The pharmaceutical agent in the form of microcapsules and method thereof

 

(57) Abstract:

The pharmaceutical agent in the form of microcapsules is intended for oral administration. The product contains the active substance with an unpleasant organoleptic properties as anhydrate the main form. The microcapsule coated. The membrane is a film of water-insoluble neutral complex with methyl and/or ethyl esters of polymethacrylic acid and/or Quaternary ammonium compounds of polymethacrylic acid and/or ethyl cellulose. To obtain pharmaceuticals in the form of microcapsules, the active substance in the form of anhydrate or hydrate main form is subjected to wet granulation. The obtained micro-granulate is applied film coating. New pharmaceutical tool provides complete masking of unpleasant and bitter taste of many active substances. 2 S. and 19 C.p. f-crystals, 1 table.

The invention relates to pharmaceutical facilities intended for use orally, in particular to the pharmaceutical agent in the form of microcapsules and method of its production.

It is known pharmaceutical agent in the form of microcapsules containing the active substance are available for free vigora preferably consists of Carnauba wax, bee wax and ethyl cellulose or mixtures thereof (application EP N 273890, class A 61 K 9/50, 1988). Known means are given orally together with pharmaceutically tolerable, non-aqueous liquid.

Active substances with an extremely unpleasant and long-lasting bitter taste are, in particular, substances with antimicrobial action, such as gyrase inhibitors, in particular substances of the type naphthyridin and hinolincarbonova acids, especially ciprofloxacin, norfloxacin, ofloxacin, enoxacin.

In addition to the complete taste masking many active substances require necessarily rapid and complete release, so that it was possible for the body in the appropriate tablet extent to host the active substances. This causes problems, because for many resorption area in the small intestine, while the rear parts of the intestinal resorption is reduced (S. Harder, U. Fuhr, D. Beermann, A. H. Staib, Br. J. Clin. Pharmac. N 30, 35 C., 1990). You must also consider the possibility of deviation values of pH in the stomach may be reduced acidity, often observed in the elderly. This means that in weakly acidic conditions, at a pH of about 4.5, must be ensured rapid dissolution of the active ve the active substance in free form or in salt form in the molten wax and its translation into microcapsules by drying the dispersion, followed by adding to the nonaqueous liquid as a carrier.

With well-known pharmaceutical agent cannot provide the ability for the body to quickly and fully to be active substances having a very unpleasant organoleptic properties, nor in the presence of active compounds in free form or, if available, in the form of salt.

The objective of the invention is to provide a complete taste masking of the active substances having a very unpleasant taste, while providing opportunities for body quickly and completely to host the active substance.

The problem is solved in the proposed pharmaceutical agent in the form of microcapsules containing the active substance with an extremely unpleasant organoleptic properties enclosed in the shell, due to the fact that the substance is available in the form of anhydrite its basic form, and the shell consists of a lacquer of the water-insoluble neutral complex with methyl and/or Eolian episoadele polymethacrylic acid and/or Quaternary ammonium compounds of polymethacrylic acid and/or ethyl cellulose, which may contain additional water-soluble polymers, plasticizers, wetting and other conventional excipients. The shell may have a coating of polishing is Uchenie active substances with a very unpleasant organoleptic properties of the microcapsules, if necessary, translate into intended for use orally formula, due to the fact that existing active substance in the form of anhydrate or hydrate its basic form is subjected to granulation in the wet state, and then, if necessary, by drying the moisture content of the active substance is brought to 0 to 30 wt.%, the resultant micro-granulate supply shell of varnish based on a neutral complex with methyl and/or ethyl esters and/or Quaternary ammonium compounds of polymethacrylic acid and ethyl cellulose, which may contain water-soluble polymers, plasticizers, wetting and other conventional excipients, and then, if necessary, the degree of humidity of the active substance is brought to the desired value by drying, thus obtaining the microcapsules, and if necessary translate them in the sachet or oil juice.

In General, substances with antimicrobial action, are structures that contain acidic or basic functional groups, or both, for example, the group of carboxylic acids and amines in one molecule (betaines). These patterns, according to the invention, referred to as "the principal active form the finished microcapsules contain the active substance in the form of his anhydrate.

According to the definition anhydrate active substances in their basic form in the proposed microcapsules contain less than 5%, in particular less than 3.0%, and water in the form of water of crystallization or other water adducts.

The invention is illustrated below in an example of the active substance is ciprofloxacin [= 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinil)-3-quinoline-carboxylic acid (application EP N 0176846, class C 07 C 101/34, 1986, 4th column)].

The proposed microcapsules obtained as follows.

