MXPA06006264A - Spray-congeal process using an extruder for preparing multiparticulate crystalline drug compositions containing preferably a poloxamer and a glyceride - Google Patents

Abstract

Reduced levels of drug degradation in drug-containing multiparticulates are obtained by an extrusion/melt-congeal process.

Description

SPRAYING PROCEDURE-GELIFlCATION USING AN EXTRUDER TO PREPARE DRUG COMPOSITIONS MULTIPARTICULATED CRYSTALS THAT CONTAIN PREFERABLY A POLOXAMER AND A GLYCERID BACKGROUND OF THE INVENTION Multiparticulates are well-known dosage forms comprising a multiplicity of particles whose totality represents the desired dose of a therapeutically useful drug. When taken orally, multiparticulates generally disperse freely in the gastrointestinal tract, maximize absorption, and minimize side effects. See, for example, Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989). A typical multiparticulate formulation consists of a drug distributed substantially uniformly in a vehicle. A conventional method for producing such multiparticulates is to add the drug and the vehicle to a heated tank to produce a molten mixture that is atomized into droplets and the droplets gel to form the multiparticulates. This method is capable of forming small, round, regular multiparticulates in which the drug is encapsulated in the vehicle. However, conventional pharmaceutical manufacturing processes typically require an average residence time of the drug in the molten mixture of several hours or more for the economical production of the multiparticulates. For some drugs, such long average residence times can lead to rapid degradation of the drug or undesirable reactions of the drug with the vehicle. Because of this, conventional pharmaceutical melting-gelling procedures are not considered useful for preparing multiparticulates of labile drugs. It is also known to form multiparticulates using other methods which do not form a molten mixture, such as extrusion sphering or wet granulation. However, such procedures often result in multiparticulates in which the drug is not completely encapsulated in the vehicle. In addition, such procedures can result in multiparticulates having irregular or rough outer surfaces. Such multiparticulates may have poor flow properties and be difficult to coat. In addition, irregular or rough multiparticulates present a gritty feeling in the mouth. U.S. Patent Nos. 6,261, 599 and 6,335,033 describe a controlled release dosage form comprising an opioid analgesic and a vehicle. The analgesic and the vehicle are mixed and then heated to a temperature high enough to extrude the mixture into a strand having a diameter of 0.1 to 3 mm. The strand cools and then divides to form multiparticulates. There is no discussion of the use of an atomizer to form multiparticulates from the extrusion product, nor is there recognition of improved chemical stability obtained by using an extruder to form the molten mixture. U.S. Patent No. 6,248,363 discloses a spraying-gelling process for forming drug-containing powders that flow freely from molten materials. The drug is allowed to melt, disperse or dissolve in a hot melt of a vehicle and is then atomized into an air chamber where the temperature is below the melting point of the components, thus providing gelled spherical pellets. The procedure is established to be suitable for heat-labile substances since the ambient temperature is used to dry the pellets. However, there is no discussion of the use of an extruder to produce a molten mixture that will be atomized, nor is there a need to minimize the average residence of the drug in the molten mixture to improve chemical stability. U.S. Patent No. 5No. 824,342 discloses surfactant aggregates adsorbed to surfaces consisting of a solid suspension of a non-greasy solid substrate having an active ingredient associated therewith, the non-greasy substrate and the active ingredient being dispersed non-uniformly in a fatty solid carrier. Surfactant aggregates adsorbed to surfaces can be manufactured by an "instantaneous shear" method in which the temperature of a supply material is increased to a point where the vehicle undergoes intraparticle flow. The ultra-fast shear procedure is established to be a "cold flow" procedure that has no residence times in the vehicle and thus avoids the problems associated with a thermal history caused by long residence times. U.S. Patent No. 6,139,872 discloses an extrusion process for producing a nutritional supplement powder consisting of forming a supply material in a plastic mass that is not completely melted, then molding, cooling and crushing the plastic mass to obtain the dust U.S. Patent No. 5,100,592 describes a process for forming particles from a pulverized material wherein the pulverized material is discharged onto a heated rotary disperser. A part of the powder material is melted in the rotary disperser, coating unmelted particles, which are then discharged as larger particles from the periphery of the rotary disperser. U.S. Patent No. 4,086,346 describes a method for melting-spraying the thermally sensitive drug phenacetin alone by means of a multi-spindle extruder having extremely narrow clearances between the spindle shafts and between the spindles and the housing, the extruder melts the drug, administers the molten drug to an atomizer and cools and solidifies the molten-sprayed drug. U.S. Patent No. 5,766,521- describes a process for melting-gelling the crystallized beads of the glyceryl guaiacolate drug, through which the drug is melted, atomized, then cooled below the glass transition temperature of the drug. to form beads, placing the beads thus formed in contact with crystallization seeds and then crystallizing the beads by heat. The United States patent application published No. 2001/0006650 discloses small beads of solid drug solution, a fatty acid or ester and a surface active agent formed by spraying-gelling, which consists of mixing drug particles in the fatty acid or molten ester, then spraying the resulting sample into a tower of spray-gelling that has cold air flowing through the tower to solidify the small beads. However, there is no discussion of the use of an extruder to form a molten drug / vehicle mixture, nor does it suggest a solution to the problem of degradation of labile drugs used in the process. There is therefore a need in the art for an efficient melting-gelling process to form multiparticulates containing labile drugs in which the degradation of the drug is maintained at an acceptably low level during the process, and which results in multiparticulates that they are regular, round, and in which the drug is substantially encapsulated in the vehicle.

BRIEF DESCRIPTION OF THE INVENTION The inventors have discovered that the drawbacks of the prior art melting-gelling processes can be overcome by the use of an extruder in combination with an atomizer, such as a rotating disk atomizer. In this process, a molten mixture, comprising a labile drug and a carrier is formed using an extruder, such as a twin screw extruder. The molten mixture is directed to an atomizer to produce droplets of the molten supply. The droplets gel to form multiparticulates. This procedure has the advantage of reducing the drug degradation of the labile drugs while at the same time forming multiparticulates that have good physical characteristics. The use of an extruder to form the molten mixture reduces the amount of time during which the drug is exposed to high temperatures with respect to the conventional method using a heated reservoir. However, by administering a molten mixture to an atomizer, the process is capable of forming small, round, regular multiparticulates in which the drug is substantially encapsulated in the vehicle. The multiparticulates formed by the process of the present invention can be for immediate, sustained, delayed or controlled drug release after their introduction into an environment of use. As used herein, an "environment of use" may be either the in vivo environment of the gastrointestinal tract of an animal such as a mammal or human, or the in vitro environment of a test solution. Exemplary test solutions include aqueous solutions at 37 ° C comprising (1) 0.1 N HCl, simulating gastric juice without enzymes; (2) HCl 0.01 N, simulating the gastric juice that prevents the excessive acid degradation of azithromycin, and (3) 50 mM KH2PO4, adjusted to pH 6.8 using KOH or 50 mM Na3P04, adjusted to pH 6.8 using NaOH, both simulate intestinal fluid without enzymes. The inventors have also found that some formulations, an in vitro test solution comprising 100 mM Na2HPO4, adjusted to pH 6.0 using NaOH provides a discriminating means for differentiating between different formulations based on a dissolution profile. It has been determined that in vitro dissolution tests in such solutions provide a good indicator of in vivo performance and bioavailability. Additional details of in vitro tests and test solutions are described in this document. The detailed guidelines on selection of processing conditions, vehicles and interrelationships are explained below in the Detailed Description of the Preferred Modalities.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The compositions formed by the process of the present invention comprise a plurality of "multiparticulates" containing drug. The term "multiparticulate" is intended to encompass a dosage form comprising a multiplicity of particles whose totality represents the therapeutically useful desired dose of the drug in question. The particles are generally of an average diameter of from about 40 to about 3000 μm, preferably 50 to 1000 μm, and more preferably 100 to 300 μm. Multiparticulates are advantageous drug forms because they are susceptible to use in ascending dosage forms according to the weight of an individual animal in need of treatment simply by raising the mass of particles in the dosage form to behave in accordance with the weight of the animal They are additionally advantageous in that they allow the incorporation of a large amount of drug into a simple dosage form such as an envelope that can be formulated into a suspension that can be easily consumed orally. Multiparticulates also have numerous therapeutic advantages over other dosage forms, especially when taken orally, including (1) improved dispersion in the gastrointestinal tract (Gl), (2) relatively rapid and reproducible passage from the stomach, (3) time of transit through the more uniform Gl tract, and (4) reduced inter and intrapatient variability. As used herein, the term "approximately" means ± 10% of the value. Although the multiparticulates may have any shape and texture, it is preferred that they be spherical with a regular surface texture. These physical characteristics lead to excellent flow properties, improved "mouthfeel", ease of swallowing and ease of uniform coating, if required.

