Methods for azitromicine wet granulation

FIELD: pharmaceutical industry.

SUBSTANCE: method for granulation of non-dehydrated azitromicine includes mixing of non-dehydrated azitromicine particles with granulating amount of non-aqueous granulating liquid followed by drying of wet granules to remove non-aqueous granulating liquid. Non-dehydrated azitromicine is selected from group containing from hemi-ethanol solvate of azitromicine monohydrate, hemi-n-propanol solvate of azitromicine monohydrate, azitromicine sesquihydrate, and hemi-isopropanol solvate of azitromicine monohydrate. Also disclosed are pharmaceutical compositions containing granules of non-dehydrated azitromicine and method for treatment of protosoal or bacterial infections in mammalian by administration of said pharmaceutical composition.

EFFECT: granules of non-dehydrated azitromicine with improved quality.

10 cl, 8 tbl, 9 ex

 

Background of the invention

Granulation is the process of pellet formation of no medicinal substance in the presence or in the absence of fillers to improve the properties of no drugs or formulations. The granules are preparations consisting of solid, dry agglomerates of powder particles having a sufficient strength during processing. Typically, the granules contain one or more active ingredients in the presence or in the absence of excipients. The granules may be used as dosage forms or in the process of getting tablets and capsules, taking into account their superior compaction, fluidity and limited paleocristiana. The size of the pellets may be increased in the process of granulation in the presence of moisture, for example, during wet granulation.

Wet granulation is different from the dry granulation of the fact that in wet granulation to obtain granules use such granulating liquid, such as water, organic liquids or mixtures thereof. The advantage of wet granulation is to improve cohesion ability and compactibility of powders, improved density, good distribution, providing uniform content of finely dispersed or finely chopped small doses of medicines, to reduce the number of dust and airborne contaminants and preventing segregation of the components.

Azithromycin, or 9 deoxo-9a-Aza-9a-methyl-9a-homoerythromycin And is a derivative of erythromycin And with a wide spectrum of antibacterial action.

Azithromycin can be obtained in a variety of forms. For example, the modern commercial form of azithromycin is a stable crystalline proof, non-hygroscopic dehydrate, also known as form A, which is obtained in accordance with the method described in U.S. patent No. 6268489. Commercial tablet form in the subsequent wet granulation dihydrate using water as a granulating liquid.

It is also known several crystalline, redigering forms of azithromycin. For example, in U.S. patent No. 4474768 disclosed hygroscopic crystalline hydrate of azithromycin, which in the present description also referred to as form C. This form of azithromycin is difficult to handle in the course of the formulation, due to its tendency to absorb different quantities of water.

It is desirable to obtain granules redigering forms of azithromycin using the method of wet granulation.

Summary of the invention

The present invention relates to a method of forming redigering azitromicina granules, consisting efficient when blended and redigering azitromicina particles with granulating amount of granulating fluid and, optional, with particles of one or more inert fillers, to obtain wet granules containing nativitatis azithromycin and granulating fluid. The resulting granules are then subjected to drying to remove granulating liquid.

In the method of the present invention, nativitatis azithromycin choose from B, D, E, G, H, J, M, N, O, P, Q, R form of azithromycin and mixtures thereof. Can also be used azithromycin form f

The invention also relates to pharmaceutical compositions containing granules redigering azithromycin and at least one optional pharmaceutically acceptable excipient.

In addition, the present invention relates to pharmaceutical compositions containing granules redigering azithromycin.

The present invention also relates to granules dihydrate azithromycin containing, calculated on the total weight of 98% or more dihydrate azithromycin and 2-0% of one or more pharmaceutically acceptable inert fillers.

Detailed description of the invention

All given in the text percentages, unless otherwise noted, are given in mass terms.

The present invention relates to granules of azithromycin formed by the method of aqueous or non-aqueous wet granulation. Preferably, the azithromycin was particularly the crystalline substance. On the other hand, the azithromycin may be a noncrystalline or amorphous substance.

Also preferably, the azithromycin was nativitatis azithromycin. More preferably, the azithromycin was a crystalline, nativitatis azithromycin.

Used in the present invention, the term "granules" refers to particles of azithromycin and, optionally, particles of at least one inert filler, which are connected to each other by adhesion or agglomeration.

Used in the text, the term "particles" refers to the powder redigering of azithromycin powder pharmaceutically acceptable inert filler, or granules, which are pre-formed from a powder redigering azithromycin and at least one optional pharmaceutically acceptable inert filler.

The term "nativitatis azithromycin" refers to all amorphous and crystalline forms of azithromycin, including all polymorphs, isomorphy, clathrates, salt, solvate and hydrate, other than digitata form of azithromycin (form A).

Several crystal, redigering forms of azithromycin, including forms D, E, F, G, H, J, M, N, O, P, Q and R, are disclosed in patent application U.S. 10/152106 dated may 21, 2002, the contents of this document are included in the us is Aasee description as a reference in the full volume.

In accordance with one alternative embodiment of the present invention, the granules obtained from (1) redigerare forms of azithromycin, selected from forms B, D, E, G, H, J, M, N, O, P, Q and R, or mixtures thereof, and (2) one or more optional pharmaceutically acceptable inert fillers. Below is the definition of these forms redigering azithromycin.

Isomorphy Family I and Family II are a hydrate and/or solvate of azithromycin. In the special conditions of solvent molecules in the cavities of the matrix tend to exchange between solvent and water. In this regard, 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 azithromycinum Family and I to monoclinic P21the space group with the following dimensions of the unit cell: a=16,3±0,3b=16,2±0,3c=18,4±0,3and beta = 109±2°. Forms D, E and R belong to azithromycinum Family II and orthorhombic P212121the space group with the following dimensions of the unit cell, a=8,9±0,4b=12,3±0,5and C=45,8±0,5. The form Q is different from families I and II.

P is the established levels of the single crystal of azithromycin form D corresponds to the formula C 38H72N2O12·H2O·C6H12and this shape represents azithromycin monohydrate monocyclohexyl MES. The samples in powder form D is additionally characterized by the fact that contain 2-6% water and 3-12 wt.% cyclohexane. The amount of water and cyclohexane, calculated from data on the structure of crystal form D, form 2.1 and 9.9 percent, respectively.

Form F azithromycin corresponds to the formula C38H72N2O12·H2O·C4H8O and represents azithromycin monohydrate monteregian MES. According to the analysis of a single crystal form E is a monohydrate and mono-THF MES.

The structure of the single crystal of azithromycin form G has the formula C38H72N2O12·1,5H2O, which polutorakratnom of azithromycin. In addition, the shape of G is additionally characterized by the fact that it contains 2.5 to 6% of water and <1% of organic solvent based on the weight of the powder sample. The structure of crystal form G consists of two molecules of azithromycin and three water molecules per asymmetric unit. This corresponds to Politologija with theoretical water content of 3.5%. The water content of the powdered samples of the form G 2.5-6%. The total amount of residual organic solvent composition is yet less than 1% of the corresponding amount of solvent, used for crystallization.

Form N azithromycin is of the formula C38H72N2O12·H2O·C3H8O representing Hemi-1,2 proportionalist monohydrate azithromycin. Form H is a monohydrate/semiproportional MES of azithromycin in the form of free base.

Monocrystalline structure of the form J azithromycin is of the formula C38H72N2O12·H2O·0,5C3H7OH, representing Hemi-n-propanol MES monohydrate azithromycin. Form J is additionally characterized by the fact that it contains 2-5% water and 1-5% propanol-1 in the calculation of the mass of powdered samples. The estimated solvent content is about 3.8% n-propanol and about 2.3% of water.

Form M of azithromycin is of the formula C38H72N2O12·H2O·0,5C3H7OH, which is Hemi-isopropanol-MES monohydrate azithromycin. Form M is additionally characterized by the fact that it contains 2-5% water and 1-4% propanol-2 in the calculation of the mass of powdered samples. Monocrystalline structure of the form M corresponds monohydrate/Hemi-isopropanolate.

Form N azithromycin is a mixture of isomorph Family I. This mixture may contain a different percentage of the number of isomorphs F, G, H, J, M, and the other, as well as different amounts of water and these organic solvents, such as ethanol, isopropanol, n-propanol, propylene glycol, acetone, acetonitrile, butanol, pentanol etc. the Amount of water can be 1-5,3 wt.%, while the total number of organic solvents may be 2-5 wt.% when the content of each solvent in the amount of 0.5-4 wt.%.

Form Of azithromycin is of the formula C38H72N2O12·0,5H2O·0,5C4H9OH, representing, in accordance with the data about the structure of the single crystal, hemihydrate Hemi-n-butanolate of azithromycin in the form of free base.

Form f azithromycin is of the formula C38H72N2O12·H2O·0,5C5H12O, which is the Hemi-n-intersoliton monohydrate azithromycin.

Form Q azithromycin is of the formula C38H72N2O12·H2O·0,5C4H8O representing Hemi-tetrahydropyrazolo monohydrate azithromycin. This form contains 4% water and about 4.5% THF.

Form R of azithromycin is of the formula C38H72N2O12·H2O·C5H12O, which is the MES monomethyltetrachloro ester monohydrate azithromycin. theoretical water content of the form R is 2.1 wt.%, and theoretical contents methylcrotonyl the new ether is 10.3 wt.%.

In accordance with an alternative embodiment of the present invention, the granules obtained from (1) of azithromycin form F and (2) one or more optional pharmaceutically acceptable inert fillers. Single crystal structure of form F azithromycin is of the formula C38H72N2O12·H2O·0,5C2H5OH, representing Hemi-ethanol MES monohydrate azithromycin. Form F is additionally characterized in that it contains 2-5% water and 1-4% ethanol based on the weight of the powdered samples. The single crystal form F crystallizes in the monoclinic space group, P21with asymmetric link containing two molecules of azithromycin, two water molecules and one molecule of ethanol, in the form of a monohydrate/Hemi-ethanolate. This form is isomorphic to the whole family I crystalline forms of azithromycin. theoretical content of water and ethanol is 2.3%and 2.9%, respectively.

In accordance with another alternative embodiment of the present invention, the granules contain at least about 98% of azithromycin form a, and about 2-0% of one or more pharmaceutically acceptable inert fillers. This variant embodiment is additionally illustrated in example 1.

In the method of the present invention granulating liquid is defined as fluid is here, which when mixed with azithromycin and particles optional inert filler, stimulates adhesion or agglomeration of the particles with the formation of granules.

Granulating the amount of granulating liquid is an amount of fluid sufficient to perform adhesion or agglomeration of the particles, without significant dissolution of azithromycin.

In the present invention can be used as non-aqueous and aqueous granulating liquid.