The active substance in a known manner is subjected to wet granulation, and as excipients granulation can use water or mixture of alcohol and water, for example a mixture of ethanol and water. To obtain the micro-granulate by aqueous wet granulation is advisable to use active substance in the form of a hydrate main form. If to obtain use micro-granulate of active substance in the form of anhydrite the main form, the wet granulation is preferably carried out with a mixture of alcohol and water. The wet granulate is dried and sieved. The fraction with the desired size of the particles used for the subsequent formation of microcapsules. Predpochtitel, E N 3806116 and EP N 0332929 way. When this aqueous suspension of the active substance, which can contain further auxiliary substances in dissolved or suspended form, using a special method can be directly translated in a very uniform product of spherical agglomerates of the active substance and excipients. Be sure to obtain the data of microgranulates use a higher basic form of the active substance. Upon receipt of the micro-granulate with ciprofloxacin using spray granulation in the fluidized layer is also preferably used micronized hydrate ciprofloxacin to obtain a suspension for spraying. The use of the active substance in the above form allows to obtain a water suspension of extremely fine particles without the need for additional wet grinding.

As a binding agent to improve the mechanical hardness of the micro-granulate can be used, for example, acacia rubber, alginic acid and alginates, carboxymethylcellulose, ethylcellulose, gelatin, oxypropylation, oksipropilmetiltselljuloza, methylcellulose, xanthan rubber, pectin, tragant, microregion, polyvinylpyrrolidone, polyvinyl alcohol, poliakrilovu acid, gum Arabic, lactose, starch (wheat, corn, potato, rice starch, sucrose, glucose, mannitol, sorbitol, xylitol, stearic acid, gidrirovannoe cottonseed oil, gidrirovannoe castor oil, copolymers of vinylpyrrolidone and vinyl acetate, fructose, methylacetylene, agar-agar, carrageenan, rubber type punish DIN, chitosan, hydrolysates of starch and other Particularly preferred use of polyvinylpyrrolidone at a concentration of 25, part 1 - 10% of micro-granulate.

The proposed microcapsules obtained by the supply of cores in a suitable apparatus proposed lacquer layer, and the surface of the granulate fully varnished. While the lacquer composition for the formation of microcapsules must be chosen so as to have sufficient permeability to aqueous media and the rapid release of the active substance. Due to the lacquer composition and thickness of the microcapsules dissolve only after passing the gustatory zone, however, the active substance should be provided in a timely manner before reaching resorcinol zone. Therefore it is not suitable varnishes, leading to the formation of resistant Gelu the e passage through the stomach.

For reasons of environmental protection and security, preferably using water spray suspensions.

As a foaming agent to obtain a varnish layer on microgranulate you can use only a neutral complex with methyl and/or ethyl esters of polymethacrylic acid, for example available in trade Eudragit 30 D company "REM", , Darmstadt, DE, and/or Quaternary ammonium compounds of polymethacrylic acid, for example available in trade Eudragit RL 30 D or Eudragit P 530 D company "REM", , Darmstadt, DE, ethylcellulose, such as those available in the trade Aquacoat firm "FMC Corporation. The lacquer layer can be applied by a known device, for example by means of a device operating according to the method of Wurster. For environmental reasons it is advisable to choose a concentration lacquer slurries as high as possible.

These varnishes, which are in principle nevadacalifornia, to improve permeability can be used in combination with water-soluble polymers, providing the formation of pores in the lacquer coating. As water-soluble compounds for the formation of pores can be called, for example, oxypropylation, oksipropilmetiltselljuloza Ivanilova alcohols, polyvinylpyrrolidone, starch and starch hydrolysates, for example, modified starch (gelatinising starch, commercially available one HUNDRED-RKS 1500, Solutab, maltodextrins), sugar and sugar substitute substances such as mono-, di - and oligosaccharides, sucrose, lactose, invert sugar, mannitol, sorbitol and xylitol, alginic acid and alginates, tragant, pectins, gum Arabic and gelatine. In the framework of the invention the preferred drivers then are oxypropylation, oksipropilmetiltselljuloza and methylcellulose.

Preferred combinations of water-insoluble and water-soluble components to obtain a varnish is a mixture of Eudragit 30 D oksipropilmetiltselljulozy. In the relevant experiments have revealed that suitable mixtures of these substances, for example in a ratio of 100 : 20 to 100 : 50, preferably 100 : 20 to 100 : 40, particularly preferably 100 : 40, optimum taste masking and rapid and complete release of the active substance in the microcapsules in an environment with a pH value comprising 1 to 4.5.

