JP2009501206A - Method for producing amorphous azithromycin particles - Google Patents

Abstract

The present invention provides an amorphous process comprising: producing a solution comprising azithromycin and a solvent; atomizing the solution; and subsequently evaporating at least a portion of the solvent from the solution to produce amorphous azithromycin. The present invention relates to a method for producing quality azithromycin.

Description

  The present invention relates to a method for producing amorphous azithromycin particles using a rapid solvent evaporation method.

  Azithromycin has the following structural formula:

  Azithromycin is described in US Pat. Nos. 4,517,359 and 4,474,768. Azithromycin is also known as 9-deoxo-9a-aza-9a-methyl-9a-homoerythomycin A.

  Amorphous forms of some drugs have been shown to exhibit different solubility characteristics and possibly different bioavailability patterns compared to crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38: 2003-2007). In some therapeutic indications, one bioavailability pattern may be preferred over the other.

  The preparation of amorphous azithromycin has been previously described. For example, US Pat. No. 6,245,903 describes an anhydrous form of azithromycin, as well as a method for the purification of amorphous anhydrous azithromycin by use of chromatographic procedures or solvent evaporation methods.

  US Pat. No. 6,451,990 B1 describes the evaporation of a solution of azithromycin in tert-butanol (2-methyl-2-propanol) or a cyclic ether by lyophilization and of azithromycin in an aliphatic alcohol such as ethanol or isopropanol. Describes the procedure for the preparation of amorphous (ie amorphous) azithromycin.

  WO2004 / 009608A2 produces an orthorhombic isomorphic pseudopolymorph of azithromycin, which is then converted into an amorphous product by removal of the solvent and excess water by lyophilization or vacuum drying. Is described.

  WO 02 / 094843A1 describes amorphous azithromycin produced by removing water and / or solvent from the azithromycin crystal lattice. Amorphous azithromycin is produced by heating crystalline form A of azithromycin in vacuo.

  Published US Patent Application No. 2002/0111318 describes a process for preparing non-hygroscopic azithromycin dihydrate.

  An effective means for preparing small, uniform particle amorphous azithromycin continues to be sought.

  The invention includes (a) producing a solution containing azithromycin and a solvent, (b) atomizing the solution into droplets, and (c) evaporating at least a portion of the solvent from the solution to produce amorphous Producing amorphous azithromycin, the method comprising the steps of: The solvent is preferably removed by spray drying or spray coating.

  It has been discovered that amorphous azithromycin is produced when azithromycin is dissolved in a solvent and the solvent is rapidly evaporated. Azithromycin has good solubility in a wide range of solvents, and the method of producing amorphous azithromycin can be improved by reducing the required amount of solvent. Furthermore, when a small particle size is realized by such a rapid production method, the need for a grinding step is reduced, thereby reducing the number of unit operations in the production of commercially available materials.

  Rapid evaporation provides yet another advantage that particles with relatively uniform particle size distribution and shape are produced. Amorphous azithromycin produced by mechanically crushing glassy foams, such as those produced by freeze-drying methods, tends to have a wide size distribution, and individual particles have jagged or sharp edges. Tend to have. In contrast, particles produced by rapid evaporation tend to be rounder and have a narrow size distribution. Particles produced by rapid evaporation have better flow properties and are less prone to separation during manufacturing, such as during handling to produce tablets or other dosage forms. Thus, the present invention can reduce separation during dosage form manufacture by providing amorphous azithromycin that is easier to handle.

  It is also believed that the small particle size achieved by rapid evaporation results in particles with more rapid dissolution characteristics. This can be attributed to the large surface area of small particles.

  The foregoing and other objects, features, and advantages of the invention will be more readily understood in view of the following detailed description of the invention.

  In this method, azithromycin is dissolved in a solvent, the resulting solution is atomized, and the solvent is evaporated to produce amorphous azithromycin. The term “amorphous” as used herein refers to a particular solid form of azithromycin that does not have a translational long-range three-dimensional order. The term “amorphous” refers not only to materials that are essentially unordered, but may also have a slightly lesser degree of order, but the order is less than three dimensional and / or only at short distances. Including unacceptable materials. Partially crystalline materials and crystalline mesophases, for example, having one or two dimensional translational order (liquid crystal), having orientation disorder (alignment disordered crystal), or having conformational disorder Also included are conformational disorder crystals. Amorphous materials can be characterized by techniques known in the art, such as thermal techniques such as powder X-ray diffraction (PXRD) crystallography, solid state NMR, or differential scanning calorimetry (DSC). . The amount of crystalline azithromycin present in the resulting amorphous drug is small. It is preferred that at least 90% by weight of the azithromycin produced by the method of the present invention is amorphous. More preferably, at least 95%, even more preferably at least 99% by weight of the azithromycin produced by the method of the present invention is amorphous.