In the present description non-aqueous granulating fluid is defined as an organic solvent with a water content of 25 vol.% or less. Suitable organic solvents without restrictions only they are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, 2-methoxyethanol, methylethylketon, methylcyclohexane, N-organic, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,2-trichloroethane, xylene, acetic acid, acetone, anisole, butyl acetate, tert-butylethylamine ether, cumene, dimethyl sulfoxide, ethyl acetate,, ethyl simple ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropylacetate, methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, pentanal, propyl, Tetra is hydrofuran, alcohols With1-C6and mixtures thereof.

Non-aqueous granulating fluid can also be a mixture of one or more organic solvents and/or water.

Preferred non-aqueous granulating fluid of the present invention include ethanol, isopropanol, and their mixing with the water mixture, which further described in examples 1-8. Of the above non-aqueous granulating fluid, ethanol is the preferred substance for granulation forms F. Isopropanol is the preferred substance for granulation of the form M

In the present description aqueous granulating liquid is defined as granulating liquid containing more than 25% of water and less than 75% of one or more of the above suitable organic solvents. Preferred aqueous granulating liquid of the present invention is a mixture of water and ethanol, which are additionally described in examples 1-8.

Used in the text, the term "pharmaceutically acceptable" means that the excipient must be compatible with other ingredients of the composition, and to be harmless to its recipient.

Pharmaceutically acceptable inert fillers of the present invention include a binder components, diluents, disintegrators, lubricants, fillers, wear and etc. In addition, inert fillers may be hygroscopic and non-hygroscopic substances.

Binders are used to impart cohesive granular properties and, thus, contribute to intactness of the granules after drying and grinding. These substances are also important to ensure uniformity of distribution of the granular particle size, and the ability of the granules to compaction. Suitable binders, without limitation, only they are starch (including corn starch and pre-gelatinising starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, natural and synthetic resins, for example, Arabian gum, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethyl cellulose and the like). Preferred binders for aqueous granulating solutions include hydroxypropylcellulose, polyvinylpyrrolidone, pre gelatinising starch, and sugar, for example sucrose.

Lubricants can be used in the production of some standard dosage forms, and they are usually used in the manufacture of tablets. According to the present invention, the lubricant of the commonly add to tableting. Typically, the lubricating substance is added directly before the stage tabletting and mixed with the granules in a short period of time in order to achieve a good degree of dispersion. Typically, the mixing is carried out in a period of time of about five minutes. As the lubricant used in the compositions of the present invention can be used one or more substances. Examples of suitable lubricants, without limitation only they can serve as magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, beginat glycerin, polyethylene glycol, polietilenoksidnoy polymers (for example, manufactured by the company Union Carbide, Inc., Danbury, CT, under the trademark Carbowax, in the case of polyethylene glycol, and Polyox, in the case of polyethylene oxide), sodium lauryl sulfate, lauryl sulfate, magnesium, sodium oleate, sodium fumarate, DL-leucine, colloidal silicon dioxide, and other substances known in this field. Preferred lubricants are magnesium stearate, calcium stearate, zinc stearate, and mixtures of magnesium stearate with sodium lauryl. The number of lubricants may be from about 0.25 to about 10% by weight of the tablet, preferably from about 0.25 to about 3% for the preferred lubricants.

Suitable diluents can use the SJ one or more substances, capable of computermemory and good properties of fluidity. As fillers and diluents can be used a large number of different substances. Suitable non-limiting examples of diluents or fillers include spray dried lactose monohydrate or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose; Avicel), digidrirovanny or anhydrous dibasic calcium phosphate (commercially available under the registered trademark Emcompress from Mendell, or A-Tab and Di-Tab from Rhone-Poulenc, Inc., Momouth Junction, N.J.), calcium carbonate, calcium sulfate, and other substances known in this field.

According to the present invention, the disintegrator can be entered intragranular and/or extraglandular. Disintegrator are used to facilitate the disintegration or destruction of the tablets after application and are usually starches, clays, cellulose, algina, resins or crosslinked polymers. Suitable non-limiting examples of disintegrators include crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, croscarmellose sodium.

Optionally, the pharmaceutical granule composition may also contain small amounts of such non-toxic auxiliary substances such as wetting and emulsifying Genty, pH buffered agents and the like, for example, sodium acetate, monolaurate, the acetate triethanolamine, triethanolamine oleate, sodium lauryl sulfate, sulfosuccinate dictinary, esters of polyoxyethylenesorbitan and fatty acids, etc.

According to the method of forming granules containing nativitatis azithromycin, its powder is mixed with granulating number of suitable granulating fluid with the formation of a good pellet in a volume of a liquid mixture of granules and granulating fluid, which hereinafter cited as "wet granulate".

Good pellets usually contain minor amounts of fine particles have a uniform size and remain intact after drying and fractionation. Fractionation may be performed, for example, by sieving or grinding. Experienced worker often produces subjective selection based on consistency of the granules.

According to alternative embodiments, granulating liquid mixed with particles redigering azithromycin and with particles of at least one inert filler order to obtain granules. Then the obtained granules are dried using suitable means of obtaining a pharmaceutical composition, which comprises granules containing nativitatis azithromycin and a pharmaceutically acceptable inert fill is I.

Azithromycin and inert fillers may optionally pre-mixed with each other prior to mixing with the granulating liquid. Preliminary mixing may be conducted by mixing, stirring, mixing, shaking, haltiwanger, by rolling or by any other means, providing a homogeneous mixture. Preferably the mixing azithromycin and inert fillers in the conditions with little effort shift in such a suitable device, as a V-shaped mixer, a mixer with handle, cone crusher and any other device capable of operating in the preferred small effort shift.

In accordance with another alternative embodiment, the particles redigering azithromycin be mixed with a granulating liquid, and an optional inert fillers, is subjected to preliminary granulation. In addition, such pre-granulated particles of azithromycin can optionally contain inside granules pharmaceutically acceptable neutral fillers.

In accordance with the method of the present invention, the particles are mixed with a granulating liquid in a time interval of from about 5 to about 45 minutes. In industrial scale, preferred time of mixing the leaves from about 20 to about 35 minutes. When conducting operations on a small scale, the preferred mixing time is from about 3 to about 10 minutes. Wet granulation is usually carried out at a temperature in the range of from about 20 to about 30°and, preferably, at room temperature.

To contact granulating fluid with particles can be any device that provides a uniform distribution of granulating fluid and good contact of the particles. For example, small-scale production can be carried out by mixing and wetting of the mass in the mortar or the cones of stainless steel, whereas to obtain large quantities of the product can be used with V-shaped mixer with reinforced rods, planetary mixers, rotary granulators, wysokosciowe a stirrer and a device for the granulation in the fluidized bed.

The degree of formation of granules can be determined visually and manually, which is traditional for this area of technology. The degree of formation of granules can also be determined using sieve analysis, measurement of moisture content as, for example, the definition of loss in drying (LOD), or other suitable means, such as instrumental analysis for the final result, through a measurement of torque and energy consumption.

The choice of an appropriate granulating what idcol system depends on a number of factors, for example, forms used azithromycin, and may be based on the desired processing characteristics. For example, it was found that different crystalline forms of azithromycin differ in the profile of solubility in different solvents. So, for example, form a has a much lower solubility in solutions of water and isopropanol, in comparison with other forms. However, all studied crystalline forms have the same solubility in ethanol.

In addition, many granulating liquids based on organic solvents, for example, in systems such as ethanol/water, isopropanol/water, isopropanol and ethanol, pellets of azithromycin may be formed without the inclusion of inert filler, in particular, without binders. So, when you are not using the binder, the resulting granules may contain a greater number of drugs.

On the contrary, the use of binders is preferred in the case of granulation of azithromycin in the water.

When carrying out process in the water, the remaining quantity may be removed from the granules in the drying with the use of readily available equipment, whereas for processes involving the use of organic solvents may require additional stages of removal is of astorias.

According to the present method, preferably, the azithromycin was subjected to wet granulation in accordance with the instructions of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use that are listed in the Harmonized Tripartite Guideline: Impurities: Guideline for Residual Solvents recommended for adoption July 17, 1997

After the formation of the granules, the granules in the wet granulate is subjected to drying by using a suitable device to remove granulating fluid. The conditions and duration of drying depends on the type of liquid and the weight of the material. Non-limiting examples of suitable methods of drying can serve as a shelf drying, drying with forced air supply, microwave drying, vacuum drying and drying in a fluidized bed. Before drying the wet granulate may be optional classification. Relevant operations classification include wet grinding and sifting.

Typically, the pharmaceutical composition is in contact with the granulating liquid contains from about 30 to about 98%, more preferably from about 50 to about 60 wt.% azithromycin and at least one inert filler. Suitable pharmaceutical compositions for wet granulation can contain from about 20 to about 90% of azithromycin, from about 0.25 to about 85% of binder, preferably from about 0.5 to about 30%binder, more preferably, from about 0.5 to about 6% binder, and from about 0 to about 80% filler and from about 0.5 to about 25% of the cage, more preferably, from about 0.5 to about 15% of the cage, most preferably, from about 1 to about 6 per cent of the cage.

When using a binder, the material can be dissolved in aqueous or non-aqueous granulating fluid. When dissolved in the granulating liquid, the binder may be used in quantities of from about 0.45 to about 25% (mass/volume of liquid), more preferably, in quantities of from about 5 to about 10% (mass/volume). Alternatively, the binder in dry form may be injected into the powder before granulation. With the introduction of the dry powder before granulation binder may be used in amounts from about 0.25 to about 85 wt.%, in the calculation of the mass of powder, preferably in an amount of from about 0.5 to about 30 wt.%, based on the weight of the powder, more preferably in an amount of from about 0.5 to about 6 wt.% in the calculation of the mass of powder. Specific mass percentage of binder will depend on the type of binder that is the prerogative of the experienced developer formulations. Alternatively, the binder may be included as part of granulating liquid and the powder.

The number is about the granulating liquid, used to prepare the granules may vary depending on the type of granulating fluid and forms of drugs.

According to the method of the present invention, when forming pellets from redigering of azithromycin, the amount of granulating liquid (expressed in percent by weight of the powder)used to obtain good pellets may vary depending on the number of medications, use of azithromycin form F or other form, to the introduction of the inert hygroscopic fillers, as well as from the use of aqueous or non-aqueous liquid.

So, for example, with the introduction of such inert hygroscopic fillers, as croscarmellose sodium requires large quantities of water granulating fluid. To hygroscopic inert fillers include fillers, which are capable of hygroscopic absorption of more than 20% moisture at moderate values of the relative humidity of the order of 35-50%, for example, croscarmellose sodium, A.H.Kibbe, ed. Handbook of Pharmaceutical Excipients third edition, American Pharmaceutical Association, 2000. Type of equipment used can also influence the amount of granulating liquid. For example, when using wysokosciowe equipment and large-scale equipment requires less fluid to the brink is acii.

Examples nephroscopes inert fillers are sodium starch glycolate, polyvinylpyrrolidone, crosslinked PVP (PVP-XL), and hydroxypropylcellulose.

