A method of obtaining a pharmaceutical composition, pharmaceutical composition, pharmaceutical preparation, the method of obtaining pharmaceutical drug

 

(57) Abstract:

The invention relates and the chemical-pharmaceutical industry and relates to a method of producing a pharmaceutical composition in the form of agglomerates, also pharmaceutical compositions in the form of agglomerates, a pharmaceutical product and method of its production. The inventive method consists in obtaining pharmaceutical compositions in the form of agglomerates containing 70-97 wt.% 2-(4-isobutylphenyl)propionic acid or its pharmaceutically acceptable salt and 3-30 wt. % starch component, and the method comprises the stages: the preparation of the emulsion containing 70-97 wt.% 2-(4-isobutylphenyl)propionic acid or its salts, solvents, 3-30 wt.% component of starch, water and optionally a surfactant, crystallization obtaining slurry containing crystals of 2-(4-isobutylphenyl)propionic acid or a salt thereof in direct contact with a component of starch, mixing the specified suspension with the formation of agglomerates containing uniformly distributed mixture of 2-(4-isobutylphenyl)propionic acid or a salt thereof and a component of starch, collection of these agglomerates and optional drying specified and is 2-100,0% pharmaceutically acceptable excipient, which are suitable for direct tabletting. The invention provides high output, there is minimal loss of material in the process of implementation of the method and the product has a high content of active ingredient, but is smaller. 4 C. and 21 C.p. f-crystals, 8 PL.

The present invention relates to a method for producing pharmaceutical compositions containing 2-(4-isobutylphenyl)propionic acid or its salt, to compositions obtained by the above method, and to pharmaceutical preparations containing these compositions.

2-(4-Isobutylphenyl)propionic acid, ibuprofen, is a potential and is quite tolerant anti-inflammatory, analgesic and antipyretic connection. Racemic mixture consists of two enantiomers, namely S(+)-2-(4-isobutylphenyl)propionic acid or S(+)-2-ibuprofen and R(-)-2-(4-isobutylphenyl)propionic acid or P(-)-ibuprofen. It is known that S(+)-ibuprofen is the active agent and that part of R(-)-ibuprofen is transformed into S(+)-ibuprofen in the human body. The medicine is available as a racemic mixture, but the latest data show, however, that in some circumstances it is preferable to assign DL the E. mixing the active ingredient with a low-cost, easily accessible fillers and then direct tableting the resulting mixture into tablets. This method is not suitable for ibuprofen because it doesn't happen tablets of satisfactory quality. Instead, to obtain tablets containing ibuprofen, a commonly used technology for wet granulation. This means that required under extrapolate that add value to the way tableting.

An additional problem is that when ibuprofen is subjected to wet granulation conventional methods, it is necessary to introduce a relatively high percentage of fillers, to obtain tablets of satisfactory quality. This increases the size of the tablet, and accordingly tablets high dose are less acceptable to some patients. There is therefore a need to develop ways to obtain tablets of ibuprofen smaller, with a high percentage of drugs, simple and inexpensive method of obtaining a composition on the basis of ibuprofen, which can be directly tableted into tablets. Different ways were suggested, but a fully satisfactory solution just found.

In Journal of Pharmaceutical Sciences, I. 78, page 68 (1989) discusses a method of producing microspheres with controlled release of the core product of ibuprofen with acrylic polymers agglomeration in the system ethanol - water. There is no assumption that this method could be applied to obtain tablets with a normal ability to release the main product, and tablets with controlled microstructure.

EP 298666 describes dried by spraying the composition on the basis of ibuprofen suitable for direct tabletting in tablets, consisting mainly of spray dried dispersions of ibuprofen in water, pre-gelatinizing starch. He also describes the tablets obtained from these compositions.

This method has some drawbacks. Two principal disadvantage lies in the fact that the physical properties of the finished granules cannot easily regulirovanie operation due to the large energy consumption, required for the method of drying by atomization.

US 4911921 describes granulated composition, containing 85% or more of ibuprofen, a binder, polyvinylpyrrolidone in a film-forming amount, and up to 2.0% moisture, and this granulation is carried out in the form of agglomerates of ibuprofen and a binder, supported together a binder and polyvinylpyrrolidone. Binder is selected from the group consisting of starches, cellulose, and sugars. The composition is translated into a flowing state of ibuprofen portion of the binder, melting the mixture with a water dispersion of polyvinylpyrrolidone and the balance binder and drying the resulting granules. Describes what these granules can directly tabletroute in tablets. This method requires under extrapolate, including sophisticated equipment and the relatively high cost of operation.

Thus, none of the above methods does not provide a fully satisfactory solution, because they include either (a) the introduction of a relatively expensive filler, or (b) the use of expensive plant equipment in combination with high power consumption. We now have found a cheap, effective, controlled method of obtaining a composition of 2-(4-what sloti or S(+)-enantiomer. This composition can be easily modified to obtain a pharmaceutical preparation that is suitable for direct tabletting in tablets, which have a high content of the active ingredient, but are relatively smaller than other tablets, containing the same active ingredient.