  As will be appreciated by those skilled in the art, azithromycin that is dissolved to form a solution is not only crystalline or amorphous, but also disordered crystals, liquid crystals, plastic crystals, mesophases, etc., or any of these Any form is possible, such as a mixture. Azithromycin can be readily synthesized, for example, as described in US Pat. Nos. 4,517,359 and 4,474,768. The term “azithromycin” includes free base forms, salt forms, solvates, hydrates, polymorphs, pseudomorphs, and isomorphs.

  The azithromycin used to produce amorphous azithromycin by the method of the present invention may be any form of azithromycin or a mixture of two or more forms of azithromycin. One advantage of the method of the present invention is that azithromycin does not need to be purified to a single crystalline form prior to use in the method of the present invention.

  Amorphous azithromycin is produced by solvent treatment using a solvent. A suitable solvent for solvent treatment is any solvent in which azithromycin is soluble. It is preferred that the azithromycin has a solvent solubility of at least 1% by weight, more preferably at least 5% by weight. The solvent is also volatile and preferably has a boiling point of 150 ° C. or lower. In addition, the solvent should be relatively toxic and should be removed from amorphous azithromycin to an acceptable level in accordance with the guidelines of the Harmonized International Conference (ICH). Removal of the solvent to that level may require subsequent processing steps such as tray drying. Preferred solvents include water; methanol, ethanol, n-propanol, isopropanol, alcohols such as butanol of various isomers; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; methyl acetate, ethyl acetate, propyl acetate, etc. Esters; ethers such as dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxolane, 1,4-dioxane; alkanes such as butane and pentane; alkenes such as pentene and cyclohexene; nitriles such as acetonitrile; methylene chloride, trichloroethane, chloroform, Alkyl halides such as trichlorethylene; aromatic compounds such as toluene; and mixtures thereof. Less volatile solvents such as dimethylacetamide, dimethylformamide, or dimethylsulfoxide may be used in small amounts in the mixture with the volatile solvent. A solvent mixture such as 50% methanol and 50% acetone can be used, as well as a mixture with water. Preferred solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, n-propanol, isopropanol, methyl acetate, ethyl acetate, toluene, methylene chloride, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, and these A mixture of Most preferred solvents include acetone, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, and mixtures thereof. Mixtures of the above and water may be used.

  Amorphous azithromycin is produced by (a) producing a solution containing azithromycin dissolved in a solvent, (b) atomizing the solution, and (c) rapidly evaporating the solvent. The solution can be generated by dissolving azithromycin in a solvent using techniques known in the art. This is generally accomplished by adding solid azithromycin to the solvent and then mixing. Mixing can generally be performed using mechanical means such as an overhead mixer, magnetically driven mixer and stirrer, planetary mixer, homogenizer and the like. The solution may be formed at ambient temperature or the solvent may be heated to help dissolve azithromycin. It is preferred that essentially all azithromycin in the solution is dissolved in the solvent.

  Azithromycin may be dissolved in the spray solution to the limit of solubility, but the amount dissolved is usually less than 80% of the solubility of azithromycin in the solution at the solution temperature prior to atomization. The concentration of azithromycin can range from 0.1% to 30% by weight, depending on the solubility of the drug and polymer in the solvent. The concentration of azithromycin in the solution is preferably at least about 0.1 wt%, more preferably at least about 0.5 wt%, even more preferably at least about 1 wt%, and most preferably at least about 5 wt%. It is preferred that the solution contains a high concentration of azithromycin because the volume of solvent that must be evaporated to produce amorphous azithromycin is reduced. However, the concentration of azithromycin must not be too high, or else the spray solution may become too viscous to be efficiently atomized into small droplets. The viscosity of the spray solution ranges from about 0.5 to about 50,000 cp, more typically 10 to 2000 cp.

  The spray solution may contain optional excipients in addition to the solvent as long as the azithromycin remains sufficiently soluble in the spray solution. Optional excipients are those that can be dissolved in the spray solution, suspended in the spray solution, or dissolved or suspended in any mixture thereof.

  In one embodiment, the solution contains an alkalinizing agent. The addition of an alkalizing agent to the solution may promote the chemical stability of amorphous azithromycin during processing and / or in the final product. Alkalizing agents include, for example, other pharmaceutically acceptable (1) organic and inorganic bases, (2) salts of organic and inorganic weak acids, and (3) buffers in addition to antacids. .

  Examples of such alkalizing agents include: aluminum salts such as magnesium aluminum silicate; magnesium salts such as magnesium carbonate, magnesium trisilicate, magnesium aluminum silicate, magnesium stearate; calcium salts such as calcium carbonate; Bicarbonates such as calcium and sodium bicarbonate; primary calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium phosphate, tribasic potassium phosphate, etc. Metal hydroxides such as phosphates; aluminum hydroxide, sodium hydroxide, potassium hydroxide, and magnesium hydroxide; metal oxides such as magnesium oxide; N-methylglucosamine; arginine and its salts; monoethanolamine, die Noruamin, triethanolamine, and tris amine such as (hydroxymethyl) aminomethane (TRIS); as well as mixtures thereof shall not apply.