It should be noted that for the granulation of the form F azithromycin requires a greater amount of granulating liquid than for other forms redigering azithromycin.

On the basis of the factors mentioned above provides the following options embodiments granulation different redigering forms of azithromycin.

In the wet granulation aqueous granulating fluid, which uses nativitate forms of azithromycin, except for the form of F, when the content of the medicinal product from about 30 to about 98%, and without the use of inert, non-hygroscopic fillers, aqueous granulating liquid is usually from about 10 to about 30%, preferably from about 10 to about 20%.

In the wet granulation aqueous granulating fluid, which uses nativitate forms of azithromycin, except for the form of F, when the load medicine from about 30 to about 98%, using inert, non-hygroscopic fillers, aqueous granulating liquid is usually from about 18 to about 45%, preferably from about 30 to about 40%.

In the wet granulation non-aqueous granulating fluid, in which the use nativitate form of azithromycin except for the form of F, when the load medicine from about 30 to about 98%, the amount of non-aqueous granulating fluid is typically from about 7.5 to about 50%, preferably from about 10 to about 20%.

In the wet granulation aqueous granulating liquid, with the use of azithromycin form F, with a load medicine from about 30 to about 98%, and without the use of inert, non-hygroscopic fillers, aqueous granulating liquid is usually from about 20 to about 40%, preferably from about 25 to about 35%.

In the wet granulation aqueous granulating liquid, with the use of azithromycin form F, with a load medicine from about 30 to about 98%, and using inert, non-hygroscopic fillers, aqueous granulating liquid is usually from about 30 to about 55%, preferably from about 40 to about 50%.

In the wet granulation non-aqueous granulating fluid, with the use of azithromycin form F, with a load medicine from about 30 to about 98%, the amount of non-aqueous granulating fluid is typically from about 10 to about 55%, preferably from about 20 to about 30%.

In the case of the variant embodiment in which all forms of azithromycin load medicinal product is about 50%, the use of g is anuliuosis liquids, containing less than 50% of the water normally provides obtaining pellets of improved quality. In variants of the embodiment with a 100%load azithromycin, it is preferable to use a granulating liquid containing less than 50% water, and more preferable to use non-aqueous granulating liquid containing 5% water or less.

More specifically, the amount of non-aqueous granulating fluid azitromicina forms with high load azithromycin (especially above 98%), except for F, which typically ranges from about 10 to about 25%, preferably from about 15 to about 20%.

When using form F, the number of non-aqueous granulating fluid azithromycinbuy F with high load azithromycin (in particular higher than 98%), typically ranges from about 20 to about 40%, preferably from about 25 to about 35%.

In addition, the aqueous granulating fluid azitromicina forms with high load azithromycin (in particular higher than 98%), except for F, which typically ranges from about 15 to about 30%, preferably from about 17 to about 25%.

When using form F, the aqueous granulating fluid azithromycinbuy F with high load azithromycin (in particular higher than 98%), is usually from about 40 to about 60%, more preferably from about 45 to about 55%.

Pharmaceutical compositions and pellets of the present invention, optionally, include vnutrigrudne or winegrower such additional components, such as antioxidants, suspendresume agents, thickeners, etc. Used in the text the term "winegrowers" or "winegrower" means that the specified material is added, or it is added as a dry component after granulation. Used in the text the term "nutrigenomic" or "vnutrigrudne" means that the specified material is added, or it is added as a component of the granules.

The pharmaceutical composition may also contain flavoring. Such flavorings may be selected from synthetic fragrance oils and aromatic compounds and/or natural oils, extracts from plant leaves, flowers, fruit and the like, and combinations thereof. Such flavors may include cinnamon oil, wintergrove oil, peppermint oil, clove oil, fatty Bay oil, anise oil, eucalyptus oil, thyme oil, oil of the leaves of cedar, oil of nutmeg, sage oil, oil of bitter almonds, oil of acacia. As aromatic additives can also be used vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, as well as FR kmovie essences, as Apple, banana, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. the Amount of flavouring substances may depend on a number of factors, including the desired organoleptic effect. In the tablet flavouring substance normally present in the amount of 0.5 to about 3.0 wt.% based on the weight of the tablets.

In azithromycinbuy tablets can also contain other inert fillers and coloring agents. Non-limiting examples of coloring agents include titanium dioxide and/or those known per se dyes for food products, such as F.D.& C, aluminum colorful lacquers and natural dyes such as grape skin extract, red beet powder, beta-carotene, annatto, Carmine, turmeric, red pepper, etc. Dye is an optional ingredient of the composition of the present invention, but if the use amount is up to about 3.5 percent per total weight of the tablet.

Azithromycinbuy granules and pharmaceutical compositions obtained by the method of the present invention can be used for the preparation of pharmaceutical compositions, including, but not limited to, tablets, capsules, sachets and used to obtain a liquid suspension azithromycin.

After drying, the granules can be subjected is of Uta optional additional processing, including, but not limited to, grinding, sieving or other classification stage, the addition of lubricants and/or other inert fillers, tableting or encapsulation.

As mentioned above, the granules can be subjected to additional processing, the nature of which depends on the final destination of the material. Additional stages of processing include, but are not limited to, grinding, compacting with the formation of the tablets.

In the pharmaceutical industry, grinding is often used to reduce the particle size of the solid material. There are many types of grinding devices and one of the most traditional types of mills are hammer crusher. In the grinding device of this type uses a high-speed rotor that is attached to a large number of hammers. Hammers can be attached so that the material will contact the surface of the knife or the surface of the hammer. When entering the mill material collides with the rotating hammers and broken into particles of smaller size. Below hammers is a sieve, through holes which are smaller particles. Larger particles are retained in the mill and broken hammers before the formation of extremely fine particles which are able proh is going through a sieve. In the present invention to reduce the size of the particles can be any suitable equipment.

If desired, the granules may be subjected to additional processing to form tablets from milled, sifted or unground material. Used in the text, the term "tablet" includes extruded pharmaceutical dosage forms of all shapes and sizes.

According to the present invention can be used optional equipment, facilitating the flow of granules or powder during processing. Granular or powder can be made by means of a propeller or rotor blades in the supply frame on the tablet press press or encapsulating equipment. Devices that contribute to the flow, not limited to the specific equipment type, and for this purpose may be used any known equipment, providing granules or powder.

Tablets can be obtained from the pellets by extrusion or molding. In typical methods of compression used device cap type and three stages in each of the cycles comprising 1) fill (flow components pills in the bale chamber) 2) the compacting (formation of tablets) and 3) push (upload tablets). According to one variant embodiment can be used in high-speed rotary tablet ovocny press. Examples of suitable high-speed rotary tablet press presses can serve Kilian LX2 (manufactured by IMA-Kilian, Cologne, Germany), Manesty BB4 and Manesty Mark IV (manufactured Manesty Machines Ltd., Liverpool, England).

Tablets may contain from about 10 to about 90 wt.% azithromycin, preferably, from about 25 to about 80 wt.% azithromycin, and this percentage represents the ratio of the mass of azithromycin to the total mass of azithromycin and inert fillers. Capsules can contain from about 10 to about 100% of azithromycin, preferably, from about 25 to about 95% of the azithromycin, and this percentage represents the ratio of the mass of azithromycin to the total mass of azithromycin and fillers. Sachets and powders for suspension may contain from about 0.5 to about 99% of azithromycin, preferably, from about 0.75 to about 20% of azithromycin, more preferably, from about 1 to about 10% of the azithromycin, and this percentage represents the ratio of the mass of azithromycin to the total mass of azithromycin and fillers.

The flow parameters of the mixture supplied to the high-speed tablet press of the press, are a very important factor for good regulation weight of the tablet. Using a device to force feed often improves the regulation of the mass of the tablets in the case of mixtures with poor flow characteristics. Another feature of wysokosc the speed tablet press presses is the possibility of using pre-compression. As a result of preliminary compression is soft extrusion of the mixture, when the matrix of the press is filled with the mixture and then carry out the compacting getting pills.

According to the present invention, at the stage of granulation get engineering particles having appropriate properties for tableting. The term "engineering" implies a slight manipulation, for example, in operations on the measurement, the location in the package, or filing in tabletroute or encapsulating equipment. Engineering materials have a low internal cohesive strength and can move under the action of gravity without any additional mixing.

The fluidity of the composition may be evaluated by various known methods. One way to determine the prescription of the properties of the powdered material is a measurement of bulk density. A simple way of describing the rheological properties on the measured values of bulk density is a method of determining the Carr's Compressibility index compressibility Carr). The compressibility index of Carr is a simple test to estimate the yield strength by comparing the initial and final (released (tapped)) bulk volume and speed of compression. Useful empirical yield criterion is the index of the compressible the STI Carr (Carr's Compressibility Index):

The compressibility index (%) = [(density in the released (tapped) state - the initial density)/density in the released state] × 100.

Preferably, the granules of the present invention had an index value of the compressibility of less than 34 Carr; more preferably, less than 31; and even more preferably less than 28.

The tablets obtained from the pellets of the present invention have acceptable physical characteristics, including good friability and hardness. The resistance of tablets to splitting, wear or damage under conditions of storage and transportation depends on their fragility. The desired hardness may vary depending on such factors as the size and shape of the tablets.

Test fragility is a standard test known to the person skilled in the art. Fragility is measured in standard conditions by weighing a few tablets (usually 20 or more), placing them in a rotating Plexiglas drum, in which they come up in the course of repeated spins using the radial arm, and then fall at a distance of about 8 inches. After repeated rotations (usually 100 revolutions at 25 rpm), tablet re-weigh and calculate the interest amount of the formulation subjected to abrasion or splitting. For most drugs the s and food tablets acceptable fragility in the range of from about 0 to about 3%, more preferably, from about 0 to about 1%. Particularly preferably, the value of the fragility of 0%.

Hardness specific pill depends on various factors, including the size and weight of the tablets.

In accordance with one variant of embodiment, the tablet may be in the form of a modified capsule containing about 250 MHA, with a total mass of about 450 mg of the magnitude of the tablets are 0,26"×0,53". Used the term "mga" refers to milligrams of azithromycin in the form of free base. The hardness of the tablets can be from about 6 to about 18 kPa.

In accordance with another variant embodiment, the tablet may be in the form of a modified capsule containing 500 MHA, total weight about 900 mg of the magnitude of the tablets are 0,33"×0,67". The hardness of such pills can be from about 6 to about 26 kPa. According to another variant embodiment, the tablet may be in the form of a modified oval and contain 600 MHA with a total weight of approximately 1070 mg the magnitude of the tablets are 0,41"×0,75". The hardness of such pills can be from about 6 to about 26 kPa. On possible forms of tablets refer to figure 25, page 51 Tableting Specification Manual, fourth edition, published by American Pharmaceutical Association, Washington, DC, 1995.