In addition, the film formation may require the addition of the plasticizer. It is a substance that promotes the formation of the film and increase elaste, diethylphthalate, acetyltributyl, glycerol, diethylsilane, dimethylphthalate, dibutyl phthalate, tributyltin, butilstearat, polyethylene glycols of different chain length, glycerylmonostearate, triacetin, castor oil and other natural and synthetic oils, triethylcitrate, acetyltributyl, 1,2-propylene glycol, acetylated glycerides of fatty acids, and copolymers of polyoxyethylene and polyoxypropylene.

The inclusion of surfactants in lacquered shell, on the one hand, facilitates the distribution of lacquer dispersion of solid particles in the process of formation of microcapsules, and on the other hand, leads to improved wettability of the microcapsules. In addition, it can affect the permeability of varnish.

As the plasticizer can be used, for example, sodium lauryl sulfate, Polysorbate(20, 40, 60, 80, 65, 61, 85, 21), poloxamer (block copolymers of ethylene oxide and propylene oxide) with different hydrophilic-lipophilic ratio, lecithin, oleic acid and its salts, complex sorbitane esters (chips 20, 40, 60, 80, 85), the propilenglikolmonostearata and-monolaurate, glycerylmonostearate and-monooleate, simple polietilenglikolya esters of fatty alcohol series with different hydrophilic-Lee-and so operatir D.), complex polietilenglikolya esters of fatty acids with different hydrophilic-lipophilic ratio (for example, peg-40 monostearate, polyethylene glycol-100-monostearate and others), sodium dodecyl sulphate, sulfosuccinate dictinary, ethoxylated mono - and diglycerides with different hydrophilic-lipophilic ratio, complex sucrose esters of fatty acids, salts of fatty acid (sodium, potassium, calcium, magnesium, aluminum and other salts), ethoxylated triglycerides (polyoxyethylene castor oil (40), polyoxyethylene gidrirovannoe castor oil (40 and 60, respectively), polyoxyethylene rastenii oil), sterols (cholesterol, alcohols, wool wax) at concentrations of 0.001 - 20%, preferably 0.1 to 2%.

To reduce or prevent adhesion and sintering of the particles during the formation of microcapsules, you need to add anti-adhesion agents. Suitable substances are, for example, magnesium stearate or calcium, beginat calcium, talc, colloidal silicic acid, stearic acid, preziral (a complex mixture of mono-, di - and Trifonov palmitic and stearic acids with glycerol), gidrirovannoe cottonseed oil, hiderow the agent is used in an amount of 0.1 - 90%, especially preferably 5% to 40%. In addition, lacquer shell can contain dyes.

Microcapsules can be coated polishing layer. The latter serves not only to improve appearance, but also has an important function within the proposed microcapsules, and thanks to the application of the top layer on the lacquer layer prevents direct interaction between, for example, oil juice and overlying the taste of varnish. In particular, water-soluble or at least hydrophilic polishing layer prevents direct contact of oil juice as a carrier with lacquered shell of the microcapsules and the slow release due to the interaction between oil and varnish. In addition, the tendency of the particles to sintering when applying in water the liquid is reduced.

Suitable polishing means are, for example, polyethylene glycols with different molecular weight or a mixture thereof, talc, surface-active substances (simple polietilenglikolya esters of fatty alcohol series, complex polietilenglikolya esters of fatty acids, glycerylmonostearate, poloxamer), fatty alcohols (stearyl, cetyl, lauric and ministerului si layer is applied after applying the Polish on the micro-granulate. Polishing agents can be used either in solid or in dissolved form.

The size of the microcapsules is of great importance for a pleasant acceptance received from them liquid medicinal product intended for use orally. If the capsule is too large, then in the mouth, they can cause a feeling of "sand". In addition, too a large amount of grains can lead to increased deposition of microcapsules in the dispersion medium. For this reason, the size of the microcapsules should be 10 to 1000 μm, preferably 10 to 800 μm, and particularly preferably 100 to 500 μm.

The proposed microcapsules provide, on the one hand, an excellent masking of taste, and on the other hand is a very quick release of the active substance required for pharmacokinetic reasons. Within 15 to 30 minutes can dissolve at least 70-80% of the prisoner capsules the active substance. In the in vitro experiments, this was achieved and in strongly acidic (pH = 1) and less acidic (pH = 4.5) environment. This result confirms that the proposed treatment works provides an opportunity for the body to be active substances.

The rate of release can also regulate Carol, on anhydrate the main form of the active substance can be achieved significantly faster release, making becomes superfluous usually required the use of a detonating agent, which negatively affects the efficiency of the process (in the case of an explosive agent is necessary to apply a much larger quantity of varnish, so as generally to ensure the formation of microcapsules with masking taste. This leads to a more time consuming process of formation of microcapsules and higher costs).