The present invention is a method of obtaining a pharmaceutical composition in the form of agglomerates containing 70 to 97 wt.% 2-(4-isobutylphenyl)propionic acid or its pharmaceutically acceptable salt and 3 to 30 wt. % starch component, and this method consists of the steps:

a) formation of an emulsion containing 1) 70 to 97 wt.% 2-(4-isobutylphenyl) propionic acid or a salt thereof, 2) a solvent system 3) 3 to 30 wt.% component starch 4) water and, optionally, 5) a surfactant;

b) crystallization of obtaining slurry containing crystals of 2-(4-isobutylphenyl)propionic acid or a salt thereof in close contact with a component of starch;

c) mixing the specified suspension with the formation of agglomerates containing uniformly distributed mixture of 2-(4-isobutylphenyl)propionic acid or a salt thereof and a component of starch;

d) the specified collection is designed attempts to obtain the pharmaceutical composition, suitable for direct tabletting, with a high percentage of ibuprofen, described earlier, that the relatively simple method of this invention it is possible to obtain a homogeneous agglomerates with excellent tabletiruemogo of the emulsion containing 2-(4-isobutylphenyl)propionic acid and a component of starch. Suddenly, what initially deposited particles are formed of solid agglomerates, and that these agglomerates can be easily filtered in the form in which they have excellent physical properties for further processing. The method can be carried out both periodic and continuous way. In particular, preferably, the method can be introduced as the last stage in the synthesis of 2-(4-isobutylphenyl)propionic acid with obtaining medications in the right tableting form directly, without the cost of further processing stages. Significant savings obtained by eliminating the stage of extrapolate, and savings derived from the implementation of the method as part of the chemical synthesis in a large reaction vessel, means that the present method has a significant advantage in obtaining drugs from this widely used pharmaceutical product.

Another advantage of the present invention is that the method gives a very high yield. There is minimal loss of material during the process.

Combined benefits result in a very simple and very cost-effective, efficient, reproducible way.

S(+)-ibuprofen has properties different from the properties of ibuprofen. For example, S(+)-ibuprofen melts at 51oC, which is considerably lower than the melting point of ibuprofen, which melts at 75 - 77oC. Therefore, the formation of S(+)-ibuprofen in tablets and intermediate drying and stage of processing must be performed at a lower temperature than is possible for ibuprofen. This difference in the melting point of the lake is mi for S(+)-ibuprofen. Moreover, it is difficult to crystallize S(+)-ibuprofen in the form of small crystals, possibly due to the increased solubility of S(+)-ibuprofen in organic solvents. This leads to difficulties in obtaining tablets of S(+)-ibuprofen with good strength, solubility and bioregionally. Unexpectedly, and in particular it is preferable that the method of the present invention is also suitable for use with S(+)-ibuprofen to obtain valuable compositions with excellent properties, is able to provide tablets with good disintegration and bioregionally.

Tabledirect, the ability of tablets to disintegration and solubility depend on the size of the primary agglomerated crystals in the compositions, which can be observed using scanning microscopy. Specific surface area (m2g1) is an important indicator of the size of the crystals and, therefore, ability and pelletizing. Compositions with high surface area (for example, 0.5 m2g-1) (small crystals) are easily deformed in the tabletting process with the formation of strongly bonded matrix of ibuprofen, which quickly desintegrated and insoluble. On the contrary, compositions with a low the Eski small pill. However, the latter have excellent ability to disintegration time and dissolution, because there is no continuous matrix of ibuprofen. Controlling material, in the process find a balance between crystalline structure with excellent tabletiruemogo and coarse-crystalline structure with improved disintegrability and bioregionally. In a particular advantage of the present invention is that the specific surface area required for a particular drug, can be obtained by changing the process conditions, e.g. temperature, relative amounts of starting materials, the cooling rate, etc.

Is suitable, when the specific surface area of the agglomerates is in the range from 0.05 to 0.8 m2g-1, preferably in the range of 0.1 - 0.5 m2g-1and most preferably in the range of 0.20 - 0.40 m2g-1.

The average size of the agglomerates can be selected as required for the envisaged application. Is suitable, when the average size of the agglomerates is in the range of 50 μm to 2 mm, preferably the average size of the agglomerates is in the range of 100 μm - 1 mm, more preferably the average size is in the range of 250 - 350 microns. The average size of the agglomerates can be measured by sieve analysis, for example, using shale shakers set.

Suitable 2-(4-isobutylphenyl)propionic acid is racemic acid, mainly pure (+)-enantiomer S(+)-ibuprofen), mostly pure (-)-enantiomer (R(-)-ibuprofen) or any mixture of the two enantiomers, for example, the eutectic mixture. The term "mostly clean" is used to show that the acid has an enantiomeric purity of at least 90%, which is in the range of 90 to 100%, preferably above 95%, more preferably above 99%, and most preferably above 99.5% pure, for example, above 99.9%. Can be used in any pharmaceutically acceptable salt of ibuprofen or S(+)-ibuprofen. The preferred salts are the sodium salt of S(+)-ibuprofen and (S)-lizinata salt. S(+)-ibuprofen. Most preferably, 2-(4-isobutylphenyl)propionic acid is ibuprofen or S(+)-ibuprofen.