The tablet can have optional the opening. Why is plated may include masking the taste of the medicine, facilitating swallowing pills, protection from splitting during the filling, creating a barrier to moisture and light to improve the stability of the product and improve the appearance or recognition.

The coating process may include the use of aqueous coating solution or suspension, with an acceptable viscosity for spraying and having properties of providing its adhesion with the surface tablets in the application. During the coating process, the covering solution or suspension is sprayed into small droplets that come into contact with the tablet. When drying of the droplets on the tablet formed film, which is the floor. For coating tablets use several types of devices for coating. One such device is the bowl for coating, in which the rotation of tablets and applying the coating solution on the pill during their hallowene in the bowl. Another coating process involves the suspension of the tablets in the column using air flow when spraying their surfaces covering solution (the process in the fluidized bed). The coating on the pill can be done with what omashu any known process and the method of application is not limited to the use of specific equipment.

Coating of tablets can be obtained from white or colored Opadry® (use, West Point, PA) suspension or clear Opadry® solution. Alternatively, typical cover composition may consist of such film-forming polymer, as hypromellose (HPMC), hydroxypropylcellulose (LDCs), polyvinylpyrrolidone (PVP) and will contain such ingredients as plasticizers, cloud emulsions, coloring materials and/or antioxidants.

The pharmaceutical compositions of the present invention can be used for treatment of bacterial or protozoal infections. Used in the text, the term "treatment", unless otherwise specified, refers to the treatment or prevention of bacterial or protozoal infections, including healing, decrease symptoms or slow the development of specified infectious diseases.

If not mentioned specifically, it is used in the text, the term "bacterial infection or a protozoal infection" refers to a bacterial or protozoal infectious diseases of mammals, fish and birds as well as disorders related to bacterial or protozoal infections, treatment and prevention which can be carried out by use of such antibiotics as the compound of the present invention. Non-limiting examples considered bacterial and rotating infectious diseases and related disorders, include 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 associated with infection with Streptococcus pyogenes, Groups C and g streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory infectious disease associated with infection with Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated infectious diseases of the skin and soft tissues, abscesses and osteomyelitis, and puerperal sepsis associated with infection with Staphylococcus aureus, coagulase-positive staphylococci (e.g., S. epidermidis, S. hemolyticus, etc.), Streptococcus piogenes, Streptococcus agalactiae, streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp. or Bartonella henselae; uncomplicated acute infectious diseases of the urinary tract associated with infection Staphylococcus saprophyticus or Enterococcus spp., urethritis and cervicitis, and sexually transmitted diseases related to infection with Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neisseria gonorroeae; abortion related to infection by S. aureus (food poisoning and toxic shock syndrome), or streptococci Groups a, b and C; peptic ulcer disease associated with infection by Helicobacter pylori; systemic richardcranium, related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis and microcystic associated with infection with Chlamydia trachomatis, Neisseria gonorroeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminirovanne Mycobacterium avium complex (MAC) disease related to infection with Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis related to infection with Campylobacter jejuni; intestinal protozoal infection related to infection with Cryptosporidium spp., odontogenic infectious disease associated with infection with viridans streptococci; persistent cough related to infection with Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; as well as atherosclerosis, is associated with infection Heliobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections and related disorders that can be cured or prevented in animals include, but are not limited to: respiratory disease bulls associated with infection P.haem., P.multocida, Mycoplasma bovis, or Bordetella spp., bovine enteritis associated with infection with E. coli or protozoa (e.g., coccidia, cryptosporidia, etc); mastitis dairy cows associated with Staph infection. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp., respiratory disease of pigs associated with infection A.pleuro, P.multocida is whether Mycoplasma spp., enteric disease of pigs associated with infection with E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; hoof rot cows associated with infection with Fusobacterium spp., cow metritis related to infection E.coli; hair warts cows associated with infection with Fusobacterium necrophorum or Bacteroides nodosus; acute epidemic conjunctivitis cows associated with infection with Moraxella bovis; premature abortion in cows associated with protozoal infections (e.g., neosporium); infectious diseases of the urinary tract in dogs and cats related to infection with E. coli; infections of skin and soft tissues of dogs and cats related to infection Staph. epidermidis, Staph. intermidius, coagulase neg. Staph. or P.multocida and infectious diseases of the teeth and the oral cavity of dogs and cats related to infection Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other painful conditions that can be treated by the compounds and preparations of the present invention include malaria and atherosclerosis. Other bacterial infections and protozoal infections and related diseases that can be treated or prevented using the method and compositions of the present invention described J.P.Sanford et al., "The Sanford Guide To Antimicrobial Therapy" 26th edition (Antimicrobial Therapy, Inc., 1996).

The term "effective amount" refers to the number of and the of ithromycin, the use of which prevents the beginning of the process, alleviates symptoms, stop the development or eliminates bacterial infection in mammals.

The term "mammal" refers to an individual animal that is a member of the taxonomic class of Mammals. To the class of Mammals include humans, monkeys, chimpanzees, gorillas, cattle, pigs, horses, sheep, dogs, cats, mice and rats.

In accordance with the present invention the preferred mammal is a human.

Usually the azithromycin is used in dosages of 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, 1 to 4 doses per day), although it should be borne in mind mandatory deviations from the specified values, which are related to the type, weight and condition of the object of treatment and selected by injecting drugs. The preferred dosage is from about 2 to about 50 mg/kg/day.

Azithromycin can be administered orally, or by other known methods.

EXAMPLES

The present invention is additionally illustrated by the following examples. It should be borne in mind that the invention is not limited to the details presented in the examples.

Example 1

Wet granulation forms A, G, J, M or N bulk azithromycin

The wet grain is s received from various forms of bulk azithromycin using aqueous or non-aqueous granulating fluid. Used azithromycinbuy forms A, G, J, M or N. as granulating fluid used 95% ethanol (EtOH), isopropanol (IPA) and water (H2O).

Bulk samples of medicinal products weighing from 3 to 5 g) was subjected to granulation in the flask with a capacity of 30 cubic centimeters (cm3), using an inclined turbine stirrer with paddle in 1/2", located on the high-speed drilling minipress (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370). Before use, the blade is straight by an angle sufficient to capture the granular material and to allow flow of material through the upper part of the blade. The blade is straight for about 30° relative to the vertical. The blade straight in order to simulate the characteristics of turbine agitators wysokosciowe granulator Niro SP-1 (Niro Inc., Columbia, MD). The liquid in an amount of 0.1-0.5 ml measured by pipette and within 2-3 minutes spent wet mixing before the formation of the corresponding granules, as judged visually. All experiments were formed wet granulates, however, when using water as the granulating fluid such pellets were unstable, and after drying in the case of experiments using non-aqueous liquid. All samples were dried at night for 16 hours at 40°in an air dryer with a force p is giving air. Visual observation of manual manipulation of the granules showed that the water pellets are softer and more fragile than the granules obtained with the use of non-aqueous granulating fluid. Table 1 presents the results of experiments on wet granulation.

IPA
Table 1
no experienceForm of medicationGranulating liquidDownloadThe amount of liquid* (%)Quality pellets
1AndEtOH3 g0.5 ml (17%)Good pellets
2GEtOH3 g0.5 ml (17%)Good pellets
3MEtOH3 g0.5 ml (17%)Good pellets
4NEtOH3 g0.5 ml (17%)Good pellets
5JEtOH5 g1.0 ml (20%)Good pellets
6AndIPA3 g0.5 ml (17%)Good pellets
7G3 g0.5 ml (17%)Good pellets
8MIPA3 g0.5 ml (17%)Good pellets
9NIPA3 g0.5 ml (17%)Good pellets
10JIPA5 g1.0 ml (20%)Good

granules
11AndH2About3 g0.5 ml (17%)Good

granules
12GH2About3 g0.5 ml (17%)Bad

granules
13MH2About3 g0.5 ml (17%)Bad

granules
14NH2About3 g0.5 ml (17%)Bad

granules
15JH2About5 g1.0 ml (20%)Mediocre

granules
*The percentage represents the relative amount of liquid relative to the amount of dry component

By scanning electron is Oh microscopy (SEM) conducted a study of wet granules bulk azithromycin.over medication (form A, G, J, M, and N), obtained using EtOH, IPA or H2The acting was Used, the increase in 50-1000 times. Micrographs were printed on paper size 4×5". Seed quality was evaluated visually based on the images obtained by SEM and the results of this assessment are presented in Table 1A.

Table 1A
ExperienceForm of medicationSolvent usedReducing the number of fine particlesChanges in the surface
1AndEtOHYesYes
2GEtOHYesYes
3MEtOHYesYes
4NEtOHYesYes
5JEtOHYesYes
6AIPAYesYes
7GIPAYesYes
8MIPAYesYes
9NIPAYesYes
10JIPAYesYes
11AH2ON/SN/S
12GH2ON/SN/S
13MH2ON/SN/S
14NH2ON/SN/S
15JH2ON/SN/S
N/S = small.

The SEM results confirmed the fact that a good pellets are formed for all five dosage forms using 95% EtOH and IPA. Apparently, the surface layers of the crystal medicines undergo dissolution and dissolved material performs a connecting function that contributes to the formation of granules. The appearance of the surface similar appearance thinly distributed coating on the surface of the granules. The number of fine particles is also reduced relative to their apparent number in the form of bulk drug. Not limited to a particular theory, it is assumed that the solvent dissolve the fine particles.

Water also promotes good granulation of all dosage forms, it is when they are wet, however, after drying, the granules become very fragile, indicating weak binding. Of the form J form granules of slightly better quality than from other forms, but it is, apparently, due to the large quantity of water added than in other forms. From the obtained results we can conclude that wetlands water leads to less fragile dried granules, however, they still have a lower quality than the granules obtained using non-aqueous granulating fluid. The SEM results indicate that the appearance of crystals similar appearance major source of particles. From the obtained results it is impossible to draw a clear conclusion about if they decrease the number of fine particles or dissolution of the surface layers. Water, as such, without the use of binders or more inert fillers, is bad granulating liquid azithromycin no.

Example 2

Wet granulation of the form F bulk azithromycin

The wet granules were obtained from bulk crystalline redigering of azitromicina F using aqueous or non-aqueous granulating fluid. As granulating fluid used 95% ethanol, isopropanol and water.

