HK1050489A - Pharmaceutical compositions providing enhanced drug concentrations - Google Patents

Description

Pharmaceutical compositions providing enhanced drug concentration

Background

The present invention relates to compositions comprising a drug in combination with a concentration-enhancing polymer that increases the concentration of the drug in a use environment relative to a control composition that does not comprise the concentration-enhancing polymer.

Low solubility drugs often exhibit poor bioavailability or irregular absorption, the degree of irregularity being affected by a number of factors, such as dose level, dietary status of the patient, and the form of the drug. Increasing the bioavailability of low solubility drugs is the subject of numerous studies. The increase in bioavailability is dependent on an increase in the concentration of the drug in solution, thereby improving absorption.

It is known that many low solubility drugs can be formulated to increase the maximum concentration of drug that will be dissolved in the aqueous solution tested in vitro. When such a drug is initially dissolved in a solubility-improved form in the environment of use, such as gastric fluid, the solubility-improved form of the drug first provides a higher concentration of the dissolved drug in the environment of use relative to the other forms of the drug and the equilibrium concentration of the drug. Furthermore, it has now been found that these forms can increase the relative bioavailability of a drug when tested in vivo, presumably, at least temporarily, by increasing the concentration of dissolved drug present in the Gastrointestinal (GI) tract. However, as described below, the high concentrations obtained are often only temporary, and the solubility-improved drug form rapidly converts to a lower-solubility form after transport to the use environment.

For example, it is known that some low solubility drugs may be formulated in a very soluble salt form that may temporarily improve the concentration of the drug in the use environment relative to another salt form of the drug. An example of such a drug is sertraline, which has a higher solubility in water at pH3 in the lactate salt form than the HCl salt form. However, when high solubility salt forms such as sertraline lactate are administered to aqueous solutions (in vitro or in vivo) that have both high levels of chloride material and a buffer to control pH, either the increase in solubility of sertraline lactate is maintained for a short period of time or is not achieved at all because sertraline can be rapidly converted to crystalline or amorphous HCl salt or free base forms, which have lower solubility than sertraline lactate.

Another form of a drug known to provide, at least temporarily, an increased concentration of a low solubility drug in solution consists of a hydrate or solvate crystalline form of the drug. These forms often have a higher solubility in water than the lowest solubility crystalline form, and therefore, provide a higher concentration of drug.

It is known that certain drugs, although having the same chemical composition, are capable of forming more than one crystal structure. (as opposed to salt forms, solvates or hydrates having different chemical compositions). These different crystal structures are often referred to as polymorphs. The polymorph contains another drug that can temporarily provide an increased concentration in solution. Certain polymorphic forms, also referred to herein as "high energy crystalline forms," have a higher aqueous solubility and thus can provide an increased aqueous concentration of drug over other crystal structures and equilibrium concentrations.

It is also recognized that amorphous forms of low solubility drugs that can exist in either crystalline or amorphous form can also temporarily provide greater concentrations in water in a use environment than the equilibrium concentration of the drug. It is believed that amorphous forms of a drug dissolve faster than crystalline forms of the drug, often faster than the drug can precipitate from solution. Thus, the amorphous form may temporarily provide a higher than equilibrium concentration of drug.

Another method by which a higher than equilibrium drug concentration can be temporarily provided is by incorporating a solubilizing agent in the pharmaceutical dosage form. The solubilizing agent may promote the aqueous solubility of the drug. One example of using a solubilizing agent to increase the aqueous solubility of a drug is the use of a solubilizing agent with sertraline. As described in the assigned PCT application No. 99/01120, now U.S. patent No., the solubility of sertraline is significantly increased when it is co-dissolved in aqueous solution with a solubilizing agent, such as citric acid. As noted above, the maximum sertraline concentration achieved when sertraline HCl is added to a chlorine-containing buffer solution or the GI tract along with citric acid may exceed the solubility of sertraline HCl. This increase in concentration is believed to be due in part to the lower local pH in the use environment due to the presence of citric acid and in part to the presence of citric acid counter ions, since sertraline citrate is more soluble than sertraline chloride. However, the increased concentration is typically very short-lived because sertraline rapidly converts to a low solubility form, which may be a solid crystalline or amorphous HCl salt and/or a crystalline or amorphous free base, depending on the environment of use.

