Therapeutic agents

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes composition of a pressed tablet comprising multiple of hardened melted granules of nonsteroid anti-inflammatory preparation (NSAID) with a melting point in the range 30-300oC and comprising a loosening agent dispersed uniformly in it. Granules comprise a continuum phase of indicated nonsteroid anti-inflammatory preparation and the table composition comprises additionally silicon dioxide in the amount 0.05-5.0% of composition mass. Preferably, the composition comprises also a nongranulated component containing silicon dioxide and excipient. The preferable NSAID represents ibuprofen that has a melting point in the range 75-77oC. Method provides preparing tablet showing useful industrial properties and ability for dissolving.

EFFECT: improved preparing method, valuable pharmaceutical properties of agent.

34 cl, 16 tbl, 64 ex

 

This invention relates to compositions containing non-steroidal anti-inflammatory drug, to methods for their preparation and use.

Nonsteroidal anti-inflammatory drugs (NSAID) are widely used group of drugs. They represent a well-characterized group of compounds and include phenylpropionate acids such as ibuprofen, naproxen, Ketoprofen and flurbiprofen. They are mostly used to treat one or more symptoms chosen from pain, inflammation and fever, for example, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, postoperative pain, postpartum pain and soft tissue lesions. One example is ibuprofen, which is available by prescription in the UK (for example, brufen (RTM)), usually in doses up to 3200 mg per day. Ibuprofen is also available as a drug for prescription in the UK (for example, Nurofen (RTM)) primarily for the treatment of pain and fever, including headache, migraine, rheumatic pain, muscular pain, backache, neuralgia, dysmenorrhoea, dental pain, and colds, and flu, as a rule, in doses up to 1200 mg per day.

Ibuprofen and other NSAIDs are usually acidic and mostly insoluble drugs. They are usually administered in the form of a pharmaceutical is tion of the composition for oral administration in tablet form. Thus, it is necessary to choose a pharmaceutically acceptable fillers for combination with NSAID, which NSAID is compatible and with whom he can form a tablet having satisfactory strength and also the ability to rapidly release the drug in the body, so that it becomes available for absorption.

An important issue related with the diseases mentioned above, is to improve the commencement of the NSAID, especially in the treatment of pain. I believe that the rapid disintegration of the dosage form leads to the release of the drug in the body, quickly leading to more rapid early therapeutic action compared to conventional dosage form. Therefore, it is desirable to obtain a solid dosage form for oral administration, adapted for rapid disintegration in the gastrointestinal tract. Many of NSAID are acidic drugs, therefore, the absorption can be a problem in the acidic conditions in the stomach. In addition, although in the literature suggested many dosage forms adapted for rapid disintegration, a big problem occurs with ibuprofen and other NSAID, because they can be administered in relatively high doses, for example, up to 800 mg in a single dose. Thus, there is the problem of providing, in addition to the state form, which includes NSAID together with fillers, suitable for inclusion tablets in dosage form, as well as fillers, suitable for fast disintegration, but not in the form of tablets, which is too large for the patient or cannot be obtained from a conventional large-scale production processes. In addition, the solid dosage form must be strong enough to withstand the harsh conditions of the production process (for example, to be coated during the coating film in a porous rotating drum and packaging etc), but must have the appropriate properties in relation to disintegration to ensure rapid release of the drug from the form, and the corresponding properties for dissolution. Another significant problem that must be overcome is ensuring that the composition can be extruded and to it is not stuck in the dies of the apparatus for the manufacture of tablets.

Alternatively, a common way of selecting a specific fillers and conditions tabletting or change the form of a single dosage form, one direction of research is the modification of the crystalline form of the NSAID, in order to try to optimize its performance.

In earlier statements the Ah for the grant of the patent was considered by the heat of ibuprofen, drug with a relatively low melting point to melt, and cooling with the formation of a granular composition, mixing with optional excipients for tableting and pressed into a pill. In Japan patent Kokai 81/120616 (1981) describes a method of producing granules of ibuprofen, which provides the ability to get smaller dosage forms along with the best flowability of granular material prior to pelletizing. In illustrative examples, the Japan patent 81/120616 ibuprofen melt when heated and add fillers such as fine crystalline cellulose and calcium stearate (optional with oxypropylated starch) to obtain the dispersion of insoluble ingredients in the molten ibuprofen. The mixture is then cooled and milled to obtain granules. Granules or directly pressed into tablets without adding additional fillers or mixed with Aerosil (colloidal silicon dioxide) and loaded into capsules. However, when the concentration in blood has been shown that in spite of what was achieved getting smaller dosage forms and better flowability, no significant differences in bioavailability between the tablets obtained as described in the application for the grant of a patent Japan 81/120616, and those of the previous level is I, 1981.

The application for the European patent 362728 (1990) refers to a fairly granular granular compositions of ibuprofen, which has the best properties for storage and for direct tabletting. Molten ibuprofen hardens upon contact with the cooling unit when making the seed, and then finely pulverized in a solid substance. The obtained granulate consists entirely of ibuprofen. For the described method requires the molten ibuprofen with fast freezing under certain conditions, and then make a seed, and when the molten ibuprofen hardens, the resulting flakes are crushed under certain conditions of grinding. In the illustrative examples described getting formed as a result of this method of granules and mixing them with a large amount of tableting excipients, such as microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate and pressed into tablets. In order to reduce the size of the tablets, it is desirable to reduce the number agranular fillers required to connect with granules of ibuprofen prior to pelletizing.

In U.S. patent 5240712 (1993) says that the molten ibuprofen may be filled in capsules, and provides examples of encapsulated dosage forms containing and uprofen, optionally containing fillers, in the form of a solid solution or dispersion therein. The composition of the molten ibuprofen is filled into the capsule, and then give her a chance to harden. Thus prepared dosage forms do not require additional processing and can be typed directly to the patient. However, the capsules are large, and it is desirable to obtain a solid dosage form of relatively small size.

U.S. patent 5667807 (1997) also refers to the heating of ibuprofen to melting and receiving the tablets of the granulated compositions derived from it. It provides illustrative examples of the tablets obtained initially through the formation of a mixture of ibuprofen with fillers (including microcrystalline cellulose, corn starch, magnesium stearate, and optionally colloidal silicon dioxide and sodium salt croscarmellose) and then by heating and extruding the mixture in the extruder to receive the extrudate, which is part of the active compounds melted. It is noted that viscoplastic active ingredient performs the function of a binder or solid solvent. In the second part of the method, chilled, finely crushed pellets, derived from the extrudate, pressed into tablets after the optional inclusion of lubricants. However, desire is entrusted to reduce the number of fillers, required to be included in the composition, and to improve operational quality pills.

In WO 99/40943 disclosed receipt of the combinations of active agent/surfactant using the selected operating conditions, at least in partial alignment of viscoplastic combination of active agent/surfactant in close contact with the particles of the active ingredient. The combination is heated and subjected to processing power, for example, processing in the extruder. However, the amount of filler used contributes to the increased size of the tablets obtained with it.

Thus, in the preparation of a pharmaceutical form of the granules obtained by solidification of molten ibuprofen, previously it was suggested that either (a) a large number of fillers to add to the molten ibuprofen and use pellets for direct extrusion into tablets, or (b) granules containing only ibuprofen, mixing with a large number of additional excipients for tableting and then pressed into tablets.

At present inventors found that if the baking powder is included in the molten NSAID and uniformly mixed with them, and then cooled and pulverized, to obtain granules, then the composition is provided which, capable of pelletizing with a minimum number of excipients for tableting and having useful properties in relation to tabletting, disintegration and dissolution, if it includes silicon dioxide.

Therefore, the present invention provides a composition molded tablets, including granular component containing lots of solidified melt granules of non-steroidal anti-inflammatory drug (NSAID)having a melting point in the range 30-300°and containing baking powder uniformly dispersed therein, characterized in that the granules contain a continuous phase of the specified non-steroidal anti-inflammatory drug, and additionally characterized in that the composition of the pills include silica in a quantity of 0.05 to 5.0% by weight of the composition.

It was found that the compositions obtained according to the present invention possess valuable properties against disintegration. In addition, the dissolution leads to an unexpectedly high level NSAID, dissolved in an aqueous environment over relatively short periods of time.

An additional advantage of the present invention lies in a small number of additional excipients for tableting, necessary to obtain a dosage form that results in thisway, the benefits of production and cost tablets and getting smaller dosage forms. In addition, the composition obtained prior to pelletizing, has good flowability, and the resulting tablets have good strength.

The surface area of the NSAID in the molten grains is much higher than that of the conventional crystal NSAID. In addition, particle size less than the size of the particles generated by micronisation NSAID, which is the usual preferred method of improving the solubility. Surprisingly, the effect of small amounts of silicon dioxide has the effect of causing rapid dispersion in water conditions, especially in acidic conditions (such as in the stomach), leading to a high percentage NSAID dissolved in a relatively short period of time.

The invention allows to include any relatively viscoplastic NSAID acceptable to the taste, easily disintegrating composition. A preferred group of compounds are 2-arylpropionate acid, which, as a rule, mostly insoluble and have bad taste. Basically it is envisaged that the melting point of these compounds was low enough to enable them to melt when using standard equipment. It is also important that there is no negative environmenta the e on ingredients included in the molten NSAID, such as baking powder. So that the normal melting point of viscoplasticity NSAID enclosed within 30-300°C. the Preferred NSAID have a lower melting point, so that when the melting has not been used for large amounts of energy, thus will affect the cost of production. The preferred melting point enclosed within 30-200° (as, for example, racemic naproxen has a melting point 156°C), more preferably 30-150°S, even more preferably 40-120° (as, for example, flurbiprofen has a melting point 114°C), most preferably 50-100° (as, for example, racemic ibuprofen (melting point 75-77°C), S(+)-ibuprofen (melting point 52-54° (C) and racemic Ketoprofen (melting point 96°)). Preferred viscoplastic NSAID is naproxen, Ketoprofen, flurbiprofen, ibuprofen, or their enantiomers (especially S(+)-enantiomers). The invention is particularly adapted for the medicinal product ibuprofen. The term “drug ibuprofen” includes racemic ibuprofen and S(+)-ibuprofen, which have a low melting point and a very weak taste in the mouth and throat. Most advantageous results are obtained with racemic ibuprofen, which has a high dose in combination with weak who nd solubility.