The moisture content of the microcapsules can be controlled by different methods, such as micro-granulate can before the coating process to set the desired humidity, and after varnishing it can be subjected to additional drying before anhydrate.

Microgranulate that varnished without special pre-drying and which may have the original water content amounting to a maximum of 30 wt. %, can be reduced to the desired humidity level anhydrate the main form of the active substance) by drying after the formation of the microcapsules.

Microcapsules obtained using the proposed method, may be present in the framework of preparations intended for use Oriat the following.

1. Juice oil-based (for taking a few doses)

Manufacturer of water ready juice impossible, because in the aquatic environment lacquer shell of the microcapsules after a while it becomes permeable. Therefore, it is advisable to choose for dispersion of microcapsules nonaqueous environment.

Suitable oil dispersion media are, for example, almond oil, peanut oil, olive oil, poppy seed oil, oil of groundnuts, cottonseed oil, soybean oil, corn oil, etiloleat, aerolef, isopropylmyristate and isopropyl. Due to their neutral taste and favorable viscosity especially preferred are triglycerides of medium chain length.

Liquid excipients suitable for combination with the specified oil carriers are, for example, ethanol, glycerol, propylene glycol, polyethylene glycol, 1,3-butanol, benzyl alcohol, diethylene glycol, triethylene glycol, etc.

Additives that are useful are also the wetting. Preparations in the form of oil juice sensitive to moisture. Already a small amount of water leads to a significant increase in viscosity that m is impossible. Emulsifiers, one hand, reduce the sensitivity to the effects of water, and on the other hand, they increase the wettability of the particles at their submission in an oil carrier. In addition, they reduce the viscosity of the oil suspensions. As wetting, you can use the above-mentioned substances. Particularly preferable to use lecithin in a concentration of from 0.01 to 20%, particularly preferably 0.1 to 10%, in particular 0.5 to 5% of the drug in the form of juice.

In addition, particularly suitable for reducing the sensitivity of the oily juices, in addition to containing microcapsules with active substance is also a large amount of sugar or sugar substitute substances to water is a mixture of lecithin emulsifier and water in the oil, for example esters sorbinovoj fatty acids, fatty alcohols and complex glycerole - and diesters of fatty acids.

As increasing the density of the additives, stabilizing the suspension, preferably using sucrose, mannitol, sorbitol, xylitol, fructose, glucose, lactose and other sugars and sugar substitute substances. The concentration of oil juice is 5 to 70%, preferably 15 to 60%, particularly preferably 20 to 40%. These substances should be in Mac is doctitle 3 - 20 microns. This is achieved either by use of substances in powdered form, or by homogenizing the original oil slurry by wet grinding.

The use of sucrose leads to better physical stability of oil-juice-suspensions.

As antioxidants to protect oil carriers can be used, for example, -, -, -, and-tocopherol, ascorbyl palmitate, ascorbicacid, L-cysteine, thiodipropionic acid, timelocal acid, thioglycolic acid, monothioglycerol, propylgallate, butylacetamide, butylacetyl etc.

As auxiliary antimicrobial agents are suitable, for example, phenol, cresol (o-, p-, m-cresol), p-chloro-m-cresol, benzyl alcohol, phenethyl alcohol, phenoxyethylamine alcohol, chlorbutanol, complex, methyl, ethyl, propyl or butyl ether p-oksibenzoynoy acid chloride benzalconia and other Quaternary ammonium compounds, diacetate and digluconate chlorhexidine, finalstate connection thiomersal, benzoic acid and its salts, sorbic acid and its salts, ethanol, 1,2-propylene glycol, glycerol, 2-bromo-2-nitro-propane-1,3-diol, cetrimide and simple 2,4,4'- trichloro-2'-oxygenology ether in a suitable concentration.

Capacity, which is poured suspension may consist, for example, from glass or plastic. In addition, the material from which made the vessel may contain substances that provide special protection for content, such as protection from exposure to light.

The composition of the microcapsules to be used to obtain the drug from the oil juice, in particular the quality of the active substance and its hydrate, and the composition of the film and the amount of the applied varnish is crucial for the quality of the drug. The required rapid release of the active substance can be achieved if the basic form of the active substance contained in the microcapsules suspended in the oil the juice, is available in the form of anhydrite. Appropriate means, having a higher water content, corresponding, for example, dihydrate, show unacceptably slow release of the active substance.