Another technique for temporarily achieving a concentration above equilibrium for the drug in the use environment is to formulate the drug as an aqueous or organic solution. For example, the drug may be dissolved in polyethylene glycol (PEG) or an aqueous solution of PEG, an acid or a base may be added thereto, or the drug may be dissolved in an aqueous solution of an acid or a base. Alternatively, the drug may be dissolved in a pharmaceutically acceptable organic liquid, such as glycerol, mono-, di-or triglycerides, fats or oils.

While these improved solubility drug forms initially exhibit high concentrations of the drug in the use environment, the elevated concentrations are often transient. Generally, the initial elevated drug concentration is only temporary and rapidly reverts to the lower equilibrium concentration. For example, while a particular salt form of a basic drug may exhibit improved initial aqueous concentrations, the drug often rapidly converts to another salt form (typically the HCl salt form) in gastric fluid, which has a very low equilibrium concentration. In other cases, the drug maintains acceptable solubility in low pH gastric fluid, but the free base form of the drug typically precipitates out through the higher pH small intestine, typically 4.4-7.5. Such dosage forms that do not maintain high concentrations of drug in the intestinal fluid produce only a small improvement in bioavailability because drug absorption occurs primarily in the intestinal tract. Likewise, a highly soluble salt form of an acidic drug can be rapidly converted to another salt form, which has a very low equilibrium concentration. Similar effects can be observed even for the highly soluble salt forms of zwitterionic drugs. Likewise, once a high energy crystalline form (e.g., polymorph) of a drug is dissolved, the drug often precipitates or crystallizes out of solution quickly because it changes to a low energy crystalline form or amorphous form with lower solubility, which results in the concentration of the dissolved drug approaching a lower equilibrium concentration.

One approach to improving the bioavailability of low solubility drugs involves the formation of amorphous dispersions of the drug with polymers. Examples of attempts to increase drug concentration by forming a dispersion of drug and polymer include Lahr et al, U.S. patent 5,368,864, Kanikanti et al, U.S. patent No.5,707,655, and Nakamichi et al, U.S. patent No.5,456,923.

However, there are also some drawbacks to producing amorphous dispersions of drug and polymer(s). The danger is that the drug will be altered during the process of preparing the dispersion. For example, some drugs may degrade at the elevated temperatures used to form certain dispersions. Some methods use organic solvents that must be completely removed to avoid degradation of the drug. The solvent must be selected to dissolve both the drug and the polymer. The process for preparing the dispersion is also time consuming and costly. In addition, dispersions are unstable in some cases and can chemically degrade over time at moderate temperature and humidity levels, or the drug can be converted to amorphous or crystalline forms of low energy and low solubility.

It has also been disclosed to enhance the dissolution of drugs by using a combination of drugs and polymers. For example, Martin et al, U.S. Pat. No. 4,344,934 mixed a poorly soluble drug with a polymer such as hydroxypropyl methylcellulose (HPMC) and added an aqueous surfactant solution to the drug-polymer mixture. While this can enhance dissolution, the drug concentration is only slightly increased relative to the equilibrium concentration. Piergiorgio et al, U.S. Pat. No. 4,880,623, used a solvent treatment to co-precipitate nifedipine and PEG and adsorbed onto polymers such as HPMC, or onto other excipients. Despite the increased bioavailability of the drug observed, no comparison was made between the different drug forms. Uedo et al, U.S. Pat. No.5,093,372 blends poorly soluble drugs such as brain resurfacing with polymers such as HPMC to improve bioavailability. However, it does not result in any increase in drug concentration of the drug/polymer mixture relative to the loosely crystalline form of the drug.

Moreover, combining a drug with a solubilizing polymer is generally not effective in improving the bioavailability of all low solubility drugs. Drug solubilization is generally very dependent on the chemical structure and physical properties of the particular drug, and thus the particular polymer that can solubilize the drug, if any, will vary from drug to drug. Choosing polymers that can achieve improved solubilization is often difficult and time consuming, as drug-polymer interactions are poorly understood. In general, the addition of a polymer simply accelerates the dissolution of the drug, as opposed to providing a high concentration.

Usui et al, inhibitory Effect of Water-soluble polymers on precipitation of RS-8359 ", Int' l J. of pharmaceuticals 154(1997)59-66, disclose the use of three polymers, namely hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinylpyrrolidone, to inhibit precipitation of low-solubility drugs RS-8359. The drug and polymer were dissolved in a mixture of 0.5N HCl and methanol and then added to a phosphate buffer solution. Usui et al found that certain polymers could inhibit crystallization of the drug.

