MXPA00001463A - Pharmaceutical solid dispersions - Google Patents

Abstract

A composition comprises a solid dispersion comprising a low-solubility drug and at least one polymer. At least a major portion of the drug in the dispersion is amorphous. The polymer has a glass transition temperature of at least 100 DEG C measured at a relative humidity of fifty percent. Another aspect of the invention comprises the same composition except that the dispersion has a glass transition temperature of at least 50 DEG C at a relative humidity of fifty percent.In another aspect of the invention, a composition comprises a solid dispersion comprising a low-solubility drug and a stabilizing polymer. At least a major portion of the drug in the dispersion is amorphous. The composition also includes a concentration-enhancing polymer that increases the concentration of the drug in a use environment. The stabilizing polymer has a glass transition temperature that is greater than the glass transition temperature of the concentration-enhancing polymer at a relative humidity of 50%.

Description

SOLID PHARMACEUTICAL DISPERSIONS The priority date of the provisional application serial number 60 / 119.401, filed on February 10, 1999, is claimed.

BACKGROUND OF THE INVENTION Low solubility drugs often show low bioavailability or irregular absorption, with factors such as the dose level, the patient's diet, and the formulation of the drug having an effect on the degree of irregularity. The increase in bioavailability of low solubility drugs has been the subject of much research. The increase in bioavailability depends on the improvement of the concentration of the drug in solution to improve absorption. It is known that solid amorphous dispersions comprising a drug of low solubility in a polymer can increase the maximum concentration of drug that will dissolve in an aqueous solution in in vitro tests, or that will dissolve in body fluids such as those present in the tract. gastrointestinal (Gl) in in vivo trials, and, in turn, increase the bioavailability of the drug. Solid dispersions of a drug in a matrix such as a polymer can be prepared, for example, by forming a homogeneous solution or melting the drug in the matrix material, followed by solidification of the mixture by cooling or removal of the solvent. Such solid dispersions of crystalline medicaments have been known for more than two decades and often show increased bioavailability when administered orally with respect to compositions comprising undispersed crystalline medicaments. A method of forming solid dispersions involves spray drying drug and polymer together to form drug and polymer compositions. For example, spray-dried compositions of medicaments and polymers have been described in Kai et al., 44 Chem. Pharm. Bull. 568-571 (1996), Takeuchi et al., 34 Chem. Pharm. Bull. 3800-3806 (1987), Dangprasirt et al., 21 Drug Development and Industrial Pharmacy. 2323-2337 (1995), Berde et al., U.S. Patent No. 5,700,485, Wan et al., 18 Drug Development and Industrial Pharmacy 997-1011 (1992), and Akagi, U.S. Patent No. 5,723,269. Kai et al. describe the formation of solid dispersion systems with an enteric polymer such as hydroxypropylmethylcellulose phthalate (HPCMP) or carboxymethylethylcellulose (CMEC) and with the non-enteric polymer hydroxypropylmethylcellulose (HPMC) by spray drying. It is stated that the medication is in an amorphous state. Kai et al. they state that it is well known that crystallization of a drug can occur in a polymer dispersion during storage of the solid dispersion formulation, resulting in decreased bioavailability. The dispersion was reported to be stable for 2 months in storage conditions dried at high temperature (60 ° C) in closed glass bottles, indicating that storage was in dry conditions. Takeuchi et al. describe a solid amorphous dipersion of tolbutamide in the enteric coating polymers EUDRAGIT (R) and HPMCP. The solid dispersions were prepared by spray drying. It was stated that the medicine was poorly soluble in water. The authors state that the amorphous state of the drug remained well in dry conditions. However, the authors indicated that the stability of the amorphous state of the drug in solid dispersion was sensitive to the water content around or in the sample. U.S. Patent Nos. 4,343,789. 4,404,183 and 4,673,564 all have the same description of a sustained release composition of the nicarpidine vasodilator comprising a solid amorphous dispersion of the medicament in microcrystalline cellulose, polyethylene oxide, polyvinylpyrrolidone and the cellulosic polymers hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate. However, the preferred method of forming the dispersion is by extensive and time-consuming ball milling, and there is no recognition of the increase in the concentration and stabilizing properties of the medicament of the ionizable celluloses to form the dispersion of the medicament. It is also known to form solid dispersions containing polymers by other processes, such as grinding, grinding or solvent evaporation. For example, Nakamichi, US Pat. No. 5,456,923, describes a process for the formation of solid dispersions using a twin screw extruder. Nakamichi confirms that the resulting compositions are solid dispersions, highlighting the disappearance of the characteristic peaks of the crystalline drug by X-ray diffraction analysis. Nakamichi does not discuss the stability of the drug in the dispersion. Mechanical processes, such as that used by Nakamichi, have several drawbacks. First, mechanical processes usually do not achieve uniform homogeneity of dispersion. After mixing, although the medicament may be in the amorphous state, however the dispersion may comprise drug-rich regions with low polymer concentrations. Second, the mechanical mixing process can degrade the medication. These two drawbacks are interrelated, since to increase the homogeneity of the dispersion it is necessary to mix for longer periods of time or under more severe heat and pressure conditions. Higher mixing times or more severe conditions often result in higher amounts of degraded medication. Yuasa et al., 42 Chem. Pharm. Bull. 354-358 (1994) describe a solid dispersion process used to improve the bioavailability of poorly water soluble drugs. The polymer is hydroxypropylcellulose (HPC). The HPC / drug dispersion is prepared by solvent evaporation, which is then ground and sieved. The authors report that the drug is in the amorphous state in the solid dispersion. U.S. Patent No. 5,340,591 to Nakano et al. describes solid dispersions of a sparingly soluble drug and cellulosic polymers. The dispersion is formed by mixing the drug and the polymer with heating. The inventors state that the drug is in an amorphous state. Hasegawa et al., 33 Chem. Pharm. Bull. 388-91 (1985) describe a solid dispersion prepared by the process of solvent evaporation using the HPMCP polymer. However, solid dispersions have not generally been used commercially to provide the dosage of low solubility drugs. As recognized by Kai et al., Takeuchi et al. and Ford, J.L., 61 Pharm. Acta. Helv. 75 (1986), a problem encountered by dispersions of low solubility drugs has been that these dispersions are susceptible to changes during storage and therefore are not stable over time. Stability in this context refers to physical stability, which is the tendency of the drug present in a solid amorphous dispersion of the drug in polymer, to separate into drug-rich domains and / or to transform over time, at least partially, into the state vitreous. Most drugs or pharmaceutical formulations are stored at room temperature and relative humidity (atmospheric humidity) which often exceeds 50%. These drug formulations should be as physically stable as possible in such an environment. The stability should be observed for at least a month, ideally should be observed for a period of up to two years to provide a bioavailability without changes. Otherwise, such drug formulations require special handling and restrictions on prescriptions and use by patients. A major problem with the current solid drug dispersions is that although the dispersions may show an increased bioavailability of the drug of low solubility if administered shortly after preparation, bioavailability typically decreases over time in a typical storage environment. Said solid dispersions are often physically unstable because the medicament present in the dispersion reverts to the crystalline form with storage, particularly at high temperatures and humidity. Accordingly, the dispersion can not be used to provide an appropriate dosage of the medicament because the bioavailability of the medicament changes over time. For this reason, numerous researchers have sought to improve the stability of the dispersion. It has been generally believed that stable dispersions could be obtained by using a matrix material in which the medicament was highly soluble, thus obtaining a thermodynamically stable solid solution. See, for example, Chion et al., 58 J. Pharm. Sci. 1505 (1969), Sjokuist et al., 79 International J. Pharmaceutics 120 (1992), Sheen et al., 118 International J. Pharm. 221 (1995) and Dordunoo et al., 17 Drug Dev. &; Indust. Pharm. 1685 (1991). Unfortunately, this approach also has several drawbacks. First, it is difficult to find a particular polymer for each drug of interest to form a thermodynamically stable solid solution. The thermodynamic stability depends on the interactions between the drug and the polymer, which are generally not well understood, and the number of polymers acceptable for use in oral dosage formulations is quite limited. Second, thermodynamically stable dispersions of a drug and a polymer are typically possible only at low concentrations of drug in the dispersion. This requires a large amount of polymer to be dosed with the medicament, which often makes dosing by conventional dosage forms (such as pills, tablets or capsules) impracticable. Therefore, what is desired is a composition comprising a drug dispersion of low solubility in a polymer that provides superior bioavailability, together with improved stability of the dispersion in typical storage environments, particularly for dispersions in which the drug it is present in concentrations above its equilibrium value.

BRIEF SUMMARY OF THE INVENTION In a first aspect, the present invention provides a composition comprising a solid dispersion comprising a drug of low solubility and at least one of a particular class of polymers. At least most of the drug in the resulting dispersion is amorphous. The dispersion is prepared by a process of solvent processing. The polymer has a glass transition temperature of at least 100 ° C. measured at a relative humidity of 50%. The term "medication" conventionally indicates a compound with beneficial, prophylactic and / or therapeutic properties when administered to an animal, particularly a human. Another aspect of the invention comprises the same composition, except that (1) the dispersion itself is characterized by a glass transition temperature of at least 50 ° C, measured at a relative humidity of 50% and (2) the dispersion may be formed by any procedure. In a third aspect of the invention, there is provided a composition comprising a solid dispersion comprising a drug of low solubility and a stabilizing polymer. The composition also includes a concentration potentiating polymer that increases the measured maximum concentration of the drug when exposed to an environment of use. The stabilizing polymer has a vitreous transition temperature that is higher than the vitreous transition temperature of the polymer that increases the concentration, measured at a relative humidity of 50%. In a fourth aspect of the invention, there is provided a composition comprising a solid dispersion comprising a drug of low solubility and at least one of a particular class of cellulosic polymers. At least a majority of the drug is amorphous. The polymer has a glass transition temperature of at least 100 ° C, measured at a relative humidity of 50%. In a fifth aspect of the invention, there is provided a composition comprising a solid dispersion comprising a drug of low solubility and at least one polymer. At least a majority of the drug, once dispersed in the dispersion, is amorphous. The polymer has a glass transition temperature of at least 100 ° C, measured at a relative humidity of 50%. The dispersion is substantially homogeneous. Preferably, the dispersion exhibits a single glass transition temperature. In a sixth aspect of the invention, there is provided a method for treating a disorder by administering to a patient a dispersion containing a medicament and a polymer that increases the concentration. The dispersion comprises a medicament of low solubility and at least one stabilizing polymer, the stabilizing polymer having a vitreous transition temperature which is higher than the vitreous transition temperature of the polymer which increases the concentration. The polymer which increases the concentration increases the maximum concentration of drug in an environment of use with respect to a control composition comprising an equivalent amount of undispersed medicament. The present invention has various advantages over the prior art. A solid dispersion of a drug of low solubility and a polymer can increase the bioavailability of the drug of low solubility by creating an increased concentration of the drug in an aqueous environment of use. The invention provides compositions that are surprisingly stable in typical storage environments, compared to other solid dispersions. Accordingly, the compositions of the present invention enable the use of drugs of low solubility that otherwise do not have a high bioavailability in crystalline form, and also increase the bioavailability to reduce the dose of the medicament. In addition, the invention provides superior bioavailability of the medicament in an aqueous environment of use. The above features and other advantages of the invention will be more readily understood by considering the following detailed description of the invention, taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the glass transition temperatures of various polymers as a function of relative humidity. FIG. 2 is a schematic diagram of an example of spray drying device, useful in obtaining the solid dispersions of the present invention. FIG. 3 is a graph of a differential scanning calorimetry record for example 1 at a real humidity of 0%, showing the vitreous transition temperature as described in example 15.

DETAILED DESCRIPTION OF THE INVENTION A first aspect of the present invention provides a composition comprising a solid dispersion comprising a drug of low solubility and at least one polymer. The solid dispersion and the appropriate polymer (s) will be discussed in more detail below.