Preferably, the agglomerates contain 80 - 94% of 2-(4-isobutylphenyl)propionic acid and 6 - 20% component of starch, more preferably 85 - 98% 2-(4-isobutylphenyl)propionic acid and 7 - 15% starch component, and most preferably the agglomerates contain 87 - 92% 2-(4-isobutylbenzene agglomerates contain 88 - 91% of 2-(4-isobutylphenyl)propionic acid and 9 - 12% starch component.

Component of starch may contain starch or a mixture of two or more starches. Suitable starches include, for example, potato starch, corn starch, maize starch and wheat starch. Used herein, the term "starch" includes also pre-gelatinisation starches. Pre gelatinizing starch is starch that is chemically and/or mechanically processed to break all granules or part of the granules, separated from the aggregates in the presence of water. Suitable when a component of starch consists of maize starch and/or pre-gelatinizing maize starch. Preferably component of starch contains maize starch and pre-gelatinizing maize starch in a weight ratio of maize starch to pre relativetowindow maize starch in the range from 25:1 to 1:25. More preferably the ratio of maize starch to pre relativetowindow maize starch is in the range from 10:1 to 1:10. Most preferably the ratio is from 5:1 to 1:1. In a particularly predpochtitelnei starch is 4:1. Preferably the agglomerates contain 3 to 12 wt.% maize starch and 0.1 to 6.0 wt. % pre gelatinizing maize starch. More preferably the agglomerates contain about 6.5 to 10.5 wt.% maize starch and 1.5 to 2.5 wt.% pre gelatinizing maize starch.

The solvent system may be a single solvent or a mixture of one or more solvents, which is not enough to partially or fully dissolve 2-(4-isobutylphenyl)propionic acid or its salt. Suitable when the solvent system may contain one or more of the following solvents: a ketone (e.g. acetone or methyl ethyl ketone), alcohols, preferably C1-6alcohols (e.g. methanol, ethanol, propan-1-ol and propan-2-ol), hydrocarbons (e.g. hexane, heptane and toluene), galijasevic hydrocarbon (e.g. dichloromethane), esters (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran or diethyl ether). Preferably, the solvent system contains a ketone, alcohol or hydrocarbon. More preferably, the solvent system contains Volosovsky or partially Volosovsky solvent, for example, ketones (e.g. acetone or mutilative is Stroiteley contains acetone or acetone, mixed with either hexane or heptane. The mass ratio of 2-(4-isobutylphenyl)propionic acid to the weight of the solvent system will depend on the specific system being used solvents, the solubility of the acid in this system and the physical properties such as specific surface area, which is required to obtain agglomerates. Similarly, the amount of water used in the method may be different. The exact amount of a specific system of solvents and water can be determined by known methods.

The mass ratio of 2-(4-isobutylphenyl) propionic acid to the solvent system is in the range from 1:0.01 to 1:1000. Preferably the mass ratio of the acid to the solvent system is in the range of from 1.0:0.5 to 1:100. More preferably the mass ratio lies in the range from 1: 0.1 to 1:10 and most preferably the mass ratio of the acid to the solvent system lies in the range from 1:1 to 1:5.

The mass ratio of the system solvent to water is in the range from 1: 0.1 to 1: 1000. Preferably the mass ratio of the system solvent to water is in the range from 1:0.5 to 1:100 and most preferably the mass ratio lies in the range from 1:1 to 1:50.

And who used any surfactant, which is pharmaceutically acceptable. Is suitable, when the mass ratio of 2-(4-isobutylphenyl)propionic acid to surfactant is in the range from 5000:1 to 100:1. Preferably the mass ratio is in the range from 4000:1 to 300:1 and more preferably the mass ratio of 2-(4-isobutylphenyl)propionic acid to surfactant is in the range from 3000:1 to 300: 1. Preferably surface-active agent is sodium lauryl sulphate.

The emulsion can be obtained by physical mixing system of solvents and water. Can be used with any method of mixing the organic liquid with water by physical mixing, for example, vigorous stirring, shaking and homogenization. Preferably the emulsion is obtained by mixing the solvent system and water homogenizer.

Is suitable when the emulsion is obtained at a temperature in the range of 1 - 100oC at atmospheric pressure. Preferably the emulsion is obtained in the temperature range 10 - 60oC, more preferably in the temperature range 15 - 50oC (for example, at room temperature), and most preferably in the 40oC.