Therefore, there remains a need for compositions containing a drug and providing a higher concentration of the drug in aqueous solution than the equilibrium concentration of the drug, which can maintain the concentration of the drug in the solution for a long period of time, or at least reduce the rate of decrease of the drug concentration from the high concentration to the equilibrium concentration, which can be prepared using methods that do not alter or degrade the drug, which can be made without relying on solvent processing, which remain stable under normal storage conditions, which can be made easily and inexpensively, and which ultimately can improve the bioavailability of poorly soluble drugs. The present invention satisfies these needs and others that will become apparent to one of ordinary skill in the art, which are summarized and described below.

Brief description of the invention

The present invention overcomes the deficiencies of the prior art by providing a composition comprising (1) a drug in a solubility-improved form, and (2) a concentration-enhancing polymer.

In a first aspect of the invention, the concentration-enhancing polymer is combined with a sufficient amount of the drug form such that the composition provides a maximum concentration of the drug in the use environment that is at least 1.25 times the equilibrium concentration of the drug in the use environment in the absence of the polymer. The composition also provides a concentration of the drug in the use environment that exceeds its equilibrium concentration for a longer period of time than a control composition containing an equivalent amount of the drug in a solubility-improved form, which control composition does not contain a concentration-enhancing polymer.

In a second aspect of the invention, the concentration-enhancing polymer is present in an amount sufficient such that the composition provides a dissolution area under the concentration-time curve (AUC) for a time period of at least 90 minutes over the course of 1200 minutes immediately after introduction into a use environment that is at least 1.25 times the corresponding area under the curve provided by the same control composition described above.

In a third aspect of the invention, the concentration-enhancing polymer is present in an amount sufficient to provide the composition with a relative bioavailability of at least 1.25.

In a fourth aspect of the invention, a method is provided for co-administering (1) a drug in a solubility-improved form and (2) a concentration-enhancing polymer to a patient in need of the drug. The concentration-enhancing polymer is co-administered in an amount sufficient to provide, in the use environment of the patient, a maximum concentration of the drug that is at least 1.25 times the equilibrium concentration of the drug in the use environment of the patient in the absence of the polymer. In addition, the method provides a concentration of drug in the use environment of the patient that exceeds the equilibrium concentration for a longer period of time than does the control composition described above.

In a fifth aspect of the invention, there is provided a method for co-administering to a patient in need of a drug (1) a drug in a solubility-improved form and (2) a concentration-enhancing polymer, the concentration-enhancing polymer being co-administered in an amount sufficient to provide a dissolution area under the concentration-time curve (AUC) for a time of at least 90 minutes in the use environment of the patient over the course of 1200 minutes immediately after introduction into the use environment of the patient that is at least 1.25 times the corresponding area under the curve provided by the same control composition described above.

In a sixth aspect of the invention, a method is provided for co-administering to a patient in need thereof (1) a drug in a solubility-improved form, and (2) a concentration-enhancing polymer in a sufficient amount to provide at least a 1.25-fold relative bioavailability.

The term "solubility-improved form" as used herein refers to a form of a drug having an increased solubility relative to the minimum soluble form of a known drug. The term therefore implies that a sparingly soluble form of the drug exists and is either known or has been determined, i.e. is known, for example, from the scientific or patent literature or is determined or known to the researcher. The "solubility-improved form" may consist of the highly soluble form of the drug alone, may be a composition comprising the highly soluble form of the drug and inert excipients, or may be a composition comprising the drug in a poorly soluble or highly soluble form together with one or more excipients, which has the effect of increasing the solubility of the drug, regardless of the length of time required for the solubility to increase. Examples of "solubility-improved forms" include, but are not limited to: (1) crystalline, very soluble forms of the drug, such as salts; (2) a high energy crystalline form of the drug; (3) a hydrate or solvate crystalline form of a drug; (4) amorphous form of the drug (which may exist in amorphous or crystalline form for the drug); (5) a mixture of drug (amorphous or crystalline) and solubilizer; or (6) solutions of the drug in water or organic liquids.