If, for example, oil juice with ciprofloxacin is particularly suitable microcapsules containing commercial products Eudragit 12.5, Eudragit RL 30, Eudragit RS 30 D and/or ethyl cellulose and, for example, hydroxy what about, are microcapsules, lacquer which contains a mixture of the trading product Eudragit 30 D and oksipropilmetiltselljulozy and magnesium stearate. With such a lacquer composition can be obtained stable for taste masking of the drug with oily juice. The preferred relatively lucky taste masking and release consist of sales of product Eudragit 30 D and oksipropilmetiltselljulozy in the ratio of 100 : 20 to 100 : 50 by weight.h. with the addition of magnesium stearate and tween-20. Particularly preferably, the ratio of 100 : 40 by weight.h.

Juice oil-based can be produced in different forms, namely as a ready-made juice or as so-called "oil dry juice".

The finished oil juice consists of the above components and suspended in active substances enclosed in microcapsules. The ability to store the drug should be a few years; in particular, the release of the active substance should not significantly change even when stored for several years.

Under "oil dry juice" understand the product, consisting of oil juice without the active substance and separately Packed microcapsules. Before using the patient prepares ready-however the set stable juice without the active substance and separately Packed microcapsules. Furthermore, it should be ensured stability derived from them oil juice with microcapsules for use, for example, within 5 to 15 days. The composition prepared "dry oil juice" in General identical to the composition of the finished juice.

For packaging of microcapsules can be used, for example, glass bottles or bags of suitable plastic or metal foil. The material of the bag should be impervious to water and water vapor, so as to ensure the stability enclosed in microcapsules of anhydrate active substances.

Sasha (as separate doses)

Another form of pharmaceutical preparation containing microcapsules with active substance, are powders or granules.

Microcapsules with active substance together with suitable auxiliary substances are packaged in pouches (sachets), patients are served with the appropriate amount of liquid, preferably water, and then the patient drinks a liquid medicine.

This should be ensured to prevent unwanted release of the active substance already in the dispersion medium and did not appear bitter taste, soluble active substances. This t is uncooperatively use a neutral complex of methyl and ethyl esters of polymethacrylic acid (e.g., trading product Eudragit 30 D company "REM", , Darmstadt, DE), together with oksipropilmetiltselljulozy, stearate and tween-20, as well as Quaternary ammonium compounds of polymethacrylic acid (e.g., vending products Eudragit RL 30 D and Eudragit RS 30 D company "REM", so Darmstadt, DE) in combination with triethylcitrate and talc, ethylcellulose and oksipropilmetiltselljuloza with triacetin. Preferred combinations of varnish contain a mixture of 100 wt.% shopping product Eudragit RL 30 D and/or Eudragit RS 30 D and 5 to 30 wt.% triethylcitrate. Especially preferably the microcapsules contain a mixture of Eudragit 30 D and oksipropilmetiltselljulozy, for example, in the ratio of 100 : 20 to 100 : 50, preferably 100 : 20 to 100 : 40, particularly preferably 100 : 40 in combination with the magnesium stearate and tween-20.

Because the microcapsules suspendered in the aquatic environment requires physical stabilization of the suspension. For this reason, each sachet add 1 - 5 g increase the density of a substance, such as sucrose, mannitol, sorbitol, xylitol, fructose, glucose and other common sugars and sugar substitute substances.

As increasing viscosity and inhibiting the deposition of substances can be used acacia rubber, agar-agar, agarose, alginic to the pulp, dextran, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, starch and rubber stamps "xanthan gum" Gum. Polymers are used in a concentration of from 0.01 to 1.0 g, preferably 0.01 to 0.8 g per sachet, total weight of which is 5-6, it is Very important to increase the viscosity of the material is rapidly dissolved in cold water and does not cause sintering.

To facilitate the seamless blending of the patient sachet with water, add a wetting at a concentration of 0.0001 - 0.1 g per sachet. Suitable substances mentioned above. Especially suitable Polysorbate.

For optimale the appearance of the suspension of the sachet in the water, you can add insoluble substances such as microcrystalline cellulose, titanium dioxide, and dyes.

The aromatization is carried out by adding aromas and sweet substances, such as sodium cyclamate, saccharin or aspartame. Because the aromatic substances can cause changes in the pH value of the aqueous slurry to an acidic environment and thus may occur unwanted release of the active substance requires the addition of a buffer to ensure a pH value of about 7 - 8. You can use phosphate buffers according to Sorensen, the buffers with citric acid is very, buffers with dimethylaminomethylphenol and sodium hydroxide, buffers with triethanolamine and hydrogen chloride, buffers N-dimethylaminomethylphenol and sodium hydroxide, Tris-buffers with hydrogen chloride, etc.

The sachet can be obtained either by simple physical mixing containing the active ingredient of the capsules with the required auxiliary substances, or by granulation, for example, granulation in a fluidized bed.