Fusing-gelling process The basic process of the present invention comprises the steps of (a) forming in a extruder a molten mixture comprising a labile drug and a pharmaceutically acceptable carrier, (b) administering the molten mixture of step (a) to an atomizing means for forming droplets of the molten mixture, and (c) gelling the droplets of step (b) to form multiparticulates. The molten mixture comprises a labile drug and a pharmaceutically acceptable carrier, defined in detail below. "Fused mixture" means that the mixture of drug and vehicle is sufficiently heated by extrusion to fluidize the mixture sufficiently to atomize it or put it in the form of droplets. The atomization of the molten mixture can be carried out using any of the atomization methods described below. Generally, the mixture melts in the sense that it will flow when subjected to one or more forces such as pressure, shear, and centrifugal force, such as that exerted by a centrifugal or rotating disk atomizer. Thus, the drug / vehicle mixture can be considered "molten" when any part of the vehicle and / or drug becomes sufficiently fluid so that the mixture, as a whole, can be atomized. Generally, a mixture is sufficiently fluid for atomization when the viscosity of the molten mixture is less than about 20,000 centipoise, preferably less than about 15,000 centipoise, and more preferably less than about 10,000 centipoise. Often, the mixture becomes melted when the mixture is heated by extrusion above the melting point of the drug or one or more of the components of the vehicle, in cases where the vehicle is sufficiently crystalline to have a relatively high melting point. sharp. When the vehicle components are amorphous, the mixture becomes molten when its temperature rises above the softening point of one or more of the vehicle components. Thus, the molten mixture may comprise (1) drug dissolved in the molten vehicle, (2) drug suspended in the molten vehicle, (3) vehicle suspended in the molten drug, (4) molten drug suspended in the molten vehicle, or ( 5) any combination of such states or those states that are intermediate. In a preferred embodiment, the molten mixture comprises substantially crystalline drug particles suspended in the molten carrier. In such cases, a part of the drug can be dissolved in the fluid vehicle and a part of the vehicle can remain solid. Preferably, less than about 30% by weight of the total drug is melted or dissolved in the molten vehicle.

The molten mixture is formed in an extruder. By "extruder" is meant a device or collection of devices that creates an extrusion product by heat and / or shear forces and / or produces an extrusion product uniformly mixed from a solid and / or liquid supply (eg example, cast). Such devices include, but are not limited to, single screw extruders; double screw extruders, including co-rotating, counter-rotating, intermixing, and not intermixing extruders; multiple screw extruders; water extruders, which consist of a heated cylinder and a piston to extrude the molten supply; pump extruders with gear, consisting of a pump with heated gear, generally counter-rotating, which simultaneously heats and pumps the molten supply; and transmission extruders. Transmission extruders comprise a transmitting means for transporting solid and / or powder supplies, such as a spindle transmitter or pneumatic transmitter, and a pump. At least a part of the transmission medium is heated to a temperature high enough to produce the molten mixture. The molten mixture can optionally be directed to an accumulation tank, before going to a pump, which directs the molten mixture to an atomizer. Optionally, an in-line mixer can be used before or after the pump to ensure that the molten mixture is substantially homogeneous. In each of these extruders, the molten mixture is mixed to form a uniformly mixed extrusion product. Such mixing can be achieved by various mechanical and processing means, including mixing elements, kneading elements, and shear mixing by retro-flow. Thus, in such devices, the composition is supplied to the extruder, which produces a molten mixture that can be directed to the atomizer. In one embodiment, the drug / vehicle is delivered to the extruder in the form of a solid powder. The pulverized delivery can be prepared using methods well known in the art to obtain spray mixtures with high uniformity of content (for example, as described in Remington's Pharmaceuticals Sciences, 16th edition, 1980). Generally, it is desirable that the sizes of the drug and carrier particles be similar to obtain a uniform mixture. However, this is not essential for the successful practice of the invention. An example of a process for preparing a supply of solid powder is as follows: first, the vehicle is milled so that its particle size is approximately the same as that of the drug; then, the drug and the vehicle are mixed in a V-blender for 20 minutes; then the resulting mixture is ungrouped to remove large particles, then finally mixed for about 4 additional minutes. In some cases it is difficult to grind the vehicle to the desired particle size since many of these materials tend to be waxy substances and the heat generated during the grinding process can stick to the walls of the grinding equipment. In such cases, the small particles of the vehicle can only be formed using a melting-gelling process, as described below. The resultant gelled vehicle particles can then be mixed with the drug to produce the supply for the extruder. A two-supply extruder system can also be used to produce the molten mixture. In this system, the vehicle and the drug are supplied to the extruder through the same or different supply ports. In this way, the need to mix the components is eliminated. Alternatively, the vehicle in solid form can be supplied to the extruder at one point, allowing the extruder to melt the vehicle. The drug is then added to the molten vehicle through a second supply delivery port partially along the length of the extruder, thereby reducing the residence time of the drug in the molten vehicle. The closer the second supply management port is to the extruder discharge; lower is the residence time of the drug in the molten mixture. The multi-feed extruders can be used when the vehicle comprises more than one excipient. In another method, the vehicle can first be melted in, for example, a tank, and supplied to the extruder in molten form. The drug, typically in solid form, can then be introduced to the extruder through the same port or a different administration port used to supply the vehicle to the extruder. This system has the advantage of separating the melting stage for the vehicle from the mixing stage.

In each of the above methods, the extruder must be designed in such a way as to produce a molten mixture, preferably with drug crystals distributed substantially uniformly in the vehicle. Generally, the temperature of the extrusion product should be about 10 ° C or more above the temperature at which the vehicle and vehicle mixture become fluid. In cases where the vehicle is a simple crystalline material, this temperature is typically about 10 ° C or more above the melting point of the vehicle. The various zones in the extruder should be heated to the appropriate temperatures to obtain the desired extrusion product temperature as well as the desired degree of mixing or shear, using methods well known in the art. When the drug is in the form of a hydrate or solvate or when the drug comprises a co-species which is volatile (eg, a salt form of HCl), the drug can be maintained in this way by ensuring that the activity of the volatile coespecie in the mixture The molten mixture is sufficiently high so that the volatile copecose is not removed from the drug by dissolution in the molten mixture. In order to keep the activity of the volatile co-species in the vehicle high, it is desirable to maintain the atmosphere of the gas phase above the molten mixture at a high activity of the volatile co-species. This can be achieved by adding the volatile co-species to the powder supply mixture, by injecting the volatile co-species (typically in liquid form) directly into the extruder through a separate administration port, or by both ways. In any case, sufficient volatile co-species is added to ensure that the activity is sufficiently high to maintain the crystalline form of the desired drug. This is more fully described in the commonly assigned United States patent application Serial No. 60/527316 ("Method for Making Pharmaceutical Multiparticulates," Legal Dossier No. PC25021), filed on December 4, 2003. Once the molten mixture has formed, it is administered to an atomizer that breaks the molten mixture into small droplets. Virtually any method for administering the molten mixture to the atomizer can be used, including the use of pumps and various types of pneumatic devices such as pressurized vessels or recipients with pistons. The extruder by itself can be used to deliver the molten mixture to the atomizer. Typically, the molten mixture is maintained at an elevated temperature during administration to the atomizer to prevent its solidification and to keep flowing. Generally, atomization takes place in one of several ways, including (1) by "pressure" or single fluid nozzles; (2) by two fluid nozzles; (3) by centrifugal or rotating disk atomizers, (4) by ultrasonic nozzles; and (5) by mechanical vibrating nozzles. Detailed descriptions of atomization procedures can be found in Lefebvre, Atomization and Sprays (1989) or in Perry's Chemical Engineers' Handbook (7th edition, 1997).

