Direct pressable azithromicine-containing formulations
FIELD: medicine, in particular dry azithromicine mixtures to produce azithromicine pellets by direct pressing.
SUBSTANCE: claimed formulation contains non-dehydrated azithromicine selected from group containing B, D, E, F, G, H, J, M, N, O, P, Q, R forms or mixtures thereof, and at least one pharmaceutically acceptable carrier. Pellet containing non-dehydrated azithromicine mixture and at least one pharmaceutically acceptable carrier, as well as azithromicine pellet obtained by providing of dry mixture containing non-granulated azithromicine A and at least one pharmaceutically acceptable carrier, followed by direct pressing said mixture also are disclosed.
EFFECT: direct pressable azithromicine-containing formulations; azithromicine pellets having acceptable hardness and frangibility.
14 cl, 6 ex, 1 dwg, 6 tbl
BACKGROUND of INVENTION
Direct pressing is a method of tableting, in which the tablet is produced by axial compression of powdered mixtures containing the active ingredient. Direct pressing all necessary for tableting ingredients, including the active ingredient and excipients for processing, is included in the free-flowing mixture, which is then tabletirujut. Active ingredient fillers and other substances are mixed and then pressed into tablets. Usually tablets get tablet press press by exposure to the substance by pressure.
There are a number of tablet press presses, each of which differs in its performance and design, but similar in its basic function and operation. They all shrink in the cavity of the matrix composition for tableting pressure arising between two steel punches - top and bottom.
Pharmaceutical manufacturers prefer the use of direct compression due to shorter processing period and price advantages compared to the methods of wet and dry granulation. However, the application of direct pressure is usually limited, to those cases where the active ingredient has physical properties suitable for gaining the pharmaceutically acceptable tablets.
Some active ingredients that are generally not suitable for direct compression, can be included as part of the compression direct pressing of the composition by incorporating into it before pressing one or more fillers. However, the addition of fillers to the composition increases the size of the tablets of the final product. As for using the tablet as a suitable dosage forms its size must meet specific parameters, there is a limit to the size of the tablet is exceeded with the aim of increasing amounts of fillers to enhance the sealability is impractical. As a result, manufacturers often limited to the application of the method of direct pressing for compositions containing such a low dose of the active ingredient on the pressed tablet that for the convenience of direct extrusion composition may include a significant amount of filler.
During the development of pharmaceutical dosage forms, it is important carefully to consider several different problems. Preparation of pharmaceutical dosage forms should be economical. Dosage form should also be easy to proglatavetsa. In addition, smaller dosage forms are more acceptable to patients, resulting in better compliance sick mode and treatment.
Known is about, what to get pills from a given composition must possess good flow characteristics for accurate filling substance volume of the cavity of the matrix, a suitable compressibility, compaction and better extraction from the mold to obtain tablets. Characteristics of fluidity of powders are crucial for the effectiveness of the tabletting process. The ability of a substance to flow freely into the mold is important to ensure uniform filling of the mold and the continuous feed of the substance of its source. Bad characteristics of fluidity substances can negatively affect weight, hardness and friability of the tablets. To ensure effective mixing and acceptable mass uniformity CT need a good fluidity subjected to pressing of powders.
Generally, it is believed that azithromycin, also known as 9-desoxo-9a-Aza-9a-methyl-9a-homoerythromycin A, can not be directly pressed in the production of tablets of formulations containing azithromycin.
It would be desirable to develop a containing azithromycin composition that can be directly compressed and from which can be obtained tablets with acceptable hardness and friability.
SUMMARY of the INVENTION
The present invention relates to dry MESI, used to obtain azithromycin tablets by direct compression, containing nethertown azithromycin and at least one pharmaceutically acceptable excipient.
The present invention also relates to a tablet azithromycin containing nethertown azithromycin and at least one pharmaceutically acceptable excipient. Tablet azithromycin preferably obtained by direct compression of a dry mix of the present invention to obtain the above-mentioned tablets of azithromycin.
Tablet of azithromycin according to the present invention preferably contains azithromycin at a dose of 250 MHA, 500 MHA or 600 MHA.
The present invention also relates to a tablet of azithromycin, which is obtained by forming a dry mixture in the form of form A of azithromycin and at least one pharmaceutically acceptable excipient. Then get a tablet of azithromycin by direct compression of a dry mix.
BRIEF DESCRIPTION of DRAWING
The drawing is a graph showing particle size distribution of bulk azithromycin obtained for parties of azithromycin 1-11 using analysis light scattering (Malvern Mastersizer S, Malvern Instruments, Worcestershire, UK).
In the description and the subsequent claims refer to a number of terms, the op is edelenyi whose values are the following.
Used in this document, the term "dry mixture" means, generally, a homogeneous mixture of two or more substances in the form of particles. Particles can be in powder form or, alternatively, in the form of larger aggregated or agglomerated particles.
Used in this document the term "azithromycin" includes all crystalline and amorphous forms of azithromycin, including all polymorphs, isomorphy, clathrates, salt, solvate and hydrate azithromycin, unless stated specifically. Form of azithromycin include digitalnow form and various nativitate form.
Stable dihydrate azithromycin, which is essentially non-hygroscopic in conditions where the relative humidity is conducive to containing the azithromycin composition, and disclosed in U.S. patent No. 6268489 identified in this document as "form A". This form is a crystalline dihydrate obtained by crystallization from tetrahydrofuran and aliphatic (C5-C7) hydrocarbon in the presence of at least two molar equivalents of water.
"Nethertown azithromycin" means all amorphous and crystalline forms of azithromycin, including all polymorphs, isomorphy, clathrates, salt, solvate and hydrate azithromycin, other than the form A-dihydrates form of azithromycin (dihydrate azithromycin).p> Nethertown azithromycin enables disclosed in U.S. patent No. 4474768 hygroscopic azithromycin hydrate designated in this application as "form B".
Azithromycin may be presented with several alternative crystalline nativitatem forms, including forms D, E, F, G, H, J, M, N, O, P, Q and R, which are disclosed in the application for the grant of U.S. patent No. 10/152106, filed may 21, 2002, the provisions of which are included in their entirety in the present description by reference.
Isomorphy family I and family II are a hydrate and/or solvate of azithromycin. Under certain conditions, the solvent molecules in the cavities tend to exchange between solvent and water. Therefore, the content of the solvent/water isomorph can to some extent be varied. Forms B, F, G, H, J, M, N, O, and P belong to the family I of azithromycin and belong to the monoclinic space group P21with unit cell dimensions a=16,3±0,3 Åb=16,2±0,3 Åc=18,4±0,3 Å and β=109±2about. Forms D, E and R belong to the family II of azithromycin and belong to the orthorhombic space group P212121with unit cell dimensions a=8,9±0,4 Åb=12,3±0,5 Å and c=45,8±0,5 Å. The form Q is different from families I and II.
The structure of crystal form D azithromycin corresponds to the formula C38H72N O12 .H2O.C6H12, representing monocyclohexyl of azithromycinonline. Form D is additionally characterized by the content of 2-6 wt.% water and 3-12 wt.% cyclohexane in the powdered samples. Based on nanocrystallography data, the calculated water content and cyclohexane to form D is 2.1 and 9.9%, respectively.
E form of azithromycin corresponds to the formula C38H72N2O12 .H2O.C4H8O, representing montereyherald of azithromycinonline. Based on data monokristallicheskogo analysis, form E is a mono-THF-MES monohydrate.
The structure of crystal form G azithromycin corresponds to the formula C38H72N2O12 .1,5H2O, representing azithromycin sesquihydrate. Form G is additionally characterized by a content of 2.5 to 6 wt.% water and <1 wt.% organic solvent (solvents) in powdered samples. The single crystal form G consists of two molecules of azithromycin and three water molecules in each asymmetric node of the lattice. This structure corresponds to sesquihydrate with theoretical water content equal to 3.5%. The water content of the powdered samples of the form G varies from about 2.5% to about 6. Total residual content of organic solvent does not exceed 1% of the amount of the appropriate solvent used for crystallization.
Form H of azithromycin corresponds to the formula C38H72N2O12 .H2O.C3H8O2presenting a Hemi-1,2-proportionalist of azithromycinonline. Form H is a monohydrate/Hemi-propilenglikolstearat free base of azithromycin.
The single crystal form J azithromycin corresponds to the formula C38H72N2O12 .H2O.0,5C3H7OH, representing a Hemi-n-propanolamine of azithromycinonline. Form J is additionally characterized by the content of 2-5 wt.% water and 1-5 wt.% 1-propanol in powdered samples. The calculated solvent content of approximately 3.8% of n-propanol and approximately 2.3% of water.
Form M of azithromycin corresponds to the formula C38H72N2O12 .H2O.0,5C3H7OH, representing semiseparable of azithromycinonline. Form M is additionally characterized by the content of 2-5 wt.% water and 1-4 wt.% 2-propanol in powdered samples. The structure of crystal form M can be a monohydrate/gamesupport.
Form N azithromycin pre which is a mixture of isomorph family I. The mixture may contain different percentages of isomorphs F, G, H, J, M, and others, and varying amounts of water and organic solvents such as ethanol, isopropanol, n-propanol, polyethylene glycol, acetone, acetonitrile, butanol, pentanol and so on. The water content can be 1-5,3 wt.%, and the total content of organic solvents may be 2-5 wt.% with the content of each solvent is from 0.5 to 4%.
Based on data monokristallicheskogo analysis, form O azithromycin corresponds to the formula C38H72N2O12 .0,5H2O.0,5C4H9OH, representing hemihydrate/Hemi-n-butanolate free base of azithromycin.
Form P of azithromycin corresponds to the formula C38H72N2O12 .H2O.0,5C5H12O, representing a Hemi-n-Intersolar of azithromycinonline.
Form Q azithromycin corresponds to the formula C38H72N2O12 .H2O.0,5C4H8O, representing semiterrestrial of azithromycinonline. It contains about 4% water and about 4.5% of THF.
Form R of azithromycin corresponds to the formula C38H72N2O12 .H2O.C5H12O, representing monomethyl-tert-butile solvat of azithromycinonline. theoretical water content of the form R is 2.1 wt.%, and theoretical content of methyl tert-butyl ether is 10.3 wt.%.