Alternatively, the term "solubility-improved form" refers to a form of the drug alone or a composition as described above which, when administered to an in vivo environment of use (e.g., the gastrointestinal tract of a mammal) or a physiologically relevant in vitro Solution (e.g., phosphate buffered saline or a Model Fasted Duodenal Solution (Model Fasted Duodenal Solution) as described below), provides or is capable of providing, at least temporarily, a drug concentration that is at least 1.25 times the equilibrium concentration of the drug in the environment of use. (the term "equilibrium concentration" as used herein is defined below).

The solubility-improved form of the drug is one that meets at least one of the above definitions.

Since the crystalline free base and crystalline hydrochloride forms of the basic drug generally have lower solubility than the other drug forms, and since solubilizing drugs generally precipitate one of these crystalline forms (or their amorphous counterparts) from the environment of use of the GI tract of the animal, a preferred solubility-improved form of the basic drug is a form of the drug having a solubility in water that is at least 2 times the solubility of the more soluble crystalline hydrochloride and crystalline free base drug forms.

In a preferred embodiment of the invention, the concentration-enhancing polymer has a hydrophobic portion and a hydrophilic portion. In a most preferred embodiment, the concentration-enhancing polymer is an ionizable polymer that dissolves in the use environment when significantly ionized at physiologically relevant pH.

The solid compositions of the present invention are generally in a combined form comprising the solubility-improved forms and the concentration-enhancing polymers. As used herein, "associated form" means that the solubility-improved form and concentration-enhancing polymer may be in physical contact with each other, or in close proximity to, but not necessarily physically mixed with each other. For example, the solid composition may be in the form of a multi-layered tablet, as is well known in the art, wherein one or more of the layers comprise the solubility-improving form, and one or more of the different layers comprise the concentration-enhancing polymer. Another embodiment may consist of coated tablets wherein the solubility-improved form of the drug or the concentration-enhancing polymer or both may be present in the core and the coating may contain said solubility-improved form or concentration-enhancing polymer or both. Alternatively, the combination may be in the form of a simple dry physical mixture in which the solubility-improved form and the concentration-enhancing polymer are both mixed in particulate form, and in which the individual particles, regardless of their size, each retain the same physical properties as they would have in a loose (bulk) form. Any conventional method of mixing the polymer and drug together may be used, such as physical mixing and dry or wet granulation, which does not substantially convert the drug and polymer into a molecular dispersion.

Moreover, the drug and the concentration-enhancing polymer can be administered in combination to a patient in need of the drug. The drug and concentration-enhancing polymer may be administered in separate or the same dosage form, and may also be administered simultaneously or at different times as desired.

However, compositions containing dispersions of the above-described drugs and polymers, particularly molecular dispersions wherein the dispersion is formed prior to transport to a use environment, do not form part of the present invention and are excluded therefrom. Generally, a molecular dispersion of drug and polymer is one in which the physical properties of the mixture (e.g., melting point or glass transition temperature) are transformed from those of the bulk (i.e., undispersed) polymer and drug. In the compositions of the present invention, the drug and the polymer, respectively, retain their respective physical properties, such as melting point and/or glass transition temperature, as disclosed above. Thus, solid compositions prepared by dissolving the drug and concentration-enhancing polymer in a solvent followed by drying by removal of the solvent, or by co-milling, or by heated extrusion, or by mixing a solution of the polymer with a solution of the drug to precipitate a dispersion of the polymer and drug precipitate, or by other methods of forming a molecular dispersion of the drug and concentration-enhancing polymer, form no part of the present invention.

Other aspects not forming part of the invention are the particular case where a basic drug having high intragastric (pH1-2) solubility and low enteric solubility (pH6-8) is administered in its lowest solubility form with a concentration-enhancing polymer. In this case, the high drug concentration is achieved as a result of the action of the natural acidic environment of the stomach, rather than the result of using a solubility-improved form of the drug. Since the key inventive part of the present invention is the combination of the solubility-improved drug form with the concentration-enhancing polymer, those cases in which the result of achieving high drug solubility is solely due to the natural environment of the stomach do not form an integral part of the present invention.

Various aspects of the invention may have one or more of the following advantages.