There are several types and designs of pressure nozzles, which generally administer the melt at high pressure to an orifice. The molten mixture leaves the orifice as a filament or as a thin sheet that breaks into filaments, which are subsequently broken into droplets. The pressure drop that operates through the pressure nozzles varies from 1 bar gauge to 70 bar gauge, depending on the viscosity of the molten mixture, the size of the hole, and the desired size of the multiparticulates. In two fluid nozzles, the molten mixture is contacted with a stream of gas, typically air or nitrogen, flowing at a rate sufficient to atomize the molten mixture. In the internal mixing configurations, the molten mixture and gas are mixed into the nozzle before being discharged through the nozzle orifice. In external mixing configurations, the high velocity gas on the outside of the nozzle comes into contact with the molten mixture. The gas pressure drop through such two fluid nozzles typically ranges from 0.5 bar gauge to 10 bar gauge. In centrifugal atomizers, also known as rotary atomizers or rotating disk atomizers, the molten mixture is supplied on a rotating surface, where it is caused to diffuse by centrifugal force. The rotating surface can take various forms, examples of which include a flat disc, a container, a disc with blades, and a wheel with slots. The surface of! The disc can also be heated to aid in the formation of multiparticulates. Various atomization mechanisms are observed with flat disk and centrifugal container atomizers, depending on the flow of the molten mixture to the disk, the speed of rotation of the disk, the diameter of the disk, the viscosity of the supply, and the surface tension and density of the supply. At low flow rates, the molten mixture diffuses through the disk surface and when it reaches the edge of the disk, it forms a discrete droplet, which is subsequently ejected from the disk. As the flow of the molten mixture increases toward the disk, the mixture tends to leave the disk as a filament, rather than as a discrete droplet. The filament is subsequently broken into droplets of fairly uniform size. At even higher flow rates, the molten mixture leaves the edge of the disk as a continuous thin sheet, which subsequently disintegrates into irregularly sized filaments and droplets. The diameter of the rotating surface generally varies from 2 cm to 50 cm, and the rotation speed varies from 500 rpm to 100,000 rpm or more, depending on the desired size of the multiparticulates, the properties of the molten mixture and the flow velocity at atomizer. In ultrasonic nozzles, the molten mixture is supplied through or onto a transducer and horn, which vibrate at ultrasonic frequencies, atomizing the molten mixture into small droplets. In nozzles that vibrate mechanically, the molten mixture is supplied through a needle that vibrates at a controlled frequency, atomizing the molten mixture into small droplets. In both cases, the particle size produced is determined by the liquid flow rate, frequency of ultrasound or vibration, and the diameter of the hole. In a preferred embodiment, the atomizer is a centrifugal or rotating disk atomizer, such as the rotary atomizer of -10 mm FX1 manufactured by Niro A / S (Soeborg, Denmark). The drug and vehicle are administered to the process atomization stage as a molten mixture. Preferably, the average residence time for the drug in the molten mixture before gelling is at least 5 seconds, preferably at least 10 seconds and particularly at least 15 seconds, to ensure that the drug is distributed substantially uniformly in the molten mixture. . It is also preferred that the average residence time of the drug in the molten mixture be no more than about 20 minutes to limit drug degradation reactions such as oxidation, reduction, esterification, transesterification, hydrolysis, lactonization or ring cyclization. Depending on the reactivity of the drug, it may be preferable to further reduce the time that the drug is in the molten mixture to less than 20 minutes to maintain the drug degradation at an acceptable level. In such cases, it may be preferable that such mixtures melt for less than 15 minutes, and in some cases, even less than 10 minutes. The average residence time of material in an extruder can be determined by methods well known in the art. In an exemplary method, a small amount of dye or other similar compound is added to the supply while the extruder operates under nominal conditions. The extrusion product is then analyzed during the time for staining, from which the average residence time of the dyeing in the extruder is determined. Once the molten mixture has been atomized, the droplets gel, typically by contact with a gas or liquid at a temperature below the solidification temperature of the droplets. Typically, it is desirable for the droplets to gel in less than about 60 seconds, preferably in less than about 10 seconds, more preferably in less than about 1 second. Often, gelation at room temperature results in sufficiently rapid solidification of the droplets. However, the gelling step often occurs in a confined space to simplify the collection of multiparticulates. In such cases, the temperature of the gelling medium (either gas or liquid) will increase over time as the droplets enter the closed space, leading to possible drug degradation reactions. Thus, a gas or liquid that cools is often circulating through the enclosed space to maintain a constant gelation temperature. "Drugs The multiparticulates formed by the process of the present invention comprise a labile drug and a vehicle As used herein, the term" labile "refers to drugs that degrade by at least 0.01% by weight when They are kept in a fused mixture of optional drug, vehicle and excipient (s) for 60 minutes Details on optional vehicles and excipients are discussed below The term "drug" as used herein includes, by way of example, for example and not for limitation, any physiocally or pharmacocally active substance that produces a localized or systemic effect in animals The term "animals" includes mammals, in particular humans, as well as other animals Preferably, the drug comprises about 5% by weight. weight to about 90% by weight of the total weight of the multiparticulate, more preferably from about 10% by weight to about 80% by weight, even more preferably from about 30% by weight to about 60% by weight of the total weight of the multiparticulates. Before forming the multiparticulates, the drug can be amorphous or crystalline. Preferably, at least 70% by weight of the drug is crystalline, more preferably, at least 80% by weight of the drug is crystalline, even more preferably at least 90% by weight of the drug is crystalline, and, most preferably, less 95% by weight of the drug is crystalline before forming the multiparticulates.