Crystallization can be performed in a number of ways, for example, by cooling the emulsion; by evaporating part of the solvent; persecution; regulation of pH; mixed with additional liquid in which 2-(4-isobutylphenyl)propionic acid is less soluble, for example, dilution pH; mixed with additional liquid in which 2-(4-isobutylphenyl)propionic acid is less soluble, for example, by dilution with water; or combinations thereof. Preferably, crystallization is controlled by cooling the emulsion by homogenizing or adding the emulsion to the cold water with homogenization.

The agglomerate can be obtained by physical mixing of a suspension of crystals of 2-(4-isobutylphenyl)propionic acid or a salt thereof in direct contact with the starch component; for example, by shaking or mixing. Mixing should be sufficient to maintain direct contact, but not too energetic, otherwise the structure of the agglomerate will be destroyed. It is assumed that the agglomerates are formed as a result of the surface tension of the solvent system, linking together the particles of acid and a component of starch that nah is obtaining agglomerates. It should be clear that the agglomerates are solid. Also it should be clear to experts that the crystallization and the formation of agglomerates, depending on the reaction conditions can occur so quickly that they are at the same time.

The agglomerates can be collected by filtration or by centrifugation, or by other methods known in the technology, with separation of the solid component from the surface layer of the liquid. Preferably, the agglomerates are collected by filtration or centrifugation. More preferably, the agglomerates are collected by filtration.

The agglomerates may be dried is known in the technology of ways. Is suitable when the agglomerates are dried at atmospheric or reduced pressure. Optionally, the agglomerates can be mixed or rotated during the drying process, and, optionally, the agglomerates may be dried at elevated temperature, for example, in the temperature range 20 - 60oC. If the agglomerates contain S(+)-ibuprofen, they are preferably dried in the temperature range 20 - 40oC.

The homogeneous nature of the agglomerates of the present invention can be observed by electron microscopy. In addition, the Homo is slots by liquid chromatography high resolution (IHVR).

The moisture content of the pellets, after drying, can be determined by registering the mass loss of equilibrium sample output after storage over pjatiokisi phosphorus under vacuum at room temperature. Is suitable, if the moisture content of the agglomerates is in the range from 0.1 to 3.0 wt. % Preferably the moisture content of the agglomerates is in the range from 0.5 to 1.5 wt.%.

Emulsion containing a salt of 2-(4-isobutylphenyl)propionic acid can be obtained by neutralizing the acid base with the formation of the salt in place.

In a more preferred form, the method of the present invention contains:

a) dissolving 2-(4-isobutylphenyl)propionic acid in the solvent system to obtain a solution,

b) mixing the solution with an aqueous dispersion of the starch component containing surfactant, emulsion,

c) crystallization with the formation of a slurry containing crystals of 2-(4-isobutylphenyl)propionic acid in direct contact with a component of starch,

d) mixing the specified suspension with the formation of agglomerates containing uniformly distributed mixture of acid and a component of starch,

e) collecting the decree is sustained fashion the method of the present invention is a method of obtaining a pharmaceutical composition in the form of agglomerates, containing 70 - 97% of S(+)-2-(4-isobutylphenyl)propionic acid and 3 - 30% starch component, which contains:

a) preparation of an emulsion containing

1) wt. part 2-(4-isobutylphenyl)propionic acid,

2) 0.1 to 0.2 wt. part of the solvent system,

3) 0,05 - 0,25. part of the maize starch,

4) 0.01 to 0.06 wt. part of the pre-gelatinizing maize starch,

5) of 0.5 to 3.0 wt. part of the water,

6) of 0.0001 - 0.005 wt. part of acrylourethane in the temperature range 15 - 50oC;

b) mixing the emulsion with 1 to 10 wt. parts of water in the temperature range 0 - 20oC with formation of a suspension which glomeridae,

c) collecting these agglomerates filtered and

d) drying of these agglomerates.

The pharmaceutical compositions obtained by the above methods are new, intermediate products used for pharmaceutical preparations. These pharmaceutical compositions comprise another aspect of the present invention.

Thus, the present invention is a pharmaceutical composition in the form of agglomerates containing 70 - 97% 2-(4-isobutylphenyl)propionic acid and 3 to 30 wt.% component of starch. Preferably, the and 7 15 wt.% component of starch, and most preferably, the agglomerates contain 87 - 92 wt.% 2-(4-isobutylphenyl) propionic acid and 8 to 13 wt.% component of starch. In a particularly preferred embodiment of the present invention, the agglomerate contains 88 - 91 wt.% 2-(4-isobutylphenyl)propionic acid and 9 - 12 wt.% component of starch. Preferably 2-(4-isobutylphenyl)propionic acid contains racemic form or S(+)-enantiomer is essentially in pure form.

The agglomerates of the present invention containing 2-(4-isobutylphenyl)propionic acid or its salt and starch, are suitable for introduction in pharmaceutical preparations. These drugs are another aspect of the present invention. Accordingly, the present invention is a pharmaceutical preparation containing 70 - of 99.98 wt.%, more preferably 80 to 95, and most preferably 86 - 92 wt.% compositions of the present invention together with one or more pharmaceutically acceptable filler.