The single crystal form F azithromycin corresponds to the formula C38H72N2O12 .H2O.0,5C2H5OH, representing hemiethanolate of azithromycinonline. Form F is additionally characterized by the content of 2-5 wt.% water and 1-4 wt.% ethanol in powdered samples. The single crystal form F crystallizes in the monoclinic space group P21and asymmetric node of the lattice contains two molecules of azithromycin, two water molecules and one molecule of ethanol in the form of a monohydrate/hemiethanolate. Form F is isomorphic with respect to all crystalline forms of azithromycin collection I. Theoretical content of water and ethanol is 2.3%and 2.9%, respectively.
Used in the description in respect of azithromycin, the term "form" means that the azithromycin is not subjected to dry granulation, such as by clumping of grains or by compaction by rolling, or wet granulation.
Used in the phrase "bulk azithromycin" means particles of azithromycin without added fillers.
The term "pharmaceutically acceptable" means that component, which, as a rule, what is safe, non-toxic and is not undesirable neither biologically nor otherwise, and includes those components that are acceptable for veterinary use, or for pharmaceutical use in humans.
The phrase "direct compression moulding composition" means a composition that can be pressed in a pharmaceutically acceptable tablet without preliminary stage of granulation.
The term "compressibility" refers to the degree to which the composition is reduced in volume when the air was removed.
The term "compaction" means the ease with which the composition is compressed to tablets with acceptable hardness.
Used in the description of the term "free flowing" means the ability of a substance to flow without mechanical mixing of the standard equipment for tabletting, using the induction currents of the force of gravity, such as F-press. Of substances with good fluidity get dosage forms with high uniformity by weight, which is proved for low mass dosage forms the value of the relative standard deviation (% RSD) or coefficient of variation (% CV).
Used herein, the term "fine" refers to particles whose measured according to the method of Malvern diameter is less than about 44 microns.
Used herein, the term "F-press" from OSISA to the press MANESTY F-PRESS (Manesty Instruments, UK).
The term "mga" refers to milligrams of the free base of azithromycin.
In the method according to the present invention used azithromycin can be a shredded or not granular medicine.
The dry mixture of the present invention is used to produce tablets of nethertown azithromycin by direct pressing. The dry mixture typically contains from about 1% to about 80% nethertown of azithromycin. Azithromycin in the dry mixture is preferably in the form.
Also is preferred that the azithromycin in the dry mixture included a form nethertown azithromycin chosen from forms B, D, E, F, G, H, J, M, N, O, P, Q, R, or mixtures thereof.
In addition to nethertown azithromycin dry mixture of the present invention also contains at least one pharmaceutically acceptable carrier. The media may contain auxiliary substances for processing, to improve the properties of the dry mixture to tabletroute by direct pressing.
In one variant embodiment of the present invention dry mix suitable for the production of azithromycin tablets by direct compression with the filing of the substance by gravity.
Granulometric composition of azithromycin is crucial in determining suitability for that is latinoware on tablet press press by direct pressing with the filing of the substance by gravity, especially at higher loadings of azithromycin, such as 45% or more. With increasing load azithromycin fine granular azithromycin tends to further deterioration of the flow properties of the dry mixture, as it is a higher percentage of the total number of particles of the dry mixture. Therefore, to achieve an acceptable yield on tablet press press with the filing of the substance by gravity and to ensure acceptable fragility pills you must reduce the quantity of fine pieces of azithromycin in the dry mixture.
Under "tablet press press with the filing of the substance by gravity" means that the pharmaceutical composition is fed into the mold by force, and that the current pharmaceutical composition is induced by the action of gravity. An example of a tablet press press with the filing of the substance by gravity is F-press Manesty.
In this variant embodiment of the present invention to achieve a dry mixture of suitable flow characteristics, especially at higher loads azithromycin, usually less than about 20% by volume of particles of azithromycin in the dry mixture shall have a diameter of 44 μm or less. Preferably, less than approximately 14% of the particles azithromycin shall have a diameter of 44 μm or less.
Similarly, for a dry mixture of the present is briteney preferably, to less than approximately 27% of the particles azithromycin had a diameter of 74 μm or less.
In addition to the dry mixture according to the present invention preferably less than approximately 60% of the particles azithromycin had a diameter of 105 μm or less. More preferably, less than approximately 50% of the particles azithromycin had a diameter of 105 μm or less.
Even more preferably, less than about 6% of the particles azithromycin had a diameter of 16 μm or less.
In a more preferred variant of embodiment of the present invention the dry mixture contains less than about 6% by volume of particles of azithromycin with a diameter of about 16 μm or less and less than about 20% by volume of particles of azithromycin with a diameter of about 44 μm or less. Even more preferably, less than approximately 14% of the particles azithromycin had a diameter of 44 μm or less.
In an even more preferred variant embodiment of the dry mixture contains less than about 6% by volume of particles of azithromycin with a diameter of about 16 μm or less, less than about 20% by volume of particles of azithromycin with a diameter of about 44 μm or less and less than about 27% by volume of particles of azithromycin with a diameter of approximately 74 μm or less. Even more preferably, less than p is blithedale 14% of the particles azithromycin had a diameter of 44 μm or less.
In an even more preferred variant embodiment of the dry mixture contains less than about 6% by volume of particles of azithromycin with a diameter of about 16 μm or less, less than about 20% by volume of particles of azithromycin with a diameter of about 44 μm or less, less than about 27% by volume of particles of azithromycin with a diameter of approximately 74 μm or less and less than approximately 60% by volume of particles of azithromycin with a diameter of approximately 105 μm or less. Even more preferably, less than approximately 14% of the particles azithromycin had a diameter of 44 μm or less and approximately less than 50% of the particles azithromycin had a diameter of about 105 microns or less.
Characteristics yield a dry mix can be assessed through a number of methods known in the art. One way of determining the characteristics of the powdered substance is a measurement of bulk density. A simple way of describing the flow characteristics obtained by measuring the bulk density, is the index of Carr compressibility index (Carr).
The index definition compressibility Carr is a simple test to estimate the yield strength by comparing the initial and final (after screwing) bulk volume and fill rate. Suitable empirical path illustrates the Ki flow is represented by the index of compressibility Carr:
The compressibility index (%) = [(density after screwing - initial density)/density after screwing]×100.
In the present invention it was shown that the compressibility index of Carr dry mix is a good indicator of flow characteristics and, therefore, the usability of the dry mixture to get the tablets through a tableting by direct compression with the filing of the substance by gravity. Generally acceptable for and possibility of reception of tablets on F-press was observed in compounds with values of compressibility index Carr, less than about 34, whereas the compounds with values equal to 34 or large, was observed worst within and the inability to education acceptable tablets on F-press. Therefore, the dry mixture of the present invention must have an index value of Carr compressibility of less than about 34, more preferably less than about 31, and even more preferably less than about 28.
Another way to evaluate the fluidity of the particles is the definition of angle of internal friction, which can be determined in experiments with application of the device with shear force. The main difference in the flow characteristics of liquids and powders is their internal friction. The absence of internal friction of fluids allows them taking the TB alone form surfaces, while the internal friction in the powder allows them to form irregularities or other non-linear surface.
Internal friction powders are usually estimated using the device with shear force, which represents the device in which is placed the sample powder is subjected to certain physical activities and evaluate its response to these pressures, as disclosed in "Some Measurements of Friction in Simple Powder Beds", Heistand, E.N. and Wilcox, C.J. (J. Pharm. Sci. 57 (1968) 1421), included in this document as a reference. The answer is present in the form of values of angle of internal friction. This parameter is characteristic for the measured powders and varies for different substances. The lower the value of angle of internal friction, the better the flowability of the powder has. This parameter can be used to predict differences tablets on weight during tabletting operations, since the mass of the powder filling, and hence the mass of the tablet depends on the ability of the powder to quickly drain into the mold for tableting. Dry mixes of the present invention, suitable for the production of tablets by direct compression, are the angles of internal friction of less than about 34°and more preferably, less than approximately 31°.
Even more preferably, the dry mixture according to the present the invention have the value of the index of Carr compressibility less than approximately 34 and the angle of internal friction of less than about 34° .
Most preferably, the dry mixture of the present invention have the value of the index of Carr compressibility of less than about 28 and the angle of internal friction of less than about 31°.
The dry mixture satisfying the above properties can be obtained using methods including, but not limited to, adding acceptable solvent, increasing the particle size or by changing processing conditions. Usually the addition of fillers provides methods of modification of the profile of the flow of the pharmaceutical composition with a low dosage, as commercially available fillers have good flow characteristics. For dry mixtures with higher loads azithromycin index values Carr compressibility and/or angles of internal friction within the above ranges can be achieved by taking azithromycin with the above particle size distribution.
Accordingly, the particle size distribution profile of azithromycin should be evaluated and, if necessary, azithromycin should be subjected to processing to achieve the required particle size distribution profile.
To obtain particles of azithromycin with the desired grain size bulk azithromycin may be subjected to additional treatment is by using ways including, but not limited to: 1) shredding; (2) screening; 3) recrystallization and 4) granulation, including dry and wet granulation. The above-mentioned additional processing methods can be applied individually or in combination.
When grinding the drug is exposed to such a shift effort, in which the particle size decreases. Grinding can be a aggressive process, in which the particle size is reduced significantly, or it may be a non-aggressive process in which the particle size is not reduced to a significant extent and which is only performed in order to remove lumps or break up the larger lumps of medicine, formed in the bulk drug.
In the pharmaceutical industry grinding is often used to reduce the size of solid particles. Available are many types of mills, including needle roller mills, hammer mills and jet mills. One of the most commonly used types of mills is a hammer mill. In a hammer mill uses a high-speed rotor, attached to some stationary or swinging hammers. Hammers can be attached in such a way that the substance in contact or a surface of a knife or the surface of the hammer. It is only to the substance enters the mill, it falls on the rotating hammers and broken down into smaller particles. Under the hammers is a sieve, which allows smaller particles to pass through the openings therein. Larger particles remain in the mill and continue to break under the action of the hammers up until particles of azithromycin is sufficiently small to pass through a sieve. Particles of azithromycin may be optionally sieved. When sifting granular medication is passed through a sieve or a series of sieves to obtain the desired particle size distribution of bulk drugs.