Form F bulk drugs contained soft to the available crystals, therefore, before use, the material was sieved through a sieve with holes of size 18 mesh (1.0 mm). The granulation process on a small scale described in example 1, was used for samples of bulk drugs weight of 5 was Measured by the pipette portion of liquid volume of 0.1-1.0 ml was injected into the system until a visual check of the formation of granules, after which the spent wet mixing for 3-5 minutes. In all three experiments was formed wet granulates, however, in the presence of water granulation occurred to a much lesser extent than in non-aqueous environment. All samples were dried at night for 16 hours at 40°C. In accordance with visual observation, after drying, was not achieved good fastening, indicating weak binding. In two experiments using non-aqueous liquid formed only ˜50% pellets and experience with water granulation was carried out only to a small extent. The results of experiments on granulation are shown in Table 2, and the density of the obtained granules are shown in Table 2A. If not specified, then the density of the dried granules was determined by manual sieving through a sieve with openings 18 mesh (1.0 mm), after which he made 2000 taps on Van Kel Tap Density Tester, Model 50-1200, Van Kel Industries, Edison, NJ. The change in density compared to the bulk drug was watching the camping only for non-aqueous granules.

Table 2
ExperienceLiquidNumberThe amount of liquid (%)The results of the drying granules
1EtOH5 g1.2 ml (24%)Bad ˜50% of the granules
2IPA5 g1.2 ml (24%)Bad ˜50% of the granules
3H2About5 g1.2 ml (24%)A small amount of pellets, the material is soft, powdery

Table 2A
Initial stateAfter aggregation tap (tapped)
TypeSampleVolume (cm3)Density (g/cm3)Volume (cm3)Density (g/cm3)
In mass9.0 g31,00,29020,50,439
Granulation in the environment EtOH (experiment 1)4.5 gto 12.00,3758,50,529
Granulation in the environment IA (experiment 2) 4.5 gto 12.00,3609,00,500
Granulation in the environment of H2O (experiment 3)4.5 g15,50,29010,50,429

The granulation process was repeated using an additional amount of granulating fluid to the formation of the wet granulate, like a single mass. Similar testing was performed to determine the increased compaction of the granules with additional quantities of liquid. The preparation of the compounds was carried out as described above. As follows from the data given in Tables 2 and 2B, the shape of F requires the use of much larger amounts of granulating liquid to get the same quality pellets, when granulation using other forms of azithromycin (see Example 1).

Table 2B
LiquidNumberThe amount of liquid (%)Quality pellets
EtOH (experiment 4)5 g1.5 ml (30%)Good solid granules
IPA (experiment 5)5 g1.7 ml (34%)Good solid granules
H2About (6) 5 g2.5 ml (50%)Mediocre granules, but soft granules

Table 2C
Initial stateAfter aggregation tap (tapped)
TypeSampleVolume (cm3)Density (g/cm3)Volume (cm3)Density (g/cm3)
In mass9.0 g31,00,29020,50,439
Granulation in the environment EtOH (experiment 4)4.5 g11,50,3919,00,500
Granulation in the environment IPA (experiment 5)4.5 gto 12.00,3609,00,500
Granulation in the environment of H2O (6)4.5 g13,5of 0.3339,50,474

After that, the samples manually sieved through a sieve with openings 18 mesh and determined their density, the values of which are presented in Table 2C. For the purpose of evaluation, before and after sieving the dried samples were subjected to examination by SEM method.

Three dried granulate of us who Phnom drugs sieved through 2 sieve set with the aim of quantifying the differences between the granules. Visually they all looked the same, however, based on observations during manual handling could be expected that they have different fragility. A set of sieves with a diameter of 3" was located on the top sieve No. 18 mesh (1000 microns), the next sieve No. 40 mesh (425 microns) and is located on the bottom of the receiver to collect the material. About 5 g of each of the pellets was placed on the top sieve and gently shaked for 1 minute, resulting in the movement of the hands from side to side. After that weighed quantity of granules remaining on each of the two sieves and in the receiver. The results obtained are presented in table 2D. It was found that in experiment No. 6, in which the granulating liquid used water, formed the most fragile granules. Sieve analysis (table 2D) showed that the non-aqueous liquid superior to water as a granulating liquid.

Table 2D
The liquid used >EtOHIPAH2O
SieveExperience 4%Experience 5%Experience 6%
18 mesh2,80 gto 58.12,35 g48,5 0,80 g16,9
40 mesh1,90 g39,41.85 g38,3 g2.58 g53,9 g
<40 mesh0.12 g2,50.64 g13,21.40 g29,2

To establish differences in particle size, shape and morphology of the conducted research method SEM parties pellet form F bulk azithromycin and the whole mass. Interval increase in the micrographs was 50-1000x. Micrograph size 4×5" did on film Pollaroid. According to the SEM results, in experiments 4-6 were obtained the same results. Were formed very coarse granules of irregular shape with a wide interval of the distribution of particle size. Used conventional photomasks. Pellets formed with the water, had the same form as granules, obtained using non-aqueous granulating fluid. Not limited to a particular theory, it is possible to assume that the non-aqueous liquid dissolve the fine particles or reduce their number.

Example 3

Wet granulation formulations redigering azithromycin

The wet granules were prepared from the compositions of the crystalline, redigering azithromycin, using aqueous and non-aqueous granulating fluid, when naked is the DCU drug 58-83%.

In the formulations of azithromycin used various forms of medications, different loads medicine, as well as various diluents, binders, disintegrators and granulating fluid. Diluents include insoluble microcrystalline cellulose (Avicel PH 102, FMC Biopolymer, Philadelphia, PA), anhydrous dibasic calcium phosphate, and soluble anhydrous lactose and water. As the binders used hydroxypropylcellulose (Klucel EF and EXF, Hercules Incorporated, Aqualon Division, Wilmington, DE), pre-gelatinising starch (Starch 1500, use, West Point, PA), and povidone (PVP, Plasdone C-30, International Specialty Products, Wayne, NJ). Used disintegrator included croscarmellose sodium Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA), sodium starch glycolate (Explotab, Penwest Pharmaceuticals Co., Cedar Rapids, IA) and cross-linked PVP (PVP-XL, International Specialty Products, Wayne, NJ). As granulating fluid used water, 95% ethanol, isopropanol and mixtures thereof. All the components winegrowers was added 2% mixture of stearate and sodium lauryl (9:1) as a lubricant. The composition of the used compositions are presented in Table 3.

F (58%)
Table 3
ExperienceForm of the drug (load)The diluent (%)Binder 5%Disintegrator 5%G is anuliruyut liquid (added in %)*
1G (83%)Avicel PH102 (10%)NoAc-Di-SolIPA:H2O(80:20) (17%)
2G (58%)Anhydrous lactose (30%)PVP C-30ExplotabH2O (13%)
3M (58%)Secondary acidic phosphate CA (30%)Klucel EFAc-Di-SolH2O (30%)
4M (58%)Avicel PH102 (30%)Starch 1500ExplotabH2O (14%)
5N (83%)Anhydrous lactose (10%)NoExplotabEtOH:H2O(50:50) (15%)
6N (58%)Secondary acidic phosphate CA (30%)Klucel EFAc-Di-Sol (winegrowers)H2O (13%)
7F (58%)Secondary acidic phosphate CA (30%)Klucel EFAc-Di-SolH2O (35%)
8F (58%)Anhydrous lactose (30%)Starch 1500PVP-XLEtOH:H2O(20:80) (22%)
9F (58%)Avicel PH102 (30%)Klucel EFAc-Di-SolEtOH:H2O(50:50) (30%)
10Secondary acidic phosphate CA (30%)PVP C-30PVP-XLH2O (17%)
11J (60%)Secondary acidic phosphate CA (28%)PVP C-30Ac-Di-SolEtOH (13,3%)
12J (60%)Secondary acidic phosphate CA (28%)PVP C-30Ac-Di-SolH2O (30,6%)
13J (60%)Anhydrous lactose (28%)Klucel EXFAc-Di-SolEtOH (15,5%)
14J (60%)Anhydrous lactose (28%)Klucel EXFAc-Di-SolH2O (37,5%)
*Percentage specified volume of liquid relative to the amount of dry component

For granulation formulations used small-scale process according to example 1. To prepare 10 g batches for each experiment, the ingredients (except lubricating agent) was pre-mixed for 5 minutes in the turbula Shaker-Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The resulting mixture was granulated by the method of example 1. Portion of the liquid volume of 0.1-1.0 ml measured by pipette and stirred for 2.5-6 minutes to form pellets. All samples were dried at night for 16 hours at 40°C. the Degree of compaction is Senales depending on the composition of inert fillers. The results obtained are presented in Table 3A. When using form F compaction of the granules were absent or were observed to a small extent in comparison with a bulk form F (experiments 7-10). Due to the poor quality of such granules them tableting not performed. Good pellets were obtained using form M in experiment 3, in the presence of excipients and granulating fluid, however, using form F (experiment 7) with the same composition were obtained bad granules.

Table 3A
ExperienceSample typeForm of medicationThe initial density (g/cm3)The density after compaction tapping (g/cm3)
Medicine in bulkG0,2900,450
1GranulationG0,4290,545
2GranulationG0,4500,562
Medicine in bulkM0,3910,514
3GranulationM0,5000,600
4GranulationM 0,3600,474
Medicine in bulkN0,4500,600
5GranulationN0,5000,643
6GranulationN0,5620,692
Medicine in bulkF0,2900,439
7GranulationF0,3460,500
8GranulationF0,2650,409
9GranulationF0,3100,450
10GranulationF0,3750,500
Medicine in bulkJ0,3770,649
11GranulationJ0,5000,694
12GranulationJ0,3750,529
13GranulationJ0,4100,529
14GranulationJof 0.3330,450

The pellets are extruded at one and the same stationary press tablet press (Manesty F-Press, Liverpool, United Kingdom) with a standard 13/32" krugovorota (SRC) equipment. The weight of the tablet corresponding to ˜250 mga medications, using an original composition from 58% load drug was 431 mg for comparative purposes, it is desirable that all batches of tablets were the same size and weight. Tablet weight in 431 mg, 83% of the load contained ˜358 mga medicines. From each batch of pellets was prepared by 10-15 tablets, except in experiments 7-10, which used F-press, working manually due to the small number of granules. Test tablets strength was performed using a tester tablets model 6D Dr. Schleuniger model tablet tester (Dr. Schleuniger Pharmatron AG, Solothum, Swizerland etc.). In all experiments, the strength of the tablets was ˜11 kPa or higher, except experience 5 load medicine 83%), in which the strength mattered ˜7 kPa. The disintegration time of the tablets was determined in water at 37° (Erweka ZT72 Tablet Disintegration Tester, Erweka GmbH, Heusenstamm, Germany). In the case of the form J was testing the friability of tablets. The test results are presented in Table 3B.

Table 3B
ExperienceForm of medicationAverage weight of tablets (mg) (n=10)The average strength tablets (kPa) (n=3)Average the time of the disintegration of the tablets (min) (n=3) Fragility (loss, %) (n=10)
1G433,812,63,5ND
2G430,518,120,3ND
3M423,013,213,1ND
4M435,011,42,0ND
5N437,46,65,0ND
6N438,913,318,2ND
7FNRNRNRND
8FNRNRNRND
9FNRNRNRND
10FNRNRNRND
11J420,212,3ND0,32
12J421,712,2ND0,43
13J425,4to 12.0ND 0,20
14J418,511,9ND0,39
NR = not experience spent, the poor quality pellets.