  In another embodiment, the solution contains a substrate forming material. The substrate-forming material may stabilize amorphous azithromycin, help prevent or delay the formation of crystalline azithromycin, or improve the properties of amorphous azithromycin for processing into a dosage form But you can. The substrate forming material may be a polymer or non-polymer, and may include a mixture of several components. That is, the substrate-forming material may include a mixture of polymer components, a mixture of non-polymer components, or a mixture of polymer and non-polymer components.

  The term “polymer” means a compound made of monomers that are used in the usual manner and that are joined together to form larger molecules. The polymer component generally consists of at least about 20 monomers. Thus, the molecular weight of the polymer component is generally about 2000 Daltons or greater. The polymer component may be neutral or ionizable and may be cellulosic or non-cellulosic. In general, useful polymers have a water solubility of at least about 0.1 mg / mL. Examples of neutral non-cellulosic polymers include vinyl polymers and copolymers, ie, polyvinyl alcohol, polyvinyl alcohol / polyvinyl acetate copolymer, polyethylene glycol / polypropylene glycol copolymer, polyvinyl pyrrolidone, polyethylene / polyvinyl alcohol copolymer, and (as poloxamers) (Also known) polyoxyethylene / polyoxypropylene block copolymers. Examples of ionizable non-cellulosic polymers include polymethacrylic acid functionalized with carboxylic acid and polyacrylic acid functionalized with carboxylic acid, polyacrylic acid functionalized with amine and Polymethacrylic acid, proteins such as gelatin and albumin, and starch functionalized with carboxylic acids such as starch glycolate are included. Examples of neutral cellulosic polymers are hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylmethylcellulose, and hydroxyethylethylcellulose. Examples of cellulosic polymers that can be ionized include hydroxypropylmethylcellulose succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), carboxyethylcellulose, carboxymethylcellulose, cellulose acetate phthalate (CAP), Hydroxypropyl methylcellulose phthalate acetate and cellulose acetate trimellitate.

  "Non-polymer" means a non-polymeric component. Exemplary non-polymeric materials for use as substrate forming materials include organic acids and salts thereof such as stearic acid, citric acid, fumaric acid, tartaric acid, malic acid, and pharmaceutically acceptable salts thereof; glyceryl monooleate Long chain fatty acid esters such as glyceryl monostearate, glyceryl palmitostearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl dibehenate, mixtures of mono, di and trialkyl glycerides; polyethylene glycol stearate And glycolated fatty acid esters such as polyethylene glycol distearate; polysorbates; sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, etc. Amino acids such as alanine and glycine; sugars such as glucose, sucrose, xylitol, fructose, lactose, trehalose, mannitol, sorbitol, maltitol; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; phospholipids such as lecithin; These mixtures are included.

  Once a solution containing azithromycin and solvent is produced, it is delivered to an atomizer that breaks the solution into small droplets. In general, atomization consists of (1) a “pressure” nozzle or a one-fluid nozzle, (2) a two-fluid nozzle, (3) a centrifugal or rotating disk atomizer, (4) an ultrasonic nozzle, and (5) mechanical vibration. This is done in one of several ways, including by a nozzle. A detailed description of the atomization method can be found in Lefebvre's "Atomization and Sprays" (1989) or "Perry's Chemical Engineers' Handbook" (7th edition, 1997). In general, the droplets produced by the atomizer should be less than about 500 μm in diameter when exiting the atomizer. Examples of nozzle types that can be used to generate droplets include two-fluid nozzles, fountain nozzles, flat fan nozzles, pressure nozzles, and rotary atomizers. In one embodiment, a pressure nozzle is used.

  Once atomized, at least a portion of the solvent is removed from the solution to produce a plurality of solid particles comprising amorphous azithromycin. As used herein, removing “at least a portion” of a solvent from a solution means removing a sufficient amount of solvent from the solution to produce a solid material. The amount of solvent removed for solid material production depends on the solubility of azithromycin in the solvent, as well as the concentration of azithromycin in the solution and any optional excipients. Generally, at least about 60% by weight of the solvent originally present in the solution is removed to produce a solid material. The more solvent removed from the solution, the less crystalline azithromycin is produced. Thus, the amount of solvent removed from the solution to produce amorphous azithromycin can be at least 70 wt%, at least 80 wt%, or even at least 90 wt%.

  It is also preferred to remove the solvent rapidly from the solution to produce amorphous azithromycin. The terms “rapidly remove” and “rapidly remove” refer to removing a solvent from a solution sufficiently rapidly so that at least 90% by weight of the solvent originally present in the solution is removed within 5 minutes. means. It is believed that rapid removal of the solvent results in a product with a higher proportion of amorphous drug than methods that slowly remove the solvent. Thus, 90% by weight of the solvent may be removed within 5 minutes, 1 minute, or even 20 seconds.