There are several ways to increase the particle size of drugs, including, but not limited to, granulation and recrystallization. For example, wet granulation involves the use of granulating fluid, which causes particles of azithromycin to form agglomerates and increases thereby the particle size. Appropriate ways wet granulation to obtain particles of azithromycin disclosed in thoroughly review the preliminary application for the grant of U.S. patent No. 60/343469, entitled "Wet granulation azithromycin"filed December 21, 2001, and jointly consider the international application with registered number PC23065A, entitled "Wet granulation azithromycin". Appropriate ways dry the th granulating particles of azithromycin disclosed in thoroughly review the preliminary application for the grant of U.S. patent No. 60/354041, entitled "Dry granulating compositions azithromycin", filed February 1, 2002.
In the present invention to increase the size of the particles can be applied wet granulation bulk drugs without the use of additional fillers.
Recrystallization involves the dissolution of bulk drugs and its transformation into new crystals that are appropriate in size for receiving azithromycin tablets by direct compression.
Another way to increase the size of the particles is the sieving of bulk drugs to remove smaller particles.
Although it was found that the particle size distribution of azithromycin is important to achieve flow characteristics acceptable for tabletting equipment and supply substance by gravity, the dry mixture with a lower dose of azithromycin or undesirable amount of powdered parts can still be used to produce tablets by direct compression by adjusting, if necessary, processing conditions, equipment and/or fillers. For example, the dry mixture with a high content of finely part can be tableted by direct compression using equipment for tableting with the forced wisestamp.com promote or force-feed substances are well known in the art.
Therefore, in alternative embodiments of the present invention dry mix containing nethertown azithromycin may be subjected to mechanical processing such a way as to compensate for the poor performance of fluidity. For example, the substance can forcibly fed into the mold by means of a mechanical feeder. Mechanical feeder can be used, if the use of the pharmaceutical composition is poor control of the weight. Additionally, the characteristics of the yield of the dry mixture may also be modified by reducing the percentage of bulk azithromycin in the dry mixture.
The amount of azithromycin, additional fillers and excipients for the treatment can be varied to obtain pharmaceutical compositions suitable for direct compression properties defined dimensions, yield strength, such as described in this document, the compressibility index of Carr and the angle of internal friction.
Any other fillers such as thinner or dry binder should preferably possess good flow characteristics and compressibility. Fillers with good flow characteristics are freely available.
In the dry mixture according to the present invention, the fillers suitable for direct pre the consideration include, but are not limited to, binders, diluents, disintegrators, lubricants, fillers, carriers and the like.
Binders are used to empower tableting composition cohesive properties, thereby intactness tablets after compression. Suitable binders include, but are not limited to, microcrystalline cellulose, gelatin, sugars (including sucrose, glucose, dextrose and maltodextrin, polyethylene glycol, waxes, natural or synthetic gums, polyvinylpyrrolidone, polymers based on cellulose (including hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethyl cellulose and the like).
Lubrication can be applied in the production of certain dosage forms and are typically used in the manufacture of tablets. In the present invention the lubricant is added directly before the stage tableting, mixing with the composition within the minimum period of time to ensure good dispersion. Used in the composition according to the present invention, the lubricant may be one or more compounds. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glycerinated, the floor of the measures on the basis of polyethylene glycol and polyethylene oxide (for example, produced by Union Carbide, Inc., Danbury, Conn. under the trade names Carbowax for glycol and Polyox for polyethylene oxide), sodium lauryl sulfate, lauryl sulfate, magnesium, sodium oleate, sodium fumarate, DL-leucine, colloidal silicon dioxide, and others known in the art. The preferred lubricants are magnesium stearate, calcium stearate, zinc stearate and mixtures of magnesium stearate with sodium lauryl. Lubrication can be from about 0.25% to about 10% by weight of the tablet, more preferably from about 0.5% to about 3%.
Disintegrator are used for disintegration or decay of the tablet after administration, and, as a rule, are starches, clays, cellulose, alginates, resins and cross-linked polymers. Suitable disintegrators include, but are not limited to, cross-linked polyvinylpyrrolidone (PVP-XL), matrikamantra and croscarmellose. If desired, the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting means and emulsifiers, tools, sautereau to a certain pH value, and the like, for example, sodium acetate, sorbitanoleat, triethanolaminato, triethanolamine, sodium lauryl sulfate, dictionaryservice is at, fatty acid esters of polyoxyethylenesorbitan and so on.
Used in the compositions of the present invention, the solvent may be one or more compounds capable of compaction and good flow. As fillers and diluents can be used a number of substances. Suitable diluents and excipients include, but are not limited to, lactose (monohydrate, dried by spraying monohydrate, anhydrous and the like), sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose; Avicel), digitally or anhydrous dibasic calcium phosphate, calcium carbonate, calcium sulfate, and others known in the art. More preferably, free flowing thinners, improve over the mixture are dried by spraying monohydrate lactose (such as Fast Flo®, Foremost Farms, Rothschild, WI and Phamatose® DCL 11, DMV International Pharma, Veghel, The Netherlands), loosely agglomerated current monohydrate lactose (such as Tablettose®, Meggle GMBH, Wasserburg, Germany), granulated lactose monohydrate (such as Pharmatose® DCL 15, DMV International Pharma, Veghel, The Netherlands), dried when rolling monohydrate lactose (such as Pharmatose® DCL 21, DMV International Pharma, Veghel, The Netherlands), anhydrous subjected to pressing lactose (such as Pharmatose® DCL 40, DMV international Pharma, Veghel, The Netherlands and Anhydrous Lactose DT, Quest International Inc., Hoffman Estates, IL), dried by spraying lactose with microcrystalline cellulose (MicroLac® 100, Meggle GMBH, Wasserburg, Germany), dried by spraying lactose and cellulose (Cellactose®, Meggle GMBH, Wasserburg, Germany), and subjected to pressing sucrose (such as Sugartab®, Penwest Pharmaceuticals Co., Patterson, NY and Nu-Tab, DMV International Pharma, Veghel, The Netherlands), crystallized together sucrose and modified dextrins (Di-Pac, Domino Foods Inc, Baltimore, MD), dried by spraying dexterity (Emdex®, Penwest Pharmaceuticals Co., Patterson, NY), coarse dextrose (such as Cerelose® Coarse Dextrose 2037, Corn Products International, Inc., Westchester, IL), agglomerated dextrose (such as Unidex® 2034, Corn Products International, Inc., Westchester, IL), dried with maltodextrin spray (such as Maltrin® M 510, Grain Processing Corp., Muscatine, IA), finely ground granulated maltodextrin (such as Maltrin® 150 M, Grain Processing Corp., Muscatine, IA), dried by spraying maltose (Advantose™ 100 Maltose Powder, SPI Pharma, New Castle, DE), dried by spraying mannitol (such as Mannogem™ EZ Spray Dried Mannitol, SPI Pharma, New Castle, DE and Parteck™ M, EM Industries, Inc., Hawthorne, NY), granular mannitol (such as Mannitol Granular 2080, SPI Pharma, New Castle, DE and Granular Mannitol, SPI Pharma, New Castle, DE), dried by spraying sorbitol (such as Parteck™ SI [Sorbitol Instant™], EM Industries, Inc., Hawthorne, NY), coarse sorbitol (such as grades 834, 2016 and 1162 Crystalline Sorbitol, SPI Pharma,New Castle, DE), dried together with the starch subjected to pressing fructose (Advantose™ FS95 Fructose, SPI Pharma, New Castle, DE), pre-relatively corn starch (such as Spress® B820, Grain Processing Corp., Muscatine, IA and Starch 1500, use Inc., West Point, PA), microcrystalline cellulose high density (such as Avicel PH302, FMC Biopolymer, Philadelphia, PA, Pharmacel® 200, DMV International Pharma, Veghel, The Netherlands and Emcocel® HD90, Penwest Pharmaceuticals Co., Patterson, NY), microcrystalline subjected to pressing cellulose (such as Avicel PH200, FMC Biopolymer, Philadelphia, PA, Pharmacel® 102, DMV International Pharma, Veghel, The Netherlands and Emcocel® Emcocel 90M and® LP200, Penwest Pharmaceuticals Co., Patterson, NY), selectiona microcrystalline subjected to pressing cellulose (such as Prosolv SMCC™ 90, Penwest Pharmaceuticals Co., Patterson, NY), fluent current grades of dibasic calcium phosphate in the form of dihydrate (such as Emcompress®, Penwest Pharmaceuticals Co., Patterson, NY and Di-Tab®, Rhodia Inc., Cranbury, NJ) and freely current grades of dibasic calcium phosphate in the form of the anhydrous salt (such as Anhydrous Emcompress®, Penwest Pharmaceuticals Co., Patterson, NY and A-Tab®, Rhodia Inc., Cranbury, NJ). The most preferred free flowing diluents are dried by spraying lactose and free current grade lactose monohydrate, grades of microcrystalline cellulose and silication microcrystalline cellulose with high density and Powergen is taken direct pressing, dried by spraying dexterity, dried spray and granular mannitol, dried by spraying and coarse sorbitol, and free current grades of dibasic calcium phosphate in the form of a dihydrate.
In the present invention it is preferable to use these diluents to reduce the index of Carr and lower values of angle of internal friction for containing azithromycin compositions, particularly in dry mixtures containing azithromycin dosage constituting approximately 30% or more. The use of these diluents is even more preferable if approximately 20% or more of particles of azithromycin have a diameter of 44 microns or less.
Flavor additives included in the composition may be selected from synthetic fragrant oils and fragrant aromatics and/or natural oils, extracts from leaves, flowers, fruits, plants and so forth, and combinations thereof. They can include cinnamon oil, oil of Grushenka, mint oil, clove oil, Bay oil, anise oil, eucalyptus oil, thyme oil, cedar oil, oil of nutmeg, oil of sage, oil of ordinary almonds, and Cassia oil. As flavor additives can also be used vanilla, citrus oil, including lemon, orange, lime and grapefruit, grapes, and extracts from fruits is, including Apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. The amount of flavoring additives may depend on a number of factors, including the desired organoleptic effect. In the case of the use of food additives and their content usually ranges from 0.5% to approximately 3.0% by weight of the total tablet.