Pharmaceutically acceptable filler may be connected to the agglomerates known in the technology of ways, for example by sedimentation or by mixing. In a preferred embodiment of the present invention, pharmace the way economical by eliminating the use of separate operations.

The agglomerates may be dried, for example, in a vacuum rotary dryer in which the agglomerates are placed in a vessel equipped with stirring blades, which are mixed agglomerates optionally under vacuum, and optionally with heating. After removal of water and solvent from the agglomerates may be added one or more pharmaceutically acceptable filler, and the mixture is stirred by agitator blades within a reasonable period of time to obtain a homogeneous pharmaceutical drug that does not need to be sifted through a sieve of the desired size before the material is directly tabletroute in tablets. Alternatively can be used clothes dryer without agitators, or other known type dryers.

Suitable pharmaceutically acceptable excipients for use in such preparations are well known in the pharmaceutical industry. Preferably, the pharmaceutically acceptable filler contains one or more diluents (e.g., lactose, calcium phosphate, dextrin, microcrystalline cellulose, sucrose, starch, calcium sulfate, or mixtures thereof); and/or one or more lubricating agents (e.g. the example, talc or silicon dioxide) and/or one or more binders (e.g., microcrystalline cellulose) and/or one or more disintegrators (e.g., microcrystalline cellulose, maize starch, sodium starch glycolate, nitrosamino oxypropylation, alginic acid or nitrocresols or mixtures thereof). The preferred product contains 90 - of 99.98 wt.% compositions of the present invention, 0.01 to 5% of a lubricating agent and 0.01 - 5% fluid additives. Can be used in any pharmaceutically acceptable lubricating agent or such fluid additive. Preferably the lubricant is magnesium stearate. Preferably the fluid additive is colloidal silicon dioxide.

In the most preferred method, one or more lubricating agents and/or one or more fluid additives are thoroughly mixed with the agglomerates during the drying process to obtain a pharmaceutical preparation that is suitable for direct tabletting in tablets.

With therapeutic use of drugs of the present invention can be scheduled for oral administration, rectally, parenterally or topically. Thus, therapeutic agents of the present invention m is inago and local applications. The preparations of the invention are usually obtained in the form of a unit dosage. Preferably the unit dosage of the active ingredient is 50 to 1000 mg, for example, 100 mg, 200 mg, 400 mg, 600 mg or 800 mg of Fillers used in obtaining these songs are fillers known in the pharmaceutical industry.

Preparations for oral administration are the preferred drugs of the invention, and are known pharmaceutical forms for such application, for example, tablets and capsules. Tablets are the preferred form because of the time, which is important mainly drugs of the present invention, which may directly tabletroute in tablets containing a high dose of ibuprofen, but with reduced overall dimensions in comparison with other tablets containing the same dose of ibuprofen. Tablets can be obtained by mixing the agglomerates of the present invention with one or more lubricating agents (e.g. magnesium stearate) and one or more fluid additives (for example, colloidal silicon dioxide) and the formation of the mixture into tablets by known methods. The introduction of a lubricating agent and/or fluid additives preferably you what their tablets, if required, can be provided with permeable surfaces, by known methods, for example, when using phthalate of acetylcellulose. Similarly capsules, for example hard or soft gelatin capsules, containing the agglomerates of the present invention with or without additional fillers can be obtained by traditional means and, if necessary, coated in a known manner permeable coatings. Tablets and capsules may conveniently each contain from 50 to 1000 mg of agglomerates of ibuprofen-starch. Preferably, the tablets contain 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg or 1000 mg of 2-(4-isobutylphenyl)propionic acid. Tablets can be obtained well-known to specialists manner so as to provide controlled release of 2-(4-isobutylphenyl)propionic acid or its salts.

Traditional ibuprofeno products containing starch, can be deficiencies caused by cracking of the film coating or sugar coating. It is believed that this occurs as a result of the expansion of the core tablet, caused by the absorption of water by the starch. This problem mainly is minimized in the preparations of the present invention, since the content chromolitho of the invention, if required, can be combined with other compatible pharmacologically active ingredients (for example, pain Central action, e.g., codeine) and/or reinforcing agents. For example, the composition can be combined with any ingredient, generally used in media from cough and colds, for example, caffeine or other kantenprofile and/or other analgesic, and/or skeletal muscle relaxant, and/or a decongestant agent, and/or calepodius, and/or expectorant.

Suitable antihistamines, which preferably are not soothing, include acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine at, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, Avastin, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setaction, tsivilis, temelastine, terfenadine, tripelennamine or triprolidine. Suitable calepodius agents include caramiphen, codeine or dextromethorphan. Suitable decongestant include pseudoephedrine, phenylpropanolamine and phenylephrine. P is Aliya and terpyridyl.