  A spray drying process can also be used to produce amorphous azithromycin. Azithromycin is dissolved in a solvent and then sprayed into a spray dryer where the solvent is rapidly removed to produce amorphous azithromycin solid particles. The term “spray-drying” is used as usual, diverting the liquid mixture into small droplets (atomization), and rapidly removing the solvent from the mixture in a propulsive spray-drying device that evaporates the solvent from the droplets. Broadly refers to the method that is to. Spray drying methods and spray drying equipment are generally described in "Perry's Chemical Engineers' Handbook", pages 20-54 to 20-57 (6th edition, 1984). For further details on spray drying methods and equipment, see Marshall, “Atomization and Spray-Drying”, 50 Chem. Eng. Prog. Monogr. Reviews in Series 2 (1954), and Masters, “Spray Drying Handbook” (4th edition, 1985). A strong driving force for solvent removal is generally obtained by keeping the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperature of the droplets during the drying process. This can be (1) keeping the pressure in the spray dryer at a partially reduced pressure (eg, 0.01-0.50 atm) or (2) mixing the liquid droplets with the warm drying gas. Or (3) realized by both (1) and (2). Furthermore, at least part of the heat required for the evaporation of the solvent can be obtained by heating the spray solution.

  The feed containing the solvent can be spray dried under a wide variety of conditions, still resulting in amorphous azithromycin. For example, various types of nozzles are used to atomize the spray solution, thereby introducing the spray solution into the spray drying chamber as a collection of small droplets. Essentially any type of nozzle as long as the droplets produced are small enough to stick to the walls of the spray drying chamber or dry sufficiently so that they do not coat (by evaporation of the solvent) May be used to spray the solution.

  The solution can be delivered to one or more spray nozzles at a wide range of temperatures and flow rates. In general, the temperature of the solution may generally range from slightly above the freezing point of the solvent to a temperature about 20 ° C. above its ambient pressure boiling point (by pressurizing the solution), and possibly even higher. The flow rate of the solution to the spray nozzle may vary over a wide range depending on the type of nozzle, the size of the spray dryer, and the spray drying conditions such as the inlet temperature and the flow rate of the drying gas. In general, the energy for evaporating the solvent from the solution in the spray drying process comes mainly from the drying gas.

  The drying gas can in principle be essentially any gas, but for safety reasons and to minimize unwanted oxidation of azithromycin, nitrogen, nitrogen-rich air, argon, etc. It is preferable to use an active gas. The drying gas is usually introduced into the drying chamber at a temperature of about 60 ° C to about 300 ° C, preferably about 80 ° C to about 240 ° C.

  When the surface area to volume ratio of the droplet is large and the driving force for solvent evaporation is large, the solidification time of the droplet is increased. The clotting time should be less than about 20 seconds, preferably less than about 10 seconds, more preferably less than 1 second. This rapid solidification is often essential for particles that maintain a uniform and homogeneous amorphous material as opposed to a material containing crystalline and amorphous azithromycin. In a preferred embodiment, as described in detail in US Pat. No. 6,766,607, the height and volume of the spray dryer is sufficient to dry before the droplets impinge on the inner surface of the spray dryer. Adjust to get time.

  After solidification, the resulting amorphous azithromycin solid powder typically stays in the spray-drying chamber for about 5-60 seconds, further evaporating the solvent from the solid powder. The final residual solvent level of amorphous azithromycin as it exits the dryer should be low. Generally, the solvent level of amorphous azithromycin as it exits the spray drying chamber should be less than 10 wt%, preferably less than 2 wt%. After production, the amorphous azithromycin is subjected to suitable drying methods such as tray drying, fluid bed drying, microwave drying, belt drying, rotary drying, vacuum drying, and other drying methods known in the art. It can be used and dried to remove the remaining solvent. The final residual solvent level after drying is preferably less than about 1% by weight, more preferably less than about 0.1% by weight.

  The resulting spray-dried amorphous azithromycin is usually in the form of small particles. The volume average diameter of the particles may be less than about 500 μm in diameter, or less than about 200 μm in diameter, or less than about 100 μm in diameter, or less than about 50 μm in diameter, or less than about 25 μm in diameter.