SOLID DISPERSIONS The solid dispersions of the present invention comprise a drug of low solubility and at least one polymer. At least a major part of the polymer in the dispersion is present in an amorphous, rather than crystalline state. By "amorphous" it is simply understood that the drug is in a non-crystalline state. The amorphous drug may exist as a phase of the pure drug, as a solid solution of the drug distributed homogeneously throughout the polymer or in any combination of these states or those intermediate between them. As used herein, the term "a major part" of the medicament means that at least 60% of the drug, once dispersed in the dispersion, is in an amorphous form, rather than in a crystalline form. Preferably, the medicament in the dispersion is substantially amorphous. As used herein, the term "substantially amorphous" means that the amount of medicament in crystalline form does not exceed 20%. More preferably, the medicament in the dispersion is "almost completely amorphous", meaning that the amount of medicament in crystalline form does not exceed 10%, as measured by powder X-ray diffraction or differential scanning calorimetry ("DSC"), or any other conventional quantitative measure. In general, a solid dispersion is not physically stable and the amorphous drug present in the dispersion tends to recrystallize with time. This is especially true when the concentration of the drug in the polymer is greater than its equilibrium value or is oversaturated. Said dispersions can be considered a solid supersaturated solution. Said solid supersaturated solutions are not thermodynamically stable. Over time it is believed that said solid dispersions will separate into a mixture of two or more phases, one phase enriched in medicament and the other phase enriched in polymer. The drug-rich phase generally contains crystalline or amorphous medication and the other phase generally contains a solid solution of the drug and the polymer in which the drug is at a lower concentration (than in the drug-rich phase) and may be in a concentration of balance in or near the polymer. The medication in the drug-rich phase may be crystalline or amorphous. In addition, over time, the amorphous drug in the drug-rich phase that has separated from the polymer may also tend to crystallize. Separation of a drug-rich phase generally results in a decrease in bioavailability, because the bioavailability of the amorphous or crystalline form of a drug of low solubility is usually much less than its bioavailability in a dispersion of amorphous drug in polymer. . Therefore, over time, the bioavailability of the drug in solid dispersions tends to decrease as increasing amounts of the drug are separated as an amorphous or crystalline drug. However, it has been determined that dispersions can be made that are physically stable over a relatively long period of time, that is, up to several months or even years. Surprisingly, it has been found that the stability of the dispersion is related to the glass transition temperature ("Tg") of the dispersion and the degree of homogeneity of the dispersion. As used herein, the change in "stability" refers to the rate of change of the drug from a dispersed amorphous state to a state in which the drug exists as a state rich in amorphous or crystalline medicament, throughout the time, in a typical storage environment. Such a change generally, in turn, decreases the bioavailability of the drug when dosed to a mammal. It has been found in many cases that the rate of change of the drug from the dispersed amorphous state to the crystalline state in the dispersion decreases with increasing Tg of the dispersion (ie the dispersion has improved its stability). Therefore, the speed at which the amorphous drug in the dispersion crystallizes can be reduced, increasing the Tg of the dispersion. This is unexpected, since the conventional approach to the stabilization of drug and polymer dispersions has been to find particular drug / polymer pairs that form thermodynamically stable dispersions. Contrary to conventional approaches to try to find thermodynamically stable dispersions, it has been determined that solid dispersions can be obtained that are essentially kinetically stable, although they may not be thermodynamically stable. Although one does not wish to stick to any particular theory, it is believed that the Tg of an amorphous material is related to the mobility of its components. The increase in the Tg of the dispersion can therefore inhibit the mobility of the drug in the dispersion. Thus, by increasing the Tg of the solid dispersion, the mobility of the drug can be decreased and thus its ability to form relatively pure domains, either amorphous or crystalline, can be inhibited. In cases where domains rich in amorphous drug are formed, the drug present in said domains generally crystallizes rapidly with respect to its crystallization rate in the original dispersion. In addition, by initially creating substantially homogeneous dispersions, i.e., dispersions in which the medicament is not present in drug-rich domains, the drug tends to be stabilized by the polymer and is not present in relatively pure drug domains that tend to be susceptible to crystallization. It is believed that the present invention is also applicable to relatively stable dispersions, whether kinetically or thermodynamically stable, which however contain drugs which, in relatively pure amorphous state, would be unstable by themselves. That is, the invention is applicable to drugs that in their pure amorphous state tend to be susceptible to crystallization. By raising the Tg of the dispersion and uniformly dispersing the drug throughout the polymer, so that the dispersion is substantially homogeneous, it would be possible to avoid the formation of relatively pure drug domains and thus stabilize the amorphous drug dispersion. In this way, the present invention finds utility in dispersions both thermodynamically stable and thermodynamically unstable. To achieve good stability, the dispersions of the present invention should have the following characteristics. First, the dispersion is substantially substantially homogeneous, so that the amorphous drug is dispersed as homogeneously as possible throughout the polymer. As used herein, "substantially homogeneous" means that the drug present in relatively pure amorphous domains in the solid dispersion is relatively small, in the order of less than 20%, and preferably less than 10%. Although the dispersion may have some drug-rich domains, it is preferred that the dispersion itself have a unique Tg, which shows that the dispersion is substantially homogeneous. This contrasts with a physical mixture of pure amorphous drug particles and pure amorphous polymer particles which generally shows two different Tg's, one from the drug and another from the polymer. However, since the degree of homogeneity is only one factor to be considered in terms of drug stabilization, even dispersions that are not substantially homogeneous can be stabilized by increasing the Tg of the dispersion. Second, the Tg of the dispersion should be relatively high. Because water is present under most practical storage conditions, the solid drug dispersion must be stable even in the presence of moderate humidity (relative humidity of the order of 50 to 70%). The content of polymer (s) and drug (% by weight of the drug making up the dispersion) should be chosen so that the Tg of the resulting dispersion, balanced with moist air of relative humidity ("RH") of about 50%, is at least 30 ° C (that is, a typical storage environment) and preferably greater than 50 ° C. As used herein, the relative humidity is given as the partial pressure of water in the storage atmosphere (typically air) divided by the partial pressure of the pure water at the storage temperature by 100%. In cases where two (or more) Tg is observed, the lower vitreous transition temperature of the resulting dispersion, when equilibrated with moist air with an RH of about 50%, is at least 30 ° C, and preferably 50 ° C. ° C. It should be noted here that the mobility of a material varies greatly depending on the temperature, particularly at temperatures close to the Tg of the material. (See for example, CM Roland and KL Ngal (104 J. Chem. Phys. 2967-2970 (1996)) and R. Bohmer, et al. (99 J. Chem. Phys. 4201-4209 (1992)) discussing the "fragility" of the glasses). Fragility is essentially a measure of the slope of the logarithm of the average relaxation of a vitreous material (tau) against the temperature near the Tg of the crystal. The fragility of glasses of the type we are considering here may be high enough so that tau, which is approximately proportional to mobility, may increase from 5 to 20 times for each 10 ° C increase in temperature. In this way, for example, for vitreous materials at temperatures just below their Tg, mobility can increase 10 times for each temperature increase of 10 ° K. In this way, by increasing the Tg of a material, even 5 or 10 ° C can substantially increase the stability of the material. Tg as used herein, is the characteristic temperature at which a glassy material, with gradual warming, undergoes a relatively rapid physical change (for example in 10 to 100 seconds) of a glassy state to a gummy state. The vitreous transition region is generally the region of temperature at which the structural relaxation time of a glassy material falls in the range of a few seconds to tens of minutes, so that relaxation can be measured in a convenient period of time . Specifically, Moynihan, et al. (279 Ann. N.Y. Acad. Sci. 15-35 (1976)) have stated that the widely accepted mean relaxation time (tau) for a material at this Tg is approximately 100 seconds. As described below, scientists have developed various techniques for measuring the Tg of a vitreous material that are consistent with this definition. In the case of polymers, there are typically various physical changes that take place with heating. Each of these changes corresponds to an increase in the mobility of the polymer. These transitions are designated as a, ß and?, In which a means the event of higher temperature, ß the next greater and? the next. Tg, as used in this, refers to transitions a- In this region of temperature there is a discontinuous change of various important material properties, such as specific heat, mechanical modulus, relaxation rate, long-range molecular mobility and volume change with temperature. Many factors influence the Tg of a polymer, the most important of which are chemical structure and molecular weight. In general, organic materials that have some of the combinations of high levels of hydrogen bonds, polar interactions and% electron interactions, rigid polymer backbones and high molecular weights, result in higher Tg values.

The Tg of an amorphous material such as a polymer, drug or dispersion can be measured by various techniques, including dynamic mechanical analyzer (DMA), dilatometer, dielectric analyzer and by differential scanning calorimetry (DSC). The exact values measured by each technique may vary somewhat, but are usually from 10 ° C to 30 ° C from each other. The reason for the variation is the nature of the measurement. For example, the DMA measures the mechanical response (elastic and inelastic) to an oscillating mechanical force. In comparison, the DSC measures the total heat flow in and out of the sample as a function of temperature. In both cases a glass transition temperature is observed, but as a rule, the Tg observed in the DMA measurement takes place at a higher temperature (typically 10-20 ° C) compared to one measured by DSC. This is due to the fact that the DSC experiment measures the heat flux necessary to break the intermolecular bonds and increase the number of conformational states that are populated, while the DMA measures how the macroscopic mechanical properties change as a result of microscopic changes, that necessarily take place at a higher temperature. It should be noted that the Tg for a homogeneous mixture of two amorphous materials can be estimated when the densities of the two materials are similar, as is the case for many drugs and polymers. The following expression, called the Gordon-Taylor equation (M. Gordon and JS Taylor, 2 J. of Applied Chem. 493-500 (1952)) approximates the Tg,?, 2 of a mixture of two components: w, tg +? w2tgl T - S l W 1. + 'K i Wr 2 where wi and w2 are the weight fractions of components 1 and 2, Tg? and Tg2 are the glass transition temperatures of components 1 and 2 (in degrees Kelvin), respectively, Tg,?, 2 is the glass transition temperature of the mixture of components 1 and 2, and K is a constant related to the free volumes of the two components. Corresponding expressions can be written for a mixture of a larger number of components. It follows from these expressions (and from the fact that the Tg of many amorphous drugs is quite low), that for the Tg of a dispersion to meet the stability criteria cited above (Tg> 30 ° C at 50% RH) , preferably Tg> 50 ° C at 50% RH), a significant part of the dispersion should first comprise a polymer with a relatively high Tg. Second, the equilibrium water content (water has an amorphous Tg of about 135-138 ° K) should be low. Third, the drug content of the dispersion should not be too high. This is particularly true if the amorphous drug itself has a low Tg in the presence of moist air. The amounts of the various components of the dispersion will be selected accordingly so that the glass transition temperature resulting from the dispersion is greater than 30 ° C, measured at a RH of 50%, and preferably greater than 50 ° C measured at a RH. 50% Therefore, the Tg of a drug dispersion can be made larger and, therefore, increase the stability of the dispersion, keeping the drug content low and the polymer content high. In a relative sense, this is true even in dispersions obtained with polymers with sufficiently low Tg that are outside the invention. Therefore, a dispersion of a drug in a polymer such as HPMCP, having a Tg at a 50% RH of about 90 ° C, can have a Tg greater than 50 ° C as long as the drug content is low (eg example, in the order of about 10 to 20% by weight or less). Despite the fact that stable dispersions can be made by homogeneously dispersing the drug at low concentration in a known polymer of moderate Tg, such dispersions are often not practical for use in a conventional dosage form such as a tablet, due to the large amount of dispersion required. Thus, for example, a medicament with a therapeutic dose of 100 mg would require 1000 mg of a 10% by weight drug dispersion, making it impractical to incorporate it into a single dosage form as a tablet. In contrast to this, a dispersion of the same drug in a high Tg polymer of the invention could have a much higher drug load (for example 20 to 30%) and still have a sufficiently high Tg for good stability (Tg >30 ° C or preferably Tg > 50 ° C).

Because the vitreous transition is a kinetic process, the time scale for the measurement of Tg also has an effect on the measured Tg. For calorimetry experiments the glass transition temperature depends on the scanning speed of the calorimeter, resulting in higher temperatures for higher scanning speeds. As used herein, when referring to the numerical values for the Tg of a material, the Tg of a material is the largest transition measured using DSC at a scanning speed of 10 ° C / min and for which the material is has pre-balanced with a specific HR. In addition, to minimize the loss of water absorbed during the DSC experiment, the sample should be sealed, after equilibration of the appropriate RH, in a steam-sealed sample container, such as an autosampler for aluminum DSC, at 2 ° C. atmospheres, 30 μl Perkin Elmer. The stability of the dispersion over time can be measured in various ways. First, the change in the maximum drug concentration ("MDC") that occurs when the dispersion dissolves in an appropriate in vitro test solution, such as a duodenum fixation model ("MFD") solution, can be measured. . This MDC measured in vitro has been shown to be related to the bioavailability of the dispersion in vivo. In addition, the change of the area under the curve ("AUC"), which is the integration of a graph of drug concentration versus time, can also be measured. The AUC can be determined for in vitro dissolution assays by depicting drug concentrations in the patient's blood over time. AUCs are well-understood tools frequently used in pharmaceutical techniques and have been extensively described in, for example, "Pharmacokinetics Processes and Mathematics", ACS Monograph 185 (1986) by Welling. In addition, stability can be determined by evaluating the change in the physical state (crystalline versus amorphous) of the drug in the dispersion. Specifically, the fraction of the crystalline drug in the dispersion can be measured by any conventional physical measurement, such as X-ray diffraction or scanning electron microscopy ("SEM"). In a preferred embodiment, the composition comprising the solid dispersion provides an increased bioavailability of the medicament. It has been determined that the in vitro dissolution of a dispersion in an MFD solution is a good indicator of activity and bioavailability in vivo. In particular, the dissolution of a dispersion can be tested by adding it to an MFD solution and stirring to stimulate dissolution. Preferably, the dispersion of the present invention provides an MDC of the medicament multiplied by a factor of at least 1.5 relative to the equilibrium concentration of a control composition comprising an equivalent amount of the undispersed medicament. The comparison composition is conventionally the drug only undispersed (eg, typically, the crystalline drug only in its thermodynamically more stable crystalline form, or in cases where a crystalline form of the medicament is not known, the control may be the amorphous drug only) or the undispersed medicament plus one weight of inert diluent equivalent to the polymer weight of the test composition. More preferably, the MDC of the medicament achieved with the solid dispersions of the present invention exceeds the equilibrium concentration of the control medicament by a factor of at least 3, and more preferably, by a factor of at least 5. Alternatively, the The dispersion of the present invention provides an AUC, for dissolution times between 0 and 90 to 1200 minutes, in an in vitro dissolution test, which is 1.25 times greater than that of the control composition comprising an equivalent amount of medicament. without dispersing. Alternatively, the dispersion of the present invention, when dosed orally to a human or other animal, provides an AUC of drug concentration in the blood that is 1.25 times greater than that observed when dosing a control composition comprising an amount equivalent of undispersed medication. A typical assay for evaluating increased bioavailability can be performed by (1) dissolving a sufficient amount of control composition, typically the drug alone, in the in vitro assay medium, typically MFD solution, to achieve the equilibrium concentration of the drug, (2) dissolution of a sufficient amount of dispersion, in an equivalent test medium, so that if all the drug is dissolved the theoretical concentration would exceed the equilibrium concentration of the undispersed drug by a factor of at least 2, and (3) ) determination of whether the measured MDC of the dispersion in the test medium is at least 1.5 times the equilibrium concentration of the drug without dispersing. The concentration of dissolved drug is typically measured as a function of time, by sampling the drug and representing the concentration versus time, so that the MDC can be calculated. To avoid the medication particles that would give a wrong determination, the test solution is either filtered or centrifuged. The "dissolved drug" is preferably taken as the material that either passes through a 0.45 μm syringe filter or, alternatively, the material that remains in the supernatant after centrifugation. Filtration can be performed using a 0.45 μm, 13 mm polyvinylidene difluoride syringe filter purchased from Scientific Resources under the trade name TITAN (R). Centrifugation is typically carried out in a polypropylene microcentrifuge tube by centrifugation at 13,000 G for 60 seconds. Other similar filtration or centrifugation methods can be used and useful results obtained. For example, using other types of microfilters, somewhat higher or lower values (± 10-40%) than those obtained with the filter specified above may be obtained, but they will still allow the identification of the preferred dispersions. It is recognized that this definition of "dissolved drug" comprises not only the solvated monomer drug molecules, but also a wide range of species such as polymer / drug assemblies having submicrometric dimensions, as aggregates of polymer and drug mixtures, micelles, polymeric micelles , colloidal particles or nanocrystals, polymer / drug complexes and other drug-containing species that are present in the filtrate or supernatant in the specified dissolution test. The bioavailability of the medicaments in the dispersions of the present invention can also be tested in vivo in animals or humans, using conventional procedures to make said determination. An in vivo assay, such as a crossover study, can be used to determine whether a dispersion provides an increased drug concentration in the blood (serum or plasma) versus the area of time under the curve (AUC) for a test subject dosed with a control composition as described above. In an in vivo crossover study, a "test dispersion composition" is dosed to half a group of 12 or more humans and, after a suitable washout period (for example one week) the same subjects are dosed with a "composition" of control "comprising an equivalent amount of the undispersed medicament as" test dispersion composition ". The other half of the group is dosed with the control composition first, followed by the test dispersion composition. Bioavailability is measured as the area under the curve (AUC) determined for each group. In vivo determinations of AUC can be made by depicting the serum or plasma concentrations of the drug along the ordinate (Y axis) versus time along the abscissa (X axis). Usually, the AUC values represent a series of values taken from all the subjects of a patient test population and are, therefore, average values averaged over the entire test population. By measuring the AUC for a population to which the test dispersion composition has been administered, and comparing it with the AUC for the same population to which the control composition has been administered, the dispersion composition of the test can be evaluated. . The determination of the AUC is a well-known procedure and is described, for example, in the same monograph of Welling ACS mentioned above.