The tablets of azithromycin may also be added other fillers and dyes. The dyes include, but are not limited to, titanium dioxide and/or food colorants, such as dyes F.D.&C, aluminum varnishes and natural dyes, such as the extract from grape skins, the powder of the common beet, beta-carotene, annatto, Carmine, turmeric, paprika and so on. The dye is an optional ingredient in the compositions of the present invention, in the case of application typically contains up to about 3.5% by weight of the total tablet.
Dry mix suitable for tableting by direct compression, the present invention contain up to about 80 wt.% nethertown azithromycin, from about 10 wt.% to about 90 wt.% binder, from 0 wt.% to about 85 wt.% diluent, from 2 wt.% to about 15 wt.% disintegrant and from about 0.25 wt.% to about 10 wt.% the strokes.
In an additional variant embodiment of the dry mixture contains up to about 80 wt.% azithromycin, from about 2 wt.% to about 10 wt.% disintegrant, from about 0.5 wt.% to about 8 wt.% lubricant and from about 0 wt.% to about 85 wt.% diluent.
To obtain a dry mixture of the various components, except the lubricant, may be a weighted, free from lumps and United. To obtain a homogeneous mixture, the mixing may be carried out over a significant period of time, after which it can be added lubrication. After this can be completed the final mixing. The dry mixture can be stored for later use or tablets on a suitable equipment.
To obtain a homogeneous mixture of the components of the dry mixture, including azithromycin and at least one filler may be combined by making the mixture, mixing, stirring, shaking, processing drum, rolling or any other method of combining the components of the mixture. It is preferable that the azithromycin and fillers were combined under conditions of low shear in a suitable apparatus, such as a V-blender, hand blender, blender with two cones or any other apparatus capable of functioning in the preferred condition is the conditions with low shear. Usually on the last stage add grease.
The present invention should not be construed as limited data conditions of the Association of components and, based on the disclosure of this document, it should be understood that the favourable properties can be achieved in other circumstances in the case, if the components retain their basic properties, and a substantial homogeneity of the blend components of the composition is achieved in any other way without any meaningful separation.
In one variant embodiment to obtain a dry mixture of the components, except the lubricant, weighed and placed in a container for mixing. To obtain a homogeneous mixture, the mixing is carried out by means of suitable equipment for mixing. For removal of lumps dry mixture can be filtered through a sieve. The sifted dry mixture may be returned to the tank for mixing and mixed for an additional period of time. Then you can add a lubricant such as magnesium stearate, and the dry mixture may be mixed for an additional period of time.
The dry mixture is generally free-flowing and can be used to obtain tablets on standard equipment for tabletting or stored for future use.
Tablet really is obreteniyu, obtained by direct pressing, are solid, intended for oral administration, with the same appearance and mechanical strength sufficient to withstand possible destruction during storage or transportation or for subsequent coating process. To obtain tablets with suitable properties through methods of direct pressing the dry mixture should have good flow characteristics, good compaction and other appropriate physical characteristics.
The dry mixture according to the present invention can be used to obtain tablets on standard equipment for tabletting, known in the industry as a process with the filing of the substance by gravity, and equipment, equipped with forced delivery of the pharmaceutical composition. In one variant embodiment of the dry mixture used to obtain the tablets on a single stationary press for tableting. Containing azithromycin tablets applicable for the treatment of bacterial and protozoal infections.
In an additional aspect of the present invention, the tablet azithromycin receive in accordance with the following stages. First, azithromycin and at least one filler are mixed together to obtain a dry mixture. Lubricant can be added to with the Hoi mixture during or immediately after mixing azithromycin and other fillers. Then the dry mixture with the added lubrication of the seal with the receiving tablets by direct compression.
Optionally, after the initial mixing of the dry mixture may be subjected to the process of removing lumps. In addition, before the final stage of pressing, to obtain tablets dry mix, with added grease can first be subjected to pre-compression on a rotary press for tableting. Before pressing the mixture with the added lubrication may not necessarily forced to go into the slot of the mold.
Before adding lubricant suitable dry mixture may contain up to about 80 wt.% azithromycin, from approximately 10% to approximately 90% binder, from 0% to approximately 85% filler, from 2% to approximately 15% of disintegrant.
The mixture is added grease may contain from about 0.25% to about 10% of the lubricant, more preferably, from about 0.5% to about 3% lubricant. A specific amount of lubricant that you want to add, may partly depend on specifically selected lubricant.
In one variant embodiment of the tablet obtained by direct compression, may contain grease in excess of about 1 wt.% and not offset the next about 6 wt.% relative to the weight of the tablet. In yet another additional embodiment, the embodiment of the tablet obtained by direct compression, may contain a lubricant in a quantity greater than or equal to about 2 wt.% and not greater than or equal to about 5 wt.% relative to the weight of the tablet. In yet another variant embodiment of the tablet obtained by direct compression, may contain a lubricant in a quantity greater than or equal to about 3 wt.% and not greater than or equal to about 5 wt.% relative to the weight of the tablets.
In one variant embodiment of the tablet obtained by direct compression, may contain a substance for imparting slip (glidant) in an amount not exceeding about 3 wt.% relative to the weight of the tablet. In yet another variant embodiment of the tablet obtained by direct compression, may contain a substance for imparting slip (glidant) in an amount not exceeding about 1 wt.% relative to the weight of the tablet. In yet another additional embodiment, the embodiment of the tablet obtained by direct compression, may contain a substance for imparting slip (glidant) in an amount not exceeding about 0.5 wt.% relative to the weight of the tablet. Suitable substances for imparting slip (glidant) include magnesium trisilicate, powdered cellulose, starch, Thal is, rejonowy calcium phosphate, stearates and colloidal silicon dioxide. The most preferred substances to give the slip (galantai) are talc, magnesium stearate and colloidal silicon dioxide.
In typical methods of compaction for tablets by direct pressure apply piston-like device with three stages in each cycle: 1) filling (add parts of the tablets in the compression chamber); 2) seal (formation of tablets); and 3) removing (deleting tablets). Then the cycle is repeated. A typical representative for tabletting press is a rotary press Manesty Express 20 produced Manesty Machines Ltd., Liverpool, England and many other media are available. The equipment can be used to supply substance by gravity or it may be equipped with a forced feed of the mixture with the added lubricant in the mold. One common way is to use the boot frame, fitted with moving blades to be filled by the mixture of the mold. It should be understood that the methods and techniques of the seal described in the description of the present invention is not limited to any particular hardware.
In one embodiment, the embodiment can be applied to high-speed press for tableting. In another embodiment, the embodiment can PR is to change a single stationary press for tableting. For a good control on the mass of tablets on high-speed presses for tabletting very important factor is good for the mix. The use of forced feeding substances usually improves control by mass pills for current bad mixes. Another common feature of high-speed presses is the possibility of pre-pressing. Precompression zameniaet mixture, when the mold is filled with the mixture, before the final pressing leads to the formation of pills.
Pills can take any shape, as long as the tablet retains its shape, allowing you to take it orally, and not prone to the formation of the shell or exceed the desirable limits of fragility. Tablets can be round, oblong, thick or thin, large or small in diameter, flat or convex, with groove or without it, and provided with printed labels. In one variant embodiment tablets are round, in another variant embodiment tablets mutated to an oval shape or form capsules.
In one variant embodiment tablets, modified to form capsules with a total weight of approximately 450 mg, contain approximately 250 MHA. In one variant embodiment of the sizes mentioned above tablets are 0,26"×0,53". In yet another variant embodiment of the table is weave modified to form capsules with a total weight of approximately 900 mg, contain approximately 500 MHA. In one variant embodiment, the dimensions of the tablet are 0,33"×0,67". In yet another additional embodiment, the embodiment tablets, modified to oval with a total weight of approximately 1070 mg, contain approximately 600 MHA. In one variant embodiment of the sizes mentioned above tablets are 0,41"×0,75". Reference to the form of tablets can be found on Fig, page 51 of the fourth edition of Tableting Specification Manual, published by American Pharmaceutical Association, Washington, DC, 1995, included in the description of the invention in its entirety by reference.
In one variant embodiment of the tablet obtained by direct compression, may contain a number of azithromycin equivalent to approximately 250 MHA. In yet another variant embodiment of the tablet obtained by direct compression, may contain a number of azithromycin equivalent to approximately 500 MHA. In yet another additional embodiment, the embodiment of the tablet obtained by direct compression, may contain a number of azithromycin equivalent to approximately 600 MHA.
The tablets obtained from the pharmaceutical composition of the present invention have acceptable physical characteristics, including good friability and hardness. The us is ascioti tablet to chipping, abrasion or breakage under conditions of storage and transport depends on its hardness and fragility.
Measuring fragility is a standard test known to a person skilled in the art. Fragility is measured in standardized conditions by weighing a certain number of tablets (usually 20 tablets or less), placing them in a rotating drum made of plexiglass, which they raise in the course of repeated cycles using circular arm and dropped from a height of approximately 8 inches. After repeated cycles 100 cycles at 25 rpm./min) tablets re-weigh and calculate the percentage composition subjected to abrasion or chipping. Friability of the tablets of the present invention is preferably in the range from approximately 0% to 3%, and the values of approximately 1% or less is considered acceptable for most medicinal or food tablets. The values of the fragility of the approaching 0%, are particularly preferred.
Optionally, the tablet may be coated. The reasons for drawing on a tablet coating may include masking the taste of medicine, ensuring tablets ability to more easily swallowed, protection from cleavage during packaging, creating a barrier for moisture and light to improve the stability of the product, and d is I improve the appearance of the product and its recognition.