ND = not determined.

Some granules manually filled shell gelatin capsules No. 0 to the target pellet weight 431 mg Completeness of filling of capsules depends on the density of the granules. The time of disintegration of the capsules was determined in water at 37° (Erweka ZT72 Tablet Disintegration Tester, Erweka GmbH, Heusenstamm, Germany). Data obtained from the test capsules are presented in Table 3C.

Table 3C
ExperienceForm of medicationThe average weight of the capsule (mg) (n=2)The average disintegration time of capsules (minutes, n=2)
1G434,22,0
2G434,42,8
3M434,52,4
4M436,72,0
5N435,12,6
6N435,43,0

Example 4

Wet granulation additional trains redigering azithromycin/p>

The wet granules were obtained from additional crystalline compounds, redigering of azithromycin form G, M and N using water and 58% load medicine. The composition contained 58.2 per cent of azithromycin, 6% pre-gelatinizing starch (Starch 1500, use, West Point, PA) as a binder, 30,9% anhydrous secondary acidic calcium phosphate as a filler, 2% croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA) as of the cage and 2.9% of a mixture of stearate and sodium lauryl (SLC) (9:1) as a lubricant.

The above ingredients were weighed (except lubricating agent), combined, and within 30 minutes mixed in the turbula Shaker-Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The dry mixture homogenized using JT Fitzmill (0,027" sieve, front knives, high speed). Gomogenizirovannogo dry mixture was returned to the mixer and mixed for another 30 minutes.

Using a Hobart mixer (Hobart Corporation, Troy, OH), dry mix (download ˜300 g) was added 90 ml of water, and the mixture was stirred until the formation of the wet mass. The obtained wet mass was dried in an oven overnight at 50°C. Then the dried granulate was grind (Fitzmill JT, 0,093" sieve, front knives, average speed) and again stirred for 15 minutes. The granulate was added lubricant and air mixture to omnitele was stirred for 5 minutes.

The final granulate is extruded at a press tablet press with a permanent base (Manesty F-Press, Liverpool, United Kingdom), equipped with apparatus for forming capsules size 0,262"×mean HDI of 0.531". Target the tablet had a weight of 450 mg, and ten of these tablets were tested for strength (kPa) and frailty (100 rotations/4 minutes). For testing tablets used Schleuniger tablet hardness tester (Dr.Schleuniger Pharmatron AG, Solothum, Swizerland etc.) and Vanderkamp Friabulator Tablet Tester (Vankel, Cary NC). The data relating to the granules and tablets, are presented in Table 4.

441,5 (1,49% (n=10)
Table 4
GranulationTablets
ExperienceForm of medicationInitial density (g/cm3)The density after compaction (g/cm3)Average weight of tablets (mg) (%CV)The average strength tablets kPa (% CV)Friability of the tablets (%)
1N0,513of 0.741440,6 (2,92% (n=10)9,5 (13,9% (n=10)0,19 (n=10)
2G0,4780,676458,0 (1,46% (n=10)13,5 (6,2% (n=10)0,20 (n=10)
3M0,5080,7199,8 (6,1% (n=10)0,61 (n=10)

Then on tablets inflicted film coating using canovaro device for coating (Model HCT30, Vector Corporation, Marion, IA). Slurry for coating was prepared in the form of a pink water Opadry II (use, West Point, PA) suspension containing 20% solids. We used the following conditions coating: water inlet temperature 60°C, outlet temperature 40°With, the spray rate of 5-7 ml/min, the speed of rotation of the tub 22 rpm, the spray pressure of 1.5 kg/cm2.

Example 5

Wet granulation formulations of azithromycin form M

The wet granules were prepared from the compositions of the crystalline, redigering of azithromycin form M using aqueous and non-aqueous granulating liquid to load drug 30-60%.

In these compositions, the solvent was a secondary acidic calcium phosphate. As the binder, the composition contained 5% povidone (PVP, Plasdone C-30, International Specialty Products, Wayne, NJ). As disintegrator considered structures include 5% croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA). Granulating fluid was a water or 95% ethanol. All the components winegrowers was added 2% mixture of stearate and sodium lauryl (9:1). Formulations of the compositions presented in Alice 5.

Table 5
Load medicationThinnerGranulating liquid*
60%28% of secondary of calcium hydrogen phosphate15,3% EtOH
60%28% of secondary of calcium hydrogen phosphate30,6% EtOH
45%43% of secondary of calcium hydrogen phosphate13,3% EtOH
45%43% of secondary of calcium hydrogen phosphate40,8% H2O
30%58% of secondary of calcium hydrogen phosphate13,3% EtOH
30%58% of secondary of calcium hydrogen phosphate40,8% H2O
*The percentage of the volume of liquid relative to the amount of dry component.

Small-scale process described in example 1 was used for granulation formulations in the party with a mass of 10 g Portion of the liquid volume of 0.1-1.0 ml measured by pipette and was stirred for 2-5 minutes to form pellets. All samples were dried at night for 16 hours at 40°in the furnace with forced hot air and then sieved through a sieve of size 18 mesh (1.0 mm). The density of the granules is presented in Table 5A.

Table 5A
Load medicationQuantity (g)The liquid usedInitial density (g/cm3)The density after compaction (g/cm3)Quality pellets
60%9,8EtOH0,4290,602Good, solid
60%9,8H2About0,3920,532Mediocre, softer
45%9,8EtOH0,5290,752Good, solid
45%9,8H2About0,3920,562Mediocre, softer
30%9,8EtOHto 0.6450,901Good, solid
30%9,8H2O0,4290,621Mediocre, softer

The granulate was added lubricant and each experience extruded fifteen tablets, after which they were tested for strength and disintegration time in accordance with the method of example 3. If the mass of the tablets in 417 mg, load the cure in 60%, 45% and 30% provide the Wali, accordingly, about 250 MHA, about 188 mga and about 125 MHA.

Test the fragility of the tablets (100 rotations/4 minutes) was performed using Vanderkamp Friabulator Tablet Tester (Vankel, Cary, NC). The results of the tests are presented in Table 5B.

Table 5B
Load medicationThe liquid usedAverage weight of tablets (mg) (n=10)The average strength of the tablets (kPa, n=3)The fragility tablets loss percentage (n=10)
60%EtOH420,4a 12.70,28
60%H2O421,313,20,30
45%EtOH424,311,70,38
45%H2O419,412,20,20
30%EtOH420,213,20,28
30%H2O426,313,20,25

Example 6

Wet granulation formulations of azithromycin form F

The wet granules were obtained from compositions redigering of azithromycin form F using aqueous and non-aqueous granulating fluid at a load of medicine 58%of Each of the compositions of this example contained 25% lactose as a diluent and two binders, in particular, 10% sucrose (American Sugar Refining Co., Domino Foods, Baltimore, MD)added to the dry mixture, and povidone (PVP, Plasdone C-30, International Specialty Products, Wayne, NJ), added with a granulating liquid. PVP was dissolved (10% mass/about) in each of the three granulating liquids: water, 95% ethanol and a mixture of water with ethanol in the ratio of 50:50. All formulations contained 5% croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA) as viagradosage of the cage and 2% mixture of stearate and sodium lauryl (9:1) as viagradosage lubricants.

For granulation formulations used for small-scale process described in example 1. Portion of the liquid volume of 0.1-1.0 ml measured by pipette and mixed with 9.3 g of a dry mix for 3-6 minutes to form pellets. Granulating fluid contained 30, 27, and 29% PVP in ethanol, water and a mixture of ethanol:water in the ratio 50:50, respectively. The amount of the liquid used was 2.5-3 ml, and the amount of solids (PVP)is added to the solution in the calculation of the final loading of 10 g was of 0.25-0.3%. All samples were dried at night for 16 hours at 40°C, then sieved through a sieve with apertures 16 mesh (1.2 mm). Density of the obtained granules are presented in Table 6.

Table 6
ExperienceSample type Initial density (g/cm3)The density after compaction (g/cm3)
Bulk medication0,2900,439
1Granulation with EtOH0,4090,563
2Granulation with H2O0,3210,429
3Granulation with a mixture of EtOH:H2O (50:50)0,3460,474

As indicated in example 3, the pellets are extruded with getting ten tablets and then tested for strength and disintegration time. For tablets weighing 431 mg loading of drug in 58% provided approximately 250 MHA. The test results are presented in Table 6A.

Table 6A
ExperienceAverage weight of tablets (mg) (n=10)The average strength tablets (kPa) (n=3)The average disintegration time of the tablets (min) (n=3)
1434,712,813,3
2436,912,55,3
3437,513,68,8

Example 7

Wet granulation formulations of azithromycin form F

Mo is that granules prepared from additional formulations of azithromycin form F using aqueous and non-aqueous granulating liquids and fillers under load medicine 40 and 58%. As diluents were selected water lactose (Foremost Farms USA, Rothschild, WI) and anhydrous secondary acidic calcium phosphate. As the binders used hydroxypropylcellulose (Klucel EXF, Hercules Incorporated, Aqualon Division, Wilmington, DE) or povidone (PVP, Plasdone C-30, International Specialty Products, Wayne, NJ). The binder in the dry state was added to the mixture prior to granulation with a granulating liquid. The disintegrator was croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA) or crosspovidone (PVP-XL, International Specialty Products, Wayne, NJ). Granulating fluid was a water, ethanol and a mixture in the ratio of 50:50. All the components prior to pelletizing, winegrowers was added 2% of a mixture of stearate and sodium lauryl (9:1) as a lubricating agent. Formulations of the compositions shown in Table 7.

Table 7
ExperienceLoad medicationThe diluent 29-48%Binder 5%Disintegrator 5%Liquid %
158%30% aqueous lactosePVP (C-30)Ac-Di-SolEtOH (23%)
258%30% aqueous lactosePVP (C-30)Ac-Di-SolEtOH:H2O 50:50 (30%)
3 58%*29% aqueous lactoseKlucel EXFAc-Di-SolH2O (40%)
458%*29% of secondary of calcium hydrogen phosphateKlucel EXFAc-Di-SolH2O (50%)
540%48% of secondary of calcium hydrogen phosphatePVP (C-30)PVP-XLH2O (30%)
*1% sodium lauryl pre-mixed with the bulk drug.

Small-scale process described in example 1 was used for granulation formulations with getting lots of weight in 10 g of Each composition was preliminarily stirred for 5 minutes in the device the turbula Shaker-Mixer (Willy A. Bachofen AG Maschinenfabric, Basel, Switzerland). After that, the mixture was subjected to granulation by the method described in example 1. The liquid in an amount of 0.1-1.0 ml measured by pipette and stirred for 4-8 minutes until the formation of granules. All samples were dried at night for 16 hours at 40°and was then screened manually through a sieve with openings 16 mesh (1.2 mm). Then were compared densities of granules with each other and with a density of no medication. The degree of compaction varied depending on the nature of the components in the composition. The obtained data are presented the table 7A.