THE DISPERSION POLYMERS Polymers that are suitable for use in the dispersions of the present invention are selected to provide a Tg for the dispersion as described above. The polymer must have at least some solubility in aqueous solution at physiologically relevant pH (for example pH 1-8). Virtually any polymer that is inert would be adequate. By "inert" is indicated simply unreactive or bioactive in an undesired way, although still able to positively affect the bioavailability of the drug. The polymer should also be biologically inert or non-toxic, in the sense that it is acceptable for oral administration to a mammal like a human. The amount of polymer present in the dispersion can range from about 20% by weight to about 99% by weight of the dispersion. A preferred class of polymers are the cellulosic polymers and esters and ethers thereof, as well as mixed esters and ethers, including both the so-called "enteric" and "non-enteric" polymers. As discussed above, the Tg of the polymer should be sufficiently high so that the resulting dispersion had a relatively high Tg (greater than 30 ° C at a 50% RH). Although polymers that have a dry Tg (for example a moisture content equivalent to an RH of around 10% or less) greater than 140 ° C can provide good stability for solid dispersions if protected from moisture, it is often they become unstable when exposed to ambient humidity levels (for example, an RH of 30 to 90%). Therefore, since the dispersion can be stored under conditions subject to a relative humidity exceeding 50%, it is necessary to select polymers having relatively high Tg at a high relative humidity. Some polymers exhibit marked decreases in Tg by increasing the water content due to water absorption. FIG. 1 shows the values of Tg measured as a function of the relative humidity of six different polymers. As shown in FIG. 1, the Tg of polyvinylpyrrolidone (PVP) falls much more rapidly with the RH increasing than the Tg of other polymers. This is because the amount of water absorbed by the PVP at a given RH is much greater than for the other polymers. Preferably, the polymer does not absorb more than 10% by weight of water at a 50% RH. In any case, the Tg of the polymer should remain relatively high balanced with moist air (50% RH). In a preferred embodiment of the invention, the polymer should have a Tg of at least 100 ° C at 50% RH, and preferably should be at least 105 ° C at 50% RH, and even more preferably at 50 ° C. minus 110 ° C at a 50% RH. As mentioned above, the stability can be drastically improved by increasing the Tg even in small amounts of 5 to 10 ° C. Polymers within the scope of the present invention include cellulose acetate phthalate (CAP) and cellulose acetate trimellitate (CAT). It should be noted that a polymer name such as "cellulose acetate phthalate" refers to any of the family of cellulosic polymers having acetate and phthalate groups linked by ester linkages to a significant fraction of the hydroxyl groups of the cellulosic polymer. Generally, the degree of substitution of each substituent group can range between 0.2 and 2.8, provided that the other polymer criteria are met. The "degree of substitution" refers to the average of the three hydroxyl per repeating unit of saccharide of the cellulose chain that has been replaced. For example, if all the hydroxyl of the cellulose have been replaced by phthalate, the degree of phthalate substitution is 3. Also included in each type of polymer family are the cellulosic polymers that have additional substituents added in relatively small amounts that do not substantially alter the activity of the polymer.

More generally, a class of polymers that meets the requirements of the present invention includes cellulosic polymers with an aromatic substituent attached by ester or ether in which the polymer has a degree of substitution of at least 0.2. Celluloses with a significant fraction of aromatic substituents generally have higher Tg values and low water absorption values, desirable for use in the present invention. Examples of aromatic substituents include benzoate, phenoxy and ethoxyphenyl. In order that said aromatic substituted polymers also have the necessary aqueous solubility, it is also desirable that sufficient hydrophilic groups, such as hydroxypropyl or carboxylic acid functional groups, are attached to the polymer. Said carboxylic acid groups can be either linked by ether to the polymer as in the case of the carboxyethyl groups, or they can be linked by ester bonds such as the succinate groups. One class of substituents which is particularly desirable is that which comprises aromatic substituents with carboxylic acid functionality, since they provide both an aromatic group for stimulating a high Tg, and an ionizable carboxylic acid group which can stimulate aqueous solubility. The aromatic groups substituted with carboxylic acids can be linked to the cellulose polymer by ester or ether bonds, by means of hydroxyl groups of the cellulose backbone or by means of hydroxyl groups of other substituents such as hydroxypropoxy. Examples of aromatic groups substituted with carboxylic acids which may be linked by ester bonds include phthalate, trimellitate, the different isomers of pyridinedicarboxylic acid, terephthalate, isophthalate and alkyl substituted derivatives of these groups. Examples of aromatic groups substituted with carboxylic acids which may be linked by ether linkages include salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, the different isomers of alkoxyphthalic acid, such as ethoxyphthalic acid and ethoxyisophthalic acid, the different isomers of alkoxynicotinic acid, such as ethoxynicotinic acid, and the different isomers of alkoxypicolinic acid such as ethoxy picolinic acid. It may also be undesirable to add other substituents to the polymer to obtain the desired physical properties. Examples of ester substituents are residues of lower carboxylic acids such as acetate, propionate and butyrate, C? -C alkoxy groups such as methoxy, ethoxy, propoxy and butoxy and C? -C4 hydroxyalkoxyls such as hydroxyethoxy, hydroxypropoxy and hydroxy butoxy. A particularly desired subset of these cellulosic polymers are those which possess both an aromatic substituent with carboxylic acid functionality and an alkylate substituent. Examples of polymers include: cellulose acetate phthalate, methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose propionate phthalate, hydroxypropylcellulose butylate phthalate, cellulose acetate trimellitate acetate , methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose trimellitate propionate, cellulose trimellitate butyrate, cellulose acetate terephthalate, cellulose acetate softalate, pyridinedicarboxylate acetate cellulose, salicylic cellulose acetate, alicylic acid hydroxypropyl cellulose acetate, ethylbenzoic acid cellulose acetate, ethylbenzoic acid hydroxypropylcellulose acetate, phthalic acid acetate cellulose, nicotinic acid ethyl acetate, and picolinic acid ethyl cellulose acetate. Even more preferred are those celluloses with both phthalate or trimellitate groups attached to ester as an alkylate group. Examples of polymers of this class include: cellulose acetate phthalate, methylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropylcellulose butylate phthalate, hydroxypropylmethylcellulose trimellitate, cellulose acetate trimellitate, cellulose trimellitate propionate, cellulose trimellitate butyrate , cellulose acetate terephthalate, cellulose acetate isophthalate. The most preferred polymers are cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.

It should be noted that in the above polymer nomenclature, the ether-linked substituents are listed second before the "cellulose", as the radical bound by the ether group (for example "(ester subst.) Ethylbenzoic-cellulose acid" has substituents of ethoxybenzoic acid) and the ester-linked substituents are listed first before the "cellulose", such as the carboxylate (for example, "ether phthalate" cellulose) has a carboxylic acid of each phthalate radical attached by ester to the polymer and the other unreacted carboxylic acid). However, for all the polymers listed above, the type and degree of substitution of the substituents should be such that the Tg of the resulting polymer meets the criteria listed above (eg, the Tg at 50% RH is> 100 °). C). In contrast, cellulosic polymers substituted with carboxylic acid functionality groups that do not meet this criterion are certain types of hydroxypropyl methylcellulose phthalate (HPMCP). In particular, HPMCP-HP50, HPMCP-HP55 and HPMCP-HP55S absorb all enough water by balancing at a 50% RH so that their respective Tg falls below 100 ° C. FIG. 1 shows Tg as a function of relative humidity for PVP polymers, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose phthalate (HPMCP), all of these polymers not included in the scope of this invention when used alone. FIG 1 also shows the Tg of CAP and CAT, both preferred embodiments of the polymers suitable for use alone in the invention. As FIG.1 shows, at high RH (for example, from 30% to 75%), the Tg of CAP and CAT are much higher than the Tg of the other respective polymers. Although specific polymers have been discussed as being suitable for use alone in the dispersions of the present invention, mixtures of polymers may also be useful. Therefore, mixtures of different polymers can be used to form the dispersions of the present invention, with some polymers with higher Tg and others lower, provided that the resulting dispersion meets the criteria discussed above. In general, this can be achieved by including a sufficient amount of polymer with a Tg above 100 ° C at a 50% RH. In addition to having a higher Tg as described above, the polymers that are preferred are those that are insoluble at gastric pH, or pH of about 1-2, but are soluble at intestinal pH, or pH of about 6-8. . This should result in a dispersion that usually does not dissolve until it reaches the duodenum of the digestive tract.

THE MEDICINE The drug in its pure state can be crystalline or amorphous, but at least a majority of the drug is amorphous when dispersed in the solid dispersion. Preferably, the medicament is in a substantially amorphous or non-crystalline state as described above. The dispersion may contain from about 1 to about 80% by weight of medicament, depending on the dose of medicament. In general, bioavailability and physical stability are maximized at low drug loads (less than 10% by weight of drug in the dispersion). However, due to the practical limit of the size of the dosage form, higher drug loads are often preferred and act well. A specific advantage of using the high Tg polymers of the invention as the dispersion polymer is that they allow higher drug loads in the dispersion to be used, achieving the given Tg of target dispersion and the target stability level. As mentioned above, the Tg of the dispersion is generally dictated by the Tg and the weight fraction of the components that are part of the dispersion. Therefore, for a given drug and relative humidity, the greater the Tg of the dispersion polymer, the greater the fraction by weight (drug loading) of the drug that can be used and still have a sufficiently high Tg (e.g., 50 ° C at 50% RH) and still have an acceptable stability. For example, for a moderate Tg polymer such as HPMCP, the dispersion Tg may fall below a value of 50 ° C at a 50% RH for any drug loading above about 10% by weight, while that for a high Tg polymer, such as CAP, the dispersion Tg may fall below a value of 50 ° C to a 50% RH only at drug loads above 35% by weight. The medicament has a sufficiently low aqueous solubility that it is desirable to increase its solubility, either in the dosage form to improve its release characteristics, or out of the dosage form to improve its concentration. Therefore, whenever it is desirable to increase the concentration of the drug in an environment of use, the invention will find utility. The medicament is a "drug of low solubility", which means that the medicament can either be "substantially insoluble in water" (which means that the medicament has a minimum aqueous solubility at physiologically relevant pH (for example pH 1-8). ) of less than 0.01 mg / ml), or "sparingly soluble in water", ie, it has a solubility in water of up to about 1 to 2 mg / ml or even less, up to a solubility in moderate water, with a solubility in water as high as about 20 to 40 mg / ml. In general, it can be said that the medicament has a ratio of dose to aqueous solubility greater than 100 ml, when the solubility of the drug is the minimum value observed in any physiologically relevant aqueous solution (for example, those with pH values between 1 and 8). ) including gastric and intestinal USP simulated buffers. In some cases, it is also desirable to increase the solubility of the medicament in the dosage form to increase the rate of diffusion or release of the dosage form, or to improve the absorption of the drug in the colon. In such cases, the invention can be applied to medicaments with solubility as high as 20 to 40 mg / ml. This is particularly true when it is desired to release a solution of the medicament. In such cases, the dose to aqueous solubility ratio may be low as from 1 to 100 ml. Virtually any beneficial therapeutic agent that meets the solubility criteria can be used as a medicament in the present invention. In addition, the medicament can be used in the form of its pharmaceutically acceptable salts as well as in anhydrous and hydrated forms. Preferred classes of medications include, but are not limited to, antihypertensive agents, anxiolytic agents, anticoagulants, anticonvulsants, blood glucose lowering agents, decongestants, antihistamines, antitussives, antineoplastic agents, beta-blockers, anti-inflammatory agents, antipsychotic agents, cognitive enhancers, cholesterol reducing agents, antiobesity agents, agents for autoimmune diseases, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinson's agents, agents against Alzer's disease, antibiotics, antidepressants and antiviral agents. Specific examples of the above and other classes of medicaments and therapeutic agents administrable by the invention are given below, by way of example only. For each named medicament it will be understood that the neutral form of the medicament, pharmaceutically acceptable salts, as well as prodrugs are included. Specific examples of antihypertensives include prazosin, nifepidine, trimazosin and doxazosin, a specific example of an anxiolytic agent is hydroxyzine, a specific example of a blood glucose lowering agent is glipizide, a specific example of an anti-impotence agent is sildenafil citrate, specific examples of antineoplastics include chlorambucil, lomustine and equinomycin, a specific example of an imidazole-type antineoplastic is tubulazole, specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, flurbiprofen and (+) - N-. { 4, - [3- (4-fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hiroxyurea, a specific example of a barbiturate is phenobarbital, specific examples of antivirals include acyclovir and virazole, specific examples of vitamin / nutritional agents include retinol and vitamin E, specific examples of beta-blockers include timolol and nadolol, a specific example of emetic is the apomorphine, specific examples of diuretics include chlorthalidone and spironolactone, a specific example of anticoagulant is dicumarol, specific examples of cardiotonics include digoxin and digitoxin, specific examples of androgens include 17-methyltestosterone and testosterone, a specific example of a corticoid mineral is deoxycorticosterone, a specific example of a hypnotic / sternoidal anesthetic is alphaxolone, specific examples of anabolic agents include fluoxymesterone and methane-stenolone, specific examples of antidepressant agents include sulpiride, [3,6-dimethyl-2- (2,4 , 6-tr¡methyl-f enoxi) -pyridin-4-yl] - (1-ethylpropyl) amine, Sd-dimethyl ^ -IS'-pentoxy ^^ '^'. ß'-trimethylphenoxyJpyridine, paroxetine, fluoxetine, venlafaxine and sertraline, specific examples of antibiotics include ampicillin and penicillin G, specific examples of anti-infection agents include benzalkonium chloride and chlorhexidine, specific examples of coronary vasodilators include nitroglycerin and myoflazine, a specific example of hypnotic is etomidate, specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorozolamide, examples Specific antifungal agents include econazole, terconazole and griseofulvin, a specific example of antiprotozoal is metronidazole, specific examples of anthelmintic agents include thiabendazole and oxfendazole, specific examples of antihistamines include astemizole, levocabastine, cetirizine and cinnarizine, specific antipsychotic examples include ziprasidone, fluspirilene and penfluoridol, e specific examples of gastrointestinal agents include loperamide and cisapride, specific examples of serotonin antagonists include cetanserin and mianserin, a specific example of anesthetic is lidocaine, a specific example of hypoglycemic agent is acetohexamide, a specific example of antiemetic is dimenhydrinate, a specific example of antibacterial is cotrimoxazole, a specific example of dopaminergic agent is L-DOPA, specific examples of agents against Alzheimer's disease are THA and donepecil, a specific example of antiulcer agent / H2 antagonist is famotidine, specific examples of sedative / hypnotic agents include chlorodiazephoxide and triazolam, a specific example of a vasodilator is alprostadil, a specific example of a platelet inhibitor is prostacyclin, specific examples of ACE / antihypertensive inhibitors include enalapril and lisinopril, examples of which are Cyclic tetracycline antibiotics include oxytetracycline and minocycline, 5 specific examples of macrolide antibiotics include erythromycin, azithromycin, clarithromycin and espriamycin, specific examples of glycogen phosphorylase inhibitors include [R- (R'S ')] - 5-chloro-N- [ 2-hydroxy-3- [methoxymethylamino] -3-oxo-1- (phenylmethyl) propyl] propyl] -1H-indole-2-carboxamide and [(1S) -benzo, -3 ((3R, 4S) -dihydroxypyrrolidine -1-l) - (2R) -hydroxy-3-oxypropyl] amide io of 5-chloro-1 H-indole-2-carboxylic acid. Additional examples of medicaments administrable by the invention are the glucose-reducing drug chloropropamide, the anti-fungal fluconazole, the anti-hypercholesterolemic atorvastatin calcium, the antipsychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride and doxepin hydrochloride, the anti-hypertensive amlodipine besylate, the anti-inflammatories piroxicam and celicoxib, and the antibiotics carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin and doxycycline hyclate. Additional examples of drugs administrable by The invention includes: an antidepressant agent, [3,6-dimethyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] - (1-ethylpropyl) amine and [3,6-dimethyl-2- (2,4,6, -trimethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine hydrochloride, an inhibitor of glycogen phosphorylase, [(1S) -benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxypropyl] -amide of 5-chloro-1 H-indole -2-carboxylic, an inhibitor of glycogen phosphorylase, [R- (R *, S *)] - 5-chloro-N- [2-hydroxy-3- [methoxymethylamino) -3-oxo-1- (phenylmethyl) propyl] -1 H-indole-2-carboxamide, an antidepressant agent, 3,6-dimethyl-4- (3'-pentoxy) -2- (2 ', 4I, 6, -trimethylphenoxy) pyridine, and an antinflmatorio (+) - N-. { 4- [3- (4-fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea.