  Another useful parameter is

で定められる「スパン」であり、式中、Ｄ_５０は、直径が等しいまたは小さい方の粒子の総体積の５０％を占める粒子の直径に相当する直径であり、Ｄ_９０は、直径が等しいまたは小さい方の粒子の総体積の９０％を占める粒子の直径に相当する直径であり、Ｄ_１０は、直径が等しいまたは小さい方の粒子の総体積の１０％を占める粒子の直径に相当する直径である。時に当業界ではＲｅｌａｔｉｖｅ Ｓｐａｎ ＦａｃｔｏｒまたはＲＳＦと呼ばれるスパンは、粒径分布の均一性の指標である無次元パラメータである。一般に、スパンが小さいほど、またサイズ分布が狭いほど、改善された流動特性がもたらされる。本方法によって生成される粒子のスパンは、約３未満であることが好ましく、より好ましくは約２．５未満、最も好ましくは約２．０未満である。非晶質アジスロマイシン粒子の大きさは、ふるい分析、顕微鏡観察、光散乱、沈降などの方法を含む、当業界でよく知られている方法を使用して測定することができる。そのような機器の例には、Ｃｏｕｌｔｅｒ ＣｏｕｎｔｅｒおよびＭａｌｖｅｒｎ Ｐａｒｔｉｃｌｅ Ｓｉｚｅ Ａｎａｌｙｚｅｒが含まれる。たとえば、「Ｒｅｍｉｎｇｔｏｎ：Ｔｈｅ Ｓｃｉｅｎｃｅ ａｎｄ Ｐｒａｃｔｉｃｅ ｏｆ Ｐｈａｒｍａｃｙ」、第２０版（２０００年）を参照されたい。

Where D ₅₀ is the diameter corresponding to the diameter of a particle that occupies 50% of the total volume of equal or smaller diameter particles, and D ₉₀ is equal in diameter or a diameter corresponding to the diameter of particles which account for 90 percent of the total volume of the smaller particles, D ₁₀ is the diameter corresponding to the diameter of particles that make up 10% of the total volume of the person of the particles or less equal to the diameter is there. The span, sometimes referred to in the art as the Relative Span Factor or RSF, is a dimensionless parameter that is an indicator of the uniformity of the particle size distribution. In general, smaller spans and narrower size distributions result in improved flow characteristics. The span of particles produced by the present method is preferably less than about 3, more preferably less than about 2.5, and most preferably less than about 2.0. The size of the amorphous azithromycin particles can be measured using methods well known in the art, including methods such as sieve analysis, microscopy, light scattering, sedimentation and the like. Examples of such devices include the Coulter Counter and the Malvern Particle Size Analyzer. See, for example, “Remington: The Science and Practice of Pharmacy”, 20th edition (2000).

  Amorphous azithromycin can also be produced by spray coating. The term “spray coating” is used as usual and refers to coating the core with amorphous azithromycin or layering. In this method, azithromycin is dissolved in a solvent as described above. The solution is then atomized into droplets that are sprayed onto the core. Solvent is removed from the droplets on the wick, producing one or more amorphous azithromycin solid layers on the wick.

  The core may be pharmaceutically inert. The core may be a solid particle or object that does not collapse in the associated body fluid. Alternatively, the core may include a disintegrant that rapidly disintegrates the layered particles in the associated body fluid. The core shall have a layer of predominantly amorphous azithromycin. Examples of core materials are non-pareil seeds, sugar beads, wax beads, glass beads, lactose, microcrystalline cellulose, polymer beads, starch, colloidal silica and the like. The core may be produced by any known method such as melting or spray congealing, extrusion / spheronization, granulation, spray drying. Alternatively, the core may be in a dosage form such as a tablet, pill, multiparticulate or capsule. The dosage form may contain azithromycin or a different drug, and may provide immediate or controlled release. Spray coating amorphous azithromycin into a dosage form can be useful in combination therapy with azithromycin and another drug.

  The core may have any shape, size and size distribution suitable for the production of the desired layered particles. In one embodiment, the core is generally spherical and has a smooth surface. In another embodiment, the core ranges in size from about 1 μm to about 3000 μm, preferably from about 10 μm to about 1000 μm, more preferably from about 50 μm to about 500 μm. In order to obtain a consistent end product, it is generally desirable to use a core with a narrow size distribution. The core may be an agglomerate, granule or particle layered in one or more layers according to the present invention. Agglomerates and granules can be produced by any method conventionally used in the art, such as extrusion spheronization, rotary granulation, melt congealing, spray drying, vacuum drying, or spray granulation.

  A pan coater (eg, a high coater available from Freund Sangyo Co., Ltd., Accela-Cota available from Manesty, Liverpool, UK), which may optionally be layered one or more times with amorphous azithromycin. , Fluidized bed coaters (eg Wurster coater or top spray equipment available from Niro Pharma Systems of Ramtair Technologies, Ramsey, NJ and Bubendorf, Switzerland), rotary granulators (eg, obtained from Freund Sangyo Co., Ltd.) The atomized solution containing azithromycin is sprayed using coating equipment known in the pharmaceutical industry, such as possible CF-granulators. The spraying process can be performed with two or three fluid nozzles while the core is suspended in the gas. Alternatively, other nozzle types such as pressure nozzles may be used. The nozzles can be placed on the top, sidewalls, or bottom of the spray processing chamber, and the chamber can be provided with a plurality of nozzles.