The coating process may include applying a coating solution or suspension, usually water, having acceptable viscosity for spraying and properties that allow them to adhere to the surface of the tablet when applying. During the coating process covering solution or suspension is sprayed into small droplets that come into contact with the tablet. After drying of the droplets on the surface of the coated tablets film is formed. There are several types of equipment for applying coatings used for coating tablets. The first type is a bowl-shaped reservoir for coating, in which the tablets are rotated in the bowl, and while tablets are rotated in the bowl, they applied the covering solution. Another coating process includes suspending the pellets in the air column, while the covering solution sprayed on the tablet (the process in the fluidized bed). One example of this process is a coating process in the column Wurster. The coating can be applied to the tablet by any known process and the method of application is not limited to any particular hardware.
Coating (coatings) tablets may be white or colored suspension of Opadry® (use, West Point, PA) or clear solution of Opadry®. Alternate is but typical of the covering part may consist of a film-forming polymer (polymers), such as hypromellose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), with additional ingredients such as plasticizers, substances, gives the material opacity, colorants and antioxidants. Can also be used floor sugars.
Dry mixes of the present invention suitable for use in the preparation of freely current pharmaceutical composition. The composition may be applied, for example, as a pre-mixture and for filling capsules.
Alternative pharmaceutical compositions containing more than about 80 wt.% azithromycin and described with good flow characteristics, can be used for other dosage forms, such as capsules. In addition, it may be useful to separate the storage of bulk azithromycin and fillers before tableting by direct compression.
Defined in this aspect of the present invention compositions comprising azithromycin, can actually contain granular medicine or granular medicine with one or more excipients, such as binders, diluents, disintegrant, lubricants, fillers, carriers and the like, as described above.
The composition can also be used in other applications, including, n is not limited to, filling encapsulated dosage forms or any other process that requires a good fluidity of the pharmaceutical composition.
The pharmaceutical compositions of the present invention can be used to treat bacterial and protozoal infections. Used in this document, the term "treatment", unless otherwise specified, means the treatment and prevention of bacterial or protozoal infections, including treatment, relieving symptoms or slowing the development of the mentioned infection.
Used in this document, the term "bacterial infection (infection or a protozoal infection (infection)", unless otherwise specified, includes both a bacterial infection or protozoal infections that occur in mammals, fish and birds, and disorders related to bacterial infections and protozoal infections that can be treated or prevented by administration of antibiotics, such as the compound of the present invention. Such bacterial and protozoal infections and disorders related to such infections include, but are not limited to, the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection with Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection with the Streptococcus pyogenes, streptococci of groups C and G, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection with Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin infections and soft tissue abscesses, osteomyelitis, and puerperal fever related to infection with Staphylococcus aureus positive for coagulase staphylococci (e.g., S.epidermidis, S.hemolyticus and so on), Streptococcus pyogenes, Streptococcus agalactiae, streptococcal groups C-F (streptococci, forming small colonies), Streptococcus Viridans group, Corynebacterium minutissimum, Clostridium spp. or Bartonella henselae; uncomplicated acute urinary tract infections related to infection Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection with Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neisseria gonorroeae; toxic diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or streptococci groups A, B, and C; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacryocystitis associated with infection with Chlamydia trachomatis, Neisseria gonorrhoeae, S.aureus, S.pneumoniae, these bacteria to antibiotics, H.influenzae, or Listeria spp.; disseminated lesions of Mycobacterium avium complex (MAC), tie the TES by infection with Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis associated with infection with Campylobacter jejuni; intestinal protozoal infection related to infection with Cryptosporidium spp.; odontogenic infection related to infection by Streptococcus Viridans group; persistent cough related to infection with Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections and disorders related to such infections that may be treated or prevented in animals include, but are not limited to, the following: respiratory disease in bulls associated with infection P.haem., P.multocida, Mycoplasma bovis, or Bordetella spp.; intestinal disease in cows, associated with infection by E. coli or protozoa (e.g., coccidia, cryptosporidia and so on); mastitis in dairy cattle associated with Staph infection. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; respiratory disease in pigs, associated with infection A.pleuro., P.multocida or Mycoplasma spp.; enteric disease in pigs, associated with infection with E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; hoof rot in cows associated with Fusobacterium infection. spp.; metritis in cows associated with infection with E.coli; hairy warts on cows associated with INFI is the key Fusobacterium necrophorum or Bacteroides nodosus; acute epidemic conjunctivitis in cows associated with infection with Moraxella bovis; abortions in cows that are associated with infection with protozoa (for example, Neosporium); urinary tract infection in dogs and cats related to infection with E. coli; infections of skin and soft tissue in dogs and cats related to infection Staph. epidermidis, Staph. intermedius, negative for Staph coagulase. or P.multocida; and infections of the teeth and oral cavity in dogs and cats related to infection Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other conditions that can be treated using compounds and compositions of the present invention, include malaria and atherosclerosis. Links to other bacterial infections and protozoal infections and associated with such infections disorders that can be treated or prevented in accordance with the method and compositions of the present invention, there are at J.P. Sanford et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition (Antimicrobial Therapy, Inc., 1996).
The term "effective amount" means the amount of azithromycin that, when introduced by the present invention prevents, ameliorate symptoms, and stop progression or eliminate bacterial or protozoal infection in a mammal.
The term "mammal" is a separate animal belonging to the taxonomic the definition of the class Mammalia. The class Mammalia includes, for example, humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice and rats.
Preferred mammals of the present invention is the man.
Usually the azithromycin is administered in doses ranging from about 0.2 mg per kg of body weight per day (mg/kg/day) to about 200 mg/kg/day in single or divided doses (for example, from 1 to 4 doses per day), although variations necessarily occur depending upon the species, weight and condition being treated patient and specifically selected route of administration. The preferred dosage is from about 2 mg/kg/day to about 50 mg/kg/day.
Azithromycin can be administered orally or by other routes of administration of azithromycin.
Although the present invention has been described in some detail to illustrate, a specialist in the art should be understood that changes and modifications may be made without straying from those described in this document the scope of the invention.
The EXPLANATION ILLUSTRATED by the EXAMPLE
The present invention will be further illustrated by the following examples. However, it should be understood that those described in these details are not intended to limit the present invention.
In the following examples, g is aulomatically composition was determined using a Malvern Mastersizer S (Malvern Instruments, Worcestershire, UK) with MS-1 device to estimate the variance in the sample with a small amount. This device allows the analysis of particle size by phase dispersion of the wet sample and the subsequent measurement of particle size using laser diffraction method. To determine the size of particles in the device for estimating the variance in the sample with a small amount was added 60-75 ml of purified water and left to mix for 15 seconds, followed by calculation using 5000 amplitude of the background count. Immediately after that, to this liquid was added bulk azithromycin up until the turbidity value was not reached 15-25%, and perform the measurement of particle size using 5000 amplitude of the background count, the results of which are presented in the drawing.
To calculate the index of Carr compressibility of bulk azithromycin was measured by the initial density in a graduated cylinder to 100 ml with 15 g of the sample. The sample was replaced (tapped) 2000 times on VanKel Tap Density Tester (Model 50-1200, Edison, NJ) and determined the density after screwing in a graduated cylinder to 100 ml with 15 g of the sample. The procedure is described in Int. J. Pharm. Tech. & Prod. Mfr., 6 (3) 10-16, 1985.
The angle of internal friction of the bulk drug was measured by the method described in "Some Measurements of Friction in Simple Powder Beds", Hiestand, E.N. and Wilcox, C.J. (J. Pharm. Sci. 57 (1968) 1421).
The device with the shear force consists of a layer then is the Cabinet, located between two parallel flat surfaces. The bottom surface is fixed and forms the base, while the upper surface (the carrier) is attached to the actuator providing a force in a linear direction parallel to the plane of surfaces. Another force is applied to the carrier from above with the use of goods with known mass. The test is repeated several times for each sample by applying each test on a different carrier cargo. Force or the resulting shear stress required for advancing the carrier through the powder layer, increases with increasing imposed on the carrier of the goods or the resulting normal stress. The situation in which the layer of powder flow during the shift effort is considered unsatisfactory. This condition means the beginning of the flow and occurs when the amount of force needed to move the sled stops growing. Data for different levels of normal stress lay on the graph as the ratio of shear stress to normal stress. This graph is known as the yield curve, while the angle between the yield curve and the abscissa is known as the angle of internal friction.
The examples are references to trade names the following fillers:
Lactose (ast Flo) manufactured by Foremost Farms, Rothschild, WI.
Microcrystalline cellulose (Avicel PH200) manufactured by FMC Biopolymer, Philadelphia, PA.
Croscarmellose (Ac-Di-Sol) manufactured by FMC Biopolymer, Philadelphia, PA.
Magnesium stearate production Mallinckrodt, Inc., St. Louis, MO.
Colloidal silicon dioxide production Cabot Corporation, Tuscola, IL.
Talc production Whitaker, Clark &Daniels, Inc., South Plainfield, NJ.
In addition, the following examples were evaluated by the following parties medications:
Part 1: Form N, unground
Part 2: Form M, unground
Part 3: Form A, unground
Part 4: Form G, unground
Part 5: Form A crushed on Fitzmill with 0,027" sieve, hammers, low speed
Party 6: Form A crushed on Fitzmill without screens, hammers, high speed
Party 7: Form A crushed on Fitzmill with 0,027" sieve, knives, average speed
Party 8: Form A crushed on Fitzmill with 0,020" sieve, knives, high speed
Party 9: Form M, chopped Fitzmill with 0,033" sieve with rubbing, core rotor with grooves, low speed
Indexes implementation tabletting
To identify all mechanical differences or intrinsic properties, which could adversely affect the ability of compositions comprising azithromycin, to form tablets by direct compression, conducted an assessment of index implementation for tabletting different forms AZ is Tropicana. This evaluation was performed in accordance with the procedures described in the "Indices of Tableting Performance H.E.N.Hiestand and D.P.Smith, Powder Technology 38 , pp.145-159.
More specifically, the failure index at small deformation (BFI) was calculated from the ratio of the normal to the tensile strength of a substance to its low tensile strength. The deformation index (SI) was determined on the basis of the test results to determine the hardness by indentation method in dynamic conditions. The index of the worst clutch was determined by evaluating the degree of adhesion of particles remaining after decompression, assuming a very short time in a compressed state and a flexible mechanism for separation of particles during decompression.