NH2 PROCEDURE FOR MAKING DISPERSIONS The dispersions of the present invention can be made according to any known process with results in at least the majority (at least 60%) of the drugs in the amorphous state. Examples of mechanical processes include grinding and extrusion, melt processes include high temperature melting and solvent modified melting, and solvent processes include non-solvent precipitation, spray coating and spray drying. Although the dispersions of the present invention can be made by any of these processes, the dispersions generally have maximum bioavailability and stability when the drug is dispersed in the polymer such that it is substantially amorphous and substantially homogeneously distributed throughout the polymer. Although in some cases the substantially amorphous and substantially homogeneous dispersions can be made by any of these methods, it has been found that said dispersions are preferably formed by "solvent processing", which consists in the dissolution of the medicament and one or more polymers in a solvent common. "Common" here means that the solvent, which may be a mixture of compounds, will simultaneously dissolve the drug and the polymer (s). After both the drug and the polymer have dissolved, the solvent is quickly removed by evaporation or by mixing with a non-solvent. Examples of processes are spray drying, spray coating (tray coating, fluidized bed coating, etc.) and precipitation by rapid mixing of the polymer and drug solution with CO2, water and some other non-solvent. Preferably, removal of solvent results in a solid dispersion which is a solid solution of drug dispersed in the polymer (s). When the resulting dispersion constitutes a solid solution of drug in polymer, the dispersion can be thermodynamically stable, this means that the drug concentration in the polymer is at or below the equilibrium value, or it can be considered as a solid solution supersaturated in the that the concentration of drug in the dispersion polymer (s) is above its equilibrium value. The solvent can be removed by means of the spray drying process. The term "spray-dried" is conventionally used and refers broadly to processes that involve breaking liquid mixtures into small droplets (atomization) and rapidly removing the solvent from the mixture in a container (spray-drying device) in which there is a powerful driving force for the solvent evaporation of the drops. The powerful driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying device below the vapor pressure of the solvent at the temperature of the drops that are dried. This is achieved, either (1) maintaining the pressure in the partial vacuum spray drying device (for example, 0.01 to 0.50 atm), (2) mixing the liquid drops with a warm drying gas, or (3) ) both. Essentially, suitable solvents for spray drying can be any organic compound in which the drug and polymer are mutually soluble. Preferably, the solvent is also volatile, with a boiling point of 150 ° C or less. In addition, the solvent should have a relatively low toxicity and be removed from the dispersion to 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 processing step such as drying on trays, following the spray drying or spray coating processes. Preferred solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol and butanol, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, esters such as ethyl acetate and propyl acetate, and various other solvents such as acetonitrile, methylene chloride, toluene, and the like. , 1, 1-trichloroethane. Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, such as mixtures with water, provided that the polymer and the medicament are sufficiently soluble to make the spray drying process practicable. Generally, non-aqueous solvents are preferred, which means that the solvent comprises less than about 40% by weight of water. Generally, the temperature and flow rate of the drying gas are chosen so that the drops of polymer / drug solution are sufficiently dry by the time they reach the wall of the device to be essentially solid, and to form a powder thin and do not stick to the wall of the device. The actual length of time to achieve that level of drying depends on the size of the drops. The droplet sizes generally range from 1 μm to 500 μm in diameter, being more typical from 5 to 100 μm. The high surface to volume ratio of the droplets and the large driving force for the evaporation of the solvent leads to real drying times of a few seconds or less. This rapid drying is often critical for the particles to maintain a homogeneous uniform dispersion instead of separating into drug-rich and polymer-rich phases. The solidification times should be less than 100 seconds, preferably less than a few seconds, and more preferably less than 1 second. In general, in order to achieve this rapid solidification of the drug / polymer solution, it is preferred that the size of the droplets formed during the spray drying process be less than 100 μm in diameter, and more preferably less than 25 μm in diameter. The resultant solid particles thus formed are less than generally 100 μ in diameter, preferably less than 50 μm in diameter and more preferably less than 25 μm in diameter. Typically, the particles are from 1 to 20 μm in diameter. Following solidification, the solid powder may be in the spray-drying chamber for 5 to 60 seconds, more solvent being evaporated from the solid powder. The final solvent content of the solid dispersion leaving the dryer should be low, since this reduces the mobility of the drug molecules in the dispersion, thus improving their stability. Generally, the residual solvent content of the dispersion should be less than 10% by weight and preferably less than 2% by weight. In some cases, it may be preferable to spray a solvent or a solution of polymer or other excipient in the spray-drying chamber to produce aggregation of the dispersion particles in larger granules., as long as the dispersion is not adversely affected. Spray drying processes and spray drying equipment are described in the Chemical Engineers' Handbook, sixth edition (RH Perry, DW Green, JO Maloney, eds.) McGraw-Hill Book Co. 1984, pages 20-54 a 20-57 by Perry. More details of spray drying processes and equipment are reviewed by Marshall "Atomization and Spray-Drying", 50 Chem. Eng. Prog. Monogr. Series 2 (1954).

COMPOSITIONS WITH STABILIZING POLYMERS AND INCREASING THE CONCENTRATION Another aspect of this invention provides a composition containing a mixture of polymers. The composition comprises a solid dispersion comprising a drug of low solubility and at least one "stabilizing polymer". At least a majority of the drug is amorphous. The composition also includes a "concentration increasing polymer" which increases the measured maximum concentration of the drug in the environment of use (MDC). The polymer that increases the concentration can, for example, inhibit or decrease the rate of precipitation or crystallization of the drug in an aqueous solution. The polymer which increases the concentration may be either part of the dispersion or may be added to the composition after the formation of the solid dispersion. The term "concentration enhancing polymer" generally means any polymer that when present in a dissolution test, as described above, results in an increase in the maximum concentration of the "dissolved drug". As described above, the dissolved medicament can be any species containing medicament that is present in the supernatant or filtrate of the dissolution test. The "stabilizing polymer" has a Tg that is greater than that of the polymer that increases the concentration at a relatively high RH, for example, RH between 30 and 75%. This results in a composition in which the medicament has a greater stability during storage than a composition containing only the medicament and the polymer that increases the concentration. Together, the combination of the two polymers results in increased bioavailability and dispersion stability greater than that achieved by the use of the polymers separately. Polymers suitable for use as a stabilizing polymer include all those which are suitable for use in solid dispersions of the present invention as described above, with the exception of the limitation of the higher Tg. The stabilizing polymer should be inert and have at least some solubility in water at physiologically relevant pH (e.g., pH 1-8). When it is simply desired to increase the stability of the composition, the stabilizing polymer can be selected so that it simply has a Tg that is greater than the polymer that increases the concentration at the relevant relative humidity, rather than a Tg that exceeds 100 ° C at a HR of 50%. For example, the following polymers can also be used as a stabilizing polymer: hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose , hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose and carboxyethylcellulose. Of course, greater stability will be obtained if the stabilizing polymer is selected such that it has a relatively high Tg at a moderate relative humidity, i.e., at least 100 ° C at a 50% RH. The optimum amount of stabilizing polymer present in the dispersion will vary depending on things such as the physical properties of the medicament (such as its solubility and amorphous Tg), the dose of medicament and the type of dosage form to be administered. In general, sufficient stabilizing polymer is added so that the resulting dispersion has sufficient stability to meet the minimum stability criterion for the pharmaceutical product. Typically this is a Tg of 30 ° C or greater and preferably a Tg of 50 ° C or greater for the dispersion having a typical water content, that is, for dispersions that have been subjected to the typical storage environment. Also, since bioavailability is also an important criterion, it may be desirable to limit the amount of stabilizing polymer to make room in the formulation for more concentration-increasing polymer, so that MDC and AUC are obtained in vitro and in vivo. acceptably high In some cases, to obtain the best compromise between stability and bioavailability, the dispersion is formed only with the drug and the stabilizing polymer (to maximize the stability) and then the polymer that increases the concentration is wet or dry. dispersion, or otherwise added to the dosage form so that the polymer that increases the concentration does not reduce the Tg of the dispersion, thus compromising its stability. The polymers that increase the concentration of the present invention increase the maximum concentration of the drug (MDC) in solution relative to a control solution comprising an equivalent amount of drug when subjected to the dissolution test described above. The solvent can be dissolved in the form of solvated monomer molecules or in any other submicron structure containing medicament, complexes, aggregates, colloids or micelles. As used herein, an "environment of use" may be either an in vivo environment of the gastrointestinal tract of an animal, particularly a human, or an in vitro environment of a test solution, such as an MFD solution. A polymer that increases the concentration can be tested in vivo or, more conveniently, assayed in vitro to determine if it is within the scope of the invention. Dissolution assays and in vivo bioavailability assays can be performed as discussed above. The polymer that increases the concentration should achieve an MDC that exceeds the equilibrium concentration of the undispersed drug of the control composition. Preferably, the concentration enhancing polymer provides an MDC in an environment of use that is at least 1.5 times the MDC provided by a control comprising an equivalent amount of the undispersed medicament. For example, if the control composition provides a maximum drug concentration of 1 mg / ml, the composition including the concentration-increasing polymer preferably provides a maximum drug concentration of 1.5 mg / ml. Like stabilizing polymers, suitable concentration-increasing polymers should be inert with respect to not reacting chemically with the solvent in a negative manner, and should have at least some solubility in aqueous solutions at physiologically relevant pH (eg, 1-8) . Almost any neutral or ionizable polymer that is soluble in water in a pH range of 1-8 can be tested to see if it is suitable for a particular drug. A preferred class of polymers are water-soluble cellulosic polymers, and another preferred class is the cellulosic polymerizable, both the enteric and the non-enteric. For example, for certain medicaments, PVP is known to be effective in inhibiting the precipitation or crystallization of the drug from a supersaturated solution. Given the low Tg of PVP at a high relative humidity (see FIG. 1), the amorphous dispersions of the drug and PVP are often not physically stable to be commercially practical. However, using both PVP and a stabilizing polymer, the drug can be stabilized and the benefits of PVP can be observed. For example, the drug, PVP and a stabilizing polymer such as hydroxypropylmethylcellulose acetate succinate (HPMCAS) can all be combined to form a single dispersion having a Tg at 50% RH greater than a dispersion of the drug and PVP alone and, as a result, an improved physical stability. Alternatively, the medicament and HPMCAS can be combined to form a dispersion and the PVP can be added to the dosage form, for example, by combination, mixing, or wet or dry granulation or even by coating on a tablet, bead or capsule. In this way, any process that results in PVP being present to facilitate the degree of dissolution and inhibit the precipitation or crystallization of the drug is adequate. The second embodiment, ie the formation of the dispersion with the medicament and HPMCAS alone (and adding the PVP to the formulation so that it is not part of the dispersion) is preferred, since, for an equivalent amount of medicament and each polymer, the Tg of the drug dispersion and HPMCAS will generally be greater than 60% RH than a drug dispersion, HPMCAS and PVP, and therefore it is expected to have improved physical stability. Other polymers increasing concentration include: hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, ethyl hydroxyethylcellulose, hydroxyethyl ethylcellulose, methylcellulose acetate succinate hydroxyethylmethylcellulose , hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinylpyrrolidone, polyethylene and polyvinyl alcohol copolymers, carboxylic acid functionalized polymethacrylates, amine functionalized polymethacrylates, chitosan and chitin. The composition can take various forms. For example, it may contain a single dispersion of solid amorphous medicament comprising a mixture of the medicament and the two polymers formed by any suitable method, but preferably by solvent processing in a common solvent. In this form the dispersion is formed, for example, by dissolving the medicament and both the stabilizing polymer and the concentration increasing polymer, in a common solvent. The solvent is then removed to form the solid dispersion, which contains the medicament and both polymers. Alternatively, the composition may contain a solid dispersion comprising the stabilizing drug and polymer (but not the concentration increasing polymer), which is formed by any suitable method. The solid dispersion is then mixed wet or dry with the polymer increasing the concentration to form the composition. Mixing processes include physical processing as well as wet granulation and coating processes. In addition, the composition may contain additional polymers, selected either by having a high Tg to add stability or to increase the concentration of the drug in solution or both. Alternatively, the low solubility drug, when dispersed with a stabilizing polymer in a solid amorphous dispersion and the concentration increasing polymer, can also be combined by co-administration of the two components to an environment of use. By co-administration it is understood that the solid amorphous dispersion comprising the drug and stabilizing polymer is administered separately, but in the same general time frame, as the polymer which increases the concentration. For example, the dispersion may be administered in its own dosage form which is taken at approximately the same time as the concentration increasing polymer, which is in a separate dosage form. The time difference between the administration of the dispersion containing the medicament and the polymer that increases the concentration is such that they come into physical contact in the environment of use. When they are not co-administered at the same time, it is generally preferable to administer the polymer which increases the concentration before administration of the drug in the dispersion.