The amount of NSAID in granular compositions will depend on the dose needed to achieve therapeutic effect. Drugs with a low dose, such as flurbiprofen and Ketoprofen can be at least 20% by weight (for example, 20-99%) of the composition, to ensure that the tablet was not too small. However, a preferred characteristic of the invention is that viscoplastic with high dose NSAID, such as ibuprofen, can be included in smaller dosage forms. Therefore, NSAID, respectively, is more than 70% wt./wt. granular component (for example, 70-99% by weight), preferably 70-95%, more preferably 75-85 wt.%./wt. granular component. NSAID will accordingly be more than 50% by weight of the tablet composition, for example, 60-97% by weight, preferably 70-95% by weight, more preferably 70-90% by weight and most preferably 75 to 85% by weight of the composition.

Baking powder has the effect loosen tablet composition NSAID in conditions corresponding to the conditions in the gastrointestinal tract. Examples of disintegrating agents include one or more components selected from wheat starch, corn starch, potato starch, sodium starch glycolate, nitrosamines hydroxypropylcellulose, alginic acid, cross-linked by the of vinylpyrrolidone, the silicate of magnesium and sodium salts of croscarmellose. The preferred leavening agents are those which swell under the influence of water, causing, thus, separation and the breakdown of the ingredients of the tablets in the aquatic environment of decay. The preferred leavening agents include one or more of the following components: sodium salt croscarmellose and sodium starch glycolate, especially sodium salts of croscarmellose. Baking powder contains effective for loosening the number, for example, up to 25% by weight of the composition, more preferably 1-25% wt./wt., more preferably 3-20 wt.%./wt. and most preferably 8-17% by weight of the composition. The baking powder will, accordingly, be 1-25% by weight of the granular component, preferably 5-23% wt./wt. and most preferably 8-20% by weight of the granular component.

Preferably, the ratio of the medicinal product ibuprofen for baking powder ranged from 30:1 to 1:1 parts by weight, preferably from 20:1 to 2:1, more preferably from 10:1 to 3:1 parts by weight.

Silicon dioxide is insoluble and therefore has a surface area of more than 50 m2g-1more preferably above 100 m2g-1especially within 150-250 m2g-1. More preferably, when silicon dioxide is to loadnum a silicon dioxide (particularly having an average particle size less than 50 nm, such as 5-40 nm), most preferably anhydrous colloidal silicon dioxide. Volume utracki silicon dioxide is preferably in the range from 0.01 to 0.2 g·cm-2.

Silicon dioxide include in the composition in the range of 0.05 to 5.0% by weight (preferably 0.1 to 3% by weight, more preferably 0.2 to 1% by weight) of the composition. Silicon dioxide can be included in the granules. Preferably, silicon dioxide, if it is included in the granules was used in the range of 0.1-1%, more preferably 0.2 to 0.8% by weight of the composition.

When receiving the granular component of the NSAID melt. In conditions of high pressure drug can be fused at a temperature below its normal melting point. The melting can be performed by known methods, including, for example, is heated in the vessel to a temperature above the melting point of the NSAID or extrusion in a heated extruder. The maximum temperature is determined by the stability of the molten mixture and the ingredients mixed with it. The drug can be heated to any suitable temperature. As a rule, the higher the temperature, the faster it will melt the drug, although this should be correlated with the cost of energy required for melting of the drug. For greater efficiency, as a rule, provides that NSAID Boo who should be heated to not more than 25° With, preferably 5-10°C, above the melting point for information, energy costs to a minimum. Thus, the preferred limits of heat are 30-180°S, more preferably 35-140°and even more preferably 40-120°C. If NSAID extruded, it is usually the extruder is heated to a certain temperature. In addition, working with NSAID configuration of the screws in the extruder also contributes to the melting of the NSAID, thereby reducing the need for external attached temperature. Therefore, the cylinder of the extruder can be heated to a temperature below the melting point of the NSAID. For example, the normal melting point of racemic ibuprofen is 75-77°With, however, in the conditions of application of force/pressure (such as may occur in the extruder or similar production device), external supplied with the necessary heat for melting of ibuprofen, can be significantly reduced due to the mechanical heat generated by the intense mixing within the extruder. Usually it is envisaged that the extruder is heated to a temperature of not less than 25°below the melting point of the drug in the range of 15°below the melting point of the drug up to 25°above the melting point of the drug, more preferably to a temperature in the range of 10°on either side of the point is Lavinia of the drug. Some extruders provide the ability to heat different areas to different temperatures in the extruder. These temperatures can choose at will, so as to completely melt NSAID.

When the NSAID is ibuprofen, then it can mainly be heated within 50-100°S, more preferably 60-100°C. When heated using conventional heating means, such as a water or steam bath, it is preferable to heat it within 75-90°S, more preferably 75-85°C. Ibuprofen also can be heated and subjected to conditions of power processing, such as extrusion of ibuprofen when heated, for example, in a twin-screw extruder. The temperature of ibuprofen in the extruder preferably lies in the range 66-96°C, preferably 70-82°C.

When NSAID basically completely melted, it forms a liquid. NSAID should be fully melt, so that upon cooling formed by a solid phase NSAID. Baking powder is combined with the molten NSAID or before melting, or after melting. Usually baking powder insoluble in the molten ibuprofen, and get a solid dispersion of the powder in the liquid melt. The dispersion is stirred so that the baking powder evenly or homogeneous mixed with the molten NSAID. Thus, it appears on the popular mixture. The mixture is allowed to cool using the methods discussed below, are not yet solid. As cooling, the mixture becomes more viscous. NSAID, which hardens, then turn in the molten granules. In the sense in which this term is used here, “solidified molten pellets” means granules obtained by mixing NSAID in a completely molten form with the baking powder and other optional excipients for tableting, cooled to a temperature below the melting point of the NSAID and the transformation of the solid mass into granules. Granulated composition includes a number of such granules.

The melt is allowed to solidify any chosen the easy way. It involves rapid cooling and slow cooling. For example, the molten NSAID can be given to cool down during the night to ordinary temperature or in a refrigerated tank. Molten NSAID may be disposed on the cooling plate, which may be stationary or moving. Stationary plates can be placed in the cooling chamber. Moving plates or tapes may have additional cooling means such as cooling water. The cooled melt forms a solid substance, and it can be scraped off with tape or collect, when he descends from one end of the continuously moving the patients.

The solidified melt, which includes baking powder, can be turned into pellets in many ways. For example, it can be sprayed into pellets. It can be crushed and/or sift. It can also pass through a spray device such as a scrubber with spray device, or a spray granulator, in which the molten material is sprayed from the head stream of the cooled air, allowing him to harden/harden, and then going. If the molten NSAID extruded, the extrudate can be cooled and then crushed into pieces of appropriate size, followed by grinding and/or sieving. Alternative extrudate can be ekstradiroval through the holes and grind into granules of appropriate size for tableting.

NSAID forms in granule solid phase. It should be noted that the crystal structure of NSAID is not interrupted another crystal structure. This may occur, for example, if a NSAID is only partially melted, when the crystal structure of the molten NSAID interrupted unmelted NSAID, thereby ensuring that the NSAID is not only one crystal structure. Crystal structure of solidified molten NSAID differs from the crystal structure of unmelted NSAID, for example, on the size of the ru particles. Thus, in the compositions according to the invention NSAID is in a single crystalline state, and thus, the solid phase NSAID includes a single crystalline phase NSAID.

Although not necessary for implementation of the present invention, if necessary, the composition is molded tablets may include additional fillers.

For example, the composition may include a portion of the water-soluble or water-insoluble diluent. Suitable water-soluble solvents include alcohols, sugars such as xylitol, sorbitol, mannitol, aritra), sugars (such as sucrose, fructose, lactose, dextrose), cyclodextrin, maltodextrin or organic acid salts (e.g. sodium citrate or potassium citrate). Lactose, sodium citrate and potassium citrate are particularly preferred diluents. Suitable water-insoluble diluents include cellulose derivatives such as microcrystalline cellulose), starch and its derivatives (such as pre-klasterizovannykh starch), dicalcium phosphate, tricalcium phosphate, calcium sulfate, calcium carbonate. Microcrystalline cellulose and dicalcium phosphate are preferred water-insoluble diluents. The tablet is adapted for cultivation in the water PE the ed reception, the level of diluent can be quite high, for example, up to 50% (such as 0-50% wt./wt., preferably 0-40 wt.%./wt.) by weight of the composition, in order to achieve the desired dispersion properties. Preferably in tablets for oral administration, the diluent should not be more than 25% by weight of the composition (e.g., 0-25% wt./wt.), because it increases the cost of the composition and the production cost. Thus, for the information of the cost to a minimum it may be preferred that the diluent was added to the composition in the amount of 0-20% by weight of the composition, more preferably 0-10% wt./wt. If it is present, it may be preferable to use it in the range of 0.1-25% by weight of the composition, more preferably 0.1 to 20% wt./wt., more preferably 0.1 to 10% wt./wt. and most preferably 1-5% by weight of the composition.

The diluent may be preferable to include as a main ingredient salt of an alkali metal, for example, carbonate, bicarbonate or citrate of an alkali metal, in the range of up to 50% by weight (for example, in the range of 1-50% by weight), preferably up to 40% by weight (for example, in the range of 1-40% by weight) composition (more preferably 2-35% wt./wt. and most preferably 10-20% wt./wt.). Preferably, the alkali metal salt was salt of sodium or potassium. More preference is sustained fashion, if the salt is a citrate, carbonate or bicarbonate of sodium or potassium, more preferably bicarbonate or sodium citrate. The ratio of NSAIDs, particularly ibuprofen) and alkali metal salt may be in the range from 100:1 to 1:1 parts by weight, preferably from 5:1 to 1:1 parts by weight. Preferably the alkali metal salt is included in any quantity until the equimolar amount relative to NSAID (eg, ibuprofen). Mainly included submontane salt of an alkali metal. Thus, the connection of the alkali metal can be up to 100% wt./wt. to NSAID, preferably 50% wt./wt., more preferably up to 10% wt./wt. to NSAID. In the preferred compressed tablet according to the invention NSAID (especially ibuprofen) is mixed with the salt of an alkali metal. Salt of the alkali metal is preferably included in the form of component for mixing with the granular component before pressing into a tablet.