  The core particles may be suspended in the gas in any convenient manner. The core particles can be conveyed upward from the bottom of the spray treatment chamber by a suitable gas flow. The core particles suspended in the gas are then hit by one or more small droplets ejected from the nozzle. In one embodiment, the spray solution is directed in the same direction as the suspended gas.

  After spraying, the solvent applied on the core particles is removed to obtain an amorphous azithromycin deposit or layer on the core. It is preferred that the chamber in which the coating is performed is also used for removing the solvent. In one embodiment, a gas that floats the wick may be used to move the wick from the spray treatment zone to an evaporation zone for drying the stratified wick.

  The gas that floats the core may be a drying gas. During the upward movement through the chamber and after the spraying process, the solvent is rapidly evaporated. Sufficient solvent is removed to prevent particles from sticking to each other after leaving the chamber.

  The solvent may be evaporated sufficiently and immediately or after storage, the particles may be subjected to a new spray and evaporation process. Processing of the stratified particles continues until a predetermined particle size or weight is obtained. Determination of the desired particle size or weight can be made according to known classification procedures. Alternatively, a predetermined amount of solution is sprayed onto a predetermined amount of core to produce particles having a desired particle size or weight, or a desired amount of azithromycin per core mass.

  The coated core preferably has a final size of less than about 3 mm, preferably less than about 2 mm, more preferably less than about 1 mm. It is preferred that the coated core has a span of less than about 3, more preferably less than about 2.5, and most preferably less than about 2.0.

  Amorphous azithromycin spray-coated cores have the added advantage of providing large, dense particles that are harder to separate than pure amorphous materials during manufacture. In addition, such coated cores have a round surface and a narrow size distribution, which improves flow characteristics and facilitates handling.

  Once amorphous azithromycin has been produced, some can be used to facilitate incorporation of amorphous azithromycin into dosage forms such as tablets, capsules, suspensions, powders for suspensions, creams, transdermal patches, depots, etc. Some processing work can be used. These processing operations include drying, granulation, and grinding.

  The present invention is also a method for treating a bacterial or protozoal infection in a mammal, fish or bird, comprising administering to said mammal, fish or bird a therapeutically effective amount of the amorphous azithromycin of the present invention. Relates to a method comprising:

  The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of an amorphous azithromycin of the present invention and a pharmaceutically acceptable excipient for treating a bacterial or protozoal infection in a mammal, fish or bird. About.

  The term “treatment”, as used herein, unless otherwise indicated, means the treatment or prevention of a bacterial or protozoal infection provided in the methods of the invention, which cures the infection and treats its symptoms. Including mitigating or slowing its progression. The terms “treat” and “treating” are defined in conjunction with the aforementioned term “treatment”.

  As used herein, unless otherwise indicated, the term “bacterial infection” or “protozoal infection” refers to bacterial and protozoal infections that occur in mammals, fish, and birds, as well as the amorphous azithromycin of the present invention. Includes disorders associated with bacterial and protozoal infections that can be treated or prevented by administration of antibiotics. Such bacterial and protozoal infections, and disorders associated with such infections include: Pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastitis associated with infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus species; Streptococcus pyogenes, C Pharyngitis, rheumatic fever, and glomerulonephritis associated with infection by group G and group G streptococci, Clostridium dipthelia, or Actinobacillus haemolyticum; pneumonia mycoplasma, Legionella pneumophila, Respiratory tract infections; Staphylococcus aureus, coagulase positive staphylococci (ie, Staphylococcus epidermidis, S. hemolyticus, etc.) Streptococcus agalactiae, Streptococcus C to F group (microcolon streptococci), Viridans streptococci, Corynebacterium minutisium, Clostridium spp., Or non-competent skin and soft tissue associated with infection by Bartonella henselae Symptom, abscess and osteomyelitis, and postpartum fever; uncomplicated acute urinary tract infection associated with infection by Staphylococcus saprophyticus or Enterococcus spp .; Trachomacrumia, flexible gonococci, syphilis treponema, Ureaplasma ureallyticum, or infection associated with Neisseria gonorrhoeae Urethritis and cervicitis, and sexually transmitted diseases; Staphylococcus aureus (food poisoning and toxicosis) Toxic disease associated with infection with A, B, and C streptococci; ulcer associated with infection with Helicobacter pylori; systemic febrile syndrome associated with recurrent fever Borrelia; infection with Lyme disease Borrelia Associated Lyme disease; Conjunctivitis, keratitis, and lacrimal inflammation associated with infection with Trachoma chlamydia, Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, or Listeria species; Infection with M. tuberculosis or Mycobacterium intracellulare Multiple avian Mycobacterium tuberculosis complex (MAC) disease associated with gastroenteritis associated with infection with Campylobacter jejuni; intestinal protozoa associated with infection with Cryptosporidium species; odontogenicity associated with infection with Streptococcus viridans Infectious diseases; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by para Clostridium perfringens or Bacteroides species; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial and protozoal infections that can be treated or prevented in animals, and disorders associated with such infections include the following. P. haem. , P.M. Bovine respiratory disease associated with infection by M. mutocida, Mycoplasma bovis, or Bordetella species; cow intestinal disease associated with infection by E. coli or protozoa (ie, coccidium, Cryptosporidium, etc.); Staphylococcus aureus, Strep. uberis, Strep. agalactiae, Strep. dairy cow mastitis associated with infection by dysgalactiae, Klebsiella species, Corynebacterium or Enterococcus species; pleuro. , P.M. Porcine respiratory disease associated with infection with Multocida or Mycoplasma species; porcine enteric disease associated with infection with E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cow hooves associated with infection with Fusobacterium species; Uteritis in cows associated with infection by cows; Hairy warts associated with infection by cows with Fusobacterium necrophorum or Bacteroides nodosus; Pink eye in cows associated with infection with Moraxella bovis; for infection with protozoa (ie neosporium) Related cow early placenta exfoliation; dog and cat urinary tract infection associated with infection by E. coli; S taph. epidermidis, Staph. intermedius, coagulase negative Staph. multicida, or P.I. canine and feline skin and soft tissue infections associated with infection with multocida; and dogs associated with infection with alkaline genus, bacteroid, clostridial, enterobacter, eubacteria, peptostreptococcus, porphyromonas, or prebotella And cat tooth or mouth infections. Other bacterial and protozoal infections that can be treated or prevented in accordance with the methods of the present invention, and disorders associated with such infections are described in P. Sanford et al., “The Sanford Guide To Antimicrobial Therapy”, 26th Edition, (Antimicrobial Therapy, Inc., 1996).