2-(4-Isobutylphenyl)propionic acid is anti-inflammatory, analgesic and antipyretic agent. The preparations of the present invention is therefore intended for use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing of spondylitis, seronegative disease of the joints, periarticular disorders and injuries of the soft tissues. They can also be used in the treatment of postoperative pain, postpartum pain, dental pain, dysmenorrhea, headache, musculoskeletal pain or pains or disorders associated with the following: respirative infections, colds or flu, gout or early kostenlose.

The invention is illustrated in the following examples. Was used ibuprofen, mass-produced company Boots Company PLC. S(+)-ibuprofen was obtained by dissolution of ibuprofen (-)-methylbenzylamine same way as described in J. Pharm. Sci., 65 (1976), 269 - 273.

Typically, the compositions of the obtained agglomerates was studied using electron microscopy. Specific surface area was measured using Micromeritis Gemini instrument with five points of analysis at a partial pressure of 0.1, 0.15, 0.2 of a, of 0.25, 0.3, using nitrogen gas. Institunie Micromeritics ASAP 200-tool.

Example 1

Ibuprofen (200,0 g) was dissolved in acetone (200 ml) at a temperature of 40oC. This solution was added under stirring and the mixture of maize starch (30.0 g), acrylourethane (240 mg) and water (1200 ml) at 40oC, 10-liter vessel with a water-cooling jacket. The resulting mixture was emulsified using a high-speed multi-purpose emulsifier of Silversea working at the minimum speed required to maintain a good emulsion. The mixture was cooled at a rate of 0.5 to 3.0oC/min to the formation of agglomerates. At this point, the emulsifier was turned off, and cooling was continued under weak stirring. The agglomerates were collected by vacuum filtration and dried at 40 - 50oC at atmospheric pressure. Specific surface area of 0.56 m2/,

Examples 2 to 6

The following examples were obtained using the techniques described in example 1, but with replacement of maize starch with a mixture of maize starch and pre-gelatinizing maize starch, as shown in table 1.

Example 7

Ibuprofen (200 g) was dissolved in warm ( > 40oC) mixture of acetone (166 ml) and hexane (7.2 ml). This solution was added to the warm mixture of maize and water (334 ml), as described in example 1. Specific surface area of the obtained product was 0.40 m2/,

Examples 8 - 10

Examples 8 to 10 were obtained analogously to example 7, but the amount of hexane was varied as shown in table 2.

Example 11

The solution of ibuprofen (9 kg) in acetone (7.5 l) and hexane (325 ml) was heated to 40oC and then added to a mixture of maize starch (720 g), pre-gelatinizing maize starch (180 g), acrylourethane (3 g) and water (15 l) at 40oC in 50-liter vessel production Giustri Cosmix cream protuction equipped with water-cooling means. The mixture was emulsified using a homogenizing head installed on the base of the vessel, and at the same time slowly stirred at a rate of approximately 30 revolutions per minute with pomoymu frame agitator with side scrapers. The temperature of the emulsion was lowered adjustable cooling 0,3oC per minute until until is exothermic precipitation. The solution was maintained at this temperature until the formation of agglomerates. Homogenizing head was off, and the cooling was continued until a temperature of 20oC. the Product was collected by vacuum filtration and then dried at analogice example 11. For each product were determined distribution of particle size (sieve analysis), specific surface area and appearance (electron microscopy, SEM ISI SS60). The results obtained are shown in table 3.

The samples were connected together in order to obtain a mixture with the same average particle size and specific surface. Examples 12, 13 and 18 were connected with the receipt of party A, and examples 15, 16 and 17 were connected with the receiving party B. These parties were received by the connection of the products of the three examples using a mixer (KEK, 50 kg drums) for 20 minutes at 24 rpm

Obtained in the examples, the agglomerates were analyzed for content of ibuprofen method GHUR. The results obtained are shown in table 4.

Example 19

Analogously to example 1 S(+)-ibuprofen (60 g) was dissolved in warm acetone (50 ml) at 35oC. This solution was added to a mixture of maize starch (4.8 g), pre-gelatinizing maize starch (1.2 g), acrylourethane (70 mg) and water (350 ml) at 35oC with homogenization. The mixture was cooled in a controlled way, and the agglomerates were collected by filtration and dried. Specific surface area of 0.36 m2/,

The use of the ibuprofen at room temperature, which was added to the mixture of starch at room temperature. The mixture is stirred at this temperature until the formation of agglomerates, which were collected by filtration and dried. Specific surface area of 0.58 m2/,

Examples 21 to 29 were obtained, as summarized in table 5, with the following notes.

Example 21

Example 21 was obtained analogously to example 19, but with the temperature change of the organic phase and the aqueous phase.

Example 22

The organic phase was obtained, as shown in table 5, and then abruptly cooled while pouring in the water phase at the 12oC with homogenization. Saw a rapid deposition of agglomerates. The transparency of the obtained liquid phase indicates that a large portion of the starch was put into these particles, and this was confirmed by the study of microphotographs.