EXCIPIENTS AND DOSAGE FORMS Although the key ingredients present in the compositions of the present invention are simply the drug to be administered and the polymer (s), the inclusion of other excipients in the composition, included in the solid dispersion or combined or subsequently mixed with the dispersion , they can be useful and even preferred. A very useful class of excipients are surfactants. Suitable surfactants include fatty acids and alkyl sulfonates, commercial surfactants such as benzene chloride (HYAMINE (R) 1622, available from Lonza, Inc., Fairlawn, NJ), DOCUSATE SODIUM (available from Mallinckrodt Spec. Chem., St. Louis, MO. ), esters of polyoxyethylene and sorbitan fatty acids (TWEEN (R), available from ICI Americas Inc., Wilmington, DE), LIPOSORB (R) P-20 (available from Lipochem Inc., Patterson NJ), CAPMUL (R) POE-0 (available from Abitec Corp., Janesville, Wl) and natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine, lecithin and other phospholipids and mono- and diglycerides. Said materials can be advantageously used to increase the rate of dissolution, for example, by facilitating the humidification, or else by increasing the obtained MDC. These surfactants may comprise up to 10% by weight of the spray dried dispersion, provided that they do not adversely affect the Tg of the dispersion to an extent that is unacceptable for physical stability. The addition of pH modifiers such as acids, bases or buffers can also be beneficial, by retarding the dissolution of the dispersion (for example, acids such as citric acid or succinic acid, when the dispersion polymer is anionic) or, alternatively, by increasing the speed of dispersion of the dispersion (for example, bases such as sodium acetate or amines). The addition of conventional matrix materials, surfactants, fillers, disintegrants or binders can be carried out as part of the dispersion itself, added by wet granulation, mechanically or by other means. When said additives are included as part of the dispersion itself, they can be mixed with medicament and polymer (s) in the spray-drying solvent, and may or may not be dissolved in the medicament and polymer (s) prior to the formation of the dispersion by spray drying. These materials may comprise up to 50% by weight of the drug / polymer / additive dispersion, provided that they do not adversely affect the Tg of the dispersion to an extent which has unacceptable physical stability. The spray-dried solutions and the resulting dispersions may also contain various additives that aid stability, dissolution, tabletting or dispersion processing. Examples of such additives include: surfactants, pH controlling substances (eg acids, bases, buffers), fillers, disintegrants or binders. Said additives can be added directly to the spray-drying solution, so that the additive is dissolved or suspended in the solution as a suspension. Alternatively, said additives may be added following the spraying process to aid in the formation of the final dosage form. Other conventional formulation excipients may be used in the compositions of the invention, including excipients well known in the art (for example, those described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania). Generally, excipients such as fillers, disintegrants, pigments, binders, lubricants, flavors and the like can be used for the usual purposes and in typical amounts without adversely affecting the properties of the compositions. These excipients can be used after the drug / polymer dispersion has been formed, to formulate the dispersion into tablets, capsules, suspensions, powders for suspensions, creams, transdermal patches and the like. Preferably, the compositions of this invention can be used in a wide variety of ways for the oral administration of medicaments. Examples of dosage forms are powders or granules which can be taken orally either dry or reconstituted by the addition of water to form a paste, suspension or solution, tablets, capsules, multiparticulas or pills. Various additives can be mixed, ground or granulated with the compositions of this invention to form a material suitable for the above dosage forms. Potentially beneficial additives are generally within the following classes: other matrix materials or diluents, surfactants, complexing or solubilizing agents of medicaments, fillers, disintegrants, binders, lubricants and pH modifiers (eg, acids, bases or buffers) . Examples of other matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, starch, polyoxamers such as ethylene oxide and hydroxypropylmethylcellulose. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing or solubilizing agents include polyethylene glycols, caffeine, xanthene, gentisic acid and cyclodextrins. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, starch and gums such as agar and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, aspartic acid, succinic acid, phosphoric acid and the like, bases such as sodium acetate, potassium acetate, calcium oxide, oxide of magnesium, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide and the like, and buffers generally comprising mixtures of acids and salts of said acids. At least one function of the inclusion of said pH modifiers is to control the rate of dissolution of the drug, polymer or both, thereby controlling the local concentration of the drug during dissolution. In some cases, it has been determined that the MDC values for some drugs are higher when the solid dispersion dissolves relatively slowly, for example, in more than 60 to 180 minutes better than in less than 60 minutes. In some cases, the dosage form may have a higher activity if coated with an enteric polymer to prevent or delay the dissolution until the dosage form leaves the stomach. Examples of enteric coatings include HPMCAS, HPMCP, cellulose acetate phthalate, cellulose trimellitate acetate, polymethacrylates functionalized with carboxylic acid and polyacrylates functionalized with carboxylic acids. A dosage form that has been found useful by the inventors for oral administration of the compositions of the present invention is an oral constitution powder (OPC). The drug-containing composition is prepared by combining the medicament and polymers as described above. A first solution containing 0.5% by weight of polyoxyethylene 20, sorbitan monooleate TWEEN 80 (R) (ICI Surfactants, Everberg, Belgium) and 9% by weight of polyethylene glycol with a molecular weight of 3350 dalton in water, and a second solution containing 0.75% by weight of hydroxypropylcellulose, METHOCEL (R) (Dow Chemical Company) in water is also prepared. The OPC is prepared by placing the drug-containing composition in a flask and adding 10 ml of the first solution. The flask is stirred for 2 minutes. After, 20 ml of the second solution is added to the flask and the solution is stirred for another 2 minutes. This OPC can be administered orally to a mammal. In addition to the aforementioned additives or excipients, the use of any conventional material and process for the formulation and preparation of oral dosage forms, using the compositions of the invention, known to those skilled in the art, is potentially useful. Other characteristics and embodiments of the invention will be oberved from the following examples, which are given for the illustration of the invention rather than to limit its intended scope.

EXAMPLE 1 A solution of the drug and polymer was made by dissolving 67 mg of the drug [3,6-dimethyl-2- (2,4,6-trmethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine hydrochloride (" Drug 1", Pfizer, Inc.) and 133 mg of CAP (Eastman, batch No. 60616, 35% of phthaloyl, 24% of acetyl, the viscosity of a solution of 15% by weight in acetone being 50-90 cp) in 15 g of acetone of HPLC purity ( Aldrich). The drug / polymer solution was then placed in a 20 ml syringe which was inserted into an injection pump. (Harvard Apparatus, model 22). The solvent was quickly removed from the above solution by spraying in the spray drying device shown schematically in FIG. 2, constituted by an atomizer in the top cap of a vertically oriented stainless steel tube generally shown as 10. The atomizer is a two fluid nozzle (Spraying Systems Co. 1650) in which the atomizing gas is nitrogen, administered through line 12 to the nozzle at 100 ° C and at a flow of 15 g / min, and the solution, at room temperature , is administered through line 14 to the nozzle at a flow rate of 1.0 g / min using the injection pump. Filter paper 16 with a support grid (not shown) is attached to the lower end of the tube to collect the spray-dried material and allow the nitrogen and evaporated solvent to come out. The resulting material was a dry, substantially amorphous white powder.

EXAMPLES 2-13 AND COMPARATIVE EXAMPLES C1-C8 Examples 2 to 13 and comparative examples C1 to C8 were prepared as in example 1, except that examples 6 and 7 and comparative examples C4 and C5 were prepared with the drug [3,6-dimethyl-2-) 2 , 4,6-trimethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine ("Drug 2", Pfizer, Inc.), examples 8 to 11 and comparative examples C6 and C7 were prepared with drug 2 - (4-fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) benzyl] nicotinamide ("Drug 3", Pfizer, Inc.) and Examples 12 and 13 and Comparative Example C8, were prepared using [ 5-Chloro-1 H-indole-2-carboxylic acid (1-benzyl-2- (3-hydroxyacetidin-1-yl) -2-oxoethyl] amide ("Drug 4"). Other variables are indicated in table 1.

TABLE 1 COMPARATIVE EXAMPLES C9 AND C10 Comparative examples C9 and C10 were simply 556 mg and 500 mg, respectively, of drug 1 and drug 2 in their crystalline equilibrium state with a crystal size of about 1 to 20 μm and 1 to 10 μm, respectively.

EXAMPLE 14 The result of dissolution of the material of Example 1, before exposure to increased temperature and humidity, was measured as follows. In a vessel with a controlled temperature of 37 ° C, 3.0 mg of the material of Example 1 was inserted into a polypropylene microcentrifuge tube (Sorensen Bioscience Inc.). The theoretical MDC in solution (ie, if all the drug is dissolved) was 490 μg / ml [(3.0 mg x 1000 μg / mg) x (0.33 g medicine / g dispersion) x 0.90 factor saline x 0.98 trial drug / 1.8 ml = 490 μg / ml]. (This value varies slightly between samples, due to small differences in the actual power of the test drug in the samples). To the tube was added an MFD solution of 1.8 ml of a phosphate-buffered saline solution (8.2 mM NaCl, 1.1 mM Na2HPO, 4.7 mM KH2PO4, pH 6.5, 290 mOs / kg) containing 14.7 mM sodium taurocholic acid and 2.8 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. The tube was closed and a chronometer was started. The contents of the tube were mixed continuously at the highest speed in a vortex mixer (Fisher Vortex Genie 2) for 60 seconds. The tube was transferred to a centrifuge (Marathon, Micro A Model), then centrifuged at 13,000 g for 60 minutes. A 50 μl sample was removed from the centrifuge tube with a pipette four minutes after starting the stopwatch. The solids in the centrifuge tube were resuspended by continuously mixing the sample in the vortex mixer for 30 seconds. The centrifuge tube was returned to the centrifuge and allowed to stand until the next sample was taken. Each sample was centrifuged, sampled and resuspended as described, then diluted with 250 μl of HPLC purity methanol (Burdick &; Jackson) and the concentration of the drug was determined by HPLC. Samples were taken after 4, 10, 20, 40 and 90 minutes, analyzed, and drug concentrations were calculated for each time point. The average drug concentration after 4 minutes was 393 μg / ml, after 10 minutes it was 409 μg / ml, after 20 minutes it was 365 μg / ml, after 40 minutes it was 334 μg / ml and after 90 minutes it was 307 μg / ml . Therefore, the MDC for this sample before storage at increased temperature and humidity was 409 μg / ml, comprising the highest average concentration observed during the in vitro dissolution test. In addition, the value of AUC90 was calculated for example 1. The value of AUCgo is the AUC calculated from 0 to 90 minutes. The AUC between two individual time points in the curve was determined as follows. First a straight line was drawn between the two data sets, points t1, d and t2, c2, where t1 and t2 are the time points, and d and c2 are drug concentrations, where t2 > t1 This defines the geometric area of a trapezoid. The area of this trapezoid is AUC = d (t2-t1) + 1/2 ((t2-t1) x (c2-d)). The AUC90 is determined by calculating the sum of these areas defined by the drug concentrations observed at t1 and t2 equal to: 0 and 4 minutes, 4 and 10 minutes, 10 and 20 minutes, 20 and 40 minutes, and 40 and 90 minutes. In comparison, the dissolution result of the crystalline form of the drug in Comparative Example C9 was measured by subjecting a similar amount of crystalline drug to the same assay. Similarly, with the other drug dispersions 1, formulated as in examples 2 to 5, their dissolution was also tested. The results of these tests are summarized in Table 2. These data show that the MDC and AUC90 values for the different drug dispersions 1 were 2.5 times to 4 times higher than for the crystalline drug alone. Similarly, with the dispersions of drug 2, formulated as in examples 6 and 7, and the crystalline form of drug 2 in comparative example C10 its dissolution was tested. The results of these tests are summarized in Table 3. These data show that the MDC and AUC90 values for the dispersions of drug 2 were 18 times to 23 times higher than for the crystalline drug alone.

TABLE 2 TABLE 3 EXAMPLE 15 This example demonstrates the improved stability of dispersions containing a higher Tg polymer. The samples prepared in Examples 1 and 2, and in Comparative Example C1 were stored under conditions of high temperature and humidity to increase the speed of the physical changes taking place in the materials, to simulate a longer storage interval in a Typical storage environment. Analysis of the dissolution result was carried out using an in vitro dissolution test and evaluation of the crystallinity using SEM, before and after said storage to evaluate the stability of the dispersion. The result of dissolution of the material of example 1, before exposure to increased temperature and humidity, was measured as described in example 14. The average drug concentration after 4 minutes was 393 μg / ml, after 10 minutes of 409 μg / ml, after 20 minutes of 365 μg / ml, after 40 minutes of 334 μg / ml and after 90 minutes of 307 μg / ml. Therefore, the MDC for this sample before storage at increased temperature and humidity was 409 μg / ml, the highest average drug concentration observed during the in vitro dissolution test. Then the materials were aged in a controlled environment. Approximately 10 mg of each of the materials prepared in Examples 1 and 2 and Comparative Example C1 were transferred to a 2 ml glass vial and placed in a vacuum chamber for 16 hours to remove residual solvent from the samples The vials were then transferred without uncovered to a controlled temperature / humidity oven (Environmental Specialties Inc., Model ES2000) at 40 ° C and a relative humidity of 44% and allowed to stand for 1 month. The samples were then taken from the oven and transferred to a vacuum desiccator for 16 hours to remove the adsorbed water from the samples. The samples were then taken from the vacuum desiccator and covered well. With the material of Example 1, the solution was then tested after one month of storage. The median concentration of medicine measured after 4 minutes was 390 μg / ml, after 10 minutes of 378 μg / ml, after 20 minutes of 335 μg / ml, after 40 minutes of 315 μg / ml and after 90 minutes of 287 μg / ml. ml. Therefore, the MDC for this sample after storage at increased temperature and humidity was 390 μg / ml. To determine the dissolution result of the material, the MDC was divided from the material after aging by the MDC of the material before aging (390 μg / ml / 409 μg / ml = 0.95), thus showing that the MDC of the aged material It was 95% of the new material. An analogous procedure was used to evaluate the dissolution result of the materials of Examples 2 and C1, before and after exposure to increased temperature and humidity. The results of the tests are summarized in table 4. It is noted that the MDC (aged / new) of the material of comparative example C1 was only 0.86, compared to 0.95 of example 1 and 1.1 for the example 2, demonstrating the measure of example 2 that the MDC really improved with aging. Similarly, the AUCgo values were determined for examples 1 and 2 and comparative example C1. To determine the dissolution result of the material, the AUCgo values of the material after aging were divided by the AUC90 of the material before aging. This calculation shows that the AUC90 (aged / new ratio) for example 1 was 0.93, for example 2 it was 1, 1 and for example C1 it was 0.46.

These data demonstrate that the dispersions of Examples 1 and 2 (dispersions obtained with CAP and CAT polymers of high Tg, respectively), were more stable after exposure to increased temperature and humidity than the dispersion of Comparative Example C1 obtained with the PVP polymer. of low Tg (at high HR).

