceutical composition that contains one or more pharmaceutically active ingredients. The melt contains masking the taste of the compound in the molten state. The melt is, of course, may contain more than one taste masking compound and it may contain the usual additives known method for coating from the melt, for example, to improve the performance of the coating composition. These additives and/or other taste masking compounds both are in the molten state or they are suspended or emulsified in the melt or they are dissolved in the melt. It is preferable that the composition used in the present method of coating by spraying the core with one or more pharmaceutically active ingredients, do not contain solvents. Nevertheless, it is possible to present a small amount of water, for example, for emulsification additives. The amount of water in the compositions is preferably about�region from 0 to 20%, more preferably in the range from 0 to 10%. Masking the taste of the layer the most distant from the core layer of the pharmaceutical composition.

Decisive for the present invention is the use of the released compounds. The released compound according to the present invention is any compound in the gastrointestinal tract, particularly the stomach, is the cause of destruction or decay of taste masking layer or improves the permeability of the taste masking layer one or more pharmaceutically active ingredients that are present in the core of the pharmaceutical composition.

Needless to say that the released compound is different from masteruser flavor compounds. Preferred releasing compound selected from the group which consists of

- compounds which react under acidic conditions (for example, the formation of duoxide carbon), in particular salts of carbonic acid, such as alkali carbonates, alkali bicarbonates, alkaline earth carbonates, alkaline earth carbonates and other,

- inorganic salts which are soluble in water solubility is preferably at least 0.5 g salt in 10 ml water or 0.1 n HCl, more preferably at least 1 g of salt in 10 ml water or 0.1 n HCl, Nai�more preferably at least 10 g salt in 10 ml water or 0.1 n HCl at 20°C), such as, for example, halides (preferably chlorides and bromides) or sulfates such as alkali halides and sulfates, alkaline earth halides and sulfates (preferred are alkali halides such as NaCl or KCl),

- contributing to the swelling agents that greatly increase their volume upon contact with the aqueous medium, such as starch, polysaccharides and other substances to improve disintegration, preferably substances to improve disintegration, known as superathletes, particularly croscarmellose, copovidone, sodium salt of glycolate starch, polyacrylic ion-exchange resins, polyacrylic acid, and carbomer,

hydrophilic polymers that are soluble in an aqueous medium, such as povidone, a copolymer of polyvinyl alcohol-polyethylene glycol and cellulose ethers,

- organic compounds that are soluble in water solubility such as described above for inorganic salts, such as carbohydrates, such as sucrose, glucose, lactose, mannitol, maltitol and sorbitol.

Used in this specification, the term "aqueous medium" means water or aqueous solutions or suspensions with a pH value in the range from 0.5 to 8. The term "aqueous environment", in particular, includes the environment, which is found in VC�arranged gastrointestinal tract of humans. The term "aqueous environment", in particular, means water and 0.1 m HCl.

Compounds that are released, the preferred depending on the structure of the pharmaceutical compositions, as will be explained below, but basically, most preferred are compounds which react under acidic conditions, inorganic salts which are soluble in the aqueous environment and contributing to the swelling agents, as defined above.

In the following description, for emphasis, it will sometimes be referred to as "pharmaceutically active ingredient" to imply that this is not a limitation only one pharmaceutically active ingredient, and that is still a lot of pharmaceutically active ingredients, if nothing else is explicitly stated or obvious in the context.

In accordance with the invention, it is preferable that the connection is released in the same layer as masking the taste of the connection. This can be achieved, including through the inclusion of the released compounds in the coating composition containing molten masking the taste of the connection. Alternatively, coating compositions that contain the melt masking the taste of connection are at the same time sprayed on the core of the pharmaceutical composition, which ODS�REIT pharmaceutically active ingredient. If the released compound is sprayed simultaneously with melt taste masking compounds, releasing the connection can be sprayed as such (for example as a powder), or can also be sprayed as a melt, mainly in the form of a suspension or solution of the released compounds in a molten compound (for example, masking the taste of the connection). Preferred is an embodiment in which the released compound included in the coating composition, which contains taste masking compound, and an embodiment in which the released connection directly sprayed (as a powder) to the core, which contains the pharmaceutically active ingredient composition of the coating, which contains molten masking the taste of the connection.

In the above embodiment, in which the released compound is used in taste masking layer, preferably, when the released compound is a compound which reacts under acidic conditions or contributing to the swelling agent, and most preferred are basic inorganic salts of carbonic acid, as described above, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixtures thereof or contribute to swelling agents, Pref�put above, such as starch, croscarmellose, copovidone, sodium salt of glycolate starch, polyacrylic ion-exchange resins, polyacrylic acid, carbomer and polysaccharides, or mixtures thereof. In the gastrointestinal tract, in particular together with the acid in the stomach, salt of carbonic acid, which is present in the taste masking layer will react with the acid to form the holes in the masking layer or taste, as a rule, to break or destroy the taste masking layer. This happens very quickly, and thus the release of active ingredient from the pharmaceutical composition only minimally or not at all is delayed by covered by immersion in a melt taste masking layer.

Compounds which react under acidic conditions, can also be organic compounds, however, the use of salts of carbonic acid as the released compounds is preferred. The number of compounds which react under acidic conditions, is not strictly limited and can easily be adapted by a skilled person in the art depending on the type of taste masking compounds, the thickness of the taste masking layer, the type of compound which reacts under acidic conditions, etc. basically, the amount of the released compounds, cat�Roy reacts under acidic conditions (in particular, the salts of carbonic acids, such as inorganic carbonates or bicarbonates) of, is in the range from 5 to 50%, based on the weight of the coating composition, more preferably in the range from 5 to 40%, more preferably in the range from 5 to 35%, most preferably in the range from 5 to 25%.

It is also possible to release the connection was an inorganic salt or organic compound or a hydrophilic polymer that is soluble in water and melts the taste masking layer, when the pharmaceutical composition reaches the gastrointestinal tract (e.g., stomach or bowel). Suitable inorganic salts are, for example, sodium chloride, potassium chloride, etc., Inorganic salts are preferably inorganic salts which have a solubility in water and/or acid, as described above. When a pharmaceutical composition with a taste masking layer containing a compound which is soluble in an aqueous medium upon reaching the gastrointestinal tract, the compound is dissolved and provides the pores in taste masking layer. The active ingredient may then pass through the taste masking layer through these pores that will lead to the rapid release of the active ingredient. Nevertheless, the release has the�the trend whereby to be somewhat more delayed, than in the embodiment in which the compound which reacts under acidic conditions, is present in the taste masking layer, and thus the embodiment in which the compound which reacts under acidic conditions, is present in the taste masking layer is preferred.

It is clear that some compounds which react under acidic conditions, as described above, are also soluble in aqueous medium. However, for the purposes of this description, a compound that meets the requirements of a compound which reacts under acidic conditions, is not considered as belonging to inorganic salts or organic compounds or hydrophilic polymers, which are soluble in an aqueous medium, as described above.

