MXPA06007625A - Solid compositions of low-solubility drugs and poloxamers - Google Patents

Abstract

Solid compositions of low-solubility drugs and poloxamers that provide concentration enhancement when administered to an aqueous environment of use are disclosed.

Description

SOLID COMPOSITIONS OF LOW SOLUBILITY AND POLOXAMERIC DRUGS FIELD OF THE INVENTION This invention relates to solid compositions of low solubility drugs and poloxamers that maintain physical stability and potentiate the concentration of the dissolved drug when administered to an aqueous use environment.

BACKGROUND OF THE INVENTION It is sometimes desired to form an amorphous drug composition and a polymer. One reason for forming such compositions is that the aqueous concentration of a poorly soluble drug can be improved by said technique. For example, EP 0 901 786 A2 of Curatolo et al. describes the formation of spray-dried pharmaceutical dispersions of poorly soluble drugs and the hydroxypropylmethylcellulose acetate succinate polymer, in which the drug is amorphous and dispersed in the polymer. The spray dried dispersions described in Curatolo et al. they provide a higher aqueous concentration with respect to the dispersions formed from other processes and with respect to the crystalline drug alone. Similarly, others have recognized the enhancement in aqueous concentration provided by the formation of drug compositions in a polymer. U.S. Patent No. 5,456,923 to Nakamichi et al. describes solid dispersions formed by the double screw extrusion of low solubility drugs and various polymers. Poloxamers (polyoxyethylene-polyoxypropylene copolymers) are routinely used in pharmaceutical techniques for various applications, primarily as emulsifying agents in intravenous fat emulsions, and as solubilizing and stabilizing agents to maintain the clarity of elixirs and syrups. Poloxamers are also used as wetting agents; in ointments, bases of suppositories and gels; and as binders and coatings for tablets. The formation of poloxamer and drug compositions is known. U.S. Patent No. 6,368,622 to Chen et al. describes a drug mixture with a poloxamer. In a particular embodiment, the drug fenofibrate having a melting point of 72 ° to 82 ° C and a vitreous transition temperature (Tg) of about -19 ° C is fused with a poloxamer. Although the data show that the drug in the composition has a faster dissolution rate than a commercial formulation, no potentiation of the concentration was demonstrated. The United States Patent Application Publication No.

US2001 / 0036959A1 of Gabel et al. discloses a composition comprising the drug carvedilol, which has a melting point of 113 ° C to 116 ° C and a Tg of about 39 ° C, in a concentration of about 5% by weight. The preparation preferably includes poloxamers. The composition can be formed using a melting process or by spray drying.

The European Patent Specification EP 0836475 B1 of Clancy et al. describes a solid composition of an active ingredient in a hydrophilic poloxamer polymer. The composition is formed by fusing the poloxamer and dispersing the active ingredient therein or by dissolving the active ingredient and the poloxamer in a solvent or organic solvents. The solvent is evaporated and the poloxamer melt is cooled and milled to obtain the formulation. However, a problem with the formation of solid compositions containing amorphous drug and a substantial amount of poloxamer is that the drug can crystallize with time leading to a low yield. Therefore, there is a continuing need to provide procedures and formulations to enhance the concentration of low solubility drugs by providing physical stability SUMMARY OF THE INVENTION In a first aspect, the invention comprises a solid composition comprising a plurality of particles. The particles comprise a low solubility drug and a poloxamer. The drug is in intimate contact with the poloxamer in the particles. Collectively, the drug and the poloxamer constitute at least 50% by weight of the particles. At least, a substantial portion of the drug in the composition is amorphous. The Tg of the drug is at least 50 ° C. Unless otherwise indicated, as used herein, Tg refers to the Tg measured at an HR of less than 10%. The composition provides potentiation of the low solubility drug concentration when administered to an aqueous use environment in vitro or in vivo. In a second aspect, the invention comprises a solid composition comprising a plurality of particles. The particles comprise a low solubility drug and a poloxamer. The drug is in intimate contact with the poloxamer in the particles. Collectively, the drug and the poloxamer constitute at least 50% by weight of the particles. At least, a substantial portion of the drug in the composition is amorphous. The drug has a log P value greater than about 6.5. The composition provides potentiation of the low solubility drug concentration when administered to an aqueous use environment in vitro or in vivo. In a third aspect, the invention comprises (1) particles comprising a low solubility drug and a poloxamer and (2) a concentration enhancing polymer. The concentration enhancing polymer is present in such a quantity that the pharmaceutical composition, after administration to an aqueous use environment in vivo or in vitro, provides a concentration enhancement to a control composition composed essentially of particles comprising the drug and the poloxamer. In a fourth aspect, the invention provides a method for preparing a solid composition comprising the steps of (1) forming a solution composed essentially of a drug of low solubility, a poloxamer and a solvent; and (2) removing the solvent from the solution to form solid particles comprising a drug of low solubility and a poloxamer, where at least a substantial portion of the drug in the particles is amorphous and the Tg of the drug is at least 50 ° C. . The solid composition provides potentiation of the low solubility drug concentration when administered to an aqueous use environment in vitro or in vivo. In a preferred embodiment, the solvent is removed from the solution by spray drying, spray coating, rotoevaporation or evaporation. The various aspects of the present invention provide a solid composition comprising a poloxamer which provides both good physical stability and an improved concentration of the drug dissolved in an environment of use. Poloxamers are block copolymers composed of polyethylene oxide (PEO) segments and polypropylene oxide (PPO) segments. The poloxamers have melting points of about 45 ° C to about 60 ° C. Without wishing to be bound by theory, it is believed that at room temperature, typically 10 to 30 ° C, the PEO segments will eventually aggregate and crystallize to form semicrystalline PEO domains while the PPO segments will remain as amorphous domains. These PPO domains have a relatively low Tg of about -65 ° C. As a result, any solute dispersed in amorphous PPO domains will have high mobility at normal storage temperatures of 5 ° C to 40 ° C. When the drug is dispersed in poloxamers and subsequently the poloxamer is brought to a temperature below its melting point, the PEO segments will generally crystallize and the drug will reside primarily in the amorphous PPO domains, where the drug will generally have high mobility. The Tg of the drug / PPO domains is generally between that of the pure PPO domains and that of the pure amorphous drug. The precise value of the Tg of said domains will also depend on the relative amounts of drug and PPO in the domains and to a lesser degree, on the interaction between the drug and the PPO. It has been found that when the Tg of the drug / PPO domains is less than the storage temperature and the concentration of the drug in the PPO domains is above its solubility in the PPO domain, the drug will tend, over time, to crystallize and amorphous compositions, therefore, will become unstable. To reduce this instability it has been found that the physical stability of the solid compositions of the low solubility drugs and poloxamers can be improved by choosing the drug having (1) a Tg of at least about 50 ° C or (2) a value of log P greater than about 6.5, or both. Solid compositions comprising a drug of low solubility having at least one of these properties and a poloxamer may have higher drug loads (ie, the fraction of drug in the solid composition may be higher) and / or improved physical stability in storage conditions than solid compositions prepared with drugs that do not have these properties. The solid compositions also provide enhancement of the concentration in an aqueous use environment. The above and other objects, features and advantages of the invention will be more readily understood after considering the following detailed description of the invention DETAILED DESCRIPTION OF THE INVENTION The present invention relates to solid compositions of a low solubility drug and a poloxamer. The solid compositions of the present invention are capable of achieving high concentrations of dissolved drug in environments of in vitro and in vivo use. The solid compositions provide good physical stability, which means that the drug in the solid compositions tends to remain in the amorphous form over time under environmental storage conditions. The nature of solid compositions, suitable poloxamers and low solubility drugs, methods for preparing the compositions and methods for determining potentiation of concentration are discussed in more detail below. POLOXAMERS The solid compositions of the present invention comprise a polyoxyethylene-polyoxypropylene block copolymer also known in the pharmaceutical arts as "poloxamer". Poloxamers are crystalline or semicrystalline materials which generally have a molecular weight ranging from about 2000 to about 15,000 dalton and have the general formula: HO (C2H4O) to (C3H6O) b (C2H4O) aH wherein a is about 10 to about 150, representing blocks of repeating units of polyethylene oxide or polyoxyethylene (referred to herein as segment PEO) and b is from about 20 to about 60, representing blocks of repeating units of polypropylene oxide or polyoxypropylene (referred to herein as a PPO segment) ), depending on the particular quality. Suitable poloxamers are marketed under the tradenames PLURONIC and LUTROL, both available from BASF Corporation of Mt. Olive, New Jersey. Preferred poloxamers have a molecular weight of at least about 4,700 dalton and a melting point of at least about 45 ° C when they are dry and, therefore, are solid at room temperature. Preferred qualities of poloxamers include poloxamer 188 (PLURONIC F68), poloxamer 237 (PLURONIC F87), poloxamer 338 (PLURONIC F108), poloxamer 407 (PLURONIC F127), the specifications of which are given in Table A, and mixtures of these poloxamers Table A Solid Particles of Drug and Poloxamer The drug and poloxamer particles are solid at temperatures of up to 30 ° C and less than 10% relative humidity (RH). To maintain a total mass of the small composition it is preferable that the particle comprises at least about 5% by weight of drug. More preferably, the particle comprises at least about 10% by weight of drug and more preferably at least about 20% by weight of drug.