TABLE 4 In the materials of Examples 1, 2 and C1 the presence of crystals and changes in particle size and morphology, before and after exposure to increased temperature and humidity, were then evaluated using SEM analysis as described below. Approximately 0.5 mg of the sample was fixed to an aluminum block with two-sided carbon tape. The sample was coated by ion spray (Hummer Sputtering System, Model 6.2, Anatech Ltd.) with an Au / Pd step for 10 minutes at 15 mV, and was studied by SEM. Samples before aging usually appear as spheres or collapsed spheres with smooth, rounded faces and surfaces. Changes in the appearance of the particles indicating physical inseatability include: fusion of individual particles, changes in surface texture, changes in the general shape of the particle and appearance of straight edges in the particle (indicating a possible crystallinity) . The electron scanning micrographs of the material of Examples 1 and 2 and Comparative Example C1 before and after exposure to increased temperature and humidity are summarized in Table 5. No significant changes were observed for the materials of Example 1 and 2 after of aging. The SEM analysis of the sample of Comparative Example C1, however, showed substantial physical changes after aging, including particle fusion, greatly increased particle roughness, and the presence of straight edge material present in the particles, which may indicate the crystallization of the medicine. This indicates that the dispersions of examples 1 and 2 were more stable than the dispersion of comparative example C1.

TABLE 5 In addition, the samples of example 1 and comparative example C1 were analyzed using powder X-ray diffraction. A sample of material of Example 1 was examined using powder X-ray diffraction before aging. No peaks were observed indicating the crystallinity of the drug. A sample of Example 1 was also analyzed after aging at 40 ° C / 44% RH for 1 month using powder X-ray diffraction. Again, no peaks were observed indicating the drug's crystallinity. The comparison of X-ray diffraction data before and after aging showed no significant differences. Similarly, material from Comparative Example C1 was examined prior to aging using powder X-ray diffraction and no peaks were observed that indicated crystallinity of the drug. A sample of Comparative Example C1 was examined after aging at 40 ° C / 44% RH for 1 month using powder X-ray diffraction, and several marked peaks were observed (at dispersion angles of 9.5, 16 and 20.5 degrees) that indicated that the crystallization of the drug had happened. Thus, the comparison of powder X-ray diffraction data before and after aging of comparative example C1 showed that crystallization of the drug had occurred in comparative example C1. The powder X-ray diffraction data again show that the dispersions of Examples 1 and 2 were more stable compared to the dispersion of Comparative Example C1.

EXAMPLE 16 This example demonstrates the improved stability of the dispersions with a high Tg polymer at low drug loads. The samples of example 3 and comparative example C2 were stored at 40 ° C / 44% RH for 1 month using the same procedure described for the samples in example 15. The in vitro dissolution test of the samples was performed as described in example 14. These results are summarized in table 6. Note that the MDC (aged / new) material of comparative example C2 is only 0, 92, compared to 0.98 in Example 3. In addition, the AUCge (aged / new) of C2 is only 0.80, compared to 0.98 in Example 3. These data show that the dispersion of the example 3 (dispersion obtained with a high Tg polymer), is more stable after exposure to increased temperature and humidity than the dispersion of Comparative Example C2.TABLE 6 In the materials of example 3 and comparative example C2 the presence of crystals and changes in the shape and morphology of the particles, before and after exposure to increased temperature and humidity, were evaluated using scanning electron microscopy as described above in the Example 15. No significant changes were observed for the material of Example 3 after aging. The SEM analysis of the samples of Comparative Example C2, however, showed substantial physical changes after aging, including molten particles and the presence of straight-edged material present in the particles, which may indicate crystallization of the drug. These results are summarized in table 7. This shows that the dispersion of example 3, obtained with the high Tg CAP polymer, is more stable than the dispersion of comparative example C2, obtained with the PVP polymer.

TABLE 7 EXAMPLE 17 This example demonstrates the stability of a dispersion having both a concentration increasing polymer and a high Tg polymer. The samples of examples 1 and 4 and comparative example C1 were stored at 40 ° C / 44% RH for 1 month using the same procedure described for the samples of example 15. The dispersion of example 4 contains both PVP and CAP, while Example 1 contains only CAP and Comparative Example C1 contains only PVP. The in vitro dissolution tests of the samples were carried out as described in example 14. These results are summarized in table 8. It is noted that the MDC (aged / new) of the material of comparative example C1 is only 0.86, comparison with the 0.95 of example 1 and 1, 02 of example 4. Similarly, the AUCgo (aged / new) of the material of comparative example C1 is 0.46, compared to 0.93 and 0.80 of examples 1 and 4, respectively.

These data demonstrate that the dispersions of example 4 (the dispersion obtained with a polymer mixture increasing the PVP concentration and CAP stabilizing polymer), is more stable after exposure to increased temperature and humidity than the dispersion of comparative example C1 (the dispersion obtained with the PVP polymer alone). In addition, the MDC of the aged dispersion of Example 4 was greater than the MDC of the aged dispersion of Example 1, indicating an improved dissolution result for the dispersion obtained with both a concentration increasing polymer and a stabilizing polymer.

TABLE 8 In the materials of example 1 and 4 and comparative example C1, the presence of crystals and changes in the shape and morphology of the particles, before and after exposure to increased temperature and humidity, were evaluated using scanning electron microscopy as described above. in Example 15, except that the SEM analysis was performed after 3 days of exposure to increased temperature and humidity. No significant changes were observed for the material of Example 1 and Example 4 after three days of aging. The SEM analysis of the samples of Comparative Example C1, however, showed substantial physical changes after three days of aging, including molten particles, rough particle surfaces and the presence of straight edge material present in the particles, which may indicate crystallization of the medication. These results are summarized in table 9. These results show the superior stability of the dispersion of examples 1 and 4, compared with the dispersion of comparative example C1.

TABLE 9 EXAMPLE 18 This example demonstrates the stability of another dispersion (example 5) with both a high Tg polymer (CAP) and a concentration increasing polymer (HPMCAS). The samples of Examples 1 and 5 and Comparative Example C3 were stored at 40 ° C / 44% RH using the same procedure described for the samples of Example 15, except that the samples were exposed to high temperature and humidity for 75 days. The in vitro dissolution tests of the samples were carried out as described in example 14. These results are summarized in table 10. It should be noted that the MDC (aged / new) of the material of comparative example C3 is only 0.46, comparison with the 0.87 of example 1 and 0.88 of example 5. Similarly, the AUCge (aged / new) of the material of comparative example C3 is only 0.31, compared to 0.80 of example 1 and 0.56 of Example 5. These data demonstrate that the dispersion of Example 5 (the dispersion obtained with a mixture of HPMCAS and CAP polymers), is more stable after exposure to increased temperature and humidity than the dispersion of Comparative Example C3 (the dispersion obtained with the HPMCAS-LF polymer alone). This shows that the addition of a stabilizing polymer such as CAP to a concentration enhancing polymer such as HPMCAS results in improved stability.

TABLE 10 In the materials of examples 1 and 5 and comparative example C3 the presence of crystals and changes in the shape and morphology of the particles, before and after exposure to increased temperature and humidity, were evaluated using scanning electron microscopy. The procedure was as described above in Example 15, except that the SEM analysis was performed after 36 days of exposure to increased temperature and humidity. No significant changes were observed for the material of Example 1 and Example 5 after 36 days of aging. The SEM analysis of the samples of Comparative Example C3, however, showed substantial physical changes after 36 days of aging, including molten particles, rough particle surfaces and the presence of straight edge material present in the particles, which may indicate crystallization of the medication. These results are summarized in table 11. These results show that the dispersions of examples 1 and 5 are more stable than the dispersion of comparative example C3.

TABLE 11 EXAMPLE 19 This example demonstrates the stability of dispersions obtained with a high Tg polymer and drug 2. The samples of example 6 and comparative examples C4 and C5 were stored at 40 ° C / 44% RH using the same procedure described for the samples of example 15 , except that the samples were exposed to high temperature and humidity for 2 weeks. In vitro dissolution assays of the samples were performed as described in example 14. These results are summarized in table 12. Note that the MDC (aged / new) material of the comparative examples C4 and C5 is 0.45 and 0.52, respectively, compared to 1.1 of Example 6. The AUCg (aged / new) of the material of Comparative Examples C4 and C5 are 0.40 and 0.37, respectively, compared to 0 , 90 of example 6. These data demonstrate that the dispersion of example 6 (the dispersion obtained with CAP polymer), is more stable after exposure to increased temperature and humidity than the dispersions of comparative examples C4 and C5 (the dispersions obtained with PVP or HPMCAS-LF polymers).

TABLE 12 In the materials of Example 6 and Comparative Examples C4 and C5, the presence of crystals and changes in the shape and morphology of the particles, before and after exposure to increased temperature and humidity, were evaluated using scanning electron microscopy. The procedure was as described above in Example 15, except that the SEM analysis was performed after 2 weeks of exposure to increased temperature and humidity. No significant changes were observed for the material of Example 6 after 2 weeks of aging. The SEM analysis of the samples of comparative examples C4 and C5, however, showed substantial physical changes after 2 weeks of aging, including molten particles and the presence of straight edge material present in the particles, which may indicate crystallization of the medication. These results are summarized in table 13. These results show that the dispersion of example 6 is more stable than the dispersions of comparative examples C4 and C5.

TABLE 13 EXAMPLE 20 This example demonstrates the stability of a dispersion (example 7) with both a high Tg polymer (CAP) and a concentration increasing polymer (HPMCAS). The samples of Examples 6 and 7 and Comparative Example C5 were stored at 40 ° C / 44% RH using the same procedure described for the samples of Example 15, except that the samples were exposed to high temperature and humidity for 2 weeks. The in vitro dissolution tests of the samples were performed as described in example 8. These results are summarized in table 14. Note that the MDC (aged / new) of the material of comparative example C5 is 0, 52, compared to the 1, 1 of example 6 and 0.95 of example 7. The AUCge (aged / new) of the material of comparative example C5 is 0.37, compared to 0.90 of example 6 and 0.65 of Example 7. These data demonstrate that the dispersion of Example 7 (the dispersion obtained with a mixture in a 1: 1 ratio of polymer that increases the HPMCAS-LF concentration and CAP stabilizing polymer), is more stable after exposure at increased temperature and humidity than the dispersion of Comparative Example C5 (the dispersion obtained with the HPMCAS-LF polymer alone).

TABLE 14 In the materials of examples 6, example 7 and comparative example C5, the presence of crystals and changes in the shape and morphology of the particles, before and after exposure to increased temperature and humidity, were evaluated using scanning electron microscopy. The procedure was as described above in Example 15, except that the SEM analysis was performed after 2 weeks of exposure to increased temperature and humidity. No significant changes were observed for the material of Example 6 and Example 7 after 2 weeks of aging. The SEM analysis of the sample of comparative example C5, however, showed substantial physical changes after 2 weeks of aging, including molten particles and the presence of straight edge material present in the particles, which may indicate crystallization of the drug. These results are summarized in table 15. These results show that the dispersion of examples 6 and 7 are more stable than the dispersion of comparative example C5.

TABLE 15 EXAMPLE 21 This example describes the thermal process used to determine the Tg of polymeric materials including dispersions of the present invention, at a specific relative humidity. In this procedure, the samples were equilibrated and sealed in an environmental chamber to incorporate a specific amount of moisture into the sample. The DSC was used for the measurement of Tg. A sample of material from Example 1 was equilibrated to 0% RH as follows. We weighed 4 aluminum containers with robotic caps of 2 atmospheres of Perkin-Elmer (piece no. B016-9320) in a microbalance (Sartorius, model M15) in container-lid pairs. Each of the four container-lid pairs weights was recorded with ± 1 μg. Approximately 5-10 mg of Example 1 was then placed in each of the four empty vessels at ambient temperature and relative humidity. All these samples (with the caps) were placed in a purged chamber with an outlet of a liquid nitrogen tank, which resulted in a humidity that was less than the detection limit of a calibrated humidity sensor. The temperature in the chamber was kept in equilibrium with the building temperature at approximately 23 ° C. The samples of Example 1 were left in the chamber for at least 20 hours to completely remove moisture from the samples. Once the samples were equilibrated with a RH of 0% in the environmental chamber, each cap of the sample was placed in its corresponding sample container and folded with a Perkin-Elmer universal folding press (part no. B013-9005 ). The folding of each sample hermetically seals the sample and ensures that the sample will not absorb any moisture during the course of the experiment. Each sample was weighed in the microbalance and the weights of the samples were recorded at 0.001 mg. Then the Tg was determined as follows. All Tg were measured with a Perkin-Elmer Pyris 1 differential scanning calorimeter. The heat flow in and out of the mixture was controlled as a function of the temperature increase. As the sample heated (energy input in the sample) in the vitreous transition region, a step of increase in heat flow was observed which corresponds to the change in the heat capacity of the sample. This region of the heat flux curve versus temperature was analyzed for the data presented below in table 16. All the calorimetric experiments on the materials of example 1 were carried out by the following procedure. The folded samples were placed in the DSC's autosampler device together with an empty container (careful not to touch the aluminum containers with bare hands) used for subtraction of the bottom. A separate 30 μl vacuum aluminum container was placed in the DSC reference oven to compensate for the heat capacity of the sample container. The DSC was programmed to load the empty container and a bottom sweep was heated from 0 ° C to 220 ° C at 10 ° C / min. At the end of this scan the empty bottom vessel was taken out of the autosampler and the first of the four samples of Example 1 was placed in the sample furnace. This sample was first heated to 100 ° C at 10 ° C / min to eliminate the thermal history of the sample that could obscure the vitreous transition (eg, transitions of side chains or ß). The sample was then cooled to approximately 100 ° C / min at 0 ° C and the final thermal sweep was performed from 0 ° C to 175 ° C at 10 ° C / min. FIG. 3 shows the resulting sweep of heat flux versus temperature in the vitreous transition region along with the coordinates used by the software to measure Tg. To measure the vitreous transition, the background sweep was subtracted to eliminate any curvature of the data and then the slope was adjusted to zero so that the vitreous transition was more easily identifiable. Using the Pyris 1 software, a region comprising the change step in the heat flux (ie the Tg) was chosen and the tangent lines (used by the software to calculate the Tg and the change in heat capacity at Tg) so that they were parallel to the heat flow before and after the Tg. The Tg was measured as the temperature at which the heat capacity is half of the CP. FIG. 3 shows the resulting sweep and the Tg and _C measurements for example 1 at a RH of 0%. In some cases, an analogous procedure was used in which the integral of a sweep as in FIG. 3 was generated, which looks like two lines that intersect with a small curvature near the point of intersection. The Tg was taken as the temperature at which the lines intersect. This procedure is described in The Physics of Polymers, by Gert Strobl, p. 237-239, Springer-Verlag (1996). The values determined by any procedure agree on 1 or 2 degrees centigrade. The Tg of the humidified samples were measured in the same way, except that the open samples were placed in a humidity chamber to balance them with a fixed humidity. All samples of example 1 (polymer sample in aluminum containers with lids) were placed in an environmental chamber (Electro-Tech Systems, Inc., model No. 518) with relative humidity maintained at a RH of 50- 52% by means of a humidifier and sonic controller. These samples were folded into the chamber to seal the absorbed water and minimize water loss during the measurement of Tg and the DSC was performed in Pyris 1. The calorimetric results are summarized in table 16. The vitreous transition temperatures were measured also for the dispersions of examples 2 to 11, comparative examples C1 to C7 and the polymers CAP, CAT, PVP and HPMCAS-LF after equilibration to HR of 0% (dry) and 50% in the same way as is described above for the dispersion of example 1. The results are summarized in table 16 TABLE 16 EXAMPLE 22 This example describes the utility of the invention with another medicine. The samples of examples 8 to 11 and comparative examples C6 and C7 were stored at 40 ° C / 75% RH for 2 weeks using the same procedure described for the samples of example 15. The in vitro dissolution tests of the samples were performed as described in example 14. These results are summarized in table 17. The MDC (aged / new) of the material of comparative example C6 is only 0.87 and the MDC (aged / new) of the material of comparative example C7 It's only 0.27. These two dispersions obtained with low Tg polymers aged significantly compared to the material of Examples 8 to 11, which was obtained with polymers of high Tg. The MDC (aged / new) of the material of example 8 is 0.90, the MDC (aged / new) of the material of example 9 is 0.94 and the MDC (aged / new) of the material of example 10 is 0.95 . Similarly, the AUCgo (aged / new) of C6 and C7 are 0.62 and 0.33, respectively, while the AUCgo (aged / new) of examples 8, 9 and 10 are 0.90, 1, 01 and 0.95. The combination of high Tg CAP with low Tg PVP (example 11) improves the stability of the dispersion obtained with PVP polymer alone.