The amount of inorganic salts or organic compounds or hydrophilic polymers, which are soluble in an aqueous medium in taste masking layer is not substantially limited, and the same number can be used as described above for compounds which react under acidic conditions. Inorganic salts or organic compounds or hydrophilic polymers, which are soluble in an aqueous medium, can be deposited on the core, which contains the pharmaceutically active ingredient, basically, in the same way as with�connected, which reacts under acidic conditions, and it is preferred to the corresponding explanations given above.

Examples of the organic compound which is soluble in an aqueous medium, are sucrose, glucose, lactose, sorbitol, mannitol, maltitol xylitol, isomalt, dextrose, fructose or salts of organic acids. However, inorganic salts which are soluble in water are preferred.

In the third embodiment of the released compound may be a compound which swells in an aqueous medium and thus breaks or decomposes taste masking layer, when the taste masking layer reaches the water, in particular an acid environment. As a rule, are well known and suitable pharmaceutically contributing to the swelling agents and agents for improving disintegration, such as starch, for example maize starch and jellied starch, polysaccharides and superathletes, such as croscarmellose, copovidone, sodium salt of glycolate starch, polyacrylic acid, carbomer and polyacrylic ion-exchange resins, are preferred contributing to the swelling agents.

The number of irreducible swelling compounds in the coating composition is not particularly limited and can be easily adjusted as customers�ANO qualified on the basis of the same considerations, as mentioned above in relation to compounds which react under acidic conditions. The number of irreducible swelling compounds in the coating composition is preferably in the same ranges as described above in relation to compounds which react under acidic conditions. Resistant to swelling of joints can be applied in the same way as described above, for example, as components of coating compositions which contain masking the taste of the connection, or they can be sprayed onto the core simultaneously with the taste masking composition as such or they can also be applied in molten form.

If the released compound is a compound which reacts under acidic conditions, in particular salt of carbonic acid such as an inorganic carbonate or bicarbonate (the preferred embodiment), split, delamination or the formation of holes) in taste masking layer mainly starts when the pharmaceutical composition reaches the acidic environment in the stomach. Thus, this embodiment is most preferred. The pharmaceutical composition can be left in the mouth for a long time without discoloration of the active ingredient, and not providing a bitter taste in your mouth. Some solutions of the compounds, which�OE reacts under acidic conditions, can be entered in the mouth, but they usually negligible.

With the other two embodiments discussed above in which the released compound is an inorganic salt or organic compound or a hydrophilic polymer that is soluble in an aqueous medium or contributing to the swelling agent, a process in which holes are formed in the masking layer or taste in which swelling occurs in the taste masking layer, may already occur in the mouth. Thus taste masking layer may be thicker, as in the case of compounds which react under acidic conditions, and in such embodiments can be some delays in the release of the active ingredient. However, the release of the active ingredient significantly improved upon incarnations of the existing prior art, which do not contain the released connection. For such purposes, particularly preferred is an embodiment in which the released compound is a compound which reacts under acidic conditions, in particular the inorganic carbonate or bicarbonate.

The above embodiments of the invention should be interpreted as those in which the released compound is present in the same layer as masking the taste of the connection. However, it is also possible�about to provide a separate layer which contains the released connection. In this embodiment the core, which contains the pharmaceutically active compound is first covered with a layer, which contains the released compound, and the layer taste masking layer is applied by coating from the melt (of course, it is also possible, but not preferable, to separate the layer with the released connection from taste masking layer through one or more intermediate layers; preferably, the intermediate layer was not between taste masking layer and release layer). Release layer may be deposited by any known method, but, basically, the process of coating by immersion in the melt will also be used for applying a releasing layer on economic grounds. In this embodiment of the released compound is particularly preferably a compound which reacts under acidic conditions, as described above, or the swelling compound, as described above, because the release layer should be able to destroy or decompose the taste masking layer, when some small amount of water or acid penetrate into the taste masking layer and reach the release layer. With regard to preferred�Uo embodiments of this release layer, they can be assigned to the information disclosed above has described the embodiment of the present invention, in which the released compound is used in taste masking layer.

Needless to say, it is also possible to use the separately released layer separately and taste masking layer and to ensure that the released compound to mask the taste of layer. In this case, small quantities of water or acid in the GI tract can more easily reach the release layer, and the collapse or fracture of taste masking layer through the destruction or deterioration of the releasing layer is improved. In this embodiment the number of the released compounds in taste masking layer can be much lower than discussed above for embodiments in which there is a separate release layer, and in this case the number of the released compounds in taste masking layer is 0.5% or more, more preferably 1% or more, but mostly not higher than 10%, preferably not higher than 8%, based on the total weight of the composition.

Masking the taste of compounds that can be deposited by a method of coating by immersion in the melt, are well known in the prior art, and, in principle, all taste masking compounds that JW�safety is known in the existing level of technology used to provide taste masking layer by means of the method of coating by immersion in the melt, can be used in the present invention. Masking the taste of compounds that can be used in the method of coating by immersion in the melt, mainly, have a melting point of more than 40°C, preferably more than 50°C, and melting point is mainly not higher than 100°C, preferably not higher than 90°C and most preferably not higher than 80°C. the melting Point of the pharmaceutically acceptable excipients that include taste masking compounds, usually indicated in the European Pharmacopoeia and the European Pharmacopoeia contains a melting point for taste masking compounds it has a melting point, to which reference is made in this specification. If the European Pharmacopoeia for a connection does not have specific melting point, but discloses a method for determining the melting point, you need to follow this method. If no melting point and no special method is not disclosed in the Pharmacopoeia or if the method referenced in the European Pharmacopoeia is not sufficiently clear or complete, the melting point is determined by DSC as follows: the melting point is measured by DSC typical differential scanning calorimeter (manufactured by Perkin Elmar Inc.) in accordance with the method in which the sample is heated from CONTROLTEMPLATES when the heating 30°C/min to 150°C (or maximum possible temperature before the collapse of the sample), hold at this temperature for 10 minutes, then drop the temperature at -20°C/min to -20°C, kept at this temperature for 10 minutes and again heated at 20°C/min, and the temperature showing the melting peak is defined as the melting point (TM). Was used a sample of 5 mg.

For qualified specialist in the art it will be clear that many taste masking compounds do not have a distinct melting point but a melting range. For example, a commercial connection Compritol 888 ATO melts in the range from 68°C to 73°C. If masking the taste of the connection does not have a distinct melting point but a melting range, the upper limit of the melting range of masking the taste of the connection must be within the limits as indicated above (at least 40°C, etc.).

Mask flavor compounds that are mainly used in the method of coating by immersion in the melt, are lipophilic compounds, and the lipophilicity of compounds can be expressed by its HLB value determined in accordance with Griffin (Griffin, W. C.: Classification of surface active agents by HLB, J. Soc. Cosmet. Chem. 1, 1949). In this regard, taste masking compounds, mainly, have an HLB value of 10 or less, more preferably 8 or less and most preferred 5 �or less. The HLB value is calculated or measured in accordance with standard procedures as described, for example, in Fiedler, Lexikon der Hilfsstoffe, Editio Cantor Verlag, 5. Ed., 2002, or, if Fiedler does not provide relevant information, in accordance with Griffin, as mentioned above.