In one embodiment, the particle has a high drug loading. The drug loading refers to the weight fraction of drug in the solid composition. In this embodiment, the drug can be present in an amount of at least about 40% by weight of the particle, at least about 45% by weight, or can even be at least about 50% by weight. Said high drug loads are desirable to maintain the total mass of the pharmaceutical composition at a small value. High drug loads are possible for physically stable compositions having a high Tg (> 50 ° C) or a drug having a high Log P, as described in more detail below. At least a substantial portion of the drug in the particles is amorphous. By "amorphous" it is meant that the drug is in a non-crystalline state. As used herein, the term "a substantial portion" of the drug means that at least 75% by weight of the drug in the particles is in the amorphous form, rather than in the crystalline form. It has been found that the aqueous concentration of drug in an environment of use tends to improve when the fraction of drug present in the amorphous state increases. Consequently, a "substantial portion" of the drug in the particles is amorphous and preferably the drug is "almost completely amorphous", which means that the amount of drug in the crystalline form is not more than 10% by weight. The amounts of crystalline drug can be measured by X-ray powder diffraction (PXRD), Scanning Electron Microscope (SEM) analysis, differential scanning calorimetry (DSC), or any other conventional quantitative measurement. More preferably the dispersion is substantially free of crystalline drug. The amorphous drug in the particles is in intimate contact with the poloxamer. The amorphous drug in the particle can exist as a pure phase, as a solid solution of drug distributed homogeneously throughout the poloxamer, or as any combination of these states or those states that are between them. Without wishing to be bound by any theory, it is believed that the two different block portions of the poloxamer, for example, the PPO and PEO segments of the poloxamer, are present as different phases in each of the particles. As indicated above, the PEO portion may be semi-crystalline, such as in the form of lamellar leaves, and as such, contains little, if any, of drug. The other phase is composed of amorphous PPO with all or part of the drug dissolved homogeneously in the PPO. In some cases, particularly at a high drug load, there may be a third phase, consisting essentially of amorphous drug inside the particle. Therefore, the drug may be present primarily in the PPO portion and may be homogeneously distributed throughout the PPO portion, or the drug may be present as drug-rich domains interspersed in the particle or it may be any combination of these two states or those states that are among them. In cases where drug-rich amorphous domains exist, these domains are generally quite small; that is, a size less than about 1 μm. Preferably, said domains are less than about 100 nm in size. The particles may have a single Tg, which indicates that the drug is homogeneously dispersed throughout the poloxamer, or they may have two Tg corresponding to a drug-rich phase and a drug-poor amorphous phase. Therefore, although the drug in the particles is amorphous, a poloxamer portion in the particles may be in a crystalline or semi-crystalline state. Analysis of the particles of the present invention by PXRD or other quantitative method to determine the crystallinity of a material will typically indicate peaks associated with crystalline or semi-crystalline poloxamer. The solid compositions of the present invention provide good physical stability. As used herein, "physically stable" or "physical stability" means the tendency of the amorphous drug present in the particles to crystallize under environmental storage conditions of 25 ° C and less than 10% relative humidity. Therefore, a solid composition that is more physically stable than another will have a lower crystallization rate of the drug in the solid composition. Specifically, the compositions of this invention have sufficient stability so that less than about 10% by weight of the drug crystallizes during storage for 3 weeks at 25 ° C and 10% RH. Preferably, less than about 5% by weight of the drug crystallizes during storage for 3 weeks at 25 ° C and 10% RH, and more preferably, after storage for 3 months at 25 ° C and 10% RH. Without wishing to stick to a particular theory or mechanism of action, it is believed that physically stable particles containing both drug and poloxamer generally fall into two categories: (1) those that are thermodynamically stable (in which there is little or no driving force) for the crystallization of the amorphous drug) and (2) those that are kinetically stable or metastable (in which there is a driving force for the crystallization of the amorphous drug although the low mobility of the drug prevents or slows down the crystallization rate to an acceptable level) . In order to achieve thermodynamically stable solid compositions, the solubility of the amorphous drug in the poloxamer should be approximately equal to or greater than the drug loading. By "drug load" is meant the weight fraction of drug in the solid particles. The particles may have a drug charge that is slightly greater than the solubility and still be physically stable since the driving force for crystalline nucleation in this case is quite low. By "slightly greater" is meant a drug loading of 10 to 20% greater than the solubility of the drug in the poloxamer. The solubility of the drug in the amorphous form of the poloxamer generally increases as the hydrophobicity of the drug increases. A common measure of hydrophobicity is Log P, defined as a logarithm in base 10 of the ratio of drug solubility in octanol to the solubility of drug in water. Log P can be measured experimentally or calculated using methods known in the art. The calculated values of Log P are often referred to by the calculation procedure, such as Clog P, Alog P, and Mlog P. It is believed that the greater the Log P of a drug, the greater its solubility in the poloxamer and , in turn, the greater the drug loading in the solid particles may be and still be physically stable. Specifically when the Log P of the low solubility drug is greater than about 4.5, the drug loading of the composition can be up to about 30% by weight. When Log P is greater than about 5.5, the drug loading can be up to about 40% by weight and, when Log P is greater than about 6.5, the drug load can be up to about 50% in weigh. Solid compositions of low solubility drugs and poloxamers, where the drug has a relatively high Log P value, can have higher drug loads and still be physically stable because the drug's solubility in the poloxamer is higher than in compositions that contain drugs with lower Log P. Therefore, the maximum drug load that a composition can have and still be thermodynamically stable increases with the increase of Log P of the drug. It should be noted that the solubility of a drug in poloxamer is, in addition to being a function of the Log P of the drug, also a function of the melting point (Tf) of the drug. In general, for a given Log P value, the solubility of the drug in the poloxamer decreases with increasing the melting point of the drug above the storage temperature. Therefore, for two drug compositions with Log P equal to 6.5, one with a Tf of approximately 80 ° C and the other drug with a Tf of approximately 120 ° C, the solubility of the first drug in the poloxamer will generally be greater than that of the second drug and therefore the amorphous compositions of the first drug may have higher drug loads and still have acceptable physical stability. When the drug loading in the particles is 10 to 20% greater than the solubility of the drug in the poloxamer (i.e., the solid composition is supersaturated in amorphous drug), the particles are not thermodynamically stable and there is a driving force for the phase separation of amorphous drug in a drug-rich phase. Said drug-rich phases can be amorphous and microscopic (less than about 1 μm in size) or amorphous and relatively large (greater than about 1 μm in size) or crystalline in nature. Therefore, after phase separation, the compositions may be composed of two or three phases: (1) a drug-rich phase comprising primarily drug; (2) a phase comprising amorphous drug dispersed in the poloxamer; and (3) an optional phase comprising semicrystalline PEO segments of the poloxamer. The amorphous drug in the drug-rich phases may convert over time from the amorphous form to the crystalline form of lower energy. The physical stability of said particles will generally be greater, for a given drug load (1) when the molecular mobility of the amorphous drug is lower; and (2) the lower the tendency of the amorphous drug to crystallize from the drug-rich phases. Molecular mobility is generally lower and physical stability greater for particles composed of a drug with a high Tg value. The Tg of the phase or phases containing drug is a measure of the molecular mobility of the drug in the particle. The higher the Tg of the drug-containing phase, the lower the mobility of the drug. Therefore, the ratio of the Tg of the drug-containing phase to the storage temperature (Ta? Ma) for the drug-containing phases of the particle (in K) is an accurate indicator of relative drug mobility. at a given storage temperature. To minimize phase separation, it is desired that the mobility of the amorphous drug in the particle be low. This is achieved by maintaining a ratio of Tg of the particle / Taimacepation greater than about 1. As the typical storage temperatures can be as high as 40 ° C, it is preferable that the Tg of the particles be at least about 40 ° C, more preferably at least about 45 ° C, and more preferably still at least about 50 ° C. Since the Tgs are a function of the water content of the particles, which in turn is a function of the relative humidity at which the particles are exposed, these Tg values refer to the Tg of the particles that has been equilibrated with an atmosphere having a low relative humidity, that is, less than about 10% saturation (or an RH of about 10% or less). As indicated above, a portion of the poloxamer in the compositions can be crystalline or semi-crystalline. Suitable pharmaceutical grades of poloxamers have melting points between about 45 ° C and about 60 ° C. Because the poloxamer in the composition can have a melting point in this range, it can be difficult to verify that the Tg of the particles is also in this same range using conventional thermal methods such as DSC, since the melting exotherm of the semicrystalline portion of the poloxamer occurs at approximately the same temperature as Tg. It has been found that the Tg of the drug can only be used as a good indicator of the physical stability of the particles that have drug loads that substantially exceed the solubility of the drug in the poloxamer. This is especially true for particles in which the Tg of the phase containing the drug is close to the melting point of the poloxamer which makes the measurement of Tg of the phase containing the drug difficult. Specifically, it has been found that a drug of low solubility having a Tg of at least about 50 ° C, generally results in physically stable solid compositions. Without wishing to adhere to a particular theory, it is believed that the higher the Tg of the drug, the higher the Tg of the amorphous drug containing phases of the solid composition, and the lower the molecular mobility of the amorphous drug in the solid composition. As a result, solid compositions formed with low solubility drugs having high values of Tg and poloxamers tend to have high Tg values themselves and, as a result, improved physical stability. Said Tg values may represent the Tg of the drug dispersed in the amorphous portions of the poloxamer or the Tg of the drug-rich phases or domains. In the case of drug-rich domains, the Tg is generally approximately that of the drug alone. In the case of drug dispersed in the poloxamer, the Tg is generally between that of the drug alone and that of the poloxamer alone. Therefore, the higher the Tg of the drug, the higher the Tg of the solid composition and therefore the greater the physical stability of the solid composition. The Tg of the drug can be at least about 60 ° C, at least about 70 ° C, or even at least about 80 ° C. The Tg of a drug can be determined using conventional analytical techniques well known in the art, including any dynamic mechanical analyzer (DMA), a dilatometer, a dielectric analyzer, and differential scanning calorimetry (DSC). In addition, the melting point of the drug, Tf, can also be used as an indicator of the physical stability of the solid composition. In general, drugs with higher melting points tend