When dissolved in the use environment, the solubility-improved form of the drug provides an initial concentration of the drug that is greater than the equilibrium concentration of the drug, while the concentration-enhancing polymer retards the rate at which the initially-elevated drug concentration decreases to the equilibrium concentration. As a result, the compositions of the present invention provide an improved area under the dissolution curve ("AUC") that is greater than the area provided by the drug alone. Although not required to be within the scope of the invention, in certain aspects, the solubility-improved form provides a maximum drug concentration that exceeds the maximum drug concentration achieved when the drug is used alone. Nevertheless, the advantages of the present invention can be achieved simply by delaying the rate at which the elevated drug concentration decreases to equilibrium concentration, even without increasing the maximum drug concentration relative to the drug used alone.

In any case, increasing AUC means that the compositions of the present invention can also increase the concentration of drug that remains dissolved in the environment of use to provide high bioavailability of the drug, particularly in the GI tract. Increasing the concentration of drug in solution can achieve higher blood levels, in some cases effective levels, or in other cases effective blood levels at lower drug dosage levels, i.e., reduce the dose of drug that must be administered, reduce the variability in blood levels, and also reduce the size of the dosage form as determined by the amount of polymer required. Therefore, the composition of the present invention ensures effective use of drugs having low aqueous solubility, which otherwise would not have sufficiently high bioavailability to be effective, and the increased bioavailability also reduces the required dosage.

Moreover, since the compositions of the present invention provide higher drug concentrations in the use environment, and because the concentration tends to remain high once a high drug concentration is achieved, they reduce the adverse effects of chemicals present in the use environment, such as chloride and hydrogen ions or bile salts, on drug absorption due to inhibition of precipitation or crystallization of the drug. Therefore, in the case where the use environment is the GI tract, the composition of the present invention exhibits little variability between humans or animals in the fed/fasted state.

Furthermore, for those forms in which the drug is present in a crystalline state, the drug appears to change its physical or chemical state rarely, for example, through multiple degradation reactions, and thus does not change its pharmaceutical properties during the preparation of the dosage form or during storage, e.g., such solid amorphous dispersions may degrade or crystallize upon storage relative to solid amorphous dispersions of the drug. In addition, because the compositions containing the crystalline drug are simple physical mixtures (as opposed to dispersions), such compositions do not suffer from many of the storage stability problems of dispersions. By virtue of having the nature of a solid mixture or simple solution, the composition is readily prepared using conventional mixing techniques.

The above and other objects, features and advantages of the present invention will be more readily understood upon consideration of the following description of the present invention.

Detailed description of the preferred embodiments

The present invention provides a composition comprising a drug in a solubility-improved form and a concentration-enhancing polymer. The solubility-improved form may be a crystalline highly soluble salt form of the drug, a high energy crystalline form of the drug (e.g., a high solubility polymorph), a hydrate or solvate crystalline form of the drug, an amorphous form of the drug, a mixture of the drug and a solubilizing agent, or a solution of the drug in water or an organic liquid. Suitable drugs and suitable concentration-enhancing polymers are described in detail below.

The solubility-improved form of the solid drug and the concentration-enhancing polymer are referred to as a "simple physical mixture" when the dry components are mixed using conventional mixing techniques such as mixing and mechanical agitation together or mixing by dry-or wet-granulation. Thus, a simple physical mixture of drug and polymer means that in the mixture the drug has properties such as melting point in the case of a crystalline drug or glass transition temperature in the case of an amorphous drug that match those of the drug alone. This is in contrast to molecular dispersions of drug/polymer, where no drug melting point is observed, and where the glass transition temperature is observed to be different from that of the polymer and drug alone and varies as a function of the drug/polymer mass ratio in the dispersion.

The drug in the solubility-improved form and the concentration-enhancing polymer can also be combined by the combined administration of the two components to the environment of use. By co-administration is meant that the solubility-improved drug form can be administered separately from the concentration-enhancing polymer, but within the same universal time frame. For example, the solubility-improved drug form may be administered in its own dosage form at about the same time as the concentration-enhancing polymer, which takes a separate dosage form. The time difference between the administration of the solubility-improved form of the drug and the concentration-enhancing polymer allows them to come into physical contact in the environment of use. When they are not co-administered at the same time, it is generally preferred to administer the concentration-enhancing polymer first, followed by administration of the drug in a solubility-improved form.