Preferred taste masking compounds of the present invention represent a similar taste masking compounds, which are used in the existing prior art and are selected from the group which consists of fatty acids, fatty alcohols, triglycerides, fatty acids, partial glycerides of fatty acids, fatty alcohol-PEG-esters, fatty alcohol-PEG-esters, esters of fatty acids, polyglycerol fatty acid and mixtures thereof. Such taste masking compounds are commercially available. Preferred taste masking compounds are stearic acid, saturated poliglecaprone glycerides, palmitostearate glycerin and beginat glycerin. Most preferred are fatty acids and fatty alcohols, and, considering the definition of fatty acids and fatty alcohols, there may be a link to Rompp Chemielexikon, 10th edition, keyword "Fettalkohole" and "Fettsauren". Needless to say, from fatty alcohols and fatty acids are suitable only those that have an appropriate melting point and HLB value is�e, such as 1-nonadienal, 1-eicosanol, heneicosane and 1-docosanol. Of fatty acids stearic acid (melting point 67°C, HLB -6) is especially preferred, but similar fatty acids, such as nonadecanoic acid (melting point 69°C, HLB -6), arachidic acid (melting point 75°C, HLB -7), behenic acid (melting point 80°C, HLB -8), palmitic acid (melting point 63°C, HLB -5), heptadecanoic acid (melting point 62°C, HLB -6), etc. are also preferred.

Especially preferred are triglycerides and partial glycerides.

The core, which contains one or more pharmaceutically active ingredients and optionally one or more pharmaceutically acceptable excipients, which is covered by the spray pattern is in accordance with the present invention, is not particularly limited. All types of cores can be used, including crystals of the active ingredient, such as such, granules, pellets, tablets, capsules, etc. Mainly, the core contains at least one active ingredient and one or more pharmaceutically acceptable auxiliary substances, but, for example, in the case of crystals of the pure active ingredient is not necessary that attended pharmaceutically acceptable excipients. Nuclei� can be prepared by any method, such as extrusion from the melt or from solution, tableting, milling, granulation, spheronization, layering techniques etc. Methods for the manufacture of cores of tablets are well known in the existing art, and in this aspect, the present invention is not limited.

The core contains at least one pharmaceutically active ingredient, but it is also possible to present a mixture of more than one pharmaceutical ingredient, for example two, three or four pharmaceutically active ingredient. Preferably, the core contains one or two, more preferably only one pharmaceutically active ingredient.

The type of the pharmaceutically active ingredient is not particularly limited, but the technology is the most preferred pharmaceutically active ingredients which have an unpleasant or bitter taste, and it is therefore necessary to mask the taste to improve their patients ' perceptions. Typical examples of such pharmaceutically active ingredients are acetaminophen, ibuprofen, flurbiprofen, Ketoprofen, acetyl salicylic acid, salicylic acid, naproxen, diclofenac, celecoxib, etoricoxib, guaifenesin, dextromethorphan, acetylcysteine, cetirizine, loratadine, desloratadine, acemetacin, caffeine, theophylline, chlorphen�min hydrogen maleate, phenylephrine, pseudoephedrine, digitalin, chlorpheniramine, diphenhydramine, ranitidine, famotidine, cimetidine, loperamide, Bisacodyl, ciprofloxacin, norfloxacin, β-lactam antibiotics, macrolide antibiotics.

Ranitidine, famotidine, cimetidine, caffeine, paracetamol, acetylsalicylic acid (ASA), cetirizine, loratadine, diphenhydramine, guaifenesin, ibuprofen, Ketoprofen, naproxen, acetamin, pseudoephedrine, phenylephrine, dextromethorphan, calcium acetate, zinc sulfate, fumarate zinc (or zinc salts in General), iron salts, acetylcysteine, Ambroxol, diclofenac, chondroitin, tramadol, Tilidine, codeine, azithromycin, clarithromycin, roxithromycin (macrolide antibiotics), beta covenants antibiotics, triptan (for example, almo-, Nara-, Reise-, Suma-, solmi-).

More preferred are the following pharmaceutically active ingredient ranitidine, famotidine, cimetidine, caffeine, paracetamol, acetylsalicylic acid (ASA), cetirizine, loratadine, diphenhydramine, guaifenesin, ibuprofen, Ketoprofen, naproxen, acetamin, pseudoephedrine, phenylephrine, dextromethorphan, calcium acetate, zinc sulfate, fumarate zinc (or zinc salts in General), iron salts. Particularly preferred are active ingredients used in the examples of the invention, called ranitidine, caffeine, paracetamol and acemetacin. More preferred�patients are paracetamol, ranitidine and caffeine.

Used in the present invention, the term "pharmaceutically active ingredient" also includes vitamins and drugs of natural origin, which very often need to disguise the flavor.p>

The core is also mainly contains pharmaceutically acceptable excipients, depending on what type of kernel used. However, the core may also consist of a crystal of the active ingredient.

Most preferred in accordance with the present invention is a method in which a nucleus that contains one or more (preferably one) pharmaceutically active ingredients and optionally one or more pharmaceutically acceptable excipients, which is coated by spraying the coating composition, which contains at least one (preferably one) taste masking compound which has a melting point at least 40°C and a HLB value of 10 or less, in which the coating composition, which contains taste masking compound has a temperature of at least 40°C when it is applied on the core, and taste masking layer provided on the core, wherein the core is coated by spraying the coating composition, which contains at least one of the released connection (premise�plant one of the released connection) which in the gastro-intestinal tract or causes destruction of the taste masking layer or improves the permeability of the taste masking layer one or more pharmaceutically active ingredients. More preferred is a single layer that contains both: and released the connection, and masking the taste of the connection.

The composition of the coating, which contains at least one of the released compound that is used in the method of the present invention may also preferably comprise one or more additional components, for example to achieve uniform distribution of the released compounds. One or more additional components that contribute to the achievement of uniform distribution of the released compound in the layer containing the released connection, in this specification referred to as "additional connections". It should be clear that the composition of the coating, which contains at least one of the released compound preferably also contains at least one taste masking compound, as described above. Most of the released compounds do not dissolve in the melt, which is used in the method for coating from the melt, and thus, one or more additional compounds JW�safety mainly used in order to ensure a favorable distribution of the released compounds in the composition of the coating and to prevent separation during the coating process. Additional compound preferably selected from the group of surfactants, polyethylene glycols, glycerol and propylene glycol. The surfactant is preferably selected from the group consisting of esters of sorbitol and fatty acids, esters of polyoxyethyleneglycol, polyoxyethylenated derivatives of castor oil, esters of fatty acids polyoxyethylenesorbitan, stearates of polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers.

Further connection, as described above, can, of course, be present in the layer that contains masking the taste of the connection, if taste masking compound is not in the same layer as the released connection.