to have higher vitreous transition temperatures as well, and therefore, may have improved kinetic stability. Therefore, in one embodiment, the drug can have a melting point of at least 130 ° C, at least 140 ° C, or even at least 150 ° C. The Tf can be determined by conventional analytical techniques well known in the art such as those described above for measuring Tg. However, physical stability is also related to the relative difference between Tm and Tg of a drug. Although the primary indicator of the physical stability of amorphous-poloxamer drug compositions with drug loads substantially greater than the solubility of amorphous drug in the poloxamer is the Tg of the drug, the drug's tendency to crystallize also has an effect on physical stability of said compositions. Without wishing to be bound by a particular theory, it is believed that the tendency for the amorphous drug to crystallize when a drug-rich phase is formed is characterized by the ratio of the drug Tg to the drug Tg (both in K). The driving force for crystallization is dominated by Tf and the kinetic barrier to crystallization is controlled primarily by Tg. The Tf / Tg ratio indicates the relative propensity for a drug to crystallize. Therefore, for a series of hypothetical drugs with equivalent Tg values of about 60 ° C, an amorphous composition of a drug with a Tf / Tg value of about 1.30 will be more physically stable than an equivalent composition with a drug. having a Tg value of about 1.35, which in turn will be more stable than an equivalent composition with a T Tg value of about 1.40. Since the conversion of the amorphous drug in the particles to the crystalline state is related to the relative values of (1) the Tg of the particles, (2) Taimacena iepto and (3) relative humidity, the drug in the particles may tend to remain in the amorphous state for longer periods than when stored at room temperature (less than 40 ° C) and relatively low humidity (less than 10% RH). In addition, the packaging of said solid compositions to prevent water absorption or the inclusion of a water-absorbing material such as a desiccant to also prevent or delay the absorption of water can maintain a high Tg for the particles during storage, helping This way to retain the amorphous state. Similarly, storage at lower temperatures can also improve the retention of the amorphous state. The primary constituents of the particles are the low solubility drug and the poloxamer. The drug and the poloxamer together constitute at least 50% by weight of the particles. The drug and the poloxamer can constitute even larger amounts of the composition and can constitute at least 60% by weight, at least 70% by weight, at least 80% by weight or even at least 90% by weight of the particles. In an embodiment, the particles are essentially composed of low solubility drug and poloxamer. The amount of drug relative to the amount of poloxamer present in the particles of the present invention depends on the characteristics of the drug and poloxamer, and can vary widely from a weight ratio of drug to poloxamer of from about 0.01 to about 100 (per example, from 1% by weight of drug to 99% by weight of drug). Preferably, the weight ratio of drug to poloxamer ranges from about 0.05 to about 49 (5% by weight of drug to 98% by weight of drug). The amount of poloxamer in the particles will depend on the dose of the drug, the stability of the resulting particles and the degree of concentration enhancement provided by the particles. In one embodiment, the poloxamer is present in the particles in an amount that is greater than any other excipient than the drug. Typically, the poloxamer is present in a percentage between at least 40% by weight up to 99% by weight of the particles. LOW SOLUBILITY DRUGS The term "drug" is conventional, denoting a compound that has beneficial prophylactic and / or therapeutic properties when administered to an animal, especially humans. Preferably, the drug is a "low solubility drug" which means that the drug has a minimum aqueous solubility at a physiologically relevant pH, (i.e., pH 1-8), of about 0.5 mg / ml or less. The invention finds greater utility when the aqueous solubility of the drug decreases. Therefore, the compositions of the present invention are preferred for drugs of low solubility having an aqueous solubility of less than about 0.1 mg / ml, more preferably less than about 0.05 mg / ml, and more preferably even less of about 0.01 mg / ml. In general, it can be said that the drug has a dose ratio to aqueous solubility greater than about 10 ml and more typically greater than about 100 ml, where the aqueous solubility (mg / ml) is the minimum value observed in any physiologically relevant aqueous solution. (ie, pH 1-8), including simulated intestinal and gastric USP buffers, and the dose is in mg. Therefore, a dose ratio to aqueous solubility can be calculated by dividing the dose (in mg) by the aqueous solubility (in mg / ml). Preferred classes of drugs include, but are not limited to, antihypertensive agents, antianxiety agents, anticoagulants, anticonvulsants, blood glucose lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta-blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, reducing agents of cholesterol, antiatherosclerotic agents, antiobesity agents, agents for autoimmune disorder, anti-potency agents, antibacterial and antifungal agents, hypnotic agents, antiparkinson agents, agents for Alzheimer's disease, antibiotics, antidepressants, antiviral agents, glycogen phosphorylase inhibitors, inhibitors of the cholesterol cholesteryl ester transfer protein. As described above, in one aspect, the drug has a Tg of at least about 50 ° C. Exemplary drugs having a Tg of at least about 50 ° C are shown below in Table B. Table B In another embodiment, the drugs have a Log P greater than about 6.5. Exemplary drugs having a Log P value greater than about 6.5 are shown below in Table C. Table C PROCEDURES FOR PREPARING DRUG AND POLOXAMER PARTICLES The drug and poloxamer particles of the present invention can be prepared according to any known method that results in at least a substantial portion, ie, at least 75% by weight of the drug, being in an amorphous state. Said methods include solvent and thermal processes. In thermal processes, a molten mixture of the low solubility drug and the poloxamer is rapidly cooled so that the molten mixture solidifies rapidly. In solvent processes, the low solubility drug and the poloxamer are dissolved in a common solvent, and the solvent is subsequently removed by evaporation or mixing with a non-solvent. The drug and poloxamer particles are very suitable for formation by solvent processes. The high Tg of the solid compositions of the present invention makes it possible to select processing conditions that lead to the formation of solid materials with a minimum phase separation of the drug and the poloxamer. By "phase separation" it is meant that a significant amount of drug in the composition is separated into amorphous drug-rich domains. When phase separation occurs and drug-rich domains are formed, the choice of the conditions in which the solvent is removed rapidly causes the domains to be quite small, generally less than about 1 μm in size, and preferably less than 200 nm of size. For those embodiments in which the ratio Tf / Tg, drug is less than about 1.4, the reduced tendency of the drug to be crystallized allows the formation of particles by the processing of the solvent where at least a substantial portion of the drug in the particles is amorphous Although thermal methods can be used to prepare the particles of the present invention, in cases where Tf of the drug of low solubility is high, processing at high temperatures is generally less desirable since degradation of the drug is more likely to occur, the poloxamer or both. Therefore, the formation of the particles by solvent processing is preferred. In solvent processes, the low solubility drug and the poloxamer are dissolved in a common solvent. "Common" herein means that the solvent, which may be a mixture of compounds, will dissolve both the drug and the polymer. After both the drug and polymer have dissolved, the solvent is removed by evaporation or mixing with a non-solvent. Exemplary processes are spray drying, spray coating (cuvette coating, fluidized bed coating, etc.), rotoevaporation and precipitation by rapid mixing of the polymer and the drug solution with CO2, water, or other non-solvent. Preferably, removal of the solvent results in the formation of a substantially homogeneous phase of amorphous drug in the PPO portion of the poloxamer. Suitable solvents for solvent processing are preferably volatile, have a boiling point of 150 ° C, or less. In addition, the solvent should have a relatively low toxicity and be removed from the particles at a level that is acceptable according to the guidelines of the International Harmonization Committee (ICH). Removal of the solvent at this level may require a subsequent processing step such as pan drying. Preferred solvents include water, alcohols such as methanol and ethanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; and various other solvents such as acetonitrile, methylene chloride and tetrahydrofuran. Lower volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used in small amounts in mixtures with a volatile solvent. Mixtures of solvents such as 50% methanol and 50% acetone can also be used, as well as mixtures with water, as long as the polymer and the drug are sufficiently soluble to make the process practicable. Generally, due to the hydrophobic nature of the drugs of low solubility, non-aqueous solvents are preferred, which means that the solvent comprises less than about 30% by weight of water. The solvent can be removed by spray drying. The term "spray drying" is conventionally used and broadly refers to processes involving the separation of liquid mixtures into small droplets (atomization) and rapid removal of the solvent from the mixture in a spray drying apparatus where there is a strong driving force for the evaporation of the solvent from the drops. Spray drying processes and spray drying equipment are generally described in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details on spray drying procedures and equipment are reviewed in Marshall, "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition, 1985). The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the dropping temperature of the drops. This is achieved by (1) maintaining the pressure in the spray drying apparatus at a partial vacuum (eg, from 0.01 to 0.50 atmosphere (1.01 to 50.66 KPa)); or (2) mixing the liquid drops with a hot drying gas; or (3) both (1) and (2). In addition, at least a portion of the heat necessary for evaporation of the solvent can be provided by heating the spray solution. The solvent-borne feed, comprising the drug and the poloxamer, can be spray dried under various conditions, and give rise to particles that still have acceptable properties. For example, various types of nozzle can be used to atomize the spray solution, thereby introducing the spray solution into the spray drying chamber as a group of small droplets. Essentially, any type of nozzle can be used to spray the solution as long as the droplets formed are small enough to dry sufficiently (due to evaporation of the solvent) and do not stick or coat the wall of the spray drying chamber . Although the maximum droplet size varies widely as a function of the size, shape and flow pattern within the spray dryer, generally the droplets should be less than about 500 μm in diameter as they exit the nozzle. Examples of types of nozzles that can be used to form the solid compositions include the two fluid nozzle, the fountain type nozzle, the flat fan type nozzle, the pressurized nozzle and the rotary atomizer. In a preferred embodiment, a pressurized nozzle is used, as described, in the copending and commonly assigned United States Application No. 10 / 351,568, the disclosure of which is incorporated herein by reference. The spray solution can be distributed to the spray nozzle or nozzles over a wide range of temperatures and flow rates. Generally, the temperature of the spray solution can vary from just above the freezing point of the solvent to about 20 ° C above its boiling point at ambient pressure (pressurizing the solution) and in some cases even higher. The flow rates of the spray solution to the spray nozzle can vary over a wide range depending on the type of nozzle, the size of the spray dryer and the spray drying conditions such as inlet temperature and gas flow rate. drying Generally, the energy for evaporation of the solvent from the spray solution in a spray drying process comes primarily from the drying gas. The drying gas can be, in principle, essentially any gas, although for safety