It is known that many drugs can exist in several forms and can be formulated in a solubility-improved form so as to provide an initial elevated concentration of the drug in water relative to the equilibrium concentration of the lowest solubility form of the drug. However, in the absence of the concentration-enhancing polymer, the initial elevated drug concentration may often rapidly decrease to near the equilibrium concentration of the drug, as the drug precipitates or crystallizes out of solution. This occurs through a different mechanism. For example, a very soluble salt form may be converted to another salt form with a lower equilibrium concentration due to the presence of other ions in the environment of use. Dissolved drugs can also change their ionic state, for example by protonation or deprotonation resulting in precipitation or crystallization from solution in a low solubility form. Alternatively, the high energy crystalline form may be rapidly converted to a low energy crystalline form upon dissolution, which has a lower equilibrium concentration. Likewise, the drug may be mixed with a solubilizing agent. For example, particularly when the drug is a base, the drug may have a higher solubility in water at low pH. Such drugs may be mixed with solubilizing agents such as inorganic or organic acids. The acid may act as a solubilizer by lowering the pH in the dosage form as well as the pH in the use environment near the dosage form, thereby increasing the local solubility of the drug. However, as the drug diffuses out of the dosage form, the pH of the use environment may increase due to the lower concentration of the solubilizing acid, thereby reducing the solubility of the drug and causing precipitation of the drug. Thus, the solubility-improved pharmaceutical forms described by themselves generally have limited success in achieving the desired increase in bioavailability. In some cases, precipitation or crystallization into the low solubility form is so rapid that the maximum solubility of the solubility-improved form is not even reached.

The present inventors have recognized that it is critical to the present invention that the initial high concentration of drug in solution provided by the solubility-improved form of the drug can be maintained, and in some cases, that the drug concentration can be increased by delaying precipitation, crystallization, or conversion of the drug to a lower solubility form through the use of a concentration-enhancing polymer. Thus, without implying any particular mechanism of action, it is believed that the concentration-enhancing polymers of the present invention may be viewed as acting as crystallization or precipitation inhibitors. Surprisingly, this can be accomplished by simply combining the concentration-enhancing polymer with the drug in solid form, as opposed to forming a dispersion of drug and polymer. Alternatively, the polymer may be coated on the drug-containing tablet or bead, or administered separately but in the same environment of use as the solubility-improved drug form, and still function to maintain a greater than equilibrium drug concentration, i.e., higher bioavailability, for an extended period of time. Furthermore, when the drug is in the form of a solution in a liquid, the polymer may be co-dissolved with the drug in the liquid, or suspended in the liquid, or even include a capsule wall or coating containing the liquid.

Since a drug can often exist in any of a number of crystalline or amorphous forms, and since the interconversion between these forms is often unpredictable, it may take very little to very long time in an aqueous solution for the dissolved drug concentration to reach its equilibrium value. In any case, the presence of the concentration-enhancing polymer may increase the time required for the drug concentration to decrease to the equilibrium concentration. In fact, when the compositions of the present invention are administered to a use environment such as the GI tract, where the dissolved drug is absorbed from the GI fluid, most or all of the drug may be absorbed before the drug is substantially converted to its lowest solubility form. Typically, the concentration of the dissolved drug is increased on the order of 1.25-fold to 20-fold, and in some cases 20-fold to 100-fold, over the equilibrium drug concentration. For example, a control composition provides an equilibrium concentration of 1mg/mL, while the composition provides a maximum drug concentration of 1.25mg/mL, which provides a 1.25-fold increase.

While not wishing to be bound by a particular theory, it is believed that the concentration-enhancing polymers of the present invention generally do not have the ability to significantly solubilize insoluble drugs (i.e., increase the equilibrium solubility of the free drug). Instead, it is believed that the concentration-enhancing polymer acts primarily to slow the rate of precipitation or crystallization of the drug after it begins to dissolve. The presence of the concentration-enhancing polymer enables the initial increased or elevated concentration provided by the solubility-improved form of the drug to be maintained, at least in part, for at least several minutes, and in some cases, for several hours. Furthermore, in cases where the dissolution of the solubility-improved form of the drug is slowed and the precipitation of the low-solubility drug form is very rapid in the absence of the concentration-enhancing polymer, the presence of the concentration-enhancing polymer can result in a maximum concentration of the drug that is much higher than that observed in the absence of the polymer.