Party bulk azithromycin 1, 2, 4, 7, 10 and 11 represent different crystalline forms of N, M, G, A, F and J, respectively. Party 1, 2 and 4 are gently crushed in a Fitzmill Model JT, The Fitzpatrick Co., Elmhurst, IL) using 0,027" sieve and knives at high speed in an attempt to fit them to the size of the smaller particles of the party 7. Party 10 and 11 were evaluated as-is because of the relatively small size of the particles in them.
The results of these evaluations are presented in table 1.
|Indexes implementation tabletting|
|no party||Index RA the violations at small deformation (BFI)||The index of the worst clutch (BLW)×102||The deformation index (SI)||Tensile strength MPa|
|No. 1 Form N||0,05||0,7||0,0044||0,75|
|No. 2 Form M||0,10||1,0||0,0048||0,79|
|No. 4 Form G||N/a||0,8||0,0043||1,03|
|No. 7 Form A||0,10||0,9||0,0044||0,99|
|No. 10 Form F||0,37||0,9||0,0041||1,62|
|No. 11 J||0,11||0,7||0,0043||0,69|
As can be seen from the above, the indices of tableting for parts 1, 2, 4, 7 and 11 (of the form N, M, G, A, and J) were similar. This suggests that the main disadvantages of these materials for the production of tablets by direct compression are their values of tensile strength from low to moderate. This can be reflected in low values of hardness of tablets. In addition, the index values of the fracture at low strain show that formed during compression due, most likely, will withstand decompression at the time when the tablet will retrieve the Chen of nest molds. The differences between the parties were insignificant. Therefore, these parties are likely to have similar ability to form structures for the formation of strong tablets by direct compression.
However, it turned out that the party 10 (form F) has a significantly different mechanical properties. It has a higher tensile strength, which indicates the formation of a stronger relationship. However, the characteristics of fluidity party of 10 were similar to those for other parties with similar particle size.
In General, receiving tablets by direct compression in case of high dosage medicines (˜60%) may be feasible in the case of good fluidity, low brittleness and application of fillers with good binding properties.
The influence of particle size
The influence of particle size of azithromycin for receiving tablets by direct compression was evaluated as follows.
Using different batches of azithromycin tablets obtained by direct compression of a dry mixture containing 59.3 wt.% azithromycin, 26.9 wt.% microcrystalline cellulose as a binder, 8.9 wt.% lactose as a diluent, 2.0 wt.% croscarmellose sodium as disintegrant and 2.9 wt.% of magnesium stearate as a lubricant.
Su is their mixture was subjected to pressing at a single stationary for tabletting press Manesty F-press (Manesty, Liverpool, United Kingdom) 0,262"×mean HDI of 0.531" modified equipment in the form of a capsule. Planned weight of tablets was 450 milligrams. Tablets were tested for hardness (scale kPa) using the determinant of the hardness of the tablets Schleuniger (Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland) and fragility (100 rotations/4 minutes) using Vanderkamp Friabulator Tablet Tester (Vankel, Cary, North Carolina, US). The test results presented in table 2.
|Experience||The angle of internal friction (°)||Index of Carr dry mix (%)||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|1||N/a||19||of 451.5 (0,67%, n=10)||6,6 (n=10)||0,6 (n=5)|
|2||N/a||25||445,1 (0,32%, n=3)||6,7 (n=3)||N/a|
|3||31,0||25||455,3 (0,21%, n=5)||6,2 (n=5)||1,1 (n=5)|
|4||30,5||30||442,4 (0,50%, n=10)||10,1 (n=10)||0,52 (n=10)|
|5||31,6||30||455 (0,36%, n=10)||8,6 (n=10)||0,32 (n=5)|
|6||32,6||30||452,5 (0,90%, n=10)||4,1 (n=10)||1,8 (n=10)|
|7||34,5||34||450,8 (to 2.06%, n=5)||12,5 (n=5)||to 3.67 (n=5)|
Evaluation of dry mixtures showed that the use of unground bulk drugs (experiments 1-4) leads to the formation of mixtures with acceptable flow characteristics with values of compressibility index of Carr from 19 to 30 on the press to tablets and tablets with acceptable weight, hardness and fragility. The use of less aggressive crushed granular medicines (experiments 5-6) also leads to the formation of mixtures with acceptable flow characteristics on the press for tableting.
As shown in table 2, the use of more aggressive crushed granular medicines (experiments 8 and 9) and unground bulk drugs with small grain size (experiment 10) prevadid the formation of mixtures with such poor flow characteristics (index values Carr from 34 to 46), what tablets can not be compressed on F-press, Manesty.
Then for extrusion of mixtures containing azithromycin from experiments 7, 8, 9 and 10, was used by the simulator seal. The simulator seals are designed as single stationary press for tabletting, in which the residence time in the compressed state can be changed to simulate different types of presses for tableting. In addition, the simulator seal is equipped with a mechanical stirrer to facilitate filling of the dry mixtures cavity of the mold to obtain a stable weight pills.
As shown in experiments 11, 12, 13A, 13B, 14A and 14B table 2A, mixed with poor flow characteristics, leading to the unacceptable tablets on F-press, Manesty, allow to obtain an acceptable tablet when pressing on the simulator seal.
|Experience||Party drugs||Index of Carr dry mix (%)||Applied on top of the compression force (kN)||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|11||7||34||5,1||457,2 (2,53%, n=5)||9,3 (n=5)||0,32 (n=5)|
|12||8||37||4,0||439,8 (1,08%, n=5)||6,4 (n=5)||0,73 (n=5)|
|13A||9||46||4,6||428,7 (1,15%, n=10)||10,6 (n=10)||0,35 (n=10)|
|13B||9||46||5,5||426,9 (1,44%, n=10)||11,9 (n=10)||0,32 (n=10)|
|14A||10||34||4,2||444,9 (0,90%, n=5)||10,4 (n=5)||0,38 (n=10)|
|14V||10||34||the 5.7||456,2 (0,62%, n=5)||14,1 (n=5)||0,41 (n=10)|
The impact of loading drugs
Impact loading of drugs on the properties of azithromycin to form tablets by direct compression was evaluated as follows. Estimated tablets azithromycin with low, medium and high loading. Used the same method for obtaining and testing, as described above in example 2.
Applied pharmaceutical compositions containing the following boot medications (percentages given in wt.%):
Experiments 1, 2, 3, 4, 5 and 6, are shown in table 3, was performed on F-press, Manesty. Used the same granular medicine, the party 8 for experiments 1-3, party of 10 for experiments 4-5 and party 11 to 6. Experiments 7, 8, 9, 10, 11 and 12, are shown in table 3A, carried out on the simulator seals using party 8 party 10 and the party 11.
Initial evaluation when loading medicines, equal ˜60% crushed party 8 and unground party 10 bulk drugs, has resulted in poor flow characteristics (Index Carr 37 and 34, respectively), and poor education tablets on F-press, Manesty, as shown in table 3 (experiments 3 and 5). However, the low loading medicines (˜30%) can improve the characteristics of the fluidity of the mixture, as shown in table 3.
|Experience||Party drugs||Index of Carr (%)||For Ruska prodrugs (%)||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|1||8||33||30||499,7 (0,56%, n=10)||7,5 (max) (n=5)||of 0.25 (n=5)|
|2||8||39||45||457,7 (3,38%, n=8)||3.7V (max) (n=4)||2,02 (n=4)|
|3||8||37||60||No tablets||No tablets||No tablets|
|4A||10||28||30||441,70 (0,95%, n=10)||11,5 (n=10)||0,27|
|4B||10||28||30||446,9 (0,89%, n=10)||20,2 (n=10)||0,31|
|5||10||34||60||No tablets||No tablets||No tablets|
|6A||11||33||30||450,2 (0,36%, n=5)||10,6 (n=2)||0,20% (n=3)|
|6B||33||30||449,0 (0,47%, n=5)||16,4 (n=2)||0,44% (n=5)|
|Experience/Party Download drugs (%)||Index of Carr (%)||Applied on top of the compression force (kN)||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|7/8 30%||33||7,2||459,6 (0,62%, n=20)||12,9 (n=10)||0,21|
|8/8 45%||39||5,8||to 455.2 (0,15%, n=15)||10,5 (n=5)||of 0.13 (n=5)|
|9/8 60%||37||4||439,8 (1,08%, n=5)||6,4 (n=5)||0,73 (n=5)|
|10/10 60%||34||4,2||444,9 (0,90%, n=10)||10,4 (n=5)||0,38 (n=10)|
|11/11 30%||33||6,8||452,0 (n=1)||18,3 (n=1)||N/a|
|12/11 30%||4,4||451,0 (0,44%, n=5)||12,3 (n=5)||0,35 (n=5)|
As presented above in table 3A, when using party 8 tablets simulations seal with an average loading of drugs, and had a significantly better hardness and brittleness compared with high loading of drug. At low loading medicines party 8 or party 11 using simulator seal received the tablets with a hardness value in excess of 12 kPa. Using simulator seal can also be obtained tablets with high loading medicines party 8 or party 10. When using the simulator seal fluidity is not the decisive parameter, so it uses a mechanical stirrer to force the filling mixture in the cavity of the mold.
The influence of lubrication
Influence of levels of lubrication on the properties of azithromycin to form tablets by direct compression was evaluated as follows. To prepare the composition for tableting by direct compression with high and low content of magnesium stearate as a lubricant. Composition with a high content of lubricant contained 59.3 wt.% azithromycin, 26.9 wt.% microcrystalline cellulose, 8.9 wt.% lactose, 2.0 wt.% crossarm lazy sodium and 2.9 wt.% the stearate. Composition with a high content of lubricant contained 59.3 wt.% azithromycin, 28.3 wt.% microcrystalline cellulose, 9.4 wt.% lactose, 2.0 wt.% croscarmellose sodium and 1.0 wt.% the stearate.
For the preparation of compounds with two levels of lubrication used azithromycin party 8. This example used the same procedures for the production and testing as in example 2.