reasons and to minimize undesirable oxidation of the drug or other materials in the solid composition, an inert gas such as nitrogen is used, or air enriched with nitrogen or argon. The drying gas is typically introduced into the drying chamber at a temperature between about 60 ° C and about 300 ° C, and preferably between about 80 ° C and about 240 ° C. The large surface to volume ratio of the droplets and the high driving force for the evaporation of the solvent leads to rapid solidification times for the drops. The solidification times should be less than about 20 seconds, preferably less than about 10 seconds, and more preferably less than 1 second. This rapid solidification is often critical for the particles to maintain a uniform homogenous phase of amorphous drug and the PPO portion. In a preferred embodiment, the height and volume of the spray dryer are adjusted to provide a sufficient time for the droplets to dry before colliding on an internal surface of the spray dryer as described in detail in the U.S. Application Ser. procedure and common assignment together with the present 10 / 353,746, the description of which is incorporated herein by reference. After solidification, the solid powder typically remains in the spray-drying chamber for about 5 to 60 seconds, further evaporating the solvent from the solid powder. The final solvent content of the particles as they exit the dryer should be low, since this reduces the mobility of the drug molecules in the particles, thereby improving their stability. Generally, the solvent content of the particles when they leave the spray drying chamber should be less than 10% by weight and preferably less than 2% by weight. After forming, the particles can be dried to remove the residual solvent using a suitable drying procedure, such as pan drying, fluid bed drying, microwave drying, ribbon drying, rotary drying, vacuum drying and other methods of known in the art. In another embodiment, the particles are formed by a rotoevaporation process. In this procedure, the drug and the poloxamer are dissolved in a common solvent as described above. The solvent is then removed by rotoevaporation to form the solid composition. The resulting thick syrup or solids can then be dried in a high vacuum line. The resulting solids are preferably formed into small particles such as using a mortar and pestle or other grinding method known in the art. The particles can be sieved and dried when necessary to obtain a material with the desired properties. In another embodiment, the particles are formed by spraying a coating solution of the drug and poloxamer onto seed cores. The seed cores can be prepared from any suitable material such as starch, microcrystalline cellulose, sugar or wax, by any known method such as melt or spray freezing, extrusion / spheronization, granulation, spray drying and the like. The coating solution can be sprayed onto said seed cores using coating equipment known in the pharmaceutical arts, such as cuvette coaters (e.g., Hi-Coater available from Freund Corp. of Tokyo, Japan, Accela-Cota, available from Manesty of Liverpool, UK), fluidized bed coaters (for example, Würster coaters) or top sprayers available from Glatt Air Technologies of Ramsey, New Jersey and Niro Pharma Systems of Bubendorf, Switzerland) and rotary granulators (for example, the granulator CF available at Freund Corp). Although solvent processes are preferred for the formation of the particles of the present invention, thermal processes, such as melt-freezing or melt-extrusion processes can also be used. In such processes, a molten mixture of the drug of low solubility and poloxamer is rapidly cooled so that the molten mixture solidifies rapidly. By "molten mixture" is meant a mixture comprising the drug of low solubility and the poloxamer which is fluid in the sense that it flows when subjected to one or more forces such as pressure, shear and centrifugal force. This generally requires that the mixture is heated to a temperature at which the drug melts or dissolves in the molten poloxamer. The low solubility drug may exist in the melt mixture as a pure phase, as a low solubility drug solution homogeneously distributed throughout the molten mixture or any combination of these states, or those states that are intermediate to each other. The molten mixture is preferably substantially homogeneous so that the drug of low solubility is dispersed as homogeneously as possible throughout the molten mixture. Preferably, the molten mixture is formed using an extruder such as a single screw or twin screw extruder, both known in the art. Generally, the processing temperature may vary from about 50 ° C to about 200 ° C, or higher, depending on the melting point of the low solubility drug and the poloxamer. However, the processing temperature should not be so high that an unacceptably high level of degradation of the drug or poloxamer occurs. In some cases, the molten mixture should be formed in an inert atmosphere to avoid degradation of the drug and / or poloxamer at the processing temperature. When relatively high temperatures are used, it is often preferable to minimize the time at which the mixture is at elevated temperature to minimize degradation. The molten mixture may also comprise an excipient which will reduce the melting temperature of the molten mixture, allowing processing at a lower temperature. For example, a volatile agent that dissolves or reduces the melting point of the drug can be included in the molten mixture. Exemplary volatile excipients include acetone, water, methanol and ethyl acetate. When such volatile excipients are added, the excipients are evaporated or otherwise removed from the particles in the process of, or after conversion of the molten mixture to a solid mixture. In such cases, the processing can be considered to be a combination of solvent processing and melt freezing or melt extrusion. The removal of said volatile excipients from the molten mixture can be achieved by breaking or atomizing the molten mixture into small droplets and contacting the droplets with a fluid so that the droplets cool and lose all or part of the volatile excipient. Once the molten mixture of the low solubility drug and the poloxamer is formed, the mixture should rapidly solidify to form the particles. By "fast solidifying" it is meant that the molten mixture solidifies sufficiently rapidly so that substantial phase separation of the drug and the polymer does not occur. Typically, this means that the mixture should solidify in less than about 10 minutes, more preferably in less than about 5 minutes, and more preferably, in less than about 1 minute. If the mixture does not solidify rapidly, phase separation may occur, resulting in the formation of low-solubility drug-rich phases having a large domain size greater than 1 μm and poloxamer-rich phases. Over time, the drug in the rich phases of low solubility drug can crystallize. Said compositions tend not to give a performance as good as compositions that solidify rapidly. Solidification often takes place primarily by cooling the molten mixture to at least about 10 ° C and preferably at least about 30 ° C below its melting point. As it mentioned above, the solidification can be further promoted by evaporation of all or part of one or more volatile excipients or solvents. To promote rapid cooling and evaporation of volatile excipients, the molten mixture often assumes a shape with a large surface area such as a stick or fiber or drops. For example, the molten mixture can be forced through one or more small holes to form long fine fibers or rods, or it can be fed to a device such as an atomizer, such as a rotating disk that breaks the molten mixture into 1 μm droplets. to 1 cm in diameter. The drops are then contacted with a relatively cold fluid such as air or nitrogen to promote cooling and evaporation. The average particle size may be less than 500 μm in diameter, or less than 100 μm in diameter, less than 50 μm in diameter, or less than 25 μm in diameter. When the particles are formed by spray drying, the resulting particles can vary in size from 1 μm to 100 μm. When the solid composition is formed by other processes such as by spray coating, rotoevaporation, evaporation, melt freezing or extrusion processes, the resulting particles can be sieved, ground or otherwise processed to produce a plurality of small particles. Once the particles comprising the drug and the poloxamer are formed, various processing operations can be used to facilitate the incorporation of the particles into the dosage form. These processing operations include drying, granulation and grinding. The particles can be granulated to increase their size and improve the handling of the particles while forming a suitable dosage form. Preferably, the average size of the granules will vary from 50 to 1000 μm. Said granulation processes may be carried out before or after drying the composition as described above. Dry or wet granulation processes can be used for this purpose. An example of a dry granulation process is roll compaction. Wet granulation processes can include so-called low shear and high shear granulation, as well as fluid bed granulation. In these processes, a granulation fluid is mixed with the composition after the dry components have been mixed to aid in the formation of the granulated composition. Examples of granulation fluids include water, ethanol, isopropyl alcohol, N-propanol, the various butanol isomers and mixtures thereof. A polymer can be added with the granulation fluid to aid granulation of the particles. Examples of suitable polymers include more poloxamer, hydroxypropylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose. If a wet granulation process is used, the granulated composition is often dried from further processing. Examples of drying procedures suitable for use in connection with wet granulation are the same as those described above. When the solid composition is prepared by a solvent process, the composition may be granulated before removal of the residual solvent. During the drying process, the residual solvent and the granulation fluid are simultaneously removed from the composition. Once the composition has been granulated, it can then be ground to achieve the desired particle size. Examples of suitable methods for milling the composition include hammer mill, ball mill, fluid energy mill, roller mill, knife mill and other milling processes known in the art. PARTICLE AND POLYMER MIXTURES OF CONCENTRATION A different embodiment of the invention comprises a combination of (1) particles comprising a drug of low solubility and a poloxamer, and (2) a concentration enhancing polymer. By "consensus enhancing polymer" is meant a polymer which, when combined with the drug and poloxamer particles and administered to an aqueous use environment, increases the concentration of drug of low solubility in the environment of use or bioavailability of the drug with respect to the particles alone. "Combination" in reference to drug, poloxamer and concentration-enhancing poloxamer means that the particles and the concentration-enhancing polymer may be in physical contact with each other or in close proximity but not physically mixed at the molecular level (i.e., a dispersion). ). The particles and the concentration-enhancing polymer may be in different regions of the composition. For example, the particles may be in the form of a multilayer tablet, as is known in the art, where one or more layers comprise the amorphous and poloxamer drug and one or more other layers comprise the concentration enhancing polymer. Yet another example may be a coated tablet in which the particles or the concentration enhancing polymer, or both, may be present in the core of the tablet and the coating may comprise the concentration enhancing polymer. Alternatively, the combination can be in the form of a simple dry physical mixture, in which both the particles and the concentration-enhancing polymer are mixed in the form of particles, and where the particles of each independently of the size, retain the same individual physical properties presented in bulk. Any conventional method can be used to mix the particles and the concentration enhancing polymer together such as physical mix and dry or wet granulation, which does not convert the particles and the concentration enhancing polymer into a molecular dispersion. Examples include V-mixers, planetary mixers, vortex mixers, mills, extruders such as twin-screw extruder and grinding methods. The ingredients can be combined in granulation processes using mechanical energy such as a ball mill or roller compactors. They can also be combined using wet granulation methods in high shear granulators or fluid bed granulators, where a solvent or wetting agent is added to the ingredients during the granulation process.