The number of additional connections or connections that are given above, in particular, are unlimited and can be adapted by a skilled person in the art depending on the identity of the additional compound or compounds and the composition of the coating, in particular from the released substances. Mainly, additional compounds are present in the coating composition in an amount up to 40%, based on the weight of the coating composition, preferably there is an additional connection in the range of up to 35%, more preferably up to 30% and preferably according to�Aina least 0.5, 1 or 2%.

In accordance with the present invention, " % " means "wt.%", if nothing else is not stipulated or not clearly.

The composition of the coating, which contains at least one taste masking compound can including to consist of masking the taste of the connection (if the released compound is present in a separate layer), but preferably the released compound and other optional additives present in the coating composition, which contains at least one taste masking compound. Therefore, it is preferable taste masking compound is present in the coating composition in amounts in the range from 30 to 100%, more preferably from 35 to 90%, most preferably from 40 to 70%, based on the weight of the coating composition.

Additives that can be included in the hot melt coating composition, which contains taste masking compound and/or the released compound are, for example, coloring additives, pigments, sweeteners or flavors.

The method of the present invention corresponds to the conventional method of hot-melt spray application, except that the released compound is also present in thermoplasma coating composition or applied separately. As to the details of the method of thermopl�Vago coating by spraying, reference may be made to the tutorial Multiparticulate oral drug delivery (Drugs and the pharmaceutical sciences, Vol.65), 1994, edited by Isaac Gebhre Sellassie, which describes a method of hot-melt coating by spraying, which is included here by reference.

In the method of hot-melt coating by spraying hot melt coating composition, which contains taste masking compound is heated to a temperature at which taste masking compound is in the melt state. This occurs mainly at temperatures above the melt temperature masking the taste compounds, however, depending on the composition of the hot melt coating composition, it is possible that the temperature of the melt composition was slightly lower than the melt temperature of each of these components, including masking the taste of the connection (the temperature of the melt). Preferably, in accordance with the invention the temperature of the composition is applied by coating from the melt, and which contains taste masking compound is at least 40°C and preferably at least the temperature of the melt taste masking compounds, more preferably at least 5°C, more preferably at least 10°C above the melt temperature masking the taste of the connection. Depending on equipment, can be recommended for elevated temperature�tours.

Masking the taste of the coating composition, for example a melt, which contains molten taste masking compound and optional other components, such as the released connection, additional connection, additives, etc., is then sprayed directly on the core, which contains the pharmaceutically active ingredient. The melt solidifies on the surface of the nuclei as a consequence of the cooling process when the air temperature and the low temperature of the product and formed a taste masking layer. This is the opposite of the normal method of coating by spraying of a solution or suspension in which the sprayed solution or suspension is applied at a low temperature (mostly room temperature), and only the process temperature is high for evaporation of solvent.

The present invention is also directed to a solid, oral pharmaceutical composition produced by the method as described above. Solid, oral pharmaceutical compositions are different from the compositions, which were prepared by the method of coating from the melt, because taste masking layer is structurally different, if it was caused by the method of coating from the melt, and not through a process of dissolution or suspension of the process. Chrome�, mask flavor compounds used in hot melt way, are mostly not stable in the mortar or slurry method, and taste masking compounds, applied by means of mortar or slurry methods, do not have a melting point of over 40°C in combination with an HLB value of 10 or less. In addition, the pharmaceutical compositions of the present invention do not contain solvent residues in taste masking layer, that is inevitable in such pharmaceutical compositions, which were covered by the mortar or slurry method.

Solid, oral pharmaceutical compositions produced in accordance with the method of the present invention, different from the known pharmaceutical compositions, which have a taste masking layer prepared through the conventional method of coating by immersion in the melt, in which pharmaceutical compositions of the present invention contain the released compound or taste masking layer, or in a separate layer.

In comparison with the pharmaceutical compositions of the present level of technology, which is prepared by the method of coating by immersion in the melt, the pharmaceutical compositions of the present invention have greatly improved the option rastvorimost�. The solubility parameter is measured in accordance with the method of the device with the blade-stirrer of the European Pharmacopoeia at 75 rpm in 900 ml aqueous buffer (pH between 1 and 7.2, depending on the solubility of the active ingredient) at 37°C followed by an additional provision of tredoustroinnosti. It may also be related to the examples for further details.

If the released compound is a compound which reacts under acidic conditions, the solubility parameter primarily measured under acidic conditions (pH=1) for 30 minutes in accordance with the European Pharmacopoeia. After those initial 30 minutes, the solubility parameter is measured with the pH value at which the active ingredient (or active ingredients) is soluble.

In other embodiments, the solubility parameter is measured with the pH value at which the active ingredient (or active ingredients) is soluble in accordance with the European Pharmacopoeia.

All solubility measurements are performed at 37°C in the instrument with the blade USP type 2. If for a particular active ingredient provided specific conditions according to the European Pharmacopoeia, should be used in such conditions. If the conditions are not stipulated in the European Pharmacopoeia, using the �ove conditions. If nothing is obvious or necessary, a suitable buffer system is used to maintain pH in the desired value. Preferred are phosphate buffers.

Using the description of the experience, as described above, after 45 minutes, preferably dissolves at least 50% active ingredient, more preferably at least 60% active ingredient, more preferably at least 70% active ingredient, most preferred at least 75% of the active ingredient and even most preferably at least 85% of the active ingredient.

Preferably after 30 minutes, dissolves at least 40%, more preferably at least 50%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80%, most preferably at least 90% of the active ingredient.

Covered by immersion in a melt of the pharmaceutical compositions of the present invention release the pharmaceutically active ingredient substantially faster than the corresponding compositions that are identical to pharmaceutical compositions of the present invention except that they do not contain the released connection. Largely fast VisualAge�communication means, after 45 minutes, preferably at least 10%, more preferably at least 15%, more preferably at least 20 and more preferably at least 25% of the active ingredient is dissolved. For example, when the pharmaceutical composition is prepared by the method of coating from the melt, which has a taste masking layer with not releasing compound (composition of the existing level of technology) after 45 min released 15% of the active ingredient, the release of active ingredient after about 45 minutes in accordance with the present invention (the same composition as the above, but with the released compound) is preferably at least 25%, more preferably at least 30%, more preferably at least 35% and most preferably at least 40%. The release of the active ingredient (for example, dissolution of the active ingredient) was measured as described above. However, mainly the present invention provides the release even faster than the above.

The following examples explain the invention in more detail, however, the present invention is not limited to these examples.

Example 1

The acetaminophen crystals were used as core material in with�next following examples.

Four coating compositions with two different taste masking compounds were prepared as follows (weight of active ingredient for each sample was 250 g).

For samples 1 and 2, 5% and 25% of calcium carbonate, respectively, relative to the weight of the coating composition was mixed with PEG 3000 (10%, based on the weight of the composition of the coating) or by surfactant tween 20 (15%, relative to the weight of the coating composition). For samples 3 and 4, 15% and 25% Amberlite IRP 88, respectively, relative to the weight of the coating composition, were mixed with PEG 3000 in the amount of 10% and 30%, respectively, relative to the weight of the coating composition. Mixture that contained PEG, were heated with stirring until then, until the PEG was melted and was obtained a homogenous suspension. The sample containing liquid surfactant tween 20, was intensively stirred until then, until there was obtained a uniform similar to the paste suspension.