Evaluation of this party of bulk drugs, containing approximately 3% lubricant, resulted in a mixture with poor fluidity (the index value of the compressibility Carr was equal to 37). As shown in table 4, the tablet could not be made on the F-press, Manesty. A mixture containing 1% of a lubricant, also had a bad turnover (index value of compressibility Carr was equal to 47), and excessive loading of the substance in the matrix of F is the press were only unacceptable tablets. Tablets were very soft, with unacceptably low weight (target weight of tablets was 450 mg) and poor control by mass (% CV=5,1%).
|Experience||Index of Carr dry mix (%)||Grease (%)||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|1||37||3||No tablets||No tablets||No tablets|
|2||47||1||418,3 (5,1%, n=10)||3,3 (n=5)||2,5|
As can be seen from experiments 3 and 4 in table 4A, mixtures with poor fluidity, which are unacceptable for the production of tablets on F-press, Manesty, are acceptable for the production of tablets on the simulator seal. When using the simulator seal fluidity is not the decisive parameter, so it uses a mechanical stirrer to force the filling mixture in the cavity of the mold. Best friability of tablets was achieved by using compression on the simulator seal with a mixture of 1% lubricant (experiment 4).
|Experience||Index of Carr dry mix (%)||Grease (%)||Applied on top of the compression force (kN)||Average weight of tablet (mg (%CV)||The average hardness of the tablets (kPa)||Friability of the tablets (%)|
|3||37||3||4,0||439,8 (1,07%, n=5)||6,4 (n=5)||0,73 (n=5)|
|4||47||1||4,2||462,8 (0,69%, n=20)||5,8 (n=10)||0,15|
The influence of the substance, give the slip (glidant)
The impact of glidant on the properties of azithromycin to form tablets by direct compression was evaluated as follows. Usually glidant add in pharmaceutical formulations to improve fluidity. As shown in this example, adding glidants to the composition can improve the fluidity.
By direct extrusion received tablets of azithromycin with galantai to assess their effects on the properties of azithromycin to form tablets by direct compression. To get all containing glidant trains used the same granular medicine batch 6. This example used the same methods of production and testing of tablets as in example 2. Experiments 1, 2, 3 and 4 were performed on an F-press, Manesty.
Received the following pharmaceutical formulations:
|Containing glidant composition||Wt.%|
|Microcryst licenca cellulose||26,9||26,7||26,8||26,8|
|Colloidal silicon dioxide||-||0,3||0,1||-|
|Experience||Index of Carr dry mix (%)||Glidant||Mass of tablets, mg (%CV)||The hardness of the tablets (kPa)||Friability of the tablets (%)|
|1||25||0.10 silicon dioxide||455,5 (0,4%, n=5)||4,6 (n=5)||to 2.29 (n=7)|
|2||27||0,10% talc||499,5 (1,2%, n=5)||3,6 (n=5)||2,68 (n=7)|
|3||28||0.25 silicon dioxide||to 455.2 (1,06%, n=10)||4,7 (n=10)||The tablet was covered with the shell|
|4||30||Without glidant||452,5 (0,9%, n=10)||4,1 (n=10)||1,8 (n=10)|
Initial evaluation of the party 6 bulk drugs, not containing glidants, resulted in acceptable fluidity of the mixture (the index value of the compressibility Carr was equal to 30) F-press, Manesty. The addition of 0.1% of silicon dioxide (experiment 1) improved fluidity, as can be seen from the values of compressibility index Carr, and mass uniformity, as seen from a lower coefficient of variation of weight (%CV).
The impact of screening
Next comes the consideration of the influence of sieving of bulk drugs for the selective removal of finely part of the party bulk azithromycin.
Party 8 was sifted through sieve #200 mesh using the oscillator analyzer screening (test oscillating sieve Endecott''s Octagon 200, Endecott, London, England) for 20 minutes with a prescribed amplitude 8. Remaining on the sieve #200 mesh medication were screened again using the same sa the second sifting process. Remaining on the sieve #200 mesh medication (sifted twice) used in the following composition for direct compression. This example used the same procedures for the production and testing as in example 2. Obtained by direct compression tablet had the following composition:
From the sifted party bulk drugs received mix with the best turnover (index value of compressibility Carr was equal to 29). If you used whole party 8, the mixture had the worst turnover (index value of compressibility Carr was equal to 37) and tablets could not be made (experiment 1) F-press, Manesty, as shown in table 6. Using whole party 8 (experiments 2a and 2b), received the tablets with acceptable hardness. Experiments 2a and 2b were carried out with different compressive effort of the upper punch. A higher setting in experiment 2b resulted in a stronger contraction. Planned weight tablets 450 mg control mass from good to excellent.
|Experience||Index of Carr dry mix (%)||Pre-treatment of the batch of bulk drugs||Average weight of tablet (mg (% CV)||The average hardness of the tablets (kPa)|
|1||37||Without treatment, whole party||No pills||No pills|
|2A||29||Sifted twice through a sieve #200 mesh||448,4 (1,48%, n=5)||5,6 (n=5)|
|2b||29||Sifted twice through a sieve #200 mesh||449,2 (0,06%, n=5)||8,3 (n=5)|
1. The dry mixture is used to produce tablets of azithromycin by direct pressing, containing:
(a) nethertown azithromycin and
(b) at least one pharmaceutically acceptable carrier,
where, as measured by the method of Malvern less than approximately 20% by volume of all particles of azithromycin have a diameter of 44 μm or less and
where the value of the angle of internal friction of the dry mixture is less than about 34°.
2. The dry mixture according to claim 1, where nethertown azithromycin is selected from the group consisting of form b, D, E, F, G, H, J, M, N, O, P, Q, R and mixtures thereof.
3. The dry mixture according to claim 1 or 2, where the index si is emoti Carr dry mixture is less than about 34.
4. The dry mixture according to claim 1 or 2, where, as measured by the method of Malvern less than approximately 14% by volume of all particles of azithromycin have a diameter of 44 μm or less.
5. The dry mix according to claim 4, where according to the measurement method Malvern less than approximately 50% by volume of all particles of azithromycin have a diameter of 105 μm or less.
6. The dry mix according to claim 4, where according to the measurement method Malvern less than about 27% by volume of all particles of azithromycin have a diameter of 74 μm or less.
7. The dry mix according to claim 4, where according to the measurement method Malvern less than approximately 6% by volume of all particles of azithromycin have a diameter of 16 μm or less.
8. The dry mixture according to claim 1 or 2, where nethertown azithromycin is in the form.
9. Tablet azithromycin containing the dry mixture nethertown azithromycin and at least one pharmaceutically acceptable carrier according to claims 1-8.
10. Tablet of azithromycin according to claim 9, where the tablet is obtained by:
(a) forming a dry mix nethertown azithromycin and at least one pharmaceutically acceptable carrier according to claims 1-8 and
(b) direct extrusion referred to the dry mixture to obtain tablets of azithromycin.
11. Tablet of azithromycin of claim 10, where the dosage of azithromycin in the above-mentioned tablet selected from the group consisting of 250, 500 and 600 MHA.
12. Tablet of azithromycin of claim 10 or 11, where nethertown azithromycin in dry mixture is in the form.
13. Tablet of azithromycin according to any one of p and 11, where nethertown azithromycin is selected from the group consisting of form b, D, E, F, G, H, J, M, N, O, P, Q, R and mixtures thereof.
14. Tablet azithromycin, where the tablet is obtained by:
(a) forming a dry mixture in the form of forms And azithromycin and at least one pharmaceutically acceptable carrier according to claims 1,3-7, and
(b) direct extrusion referred to the dry mixture to obtain tablets of azithromycin.
FIELD: pharmaceutical industry.
SUBSTANCE: invention provides composition containing 0.1-0.5% nicotinic acid, 0.01-0.05% olifen-containing preparation, 0.5-1 mln ME interferon, and solvent. Use of this composition allows interferon dose to be lowered in single time administration cases. Bioavailability and residence time in system bloodstream of preparation are increased. In addition, liver first passage effect is avoided as well as accompanying unfavorable reactions resulting in changed preparation structure. Preparation also alleviates inflammatory phenomena in focuses of primary virus contact with microorganism cells.
EFFECT: expanded therapeutical possibilities.
5 cl, 3 dwg, 3 tbl, 3 ex
SUBSTANCE: the suggested strain refers to DNA-containing Adenoviridae type being of cubic type of symmetry, has no supercapsid membrane, virions sizes - 70-80 nm, shape - icosahedral. Moreover, it is resistant to the temperature of 56°C for 30 min, not less, and to the action of both ether and chloroform. It is inactivated with formalin, theotropin, dimer ethylenimine. The strain is cultivated in hepatic cell culture of hen's embryos, about 72-96 h after infection it causes characteristic foci of granulation (cells' rounding), the formation of separate rounded cells and foci of cell degeneration. Viral titer is within 105.5 TCD50/ml. The strain enables to reproduce different forms of the disease mentioned for experimental investigations, it is highly useful for manufacturing certain diagnostic kits and vaccines, moreover, being of high antigenic and immunogenic activity.
EFFECT: higher efficiency.
FIELD: veterinary science.
SUBSTANCE: the suggested preparation includes laevomycetin 5.0 g, oxytetracycline hydrochloride 5.0 g, 1,2-propylene glycol 75 cm3, magnesium chloride 0.9 g and polyethylenoxide up to 100 cm3. In case of bronchopneumonia in calves one should inject the preparation suggested intramuscularly at the dosage of 0.3-0.4 ml/kg animal's body weight twice at an interval of 48 h. The preparation in question causes no negative impact upon animal body and has got no side effects.
EFFECT: higher efficiency of therapy.
3 ex, 4 tbl
FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.
SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.
EFFECT: valuable medicinal properties of compounds and composition.
15 cl, 57 ex
FIELD: medicine, virology, pharmacology.
SUBSTANCE: invention relates to an antiviral substance based on hemolymph of insects of subclass Pterigota. This substance is prepared by activation of immune system of insects, collection of hemolymph and the following treatment of prepared hemolymph by centrifugation, chromatography of supernatant, elution of hydrophobic components sobbed on column. Prepared eluate comprises a mixture of hydrophobic components possessing with an antiviral activity. Invention provides the direct antiviral effect and enhances resistance of body cells to viral infection by virus disruption or blocking its replication, or by other method.
EFFECT: improved preparing method, valuable antiviral properties of substance.