Alternatively, the particles and the concentration enhancing polymer can be co-administered, which means that the particles can be administered separately, although within the same general time frame as the concentration-enhancing polymer. Therefore, the particles can be administered, for example, in their own dosage form which is taken at about the same time as the concentration enhancing polymer which is in a separate dosage form. If they are administered separately, it is generally preferred to administer both the particles and the concentration enhancing polymer with a separation of 60 minutes from each other, so that the two are present together in the environment of use. When they are not administered approximately simultaneously (for example, in 1 minute or 2 minutes of each other) the concentration enhancing polymer is preferably administered before the particles. The amount of concentration-enhancing polymer present in the composition is sufficient to provide concentration enhancement as described below. In general, the ratio of drug in the particles to concentration enhancing polymer can vary from 0.01 (1 part of drug to 100 parts of polymer) to 100. Preferably, the ratio of drug to polymer enhancer varies from approximately 0, 66 to about 49, and more preferably from about 3 to about 19, and even more preferably from about 5 to about 15. Concentration enhancing polymers suitable for use in the present invention should be pharmaceutically acceptable and should have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1-8). Almost any neutral or ionizable polymer having an aqueous solubility of at least 0.1 mg / ml in at least a portion of the range of pH 1-8 may be suitable. In a preferred embodiment, the concentration-enhancing polymer has an "amphiphilic" nature, which means that the polymer has hydrophobic and hydrophilic portions. Amphiphilic polymers are preferred because it is believed that such polymers tend to have relatively strong interactions with the drug and can promote the formation of various types of polymer / drug assemblies in solution. A class of polymers suitable for use with the present invention comprises non-ionizable (or neutral) non-cellulosic polymers. Exemplary polymers include: vinyl polymers and copolymers having hydroxyl alkylacyloxy or cyclamido substituents; polyvinyl alcohols having at least a portion of their units repeated in the non-hydrolyzed form (vinyl acetate); copolymers of polyvinyl alcohol and polyvinyl acetate; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene and polyvinyl alcohol copolymers. Exemplary neutral non-cellulosic polymers include hydroxyethyl methacrylate, polyvinylhydroxyethyl ether and polyethylene glycol. Another class of polymers suitable for use with the present invention comprises non-cellulosic ionizable polymers. Exemplary polymers include vinyl polymers functionalized with carboxylic acid such as polymethacrylates functionalized with carboxylic acid and polyacrylates functionalized with carboxylic acid such as EUDRAGITS® manufactured by Rohm Tech Inc., of Malden, Massachusetts; polyacrylates and polymethacrylates functionalized with amine; proteins; and starches functionalized with carboxylic acid such as starch glycolate. Another class of polymers suitable for use with the present invention comprises ionizable and neutral cellulosic polymers with at least one ester- and / or ether-linked substituent wherein the polymer has a degree of substitution of at least 0.1 for each substituent. Exemplary cellulosic non-ionizable polymers include: hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate and hydroxyethylethylcellulose. Ionizable cellulosic polymers specimens include: hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose succinate and hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxyethyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, methylcellulose acetate phthalate ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropylmethylcellulose phthalate succinate, propionate cellulose phthalate, hydroxypropylcellulose phthalate butyrate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate , hydroxypropylmet ilcellulose acetate trimellitate, hydrixopropylcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinecarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, tribenzoic acid hydroxypropylcellulose acetate, phthalic acid ethylcellulose acetate, nicotinic acid ethylcellulose acetate and picolinic acid cellulose acetate. Although specific polymers have been analyzed as suitable for use in the compositions of the present invention, mixtures of such polymers may also be suitable. Therefore, the term "polymer" is intended to include mixtures of polymers in addition to the individual polymer species. Preferably, the concentration enhancing polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, and mixtures thereof. STRENGTHENING OF CONCENTRATION The solid compositions of the present invention are potentiators. concentration. The term "enhancement of concentration" means that the poloxamer is present in a sufficient amount in the composition as to improve the concentration of the drug in an environment of use with respect to a control composition. As used in this document, an "environment of use" may be the in vivo environment of the Gl tract, subdermal, intranasal, buccal, intrathecal, ocular, intraaural, subcutaneous spaces, vaginal tract, arterial and venous blood vessels, pulmonary tract or intramuscular tissue of an animal such as a mammal and particularly a human being, or the in vitro environment of a test solution such as phosphate buffered saline (PBS) or a fast-acting duodenal model (MFD) solution. The potentiation of the concentration can be determined by in vitro dissolution tests or by in vivo assays. It has been determined that the potentiated drug concentration in in vitro dissolution tests in the fasting duodenal model solution (MFD) or phosphate buffered saline (PBS) is a good indicator of in vivo performance and bioavailability. An appropriate PBS solution is an aqueous solution comprising 20 mM sodium phosphate (Na2HPO4), 47 mM potassium phosphate (KH2PO4), 87 mM NaCl, and 0.2 mM KCl adjusted to pH 6.5 with NaOH. An appropriate MFD solution is the same PBS solution in which a solution of 7.3 mM taurocholic acid and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine is also present. In particular, a composition of the present invention can be tested for dissolution by adding it to an MFD or PBS solution and stirring to promote dissolution. In one aspect, a composition of the present invention, when dosed to an aqueous use environment, provides a maximum drug concentration (MDC) that is at least 1.25 times the MDC provided by a control composition. In other words, if the MDC provided by the control composition is 100 μg / ml, then a composition of the present invention containing a poloxamer provides an MDC of at least 125 μg / ml. Preferably, the MDC of the drug provided by the compositions of the present invention is at least 2 times, more preferably at least 3 times, and even more preferably at least 5 times that of the control composition. When the composition comprises particles of a drug of low solubility and a poloxamer, the control composition is the drug without dispersing alone (for example, crystalline drug only in its thermodynamically more stable crystalline form or in cases in which a form is unknown crystalline drug, the control can be the amorphous drug alone) or the drug plus a weight of the inert diluent equivalent to the weight of the poloxamer in the test composition. By "inert" it is understood that the diluent is not concentration enhancer. When the composition comprises a combination of (1) particles comprising a low solubility drug and a poloxamer and (2) a concentration enhancing polymer, the control composition is the particles alone or the particles plus an equivalent inert diluent weight. to the weight of concentration-enhancing polymer in the test composition. As an alternative, the compositions of the present invention provide in an aqueous use environment an area under the curve (AUC) of concentration against time, for a period of at least 90 minutes between the time of introduction in the environment of use and approximately 270 minutes after the introduction into the use environment which is at least 1, 25 times that of the control composition. More preferably, the AUCs in the aqueous use environment, achieved with the compositions of the present invention, are at least 2 times, more preferably at least 3 times, and more preferably at least 5 times that of a control composition. Alternatively, the compositions of the present invention, when dosed orally to a human or other animal, provide an AUC in drug concentration in serum or blood plasma that is at least 1.25 times that observed when doses an appropriate control composition. Preferably, the AUC in blood is at least about 2 times, preferably at least about 3 times, even more preferably at least about 4 times, still more preferably at least about 6 times, still more preferably at least about 10 times, and most preferably at least about 20 times that of the control composition. It can also be said that said compositions have a relative bioavailability of about 1.25 times to about 20 times that of the control composition. Therefore, compositions that, when evaluated, satisfy the in vitro or in vivo performance criteria or both are considered to be within the scope of this invention. Alternatively, the compositions of the present invention, when dosed orally to a human or other animal, provide a maximum concentration of drug in blood serum or plasma (Cma?) That is at least 1.25 times that observed when an appropriate control composition is dosed. Preferably, the Cma? in blood is at least about 2 times, more preferably at least about 3 times, even more preferably at least about 4 times, still more preferably at least about 6 times, even more preferably at least about 10 times, and most preferably at less about 20 times that of the control composition. A typical in vitro assay for evaluating the potentiated drug concentration can be performed by (1) the introduction with shaking of a sufficient amount of test composition (ie, the particles of the low solubility drug and the poloxamer) to a test medium , so that if all the drug were dissolved, the theoretical concentration of drug would exceed the equilibrium concentration of the drug by a factor of at least 2.; (2) in a different assay, add an appropriate amount of control composition to an equivalent amount of the test medium; and (3) determining whether the measured MDC and / or AUC of the test composition in the assay medium is at least 1.25 times that provided by the control composition. In carrying out said dissolution test, the amount of test composition or control composition used is preferably such an amount that if all the drug were dissolved, the drug concentration would be at least 2 times, more preferably at least 10 times , and more preferably at least 100 times that of the solubility (ie, the equilibrium concentration) of the drug. For some test compositions of a drug of very low solubility and poloxamer, it may be necessary to administer even a larger amount of the test composition to determine the MDC. The concentration of dissolved drug is typically measured as a function of time, taking samples from the test medium and representing the concentration of drug in the test medium against time so that MDC and / or AUC can be determined. The MDC is taken as the maximum value of dissolved drug measured during the duration of the trial. The aqueous AUC is calculated by integrating the concentration versus time curve over a period of 90 minutes between the time of introduction of the composition in the aqueous use environment (when the time equals 0) and 270 minutes after the introduction to the environment of use (when the time is equal to 270 minutes). Typically, when the composition rapidly reaches its MDC, said time less than about 30 minutes, the time interval used to calculate the AUC is a time between equal to 0 and equal to 90 minutes. However, if the AUC of a composition in a 90 minute time period described above satisfies the criteria of this invention, then the composition formed is considered to be within the scope of this invention. To prevent the drug particles from giving an erroneous determination, the test solution is filtered or centrifuged. "The dissolved drug" is typically taken as the material that passes through a 0.45 μm pore syringe filter or alternatively, the material that remains in the supernatant after centrifugation. Filtration can be performed using a 13 mm diameter, 0.45 μm pore size polyvinylidene difluoride syringe filter marketed by Scientific Resources under the trademark TITAN®. Centrifugation is typically performed in a polypropylene microcentrifuge tube, centrifuging at 13,000 G for 60 seconds. Other similar filtration or centrifugation methods may be employed and useful results obtained. For example, using other types of microfilters, somewhat higher or lower values (± 10-40%) can be achieved than those obtained with the filter specified above, but which will still allow the identification of the preferred dispersions. It is recognized that this definition of "dissolved drug" encompasses not only monomeric solvated drug molecules but also a wide range of species such as polymer / drug assemblies having submicron dimensions such as drug aggregates, aggregates of polymer and drug mixtures, micelles , polymeric micelles, colloidal particles or nanocrystals, polymer-drug complexes, and other similar drug-containing species that are present in the filtrate or in the supernatant in the specified dissolution test. Alternatively, the compositions of the present invention, when dosed orally to a human or other animal, result in improved bioavailability or a Cma? enhanced. The relative bioavailability and Cmax of the drugs in the compositions can be tested in vivo in animals or humans using conventional methods to prepare said determination. An in vivo trial, such as a cross-over study, can be used to determine whether a drug and poloxamer composition provides relative bioavailability or enhanced Cmax compared to a control composition, as described above. In an in vivo cross-over study, a test composition comprising a drug of low solubility and poloxamer is dosed in half of a group of test subjects and after an appropriate washout period (eg, one week) , the same subjects are dosed with a control composition which is composed of an equivalent amount of crystalline drug as the test composition (but without the poloxamer present). The other half of the group is dosed with the control composition first, followed by the test composition. The relative bioavailability is measured as the area under the curve (AUC) of the concentration of the drug in the blood (serum or plasma) versus the time determined for the test group divided by the AUC in the blood provided by the control composition. Preferably, this test / control ratio is determined for each subject, and then the proportions are averaged for all study subjects. Similarly, Cmax can be determined from the blood drug concentration versus time for the test group divided by that provided by the control composition. In vivo determinations of Cmax and AUC can be performed by plotting the serum or plasma concentration of the drug along the ordinate axis (Y axis) versus time along the abscissa axis (X axis). To facilitate dosing, a dosing vehicle can be used to administer the dose. The dosing vehicle is preferably water, although it may also contain materials for suspending the test or control composition, provided that these materials do not dissolve the composition or change the solubility of the drug in vivo. The determination of Cmax and AUC is a well-known procedure and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986). EXCIPIENTS AND DOSAGE FORMS Other conventional formulation excipients may be employed in the compositions of the invention, including excipients well known in the art, for example, those described in Remington: The Science and Practice of Pharmacy (20th ed., 2000). Generally, excipients such as fillers, disintegrating agents, pigments, binders, lubricants, glidants, flavors and the like can be used for customary purposes and in typical amounts, without adversely affecting the properties of the compositions. These excipients may be used after the drug / polymer composition has been formed, to formulate the composition in the form of tablets, capsules, suppositories, suspensions, suspension prs, creams, transdermal patches, reservoirs and the like. The compositions of the present invention can be delivered by a wide variety of routes including, but not limited to, oral, nasal, rectal, vaginal, subcutaneous, intravenous, and pulmonary. Generally, oral delivery is preferred. The compositions of the present invention can be formulated in various forms so that they are supplied in the form of a suspension of particles in a liquid vehicle. Said suspensions may be formulated as a liquid or paste at the time of manufacture or they may be formulated as a dry pr, with a liquid, typically water, added at the last moment before oral administration. Said prs that are constituted in a suspension, are often called formulations in envelopes or oral pr for constitution (OPC). The dosage forms can be formulated and reconstituted by any known method. The simplest approach is to formulate the dosage form as a dry pr that is reconstituted simply by adding water and stirring. Alternatively, the dosage form can be formulated as a liquid and a dry pr which are combined and agitated to form the oral suspension. In another embodiment, the dosage form can be formulated as two prs that are reconstituted by first adding water to a pr to form a solution with which the second pr is combined with agitation to form the suspension. Generally, it is preferred that the drug dispersion be formulated for long-term storage in the dry state, since this promotes the chemical and physical stability of the drug. Other features and embodiments of the invention will become apparent from the following examples given for illustration of the invention rather than to limit its intended scope. EXAMPLES Examples 1-2 Solid compositions were formed with the glycogen phosphorylase inhibitor [(1 S) -benzyl- (2R) -hydroxy-3 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl) -3 5-chloro-1 H-indole-2-carboxylic acid oxido-phenyl-amide ("Drug 1"). This compound has a Log P value of about 2.3; a Tg, drug of 113 ° C at room temperature and a Tf of 216 ° C. Therefore, the ratio Tf / Tg, drug (in K / K) of this drug is 1.27. The aqueous solubility of Drug 1 is about 80 μg / ml. Example 1 contained 30% by weight of Drug 1, 70% by weight of poloxamer 407 (PLURONIC F127, available from BASF Corporation, Mount Olive, New Jersey) and Example 2 contained 30% by weight of Drug 1, 70% by weight of poloxamer 338 (PLURONIC F108, available from BASF Corporation). A rotoevaporation process was used to form the solid compositions in the following manner: first, 0.3 g of Drug 1 and 0.7 g of poloxamer were added to 15 ml of methanol in a round bottom flask and shaken at room temperature until a clear solution was obtained. The methanol was then removed from the solution in vacuo (less than about 0.1 atmosphere (10.13 kPa)), while the flask was rotated in a 40 ° C bath. The resulting solid composition was dried under vacuum for about 3 hours at room temperature. The dried material was removed after the flask, it was cooled in liquid nitrogen and ground with a mortar and pestle. The solid compositions of Examples 1-2 were examined to evaluate the crystallinity of the drug. Samples were examined using PXRD with a Bruker AXS D8 Advance diffractometer. The samples (approximately 100 mg) were packed in Lucite sampling cups equipped with Si plates (511) at the bottom of the cup to avoid background signaling. The mixtures were rotated in plane f at a speed of 30 rpm to minimize the effects of crystal orientation. The X-ray source (KCua,? = 1.54 A) operated at a voltage of 45 kV and at a current of 40 mA. The data for each sample was collected over a period of 27 minutes in a continuous detection scan mode with a scanning speed of 1.8 seconds / stage and a step size of 0.04 ° / stage. The diffractograms were collected in a 2T interval of 4 ° to 30 °, and showed no indication of crystalline drug - that is, the amount of drug in crystalline form was less than the limit of detection for the analysis (approximately 5% by weight) . Therefore, the drug in the composition was "almost completely amorphous". The solid compositions of Examples 1-2 were evaluated in an in vitro dissolution test to determine potentiation of the concentration of Drug 1. A sample of 12.0 mg of each solid composition was added in duplicate to a microcentrifuge tube of so that the total concentration of Drug 1 would be 2000 μg / ml if all the drug had dissolved. The tubes were placed in a temperature controlled chamber at 37 ° C and 1.8 ml of PBS containing 0.5 wt% sodium taurocholic acid and 1-palmitoyl-2-oleyl-sn-glycerol-3 were added. phosphocholine (NaTC / POPC, with a weight ratio 4/1) at pH 6.5 and 290 mOsm / kg (simulating a Model of Fasting Duodenal Solution) to each respective tube. The samples were mixed rapidly using a vortex mixer for approximately 60 seconds. The samples were centrifuged at 13,000 G at 37 ° C for 1 minute. The resulting supernatant solution was then sampled and diluted 1: 6 (by volume) with methanol and then analyzed by high performance liquid chromatography (HPLC). The contents of each respective tube were mixed in a vortex mixer and allowed to remain unchanged at 37 ° C until the next sample was taken. The samples were collected at 4, 10, 20, 40, 90 and 1200 minutes. As a control (C1), a sample of the crystalline drug was only tested in the same manner so that the concentration of Drug 1 in the MFD solution would have been 2000 μg / ml if all the drug had dissolved. The results of the dissolution tests of Examples 1-2 and C1 are shown in Table 1. Table 1 The drug concentrations obtained in these samples were used to determine the maximum drug concentration ("MDCgo") and the area under the concentration versus time curve ("AUCgo") during the initial 90 minutes. The results are shown in Table 2. Table 2 As can be seen from the data, the solid compositions of the present invention provide an enhancement of the concentration relative to the crystalline drug alone. Example 1 provided an MDCgo that was 7.8 times that of the crystal control and an AUCgo that was 7.9 times that of the crystal control. Example 2 provided an MDCgo that was 8.0 times that of the crystal control and an AUCgo that was 8.2 times that of the crystal control. Examples 3-4 Solid compositions were formed with the glucocorticoid receptor antagonist 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-N - [(2-methyl-3 -pyridinyl) methyl] -4b- (phenylmethyl) -7- (3,3,3-trifluoropropyl) -, (4bS, 7S, 8aR) -, ("Drug 2"). This drug has a Log P value of approximately 6.2, a Tg.drug of 99 ° C at 0% RH and a Tf of 225 ° C. Therefore, the ratio Tf / Tg, drug in K / K of drug 2 is 1.34. Drug 2 has an aqueous solubility of less than 1 μg / ml. The solid compositions were prepared using the rotoevaporation procedure described for Examples 1 and 2. Example 3 contained 30% by weight of Drug 2 and 70% by weight of poloxamer 407 (PLURONIC F127, BASF Corporation) and Example 4 it contained 30% by weight of Drug 2 and 70% by weight of poloxamer 338 (PLURONIC F108, BASF Corporation).