After forming multiparticulates by the process of the present invention, the drug can be amorphous or crystalline. Preferably, the drug in the multiparticulate is crystalline, including any crystalline polymorph. A "major part" of the drug in the multiparticulates can be crystalline, meaning that at least 70% of the drug is crystalline. The degree of crystallinity of the drug in the multiparticulates can be "substantially crystalline", which means that the amount of crystalline drug in the multiparticulates is at least 80%, "almost completely crystalline", which means that the amount of crystalline drug is at least 90%, or "essentially crystalline", which means that the amount of crystalline drug in the multiparticulates is at least 95%. The crystallinity of the drug in the multiparticulates can be determined using X-ray powder diffraction analysis (PXRD). In an exemplary procedure, the PXRD analysis can be carried out on a Bruker AXS D8 Advance diffractometer. In this analysis, samples of approximately 500 mg are packed in Lucite sample containers and the sample surface is smoothed using a glass microscope slide to provide a consistently smooth sample surface that is flush with the top of the sample container. sample. The samples are rotated in plane f at a speed of 30 rpm to minimize the effects of crystal orientation. The X-ray source (S / B KCua,? = 1.54 Á) is handled at a voltage of 45 kV and a current of 40 mA. The data for each sample is collected over a period of about 20 to about 60 minutes in continuous scan detector mode at a scan rate of about 1.8 seconds / stage to about 12 seconds / stage and a stage size of 0.02 ° / stage. The diffractograms are collected over the 2T interval of approximately 4o to 30 °. The crystallinity of the test sample is determined by comparison with two or more calibration standards consisting of physical mixtures of crystalline drug and vehicle. Each physical mix is mixed together approximately 15 minutes in a Turbula mixer. Using the instrument software, the area under the diffractogram curve is integrated over the 2T interval using a linear baseline. This integration interval includes as many possible drug peaks while excluding peaks related to the vehicle. A linear calibration curve of percentage of crystalline drug against the area under the diffractogram curve is generated from the calibration standards. The crystallinity of the test sample is then determined using these I calibration results and the area under the curve for the test sample. The results are reported as a crystallinity of the drug in average percentage (by mass of the crystal). The crystalline form of a drug is generally preferred since it is more chemically stable than the amorphous form. This chemical stability arises from the fact that in the crystalline form, the drug molecules are blocked in a three-dimensional rigid structure that is in a low-energy thermodynamic state. The removal of a drug molecule from this structure, for example, to react with a vehicle, will therefore take a considerable amount of energy. further"Crystal forces reduce the mobility of drug molecules in the crystal structure, the result is that the rate of degradation of the crystalline drug is significantly reduced compared to formulations containing amorphous drug. The degradation that can occur in labile drugs to degrade them includes, but is not limited to, hydrolysis, lactonization, esterification, oxidation, reduction, ring cyclization, and transesterification Labile drugs can be identified experimentally by determining whether the drug reacts chemically or degrades when kept in the molten mixture of drug, vehicle and optional excipients for 60 minutes In general, drug degradation can be measured using any conventional method to measure the purity or potency of the drug in a pharmaceutical composition. or power of the substance of f The preparation prior to the formation of the molten mixture can be measured using high performance liquid chromatography (HPLC) or other well known analytical techniques. The molten mixture comprising the drug and the vehicle is then formed and the drug is kept in the molten mixture for 60 minutes. The purity or potency of the drug is then determined after being in the molten mixture for 60 minutes. A significant decrease in potency or purity indicates that a chemical reaction has occurred and is an indication of poor chemical stability. An alternative method used to determine whether a drug is labile, is to determine the concentration of a drug breaker (s) in the multiparticulate after being kept in the molten mixture for 60 minutes. An increase in the concentration of a drug depletor compared to the concentration present in the volume drug substance would indicate the reaction of the drug. An HPLC or other analytical technique can be used to determine the concentration of the drug degrader / degraders. These techniques can be used to determine the "degree of degradation" of a drug after remaining in the molten mixture for 60 minutes subtracting the final percentage of drug purity (determined either by measuring the decrease in the drug present or the increase in impurities of the drug present) from the initial percentage of drug purity. For example, a mixture that initially contains 100 mg of drug and has no measurable impurities would have an initial drug purity percentage of 100% by weight. If, after remaining in the melted mixture for 60 minutes, the amount of drug in the sample decreases to 95 mg, the final percentage of purity of the drug would be 95% by weight and the degree of degradation would be 100% by weight less 95% by weight, or 5% by weight. Alternatively, if it is found that 100 mg of drug substance initially have 2 mg of impurities present, it would have an initial drug purity percentage of 98% by weight. If, after remaining in the melted mixture for 60 minutes, the total impurities present have been increased to 6% by weight, the final percentage of purity of the drug would be 94% by weight and the degree of degradation would be 98% by weight less 94% by weight, or 4% by weight. Alternatively, the degree of degradation can be determined by subtracting the amount of one or more specific drug-degraders present initially from the amount of specific degradant (s) present after keeping the drug in the molten mixture for 60 minutes. minutes Such a measure is useful when there are several drug-degraders, of which only one or a few are involved. For example, if a drug initially contains a specific degradant at a concentration of 3% by weight and after being kept in the molten mixture for 60 minutes the concentration of that degradant was 6% by weight, the degree of degradation would be 6% in weight less 3% by weight, or 3% by weight. The need for the present invention will generally be greater when the reactivity of the drug with or sensitivity to the molten mixture is increased. The process of the present invention is preferred for labile drugs that have a degree of degradation that is greater than 0.01% by weight after being kept in the molten mixture for 60 minutes. Thus, the process of the present invention is preferred for labile drugs having a degree of degradation of at least 0.05% by weight, preferably at least 0.01% by weight and preferably at least 0.5% by weight. The degree of degradation of a drug will depend on several factors, including (1) the chemical conformation of the drug, (2) the chemical conformation of the vehicle, (3) other excipients used in the molten mixture, and (4) the temperature of the molten mixture. A drug can be labile when used in a multiparticulate formulation, but not in another formulation. For example, the crystalline dihydrate form for the drug azithromycin is labile, as defined above, when kept in a molten mixture comprising 50% by weight of azithromycin dihydrate, 47% by weight of COMPRITOL 888 ATO (a mixture of mono). di, and glyceryl tribehenates available from the Gattefossé Corporation, Paramus, New Jersey), and 3% by weight of LUTROL F127 (poloxamer 407, a block copolymer of ethylene and propylene oxides, also known as PLURONIC F 127 available from BASF Corporation, Mt. Olive, New Jersey) at 90 ° C for 60 minutes. In contrast, the same form of azithromycin is not labile when held for 60 minutes in a molten mixture comprising 50% by weight of azithromycin dihydrate, 48% by weight of microcrystalline wax, and 2% by weight of LUTROL F 127. Examples of drugs used in the multiparticulates made by the method of the invention include, without limitation, organic and inorganic compounds that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, smooth cardiovascular muscles, circulatory system of blood, synaptic sites, sites of neuroeffector junctions, endocrine and hormonal systems, immunological system, reproductive system, autocoid systems, food and excretory systems, inhibitors of autocoids and histamine systems. Preferred classes of drugs include, but are not limited to, antihypertensives, antianxiety agents, anticoagulants, anticonvulsants, blood glucose lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, antiinflammatories, antipsychotics, cognitive enhancers, agents anti-atherosclerotic agents, cholesterol lowering agents, antiobesity agents, autoimmune disorders agents, anti-potency agents, antibacterial and antifungal agents, hypnotic agents, antiparkinsonism agents, Alzheimer's disease agents, antibiotics, antidepressants, antiviral agents, glycogen phosphorylase inhibitors, and inhibitors of the cholesterol ester transfer protein. Each named drug should be understood to include the neutral form of the drug, and pharmaceutically acceptable forms thereof. By "pharmaceutically acceptable forms" thereof is meant any pharmaceutically acceptable derivative or variation, including stereoisomers, mixtures of stereoisomers, enantiomers, solvates, hydrates, isomorphs, polymorphs, salt forms and prodrugs. Specific examples of antihypertensive drugs include prazosin, nifepidine, amlopidine besilate, trimazosin and doxazosin; Specific examples of agents that lower blood glucose are glipizide and chlorpropramide; a specific example of an anti-potency agent is sidenaphyl and sidenaphyl citrate; specific examples of antineoplastics include chlorambucil, lomustine and equinomycin; a specific example of an imidazole-type antineoplastic is tubulazole; atorvastatin calcium, specific examples of anxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride; Specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen and (+) - N-. { 4- [3- (4-fiuorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; a specific example of a barbiturate is phenobarbital, specific examples of antivirals include acyclovir, nelfinavir and virazole; specific examples of vitamins / nutritional agents include retinol and vitamin E; Specific examples of beta-blockers include timolol and nadolol; A specific example of an emetic is apomorphine; Specific examples of a diuretic include chlorthalidone and spironolactone; A specific example of anticoagulant is dicumarol; specific examples of cardiotonics include digoxin and digitoxin; Specific examples of androgens include 17-methyltestosterone and testosterone; a specific example of a mineral corticoid is deoxycorticosterone; a specific example of a hypnotic / spheroidal anesthetic is alfaxalone; Specific examples of anabolic agents include fluoxymesterone and methanstenolone; Specific examples of anti-depression agents include sulpiride [3,6-dimethyl-2- (2,4,6-trimethylphenoxy) -pyridin-4-yl] - (1-ethylpropyl). amine, 3,5-dimethyl-4 (3'-pentoxy) -2- (2 ', 4', 6'-trimethylphenoxy) pyridine, piroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specific examples of antibiotics include indanylsodium carbenicillin, bacampicillin hydrochloride, troleandomycin, doxycycline hyclate, ampycillin, amoxicillin, and penicillin G; specific examples of anti-infectives include benzalkonium chloride and chlorhexidine; Specific examples of coronary vasodilators include nitroglycerin and myoflacin; A specific example of a hypnotic is etomidate, specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorzolamide; Specific examples of antifungals are econazole, terconazole, fluconazole, voriconazole, and gruseofulvin; a specific example of antiprotozoa is metronidazole; specific examples of anthelminthic agents include thiabendazole and oxfendazole and morantel; Specific examples of antihistamines include astemizole, levocabastine, cetirizine, descarboethoxyloratadine and cinnarizine; specific examples of antipsychotics include ziprasidone, olanzepine, thiothixene hydrochloride, fluspirilene, risperidone and penfluridol; specific examples of gastrointestinal agents include loperamide and cisapride; specific examples of serotonin antagonists include cetanserin and mianserin; A specific example of an anesthetic is lidocaine; a specific example of a hypoglycemic agent is steelhexamide; a specific example of an antiemetic is dimenhydrinate; a specific example of an antibacterial is cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA; Specific examples of Alzheimer's disease agents are THA and donepezil; a specific example of an antiulcer agent / H2 antagonist is famotidine; specific examples of sedative / hypnotic agents include chlordiazepoxide and triazolam; a specific example of a vasodilator is alprostadil; a specific example of a platelet inhibitor is prostacyclin; specific examples of ACE / antihypertensive inhibitors include enalaprilic acid, quinapril, and lisinopril; Specific examples of tetracycline antibiotics include oxytetracycline and minocycline; Specific examples of macrolide antibiotics include erythromycin, clarithromycin, and spiramycin; A specific example of an azalide antibiotic is azithromycin; Specific examples of glycogen phosphorylase inhibitors include [R (R * S *)] - 5-chloro-N- [2-hydroxy-3. { methoxymethylamino} -3-oxo-1- (phenylmethyl) propyl-1H-indole-2-carboxamide and [(1S) -benzyl- (2R) -hydroxy-3 - ((3R, 4S) -d-hydroxy-pyrrolidin 5-Chloro-1 H-indole-2-carboxylic acid-1-yl) -3-oxypropyl-amide; and specific examples of cholesterol ester transfer protein inhibitors include [2R, 4S] -4- [acetyl- (3,5-bis-trifluoromethylbenzyl) -amino] -2-ethyl-6-isopropyl ester. trifluoromethyl-3,4-dihydro-2H-quinoli? a-1-carboxylic acid ethyl ester [2R, 4S] -4 - [(3,5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] -2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid and [2R, 4S] -4 - [(3,5-bis-trifluoromethylbenzyl) -methoxycarbonyl-amino] isopropyl ester] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid. A preferred drug for use with the present invention is azithromycin. Azithromycin is a generic name for the drug 9a-aza-9a-methyl-9-methyl-9-deoxo-9a-homoerythromycin A, a broad-spectrum antimicrobial compound derived from erythromycin A. Accordingly, azithromycin and certain derivatives of it are useful as antibiotics. The azithromycin may be in the form of the free base, a salt or a pharmaceutically acceptable prodrug. Azithromycin can also be in its anhydrous, hydrated or solvated forms. The invention is intended to encompass all those forms. The azithromycin present in the multiparticulates of the present invention is preferably crystalline, including any crystalline polymorph. The various polymorphs of crystalline azithromycin are described in U.S. Patent Application Publication in Procurement Assignment No. 2003016730, published August 28, 2003; U.S. Patents Nos .: 6,365,574 and 6,245,903; U.S. Patent Application Publication Nos .: 20010047089, published November 29, 2001, and 20020111318, published August 15, 2002; and International Application Publications Nos .: WO 01/00640, WO 01/49697, WO 02/10181 and WO 02/42315. In a preferred embodiment, azithromycin is in the form of a crystalline dihydrate, described in U.S. Patent No.: 6,268,489.