Masking the taste of the compound was added to a mixture of the released compounds/PEG and a hot or a mixture of the released compounds/tween 20 was added to the melted masking the taste of the mix. All the samples were heated to approximately 20°C above the melting point of taste masking compounds and stirred until then, until there was obtained a homogeneous comp�the positions of the coating.

The content of each coating composition are summarized in the following table.

Table 1

Sample # The released compound/NumberMasking the taste of the connection/NumberSurface-active substance or other substance/QuantityThe amount of coating (based on the weight of the cores)
1CaCO3/5 gPreziral ATO 5/85 gPEG 3000/10 g40%
2CaCO3/25 gStearic acid/60 gTwin 20/15 g40%
3Amberlite IRP 88/15 gStearic acid/75 gPEG 3000/10 g40%
4Amberlite IRP 88/25 gPreziral ATO 5/45 gPEG 3000/30 g40%

In the apparatus with fluidized bed equipped with heated swank�OK crystalline acetaminophen, as described above, was covered in each of the four coating compositions under the conditions as described below.

Parts of the coating apparatus, which were in direct contact with the molten coating composition were heated to avoid solidification of the melt, for example, spray nozzles and the nozzles to move the melt from the melting vessel to the spray nozzle. The composition of the coating were heated to approximately 90°C to obtain a melt with low viscosity and satisfactory spray properties.

0.25 kg of acetaminophen crystals were loaded into the device for applying the coating and the crystals were pseudouridine method of the air, which was heated and had a temperature of 20-30°C. the Melts were sprayed onto the crystals acetaminophen level when spraying from 3 to 8 g/min/0.25 kg of cores. The product temperature did not exceed 45°C during the entire spraying process. After the process of spraying the coated core was maintained under stirring method air flow to cool and then were unloaded.

Simultaneously with the spraying of each composition coating on the pellets, the released compound was also sputtered on the pellets. Following two of the released compounds were used in the amount and at RA�palitelig conditions in the following table.

Table 2

Sample # The released compound/NumberMasking the taste of the compositionThe amount of coating (based on the weight of the cores)
Masking the taste of the connection/numberSurface-active substance or other substance/quantity
5CaCO3+1% Aerosil (based on the mass of CaCO3)/5 gPreziral ATO 5/90 gPEG 3000/10 g40%
6CaCO3+Aerosil (based on the mass of CaCO3)/25 gPreziral ATO 5/45 gPEG 3000/30 g40%

This leads to a total of 6 samples whose compositions are given in the following table:

Table 3

Sample # The released compound/ NumberMasking the taste of the connection/Number Surfactant/NumberThe amount of coating (based on the weight of the cores)
1CaCO3/5 gRecital ATO 5/85 gPEG 3000/10 g40%

2CaCO3/25 g%Stearic acid/60 gTwin 20/15 g40%
3Amberlite IRP 88/15 gStearic acid /75 gPEG 3000/10 g40%
4Amberlite IRP 88/25 gRecital ATO 5/45 gPEG 3000/30 g40%
5CaCO3+1% Aerosil (based on the mass of CaCO3)/5 gRecital ATO 5/90 gPEG 3000/10 g40%
6CaCO3+1% Aerosil (based on the mass of CaCO3)/25 gRecital ATO 5/45 g PEG 3000/30 g40%

Example 2

Sticking to the rules as described in example 1 above, were prepared samples 1b - 3b, which correspond to samples 1-4, which are described above, but the connection is not released was sprayed simultaneously with masking the taste of molten coating composition. The composition of example 2 are given in the table below.

Table 4

Sample # Masking the taste of the connection/numberSurfactant/ numberThe amount of coating (based on the weight of the cores)
1bPreziral ATO 5/71.25 g %PEG/3.75 g30%
2bStearic acid/63.75 gPEG/11.27 g30%
3bStearic acid/90 gTween 20/10 g40%

Example 3

Sticking to the rules as described in example 1 above, were prepared samples of 4b-5b, which correspond to samples 1-4, which are described above, but high�boidayseada compound and a surfactant or PEG 3000 was sprayed simultaneously with masking the taste of molten coating composition. The composition of example 3 are shown in the table below.

Table 5

Sample # Masking the taste of the connection/numberThe amount of coating (based on the weight of the cores)

4bPreziral ATO 100 g40%
5bStearic acid 100 g40%

Example 4

Each sample obtained in example 1 was subjected to solvent experiment in accordance with the European Pharmacopoeia. Rules for the measurement of dissolution were as follows: dissolution was performed in 900 ml 0.1 M HCl at a temperature of 37.0±0.5°C and stirring speed of 75±3 rpm using USP apparatus 2. The concentration of dissolved active ingredient was determined by UV spectroscopy at an appropriate time.

In accordance with such rules as the above, the samples obtained in example 2 and 3 were also measured. The solvent results of tests are shown in the table below.

Table 6

Sample # The percentage of dissolution of the active ingredient
5 min10 min15 min30 min45 min60 min
19.320.229.750.663.772.3
1b6.411.716.126.634.440.4
281.091.998.0101.5--
2b5.613.118.232.536.851.8
310.028.438.961.475.083.7
3b4.87.810.619.925.830.5
465.497.8103.4104.5--
4b2.84.56.210.414.017.5
57.413.723.844.858.366.8
5b0.81.21.52.22.73.2
662.378.991.6100.3--

It is seen that the samples of the present invention, which represent the samples of example 1 are significantly improved�ing the intensity of the release compared to the comparative samples which are the samples of examples 2 and 3.

Example 5

Following the rules as given in example 1, samples were prepared 7-31. The properties of solubility of these samples were measured, following the rules as given in example 4. The results are shown in the following table. In the table the abbreviations have the following meanings:

Pre: Preziral ATO 5 (mixture of mono-, di - and triglycerides of palmitic and stearic acid, HLB=2)

Amb: Amberlite (ion exchange resin)

Cr EL: Cremophor EL (polyethoxysiloxane castor oil)

Cr A6: Cremophor A6 (polyethylene glycol 260 mono(hexadecyl/octadecyl)ether and 1-octadecanol)

Gelu: Gelucire 50/13

PEG: polyethylene Glycol 4000

Comp Capitol 888 ATO

The values in parentheses lead wt.% the value of the component in the coating:

Table 7

Sample # Masking the taste componentA surfactant or other stuffReleased connectionActive ingredientThe percentage of dissolution of the active ingredient
5 min15 min30 min60 min
7Pre (85)Cr A6 (5)Polyox (10)Paracetamol12,335,276,896,1
8Pre (75)Labrafil (5)Polyox (20)Paracetamol7,638,9At 79.392,1
9Comp (73)Gelu (12) Labrafil (5)CaCO3 (10)Paracetamol34,9103,2102,8103,6
10 Pre (69))Gelu (6) (Labrafil (5)Amb (10), CaCO3 (10)Paracetamol13,263,594,597,3
11Pre (65)PEG 6000(15)Kollidon CL-M (20)Ranitidine HCl22,868,388,693,4
12Pre (60)Cr EL (20)Carbopol 971P NF (20)Paracetamol3891,698,999
13Comp (80)Cr A6 (5)CaCO3 (15)Ranitidine HCl16,562,884,593,3
14Pre (70)Cr EL (20)Carbopol 971P NF (10)Ranitidine HCl 23,273,193,199,3
15Pre (85)Labrafil (5)Carbopol 971P NF (10)Ranitidine HCl20,658,482,1Of 89.4
16Pre (85)Labrafil (5)Sodium carboxymethylcellulose (10)ParacetamolThe 15.453,284,290,7
17Pre (85)Labrafil (5)The sodium salt of carmelose (10)ParacetamolOf 17.448,386,597,4
18Stearic acid (80)Labrafil (5)Kollidon CL (15)Paracetamol25,373,392/td> 96,7
19Stearic acid (80)Labrafil (10)Sodium chloride (highest grade) (10)Paracetamol10,9Of 28.964,472,1
20Stearic acid (75)PEG 6000 (15)Mannitol (highest grade) (10)Paracetamol12,435,868,974,3
21Pre (70)PEG 6000 (15)Fine Lactose (15)Paracetamol13,542,179,6The 92.3
22Pre (75)PEG 6000 (15)The potassium bicarbonate (10)Paracetamol54,389,396,899,7
23Pre (75)PEG 6000 (15)The potassium bicarbonate (10)Caffeine63,5Of 84.396,9101,3
24Pre (75)Labrafil (5)Amb (10), CaCO3 (10)CaffeineOf 15.367,995,398,6
25Pre (80)Labrafil (5)CaCO3 (5)+fine Lactose (10)Caffeine23,493,4100,8102,8
26Stearic acid (80)Labrafil (5)Kollidon CL (15)Caffeine19,667,785,696,7
27Stearic acid (80)PEG 6000 (10) Sodium carboxymethylcellulose (10)CaffeineOf 17.460,382,793,5
28Pre (75)Labrafil (5)Sodium carboxymethylcellulose (10)+potassium bicarbonate (10)Ranitidine HCl17,984,698,899,6
29Pre (85)Cr A6 (5)Polyox (10)Ranitidine HCl2,01Of 24.1351,2878,46
30Pre (75)Labrafil (5)Polyox (20)Ranitidine HCl3,8320,4141,2366,2
31Stearic acid (75)Labrafil (5)Amb (20)Ranitidine HCl 35,574,28994,1

Example 6

In this example embodiment of the present invention is confirmed by the example in which the released connection or some of the released compounds are plotted as a sublayer between the core, which contains the active ingredient and taste masking coating. The method was performed in such equipment, as shown in example 1, and, mainly, the same processes of coating were made. The method was adapted and the first sublayer of the released compounds was sprayed onto the core and then taste masking layer was sprayed on the intermediate product with the sublayer. The composition of the layers and the relative amount of component layers as the active ingredient shown in the table below.

Following the rules of example 4, the dissolution of the active ingredient was measured and the results are also shown in the following table.

Table 8

Sample # Masking the taste componentSurface-active substance or other substance in taste masking coatingReleased connectionActive ingredien� The percentage of dissolution of the active ingredient
5 min15 min30 min60 min
32Pre(75)PEG 4000 (25)The sublayer 5% Carbopol (based on the starting material Paracetamol)Paracetamol19,0850,5978,6194,79
33Pre (75)PEG 4000 (25)The sublayer 3% Carbopol (based on the starting material Paracetamol)Paracetamol43,0884,297,86101,18
34Pre (70)PEG 4000 (25)Amb (5) taste masking coating; the Sublayer 5% Carbopol (based on the starting material Paracetamol) Paracetamol22,0953,4979,0393,6
35Pre (75)PEG 4000 (25)The sublayer 3% Carbopol (based on the starting material Paracetamol)Ranitidine HCl43,0884,297,86101,18

1. A method of manufacturing a solid, coated pharmaceutical composition, characterized by the fact that
the core, which contains one or more pharmaceutically active ingredients selected from the group consisting of ranitidine, famotidine, cimetidine, caffeine, paracetamol, acetylsalicylic acid (ASA), cetirizine, loratadine, diphenhydramine, guaifenesin, ibuprofen, Ketoprofen, naproxen, acemetacin, pseudoephedrine, phenylephrine, dextromethorphan, calcium acetate, zinc sulfate, fumarate zinc (or zinc salts mostly), iron salts, and optionally one or more pharmaceutically acceptable excipients,
cover by spraying at least one coating composition, which contains at least one masking the taste of the compound also contains at �'ere released one connection,
or cover by simultaneous spraying of two compositions, one composition of the coating contains at least one taste masking compound and a different composition of the coating contains at least one of the released connection, thus to provide a taste masking layer which also contains at least one of the released connection,
moreover, the coating composition contains at least one taste masking compound has a melting point at least 40°C and a HLB value of 10 or less and selected from the group which consists of fatty acids, fatty alcohols, triglycerides, fatty acids, partial glycerides of fatty acids, fatty alcohol-PEG-esters, fatty alcohol-PEG-esters, esters of fatty acids and polyglycerol fatty acid
and which contains at least one of the released compound, which is defined as a compound in the gastrointestinal tract or cause the collapse or destruction of the layer of coating composition, or improves the permeability for one or more pharmaceutically active ingredients,
where the released compound selected from the group including alkali carbonates, alkali bicarbonates, alkaline earth carbonates and alkaline earth carbonates, alkaline halogenide and Sul�ATA alkaline earth halides and sulfates, croscarmelose, copovidone, sodium salt of glycolate starch, polyacrylic ion-exchange resins, polyacrylic acid and carbomer, povidone, copolymers of polyvinyl alcohol - polyethylene glycol, cellulose ethers, sucrose, glucose, lactose, mannitol, maltitol and sorbitol.

2. A method according to claim 1, wherein the taste masking compound selected from the group which consists of stearic acid, a saturated glycol poliglecaprone glycerides, palmitostearate glycerine and behenate glycerin.

3. A method according to claim 1, wherein at least one taste masking compound has a melting point in the range from 50 to 80°C.

4. A method according to claim 1, wherein the released compound selected from the group which consists of salts of carboxylic acids, polyacrylic ion-exchange resins and mixtures thereof.

5. A method according to claim 1, wherein the coating composition, which contains at least one release compound and/or at least one of masking the taste of the compound also contains at least one additional compound selected from the group of surfactants, polyethylene glycols, glycerol and propylene glycol.

6. A method according to claim 1, wherein a surfactant selected from the group which consists of sorbitane esters fat�'s acid polietilenovykh esters, polyoxyethylenated derivatives of castor oil, polyoxyethylene sorbitane esters of fatty acids, polyoxyethylene stearates and copolymers of polyoxyethylene-polyoxypropylene.