The solid compositions of Examples 3-4 were examined using PXRD for evaluating the crystallinity of the drug as described in the Examples 1-2. The results showed that Drug 2 in the solid compositions of Examples 3-4 was almost completely amorphous, with no detectable amounts of crystalline drug 2. Examples 3-4 were tested by in vitro dissolution tests to determine potentiation of the Drug concentration as in Examples 1-2, except that a sufficient amount of material was added to the fasting duodenal model solution to obtain a drug concentration of 200 μg / ml, if all the drug had dissolved. Crystalline Drug 2 was used alone as control (C2). The results of these tests are shown in Table 3.

Table 3 The drug concentrations obtained in these samples were used to determine the MDCgo and the AUCgo during the initial 90 minutes. The results are shown in Table 4. Table 4 As can be seen from the data, the solid compositions of the invention provided an enhancement of the concentration with respect to the crystalline drug. The solid composition of Example 3 provided an MDCgo that was 113 times that of the crystalline control and an AUCgo that was 72 times that of the crystal control. The solid composition of Example 4 provided an MDCgo that was 110 times that of the crystal control and an AUCgo that was 81 times that of the crystal control. Examples 5-8 Solid compositions were formed with the retroviral protease inhibitor N- (1,1-dimethylethyl) decahydro-2 - [(2R, 3R) -2-hydroxy-3 [(3-hydroxy-2-methylbenzoyl) amino3 -4- (phenylthio) butyl] -3-isoquinolinecarboxamide (3s, 4aS, 8aS) -monomethanesulfonate also known as nelfinavir mesylate or VIRACEPT® ("Drug 3"). This drug had a Log P value of approximately 4.1; a Tg ^ pnaco of 119 ° C at a RH of 0% and a Tm of 190 ° C; therefore, the ratio Tf / Tg, drug in K / K is 1, 18. The aqueous solubility for Drug 3 is about 6 μg / ml. The solid compositions were prepared so as to contain 50% by weight of Drug 3 and various poloxamers as Examples 1-2. The materials used to prepare the solid compositions are summarized in Table 5. Table 5 The solid composition of Example 5 was examined using PXRD to evaluate the crystallinity of the drug as in Examples 1-2. The results showed that Drug 3 in the solid composition of Example 5 was almost completely amorphous without discernible peaks for the Crystal drug 3. The solid composition of Example 5 was stored for 3 weeks in a controlled atmosphere of 40 ° C and 75% relative humidity and showed no evidence of crystallization of the drug. Examples 5-8 were tested in in vitro dissolution tests to determine potentiation of drug concentration 3 as in Examples 1-2 except that the dissolution medium was PBS and a sufficient amount of the solid composition was added in a manner that the concentration of Drug 3 would have been 1000 μg / ml if all the drug had dissolved. Crystalline Drug 3 alone (C3) was also tested as a control. The results are shown in Table 6. Table 6 The drug concentrations obtained in these samples were used to determine the MDCgo and the AUCgo during the initial 90 minutes. The results are shown in Table 7. Table 7 As can be seen from the data, the solid compositions of the invention provided an enhancement of the concentration relative to that of the crystalline drug. The solid compositions of Examples 5-8 provided MDCgo values that were 16.0 to 51.3 times that of the crystal control and AUCgo values that were 15.3 to 65.8 times that of the crystal control. Example 9 A solid composition of 50% by weight of Drug 3 and 50% by weight of poloxamer 407 (PLURONIC F127) was prepared by a spray drying process. A spray solution was formed by dissolving 500.1 mg of drug 3 and 499.8 mg of PLURONIC F127 in 35 ml of acetone. The solution was pumped into a "mini" spray drying apparatus by means of a speed control syringe pump at a Colé Parmer 74900 series speed of 30 ml / hour. The spray solution was atomized through a Spraying Systems Co. two stream nozzle, module No. SU1A using a heated stream of nitrogen (80 ° C). The spray solution was sprayed in a stainless steel chamber 11 cm in diameter. The resulting solid composition was collected on filter paper, dried under vacuum and stored in a desiccator. The dispersion was analyzed by PXRD as described above and no peaks corresponding to Crystalline Drug 3 were observed. The solid composition of Example 9 was tested in an in vitro dissolution test to demonstrate potentiation of Drug 3 concentration as in Examples 5-8. The results are shown in Table 8.