Examples 23 - 29

In each example, the organic phase was combined with the aqueous phase with low water content at 40oC. the Composition of each phase is provided in table 6. This mixture was homogenized to obtain a stable emulsion. To the emulsion was added an additional water volume and temperature, as in table 5, were formed agglomerates, which were collected Micromeritics Gemini instrument with nitrogen as the adsorbed gas, and for the products of examples 22, 23 and 24 were removed electron micrograph (ISI SS60 SEM).

The results are shown in table 6.

Obtaining tablets - Racemic ibuprofen

Five kg agglomerate of example 11 was taken as the basis and mixed with magnesium stearate (0.8 wt. %) and colloidal silicon dioxide (0.1 wt.%). This material was preformed on the installation Manesty Betapress machine with 12.7 mm forming tool deep curvature. Received blank by weight of 666 mg, giving dozirovku ibuprofen 600 mg tablet (90% of ibuprofen). Installation was configured for the production of tablets with resistance to crushing, equal to 7 kg, with a low level of pre-compaction. No problems with fluidity, stratification or lipomastia. The obtained tablets were sealed in containers for 24 h before testing resistance to crushing and disintegration time (the way of the British Pharmacopoeid (BP), 1973). The measured characteristics are summarized in table 7.

Determination of stability

Tablets obtained from agglomerates ibuprofen-starch from example 11 were coated with 35 mg film coating based on oksipropilmetiltselljulozy and compared with 600 mg tablets of ibuprofen with play. Tests for long-term stability were conducted between these tablets and conventional production batch of 600 mg tablets of ibuprofen coated. In all cases, the samples were stored in containers made of high density polyethylene with a bowl-shaped pads of waxed aluminum. The results of stability testing are given in table 8. Tests for solubility were performed using the method of US Pharmacopeia XXII, Apparatus II. The values of T50 and T90 is the time to reach 50% and 90% respectively of the standard concentrations of drugs, certain spectrographically in the process of testing the solubility. The initial time the solubility of the tablets of the agglomerates ibuprofen-starch is higher than the time usually associated with tablets of ibuprofen. The results obtained during the 12-month period of time, show that the tablets obtained from agglomerates ibuprofen-starch, remain almost constant values of solubility used in all test conditions for stability.

Receive 2 tablets

Magnesium stearate (0.8 wt. %) and colloidal silicon dioxide (0.1 wt.%) were sieved (500 μm) and added to parties A and B (see above), respectively. The floor is rtia B (mixed) were preformed using the simulator tableting.

Obtaining tablets of S(+)-ibuprofen

The products of examples 22, 23 and 24 were sifted through a sieve to 1400 microns and mixed with colloidal silicon dioxide (0.1 wt.%) and stearate 0.8 wt.%. This material was preformed on the simulator tabletting by imitating get 11 mm pellets deep curvature with a given weight of 444 mg (400 mg of S(+)-ibuprofen per tablet).

The resulting tablets had a resistance to crushing than 4 kgf and a disintegration time of less than 2 minutes

1. A method of obtaining a pharmaceutical composition in the form of agglomerates containing 2-(4-isobutylphenyl)propionic acid or its pharmaceutically acceptable salt and starch, including: preparation of emulsion containing 2-(4-isobutylphenyl)propionic acid or its salts, solvents, starch and water, crystallization of obtaining slurry containing crystals of 2-(4-isobutylphenyl)propionic acid or a salt thereof in direct contact with a component of starch, mixing the specified suspension with the formation of agglomerates containing uniformly distributed mixture of 2-(4-isobutylphenyl)propionic acid or its salt and starch, the collection of these agglomerates, characterized in that the agglomerates contain 70,0 - 97,0 wt.% 2 is shown the emulsion additionally contains a surfactant.

3. The method according to p. 1, characterized in that it includes the drying of these agglomerates.

4. The method according to any of paragraphs.1 to 3, characterized in that the agglomerates contain 87,0 - 92,0 wt.% 2-(4-isobutylphenyl)propionic acid and 8,0-13,0 wt.% component of starch.

5. The method according to any of paragraphs.1 to 4, characterized in that the specific surface area of the agglomerates is from 0.1 to 0.5 m2/,

6. The method according to any of paragraphs.1 to 5, characterized in that the average particle size of the agglomerates is in the range 200 - 500 microns.

7. The method according to any of paragraphs.1 - 6, characterized in that the mass ratio of 2-(4-isobutylphenyl)propionic acid to the solvent system is in the range from 1 : 1 to 1 : 50.

8. The method according to any of paragraphs.1 to 7, characterized in that the solvent system consists of one or more members of the group consisting of hydrocarbon, ketone or alcohol.

9. The method according to any of paragraphs.1 to 8, characterized in that the solvent system consists of one or more members of the group consisting of videofestival or partially videofestival ketone, C1-6alcohol, hexane or heptane.

10. The method according to any of paragraphs.1 to 9, characterized in that the starch contains maiso artelino gilotinirovaniya maize starch is in the range from 25 : 1 to 1 : 25.