7. A method according to claim 1, wherein the coating composition, which contains at least one of the released compound contains one or more of the released compounds in a total amount of from 5% to 50%, based on the weight of the composition of the coating.

8. A method according to claim 1, wherein the coating composition, which contains at least one taste masking compound contains one or more taste masking compounds in a total amount of at least 50%, based on the total weight of the composition of the coating.

9. A method according to claim 1, wherein the release compound is present in the coating composition in amounts ranging from 5% to 30%, based on the weight of the composition of the coating.

10. A method according to claim 1, wherein the taste masking compound is present in the coating composition in amounts in the range from 70% to 95%, based on the weight of the composition of the coating.

11. Solid, coated pharmaceutical composition for zamaskirovana bitter and/or unpleasant taste of the active ingredient that is obtained according to the method of any one of claims. 1-10.

12. Solid, coated pharmaceutical composition according to claim 11, in which visualaids�yosia compound is an alkali carbonates, alkaline hydrogen carbonates, alkaline earth carbonates and alkaline earth bicarbonates.

13. Solid, coated pharmaceutical composition according to claim 12, in which the released compound is an alkali halides and sulfates, alkaline earth halides and sulfates, or saharso, glucose, lactose, mannitol, maltitol and sorbitol, or povidone, copolymers of polyvinyl alcohol - polyethylene glycol and cellulose ethers.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention represents an oral anti-enteroviral and immunostimulant agent in the form of capsules containing interferon and additives, differing by the fact that a therapeutic substance is human recombinant interferon alpha-2b immobilised on polyethylene glycol, having a molecular weight of 1.5 kD by a physical method of binding by an accelerated electron flow in a dose of 1.5 Mrad. The ingredients in the agent are taken in a certain ratio.

EFFECT: extending the range of anti-enteroviral agents possessing immunostimulant properties.

6 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: presented egg-shaped vaginal suppositories contains the following mass ratio in 1 capsule (egg-shaped vaginal suppository): sulphadimine 0.05 g; metronidazole 0.01 g, potato starch 0.02 g, glucose 0.04 g, 5% polyvinyl alcohol 0.07 g, 15% oily extract of propolis 1.0 g; gelatine 0.2 g; dimethicone 0.04 g; glycerol 0.4 g; purified water 0.37 g.

EFFECT: using the invention increases the therapeutic effect and bioavailability of the capsules, increases the prolonged action time, provides the control release of the active substances.

3 cl, 1 dwg, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns a simplified capsular form of clofazimine, containing clofazimine, bee wax, soya bean lecithin, butylhydroxy toluene, soya bean oil, gelatine, glycerol, sorbitol, methylparabene, propylparabene, titanium dioxide, brown chocolate and purified water with preserving high efficacy.

EFFECT: simplifying the form.

4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention represents an encapsulated liposomal antiviral agent based on human interferon alpha-2b for vaginal application, characterised by the fact that each capsule is made in the form of a hollow coating, which encloses a powder excipient and liposomes distributed in the excipient, and sodium alginate, a water-soluble polymer gel former; the excipient consists of lactose, sodium chloride, 12-aqueous disodium hydrogen phosphate and sodium dihydrogen phosphate, whereas each of the liposomes represents a hollow coating containing lecithin, cholesterol and alpha-tocopherol, and a nucleus inside the coating and containing recombinant human interferon alpha-2; the ingredients of the agents are taken in a certain ratio, mg.

EFFECT: maintaining the storage activity of recombinant human interferon alpha-2 and prolonged action in vaginal application.

2 cl, 3 dwg, 6 tbl, 6 ex

Abt-263 capsule // 2550956

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular, described is a capsule, containing a capsule envelope, which includes an encapsulated liquid solution of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)3-(morpholin-4-yl)-1-(phenylsulphanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulphonyl)benzenesulphonamide (ABT-263) or its bis-hydrochloride salts in a non-ethanol carrier. As filling agents used are: a phospholipid, a solubilising agent for the phospholipid, selected from glycols, glycolides, glycerides and their mixtures, a surface-active substance of a non-phospholipid type and a sulphur-containing antioxidant in an amount, effective for the reduction of oxidising ABT-263 degradation in storage. The sulphur-containing antioxidant is selected from sulphites, bisulphites, metabisulphites and thiosulphites and their mixtures. A method of the capsule obtaining is also described. The capsule is used for treating a disease, characterised by the overexpression of one or several anti-apoptotic proteins of the Bcl-2 family, for instance, cancer.

EFFECT: invention provides a long storage term for the said capsule.

33 cl, 3 dwg, 20 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to a formulation of a cough medical composition. The formulation of the cough medical composition contains an active substance presented by thermopsis herb powder or a dry extract of thermopsis and sodium hydrocarbonate, as well as an excipient, a granulating agent and a lubricant taken in certain relations (versions).

EFFECT: composition of the cough medical composition possesses improved pharmaceutical (appearance, taste) and technological characteristics (hardness, disintegration).

11 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a storage-stable pharmaceutical composition and a pharmaceutical formulation containing at least one active pharmaceutical ingredient presenting a nitrocatechol derivative, 2,5-dichlor-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, at least one excipients and at least one binding agent, wherein at least one excipient is other than a phosphate derivative, wherein at least one binding ingredient is other than a polyvinylpyrrolidone compound, and wherein the above active pharmaceutical ingredient is present in the granulated form.

EFFECT: compositions and/or formulations according to the invention are stable for a long period of time and show a high stability if stored in the high temperature and moisture environment.

26 cl, 8 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains anastrozole, poly(lactic-co-glycolic acid), polyvinyl alcohol and D-mannitol. The therapeutic agent represents sub-micron particles and can be presented in the form of capsules, granules, powder, as well as a suspension for injections.

EFFECT: using the developed therapeutic agent enables achieving the therapeutic effect with lower therapeutic doses and making the antitumour therapy more comfortable for the patient.

2 cl, 1 tbl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for producing soft capsule coatings contains corn starch, carrageenan, water and a softening agent in certain proportions.

EFFECT: composition prolongs the shelf life of the soft capsule coatings without usability deterioration.

2 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, and a method for preparing it. The composition contains 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid in an amount of 40 to 80 wt %, an amino-containing compound and pharmaceutically acceptable excipients. The amino-containing compound is specified in a group of trometamol, methyl glucamine and L-lysine; 1 mole of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid is accounted for 0.05 to 0.25 mole of the above amino-containing compound. The composition also contains lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients. According to the method for preparing the composition, taking 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid and amino-containing compound in molar ratio 1:0.05 to 1:0.25, pre-mixing, moisturising with a aqueous or alcohol solution of a binding agent, adding pharmaceutically acceptable excipients in such an amount to provide the content of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid from 40 to 80 wt %, granulating the mixture, drying and producing tablets or capsules according to the known technique.

EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition in the form of a tablet with an erodible matrix, which contains one or more fumaric acid ethers, as well as a rate-controlling agent, representing hydroxypropylcellulose and a binding agent, representing lactose, with the decomposition of the said degradable matrix providing the controlled release of the said fumaric acid ether (ethers).

EFFECT: provision of the controlled release of fumaric acid ether (ethers).

19 cl, 43 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid pharmaceutical product for oral administration which contains a photosensitiser representing a compound of general formula I:

wherein R1 represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and each R2 independently represents a hydrogen atom or optionally a substituted alkyl group or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. The above pharmaceutical product is presented in the form of a tablet, a pill or a capsule having an enteric and gastroresistant coating, or in the form of the tablet or the capsule containing a number of balls, drops, granules or mini-pills with an enteric and gastroresistant coating. The above coating disintegrates in the lower gastrointestinal tract. The invention also refers to using the above photosensitiser in preparing the solid pharmaceutical product applicable in photodynamic treatment or diagnostics of a cancer condition in the lower gastrointestinal tract. What is also described is a photodynamic method of treating or diagnosing the cancer condition in the lower gastrointestinal tract by administering the solid pharmaceutical product containing the photosensitiser.

EFFECT: invention provides photosensitiser delivery to the lower gastrointestinal tract, and homogenous distribution of the photosensitiser in the target region, thereby improving the response to photodynamic treatment or diagnostics.

20 cl, 2 dwg, 2 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: solid pharmaceutical composition applicable for oral administration contains 3-(1.H.-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione or a pharmaceutically acceptable salt thereof, and at least one lubricating agent in the amount of 2.5 to 12 wt %. The composition is presented in the form of a tablet. What is also described is a method for preparing and using the pharmaceutical compositions.

EFFECT: composition under the invention is non-adhesive and shows a low fragility less than 1 wt/wt %.

14 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to medicine, namely to solid peroral dosage form, obtained by rotation pressing, which includes therapeutically effective quantity of aliskiren or its pharmaceutically acceptable salt, and active ingredient is present in said dosage form in amount higher than 38% by weight of peroral dosage form, as well as to method of obtaining said solid peroral dosage form.

EFFECT: method with application of rotational pressing makes it possible to exclude application of solvent, requires for wet granulation, method ensures high content of drug agent in composition.

23 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition in form of solid dosage form for treatment or prevention of diabetes, which contains therapeutically efficient quantity of metformin, polyvinylpyrrolodone, stearic acid and/or its salt, starch, silicon dioxide, characterised by the fact that as polyvinylpyrrolidone it contains polyvinylpirrolidone with molecular weight from 1000000 to 1500000 and additionally glycerol and/or basic finely dispersed magnesium carbonate.

EFFECT: pharmaceutical composition possesses high strength and ensures high degree of active substance release.

10 cl, 1 tbl, 5 ex

FIELD: food industry.

SUBSTANCE: invention relates to a glazed product and to its preparation method. The glazed product contains the core and erythritol based solid glaze wherein one layer contains erythritol and one or several crystallisation modifiers. Erythritol accounts for no less than 85 wt % of one glaze layer, the crystallisation modifier accounts for 10 wt % of one glaze layer and is chosen from group (A) consisting of microbial gums, agar agar, pectin, beta- glucan, carrageenan, glucomannan, ghatti gum, karaya gum, tara gum, fenugreek gum and a mixture of two or several of them; alternatively, the crystallisation modifier accounts for up to 15 wt % of one glaze layer and is chosen from group (B) consisting of maltitol, hydrolysed fibres, partially hydrolysed fibres, water-soluble food fibres, glycerine, gluconic acid and gluconic acid derivatives, glucaric acid and glucaric acid derivatives, glucuronic acid and glucuronic acid derivatives, mono-, di- and triglycerides and their derivatives, phospholipids, fatty-acids ethers of non- glycerine polyalcohols or monoatomic alcohols, ethers of mono-, di- or tricarboxylic acids with fatty acids, mono-, di- or oligosaccharides, sugar ethers and their mixtures; alternatively, the crystallisation modifier is represented by a combination of at least one compound of group (A) and at least one compound of group (B) in an amount up to 15 wt % of at least one glaze layer. According to the invention, the glazed product is manufactured by way of application of a glazing solution, including a solvent and a glazing mixture containing erythritol and the crystallisation modifier, onto bodies with subsequent drying.

EFFECT: invention allows to ensure uniform crystallisation and adhesion of crispy glaze to the product core.

11 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form with delayed release for delivery of medication into large intestine. Drug form includes part with core and core coating, where core includes medication and coating. Coating includes mixture of sensitive to influence of large intestine bacteria substance and film-forming polymeric substance, which is not soluble at Ph lower than 5 and soluble at pH higher than 5. As sensitive to influence of large intestine bacteria substance used is starch, containing not more than 75% of amilose. Invention also relates to method of obtaining said drug form, which lies in formation of core and covering core with covering composition, which includes mixture of starch, which contains not more than 75% of amilose, and film-forming polymeric substance.

EFFECT: invention relates to application of claimed drug form for production of medication for treatment of inflammatory disease of intestine and carcinoma, as well as to methods of treating said diseases by introduction of therapeutically efficient amount of claimed drug form.

28 cl, 17 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine. The group of inventions involves pharmaceutical compositions containing 5-azacytidine for the oral introduction wherein the compositions release a cytidine analogue substantially in stomach, a method of treating an individual suffering a disease associated with abnormal cell proliferation which involves the oral introduction of the pharmaceutical composition into the individual, using 5-azacytidine for preparing the pharmaceutical composition for treating the disease associated with abnormal cell proliferation.

EFFECT: invention provides higher clinical effectiveness.

9 tbl, 9 ex, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention describes a method for stabilising a sensitive ingredient for biological absorption in the oral intake in a therapeutic composition involving the stages of combining pregelatinised starch with at least one sensitive ingredient, and mixing the sensitive ingredient with pregelatinised starch. Pregelatinised starch is used in the amount of 5% to 80% of composition weight. The sensitive ingredient is specified in vitamin C, phenylephrine and their combinations. The sensitive ingredient is used in the amount of 0.1% to 20% of composition weight. Said sensitive ingredient is uniformly distributed in pregelatinised starch and adsorbed on pregelatinised starch.

EFFECT: stability of said sensitive ingredients and maintenance of their activity and availability for biological absorption in the oral intake of the therapeutic composition.

17 cl, 15 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the medicinal preparation zolpidem. Pharmaceutical composition comprises zolpidem hemitartrate as active substance taken in the effective dose and ludipress, aerosil and stearate as special additives. Pharmaceutical composition is made preferably as a tablet covered by envelope. Invention solves the problem for the development of the nonprolonged soporofic medicinal agent based on zolpidem corresponding to all requirements of the State Pharmacopoeia of XI Edition. Proposed nonprolonged formulation of zolpidem is suitable for workers contingent suffering with insomnia, especially, in professions requiring attention and concentration.

EFFECT: improved and valuable medicinal properties of composition.

6 cl, 2 tbl, 3 ex

Up!