Granular component may also include a surfactant in an amount corresponding to the properties of surface-active substances, preferably 0.05 to 10% by weight of the composition. Preferred surfactants are sodium lauryl sulphate, poloxamer. They can be used in the range of 0.05-8% by weight of the s composition, preferably 0.1 to 5%, more preferably 0.2 to 2% by weight) of the composition.

Preferred granular component includes NSAID (preferably ibuprofen), baking powder, surfactant and optional diluent. Preferred granular component consists mainly of NSAID (preferably ibuprofen), baking powder and surfactant. Even more preferred granular component consists mainly of NSAID (preferably ibuprofen), baking powder, surfactant and diluent.

Molten granules in granular compositions preferably have an average particle size in the range 10-2000 μm, more preferably 50-1000 μm, and most preferably 100-400 μm. Valuable results are achieved when the volume density of the molten granules is in the range of 0.1-1 GDF-1more preferably 0,3-0,6 GDF-1. Even more preferred properties get when the volume of utracki is 0,3-0,7 GDF-1(more preferably 0.4 to 0.6 GDF-1).

In the composition according to the invention it is preferable that the granular component of the molten granules were mixed with the form component. Preferably, the composition includes granular component in the amount of 60-99,95%, more preferably 7099,9%, in particular, 75-99,9%, in particular 80-99,9%, and most preferably 95 to 99,9% by weight of the composition, and 0.05-40% in the form of a component, preferably 0.1 to 30%, in particular 0.1 to 25%, in particular 0.1 to 20%, and most preferably 0.1 to 5%, by weight of the composition.

The form component includes ingredients that are included in the pressed tablet, which is not contained in the solidified molten granules. They can be mixed with the molten granules at the same time or at subsequent stages of the method of producing tablets. A particular advantage of the present invention is that preferably all the ingredients in the form of component is mixed with a granular component at the same time, and that there is no significant treatment ingredients in the form of a component before mixing with granular derived. Molded tablet includes a homogeneous mixture of granular component and the form of the component. The form of the component, respectively, uniformly distributed in the composition.

The preferred composition is compressed tablets according to the invention includes

a) 60-99% granular component by weight of the composition, where the specified granular component comprises from 0.005 to 1 parts by weight razryhlitel is on part by weight non-steroidal anti-inflammatory drug;

b) 0.05 to 40% in the form of a component by weight of the composition.

Preferably silicon dioxide is present in the form of a component. More preferably silicon dioxide is present in the form of a component within 0.1-3%, more preferably 0.2 to 2% by weight of the composition.

Not necessarily in the form of a component can be included lubricating substance for mixing with the granular component. For tablets of ibuprofen can use conventional lubricants, for example, stearic acid, sodium lauryl sulfate, polyethylene glycol, hydrogenated vegetable oil, sodium fumarate, magnesium stearate or calcium stearate. They can be in the amount of 0.05-5% by weight, preferably 0.1 to 2% by weight of the composition. Optionally, you can include antiadhesive, such as talc, up to 4% by weight of the dosage form, for example, 0.5 to 2% by weight of the dosage form, preferably as part of the form component.

The preferred composition of the tablets according to the invention contains in the form of a component that includes silicon dioxide and grease. They can form a homogeneous mixture with the specified granular component before pressing into a tablet. Preferably in the form of a component with the her mainly of silica and the lubricant in the ratio of one part by weight of silicon dioxide to 0.5-5 parts by weight of the lubricant, more preferably 0.5 to 2 parts by weight of the lubricant.

Although it is not necessary to obtain compositions according to the invention, if necessary, the dosage form may optionally include fillers for tableting, such as compression diluent. It can be melted granule (as discussed above) or may be connected with the form of ingredients before pressing as part of the form component, or may be incorporated, if desired, in both components. Examples of such compression diluents include one or more of a derivative of cellulose, such as microcrystalline cellulose), starch and its derivatives (for example, pre-klasterizovannykh starch), soluble sugars (e.g. lactose, fructose, dextrose, sucrose, dextrin), sugar alcohols (e.g. xylitol, sorbitol, mannitol, aritra), sodium chloride, dicalcium phosphate, tricalcium phosphate, calcium sulfate, mannitol, sorbitol, cyclodextrin and maltodextrin and salts of organic acids (for example, sodium citrate and potassium citrate). Microcrystalline cellulose and salts of organic acids are preferred, as discussed above.

If it is necessary for tableting drug at a low dose, the diluent may with the presentation up to 80% by weight of the composition. It is preferable to use it within 0-30% by weight of the composition and more preferably 0-20% of the whole composition. If desired, the diluent can be added in an amount up to 30% by weight in the form of component, although in order to minimize the size and cost of the dosage form, it is desirable to include the minimum number of such additional fillers. Therefore, if it is used, the diluent can, respectively, be included in the form of a component within up to 20% by weight (i.e. about 0.1-20%), preferably 0.1 to 15%, more preferably 0.1 to 10%, preferably 1-5% by weight. As discussed above, the diluent may be in a granular component, for example, in the range of 0-20% (for example, 0.1 to 20%) by weight of the composition and/or in the form of component, for example, in the range of 0-20% (for example, 0.1 to 20%) by weight of the composition.

In the composition of the compressed tablet according to the invention, if desired, you can include other conventional excipients for tableting, well-known experts in this field, although, obviously, it is clear that the main advantage of the present invention is that the amount of filler required to achieve rapid disintegration of the tablet with good dissolution properties, minimal.

The preferred composition is molded t is blacki includes a homogeneous mixture

a) a granular component comprising the solidified melt of ibuprofen containing baking powder, homogeneous dispersed therein; and

b) 0.05 to 5.0% of silicon dioxide by weight of the composition.

In an additional preferred embodiment of the composition of compressed tablets according to the invention provides molded mixture

a) solidified melt granules containing 70-97% of ibuprofen by weight of the granules, preferably 70-95% by weight), 3-25% sodium salt croscarmellose by weight of the granules, preferably 5-20% by weight) and 0-20% of a diluent by weight of the granules, preferably 8-16% by weight), evenly distributed in them, where the ibuprofen is present in the continuous phase;

b) from 0.05 to 5.0% wt./wt. silicon dioxide and is optional

c) lubricants.

Additional preferred composition according to the invention is provided preferably in the form of a homogeneous mixture

a) 90-99,95% granular component by weight of the composition, where the specified granular component contains solidified molten granules of ibuprofen containing the sodium salt of croscarmellose and optional diluent, uniformly dispersed therein, where the specified ibuprofen is present in a single solid phase and in the amount of 70-99% by weight of the composition, where this sodium salt crockarell the PS is present in the amount of 1-25% by weight of the composition, and where the specified diluent is present in the amount of 0-20% by weight of the composition; and

b) 0.05 to 10% in the form of a component by weight of the composition, including

i) 0.1 to 3% lubricant by weight of the composition; and

ii) 0.05 to 2% silicon dioxide by weight of the composition.

The preferred composition is compressed tablets according to the invention comprises a homogeneous mixture

a) a granular component containing

i) 70-90% of ibuprofen by weight of the composition, where the specified ibuprofen is present as a continuous phase;

ii) 8-20% sodium salt croscarmellose by weight of the composition;

iii) 0-20% of a diluent by weight of the composition; and

the form of the component containing the

iv) 0.5 to 2% stearic acid or its salts by weight of the composition;

v) 0.1 to 2.5% silicon dioxide by weight of the composition,

where the sum of components (i)to(v) above 99% by weight of the composition.

Most preferably, if the granular component consists mainly (i.e. more than 98% by weight of the composition) of ibuprofen, sodium salt croscarmellose and diluent (preferably salts (e.g. alkali metal salt) organic acids or microcrystalline cellulose). Additional predominant composition of the granular component consists mainly of ibuprofen, sodium salt croscarmellose and surface-AK is active substances. Particular advantages are also achieved, if the granular component consists mainly of ibuprofen, sodium salt croscarmellose, diluent (preferably microcrystalline cellulose or salts of alkaline metal and an organic acid and a surfactant, preferably sodium lauryl or poloxamer). For example, a preferred composition may consist mainly (i.e. more than 98% by weight of the composition) of a homogeneous mixture of 75-95% of ibuprofen by weight of the granular composition, 5-20% of baking powder by weight of the granular composition and 0-20% of a diluent by weight of the granular composition, where the composition comprises solidified molten granules of ibuprofen and ibuprofen is present in the form of a single solid phase.

The composition is compressed tablets according to the invention can, if necessary, to include other compatible pharmacologically active ingredients and/or reinforcing agents. For example, the dosage form may include any other ingredient normally used in compositions suitable for the treatment of pain, inflammation and/or fever, for example, caffeine or other xanthine derivative, other analgetic, for example, codeine, relaxant skeletal muscle: an antihistamine (e.g., acrivastine, astemizole, Azat is in, azelastin, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine at, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, Bastin, ketotifen, yodkamol, loratidine, levocabastine, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setaction, tsivilis, temelastine, terfenadine, tripelennamine or triprolidine (preferably used nnegative antihistamines); a decongestant (such as pseudoephedrine, phenylpropanolamine and phenylephrine); the vast cough remedy (for example, caramiphen, codeine or dextromethorphan); and/or an expectorant (for example, guaifenesin, potassium citrate, guaiacolsulfonate potassium, potassium sulfate and Turpin hydrate).

Such additional active ingredients and/or reinforcing agents may be included in the molten granules or in the form of a component that is mixed with the molten pellet before becoming a pressed pill.

The present invention also provides a composition comprising a granular component, consisting mainly of a homogeneous mixture of viscoplasticity NSAIDs, particularly ibuprofen) and sodium salt croscarmellose in the form of a solidified melt granules.

In an additional aspect, the present invention provides a granulate, which includes many of esto solidified melt granules, where these granules contain a continuous phase of ibuprofen and consist essentially of a homogeneous mixture of 70-95% of ibuprofen by weight of the granules, 5-20% of baking powder by weight of the granules and 0-20% of a diluent by weight of the granules. A preferred characteristic of the granules is the additional inclusion of surface-active substances.