  Other features and embodiments of the present invention will become apparent from the following examples which are given to illustrate the invention rather than to limit the intended scope of the invention.

Example 1
Amorphous azithromycin was prepared using a solvent method using the following procedure. A spray solution was made by dissolving 125 gm azithromycin dihydrate in 1125 gm acetone to produce a 10 wt% azithromycin solution in acetone. Using a high-pressure pump (Bran Lubebe N-P31), a spray dryer (Litro-DrPyrPrPrP with a Liquid-Feed Process Vessel) equipped with a pressure atomizer (Spraying Systems Pressure Nozzle and Body (SK80-16)) The spray solution was fed into PSD-1]). PSD-1 was equipped with a 9-inch chamber extension. The spray dryer was also equipped with a diffuser plate with 1% open area. During operation, the nozzle was in contact with the diffusion plate. The atomizing pressure was about 125 psig (9.5 atm) and the spray solution was fed to the spray dryer at about 78 gm / min. Drying gas (nitrogen) was delivered to the diffusion plate at an inlet temperature of about 100 ° C. The evaporated solvent and wet drying gas exited the spray dryer at a temperature of about 58 ° C. The resulting amorphous azithromycin was then stored until use in a room temperature vacuum desiccator.

Samples of azithromycin before spray drying (crystalline dihydrate) and azithromycin after spray drying (amorphous azithromycin) were analyzed by powder X-ray diffraction (PXRD) analysis using a Bruker AXS D8 Advance diffractometer. A Lucite sample cup fitted with a Si (511) plate as the lower part of the cup so that no background signal is emitted is filled with a sample of azithromycin (about 100 mg) before and after spray drying, and the surface of the sample using a glass microscope slide And a consistently smooth sample surface of the same height as the top of the sample cup was prepared. The sample was rotated in the φ plane at a speed of 30 rpm to minimize crystal orientation effects. The X-ray source (KCu _α , λ = 1.54Å) was operated with a voltage of 45 kV and a current of 40 mA. The data for each sample was obtained in a continuous detector scan mode with a scan speed of about 1.2-1.8 seconds / step, a step size of 0.02 ° to 0.04 ° per step, and about 20 Collected over ~ 60 minutes. Diffractograms were collected over the 2θ range of 4 ° to 40 °.

  The result of this analysis before spray drying is shown in FIG. This diffractogram shows the characteristic peak of the crystalline dihydrate form of azithromycin.

  FIG. 2 shows the diffractogram of spray-dried azithromycin of Example 1. This figure shows an amorphous halo, and no crystal peaks have been detected within the accuracy of this analysis. These data indicate that the azithromycin produced by the spray drying method of Example 1 was almost completely amorphous.

(Example 2)
The chemical stability of the amorphous azithromycin of Example 1 after storage for 1 and 3 weeks in an uncovered petri dish was investigated under the different conditions listed in Table 1. Stability samples were tested by powder X-ray diffraction and reverse phase high performance liquid chromatography (RP-HPLC). RP-HPLC analysis was performed using an Agilent HP1100 system with an electrochemical detector, and ES Industries Alumina γRP-1 guard column and ES Industries Alumina γRP-1 analytical column. The column temperature was ambient and the flow rate was 0.6 ml / min. An isocratic method using a mobile phase (pH = 10.7) consisting of 77% 0.02M KH ₂ PO ₄ /23% acetonitrile was used.