Reduced Levels of Degradation The drug in the multiparticulates manufactured by the method of the invention has reduced levels of degradation compared to the same drug in multiparticulate control. The multiparticulate controls are the same as those performed by the method of the invention with the exception that the time that the drug is in the molten mixture is 60 minutes. The 60 minute period was chosen as an appropriate control, since it generally represents the shortest time in which a drug is present in the molten mixture in a conventional economical melting-gelling process to form multiparticulates of drugs. A "relative degree of improvement in drug degradation" can be used to measure the reduced levels of degradation obtained using the method of the invention. The measurement is determined by dividing (i) the degree of degradation of the drug in multiparticulate control media (ii) the degree of degradation of the drug in the multiparticulate manufactured according to the method of the invention. For example, where the degree of degradation of a drug in the multiparticulate control is 50% by weight and the degree of degradation of the multiparticulate manufactured by the process of the invention is 1% by weight, the relative degree of the increase is 50% by weight + 1% by weight, or 50. The multiparticulates made by the process of the present invention provide a measurable increase in drug degradation of the drug relative to the drug-containing control multiparticulates. By "measurable improvement" in the degradation of the drug it is meant that the relative degree of improvement in drug degradation is at least 1.05. When the drug is particularly unstable, relatively higher degrees of improvement may be necessary for the degradation of the multiparticulate drug to be pharmaceutically acceptable. In such cases, the method of the invention provides reduced levels of drug degradation when the relative degree of improvement is at least about 1.10, preferably at least about 1.25, more preferably at least about 2, even more preferably at least about 5, and most preferably at least 10. In fact, some multiparticulates made by the process of the invention can achieve a relative degree of improvement in drug degradation greater than 100.

Vehicles Multiparticulates formed by the process of the present invention include a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the vehicle must be compatible with the other ingredients of the composition, and not deleterious to the patient. The vehicle functions as a matrix of the multiparticulate or to affect the rate of release of the drug from the multiparticulate, or both. The vehicles used in the process of the present invention will generally comprise from about 10% by weight to about 95% by weight of the multiparticulate, preferably from about 20% by weight to about 90% by weight, and more preferably from about - 40% by weight to about 70% by weight of the multiparticulate, based on the total mass of the multiparticulate. The vehicles are preferably solids at temperatures of about 40 ° C. The inventors have found that if the vehicle is not a solid at 40 ° C, there may be changes in the physical characteristics of the composition over time, especially when stored at high temperatures, such as 40 ° C. Thus, it is preferred that the vehicle be a solid at temperatures of about 50 ° C, and more preferably at about 60 ° C. Exemplary vehicles include waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and white and yellow beeswax.; long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; esters of long chain fatty acids, also known as fats, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated derivatives of castor oil, hydrogenated vegetable oils, mono-, di- and trialkylglycerides, glyceryl monobehenate, glyceryl disibenate, glyceryl tribehenate, glyceryl tristearate, glyceryl tripalmitate, and mixtures thereof.

Optional Excipients Multiparticulates may optionally include excipients to aid in the formation of the multiparticulates, to affect the rate of azithromycin release of the multiparticulates, or for other purposes known in the art. Multiparticulates may optionally include a solution enhancer. The solution enhancers generally increase the s of drug solution from the vehicle. In general, the solution potentifiers are amphiphilic compounds and are generally more hydrophilic than the vehicle. The enhancers of the solution generally constitute from about 0.1 to about 30% by weight of the total mass of the multiparticulate. Exemplary enhancers of the solution include alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, surfactants, such as poloxamers (such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), docusate salts, polyoxyethylene alkyl ethers, derivatives of castor oil with polyoxyethylene, polysorbates, polyoxyethylene esters, sodium lauryl sulfate, and sorbitan monoesters; sugars such as glucose, sucrose, xylitol, sorbitol, and maltitol; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and sodium phosphate; amino acids such as alanine and glycine; and mixtures-of the same. Preferably, the solution enhancer is a surfactant, and most preferably, the solution enhancer is a -poloxamer.