Ibuprofen and its derivatives are mainly anti-inflammatory, analgesic and antipyretic agents, but were also proposed for other therapeutic applications, including treatment of periodontal bone loss, itching and Alzheimer's disease. Therefore, the dosage form according to the invention are intended for use in the treatment of all diseases for which effective ibuprofen, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, arthropathy with equivocal reaction, periarticular diseases and soft tissue injuries. They can also be used for the treatment of postoperative pain, postpartum pain, dental pain, dysmenorrhea, headache, migraine, rheumatic pain, muscular pain, backache, neuralgia, and/or musculo-skeletal pain, or pain or discomfort associated with respiratory infections, colds or flu, rigidity gout or in the morning.

Therefore, in another aspect of the present invented the I is provided a composition according to the invention for use in the treatment of pain and/or inflammation and/or fever. In addition, the invention also provides a method of treating pain and/or inflammation and/or fever, which includes the introduction of the mammal, if necessary, the compositions according to the invention.

Single dose for effective treatment is well known to specialists in this field for each NSAID. For example, they may contain NSAID within 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg and 800 mg When derivatives are used, it is usually accurate single dose elect to obtain equivalent doses of NSAID above. For the treatment described here, the maximum daily dose of ibuprofen, as a rule, is 3200 mg One single daily dose may be 100 mg. Preferred daily dose is enclosed within 100-400 mg, more preferably 100-300 mg and especially 200 mg of ibuprofen. Normally, the maximum daily dose of flurbiprofen 300 mg One single dose can be equal to 12.5 mg. Preferred single dose are in the range of 12.5 to 150 mg, more preferably 25-100 mg and especially 50 mg flurbiprofen. The maximum daily dose of naproxen is typically 1500 mg One single daily dose may be equal to 125 mg. Preferred single dose are within 220-750 mg, more preferably 220-500 mg and especially 220-250 mg of naproxen. Maxim is supplemented flax daily dose of Ketoprofen is usually 200 mg One single dose can be equal to 25 mg. Preferred single dose are in the range 25-100 mg, more preferably 25-75 mg and especially 50 mg Ketoprofen.

The composition is molded tablet preferably includes a combination of granulated component in the form of a component containing silicon dioxide, and optionally a lubricating substance. This combination may take the form of a uniform or homogeneous mixture, able to mix with other ingredients which are desired, and pressoffice in tablets. Tablet composition can be swallowed or dispersed in water before taking. Preferably, the ibuprofen of the tablet composition is released in the stomach or gastrointestinal tract.

In an additional aspect, the present invention provides the use of silicon dioxide in the form of component, mixed with a granular component in the molded composition, where the specified granular component contains lots of solidified melt granules of viscoplasticity (for example, the melting point lies in the range 30-300° (C) non-steroidal anti-inflammatory drug, which includes baking powder and optional diluent, homogeneous dispersed therein, where the composition contains 0.05-5% silicon dioxide by weight to what notizie, and granules include solid phase specified non-steroidal anti-inflammatory drug.

In yet another additional aspect, the present invention provides a method of obtaining a composition molded tablet containing non-steroidal anti-inflammatory drug having a melting point in the range 30-300°With different

a) mixing a specified drug in the fully molten form with the baking powder, obtaining a homogeneous mixture;

b) cooling of this mixture with obtaining a solidified melt;

c) converting the specified solidified melt into pellets;

d) pressing these granules, not necessarily in the form of component, obtaining composition molded tablets.

Baking powder may be the only ingredient that is included in the molten granules NSAID (preferably ibuprofen) or can be mixed with the diluent, and optionally with a surface-active agent and other excipients for tableting. Consequently, the granular composition may consist mainly (i.e. more than 98% by weight of the composition) of ibuprofen and baking powder, or may consist of ibuprofen, baking powder, diluent and optionally a surfactant. Thus, the diluent and optionally surface-AK the active substance can be mixed with baking powder and medicines, fully molten form. Tablet composition according to the invention can be obtained by incorporating silicon dioxide and optionally other excipients in the composition, which tabletroute, preferably to produce a powder mixture, followed by pressing into tablets.

The above method can be performed several ways. In the same way NSAID is heated in a suitable vessel until melted. Then to the molten mass, you can add baking powder and mix thoroughly to obtain a homogeneous mixture. You can also make other optional fillers in the molten NSAID simultaneously or sequentially. The molten mixture can then be uploaded to the appropriate cooling system, for example, chilled tape, which can be continuously moved in a circle, and to deliver the cooled melt in a grinding device, such as a scraper bar and/or mill.

Additional way of non-steroidal anti-inflammatory drug can be mixed with baking powder and optional excipients for tableting, for example, a diluent, and then heated together until the specified non-steroidal anti-inflammatory drug is not completely melted. In yet another additional way NSAID and baking powder are mixed and heated in the natural, until the specified NSAID is not completely melted, and any other desired excipients for tableting uniformly mixed with the mixture.

In another way NSAID and baking powder are placed in an extruder (preferably first United mixing with each other). Substances are heated and mixed in the extruder, NSAID until fully melted and a homogeneous mixture. NSAID and baking powder ekstragiruyut, and the extrudate is cooled. Preferably NSAID and baking powder ekstragiruyut in co-rotating twin screw extruder. Extruded mass of hot (containing NSAID and baking powder) forms an agglomerated mass, which can be collected and, if necessary, crushed to obtain granules.

In additional method after heating or extrusion by heating NSAID and baking powder can be cooled by the flow in the dryer type scrubber with spray device in which the molten mass is sprayed in a stream of cold air, and the dried solid mass is collected.

Granular component may be tableted directly in the absence of the form of the component, or it can be mixed in the form of component and submit to the office for izgotovleniya for pressing into tablets. Preferably in the form of a component includes silicon dioxide and not battelino grease. Additionally preferably, in the form of a component contained silicon dioxide and grease.

In a preferred aspect of the present invention provides a method of obtaining a granulated composition of ibuprofen, which includes the melting of ibuprofen (preferably ibuprofen), uniform incorporation of baking powder in the molten ibuprofen, enabling ibuprofen cooled to obtain a solid substance, and grinding the specified melt with obtaining a granular composition. Baking powder is usually mixed with ibuprofen, obtaining a homogeneous mixture of solid powder in a liquid melt of ibuprofen before cooling.

The composition is compressed tablets according to the invention can be optionally covered with a film cover, for example, cellulose polymer, such as hypromellose, or ordinary sugar shell, for example, on the basis of sucrose or lactose.

Granulated composition may, optionally, be connected with acid for flowability such as silicon dioxide, and placed in capsules. You can get winning results in dissolution. This is not included in the scope of the present invention.

The invention is illustrated in further non-limiting examples. In the examples using the s racemic racemic ibuprofen and flurbiprofen production Knoll Pharma, Nottingham, UK; colloidal silicon dioxide (also known as colloidal silica) manufactured by Degussa, Frankfurt, Germany under the trade name Aerosil 200; sodium salt croscarmellose production FMC Corporation, Brussels, Belgium under the trade name Ac-Di-Sol and sodium starch glycolate production Edward Mendell, Reigate, UK under the trade name Explotab; poloxamer production BASF, Germany under the trade name Pluronic F68; dicalcium phosphate under the trade name Emcompress; hydrogenated castor oil production BASF, Germany under the trade name Cremophor RH40, microcrystalline cellulose production FMC Corporation, Brussels, Belgium under the trade name Avicel PH 101.

Determination of dissolution

Dissolution was determined using dissolution method described in the US Pharmacopoeia, volume 23, str, the apparatus 2 using a stirrer speed of 50 rpm and phosphate buffer (selected at pH 7.2 and/or pH 6.0, and/or pH of 5.8).

The definition of fragility

This test strength tablet is a standard test for fragility, namely, when the rotation of 20 tablets within a certain period of time at a speed of 25 rpm in apparatus for determining the fragility (TAR20 production ERWEKA). Conducted the following definitions:

1. The number of damaged and broken tablets.

2. Weight loss is each pill in %.

Determination of crushing strength

The crushing strength is a measure of the strength of the tablets. It is determined when measuring the transverse tensile crushing when the tablet break when placed between the moving clamps of the tester to determine the crushing strength Schleuniger. Presents the values of strength, crushing five tablets obtained in the compositions of each of examples.

The disintegration time (minutes)

The disintegration time can be determined using the method of determining the disintegration of the European Pharmacopoeia 1986, Ref. V.5.1.1 (revised in 1995) with the use of tap water (pH about 7) as a liquid. The method gives the time during which six of the tablets obtained in each of the example compositions are subjected to disintegration.

Apparatus for granulating

Spray granulator was PFB 28 production APV, Denmark. Scrubber with spray device served FBSD 66 production APV, Denmark. Twin screw extruders have served MR (cylinder 19 mm) and MR PC (drum 40 mm) manufactured by APV, UK.

Example 1

 (% wt./wt.)
Granular component:
Ibuprofen93.9
Sodium salt croscarmellose4.7
The form component:
Colloidal silica0.5
Stearic acid0.9

Example 1: getting granular component

In the illustrative method, the ibuprofen was first melted by heating to about 75°C in stainless steel tanks until completely melted. Then molten ibuprofen was added baking powder (sodium salt croscarmellose) and was stirred for 5-10 min, until a uniform dispersion. The molten mixture was poured on a plate of stainless steel and cooled over a period of time up to 60 min to ensure that the formed suspension. Thus obtained mass was crushed by passing through the cone crusher equipped with a sieve size of round holes 1 mm Collected the obtained granules.

Example 1(b): obtaining tablets

Main ingredients, namely, silicon dioxide and stearic acid (grease), at the same time mixed with the granulated composition within about 15 minutes in the mixer. The mixed material was applied to the apparatus for manufacturing tablets and extruded into tablets containing 200 mg of ibuprofen.

Examples 2-4

 Example 2 (% wt./wt.)Example 3 (% wt./wt.)Example 4 (% wt./wt.)
Ibuprofen91.389.785.8
Sodium salt croscarmellose7.39.012.9
Colloidal silica0.50.40.4
Stearic acid0.90.90.9

Examples 2-4 were obtained in the same manner as described in example 1, to obtain tablets containing 200 mg of ibuprofen.