Table 8 The drug concentrations obtained in these samples were used to determine the MDC90 and the AUC90 during the initial 90 minutes. The results are shown in Table 9, together with the results of the C3 crystal control for comparison. Table 9 As can be seen from the data, the solid composition of Example 9 provided an enhancement of the concentration relative to that of the crystalline drug. The MDCgo value was 37.5 times that of the crystalline control and the value of AUC90 was 41.7 times that of the crystalline control. Comparative Examples C4 and C5 These examples demonstrate that particle formation of a low solubility drug having a low Tg value and a high Tf / Tg ratio, drug, and a poloxamer results in a crystalline drug in the solid composition. A formulation was prepared using the drug nifedipine. Nifedipine has a Log P value of approximately 2.4, a Tg? FaptlaCo of 46 ° C at ambient RH and a Tf of 175 ° C; therefore, the ratio Tf / Tg (in K / K) for nifedipine was 1, 40. Comparative Example C4 contained 50% by weight of nifedipine and 50% by weight of poloxamer 407 (PLURONIC F127, BASF Corporation), and Comparative Example C5 contained 25% by weight of nifedipine and 75% by weight of poloxamer 407 (PLURONIC F127 , BASF Corporation). The formulations were prepared using the procedures described in European Patent No. EP0836475B1, in the following manner. The desired amount of poloxamer 407 was weighed into a glass vial and then stirred and heated to 80 ° C until the poloxamer melted. Then, the appropriate amount of nifedipine was gradually added and the mixture was stirred at 80 ° C for 2 hours. The resulting mixtures were cooled to room temperature, removed from the vial, cooled in liquid nitrogen and ground with a mortar and pestle. The resulting materials were analyzed by PXRD using the procedures described above. The diffractograms for both Comparative Examples C4 and C5 showed sharp peaks corresponding to crystalline drug, indicating that at least about 50% by weight of the drug was in crystalline form. Examples 10-13 Solid compositions of [2R.4S] 4 - [(3, 5-bis-trifluoromethyl-benzyl) -methoxycarbonyl-amino] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid, also known as Torcetrapib ("Drug 4") and the poloxamers PLURONIC F127 and PLURONIC F108 (both supplied by BASF) by a melt-freezing process using the following procedure. Drug 4 has a Log P value of about 7.5, a Tg of about 28 ° C at ambient relative humidity and a Tm of about 95 ° C, therefore, the ratio Tf / Tg (in K / K) is 1, 2. For each example, the amount of Drug 4 and poloxamer given in Table 10 was accurately weighed and placed in a container. The vessel was then placed in a hot oil bath, maintained at 105 ° C. After about 15 minutes, the mixture had melted and stirred using a magnetic stirrer for about 15 minutes. The molten mixture was clear without apparent color. Next, the vessel containing the molten mixture was removed from the hot oil bath and placed in liquid nitrogen resulting in the solidification of the molten mixture in a few seconds. The vessel was removed from the liquid nitrogen after about 60 seconds and allowed to warm to room temperature. The resulting amorphous opaque solid composition was removed after the container using a spatula and broke into small pieces of approximately 1 mm thickness. The pieces were then placed in a mortar with some liquid nitrogen and ground into a white powder with a pestle. Table 10 The solid compositions of Examples 10-13 were evaluated in an in vitro dissolution test as in Examples 1-2 except that the dissolution medium was PBS. The amount of each composition added to the microcentrifuge tube was adjusted so that the concentration of Drug 4 in solution if all the drug had dissolved would be 1000 μg / ml. The results of these tests are presented in Table 11. Table 11 The results are summarized in Table 12, which also includes the data for the crystalline drug 4 alone (Control C6) that was tested under the same conditions. The results show that the Cma? 90 values of the compositions of Examples 10-13 were greater than 262 times at 930 times that of the crystalline drug alone and AUCgo values that were greater than 218 times at 804 times that of the crystalline drug alone. .