Another useful class of excipients that can optionally be included in the multiparticulates includes materials used to adjust the viscosity of the molten mixture used to form the multiparticulates. The viscosity of the molten mixture is a variable key in obtaining multiparticulates with a narrow particle distribution. The excipients that adjust the viscosity generally constitute from 0 to 25% by weight of the multiparticulate, based on the total mass of the multiparticulate. Generally, when a rotary disc melting-gelling process is employed, it is preferred that the viscosity of the melt mixture be at least about 1 cp and less than about 10,000 cp, more preferably at least 50 cp and less than about 1000 cp. . If the molten mixture has a viscosity outside these preferred ranges, an excipient that adjusts the viscosity to obtain a molten mixture within the preferred viscosity range can be added, examples of viscosity reducing excipients include stearyl alcohol, cetyl alcohol, polyethylene glycol of low molecular weight (less than about 1000 daltons), isopropyl alcohol, and water, examples of excipients that increase viscosity include microcrystalline wax, paraffin wax, synthetic wax, high molecular weight polyethylene glycols (greater than about 5000 daltons), dioxide of colloidal silicon, magnesium silicate, sugars, and salts. Other excipients may be added to adjust the release characteristics of the multiparticulates or to improve the processing and typically will comprise from 0 to 50% of the multiparticulate, based on the total mass of the multiparticulate. For example, acids or bases can be used to retard or hasten the release of the drug depending on the nature of the drug and other excipients. Examples of bases that may be included in the composition include di- and tribasic sodium phosphate, di- and tribasic calcium phosphate, mono-, di- and triethanolamine, sodium bicarbonate, sodium citrate dihydrate, polymers and methacrylate copolymers. functionalized with amino, such as EUDRAGIT E100 from Rohm GmbH, as well as other salts of oxide, hydroxide, phosphate, carbonate, bicarbonate and citrate, including various hydrated and anhydride forms known in the art. Even other excipients can be added to reduce the load static in the multiparticulates; examples of these agents include talc and colloidal silicon dioxide. Flavors, colorants, and other excipients may also be used in their usual amounts for their usual purposes. In one embodiment, the vehicle and one or more excipients form a solid solution, which means that the vehicle and one or more optional excipients form a single thermodynamically stable phase. In such cases, excipients that are not solids at a temperature of less than 40 ° C may be used, provided that the carrier / excipient mixture is solid at a temperature of more than about 40 °. This will depend on the melting point of the excipients used and the relative amount of vehicle included in the composition. Generally, the higher the melting point of an excipient, the greater is the amount of a low melting point excipient that can be added to a composition while still maintaining a vehicle in a solid phase at 40 ° C. In another embodiment, the vehicle and one of the more optional excipients do not form a solid solution, which means that the vehicle and one or more optional excipients form one or more thermodynamically stable phases. In such cases, the vehicle / excipient mixture can be completely melted at processing temperatures used to form multiparticulates or one material can be solid while the other / others melt, resulting in a suspension of a material in the molten mixture. . When the vehicle and one or more optional excipients do not form a solid solution but one is desired, for example, to obtain a specific controlled release profile, a third excipient may be included in the composition to produce a solid solution comprising the vehicle, the one or more optional excipients, and the third excipient. For example, it may be desirable to use a carrier compound comprising microcrystalline wax and a poloxamer to obtain a multiparticulate with the desired release profile. In such cases no solid solution is formed, in part due to the hydrophobic nature of the microcrystalline wax and partly because of the hydrophilic nature of the poloxamer. By including a small amount of a third component, such as stearyl alcohol, in the formulation, a solid solution can be obtained resulting in a multiparticulate with the desired release profile. It is preferred that the drug has a low solubility in the vehicle where the solubility was defined as the mass of the drug dissolved in the vehicle divided by the total mass of the vehicle and the drug dissolved at the processing conditions at which the mixture is formed. melted The low solubility limits the amorphous drug formation during the multiparticulate forming process. Preferably, the solubility of the drug in the carrier is less than about 20% by weight, more preferably less than about 10% by weight and even more preferably less than about 5% by weight. The solubility of the drug in a vehicle can be measured by the slow addition of crystalline drug to a molten sample of the vehicle and determining the point at which the drug will not dissolve further in the molten sample, either visually or through analytical quantitative techniques. , such as light scattering. Alternatively, an excess of crystalline drug was added to a sample of the molten vehicle to form a suspension. This suspension can then be filtered or centrifuged to remove an undissolved crystalline drug and the amount of drug dissolved in the liquid phase can be measured using standard quantitative techniques, such as by HPLC. When performing these tests, the activity of any volatile species in the vehicle, atmosphere or gas to which the drug is exposed should be kept high enough so that the crystalline form of the drug does not change during the test, as previously mentioned. In one embodiment, the multiparticulate comprises from about 20 to about 75% by weight of drug, from about 25 to about 80% by weight of a carrier, and from about 0.1 to about 30% by weight of a carrier. solution enhancer based on the total mass of the multiparticulate. In a preferred embodiment, the multiparticulate comprises from about 35% by weight to about 55% by weight of the drug; from about 40% by weight to about 65% by weight of a selected excipient of waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyethoxylated derivatives of castor oil, hydrogenated vegetable oils, glyceryl mono-, di- and tribehenates, glyceryl tristearate, glyceryl tripalmitate; and mixtures thereof; and about 0.1% by weight to about 15% by weight of a solution enhancer selected from surfactants, such as poloxamers, polyoxyethylenealkyl ethers, polysorbates, polyoxyethylenealkyl esters, sodium lauryl sulfate, and sorbitan monoesters; alcohols, such as stearyl alcohols, cetyl alcohol, and polyethylene glycol; sugars such as glucose, sucrose, xylitol, sorbitol, and maltito !; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, potassium phosphate; amino acids such as alanine and glycine; and mixtures thereof. In another preferred exemplary embodiment, the multiparticulates manufactured by the method of the present invention comprise (a) crystalline drug; (b) a glyceride carrier having at least one alkylated substituent of at least 16 carbon atoms; and (c) a polyoxyethylene-polyoxypropylene block copolymer (poloxamer). At least 70% of the drug in the multiparticulate is crystalline.

The choice of these particular vehicle excipients allows precise control of the rate of drug release over a wide range of release rates. Small changes in the relative amounts of the glyceride vehicle and the poloxamer result in large changes in the rate of drug release. This allows the rate of drug release from the multiparticulate to be controlled accurately by selecting the appropriate ratio of the drug, glyceride vehicle and poloxamer. These matrix materials have the additional advantage that they release almost all of the drug from the multiparticulate. Such multiparticulates are more fully discussed in the commonly assigned United States patent application Serial No. 60/527329 ("Multiparticulate Crystalline Drug Compositions Having Controlled Relay Profiies", Legal File No .: PC2520), filed December 4 of 2003.

Dosage Forms Multiparticulates are susceptible to use in dosage forms in scale according to the weight of each individual animal in need of treatment simply by making a scale of the mass of the particles in the dosage form to behave in accordance with the weight of the animal. Multiparticulates can be administered using any known dosage form, including: powders or granules that can be taken orally either dry or reconstituted by adding water or other liquids to form a paste, slurry, suspension or solution; tablets; capsules; a unit dose packet, sometimes referred to in the art as a "small bag" or an "oral powder for constitution" (POC); and pills. Various additives have been mixed, ground, or granulated with the compositions of this invention to form a material suitable for the above dosage forms. The multiparticulates manufactured by the method of the invention are designed for immediate release, controlled release, delayed release, or sustained release of drug after its introduction in an environment of use. As used herein, an "environment of use" may well be the in vivo environment of the gastrointestinal, subdermal, intranasal, buccal, intrathecal, ocular, traumatic, subcutaneous, vaginal tract, arterial and venous blood vessels, lung tract or intramuscular tissue of an animal, such as a mammal and particularly a human; or the in vitro environment of a test solution, such as a simulated gastric pH regulator (GB), a simulated intestinal pH regulator (IB), a phosphate buffered saline solution regulated in its pH (PBS), or a model solution of the fasting duodenum (MFD). Multiparticulates can also be post-treated to improve the crystallinity and / or stability of the multiparticulate drug. In one embodiment, the multiparticulates comprise a drug and a vehicle, the vehicle having a melting point of Tm ° C; the multiparticulates are treated at least by means of one of (i) heating the multiparticulates at a temperature of at least 35 ° C and less than about Tm ° C-10 ° C), and (ii) exposing the multiparticulates to a mobility enhancing agent. This post-treatment step results in an increase in the crystallinity of the drug in the multiparticulates, and typically an improvement in at least one of the physical stability, chemical stability, and solution stability of the multiparticulates. Post-treatment procedures are more fully described in the commonly assigned United States patent application Serial No. 60/527245, ("Multiparticulate Compositions with Improved Stability," legal file No .: PC11900) filed on December 4, 2003. Without further elaboration, it is believed that one of ordinary skill in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the following specific embodiments are to be construed as merely illustrative and not restrictive of the scope of the invention. Those of ordinary skill in the art will understand that known variations of the conditions and procedures of the following examples may be used.