11. The method according to any of paragraphs.1 to 10, characterized in that the mass ratio of the system solvent to water is in the range from 1 : 0.1 to 1 : 1000.

12. The method according to any of paragraphs.1 - 11, characterized in that there is a surface-active substance and the mass ratio of 2-(4-isobutylphenyl)propionic acid to surfactant is in the range from 5000 : 1 to 100 : 1.

13. The method according to any of paragraphs.1 - 12, characterized in that 2-(4-isobutylphenyl)propionic acid is crystallized by cooling the emulsion or by dilution with water.

14. The method according to any of paragraphs.1 - 13, characterized in that the agglomerates are collected by filtration.

15. The method according to any of paragraphs.1 to 14, characterized in that 2-(4-isobutylphenyl)propionic acid is in racemic form.

16. The method according to any of paragraphs.1-15, characterized in that the acid is essentially pure S(+)-2-(4-isobutylphenyl)propionic acid.

17. Pharmaceutical composition in the form of agglomerates, which has anti-inflammatory, analgesic and antipyretic action, containing the active ingredient and a pharmaceutically acceptable excipient, characterized in that it contains as active substance 2-(4-isobutyronitrile)propionic acid 70,0 - 97,0; starch 3,0 - 30,0.

18. The composition according to p. 17, characterized in that it consists mainly of 87.0 - 92,0 wt.% 2-(4-isobutylphenyl)propionic acid and 8,0 - 13,0 wt.% component of starch.

19. The composition according to p. 18, characterized in that the starch contains about 6.5 to 10.5 wt.% maize starch and 1.5 to 2.5 wt.% pre gelatinising maize starch.

20. The composition according to PP. 17 to 19, characterized in that 2-(4-isobutylphenyl)propionic acid is in racemic form.

21. Composition according to any one of paragraphs.17 to 19, characterized in that the acid is the pure S(+)-2-(4-isobutylphenyl)propionic acid.

22. Pharmaceutical preparation, characterized in that it includes 70,0 - of 99.98 wt. % the composition of PP.17 - 21 with a pharmaceutically acceptable filler.

23. The drug under item 22, wherein the pharmaceutically acceptable filler contains one or more diluents, one or more lubricating agents, one or more fluid additives, and/or one or more binders and/or one or more of disintegrants.

24. Drug for p. 23, characterized in that the pharmaceutical preparation contains 90,0 - 99,90 wt.% the composition of PP.17 - 21, from 0.01 to 5.0% of a lubricating agent, 0.01 to citiesi acceptable filler is mixed with a pharmaceutical composition according to paragraphs. 22 - 24 in the drying process of the pharmaceutical composition.

 

Same patents:
The invention relates to medicine, in particular to the production of viral vaccines in pill form
The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to a method of obtaining a tablet form of the drug

The invention relates to medicine, namely to the pharmaceutical industry, to receive funds, with preventive and restorative action
The invention relates to medicine and pharmacy, in particular to the manufacture of dosage forms for the treatment of wounds, as well as methods of treatment last

The invention relates to medicine and relates to a composition with antiulcer effect

The invention relates to new peptides with organizaitnal activity with high biological activity of the same type as the natural compound HRV, but with a shorter amino acid chain

The invention relates to medicine, namely to funds on the basis of biologically active substances of plant origin, and can be used as a means of providing anti-inflammatory, immunomodulatory, anabolic effects
The invention relates to medicine, namely the subject of the invention are tablets based on partially or fully water-soluble natural and/or synthetic polymers selected from rubbers, alginates, Cartagena, starch, pectin and gelatin containing poly-(dimethyl-siloxanes) (Dimethicone, simethicone), and the method of their manufacture

The invention relates to the protection of certain 3-substituted-2-oxindole-1-carboxamide formula

< / BR>
and their pharmaceutically acceptable basic salts, where X is H, Cl, or F; Y is H or Cl; and K represents benzyl or thienyl, each optionally substituted by Cl or F; from decomposition in the presence of light using a dye absorbing light or packing material
The invention relates to pharmaceutical industry and relates to the beads of micron or submicron size with a polymeric shell, filled with air or gas, and the method of their manufacture
The invention relates to the pharmaceutical industry, in particular, to the production of medicines used for colds, relieving headaches and neuralgia

The invention relates to the field of pharmaceutical controlled release in the body of the active substance
The invention relates to medicine, namely to the use of vegetable origin as a tonic and restorative means

The invention relates to a method for improved control of pharmacokinetic and pharmacological characteristics of the pharmaceutically active substance that can be administered parenterally by injection mammals or other animals

The invention relates to new pharmaceutical compositions containing ACE-inhibitor and an acid stabilizer

The invention relates to chemical-pharmaceutical industry, particularly, to a method of obtaining vitamin b12stable to prolonged storage, which is used in medical practice for the treatment of anemia of different origin and other diseases
The invention relates to medicine, namely to dentistry
Up!