Table 7A
ExperienceSample typeThe initial density (g/cm3)The density after compaction (g/cm3)
No medication0,2900,439
1Granulation with EtOH0,3910,562
2Granulation with EtOH:H2O (50:50)0,2810,409
3Granulation with H2About0,2810,391
4Granulation with H2About0,3100,429
5Granulation with H2About*0,4090,562
*Note: load the cure 40%.

According to the method of example 3, the pellets were extruded ten tablets and then tested for strength and disintegration time. For tablets weighing 431 mg, load medicine in 58% and 40% provided about 250 MHA and about 172 MHA, respectively. The results are given in Table 7B.

Table 7B
ExperienceAverage weight of tablets (mg) (n=10) The average strength tablets (kPa) (n=3)The average disintegration time of the tablets (min) (n=3)
1439,510,67,1
2437,2the 13.47,0
3435,011,79,3
4435,011,38,0
5438,010,64,1

Example 8

Wet granulation of azithromycin form

The wet granules were obtained from redigering azitromicina forms using various granulating quantities of water in the granulator, high shear force. Each of the four compositions contained 58.2 per cent of azithromycin form, 6% pre-gelatinizing starch (Starch 1500, use, West Point, PA) as a binder, 30,9% anhydrous acid secondary calcium phosphate as a diluent, 2% croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA) as of the cage, and 2.9% of a mixture of stearate with lauryl sulfate (SLS) (9:1) as a lubricating agent.

In each of the compositions in the number 3375 g azithromycin and starch were mixed in the P-mixer (Patterson-Kelley Co., East Stroudsburg, PA). After that, the mixture was grinded using a high-speed device JT Fitz Mill (The Fitzpatrick Co. Elmhurst, IL) with a #0 plate (0,033) and front hammers (part 1). After that, the secondary acidic calcium phosphate and croscarmellose sodium were mixed with each other in the P-To the mixer (part 2). Granulation was carried out in wysokosciowe granulator Nitro-Fielder (Nitro Inc., Columbia, MD). The mixture was stirred for one minute using a turbine stirrer with a speed of 300 Rev/min In each of the four formulations was added water in an amount of from 22 to 37% and the system was stirred for two minutes with a speed of 300 rpm and Then the crusher two minutes switched to low speed and 40 seconds on high speed. After it was unloaded granules. The wet mass was divided into two equal parts for the purpose of studying the actions drying equipment (shelf dryer or fluidized bed) and dried at 50°C. Next to the dried granules was added magnesium stearate and the mixture was stirred for five minutes in the P-To the mixer. Tablets were obtained using a Kilian rotary tablet press press (Kilian-IMA, Koln, Germany) c 13/32" standard set of tools for krugovorota (SRC) tablets. The average weight of the tablets was 451 mg, with an average thickness of tablets 0,200". Test tablets strength was performed using Dr.Schleuniger model 6D tablet tester (Dr. Schleuniger Pharmatron AG, Solothum, Swizerland etc.). Six tablets from each experiment were tested during their disintegration using Erweka Disitegration Tablet Tester (Erweka GmbH, Heusenstamm, Germany). Data granules and tablets are shown in Table 8.

Table 8
ExperienceGranulesTablets
% waterThe method of dryingInitial density (g/cm3)Density after precipitation (g/cm3)Average strength (kPa)The average disintegration time (min, n=6)
129,6%Shelf drying0,5780,7699,823,2
229,6%Fluidized bed0,5780,7699,831,2
322,2%Shelf drying0,5990,7529,629,0
422,2%Fluidized bed0,6130,7527,646,5
537,1%Shelf drying0,5990,752a 12.728,5
626,9%Shelf drying0,5780,69911,532,0
7 26,9%Fluidized bed0,6130,752the 9.754,0

Example 9

Test the solubility of azithromycin

The equilibrium solubility of several different forms of azithromycin in typical liquids used in the process of wet granulation, was evaluated by the following method.

The equilibrium solubility of form A, F, G, J, M, and N of azithromycin was determined in water, isopropanol (IPA) and 95% ethanol (EtOH)and water-alcohol mixtures containing 67 and 33% alcohol. The excess of azithromycin in the form of a solid substance was added in each test fluid and perform the mixing in a Labquake Rotating Mixer® the rotation speeds of 7 revolutions per minute (RPM). For each of the experimental conditions used in two samples. The excess of medicinal material was added to achieve saturation of the solution. After reaching saturation, the samples were rotated for 48 hours, taking samples of the solution after 24 and 48 hours. Azithromycin forms And were subjected to 7-day analysis on the determination of equilibrium solubility to ensure a balance for more than 48 hours. After each sampling, approximately half (1 ml) of sample was transferred into a polyethylene tube of microcentrifuge and centrifuged with a speed of 15000 RPM for 20 minutes using the Eppendorf Centifuge Model #5403. After centrifugation the liquid layer was collected by pipette and diluted with a mixture of 0.04 M sour secondary potassium phosphate (pH 8):acetonitrile (4:6). Dilution was carried out before hitting the peak area in the linear range of the standard curve (0,15-1,5 mga/ml). The samples were analyzed by the method GHUR (HP-1100 system, Agilent Technologies, Wilmington, DE) with UV detection at 210 nm. Experimental data were processed by linear regression from the standard curve for azithromycin form A.

The following results were obtained for the equilibrium solubility of various forms of azithromycin.

The solubility of form a mga/ml after 24 hours amounted to 0.10 in the water, 1,30 in a mixture of 33% EtOH in water V/V, 27,48 in a mixture of 67% EtOH in water V/V, 219,74 in pure 100% EtOH, 5,50 in a mixture of 33% IPA in water V/V, 68,71 in a mixture of 67% IPA in water V/V, and 291,91 in pure 100% IPA.

The solubility of form a mga/ml after 48 hours amounted to 0.14 in the water, 1,23 in a mixture of 33% EtOH in water V/V, 27,25 in a mixture of 67% EtOH in water V/V, 211,59 in pure 100% EtOH, 5.25 in a mixture of 33% IPA in water V/V, 67,70 in a mixture of 67% IPA in water V/V, and 280,91 in pure 100% IPA.

The solubility of form a mga/ml after 7 days was 0.11 in the water, 1.27 in a mixture of 33% EtOH in water V/V, 27,02 in a mixture of 67% EtOH in water V/V, 214,76 in pure 100% EtOH, 5.25 in a mixture of 33% IPA in water V/V, 66,63 in a mixture of 67% IPA in water V/V, and 286,45 in pure 100% IPA.

The solubility of form F, mga/ml after 24 hours was 0.19 in the water, 0.98 in a mixture of 33% EtOH the water about/about, 27,86 in a mixture of 67% EtOH in water V/V, 228,34 in pure 100% EtOH, 10,04 in a mixture of 33% IPA in water V/V, 94,09 in a mixture of 67% IPA in water V/V, and 367,02 in pure 100% IPA.

The solubility of form F, mga/ml after 48 hours was 0.21 in the water, 1.06 in a mixture of 33% EtOH in water V/V, 27,56 in a mixture of 67% EtOH in water V/V, 229,87 in pure 100% EtOH, 9,41 in a mixture of 33% IPA in water V/V, 79,90 in a mixture of 67% IPA in water V/V, and 362,64 in pure 100% IPA.

The solubility of form G, mga/ml after 24 hours was 0.21 in the water, 0,94 in a mixture of 33% EtOH in water V/V, 27,52 in a mixture of 67% EtOH in water V/V, 221,46 in pure 100% EtOH, 8,29 in a mixture of 33% IPA in water V/V, 88,74 in a mixture of 67% IPA in water V/V, and 313,04 in pure 100% IPA.

The solubility of form G, mga/ml after 48 hours amounted to 0.23 in the water, 1,05 in a mixture of 33% EtOH in water V/V, 27,03 in a mixture of 67% EtOH in water V/V, 221,49 in pure 100% EtOH, 6,87 in a mixture of 33% IPA in water V/V, 79,85 in a mixture of 67% IPA in water V/V, and 311,38 in pure 100% IPA.

The solubility of form J, mga/ml after 24 hours was 0.18 in the water, 0.95 in a mixture of 33% EtOH in water V/V, 27,15 in a mixture of 67% EtOH in water V/V, 224,77 in pure 100% EtOH, 9,81 in a mixture of 33% IPA in water V/V, 113,05 in a mixture of 67% IPA in water V/V, and 315,94 in pure 100% IPA.

The solubility of form J, mga/ml after 48 hours amounted to 0.22 in the water, 0,99 in a mixture of 33% EtOH in water V/V, 26,30 in a mixture of 67% EtOH in water V/V, 208,99 in pure 100% EtOH, 9,40 in a mixture of 33% IPA in water V/V, 106,51 in a mixture of 67% IPA in water V/V, and 295,88 in pure 100% IPA.

The solubility of form M, mga/ml after 24 h the sa amounted to 0.22 in the water, 0,97 in a mixture of 33% EtOH in water V/V, 25,86 in a mixture of 67% EtOH in water V/V, 211,38 in pure 100% EtOH, 8,56 in a mixture of 33% IPA in water V/V, 110,67 in a mixture of 67% IPA in water V/V, and 333,39 in pure 100% IPA.

The solubility of form M, mga/ml after 48 hours was 0.21 in the water, 1,10 in a mixture of 33% EtOH in water V/V, 27,00 in a mixture of 67% EtOH in water V/V, 222,38 in pure 100% EtOH, 8,92 in a mixture of 33% IPA in water V/V, 82,95 in a mixture of 67% IPA in water V/V, and 353,19 in pure 100% IPA.

The solubility of the form M mga/ml, 72 hours was 71,35 in a mixture of 67% IPA in water V/V, and 322,55 in pure 100% IPA.

The solubility of form N mga/ml after 24 hours amounted to 0.20 in water, 1.06 in a mixture of 33% EtOH in water V/V, 27,33 in a mixture of 67% EtOH in water V/V, 228,14 in pure 100% EtOH, 9,23 in a mixture of 33% IPA in water V/V, 113,08 in a mixture of 67% IPA in water V/V, and 334,22 in pure 100% IPA.

The solubility of form N mga/ml after 48 hours amounted to 0.24 in the water, 1,11 in a mixture of 33% EtOH in water V/V, 27,20 in a mixture of 67% EtOH in water V/V, 225,78 in pure 100% EtOH, of 7.36 in a mixture of 33% IPA in water V/V, 106,48 in a mixture of 67% IPA in water V/V, and 322,91 in pure 100% IPA.