41 cl, 1 tbl, 1 dwg, 1 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.
EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.
24 cl, 14 tbl, 1 dwg, 45 ex
FIELD: medicine, dermatology, venerology.
SUBSTANCE: invention proposes three-layered napkins "Dalcex-trypsin" as an agent for topical treatment of infiltrative-suppurative forms of head hair trichophytosis for 48 h on the background of the conventional systemic anti-mycotic therapy. Using the invention expands the assortment of anti-inflammatory and regenerating topical agents used in treatment of infiltrative-suppurative forms of head hair trichophytosis, enhances effectiveness and reduces the treatment period.
EFFECT: enhanced effectiveness of agent.
FIELD: organic chemistry, antibiotics, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of carbapenem possessing high antibiotic activity with respect to methicillin-resistant microorganism Staphylococcus aureus, penicillin-resistant microorganism Streptococcus pneumoniae, influenza virus and microorganisms producing β-lactamase, and showing stability with respect to renal dehydropeptidase. Proposed derivatives of carbapenem represent compounds of the formulae (I) and (II) or their pharmaceutically acceptable salts wherein R1 represents hydrogen atom or methyl; each R2 and R3 represents independently hydrogen, halogen atom, carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylthio-group or formyl; n = 0-4; Hy represents 4-7-membered monocyclic or 9-10-bicyclic saturated or unsaturated heterocyclic group comprising 1-4 heteroatoms chosen from the group consisting of nitrogen and sulfur atoms wherein Hy group can be optionally substituted with halogen atom; substituted or unsubstituted lower alkyl, (lower alkyl)-thio-group, (lower alkyl)-sulfonyl, carboxyl, amino-group, aryl; or 6-membered monocyclic heterocyclic group comprising one or some nitrogen atoms. Also, invention describes the methods for treatment and/or prophylaxis of infectious diseases caused by gram-positive and gram-negative microorganisms that involve administration of indicated derivative of carbapenem in therapeutically and/or prophylactically effective doses to mammals including humans.
EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.
22 cl, 2 tbl, 73 ex
FIELD: organic chemistry, chemical technology, medicine, veterinary science.
SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.
EFFECT: improved preparing method, valuable properties of compound and composition.
15 cl, 1 tbl, 10 ex
FIELD: organic chemistry of natural compounds, pharmacy.
SUBSTANCE: invention relates to derivatives of mutilins of the formula (I): wherein R means hydrogen atom or alkyl; R1 means group of the formula: wherein X means sulfur or oxygen atom, -NR10 or -N+(R'10)2; R9 means amino-group, alkyl, aryl, heterocyclyl or mercapto-group, and if X means oxygen atom then hydrogen atom represents the additional value for R9; R2 means phenylene; R4 means hydrogen atom or alkyl; R5 means hydrogen atom or alkyl; each among R3, R'3, R7 and R8 means independently of one another hydrogen or deuterium atom; or R and R2 in common with nitrogen atom to which they are bound form 5- or 6-membered ring; R1 means group of the formula: . Also, invention describes pharmaceutical composition based on compounds of the formula (I), method for treatment of diseases caused by microorganisms, and using these compounds as antibacterial agents in medicine and veterinary science.
EFFECT: valuable medicinal and veterinary properties of compounds and pharmaceutical composition.
12 cl, 2 tbl, 52 ex
SUBSTANCE: invention provides (i) compacted vaccine composition containing lyophilized antigenic component and an auxiliary component enhancing dissolution and (ii) stable compacted vaccine composition containing a second lyophilized component including neutralizing antibodies against above lyophilized antigenic component. Invention further provides syringe containing vaccine composition, kit, and method of immunizing veterinary animal.
EFFECT: increased stability of composition.
50 cl, 11 ex
SUBSTANCE: the suggested solid dosed form of disinfectant contains a quaternary ammonium compound as an active substance and/or its compounds as clathrates, preferably, clathrate carbamide didecyldimethylammonium bromide and/or chloride, and additional substance - an acid component chosen out of boric acid, water-soluble acidic salts of phosphoric acids, acidic salts of sulfuric acid. The innovation provides wide range of antimicrobial activity being of high stability, solubility, low toxicity, comfort in usage and transportation.
EFFECT: higher efficiency.
17 cl, 8 ex, 2 tbl
FIELD: medicine, pharmacy, pharmaceutical industry.
SUBSTANCE: invention proposes a pharmaceutical composition used as a nootropic agent. The nootropic agent represents the condensed extract from the plant Atragene sibirica (family Ranunculaceae) prepared by condensing the liquid alcoholic extract from plant the Atragene sibirica under vacuum at temperature 50°C up to the moisture content 25%, and filling agents comprising lactose, microcrystalline cellulose, polyplazdon XL-10, potato starch, aerosil, magnesium stearate chosen in the definite ratio of components. Agent possesses the effective nootropic effect.
EFFECT: valuable medicinal property of pharmaceutical composition.
2 cl, 7 tbl, 4 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a soluble, carbonated, anti-inflammatory, analgesic and antipyretic agent as a tablet. Agent comprises acetylsalicylic acid, caffeine, ascorbic acid, paracetamol, basic component, acidic component and accessory substances. Invention provides the possibility of rapid release of the preparation in blood, decreasing time for undesirable contact of the preparation with stomach mucosa and its high activity.
EFFECT: valuable medicinal and pharmaceutical properties of agent.
6 cl, 6 tbl, 11 ex
FIELD: medicine, pharmacology, pharmacy.
SUBSTANCE: invention relates to the development of a new medicinal agent representing the complex enzyme preparation with the digestive effect. Agent comprises enzyme pectate lyase providing effective cleavage of vegetable food intercellular substances, in particular, pectin and protopectin that results to formation of the homogenous and easily digestible mass, and promotes to assimilation vegetable food that is not assimilated by human organism that results to the more complete digestion of food, its cleavage and assimilation of nutrient substances. The optimal content of enzyme pectate lyase and pancreatin in a tablet covered by the enterosoluble envelope promotes to the more rapid and complete digestion of food in intestine and shows significant advantages as compared with the known digestive preparations.
EFFECT: improved and valuable properties of agent.
5 cl, 11 tbl
FIELD: medicine, endocrinology.
SUBSTANCE: invention elates to a method for treatment of diabetes mellitus type 2, method for declining the glucose content in patient blood and method for reducing resistance to insulin, diminishing the hemoglobin A1c content, enhancing the insulin level after eating, and reducing the amplitude change content ("mobility") of glucose in diabetic patients. Method involves administration of metformin to patient in the low dose (160-750 mg) in combination with the second anti-diabetic agent chosen from the group including glucose oxidase inhibitor, glucagons-like peptide-1 (GLP-1), insulin, α/β-double agonist of PRAP other than thiazolidinedione, meglitimide and inhibitor aP2 wherein the second anti-diabetic agent is administrated as a daily dose in interval between the initial daily dose comprising 20-60% of the initial daily dose of this anti-diabetic agent used in usual medicinal practice in therapy of the first order in treatment of diabetes mellitus up to the daily supporting dose comprising 40-60% of the daily supporting dose of this anti-diabetic agent used in usual medicinal practice as therapy of the first order in treatment of diabetes mellitus. Invention provides the effectiveness in treatment of diabetes mellitus that is equivalent practically to effectiveness of treatment by using combination of metformin and other indicated anti-diabetic agent used in doses prescribing in usual medicinal practice but with significantly less adverse effects.
EFFECT: improved method for treatment of diabetes mellitus.
7 cl, 10 dwg, 4 tbl, 3 ex
SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.
EFFECT: tablets with increased hardness and enhanced pharmacological activity.
2 cl, 2 ex
FIELD: pharmaceutical industry, in particular medicine X-ray contrast diagnosis agent.
SUBSTANCE: claimed pellet-shaped agent contains oxymethyl uracil, barium sulfate for fluoroscopy and potato starch in ratio of 4:1 or 6:1, wherein corn is coated with 5 % alcohol/acetone acetylphthalylcellulose solution, 10 % low molecular polyethylene solution in hexane and medical adhesive. Agent of present invention provides disintegration ability of active ingredient in intestine for 2, 4, 6 hours.
EFFECT: system for intestinal diagnosis with treating action, improved convenience and sanitary effect.
FIELD: medicine, contraception.
SUBSTANCE: invention proposes antibacterial and contraceptive compositions that comprise the following components: (1) matrix-forming substance; (2) bioadhesive substance; (3) buffer substance; (4) moistening substance, optionally; (5) preserving agent, optionally, and (6) water. Proposed compositions are suitable for their placement into vagina wherein compositions form semisolid matrix in contact with testicular fluid, cause thickening cervical mucus, form a bioadhesive layer on vagina surfaces, maintain the natural acid pH value in vagina about less 5 in the presence of testicular fluid ejected by a male and don't disturb essentially the natural microbiological balance in vagina. Compositions and methods decrease and/or prevent transfer of diseases transferring by sexual way and act as vaginal contraceptives with less adverse effect as compared with conventional vaginal contraceptives and can be used therefore for a long time. Compositions and methods are simple for using and don't require a physical device for their retention into vagina during using.
EFFECT: improved and valuable properties of compositions and methods.
36 cl, 17 tbl, 11 ex
FIELD: pharmaceutical technology, pharmacy.
SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.
EFFECT: improved preparing method, improved pharmaceutical properties of composition.
30 cl, 12 tbl, 28 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical composition used for stabilization of homeostasis and arresting pathological processes in the body. Invention proposes a pharmaceutical composition as powder with particles size from 250 to 400 mcm comprising the following components by the first variant, wt.-%: carbon, 10.01-53.02; oxygen, 30.10-53.10; potassium, 0.26-1.99, and calcium, 0.20-31.37, and comprising the following components by the second variant, wt.-%: calcium, 0.35-31.20; carbon, 10.99-50.21; oxygen, 34.55-51.03; sulfur, 0.73-14.81, and phosphorus, 0.08-3.30. Invention provides compensation of trace elements unbalance that causes and accompanies many diseases, possibility for stabilization of trace element homeostasis and arresting pathological processes of different etiology.
EFFECT: improved and valuable medicinal properties of composition.
12 cl, 13 ex