As a primary means for packaging sachets, representing a single dose, preferably use glass bottles or bags of suitable plastic or metal foil. The material of the bag should be impervious to water and water vapor, in order to ensure stability contained in the microcapsules of anhydrate active substances.

Example 1. 10 mg of ciprofloxacin and 0.7 mg of polyvinylpyrrolidone 25 by means of wet granulation is transferred to microgranulate that put a varnish containing 1,517 mg trade product Eudragit 30 D (dry matter), 0,304 mg oksipropilmetiltselljulozy 3 SP, 0,304 mg stearate and 0.015 mg of tween-20. The ratio between trading product Eudragit 30 D and oxypropylated ciprofloxacin is available in the form of anhydrite original form, have the following characterization of release (according to pharmaceutical standards of the U.S. under the following conditions: 900 ml, 75 rpm, 37oC.

pH 1 (0,1 N hydrochloric acid): 85% after 5 min, 100% after 10 min;

pH 4.5 (of 0.05 M acetate buffer): 30% after 5 min, 45% after 10 min, 58% after 15 min, 80% after 30 min, 90% after 45 min, 100% after 60 minutes

Comparative example A. Repeat example 1 with the difference that produce microcapsules, in which there is present in the form of a hydrate main form. Thus get the following characterization of the release:

pH 1: 52% after 5 min, 79% after 10 minutes, 90% after 15 min, 99% after 30 min;

pH 4.5: 19% after 10 min, 47% after 30 min, 70% after 45 min, 80% after 60 minutes

Examples 2 to 5. Repeat example 1 with the difference that the use of lacquer containing commercial product Eudragit 30 D (dry matter), oksipropilmetiltselljuloza 3 SP, magnesium stearate and tween-20 in the following quantities (µg): at 1,138, 0,228, 0,228 and 0,012 (example 2); 1,660, 0,167, 0,298 and 0.015 (example 3); 1,440, 0,432, 0,252 and 0.015 (example 4); 1,897, 0,380, 0,380 and 0,019 (example 5). The ratio of the trading product Eudragit 30 D to oxytropidoceras 15%, 20%, 20% and 25%, respectively.

Feature release of the active substance in the microcapsules according to examples 2 to 5 are similar to the characteristics of the microcapsules according to example 1.

Example 6. 10 mg of ciprofloxacin and 0.7 mg of polyvinylpyrrolidone 25 by means of wet granulation is transferred to microgranulate that put a varnish containing at 2,324 mg trade product Eudragit 30 D (dry matter), 0,929 mg oksipropilmetiltselljulozy 3 SP, 0,464 mg stearate and 0,026 mg of tween-20. The ratio between trading product Eudragit 30 D and oksipropilmetiltselljulozy is 100 : 40, and the number of the applied varnish (theoretically) - 35%. The resulting microcapsules, in which ciprofloxacin is available in the form of anhydrite original form, have the following characterization of release (according to pharmaceutical standards of the U.S. under the following conditions: 900 ml, 75 rpm, 37oC).

pH 4.5 (0.05 M acetate buffer): 40% after 5 min, 70% after 10 min, 85% after 15 min, 100% after 20 minutes

Examples 7 and 8. Repeat example 6 with the difference that the use of lacquer containing commercial product Eudragit 30 D (dry matter), oksipropilmetiltselljuloza 3 SP, magnesium stearate and Tom ratio trading product Eudragit 30 D to oksipropilmetiltselljuloza is 100 : 20 and 100 : 40, accordingly, when theoretical amount of the applied varnish equal to 20 and 40%, respectively.

Feature release of the active substance in the microcapsules according to examples 7 and 8 is similar to the characteristics of the microcapsules according to example 6.

Example 9. 10 mg of ciprofloxacin and 0.7 mg of polyvinylpyrrolidone 25 by means of wet granulation is transferred to microgranulate that put a varnish containing 3,984 mg trade product Eudragit 30 D (dry matter), 1,593 mg oksipropilmetiltselljulozy 3 SP, 0,795 mg stearate and 0,045 mg of tween-20. The ratio between trading product Eudragit 30 D and oksipropilmetiltselljulozy is 100 : 40, and the number of the applied varnish (theoretically) -60%. The resulting microcapsules, in which ciprofloxacin is available in the form of anhydrite original form, have the following characterization of release (according to pharmaceutical standards of the U.S. under the following conditions: 900 ml, 75 rpm, 37oC).

pH 1 (0,1 N hydrochloric acid): 50% after 5 min, 98% after 15 min;

pH 4.5 (of 0.05 M acetate buffer): 50% after 5 min, 100% after 15 minutes

Example 10. Repeat example 9 with the difference that the use of a varnish containing the auction is the following quantities (µg): 3,320, 1,328, to 0.662 and 0,038, and the ratio of the trading product Eudragit 30 D to oksipropilmetiltselljuloza is 100 : 40 when theoretical amount of the applied varnish of 50%.