EXAMPLES Control C1 The inventors have found that azithromycin can form azithromycin esters by direct esterification and by transesterification when maintained in a melt containing a vehicle having acidic substituents and / or esters. Under these conditions, azithromycin is labile. For control C1, multiparticulates comprising 50% by weight of azithromycin dihydrate, 45% by weight of COMPRITOL 888 ATO and 5% by weight of LUTROL F127 were made by first adding the components to a beaker and heating the contents to 90.degree. ° C with stirring to form the molten mixture. This molten mixture was maintained at 90 ° C for 60 minutes. The molten mixture was then administered to a rotary disk atomizer at a rate of 140 g / minute to form multiparticulates. The rotating disc atomizer, which is made according to the customer's specifications, consists of a 10.1 cm diameter stainless steel disc shaped like a bolus. The surface of the disc was heated with a. Thin layer heater under the disc at approximately 90 ° C. That disk was mounted on an engine that drives the disk up to approximately 10,000 RPM. The entire assembly was enclosed in a plastic bag of approximately 2.43840 m in diameter to allow gelation and to capture the microparticles formed by the atomizer. Air was introduced from a port below the disk to provide cooling of the multiparticulates following gelation and to inflate the bag to its extended size and shape. The surface of the rotating disk atomizer was maintained at 90 ° C and the disk was rotated at 5500 rpm while forming the multiparticulates of azithromycin. A suitable commercial equivalent to this rotary disk atomizer is the 100 mm FX1 rotary atomizer manufactured by Niro A / S (Soeborg, Denmark). The multiparticulates thus formed were then post-treated by placing them in a shallow tray at a depth of less than about 2 cm.This tray was then placed in a controlled atmosphere oven at 40 ° C and 75% RH for 5 days. the conditions used to form the multiparticulates of control C1 The samples of the multiparticulates were analyzed for azithromycin esters by first extracting the sample with methanol at a concentration of 1.25 mg azithromycin / ml and sonication for 15 minutes. The sample solutions were then filtered with a 0.45 μm nylon syringe filter.The sample solutions were then analyzed by HPLC using a 4.6 × 250 mm Hypérsil BDS C18 HPLC column (5 μm) in a Hewlett liquid chromatography. Packard HP1100.The mobile phase used for the sample elution was a gradient of isopropyl alcohol and 25 mM pH regulator of ammonium cetate (pH of about 7) as follows: 50/50 (v / v) initial conditions of isopropyl alcohol / amino acetate; the percentage of isopropyl alcohol was then increased to 100% for 30 minutes and maintained at 100% for an additional 15 minutes. The flow rate was 0.80 ml / min. The method used an injection of 75 μl of volume and a column temperature of 43 ° C. A Finnigan LCQ Classic mass spectrometer was used for detection. The source of chemical ionization at atmospheric pressure (APCI) was used in a positive ionic mode with a selective ion tracking procedure. The azithromycin ester values were calculated from the MS peak areas based on an external standard of azithromycin. The azithromycin ester values were indicated as a percentage of the total azithromycin in the sample. The results of this analysis are shown in Table 2 and show that the multiparticulates of control C1 contained 0.52% by weight of azithromycin esters, corresponding to a degree of degradation of 0.52% by weight. These data verify that azithromycin, when used in the control formulation C1, is labile.

EXAMPLE 1 This example demonstrates that the multiparticulates containing azithromycin manufactured by the process of the present invention result in reduced levels of azithromycin degradation. The multiparticulates were made comprising 50% by weight of azithromycin dihydrate, 45% by weight of COMPRITOL 888 ATO, and 5% by weight of LUTROL F127, using the method of the present invention. First, 4.75 of azithromycin dihydrate, 4,275 kg of COMPRITOL 888 ATO and 0.475 kg of LUTROL F127 were mixed in a two layer blender for 20 minutes. This mixture was then ungrouped using a Fitzpatrick L1A mill at 3000 rpm, the front knives using a 0.165 cm screen. The mixture was mixed again in a two layer blender for 20 minutes, forming a premix feed. The premix feed was delivered to a Leistritz twin-screw 27 mm extruder (Model ZSE-27, American Leistritz Extruder Corporation, Somerville, NJ), at a rate of 140 g / min, producing a molten mixture comprising a suspension of azithromycin dihydrate in COMPRITOL 888 ATO / LUTROL F127 at a temperature of approximately 90 ° C. The supplied suspension was then administered to the center of the rotating disc atomizer used to form the multiparticulates of C1, heated to 90 ° C and rotating at 5500 rpm.

The average residence time of the azithromycin in the extruder was approximately 60 seconds and the total time that the azithromycin was in the molten suspension was less than 3 minutes and the total time that the azithromycin was kept in the molten mixture was less than about 5 minutes. The particles formed by the rotating disk atomizer were gelled in the ambient air and collected. The properties of the melted-gelled microspheres such as particle size can be controlled by the melt viscosity and the processing conditions. Given the combination of the materials in the preferred embodiments in the present invention, the viscosity of the melt does not change as long as the temperature of the system is maintained at 90 ° C. The size of the azithromycin multiparticulates can be controlled by the speed of supply to the disk (the amount of molten materials supplied in the rotating disk atomizer) and the speed of the disk. For example, particles with a diameter of approximately 200 μm can be formed by a combination of (1) flow velocity at 8.4 kg / hour and disk speed at 5500 RPM or (2) feed rate at 20 kg / hour and disc speed at 5800 RPM or (3) delivery speed at 25 kg / hour and disc speed at 7100 RPM. The conditions for forming the multiparticulates of Example 1 are summarized in Table 1. The multiparticulates thus formed were post-treated as follows. The multiparticulate samples were placed in a shallow pan at a depth of approximately 2 cm. This tray was then placed in a controlled atmosphere oven at 40 ° C and 75% RH for 5 days. The samples of the multiparticulates of Example 1 were analyzed for azithromycin esters as in control 1. The results of this analysis are shown in Table 2 and show that the multiparticulates formed in the process of the present invention contained 0.04% in weight of azithromycin esters, corresponding to a degree of degradation of 0.04% by weight. Thus, the method of the present invention resulted in a relative degree of 0.04%. Thus, the process of the present invention resulted in a relative degree of improvement in the degradation of drug 13 (0.52% by weight * • 0.04% by weight) relative to control C1.

Controls C2 and C3 For controls C2 and C3, the multiparticulates were manufactured as in control C1 with the exceptions highlighted in table 1. The concentrations of azithromycin esters were determined as in control 1 and were indicated in table 2. These results confirm that azithromycin in formulations C2 and C3 is labile.