Examples 5-8

 Example 5 (% wt./wt.)Example 6 (% wt./wt.)Example 7 (% wt./wt.)Example 8 (% wt./wt.)
Ibuprofen93.991.389.785.8
Sodium starch glycolate4.77.39.012.9
Colloidal silica0.50.50.40.4
Stearic acid0.90.90.90.9

Examples 5-8 were obtained in the same manner as described in example 1, except for the fact that as of baking powder used sodium starch glycolate. Received tablets containing 200 mg of ibuprofen.

Examples 9-12

 Example 9 (% wt./wt.)Example 10 (% wt./wt.)Example 11(% wt./wt.)Example 12 (% wt./wt.)
Granular component:
Ibuprofen66.273.963.386.6
Sodium salt croscarmellose5.35.95.16.9
The form component:
 Example 9 (% wt./wt.)Example 10 (% wt./ wt.)Example 11 (% wt./ wt.)Example 12 (% wt./wt.)
Colloidal silica1.01.10.61.3
Stearic acid0.70.70.90.9
Sodium carbonate-18.4--
Sodium bicarbonate26.8---
Sodium citrate--30.14.3

Examples 9-12 were obtained in the same manner described in example 1, except that the filler tube (sodium citrate/sodium carbonate/sodium bicarbonate) included in the form of component for mixing with the granular component. Got pills or component containing 200 mg of ibuprofen. Data on dissolution of the tablets before storage are presented in table 1. Presented in table 2 data on dissolution for examples 2 and 4 after storage for 3 months at 40°C and 75% relative humidity, show that good performance is maintained even when the storage. Table 3 refers to the dissolution of the tablets of example 9 at different pH values. The table shows that even at low pH value of the medium for dissolving out the valuable properties in respect of dissolution.

Table 1

Data on dissolution at pH 7.2 tablets of examples 1-9 before
The time of dissolution10 min20 min30 min45 min60 min
Example:
1>100% >100%>100%>100%>100%
298.2%>100%>100%>100%>100%
Data on dissolution at pH 7.2 tablets of examples 1-9 before
The time of dissolution10 min20 min30 min45 min60 min
Example:
388.5%>100%>100%>100%>100%
484.6%94.4%95.9%96.0%96.2%
587.3%>100%>100%>100%>100%
6>100%>100%>100%>100%>100%
775.0%98.4%>100%>100%>100%
8 88.2%>100%>100%>100%>100%
989.2%98.4%98.4%98.8%98.5%
Table 2
Data on the dissolution at pH 7,2 with storage of examples 2 and 4 for 3 months at 40°With 75% relative humidity
The time of dissolution10 min20 min30 min45 min60 min
Example:
283.9%97.9%99.4%99.6%99.3%
484.5%91.3%90.5%92.3%92.3%
Table 3
Example 9:data on dissolution: pH of 7.2 and 5.8
The time of dissolution10 min20 min30 min45 min60 min
pH 7.289.2%98.4%98.4% 98.8%98.5%
pH 5.846.3%61.6%69.9%77.5%83.8%

It is noted that, despite the fact that at low pH value soluble lower percentage of ibuprofen, this reflects the problems associated with the dissolution of ibuprofen in an acidic environment. Shows the valuable properties of this composition, in the sense that more than 60% of ibuprofen was dissolved within 20 minutes, even at pH of 5.8.

Examples 13-17

 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)Note 17 (% wt./wt.)
Ibuprofen85.785.485.184.784.4
Sodium salt croscarmellose12.912.812.812.712.7
Colloidal silica0.50.91.21.72.1
Stearic acid0.90.90.90.90.8

Examples 13-17 were obtained in the same manner described in example 1, to obtain tablets, content is among 200 mg of ibuprofen. Data on dissolution are presented in tables 4 (pH of 7.2) and 5 (pH 5,8) below.

Table 4
Data on dissolution at pH 7.2
Time (min)PrimPrimPrimPrimNote 17
00.0%0.0%0.0%0.0%0.0%
577.1%66.3%69.6%73.2%89.4%
1087.3%82.0%85.9%86.6%98.1%
2096.8%98.4%99.1%98.6%>100%
3098.2%99.6%99.6%99.3%>100%
4598.3%99.6%99.6%99.4%>100%
6098.3%99.7%99.6%99.4%>100%
Table 5
Data on dissolution at pH 5.8
Time (min)PrimPrimPrimPrimNote 17
00.0% 0.0%0.0%0.0%0.0%
530.4%28.5%24.1%29.1%35.3%
Data on dissolution at pH 5.8
Time (min)PrimPrimPrimPrimNote 17
1051.2%47.0%43.0%48.0%56.3%
2069.9%64.3%63.7%66.0%71.4%
3077.6%72.8%75.8%79.0%75.9%
4583.7%85.0%90.3%91.3%78.4%
6088.0%93.2%95.5%96.3%80.0%

Examples 18-21

 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)21 (% wt./wt.)
Granular component:
Ibuprofen79.084.184.085.7
Sodium salt croscarmellose11.912.612.612.9
Poloxamer7.92.1--
Sodium lauryl sulfate--2.20.2
The form component:
Colloidal silica0.40.40.40.4
Stearic acid0.80.80.80.8

Examples 18-21 were obtained in the same manner described in example 1, except that the surfactant (poloxamer/sodium dodecyl sulfate) was dispersible in the molten ibuprofen once in the molten ibuprofen was evenly dispersed sodium salt croscarmellose. Received tablets containing 200 mg of ibuprofen.

Data on dissolution of the tablets of examples 18-21 at pH of 7.2 and 5.8 are presented in tables 6(a) and 6(b) below.

Table 6(a)
Data on dissolution
Example 18Example 19
Time (min)pH 7.2pH 5.8pH 7.2pH 5.8
00.0%0.0%0.0%0.0%
538.5%24.0%44.6%26.0%
1079.2%59.1%95.5%73.7%
2096.2%91.3%99.5%95.2%
3096.4%98.0%99.6%>100%
4596.4%>100%99.6%>100%
6096.4%>100%99.6%>100%
Table 6(b)
Data on dissolution
Example 20Example 21
Time (min)pH 7.2pH 5.8pH 7.2pH 5.8
00.0%0.0%0.0%0.0%
531.9%19.1%90.1%54.8%
1073.7%57.8%96.6%76.9%
2095.9%90.4%97.0%89.8%
3097.4%96.6%97.2%94.0%
4597.5%98.1%97.3%96.3%
6097.5%8.1% 97.3%97.2%

Examples 22-26

 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)Note 25 (% wt./wt.)Prim (% wt./wt.)
Granular component:
Ibuprofen82.482.479.082.470.6
Sodium salt Croscarmellose12.312.311.912.310.6
 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)Note 25 (% wt./wt.)Prim (% wt./wt.)
The form component:
Microcrystalline cellulose4.1   17.6
Lactose-4.17.9--
Dicalcium phosphate   4.1-
Colloidal silicon dioxide0.40.40.40.40.4
Stearic acid 0.80.80.80.80.8

Examples 22-26 received in the same way described in example 1, except that in the form of a component included diluent (microcrystalline cellulose/lactose/dicalcium phosphate). Received tablets containing 200 mg of ibuprofen.

Data on dissolution for each example at a pH of 7.2 is presented in table 7.

Table 7
Data on dissolution at pH 7.2
Time (min)PrimPrimPrimNote 25Prim
00.0%0.0%0.0%0.0%0.0%
578.8%71.5%85.2%79.0%84.1%
1087.7%82.9%94.3%87.3%95.6%
2095.4%91.2%98.2%93.9%>100%
30100.0%94.6%98.6%96.6%>100%
45>100%95.1%98.7%96.7%>100%
60&g; 100%95.1%98.7%96.7%>100%

Examples 27-28

 Prim (% wt./Mac)Prim (% wt./wt.)
Granular component:
Ibuprofen79.070.6
Sodium salt croscarmellose11.910.6
Microcrystalline cellulose7.9-
Dicalcium phosphate-17.6
The form component:
Colloidal silicon dioxide0.40.4
Stearic acid0.80.8

Examples 27 and 28 were obtained in the same manner described in example 1, except that the diluent (microcrystalline cellulose/dicalcium phosphate) was dispersible in the molten ibuprofen after sodium salt croscarmellose was uniformly dispersed in the molten ibuprofen. Received tablets containing 200 mg of ibuprofen. Data on dissolution at pH of 7.2 is presented in table 8.

Examples 29-30

 Prim (%wt./wt.) Prim (%wt./wt.)
Granular component:
Ibuprofen70.679.1
Sodium salt croscarmellose10.611.9
Lactose8.8-
Dicalcium phosphate-3.9
The form component:
Colloidal silicon dioxide0.40.4
 Prim (%wt./wt.)Prim (%wt./wt.)
Stearic acid0.80.8
Lactose8.8-
Dicalcium phosphate-3.9

Examples 29 and 30 were obtained in the same manner described in example 1, except that half of diluent (lactose/dicalcium phosphate) was dispersible in the molten ibuprofen after the powder was uniformly dispersed in the molten ibuprofen, and the remainder of the diluent was included in the form of a component. Received tablets containing 200 mg of ibuprofen. Data on dissolution for each example at a pH of 7.2 is presented in table 8.

Table 8
Data on dissolution at pH 7.2
Time (min)PrimPrimPrimPrim
00.0%0.0%0.0%0.0%
587.7%50.6%82.5%82.8%
1095.3%59.5%93.0%90.1%
2098.4%67.0%95.8%92.3%
3098.8%71.3%95.7%93.0%
4598.9%75.6%95.7%93.7%
6098.9%78.8%95.7%94.1%

Example 31

 Example 31 (% wt./wt.)
Flurbiprofen21.7
Sodium salt croscarmellose3.3
Colloidal silicon dioxide0.1
 Example 31 (% wt./wt.)
Stearic acid0.2
Microcrystalline cellulose74.7

Example 31 was obtained by the method described in example 1, except for the CSOs, what used flurbiprofen as an NSAID, and microcrystalline cellulose included in the form of a component, i.e. with colloidal silicon dioxide and stearic acid. Received tablets containing 50 mg of flurbiprofen. Data on dissolution at pH of 7.2 are presented in table 9.