Feature release of the active substance in the microcapsules according to example 10 is similar to the characteristics of the microcapsules according to example 9.

Example 11. Repeat example 1 with the difference that the use of lacquer containing commercial product Eudragit 30 D (dry matter), oksipropilmetiltselljuloza 3 SP, magnesium stearate and tween-20 in the following quantities (µg): 1,328, mean HDI of 0.531 0,265 and 0.015, and the ratio of the trading product Eudragit 30 D to oksipropilmetiltselljuloza is 100 : 40 when theoretical amount of the applied varnish equal to 20%. In addition, microcapsules applied polishing layer of 0,642 mg of polyethylene glycol.

Feature release of the active substance in the microcapsules according to example 11 is similar to the characteristics of the microcapsules according to example 1.

Example 12. 10 mg of ciprofloxacin and 0.7 mg of polyvinylpyrrolidone by wet granulation was transferred to microgranulate that put a varnish containing 2,638 mg trade product Eudragit 30 D (in the form of dry Eudragit 30 D and triethylcitrate is 100 : 20, and the number of the applied varnish (theoretically) - 50%. The resulting microcapsules, in which ciprofloxacin is available in the form of anhydrite original form, have the characteristics of release of the active substance, such microcapsules according to examples 1 to 11.

Example 13. Repeat example 12 with the difference that the use of lacquer containing commercial product Eudragit 30 D (dry matter), sifted talc and triethylcitrate in the following quantities (µg): 3,320, 2,760 and 0,340, and the ratio of the trading product Eudragit 30 D to triethylcitrate is 100 : 10 when theoretical amount of the applied varnish at 60%.

Feature release of the active substance in the microcapsules according to example 13 is similar to the characteristics of the microcapsules according to examples 1 to 11.

Comparative example B (as per prototype). According to the instructions of the prototype, in the molten Carnauba wax suspended ciprofloxacin in the ratio of 85 : 15, and the resulting suspension is subjected to spray solidification. The resulting microcapsules have the following characterization of the release of the active substance (defined according to example 1):

pH 1 (0,1 N hydrochloric acid): 4% after 18 min, 6% in 8% after 60 minutes

Examples 14 and 15, see table.

The ratio of the trading product Eudragit 30 D to oksipropilmetiltselljuloza is 100 : 40; spray in number to 48.6% (example 14); 50% (example 15).

Example 16. Microcapsules with ciprofloxacin in drug-based oil juice) (data for production of 140 ml of juice with 5% ciprofloxacin)

Ciprofloxacin - 7,000

Polyvinylpyrrolidone 25 - 0,490

Trading product Eudragit 30 D - 2,257

Oksipropilmetiltselljuloza 3 SP - 0,910

Magnesium stearate - 0,455

Twin 20 - 0,018

Miglyol 812 - 98,214

Sucrose super fine grain - 39,025

Lipoid C 75 - 1,405

Strawberry incense - 0,156

Microcapsules: the ratio of the trading product Eudragit 30 D to oksipropilmetiltselljuloza is 100 : 40; and spray in the amount of 48.6 per cent.

1. The pharmaceutical agent in the form of microcapsules containing the active substance with an unpleasant organoleptic properties enclosed in a shell, characterized in that it contains the active substance in the form of anhydrite the main form, and the shell of the microcapsules is a film of water-insoluble neutral complex with methyl and/or ethyl esters by ptx2">

2. Means under item 1, characterized in that the shell of the microcapsules additionally contain water-soluble polymers, plasticizers, wetting and other excipients.

3. Means under item 1 or 2, characterized in that the shell of the microcapsules provided with a coating of polishing agent.

4. A tool according to any one of paragraphs.1 to 3, characterized in that the shell of the microcapsules is a film containing commercial products Eudragit E 12.5, and/or Eudragit 30 D, and/or Eudragit RL 30 D, and/or Eudragit RS 30 D, or ethylcellulose and triethylcitrate.

5. Means on p. 4, characterized in that the shell of the microcapsules is a film, optionally containing oksipropilmetiltselljuloza.

6. A tool according to any one of paragraphs.1 to 5, characterized in that the shell of the microcapsules is a film containing a mixture of 100 wt.h. shopping product Eudragit 30 D and 20 - 50 wt.h. oksipropilmetiltselljulozy.

7. Means on p. 6, characterized in that the shell of the microcapsules is a film, optionally containing excipients.

8. A tool according to any one of paragraphs.1 to 7, characterized in that the microcapsules have a size of 10 to 800 μm.