EXAMPLES 2-3 These examples further demonstrate that the method of the present invention results in an improvement in drug degradation for the multiparticulates containing azithromycin. The multiparticulates were manufactured as in example 1 comprising azithromycin dihydrate, COMPRITOL 888 ATO, and LUTROL F127 in various ratios with the variables highlighted in table T. The concentration of azithromycin esters in the multiparticulates of examples 2 and 3 was determined as in control 1. The results of these tests were indicated in table 2 and show low concentrations of azithromycin esters. These data show that the multiparticulates of Examples 2 and 3 are made by the method of the present invention which provides a relative degree of improvement in drug degradation of 25 and 27 relative to controls C2 and C3, respectively.

TABLE 1 ^ 3.45% by weight of water added to the premix supply TABLE 2 Azithromycin Release Rates of Examples 1-3 The rates of azithromycin release from the multiparticulates of Examples 1-3 were determined using the following procedure. For Examples 1-2, a 750 mg sample of the multiparticulates was placed in a USP Type 2 automatic sampler flask equipped with Teflon coated vanes rotating at 50 rpm. The flask contained 900 ml of pH buffer of 50 mM Na3PO4 adjusted to pH 6.8 with NaOH, maintained at 37.0 ± 0.5 ° C. The multiparticulates were pre-wetted with 10 ml of the pH regulator before being added to the flask. A 3 ml sample of the fluid in the flask was collected at 5, 15, 30, 60, 120, and 180 minutes after the addition of the multiparticulates to the flask. Samples were filtered using a 0.45 μm syringe filter before analyzing by HPLC (Hewlett Packard 1100, Waters Symmetry C8 column, 45:30:25 acetonitrile: methanol: 25 mM pH buffer from KH2PO at 1.0 ml / minute, absorbance measured at 210 nm with a diode selection spectrophotometer). The same procedure was used to evaluate the multiparticulates of Example 3, except that a sample of 1048 mg of the multiparticulates was used, and the average solution was 50 mM of KH2P04 adjusted to pH 6.8 using KOH. The results of these solution tests were indicated in Table 3 and showed that the multiparticulates of Examples 1-3 exhibited controlled release of azithromycin TABLE 3 EXAMPLE 4 The multiparticulates were made comprising 50% by weight of azithromycin dihydrate, 47% by weight of COMPRITOL 888 ATO, and 3% by weight of LUTROL F127 using the following procedure. First, 140 kg of azithromycin dihydrate was weighed and passed through a Quadro Cornil 196S with a mill speed of 900 rpm. The mill was equipped with a screen No. 2C-075-H050 / 60 (special turn, 0.075"), an impeller No. 2F-1607-254, and a 0.571 cm spacer between the impeller and the screen. Next, 8.4 kg of LUTROL F127 and then 131.6 kg of the COMPRITOL 888 ATO were weighed and passed through a Quadro Cornil 194S mill. The speed of the mill was adjusted to 650 rpm. The mill was equipped with a No. 2C-075-R03751 (0.075") screen, a No. 2C-1601-001 impeller, and a 0.571 cm spacer between the impeller and the screen.The ground mixture was mixed using a mixer Gallay of 11.5824 m3 stainless steel mixing vessel rotating at 10 rpm for 40 minutes, for a total of 400 rotations, forming a premix feed The premix feed was delivered to a twin screw Leistritz 50 mm twin screw extruder (Model ZSE, American Leistritz Extruder Corporation, Somerville, NJ), at a rate of approximately 20 kg / hour.The extruder was operated in co-rotative mode at approximately 100 rpm, and interconnected with a melting / spray-gelling unit.The extruder has five Segmented barrel zones and a general extruder length of 20 spindle diameters (1.0 m) The water was injected into barrel number 2 at a rate of 6.7 g / minute (2% by weight). extru This was adjusted to produce a suspension of the molten azithromycin dihydrate supply in COMPRITOL 888 ATO / LUTROL F127 at a temperature of about 90 ° C. The suspension of the supply was administered to the rotary disc atomizer of example 1, which rotates at 6400 rpm and was maintained at a temperature of 90 ° C. The total maximum time that azithromycin was exposed to the molten suspension was less than 10 minutes. The particles formed by the rotating disk atomizer were cooled and gelled in the presence of cooled air that circulated through the product collection chamber. The average particle size was determined to be approximately 200 μm using a Malvern particle size analyzer. The multiparticulates thus formed were post-treated by placing a sample in a sealed barrel which was then placed in a controlled atmosphere chamber at 40 ° C for 10 days. Samples of the post-treated multiparticulates were evaluated by PXRD, which showed that approximately 99% of the azithromycin in the multiparticulates was in the crystalline dihydrate form. Samples of the multiparticulates of Example 4 were analyzed for azithromycin esters as in control C1, which showed that the multiparticulates formed by the method of the present invention contained less than about 0.05% azithromycin esters. The terms and expressions which have been employed in the foregoing specification are used therein as terms of description and not limitation, and there is no intent in the use of such terms and expressions to exclude equivalents of the characteristics shown and described or of parts thereof. thereof, it is recognized that the scope of the invention is defined and. limited only by the claims that follow.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for the formation of chemically stable multiparticulates containing drug, characterized in that it comprises: (a) forming in a extruder a molten mixture comprising a labile drug and a pharmaceutically acceptable vehicle, (b) administering said molten mixture to a medium of atomization to form droplets of the molten mixture; and (c) gelling said droplets to form multiparticulates.

2. The method according to claim 1, further characterized in that the mean time in which said drug is present in said molten mixture is greater than 5 seconds but less than or equal to 20 minutes.

3. The method according to claim 2, further characterized in that the mean time in which said drug is present in said molten mixture is greater than 10 seconds but less than or equal to 10 minutes.

4. The process according to any of claims 1-3, further characterized in that said extruder is selected from the group consisting of single screw extruders, twin screw extruders, multiple screw extruders, water hammer extruders, pump extruders with gear, and transmitting extruders.

5. - The method according to any of claims 1-3, further characterized in that said atomizing means are selected from the group consisting of rotating disk atomizers, pressure nozzles, single fluid nozzles, two fluid nozzles, ultrasonic nozzles, and mechanical vibration nozzles.

6. The method according to any of claims 1-3, further characterized in that said drug is at least 70% by crystalline weight.

7. The method according to any of claims 1-3, further characterized in that said molten mixture is at least one of (/) a homogeneous mixture of said drug in said vehicle and (ii) a homogeneous suspension of said drug in said vehicle. said vehicle.

8. The method according to any of claims 1-3, further characterized in that said vehicle is selected from the group consisting of waxes, long chain alcohols, esters of long chain fatty acids, and mixtures thereof.

9. The method according to claim 8, further characterized in that said vehicle is selected from the group consisting of synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, white and yellow beeswax, stearyl alcohol, cetyl alcohol, polyethylene glycol, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oils, mono-, di- and trialkylglycerides, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, glyceryl tristearate, glyceryl tripalmitate, and mixtures thereof. same.

10. The method according to any of claims 1-3. further characterized in that said molten mixture includes a solution enhancer.

11. The process according to claim 10, further characterized in that said solution enhancer is selected from the group consisting of alcohols, surfactants, sugars, salts, amino acids, and mixtures thereof.

12. The process according to claim 11, further characterized in that said solution enhancer is selected from the group consisting of stearyl alcohol, cetyl alcohol, polyethylene glycol, poloxamers, docusate salts, polyoxyethylene alkyl ethers, castor oil derivatives with polyoxyethylene , polysorbates, polyoxyethylene esters, sodium lauryl sulfate, sorbitan monoesters, glucose, sucrose, xiiitol, sorbitol, maltitol, sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, sulfate of potassium, sodium carbonate, magnesium sulfate, potassium phosphate; alanine, glycine, and mixtures thereof.

13. The method according to claim 12, further characterized in that said vehicle is a mixture of glyceryl mono-, di- and tribehenates and said solution enhancer is a poloxamer.

14. - The method according to any of claims 1-3, further characterized in that said multiparticulates have a relative degree of improvement in drug degradation of at least 1.05.

15. The method according to claim 14, further characterized in that said relative degree of improvement in degradation of the drug is at least 10.