TABLE 17 In the materials of examples 8 to 11 and comparative examples C6 and C7, the presence of crystals and changes in the shape and morphology of the particles were evaluated, after exposure to increased temperature and humidity, using scanning electron microscopy. These results are summarized in table 18.

TABLE 18 Examples 8 and 9 (dispersione CAT and CAP) showed no aging effects after 2 weeks at 40 ° C / 75% RH. Example 10 (HPMCP dispersion) showed molten particles, but no crystal formation. Example 11 (CAP / PVP combination) showed significant morphological changes, however obvious crystals were not observed. (The presence of straight edge material present in the particles may indicate the crystallization of the drug). Example 11 can be compared to example C7 (drug dispersion with PVP alone), which showed many obvious crystals present. This demonstrates an improvement in stability with the addition of high Tg polymer. Comparative example C6 also showed crystals after exposure to increased temperature and humidity.

EXAMPLE 23 This example demonstrates the utility of the invention with another medicine. The samples of Examples 12 and 13 and Comparative Example C8 were stored at 40 ° C / 75% RH for 3 months using the same procedure described for the samples of Example 15. The in vitro dissolution tests of the samples were performed as described in example 14. These results are summarized in table 18. The MDC (aged / new) of the material of comparative example C8 is only 0.89. This dispersion obtained with a low Tg polymer aged significantly compared to material of Examples 12 and 13, obtained with high Tg polymers. The MDC (aged / new) of the material of example 12 is 1, 10, and the MDC (aged / new) of the material of example 13 is 1, 11. Similarly, the AUCgo (aged / new) of C8 is 0.76, while the AUCgo (aged / new) of examples 12 and 13 are 1, 05 and 1, 10.

TABLE 19 The terms and expressions that have been employed in the foregoing memory are used herein as descriptive and non-limiting terms, and there is no intention, in the use of such terms and expressions, to exclude equivalents of the features shown or parts thereof, recognizing that the scope of the invention is defined and limited only by the following claims.