To perform the RP-HPLC test, the powder sample was dissolved in 5 mL acetonitrile and 95 mL 77% 0.02 M KH ₂ PO ₄ /23% acetonitrile (pH = 8.0) and the solution was injected onto the HPLC column. . The peaks were integrated to determine the extent of decomposition. Table 1 shows the content of the main decomposition products. The degradation product showed increased levels at 70 ° C./30% RH and 70 ° C./75% RH after 3 weeks, but no increase was observed at other storage conditions. Furthermore, the sample remained amorphous under all conditions except 70 ° C./75% RH. These data indicate that the spray-dried amorphous azithromycin is stable at temperatures below about 70 ° C.

(Example 3)
To further test the physical stability of amorphous azithromycin prepared using the method of Example 1, samples were stored at 40 ° C. and 75% RH for 5 months, then removed and subjected to Example 1 by PXRD. It was analyzed as follows. The results of this analysis shown in FIG. 3 indicate that azithromycin was essentially all amorphous after storage for 5 months under these conditions.

(Example 4)
A sample of amorphous azithromycin produced by spray drying was analyzed by scanning electron microscopy (SEM). 4A shows an SEM image of the amorphous material at a magnification of 1000 times, and FIG. 4B shows an SEM image of the amorphous material at a magnification of 6500 times. These images show that the spray-dried amorphous particles produced by this spray-drying method tend to be spherical, generally crushed. Because of this shape, amorphous azithromycin produced by spray drying has improved properties compared to crystalline azithromycin, and amorphous particles have sufficient flow properties and are less brittle.

  For comparison, FIG. 5 shows SEM images of crystalline azithromycin dihydrate being jet milled at 1000 × (FIG. 5A) and 6500 × (FIG. 5B) magnification. These images show that the crystalline material has an irregular shape with many straight edges indicating that it is a crystalline material.

(Example 5)
Amorphous azithromycin is prepared by the following procedure. A solution consisting of about 2000 mg of azithromycin in a volatile solvent such as acetone and about 250 mg of the alkalizing agent trisodium phosphate (TSP) is produced. This solution is then spray dried using the method described in Example 1 to produce amorphous azithromycin.

  The terms and expressions used in the foregoing specification are used therein as descriptive terms rather than limiting terms, and the use of such terms and expressions may include equivalents or characteristics thereof having the characteristics shown and described. It is not intended to be excluded in part, and the scope of the present invention will be defined and limited only by the appended claims.

2 is a PXRD diffractogram of azithromycin dihydrate used to produce the spray solution of Example 1. FIG. 2 is a PXRD diffractogram of amorphous azithromycin produced by the spray drying method of Example 1. FIG. FIG. 5 is a PXRD diffractogram of amorphous azithromycin after storage for 5 months at 40 ° C. and 75% relative humidity (RH). It is a scanning electron microscope (SEM) image of the amorphous azithromycin produced | generated by the spray-drying method. 1 is a scanning electron microscope (SEM) image of jet milled crystalline azithromycin dihydrate.

Claims (12)

(A) producing a solution comprising azithromycin and a solvent;
(B) atomizing the solution into droplets;
(C) evaporating at least a portion of the solvent from the solution to produce amorphous azithromycin; and a method for producing amorphous azithromycin.   The method of claim 1, wherein at least 70% by weight of the solvent is evaporated from the solution.   The method of claim 2, wherein at least 90% by weight of the solvent is evaporated from the solution.   The method of claim 1, wherein at least 90% by weight of the solvent is evaporated from the solution within 5 minutes.   The method of claim 1, wherein at least 90% by weight of the solvent is evaporated from the solution within 1 minute.   The solvent is selected from the group consisting of water, alcohol, ketone, ester, alkane, alkene, alkyl halide, nitrile, aromatic compound, acetone, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, and mixtures thereof. The method of claim 1, wherein:   The method of claim 1, wherein the solvent is evaporated by spray drying.   The method of claim 1, wherein the solvent is evaporated by spray coating the solution onto a core.   9. The method of claim 8, wherein the core is selected from the group consisting of non-pareil seeds, sugar beads, wax beads, glass beads, lactose, microcrystalline cellulose, polymer beads, starch, and colloidal silica.   The method of claim 1, wherein the amorphous azithromycin is in the form of particles having a volume average diameter of less than about 200 μm.   The product of the process according to any one of claims 1 to 10. A method for treating a bacterial or protozoal infection in a mammal, fish or bird, wherein the mammal, fish or bird has a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 10. A method comprising administering.

Images