Table 9
Data on dissolution at pH 7.2
Time (min)Example 31
00.0%
582.8%
1085.6%
2086.0%
3086.1%
4586.2%
6086.3%

Examples 32-34

 Prim (%wt./wt.)Prim (%wt./wt.)Prim (%wt./wt.)
Ibuprofen82.379.076.0
Sodium salt croscarmellose16.519.822.8
Colloidal silicon dioxide0.40.40.4
Stearic acid0.80.80.8

Examples 32-34 were obtained in the same way is, what is described in example 1, to obtain tablets containing 200 mg of ibuprofen. Data on dissolution are presented in tables 10 (pH 7,2) and 11 (pH 5,8) below.

Table 10
Data on dissolution at pH 7.2
Time (min)PrimPrimPrim
00.0%0.0%0.0%
558.0%70.9%39.7%
1076.9%82.2%60.9%
2089.6%92.3%80.8%
3096.8%95.9%90.9%
4598.5%97.2%97.1%
6098.6%97.2%97.3%
Table 11
Data on dissolution at pH 5.8

Time (min)PrimPrimPrim
00.0%0,0%0.0%
534.7%37.9%23.1%
1062.1%68.7%47.3%
2087.1%90.6% 70.8%
3095.7%97.3%85.7%
4599.0%99.2%93.1%
6099.7%99.0%94.3%

Examples 35-38

 Prim (%wt./wt.)Prim (%wt./wt.)Prim (%wt./wt.)Prim (%wt./wt.)
Granular component:
Ibuprofen85.685.184.884.4
Sodium salt croscarmellose12.812.812.812.8
 Prim (%wt./wt.)Prim (%wt./wt.)Prim (%wt./wt.)Prim (%wt./wt.)
Colloidal silicon dioxide0.81.31.62.0
The form component:
Stearic acid0.80.80.80.8

Examples 35-38 received in the same way described in example 1 except that colloidal silica was evenly dispersible in the molten ibuprofen. Received tablets containing 200 mg of bis is Rowena. Data on dissolution are presented in table 12.

Table 12
Data on dissolution at pH 7.2
Time (min)PrimPrimPrimPrim
00.0%0.0%0.0%0.0%
572.7%64.8%72.7%78.1%
1085.0%75.8%90.1%89.4%
2092.8%84.5%96.1%95.2%
3097.8%95.2%97.4%98.1%
4598.3%99.0%98.4%98.2%
6098.5%99.5%98.4%98.2%

Examples 39-42

 Example 39 (%wt./wt.)Example 40 (%wt./wt.)Example 41 (%wt./wt.)Example 42 (%wt./wt.)
Granular component:
Ibuprofen85.8285.685.582.3
Sodium salt croscarmellose12.86 12.912.812.3
Sodium lauryl sulfate0.040.20.44.1
The form component:
 Example 39 (%wt./wt.)Example 40 (%wt./wt.)Example 41 (%wt./wt.)Example 42 (%wt./wt.)
Colloidal silicon dioxide0.430.40.40.4
Stearic acid0.850.90.90.9

Examples 39-42 was obtained by the method described in example 1, except that sodium lauryl sulfate was evenly dispersible in the molten ibuprofen after the powder was uniformly dispersed in the melt of ibuprofen. Received tablets containing 200 mg of ibuprofen. Data on dissolution are presented in table 13.

Table 13
Data on dissolution at pH 7.2
Time (min)Example 39Example 40Example 41Example 42
00.0%0.0%0.0%0.0%
595.7%76.0% 62.7%24.0%
10>100%95.9%81.8%50.0%
20>100%98.7%97.3%74.4%
30>100%98.8%99.2%89.4%
45>100%98.8%99.2%>100%
60>100%98.8%99.2%>100%

Example 43

 (% wt./wt.)
Granular component:
Ibuprofen82.6
Sodium salt croscarmellose12.4
Hydrogenated castor oil2.1
The form component:
Colloidal silicon dioxide2.1
Stearic acid0.8

Example 43 was obtained in the same manner described in example 1, except that the hydrogenated castor oil was evenly dispersible in the molten ibuprofen after the powder was uniformly dispersed in the melt of ibuprofen. Received tablets containing 200 mg of ibuprofen. The data is about the dissolution is presented in table 14.

Table 14
Data on dissolution at pH 7.2
Time (min) 
00.0%
576.6%
1098.7%
2099.1%
3099.1%
4599.1%
6099.1%

Examples 44-45

 Example 44 (% wt./wt.)Example 45 (% wt./wt.)
Granular component:
Ibuprofen79.172.2
Sodium salt croscarmellose11.910.8
Potassium citrate monohydrate7.7-
Sodium citrate-15.7
 Example 44 (% wt./wt.)Example 45 (% wt./wt.)
Sodium lauryl sulfate0.20.2
The form component:
Colloidal silica 0.40.4
Stearic acid0.70.7

Examples 44 and 45 were obtained in the same manner described in example 1, except that at the beginning the baking powder evenly was dispersible in the molten ibuprofen, then the diluent (potassium citrate monohydrate/sodium citrate) were evenly dispersible in it, and finally, sodium lauryl sulphate was dispersible in the molten ibuprofen. Received tablets containing 200 mg of ibuprofen. Data on dissolution are presented in table 15.

Table 15
Data on dissolution
 Example 44Example 45
Time (min)rnrnrnrn
00.0%0.0%0.0%0.0%
549.4%40.6%59.8%47.8%
1094.7%80.7%95.2%85.9%
2099.5%93.2%97.4%97.6%
3099.5%96.2%97.4%98.4%
45 99.5%97.2%97.4%98.0%
6099.5%97.2%97.4%97.8%

Example 46

 (% wt./wt.)
Granular component:
Ibuprofen86.3
Sodium salt croscarmellose12.9
Sodium lauryl sulfate0.2
The form component:
Colloidal silica0.4
Sodium lauryl sulfate0.2

Example 46 was obtained in the same manner described in example 1, except that sodium lauryl sulfate is also included in the form of the component, and the granular component. Received tablets containing 200 mg of ibuprofen.

Example 47

 (% wt./wt.)
Granular component:
Ibuprofen31.5
Sodium salt croscarmellose4.7
Sugar31.5
Sodium bicarbonate12.8
Agranular the cell component:
Colloidal silica0.2
Stearic acid0.3
Citric acid monohydrate1.6
Sorbitol15.7
Flavors/sweeteners1.7

Dispersible tablet, adapted to be diluted in water before the meal was obtained in the same manner described in example 1, including sugar and bicarbonate of sodium in the molten granules and citric acid, powdered sorbitol, flavoring agents and sweeteners in the main ingredients. Received tablets containing 200 mg of ibuprofen.

Example 48

Received composition comprising the following ingredients by the method schematically presented below:

 Example 48 (% wt./wt.)
Granular component:
Ibuprofen85.8
Sodium salt croscarmellose12.9
Main components:
Colloidal silica0.4
Stearic acid0.9

Example 48A

Ibuprofen was added to the tank with a steam jacket and heated to 75-80°while ibuprofen the totally what Yu will not fuse. To the molten ibuprofen was added sodium salt of croscarmellose and stirred to obtain a suspension of the sodium salt croscarmellose in the molten ibuprofen. The mixture was poured on a plate of stainless steel and allowed to cool. After all the mass has hardened, it was passed through a cone crusher, equipped with a sieve size of round holes 1 mm was Collected granulate with an average particle size in the range of 150-250 microns.

The granulate was added colloidal silicon dioxide and stearic acid and stirred until a homogeneous mixture. The stirred mixture was pressed into tablets in a conventional apparatus for manufacturing tablets with obtaining tablets containing 200 mg of ibuprofen. Optionally, the tablets can be coated usual sugar-or film-coated.

It was found that the resulting tablets had the following characteristics:

The strength of the pill crushing - 30-80 N

The fragility tablets - no damaged or broken tablets in 10 minutes

Weight loss <0,1%

Example 48b

In the following example describes one method includes melting, cooling and granulation in the same tank (as described above) to obtain a granulation of the melt. The equipment includes a vessel with a shirt, which gives the possibility of the activity of the heating steam and cooling water, equipped with a low shear mixer and high speed cutter/granulator. Equipment of this type is available from Niro/Fielder Limited. Another example is the mixer Colette.

Ibuprofen and sodium salt croscarmellose was added in the form of dry powders in a container with a shirt. They were heated to 75°with stirring, until the ibuprofen is not completely melted, and the sodium salt of croscarmellose kept in suspension in the liquid ibuprofen. At this stage, was stopped by heating the steam, and the tank was cooled by circulating cold water in the jacket. When cooled mixture, it became more viscous. Powered high-speed cutter to break the hardened mass into granules. The granulate is optionally crushed to obtain granules having an average particle size in the range of 150-250 microns.

Colloidal silicon dioxide and stearic acid were added to the granules and mixed until a homogeneous mixture. The stirred mixture was pressed into tablets containing 200 mg of ibuprofen. Optionally, the tablets can be coated usual sugar-or film-coated.

It was found that the resulting tablets have the following characteristics:

The strength of the pill crushing - 30-80 N

The fragility tablets - no damaged or broken tablets in 10 minutes

Mass loss of the < 0,1%

Example 48S

In the following example describes how to obtain granulated melt spraying granulation. In this way the ingredients were melted in a suitable vessel and submitted by the pump spray head of the spray granulator. The melt was sprayed in a stream of cold air, and the resulting granulate was made by melt agglomeration in the hardened.

Ibuprofen and sodium salt croscarmellose was added in the form of dry powders in a tank shirt. They were heated to 75°with stirring, until the ibuprofen is not completely melted, and the sodium salt of croscarmellose kept in suspension in the liquid ibuprofen.

The mixture was transferred into a spray granulator through heated lines. The molten dispersion is sprayed in a stream of cold air, adjusting the spray rate of the feed material and the removal rate of particles until they received particles suitable for tabletting size. The granulate was unloaded into a container.

Colloidal silicon dioxide and stearic acid were added to the granules and mixed until a homogeneous mixture. The stirred mixture was pressed into tablets containing 200 mg of ibuprofen. Optionally, the tablets can be coated usual sugar-or film-coated.

It was found that the resulting tablets had the following the features:

The strength of the pill crushing - 30-80 N

The fragility tablets - no damaged or broken tablets in 10 minutes

Weight loss <0,1%

Example 48d

Received molten composition using the dryer type scrubber with spray device. This method is similar to the spray granulating, but differs in that the granulate was obtained by one-step spray dispersion.