Claims (5)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A composition comprising a solid dispersion comprising a drug of low solubility and at least one polymer, at least a majority of said drug being amorphous, once dispersed in said dispersion, said polymer having a vitreous transition temperature of at least 100 ° C measured at a relative humidity of 50%, and said dispersion being formed by solvent processing.
2. 2. The composition of claim 1, wherein said polymer has a glass transition temperature of at least 105 ° C measured at a relative humidity of 50%.
3. 3. The composition of claim 1, wherein said polymer has a glass transition temperature of at least 110 ° C measured at a relative humidity of 50%.
4. 4. The composition of claim 1, wherein said polymer has a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%.
5. 5. The composition of claim 1, wherein said polymer has a glass transition temperature of at least 50 ° C measured at a relative humidity of 50%. 6. - The composition of claim 1, wherein said polymer is cellulosic. 7. The composition of claim 6, wherein said polymer has at least one aromatic substituent attached by ester and an aromatic substituent attached by ether. 8. The composition of claim 7, wherein at least one of said ester-linked aromatic substituents is an aromatic substituent with carboxylic acid functionality bonded by ester and said aromatic substituent attached by ether is an aromatic substituent with functionality of carboxylic acid bound by ether. 9. The composition of claim 8, wherein said polymer has a degree of substitution of at least 0.2, for said aromatic substituent with carboxylic acid functionality and said aromatic substituent with carboxylic acid functionality bound by ether. 10. The composition of claim 8, wherein at least one of said aromatic substituents with carboxylic acid functionality attached by ester is selected from the group consisting of the various structural isomers of phthalate, trimellitate and pyridinedicarboxylic acid and alkyl substituted derivatives of these, and the aforementioned aromatic substituent with ether-bound carboxylic acid functionality is selected from the group consisting of the various structural isomers of salicylic acid, ethoxybenzoic acid, propoxybenzoic acid, butoxybenzoic acid, ethoxyphthalic acid, propoxyphalic acid, butoxyphalic acid, ethoxynicotinic acid , propoxinicotinic acid, butoxinicotinic acid and alkyl substituted derivatives thereof. 11. The composition of claim 10, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, acetate phthalate succinate of hydroxypropylcellulose, cellulose propionate phthalate, hydroxypropylcellulose butylate phthalate, cellulose acetate trimellitate, methylcellulose trimellitate acetate, ethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate acetate, cellulose trimellitate propylate, butyrate cellulose trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, salicylic acid hydroxypropyl cellulose acetate, ethylbenzoic acid cellulose acetate bear, ethylbenzoic acid hydroxypropylcellulose acetate, ethylphthalic acid cellulose acetate, nicotinic acid ethylcellulose acetate and picolinic acid ethylcellulose acetate. 12. The composition of claim 10Wherein said polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate phthalate, methylcellulose acetate phthalate ethylcellulose, cellulose acetate phthalate hydroxypropyl cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate propionate, cellulose butyrate phthalate, hydroxypropyl cellulose acetate trimellitate cellulose acetate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose trimellitate propionate, cellulose trimellitate butyrate, cellulose acetate terephthalate, cellulose acetate isophthalate, acetate of salicylic cellulose acid, ethylbenzoic acid cellulose acetate. 13.- The composition of claim 10, wherein said polymer selected from the group consisting of cellulose acetate phthalate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, cellulose acetate terephthalate and cellulose acetate isophthalate. 14. The composition of claim 1, wherein said medicament and said polymer are soluble in a common non-aqueous solvent. 15. The composition of claim 14, wherein said dispersion is formed by spray drying. 16. The composition of claim 1, further comprising a polymer that increases the concentration, increasing the said polymer increasing the concentration, the maximum concentration of drug in an environment of use with respect to a control composition comprising an equivalent amount of medication without dispersing. 17.- The composition of claim 16, wherein said polymer concentration increases is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hidroxipropiimetilcelulosa, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxymethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinylpyrrolidone, copolymers of polyethylene and polyvinyl alcohol, polymethacrylates functionalized with carboxylic acids, polymethacrylates functionalized with amine s, chitosan and chitin. 18. The composition of claim 16, wherein said concentration-increasing polymer is co-dispersed with the other polymers. 19. The composition of claim 16, wherein said concentration-increasing polymer is mixed with said dispersion following the formation of said dispersion. 20. The composition of claim 1 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the undispersed medicament. 21. The composition of claim 1, wherein said dispersion is substantially homogeneous. 22. The composition of claim 1, wherein said medicament is substantially amorphous. 23. The composition of claim 1, wherein said medicament is almost completely amorphous. 24. The composition of claim 1, wherein said vitreous transition temperature of said polymer measured at a relative humidity of 0% is at least 140 ° C. 25. The composition of claim 24, wherein said polymer absorbs less than 10% by weight of water at a relative humidity of 50%. 26. A composition comprising a solid dispersion comprising a drug of low solubility and at least one polymer, at least a majority part of said drug being amorphous once dispersed in said dispersion, and said dispersion having a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%. 27. The composition of claim 26, wherein said dispersion has a glass transition temperature of 50 ° C measured at a relative humidity of 50%. 28. The composition of claim 26, wherein said low solubility drug comprises at least 15% by weight of said solid dispersion. 29. The composition of claim 26, wherein said polymer has a glass transition temperature of at least 100 ° C measured at a relative humidity of 50%. 30. The composition of claim 26, wherein said polymer is cellulosic. The composition of claim 30, wherein said polymer has at least one aromatic substituent attached by ester and an aromatic substituent attached by ether. 32. The composition of claim 31, wherein at least one of said ester-linked aromatic substituents is an aromatic substituent with ester-linked carboxylic acid functionality and said ether-linked aromatic substituent is an aromatic substituent with functionality of carboxylic acid bound by ether. 33. The composition of claim 32, wherein said polymer has a degree of substitution of at least 0.2 for said substituents. 34. The composition of claim 33, wherein at least one of said aromatic substituents with ester-linked carboxylic acid functionality is selected from the group consisting of the various structural isomers of phthalate, trimellitate and pyridinedicarboxylic acid and alkyl substituted derivatives of these, and the aforementioned aromatic substituent with ether-bound carboxylic acid functionality is selected from the group consisting of the various structural isomers of salicylic acid, ethoxybenzoic acid, propoxybenzoic acid, butoxybenzoic acid, ethoxyphthalic acid, propoxyphalic acid, butoxyphalic acid, ethoxynicotinic acid , propoxinicotinic acid, butoxinicotinic acid and alkyl substituted derivatives thereof. The composition of claim 34, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, acetate phthalate succinate of hydroxypropylcellulose, cellulose propionate phthalate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellithate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose trimellitate propionate, butyrate cellulose trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic cellulose acetate, salicylic acid acetate hydroxypropyl cellulose, ethylbenzoic acid cellulose acetate, Ethylbenzoic acid hydroxypropyl cellulose acetate, ethyl phthalic cellulose acetate, nichotinic acid ethyl cellulose acetate and picolinic acid ethyl cellulose acetate. 36. The composition of claim 34, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, phthalate propionate, and cellulose, hydroxypropylcellulose phthalate butyrate, cellulose trimellitate acetate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose trimellitate propionate, cellulose trimellitate butyrate, acetate terephthalate of cellulose, acetate, cellulose softalate, salicylic cellulose acetate, ethylbenzoic acid cellulose acetate. 37. The composition of claim 34, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate trimellitate, methyl cellulose trimellitate acetate, cellulose acetate terephthalate and cellulose acetate softalate. 38.- The composition of claim 26, wherein said medicament and said polymer are soluble in a common non-aqueous solvent. 39.- The composition of claim 38, wherein said dispersion is formed by eliminating said solvent from said medicament and said polymer. 40.- The composition of claim 39, wherein said dispersion is formed by spray drying. 41. The composition of claim 26, further comprising a polymer concentration increases, increasing said polymer concentration increases, the extent of drug concentration in a use environment relative to a control composition comprising an equivalent quantity of medication without dispersing. 42. The composition of claim 41, wherein said polymer concentration increases is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinylpyrrolidone, copolymers of polyethylene and polyvinyl alcohol, polymethacrylates functionalized with carboxylic acids, functionalized polymethacrylates c on amines, chitosan and chitin. 43.- The composition of claim 41, wherein said polymer increasing the concentration is co-dispersed with the other polymers. 44. The composition of claim 41, wherein said polymer concentration increases mixed with said dispersion subsequent to formation of said dispersion. 45. The composition of claim 26 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the undispersed medicament. 46.- The composition of claim 26, wherein said dispersion is substantially homogeneous. 47. The composition of claim 26 wherein said medicament is substantially amorphous. 48. The composition of claim 26, wherein said medicament is almost completely amorphous. 49. The composition of claim 26, wherein said vitreous transition temperature of said polymer at a relative humidity of 0% is at least 140 ° C. 50.- The composition of claim 49, wherein said polymer absorbs less than 10% by weight of water at a relative humidity of 50%. 51. A composition comprising: (a) a solid dispersion comprising a drug of low solubility and a stabilizing polymer, at least a majority of said drug being amorphous, and (b) a polymer that increases the concentration which increases the maximum concentration of medicament in an environment of use with respect to a control composition comprising an equivalent amount of the undispersed medicament, said stabilizing polymer and said concentration-increasing polymer each having a respective vitreous transition temperature measured at a relative humidity of 50%, said vitreous transition temperature of said stabilizing polymer being higher than the vitreous transition temperature of said polymer increasing the concentration. 52. The composition of claim 51, wherein the vitreous transition temperature of said stabilizing polymer is at least 10 ° C higher than said vitreous transition temperature of said polymer increasing the concentration at a relative humidity of 50% . 53. The composition of claim 51, wherein said vitreous transition temperature of said stabilizing polymer is at least 20 ° C higher than said vitreous transition temperature of said polymer increasing the measured concentration at a relative humidity of the fifty%. 54.- The composition of claim 51, wherein said stabilizing polymer is cellulosic. The composition of claim 54, wherein said stabilizing polymer is selected from the group consisting of cellulose acetate phthalate, methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, phthalate acetate hydroxypropylcellulose succinate, cellulose propionate phthalate, hydroxypropylcellulose butylate phthalate, cellulose acetate trimellithate, methylcellulose trimellitate acetate, ethylcellulose acetate trimellitate acetate, hydroxypropylcellulose trimellitate acetate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate acetate, cellulose trimellitate propionate, cellulose trimellitate butyrate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic cellulose acetate, salicylic acid acetate hydroxypropyl cellulose, ethyl acetate nzoicocelulosa acetate etilbenzoicohídroxipropilcelulosa acid, ethyl etilftálicocelulosa acid, ethyl nicotínicoetílcelulosa acid, ethyl picolínicoetilcelulosa acid, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethyl ethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose and carboxyethylcellulose. 56. The composition of claim 54, wherein said stabilizing polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, phthalate propionate of cellulose, butyrate phthalate of hydroxypropyl cellulose, acetate trimellitate of cellulose, methyl trimellitate acetate of methylcellulose, acetate trimellitate of ethylcellulose, acetate trimellitate of hydroxypropylmethylcellulose, propionate trimellitate of cellulose, butyrate trimellitate of cellulose, acetate terephthalate of cellulose, acetate isophthalate of cellulose, acetate of salicylic acid cellulose, ethylbenzoic acid cellulose acetate, hydroxypropylmethylcellulose acetate succinate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose. 57. The composition of claim 54, wherein said stabilizing polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose trimellitate acetate, methyl cellulose trimellitate acetate, trimellitate acetate of hydroxypropylmethylcellulose, cellulose acetate terephthalate, cellulose acetate isophthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose. 58.- The composition of claim 51, wherein said medicament and said stabilizing polymer are soluble in a common solvent. 59. The composition of claim 58, wherein said dispersion is formed by removing said solvent from said medicament and said stabilizing polymer. 60.- The composition of claim 59, wherein said dispersion is formed by spray drying. 61.- The composition of Example 51, wherein said concentration-increasing polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose , methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinylpyrrolidone, copolymers of polyethylene and polyvinyl alcohol, polymethacrylates functionalized with carboxylic acids, polymethacrylates functionalized with amines, itosan and chitin. 62.- The composition of claim 51, wherein said concentration-increasing polymer is co-dispersed with said stabilizing polymer. 63.- The composition of claim 51, wherein said concentration increasing polymer is mixed with said dispersion next to the formation of said dispersion. 64.- The composition of claim 51 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the undispersed medicament. The composition of claim 51, wherein said dispersion is substantially homogeneous. 66. The composition of claim 51 wherein said concentration-increasing polymer provides a maximum concentration of said medicament in said environment of use at least 1.5 times greater than that of a control comprising an equivalent amount of the drug without dispersing in an equivalent amount of said stabilizing polymer and in the absence of said polymer increasing the concentration. 67.- The composition of claim 51, wherein said medicament, once dispersed in said dispersion, is substantially amorphous. The composition of claim 51, wherein said medicament, once dispersed in said dispersion, is almost completely amorphous. 69.- A composition comprising: (a) a solid dispersion comprising a drug of low solubility and at least one polymer, at least a majority of said drug being amorphous, once dispersed in said dispersion, said polymer having said a vitreous transition temperature of at least 100 ° C measured at a relative humidity of 50%, and (b) wherein said polymer is cellulosic and has at least one aromatic substituent with carboxylic acid functionality attached by ester and a substituent aromatic with carboxylic acid functionality bound by ether, said aromatic substituent selected having an ester-linked carboxylic acid functionality from the group consisting of the various structural isomers of trimellitate and pyridinedicarbixyl acid and alkyl substituted derivatives thereof and selecting said aromatic substituent with carboxylic acid bound by ether of the constituted group by the various structural isomers of salicylic acid, ethoxybenzoic acid, propoxybenzoic acid, butoxybenzoic acid, ethoxyphthalic acid, propoxyphalic acid, butoxyphthalic acid, ethoxynicotinic acid, propoxynicotinic acid, butoxynicotinic acid and their alkyl substituted derivatives. The composition of claim 69, wherein said polymer has a glass transition temperature of at least 105 ° C measured at a relative humidity of 50%. 71. The composition of claim 69, wherein said polymer has a glass transition temperature of at least 110 ° C measured at a relative humidity of 50%. 72. The composition of claim 69, wherein said dispersion has a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%. The composition of claim 69, wherein said dispersion has a glass transition temperature of at least 50 ° C measured at a relative humidity of 50%. The composition of claim 69, wherein said polymer has a degree of substitution of at least 0.2 for said substituents. 75. The composition of claim 69, wherein said polymer is selected from the group consisting of cellulose trimellitate acetate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate acetate succinate , cellulose trimellitate propionate, cellulose trimellitate butyrate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic cellulose acetate, salicylic acid acetate hydroxypropyl cellulose, ethylbenzoic acid cellulose acetate, ethylbenzoic acid hydroxypropyl cellulose acetate, ethylphthalic cellulose acetate , nicotinic acid ethyl cellulose acetate and picolinic acid ethyl cellulose acetate. The composition of claim 69, wherein said polymer is selected from the group consisting of cellulose trimellitate acetate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose trimellitate acetate, hydroxypropylmethylcellulose trimellitate acetate, trimellitate succinate acetate of hydroxypropyl cellulose, cellulose trimellitate propionate, cellulose trimellitate butyrate, cellulose acetate terephthalate, cellulose acetate isophthalate, salicylic cellulose acetate, ethylbenzoic acid cellulose acetate. The composition of claim 69, wherein said polymer is selected from the group consisting of cellulose trimellitate acetate, methylcellulose trimellitate acetate, cellulose acetate terephthalate and cellulose acetate isophthalate. The composition of claim 69, wherein said medicament and said polymer are soluble in a common non-aqueous solvent. 79. The composition of claim 78, wherein said dispersion is formed by spray drying. The composition of claim 69, further comprising a polymer that increases the concentration, increasing said concentration-increasing polymer, the maximum measured concentration of said medicament in an environment of use with respect to a control composition comprising a equivalent amount of medication without dispersing. 81.- The composition of example 80, wherein said polymer increasing the concentration is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose , methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxymethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol copolymers and polypropylene glycol, polyvinylpyrrolidone, copolymers of polyethylene and polyvinyl alcohol, polymethacrylates functionalized with carboxylic acids, polymethacrylates functionalized with amines, quito healthy and chitin. 82. The composition of claim 81, wherein said polymer increasing the concentration is co-dispersed with the other polymers. 83. The composition of claim 81, wherein said polymer increasing the concentration is mixed with said dispersion following the formation of said dispersion. The composition of claim 69 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the undispersed medicament. 85.- The composition of claim 69, wherein said dispersion is substantially homogeneous. 86.- The composition of claim 69, wherein said medicament is substantially amorphous. 87. The composition of claim 69, wherein said medicament is almost completely amorphous. 88. The composition of claim 69, wherein said vitreous transition temperature of said polymer measured at a relative humidity of 0% is at least 140 ° C. 89.- The composition of claim 88, wherein said polymer absorbs less than 10% by weight of water at a relative humidity of 50%. 90.- A composition comprising (a) a solid dispersion comprising a drug of low solubility and at least one polymer, at least a majority of said drug being amorphous once dispersed in said dispersion, and said polymer having a vitreous transition temperature of at least 100 ° C measured at a relative humidity of 50%, and (b) selecting said polymer from the group consisting of methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate , hydroxypropylcellulose acetate phthalate acetate, cellulose propionate phthalate and hydroxypropylcellulose phthalate butyrate. 91.- The composition of claim 90, wherein said polymer has a glass transition temperature of at least 105 ° C measured at a relative humidity of 50%. 92. The composition of claim 90, wherein said polymer has a glass transition temperature of at least 110 ° C measured at a relative humidity of 50%. The composition of claim 90, wherein said dispersion has a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%. 94. The composition of claim 90, wherein said dispersion has a glass transition temperature of at least 50 ° C measured at a relative humidity of 50%. The composition of claim 90, wherein said polymer has a degree of substitution of at least 0 2 for the phthalate substituent 96 - The composition of claim 90, wherein said medicament and said polymer are soluble in a common non-aqueous solvent 97 - The composition of claim 96 , wherein said dispersion is formed by solvent processing 98 - The composition of claim 97, wherein said dispersion is formed by spray drying 99 - The composition of claim 90, further comprising a polymer that increases the concentration, increasing the aforementioned polymer that increases the concentration, the maximum measured concentration of said medication in an environment of use 100 - The composition d Example 99, wherein the said concentration-increasing polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol and polypropylene glycol copolymers, polyvinylpyrrolidone, polyethylene copolymers and polyvinyl alcohol , polymethacrylates functionalized with carboxylic acids, polymethacrylates functionalized with amines, chitosan and chitin. 101. The composition of claim 99, wherein said polymer increasing the concentration is co-dispersed with the other polymers. The composition of claim 99, wherein said polymer increasing the concentration is mixed with said dispersion following the formation of said dispersion. The composition of claim 99 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the undispersed medicament. 104.- The composition of claim 90, wherein said dispersion is substantially homogeneous. The composition of claim 90, wherein said medicament is substantially amorphous. 106. The composition of claim 90, wherein said medicament is almost completely amorphous. 107. The composition of claim 90, wherein said vitreous transition temperature of said polymer measured at a relative humidity of 0% is at least 140 ° C. 108. The composition of claim 107, wherein said polymer absorbs less than 10% by weight of water at a relative humidity of 50%. 109. A composition comprising a solid dispersion comprising a drug of low solubility and at least one polymer, at least a majority of said drug being amorphous once dispersed in said dispersion, and said polymer having a transition temperature vitrea of at least 100 ° C measured at a relative humidity of 50%, and said dispersion being substantially homogeneous. 110. The composition of claim 109, wherein said polymer has a glass transition temperature of 105 ° C measured at a relative humidity of 50%. 111. The composition of claim 109, wherein said dispersion has a glass transition temperature of at least 110 ° C measured at a relative humidity of 50%. The composition of claim 109, wherein the said dispersion has a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%. 113. The composition of claim 109, wherein said dispersion has a glass transition temperature of at least 50 ° C. measured at a relative humidity of 50% 114. The composition of claim 109, wherein said polymer is cellulosic. The composition of claim 114, wherein said polymer has at least one aromatic substituent attached by ester and an aromatic substituent attached by ether. The composition of claim 115, wherein at least one of said ester-linked aromatic substituents is an aromatic substituent with ester-linked carboxylic acid functionality and said ether-linked aromatic substituent is an aromatic substituent with functionality of carboxylic acid bound by ether. The composition of claim 116, wherein said polymer has a degree of substitution of at least 0.2 for said aromatic substituent with carboxylic acid functionality bonded by ester and said aromatic substituent with carboxylic acid functionality attached by ether. The composition of claim 116, wherein the at least one of said aromatic substituents with carboxylic acid functionality attached by ester is selected from the group consisting of the various structural isomers of phthalate, trimellitate and pyridinedicarboxylic acid and alkyl-substituted derivatives thereof, and said ether-bound carboxylic acid-containing aromatic substituent is selected from the group consisting of the various structural isomers of salicylic acid, ethoxybenzoic acid, propoxybenzoic acid, butoxybenzoic acid, ethoxyphthalic acid, propoxyphalic acid, butoxyphthalic acid, ethoxynicotinic acid, propoxinicotinic acid, butoxinicotinic acid and alkyl substituted derivatives thereof. 119. The composition of claim 118, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, acetate phthalate succinate of hydroxypropyl cellulose, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose trimellitate acetate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose trimellitate acetate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose trimellitate propionate, butyrate cellulose trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic cellulose acetate, salicylic acid acetate hydroxypropyl cellulose, ethylbenzoic acid acetate slab, ethylbenzoic acid hydroxypropylcellulose acetate, ethylphthalic cellulose acetate, nicotinic acid ethylcellulose acetate and piccolinic acid ethylcellulose acetate. The composition of claim 118, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methylcellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate, phthalate propionate, cellulose, hydroxypropylcellulose butyrate phthalate, cellulose trimellitate acetate, methylcellulose trimellitate acetate, ethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate, hydroxypropylmethylcellulose trimellitate acetate, hydroxypropylcellulose acetate trimellitate succinate, cellulose trimellitate propionate, cellulose trimellitate butyrate, acetate terephthalate of cellulose, cellulose acetate isophthalate, salicylic cellulose acetate, ethylbenzoic acid cellulose acetate. 121. The composition of claim 118 wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate trimellitate, methyl cellulose trimellitate acetate, cellulose acetate terephthalate and cellulose acetate isophthalate. 122. The composition of claim 109, wherein said medicament and said polymer are soluble in common non-aqueous solvent. 123. The composition of claim 122, wherein said dispersion is formed by spray drying. 124. The composition of claim 109, further comprising a polymer that increases the concentration, increasing said polymer increasing the concentration, the maximum concentration of drug in an environment of use with respect to a control composition comprising an equivalent amount of medication without dispersing. 125 -. 125 - The composition of claim 124, wherein said concentration-increasing polymer is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose , methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethyl ethylcellulose, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxymethylcellulose, carboxyethylcellulose, polyvinyl alcohol, polyvinyl alcohol copolymers and polyvinyl acetate, polyethylene glycol, polyethylene glycol copolymers and polypropylene glycol, polyvinylpyrrohondone, copolymers of ethylene and polyvinyl alcohol, polymethacrylates functionalized with carboxylic acids, polymethacrylates functionalized with amines, quito healthy and chitin 126 - The composition of claim 124, wherein said concentration increasing polymer is co-dispersed with the other polymers 127 - The composition of claim 124, wherein said increasing concentration polymer is mixed with said dispersion following the formation of said dispersion 128 - The composition of claim 109 wherein said composition provides a maximum concentration of said medicament in an environment of use that is at least 1-5 times that of a control that it comprises an equivalent amount of the undispersed medicament. 129.- The composition of claim 109 wherein said medicament is substantially amorphous. 130. The composition of claim 109, wherein said medicament is almost completely amorphous. 131. The composition of claim 109, wherein said vitreous transition temperature of said polymer measured at a relative humidity of 0% is at least 140 ° C. 132. The composition of claim 131, wherein said polymer absorbs less than 10% by weight of water at a relative humidity of 50%. 133. The composition of claim 109, wherein said dispersion exhibits a single vitreous transition temperature. 134. The use of a composition according to claim 1 for the manufacture of a medicament for the treatment of a disorder in a patient. The use of a composition according to claim 26 for the manufacture of a medicament for the treatment of a disorder in a patient. The use of a composition according to claim 51 for the manufacture of a medicament for the treatment of a disorder in a patient. The use of a composition according to claim 68 for the manufacture of a medicament for the treatment of a disorder in a patient. 138.- The use of a composition according to claim 90 for the manufacture of a medicament for the treatment of a disorder in a patient. 139.- The use of a composition according to claim 109 for the manufacture of a medicament for the treatment of a disorder in a patient. 140.- A method of administering a medicament, comprising administering to a patient in need of said medicament: (a) a solid dispersion comprising a drug of low solubility and at least one stabilizing polymer, with at least one part being amorphous majority of said medicament once dispersed in said dispersion, and (b) a polymer that increases the concentration, increasing the said polymer increasing the concentration, the measured concentration of said medicament in an environment of use with respect to a control comprising a equivalent amount of the undispersed medicament, wherein the stabilizing polymer has a vitreous transition temperature which is higher than the vitreous transition temperature of the polymer increasing the concentration. 141. The method of claim 140, wherein said medicament is administered separately from said polymer which increases the concentration. 142. - The method of claim 140, wherein said medicament and said concentration increasing polymer are administered essentially simultaneously. 143. The method of claim 140, wherein said medicament is administered in a formulation also comprising said polymer which increases the concentration. 144. The method of claim 140, wherein said dispersion has a glass transition temperature of at least 30 ° C measured at a relative humidity of 50%. 145. The method of claim 140, wherein said dispersion has a glass transition temperature of 50 ° C measured at a relative humidity of 50%.