All forms of azithromycin have comparable solubility, with the exception of the form a (dihydrate), which has approximately twice lower solubility in pure water and a lower solubility in isopropanolic solutions compared to all other forms. All forms of azithromycin show similar values of solubility in ethanol medium. All lyrics by the teas, more lipophilic isopropanol is the best solvent/co-solvent than ethanol.

1. The method of forming granules redigering of azithromycin, which includes stages:

a) mixing

(i) particles redigering of azithromycin

(ii) granulating the number of non-aqueous granulating fluid and,

(iii) optionally, particles of one or more pharmaceutically acceptable inert fillers,

with the formation of wet granules, and the wet granules contain nativitatis azithromycin and non-aqueous granulating fluid; and

b) drying the wet granules to remove non-aqueous granulating liquid and the formation of granules redigering azithromycin;

where nativitatis azithromycin is selected from the group consisting of gamitana of MES monohydrate azithromycin, Hemi-n-propanol of MES monohydrate azithromycin, azithromycin sesquihydrate and semisopochnoi of MES monohydrate azithromycin.

2. The method according to claim 1, in which the particles redigering azithromycin is chosen from the group consisting of powder redigering azithromycin and granules redigering azithromycin.

3. The method according to claim 2, in which nativitatis azithromycin is a Hemi-ethanol MES monohydrate azithromycin.

4. Pharmaceutical composition for treating the bacteria is territorial or protozoal infectious diseases, including granules redigering azithromycin and at least one pharmaceutically applicable inert filler, where nativitatis azithromycin is selected from the group consisting of gamitana of MES monohydrate azithromycin, Hemi-n-propanol of MES monohydrate azithromycin, azithromycin sesquihydrate and semisopochnoi of MES monohydrate azithromycin.

5. The pharmaceutical composition according to claim 4, in which nativitatis azithromycin is gamitana MES monohydrate azithromycin.

6. Pharmaceutical composition for treatment of bacterial or protozoal infectious diseases, which is a tablet, sachet or powder to obtain a slurry containing

a) granules redigering azithromycin and

b) at least one pharmaceutically acceptable excipient;

where nativitatis azithromycin is selected from the group consisting of gamitana of MES monohydrate azithromycin, Hemi-n-propanol of MES monohydrate azithromycin, azithromycin sesquihydrate and semisopochnoi of MES monohydrate azithromycin.

7. Pharmaceutical composition for treatment of bacterial or protozoal infectious diseases, which is a capsule containing

a) granules redigering azithromycin and

b) at measures which, one pharmaceutically acceptable excipient;

where nativitatis azithromycin is selected from the group consisting of gamitana of MES monohydrate azithromycin, Hemi-n-propanol of MES monohydrate azithromycin, azithromycin sesquihydrate and semisopochnoi of MES monohydrate azithromycin.

8. The pharmaceutical composition according to claim 6 or 7, in which nativitatis azithromycin is selected from the group consisting of gamitana of MES monohydrate azithromycin and semisopochnoi of MES monohydrate azithromycin.

9. The pharmaceutical composition according to claim 6 or 7, in which nativitatis azithromycin is gamitana MES monohydrate azithromycin.

10. The method of treatment of bacterial or protozoal infectious diseases of mammals, consisting in the introduction to the specified mammal an effective amount of the pharmaceutical composition according to any one of p-9.



 

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15 cl

FIELD: medicine, biotechnology.

SUBSTANCE: invention relates to preparing biologically active substances from human and animal tissues. Invention proposes an antibacterial agent from pig and cattle platelets of molecular mass 0.5-15 kDa. Agent is prepared by freezing and defrosting platelet mass at temperature (-15)-(-20)°C for 24 h, centrifugation at 1000g, filtration of supernatant through dialysis membranes 15000 and 500 and elution of component comprising peptides by acetonitrile linear gradient from Sephadex G-50. Invention provides the synergetic antibacterial effect of peptides as component of the agent.

EFFECT: improved preparing method, valuable properties of agent.

8 cl, 6 tbl, 7 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to agents representing a water-soluble silver compound based on natural polysaccharide arabinogalactane. The agent represents water-soluble articles of size 10-30 nm and elicits the antibacterial effect with respect to pathogenic microorganisms Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Bacillus subtilis and Candida albicans. Invention provides preparing the medicinal agent as an alternative agent for antibiotics.

EFFECT: valuable medicinal properties of agent.

1 tbl, 4 ex

FIELD: veterinary science.

SUBSTANCE: invention relates to a preparation used in treatment of respiratory diseases of bacterial etiology in cattle young stock. The proposed preparation comprises laevomycetin, dioxydine, 1,2-propylene glycol, distilled water and polyethylene oxide in the definite ratio of components. Invention provides enhancing the effectiveness of treatment of respiratory diseases in cattle young stock, and this preparation has no contraindications and it doesn't show adverse signs and complications.

EFFECT: improved and valuable properties of preparation.

4 tbl, 3 ex

FIELD: medical engineering.

SUBSTANCE: device has porous ceramic carrier layers and transverse bracing members, connected carcass having pores most of which have size from 20 to 1000 mcm and possessing density of 40% with respect to the theoretical one. Volume of the pores is optionally filled with a drug known to have controllable release rate from the filler.

EFFECT: enhanced effectiveness in providing controllable drug release rate from the filler.

30 cl, 3 dwg, 1 tbl

FIELD: pharmaceutical composition in form of tablet, sachet or powder for suspension.

SUBSTANCE: claimed composition contains particles of azithromicine non-dehydrated form obtained by dry granulation method and optionally one or more pharmaceutically acceptable excipient. Pharmaceutical composition preferably represents tablet containing approximately 40-85 mass % non-dehydrated azithromicine. More preferably pharmaceutical composition contains non-dehydrated azithromicine selected from F, G, J, M forms or mixtures thereof. Most preferably pharmaceutical composition contains azithromicine (A) in dose of 250 mgA, 500 mgA, 600 mgA, or 1000 mgA. Also disclosed is azithromicine particles obtained by dry granulation method that containing azithromicine form selected from F, G, J, M forms and mixtures of non-dehydrated forms, and at least one pharmaceutically acceptable excipient.

EFFECT: new azithromicine compositions.

17 cl, 7 tbl, 7 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a pharmaceutical composition comprising a medicinal agent, wax-like substance and synthetic aluminum silicate and/or aqueous silicon dioxide, and oral pharmaceutical component comprising such composition. The pharmaceutical composition is prepared by granulation by spraying. Also, invention relates to an agent used for prevention in usage of granulated product to internal walls of granulator device during the granulation process by spraying. This agent represents synthetic aluminum silicate and/or aqueous silicon dioxide. Invention minimizes sticking granules in granulator device during granulation of the pharmaceutical composition and prevents caking granules.

EFFECT: improved preparing method, improved and valuable properties of composition.

13 cl, 4 tbl, 6 ex

FIELD: methods of preparation of pharmaceutical composition.

SUBSTANCE: pharmaceutical composition has to be solid amorphous homogenous dispersion of medicinal preparation. The composition increase content of polymer due to switching of high pressure sprayer and dissipating plate on to improve flow of drying gas and to increase sizes of drying chamber which improves time of drying.

EFFECT: improved characteristics of fluidity of dispersions; improved efficiency of collection of particles.

15 cl, 9 tbl, 7 dwg, 3 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to formulations comprising heparin as an active component and a base consisting of lipid and polymeric components for oral using. The lipid component is able preferably to enhance effect of the main component while the polymeric component possesses ability to dissolving or swelling, and at least part of the lipid component is incorporated into the polymeric matrix being in the molecular-dispersed state. Invention provides the sufficient complete absorption of active substance in digestive tract after its oral intake.

EFFECT: valuable properties of formulation.

9 cl, 2 dwg, 8 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, endocrinology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to nateglynide-containing preparation used in treatment of diabetes mellitus that comprises nateglynide as an active component and a carrier wherein nateglynide in amorphous form and indicated carrier represents hydrophilic material. Amorphous property of crystalline nateglynide is provided by the following methods: 1) by dissolving nateglynide crystals in pharmacologically acceptable solvent in common with hydrophilic materials taken among the group consisting of water-soluble polymers, water-swelling polymers, sugar alcohols and salts followed by granulation in fluidized layer, granulation by stirring at high rate, drying by spraying and process for coat applying for granulation of amorphous nateglynide; 2) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following application of the high shift force to the prepared mixture; 3) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following plasticizing the prepared mixture in melt by heating and milling at cooling; 4) by dissolving nateglynide crystals in pharmacologically acceptable liquid additives wherein liquid additives represent water-soluble polymers that are liquid at 37°C. Using amorphous nateglynide allows preparing the nateglynide preparation with immediate release wherein the dissolving rate of medicinal agents is high and without crystalline transition during preparing or preserving preparations.

EFFECT: valuable pharmaceutical properties of preparation.

6 cl, 3 tbl, 9 dwg

FIELD: pharmacy.

SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.

EFFECT: improved and valuable properties of composition.

15 cl, 5 tbl, 6 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for pressing in preparing a medicinal formulation of phenytoin sodium, method for pressing in rollers and preparing a pharmaceutical composition involves stages of addition of phenytoin sodium into a mixer receiver and addition of at least one excipient into indicated mixer. Mixture is stirred and transferred into roller thickener wherein pressure is applied on the mixture of phenytoin sodium and excipient. The prepared compact-(briquette) is ground and prepared granulate is mixed repeatedly that is suitable from further processing to a medicinal formulation. Excipients involve magnesium stearate, sugar, lactose monohydrate and talc, or talc is added directly before the second mixing the granulate.

EFFECT: improved pressing method.

15 cl, 10 tbl, 2 dwg, 4 ex

FIELD: pharmacology.

SUBSTANCE: according to the present invention pharmacological composition is in form of quick soluble granules, containing particles of at least two different carrier materials with surface being at least partially coated with at least one layer, comprising 50-120 wt.pts, preferably, 60-100 wt.pts of at least one active ingredient based on 100 wt.pts of carrier material. Active ingredient is preferably insoluble or low soluble substance such as amino acids or antioxidants. The first carrier material comprises about 50-80 wt.% of total carrier material and has bulk density of 58-100 g/ml, preferably of 63-90 g/100 ml. The second carrier material has bulk density of 30-55 g/100 ml, preferably of 33-50 g/100 ml. Granulated composition has high solubility, high content of active ingredient and little amount of excipients. Further composition is quickly suspended in little amount of water, doesn't form agglomerates for a long time, ant has acceptable taste.

EFFECT: pharmacological composition in form of quick soluble granules with improved quality.

22 cl, 4 tbl, 5 ex

FIELD: pharmaceutical industry.

SUBSTANCE: claimed composition for sublingual application contains apomorphine as active ingredient and succinic acid as apomorfine stabilizer and filler, as well as other additives.

EFFECT: sublingual tablet with sufficient strength and resolvability.

4 cl, 1 tbl, 2 ex

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