Ibuprofen and sodium salt croscarmellose was added in the form of dry powders in a tank shirt. They were heated to 75°with stirring, until the ibuprofen is not completely melted, and the sodium salt of croscarmellose kept in suspension in the liquid ibuprofen.

The mixture was transferred to a spray head located in the upper part of the scrubber with spray device, the heated line. The molten dispersion is sprayed in a stream of cold air until the formed particles directly in the melt hardens into solid particles. Chilled hardened granules were collected and placed in the container.

Colloidal silicon dioxide and stearic acid were added to the granules and mixed until a homogeneous mixture. The stirred mixture was pressed into tablets containing 200 mg of ibuprofen. Optionally, the tablets can be coated usual sa is a subsidiary or film-coated.

It was found that the resulting tablets had the following characteristics:

The strength of the pill crushing - 30-80 N

The fragility tablets - no damaged or broken tablets in 10 minutes

Weight loss <0,1%

Example 48th

Ibuprofen and sodium salt croscarmellose stirred to obtain a homogeneous powder mixture, which was then introduced into a heated chamber rotating twin screw extruder screw through the hopper. The cylinder of the extruder was heated to a temperature of below. The ingredients were heated and processed in the extruder until fully ibuprofen melts. Solid molten ribbon of the extruder was unloaded at a chilled stainless steel belt, to allow the extrudate to cool for a period of time up to 1 minutes of the Hardened mass was crushed and passed through a cone crusher, equipped with a sieve size of round holes of 1 mm, to obtain granules having an average particle size in the range of 150-250 μm, was mixed with colloidal silicon dioxide and stearic acid, until he had a homogeneous mixture. The mixture was extruded to obtain tablets containing 200 mg of ibuprofen. On tablets, you can apply an optional sugar or film membrane using conventional technology.

Were tested following extrude the s:

 The model of the extruderThe ratio d/DThe temperature of the cylinderOutput
1Mr 1940:177°10 kg/h
2Mr 1925:180°10 kg/h
3Mr 1917.5:180°10 kg/h
4Mr RS17.5:190°100 kg/hour
*The ratio d/D = length/diameter

It was found that the resulting tablets had the following characteristics:

The strength of the pill crushing - 30-80 N

The fragility tablets - no damaged or broken tablets in 10 minutes

Weight loss <0,1%

Data on dissolution - see table 16 (Extruder MR; the ratio d/D 17,5:1)

Table 16
Data on dissolution at pH 7.2
Time (min) 
00.0%
582.4%
1096.9%
2098.9%
30 99.1%
4599.2%
6099.2%

In the same way it is possible to obtain tablets containing 50 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg of ibuprofen and S(+)-ibuprofen, flurbiprofen, S(+)-flurbiprofen, Ketoprofen, S(+)-Ketoprofen, naproxen and S(+)-naproxen. Optionally you can also include an inert diluent, such as sugar and/or cellulose, taking into account differences in the dosages required to achieve a therapeutic effect, compared to the amount of ibuprofen, are usually included in solid dosage forms.

In addition, you can use the following baking powder instead of baking powder, presented here in each of the illustrative examples: wheat starch, corn starch, potato starch, nizkozameshhennoj hydroxypropylcellulose, aginova acid, cross-linked polyvinylpyrrolidone and magnesium aluminosilicate.

For example, you can receive the following examples in a similar way to the illustrative examples described earlier:

Examples 49-55

 Example 49 (%wt./wt.)Example 50 (%wt./wt.)Example 51 (%wt./wt.)
Granular component:
Ibuprofen67.665.3 63.3
Sodium salt croscarmellose3.46.59.5
The form component:
Colloidal silica1.01.01.0
Stearic acid0.70.70.7
Sodium bicarbonate27.326.525.5

 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)
Granular component:
Ibuprofen82.382.382.382.3
Sodium salt croscarmellose16.312.412.412.2
Sodium citrate-4.1-4.1
Potassium citrate--4.1-
Sodium lauryl sulfate0.2 -0.2
The form component:
Colloidal silicon dioxide0.40.40.40.4
Stearic acid0.80.80.80.8
Sodium lauryl sulfate----

Examples 56-61

 Prim (% wt./wt.)Prim (% wt./wt.)Prim (% wt./wt.)
Granular component:
Ibuprofen79.079.082.3
Sodium salt croscarmellose11.911.912.2
Sodium citrate7.9--
Potassium citrate-7.94.1
Sodium lauryl sulfate--0.2
The form component:
Colloidal silicon dioxide0.40.40.8
Stearic acid0.80.8-
Laure is sulfate sodium --0.2
 Example 59 (% wt./wt.)Example 60 (% wt./wt.)Example 61 (% wt./wt.)
Granular component:
Ketoprofen (50 mg/pill31.345.5-
Naproxen (250 mg/tablet)--88.3
Sodium salt croscarmellose5.07.210.6
The form component:
Colloidal silica0.60.90.4
Stearic acid0.60.90.7
Microcrystalline cellulose62.545.5-

Examples 62-64

 Example 62 (% wt./wt.)Example 63 (% wt./wt.)Example 64 (% wt./wt.)
Granular component:
Ibuprofen 79.179.172.2
Sodium salt croscarmellose11.919.511.0
Sodium citrate7.6-15.7
Sodium lauryl sulfate0.20.2 
The form component:
Colloidal silicon dioxide0.40.40.4
Stearic acid0.80.80.7

Comparative examples

Comparative example 1

(Pressed tablets without silica)

Granular component for the comparative examples were obtained in the same way, which is described in the illustrative examples. The granular component of comparative examples A-D contained only the molten granules of ibuprofen together with different amounts of sodium salt croscarmellose as baking powder. Tablets were obtained by pressing granular component without the form component. The granular component of comparative examples E-H contain ibuprofen and sodium salt croscarmellose in different ratios. Granular component was mixed with 1% stearic acid as the sole ingredient n the granular component.

Comparative example 1

The time of dissolution10 min20 min30 min45 min60 min
Example     
A (5% powder)2.6%5.7%9.6%14.3%18.8%
(8% baking powder)2.2%7.3%10.1%15.5%19.9%
(10% of baking powder)0.1%0.0%-0.1%0.0%0.0%
D (15% of baking powder)-0.9%3.4%6.7%10.8%15.8%
E (5% powder)1.2%5.5%8.8%13.2%17.9%
F (8% baking powder)0.4%5.8%8.6%13.5%16.6%
G (10% baking powder)2.4%5.9%9.7%15.5%20.4%
N (15% baking powder)1.3%5.4%9.8%14.2%20.7%

It is obvious that the above comparative example 1 shows the relatively weak dissolution in comparison with the examples according to the invention.

Comparative example 2

The next example is taken from the patent application of Japan 120616 (1981) (example 5). In this example, the prepared tablets containing 200 mg of ibuprofen containing the ingredients listed below.

 (% wt./wt.)
Ibuprofen79.4
Microcrystalline cellulose7.9
Oxypropylated starch11.9
Calcium stearate0.8

Data on dissolution at pH of 7.2 is presented in a comparative table 2.

Comparative table 2

Data on dissolution at pH 7.2
Time(min) 
00.0%
513.1%
1023.4%
2035.7%
3043.5%
4551.8%
6058.0%

It is obvious that the above comparative example 1 gives a relatively weak dissolution in comparison with the examples according to the invention.

Comparative example 3

The composition of example 48 was put through the extruder the P19 (the ratio d/D 17,5:1), in which the cylinder was heated to 75°With (experience) or 50°With (experience). In experience And ibuprofen fully melted. However, experience a significant amount of ibuprofen is not melted, and thus, the ibuprofen was in two phases. Data on dissolution at pH of 5.8 to experience and experience as presented in the comparative table 3.

Comparative table 3

Data on dissolution at pH 5.8
Time (min)ExperienceExperience
00.0%0.0%
541.6%23.9%
1066.7%45.3%
2085.4%71.3%
3092.4%85.5%
4596.2%94.0%
6097.5%96.6%

It is obvious that the dissolution of the comparative example (the experience) is much less than the dissolution of the compositions according to the invention (experiment A).

1. The composition is compressed tablet comprising a granular component containing lots of solidified melt granules of non-steroidal anti-inflammatory drugs having a melting point in the range 30-300°and containing the th baking powder, uniformly dispersed therein;

wherein the non-steroidal anti-inflammatory drug is completely inside the granules in the form of a single continuous crystalline phase, and the specified composition tablet contains silicon dioxide in an amount of 0.05 to 5.0% by weight of the composition.

2. The composition is compressed tablet according to claim 1, characterized in that silicon dioxide is present in the form of degranulating component.

3. The composition is compressed tablet according to claim 2, characterized in that agronomy component further comprises a lubricating agent.

4. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that the granular component additionally contains a surface-active substance.

5. The composition is compressed tablet according to any one of claims 1 to 4, characterized in that it contains

a) 60-99,95% granular component by weight of the composition, where the specified granular component comprises from 0.005 to 1 parts by weight of baking powder to one part by weight of non-steroidal anti-inflammatory drugs;

b) 0.05 to 40% degranulating component by weight of the composition.

6. The composition is compressed tablet according to any one of the preceding paragraphs, wherein the non-steroidal anti-inflammatory medication is the main means selected from ibuprofen, flurbiprofen, Ketoprofen and naproxen or their enantiomers.

7. The composition is compressed tablet according to any one of the preceding paragraphs, wherein the non-steroidal anti-inflammatory drug is ibuprofen.

8. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that the baking powder is selected from sodium starch glycolate, and sodium salt croscarmellose.

9. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that it contains 0.1 to 3% silicon dioxide by weight of the composition.

10. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that it contains 0.1 to 20% diluent by weight of the composition.

11. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that the granular component contains 70-95% of non-steroidal anti-inflammatory drugs on the mass of the granular component.