9. Tool p is STV.

10. A tool according to any one of paragraphs.1 to 9, characterized in that the active substance is an inhibitor of gyrase from the group naphthyridin and hinolincarbonova acids.

11. A tool according to any one of paragraphs.1 to 10, characterized in that the active substance is ciprofloxacin.

12. A tool according to any one of paragraphs.1 - 11, characterized in that it is made in the form of a suspension of microcapsules in an oil environment.

13. A tool according to any one of paragraphs.1 - 11, characterized in that it is made in the form of sachets.

14. The method of obtaining pharmaceuticals by the conclusion of the active substance with an unpleasant organoleptic properties in microcapsules with a shell, characterized in that the active substance in the form of anhydrate or hydrate main form is subjected to wet granulation, and the thus obtained micro-granulate is applied film coating of water-insoluble neutral complex with methyl and/or ethyl esters of polymethacrylic acid and/or Quaternary ammonium compounds of polymethacrylic acid and/or ethyl cellulose.

15. The method according to p. 14, characterized in that the micro-granulate is applied film coating, optionally containing water-soluble polymers, n is the, before applying the film coating humidity of the active substance is brought to a value not more than 30 wt.% by drying the micro-granulate.

17. The method according to any of paragraphs.14 to 16, characterized in that after the film coating humidity of the active substance is brought to the desired value by drying.

18. The method according to any of paragraphs.14 to 17, characterized in that the microcapsules provide a coating of polishing agent.

19. The method according to any of paragraphs.14 to 18, characterized in that the microcapsules are transferred in oral dosage form.

20. The method according to any of paragraphs.14 to 19, characterized in that the microcapsules are transferred in the form of sachets.

21. The method according to any of paragraphs.14 to 19, characterized in that the microcapsules are transferred in the form of a suspension in an oil environment.

 

Same patents:

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to the compounds and their pharmaceutically acceptable salts and methods for treating HIV infections and related viruses and/or treatment of acquired immunodeficiency syndrome (AIDS)

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production

Imidazopyridine // 2092487
The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with medicinal preparations designed as solution and indicated for therapeutic needs. Eye drops contain ciprofloxacin hydrochloride monohydrate being equivalent to 0.3% free foundation, a buffer system that keeps pH within 3.5-5.5 interval, as a conserving agent - benzalconium chloride and a s a stabilizer - the salt of disodium ethylenediamine tetraacetic acid, moreover, their range of osmolality values correspond to 150-450 mM/kg H2O. Eye drops should be obtained by preparing buffer system in which mannitol should be dissolved followed by the salt of disodium ethylenediamine tetraacetic acid, benzalconium chloride, ciprofloxacin hydrochloride. Then one should perform the control for the quality of obtained solution to be then filtered by applying sterilizing elements and packed. This innovation provides treatment of eyes at creating the pressure in an eye and at certain desired osmolality.

EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

EFFECT: endoparasitic agent with synergetic agent.

6 cl, 7 ex, 7 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: at performing curative endoscopy one should apply pneumoapplication of granulated sorbent - diovine at the quantity of 0.2 g, the pressure being 15 atm. at the distance of 1.5 cm against the defect onto the surface of bleeding rupture of gastric mucosa. Diovine's coarse-grained structure enables to keep the integrity of mucous-bicarbonate barrier due to providing normal vapor exchange and moisture medium in the defect. Moreover, diovine's antimicrobial action helps to suppress gram-positive and gram-negative microflora that enables to shorten terms for defects healing and decrease the frequency of repeated hemorrhages.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: medicine, neurology, pharmacy.

SUBSTANCE: invention proposes using levetiracetam and the corresponding levetiracetam-base pharmaceutical composition used in treatment of bipolar disorders, mania and migraine. Also, invention relates to a pharmaceutical composition based on levetiracetam and at least one inhibitor of GABA type A neuronal receptors that is used in treatment of epilepsy, alcohol withdrawal syndrome, tremor, bipolar disorders, obsessive-compulsive disorder, panic state, depression, headache, pain, ischemia and head trauma, to corresponding methods for treatment, to a method for selective enhancing the therapeutic effect of inhibitors of GABA type A neuronal receptors, to a method for treatment of patient with inhibitor of GABA type A neuronal receptors involving the combined administration of indicated inhibitor of GABA type A neuronal receptors with levetiracetam. Invention shows the possibility for using levetiracetam for treatment of chronic and neuropathic pain in lower doses as compared with doses causing secondary effects, and shows its property to enhance activity of inhibitor of GABA type A neuronal receptors.

EFFECT: improved and valuable medicinal properties of agent.

18 cl, 18 tbl, 7 ex

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