Table 12 EXAMPLES 14-15 Solid compositions spray dried from drug 4 and the poloxamers PLURONIC F-127 and PLURONIC F-108 were prepared by the following procedures. The drug and polymer were first added to acetone and mixed to form a solution. Each solution was pumped into a "mini" spray drying apparatus by a syringe pump at a speed of 0.7 ml / min. The polymer solution was atomized through a spray nozzle using a stream of nitrogen heated to 90 ° C. The resulting solid spray-dried composition was collected on a filter paper and dried in a vacuum desiccator. Table 13 summarizes the preparation parameters.

Table 13 The spray dried compositions of Examples 14-15 were evaluated in an in vitro dissolution test as in Examples 10-13. The amount of each composition added to the microcentrifuge tube was adjusted so that the concentration of Drug 4 in solution if all the drug had dissolved would be 1000 μg / ml. The results of these tests are presented in Table 14. Table 14 The results are summarized in Table 15, which also includes the data for Control 6, which was tested under the same conditions. The results show that the dissolution results for the compositions of Examples 14-15 were much better than for the crystalline drug alone (Control 6) providing Cmaxgo values that were greater than 267 times and 508 times that of the crystalline drug alone, respectively , and AUCgo values that were greater than 193 times and 365 times that of the crystalline drug alone, respectively. Table 15 Example 16 A solid amorphous composition comprising 25 wt% Drug 4 poloxamer 407 (PLURONIC F127) through a freezing process melt as in Examples 10-13 except as noted in Table 16. Table was prepared 16 This composition was evaluated in the in vitro dissolution test as in Examples 10-13. The results of these tests are presented in Table 17. Table 17 The summaries are summarized in a to a, which also includes data for the C6 Control that was tested under the same conditions. The results show that the dissolution results for the composition of Example 16 were much better than those of crystalline drug alone, providing a value Cmaxgo that was greater than 789-fold that of crystalline drug alone and a value of AUCgo that was greater than 665 times that of the crystalline drug alone. Table 18 The composition of Example 16 was used as an oral powder, for constitution (OPC) to evaluate the performance of the compositions in in vivo assays using male beagle dogs. The OPCs were dosed as a suspension in a solution containing 0.5% by weight of METHOCEL® hydroxypropylcellulose (from Dow Chemical Co.), and prepared in the following manner. First, 7.5 g of METHOCEL® was weighed and slowly added to approximately 490 ml of water at 90-100 ° C to form a suspension of METHOCEL®. After all the METHOCEL® had been added, 1000 ml of cold water / room temperature was added to the suspension, which was then put in an ice water bath. When all METHOCEL® had dissolved, 2.55 g of polyoxyethylene sorbitan monooleate (TWEEN 80) was added and the mixture was stirred until all of TWEEN 80 had dissolved, thus forming a stock suspension solution. To form the OPC, a sufficient amount of the test composition was weighed to yield an amount of 90 mg of Drug A 4 and placed in a mortar and pestle ("mg of A" refers to mg of active drug) . An amount of 20 ml of the stock suspension solution was added to the mortar and the test composition was mixed with a pestle. Additional suspension of METHOCEL® was added gradually with mixing until a total of 400 ml of the stock suspension solution had been added to the mortar. The suspension was then transferred to a flask thus forming the OPC. In addition, an OPC containing 90 mg of amorphous Drug 4 A (Control C7) was prepared using the same procedure. Six male beagle dogs were each dosed with the OPC. On the day of the study, the dogs were in a state of fasting. They were dosed with the OPC using a probe tube and a syringe. Whole blood samples were taken from the jugular vein and analyzed to determine the concentration of Drug 4 using the following procedure. To 100 μl of each plasma sample, 5 ml of methyl tert-butyl ether (MTBE) and 1 ml of 500 mM sodium carbonate buffer (pH 9) were added.; the sample was vortexed for 1 minute and then centrifuged for 5 minutes. The aqueous portion of the sample was frozen in a dry ice / acetone bath, and the MTBE phase was decanted and evaporated in a vortex evaporator. The dried samples were reconstituted in 100 μl mobile phase (33% acetonitrile and 67% 0.1% formic acid in water). The analysis was performed by HPLC. The results of these tests are presented in Table 19 and show that the compositions of the present invention provided an enhancement of the drug concentration and enhanced the relative bioavailability compared to the control amorphous drug 4 (C7). Table 19 The composition of Example 16 provided a Cma? which was more than 5440 times that of amorphous control and a relative bioavailability that was greater than 10 times. Comparative Example C8 This example demonstrates that a solid composition prepared using a low solubility drug having a low Tg at a high drug loading is not physically stable. A solid composition composed of 50% by weight of Drug 4 and 50% by weight of poloxamer 407 (PLURONIC F127) was prepared using a thermal method. In this procedure, 4.9 g of PLURONIC was placed in a glass vial and melted in an oil bath at 110 ° C. Next, 4.9 g of drug 4 was added to the molox poloxamer, forming a clear solution. Next, the vessel containing the molten mixture was removed from the hot oil bath and placed in liquid nitrogen, resulting in solidification of the molten mixture in a few seconds. The vessel was removed from the liquid nitrogen after about 60 seconds and allowed to warm to room temperature. The resulting opaque solid composition was removed after the container using a spatula and broke into small pieces of approximately 1 mm thickness. The pieces were then placed in a mortar with some liquid nitrogen and ground into a white powder using a pestle. Analysis of the solid composition by PXRD showed that a substantial portion of the drug in the composition was amorphous. The above composition was stored for 3 weeks in a controlled atmosphere of 40 ° C and 25% RH. Analysis of the sample by PXRD showed that approximately 50% by weight of drug in the composition had crystallized, which clearly indicated physical instability. Example 17 Particles were formed with (2R) -3 - [[3- (4-chloro-3-ethylphenoxy) phenyl] [[3- (1,1-, 2,2-tetrafluoroethoxy) phenyl] methyl] amino] -1 , 1,1-trifluoro-2-propanol ("Drug 5"). This drug had a Log P value of about 10.0, a Tg.drug of about -15 ° C, a Tf of about 10 ° C; therefore, the T Tg ratio in K / K was 1, 1. To form the particles 125 mg of Drug 5 and 500 mg of PLURONIC F127 were weighed in a scintillation vial. A stir bar was added and the vial was placed in an oil bath at 80 ° C. The mixture was heated and stirred until the PLURONIC was melted and a clear solution was obtained. The mixture was cooled in liquid nitrogen and ground into particles using a mortar and pestle. The particles thus formed were tested in vitro to determine the concentration enhancement of Drug 5 as in Examples 1-2 at a dose of 120 μg / ml. Control C9 was composed of drug 5 amorphous alone. The results of these dissolution tests of the particles of Example 17 and Control C9 are shown in Table 20. Table 20 The drug concentrations obtained in these samples were used to determine Cma? 9o and AUCgo during the initial 90 minutes. The results are shown in Table 21. Table 21 As can be seen from the data, the composition of Example 17 provided an enhancement of the concentration with respect to that of the amorphous drug because its Cma? 9o was 4.5 times that of the amorphous control and its AUCgo was 7.9 times that of the amorphous control.

The terms and expressions that have been used in the previous description are used therein as terms of description and not limitation, and there is no intention, in the use of said terms and expressions to exclude the equivalents of the characteristics shown and described or portions thereof, it being recognized that the scope of the invention is defined and limited only by the following claims.

Claims (26)

1. A solid composition comprising a plurality of particles comprising said particles a low solubility drug and a poloxamer, at least a substantial portion of said drug in said particles is amorphous, said amorphous drug being in intimate contact with said poloxamer in said particles, and said drug and said poloxamer together comprise at least 50% by weight of said particles, wherein said drug has a glass transition temperature of at least 50 ° C.

2. A solid composition comprising a plurality of particles, said particles comprising a drug of low solubility and a poloxamer, at least a substantial portion of said drug in said particles is amorphous, said amorphous drug being in intimate contact with said poloxamer in said particles, and said drug and said poloxamer together comprise at least 50% by weight of said particles, wherein said drug has a Log P value greater than about 6.5.

3. The solid composition of claim 2, wherein said drug has a glass transition temperature of at least 50 ° C.

4. The solid composition of claim 1, wherein said drug has a Log P value greater than about 6.5.

5. The solid composition of any of claims 1-4, wherein said glass transition temperature of said drug is at least 60 ° C.

6. The solid composition of any of claims 1-4, wherein said glass transition temperature of said drug is at least 70 ° C.

7. The solid composition of any of claims 1-4, wherein said Log P value of said drug is at least 7.0.

8. The solid composition of any of claims 1-4, wherein said Log P value of said drug is at least 8.

9. The solid composition of any of claims 1-4, wherein said drug has a melting point of Tf in K, and a vitreous transition temperature Tg.drug in K and where the ratio Tf / Tg, drug is less than approximately 1.4.

10. The solid composition of claim 8, wherein said f / Tg ratio, drug is less than about 1.35.

11. The solid composition of claim 9, wherein said f / Tg.drug ratio is less than about 1.3.

12. The solid composition of any of claims 1-4, wherein said drug is almost completely amorphous.

13. The solid composition of any of claims 1-4, wherein said drug constitutes at least about 40% by weight of said particles.

14. The solid composition of claim 13, wherein said drug constitutes at least about 45% by weight of said particles.

15. The solid composition of claim 14, wherein said drug constitutes at least 50% by weight of said particles.

16. The solid composition of any of claims 1-4, wherein less than 10% by weight of said drug in said composition crystallizes during storage for 3 weeks at 25 ° C and 10% relative humidity.

17. The solid composition of any of claims 1-4, wherein said dispersion, after administration to an aqueous use environment in vivo or in vitro, provides concentration enhancement with respect to a control composition composed essentially of the drug. alone, wherein said concentration enhancement is characterized by at least one of (a) a maximum drug concentration in said aqueous use environment that is at least 1.25 times that provided by said control composition; and (b) an area under the concentration curve versus time in said aqueous use environment for a period of at least 90 minutes between the time of introduction of said dispersion in said aqueous use environment and approximately 270 minutes after the introduction. in said aqueous use environment which is at least 1.25 times that provided by said control composition.

18. The solid composition of any of claims 1-4, wherein said dispersion, after administration to an environment of in vivo use provides concentration enhancement with respect to a control composition composed essentially of said drug alone, wherein said potentiation of the concentration is characterized by at least one of: (a) a maximum concentration in the blood that is at least 1, 25 times that provided by said control composition; and (b) a relative bioavailability that is at least 1.25 fold relative to said control composition.

19. A pharmaceutical composition comprising: (1) a solid composition of any of claims 1-4, and (2) a concentration enhancing polymer, wherein said concentration enhancing polymer is present in a sufficient amount such that said composition Pharmaceutical, after administration to an aqueous use environment in vivo or in vitro, provides potentiation of the concentration relative to a control composition composed essentially of said solid composition.

20. The pharmaceutical composition of claim 19, wherein said concentration enhancing polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, and mixtures thereof.

21. The pharmaceutical composition of claim 19, wherein said concentration enhancement is characterized by at least one of: (a) a maximum drug concentration in said aqueous use environment that is at least 1.25 times that provided by said control composition; and (b) an area under the concentration curve versus time in said aqueous use environment for any period of at least 90 minutes between the time of introduction of said dispersion in said aqueous use environment and approximately 270 minutes after the introduction. to said aqueous use environment which is at least 1, 25 times that provided by said control composition.

22. The pharmaceutical composition of claim 19, wherein said environment of use is in vivo and said concentration enhancement is characterized by at least one of: (a) a maximum concentration in the blood that is at least 1.25 times that provided by said control composition; and (b) a relative bioavailability that is at least 1.25 fold relative to said control composition.

23. A process for preparing a solid composition comprising the steps of: (1) forming a solution that is essentially composed of a drug of low solubility, a poloxamer and a solvent; and (2) removing said solvent from said solution to form said solid composition composed essentially of said low solubility drug and said poloxamer, at least a substantial portion of said drug in said composition is amorphous, wherein said drug has a glass transition temperature. of at least 50 ° C.

24. A process for preparing a solid composition comprising the steps of: (1) forming a solution that is essentially composed of a drug of low solubility, a poloxamer and a solvent; and (2) removing said solvent from said solution to form said solid composition composed essentially of said low solubility drug and said poloxamer, at least a substantial portion of said drug in said composition is amorphous, wherein said drug has a Log P value. greater than about 6.5.

25. The process of claim 23 or 24, wherein the step (2) is selected from the group consisting of spray drying, spray coating, rotoevaporation and evaporation.

26. The product of the process of claim 23 or 24.