12. The composition is compressed tablet according to claim 7, characterized in that it includes

a) 90-99,95% granular component by weight of the composition, where the specified granular component comprises a solidified molten granules of ibuprofen containing the sodium salt of croscarmellose and optional diluent, uniformly dispersed in n the m moreover, the specified ibuprofen is present in an amount of 70-99% by weight of the composition specified sodium salt croscarmellose is present in an amount of 1-25% by weight of the composition, and the specified diluent is present in the amount of 0-20% by weight of the composition; and

b) 0.05 to 10% degranulating component by weight of the composition, including

i) 0.1 to 3% lubricant by weight of the composition; and

ii) 0.05 to 2% silicon dioxide by weight of the composition.

13. The composition is pressed tablets of item 12, wherein the granular component consists mainly of ibuprofen, sodium salt croscarmellose and diluent selected from microcrystalline cellulose and salts of organic acids.

14. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that it contains 70-95% of ibuprofen by weight of the composition.

15. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that it contains 3-20% sodium salt croscarmellose by weight of the composition.

16. The composition is compressed tablet according to any one of the preceding paragraphs, characterized in that it contains agronomy component, consisting mainly of silica and the lubricant in the ratio of 1 part by weight of silicon dioxide 0.5-5 parts by weight of the lubricant.

17. Songs which I compressed tablet according to any one of the preceding paragraphs, characterized in that it contains a homogeneous mixture

a) a granular component comprising

i) 70-90% of ibuprofen by weight of the composition;

ii) 8-20% sodium salt croscarmellose by weight of the composition;

iii) 0-20% of a diluent by weight of the composition; and

b) degranulating component, including

iv) 0.5 to 2% stearic acid or its salts by weight of the composition;

v) 0.1 to 2.5% silicon dioxide by weight of the composition,

where the sum of components (i)to(v) above 99% by weight of the composition.

18. Composition according to any one of claims 1 to 17 for use in the treatment of pain and/or inflammation and /or fever.

19. Composition according to any one of claims 1 to 17 for the manufacture of a medicinal product for the treatment of pain and/or inflammation and/or fever.

20. The granulate suitable for use in the compositions of the tablets according to claim 1 and which includes a set of solidified melt granules of ibuprofen, characterized in that the entire ibuprofen is present within the granules in the form of a single continuous crystalline phase, and granules mainly consist of a homogeneous mixture of 70-95% of ibuprofen by weight of the granules, 5-20% of baking powder on the mass of the granular composition and 0-20% of a diluent selected from lactose, salts of alkaline metal, microcrystalline cellulose or dicalcium phosphate, by weight of the granules.

21. The granulate according to claim 20, trichosis fact, what baking powder is present in an amount of from 8 to 20% by weight of the granular composition.

22. The granulate according to claim 20 or 21, characterized in that the diluent comprises a salt of an alkali metal, preferably sodium bicarbonate or sodium citrate.

23. The granulate according to any one of p-22, characterized in that the diluent is present in an amount up to 20% by weight of the granular composition.

24. The granulate according to any one of p-22, characterized in that it further comprises a surfactant present in an amount of from 0.05% to 10% by weight of the granular composition.

25. The granulate according to claim 20 for the manufacture of a medicinal product for the treatment of pain and/or inflammation and/or fever.

26. The use of silicon dioxide as an agent to improve the disintegration of the molded composition in terms of the water environment, where the molded composition includes granular component containing lots of solidified melt granules of non-steroidal anti-inflammatory drug that is present in the granules in the form of a single continuous crystalline phase and having a melting point in the range 30-300°, baking powder, and optional diluent, homogeneous dispersed therein, and silicon dioxide is present in anagramarama component, mixed with the granular component, the amount of 0.05-5 wt.% of the mass of the molded composition.

27. A method of obtaining a composition compressed tablet according to claim 1, characterized in that

a) get a homogeneous mixture of the specified drugs in the fully molten form with the baking powder, need not be silicon dioxide;

b) cool this mixture with the formation of the solidified melt;

C) make specified the solidified melt granules;

d) press these granules, optional with agranular component containing silicon dioxide, with the formation of the composition molded tablets;

where preformed composition contains silicon dioxide in amounts of from 0.05 to 5.0% by weight of the composition.

28. The method according to item 27, wherein the specified non-steroidal anti-inflammatory drug and the specified baking powder are mixed, and then heated together until the specified non-steroidal anti-inflammatory drug is not completely melted.

29. The method according to any of item 27 or 28, characterized in that the medicinal product and the specified baking powder is extruded.

30. The method according to clause 29, characterized in that the medicinal product and the specified baking powder is extruded in a twin screw extruder.

31. The method according to any of PP-30, characterized in that the granules are mixed with degranol rim component, containing grease and silicon dioxide, before pressing into tablets.

32. The method according to any of p-31, where the diluent and optionally a surfactant is mixed with the baking powder and medicine in a completely molten form.

33. The method according to any of p-32, where the specified drug includes ibuprofen.

34. A method of treating pain and/or inflammation and/or fever, which includes the introduction of a composition according to any one of claims 1 to 17 mammal if necessary.

Priority points and features:

09.12.1999 according to claims 1-3, 6-9, 18, 19, 28, 29, 33 and 34 relate to ibuprofen;

30.11.2000 according to claims 1-3, 6-9, 18, 19, 28, 29, 33 and 34 relate to non-steroidal anti-inflammatory drugs (NSAID) and claims 4, 5, 10-17, 20-27, 30, 31 and 32.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new spiroimidazolidine derivatives of the formula (1):

wherein R1 represents hydrogen atom or methyl; R2 represents phenyl or (C1-C4)-alkyl; X represents -CH2-CH2- or -CH2-CH2-CH2-; W represents isopropyl or cyclopropyl; V represents hydrogen atom or methoxy-group; E represents -CO-R3 wherein R3 represents hydroxy-group, (C1-C4)-alkoxy- or amino-group; phenyl represents unsubstituted phenyl residue or phenyl residue substituted with one or some similar or different substitutes taken among the group consisting of (C1-C4)-alkoxy-, methylenedioxy- and ethylenedioxy-group in all its stereoisomeric forms and their mixtures in all ratios, and to its physiologically acceptablesalts. Also, invention relates to a method for preparing compounds of the formula (1) and pharmaceutical composition based on these compounds. Invention provides preparing new compounds eliciting the inhibitory effect with respect o leukocytes adhesion.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

16 cl, 1 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-descimated the

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to new compounds which are inhibitors of interleukin-1-converting enzyme (IAP), is characterized by a specific structural formula; to pharmaceutical compositions having the ability to inhibit interleukin-1-converting enzymes, method of treatment and prophylaxis of diseases selected from the group consisting of IL-1-mediated autoimmune inflammatory, neurodegenerative diseases, as well as the selection method of the IAP inhibitor

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to organic chemistry and can find application in medicine

The invention relates to medicine, in particular the production of medicinal substances from the funds of vegetable origin

FIELD: medicine, pharmacy.

SUBSTANCE: invention discloses compositions with sustained-release of active component and masking taste that comprise one of more active components included in tricomponent matrix structure as a globule. This structure is formed successively by amphiphilic, lipophilic or inert matrices and included as globule or dispersed in hydrophilic matrix. Applying large amount of systems for regulation of dissolving active component provides modulating the dissolving rate of active component in aqueous and/or biological fluids by regulating thus kinetics in releasing active component in digestive tract.

EFFECT: valuable pharmaceutical properties of compositions.

14 cl, 14 ex

FIELD: medicine.

SUBSTANCE: biologically active additive has propolis and pot marigold tincture, ascorbic acid, calcium gluconate, benadryl, rutin and auxiliary substances like starch, calcium stearate, talc taken in known proportion. The biologically active additive is produced as tablets of mass 0.55 g.

EFFECT: enhanced effectiveness of prophylaxis.

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a tablet decomposing rapidly in the buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of a medicinal agent and excipient. Tablet is made by uniform mixing saccharide with low melting point with tablet mass to form bridge between particles of named medicinal agent and/or excipient through melting product followed by hardening mentioned saccharide with low melting point. Except for, invention relates to a method for making tablet decomposing rapidly in buccal pocket and comprising a medicinal agent, excipient and saccharide with relatively lower melting point than that of medicinal agent and excipient. Method involves: (a) the parent components of tablet comprising a medicinal agent, excipient and saccharide with relatively lower melting point that that of a medicinal agent and excipient are pressed under low pressure to provide the required tablet form; (b) pressed product obtained after stage (a) is heated to temperature when saccharide with low melting point is melted; (c) melted product obtained after stage (b) is cooled to temperature when melted saccharide with low melting point is hardened. Invention represents a tablet decomposing rapidly in buccal pocket and having the tablet strength providing its using in tablet-making machines for dosed formulations and giving the possibility for making tablet using common tablet-making machines, and to a method for making tablets. Except for, invention represents a tablet decomposing rapidly in buccal pocket being this table as compared with common tablets has enhanced tablet strength and improved frangibility without prolonged decomposing time in buccal pocket, and a method for tablet making.

EFFECT: improved making method.

63 cl, 4 tbl, 1 dwg, 21 ex

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

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

The invention relates to the field of creation of biologically active additives and can be used as a General tonic antihypoxic contribute to a reduction of toxic effects of alcohol
The invention relates to pharmaceutical industry and relates to the creation of tools, plant-based, and can be used as a therapeutic and preventive antiaggregatory, cardio, ventunesimo and improves microcirculation funds in vascular disorders

The invention relates to the pharmaceutical industry and is used as an auxiliary bracing means with hypothermia, to reduce the risk of chronic inflammatory diseases of the musculoskeletal system

The invention relates to the pharmaceutical industry and is used as a means of improving the quality of thinking, memory, the body's resistance to physical and mental stress

FIELD: medicine, dermatology, pharmacy.

SUBSTANCE: invention proposes a cosmetic agent for prophylaxis of skin infectious diseases that comprises an active substance and a conducting agent - multilamellar liposomes additionally. As an active substance dioxydin is used in the amount 0.00001-0.02 wt.-% to the external agent mass. Method for prophylaxis of skin infectious diseases involves using a cosmetic agent in the form of spoon or shampoo, or gel, or cream in the dose depending on selection of the composition and properties of cosmetic agent. Applying the agent results to reducing injurious effect on skin normal microflora, reducing danger from penetration of preparation in blood and providing high protection of skin against all species of infection. Invention can be used for prophylaxis of skin diseases in humans.

EFFECT: valuable medicinal properties of agent.

2 cl, 2 ex

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