One possible mechanism for modifying drug concentration involves the association of the concentration-enhancing polymer with the dissolved drug, forming a "polymer/drug combination". Such assemblies may be constructed in a variety of forms including polymeric micelles, energetic polymer-drug aggregates ranging in size from nanometers to 1000 nanometers, polymer stabilized drug colloids or polymer/drug complexes. Another view is that the dissolved material begins to precipitate or crystallize from solution (e.g., due to the onset of nucleation), and the polymer adsorbs onto these drug aggregates or nuclei, preventing or at least delaying the nucleation or crystal growth process. In any case, the presence of the polymer can increase the amount of drug that is dissolved or at least absorbable. The drug present in the different drug/polymer combinations described above is obviously rather unstable and may contribute to the absorption process of the drug.

When tested for dissolution, the concentration-enhancing polymers of the present invention provide high concentrations of drug in a use environment that exceed the equilibrium concentration for a longer period of time than a control composition containing an equivalent amount of the drug in a solubility-improved form. That is, while the control composition can provide a high concentration of drug above the equilibrium concentration in the use environment, the control composition provides a shorter period of time than the composition of the present invention containing the drug concentration-elevating polymer. More preferably, the compositions of the present invention provide a high drug concentration greater than the equilibrium concentration for a period of at least 15 minutes, preferably at least 60 minutes, and more preferably at least 90 minutes, longer than the drug concentration provided by a control composition that does not contain a concentration-enhancing polymer.

As used herein, the term "concentration of drug" in solution or in the environment of use refers to a drug that can be dissolved in the form of solvated monomeric molecules, referred to as "free drug," or any other submicron structure, assembly (assembly), aggregate, colloid, or micelle containing the drug. As used herein, a "use environment" can be an in vivo environment of the GI tract, subcutaneous space, vagina, arterial and venous blood vessels, pulmonary tract, or intramuscular tissue of an animal (e.g., a mammal and particularly a human), or an in vitro environment of a test solution, such as Phosphate Buffered Saline (PBS) or a Model Fasted Duodenal (MFD) solution. A suitable PBS solution is an aqueous solution containing 20mM sodium phosphate, 47mM potassium phosphate, 87mM NaCl and 0.2mM KCl, adjusted to pH 6.5. One suitable MFD solution is the same PBS solution in which 7.3mM sodium taurocholate and 1.4mM 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine are additionally present.

The inventors have found that in some cases, there is strong evidence that the drug is in the form of polymer/drug aggregates when the composition of the invention is dissolved in the environment of use. In particular, it has been found that when a drug in a solubility-improved form is dissolved in a use environment with a concentration-enhancing polymer to a level that exceeds its equilibrium solubility value, the light scattering of the solution is greatly increased. Dynamic light scattering measurements show that when only polymers (e.g. HMPCAS or CAP) are dissolved, the presence of a few polymer aggregates therein is in the average particle size range of 10nm to 20 nm. When a drug is added to the solution, the light scattering signal typically changes little until the total concentration of the drug exceeds the equilibrium solubility of the drug. At these higher drug levels, the light scattering signal increases significantly, and dynamic light scattering analysis shows that the average particle size of the microparticles in solution is of very large size, typically 50nm to 1,000nm, and in some cases less than 10 and up to 2,000 nm.

NMR analysis of such solutions (generated from the compositions of the invention) and chemical analysis of any undissolved precipitate showed that the particles that increased the light scattering signal were composed of polymer and drug. Although the composition of these polymer/drug aggregates varies with the particular characteristics of the drug and concentration-enhancing polymer and their content, the polymer/drug aggregates generally contain from about 5% to about 90% by weight of the polymer, with the remainder comprising the non-crystalline drug. In addition, the polymer/drug aggregates also contain a significant amount of water. Once the proper conditions exist, polymer/drug aggregates are typically formed rapidly within minutes and are fairly stable, often only changing in content and size by 20% -50% or less over a period of 1 to 20 hours, a physiologically relevant timeframe.

Furthermore, NMR analysis of such solutions formed by dissolution of the compositions of the present invention in the environment of use has been shown to have "free drug" concentrations that exceed the concentration of the crystalline drug solubility by a factor of 1.5-10 or more and which may even exceed the solubility of the amorphous drug. Such "supersaturated" drug concentrations can be maintained for periods of time ranging from 1 hour to 20 hours or more, over a period of time sufficient to increase the rate of drug absorption and the total amount of drug absorbed from the GI tract.

The compositions of the present invention may be tested in vivo, or more commonly in vitro, to determine if they fall within the scope of the present invention. The dissolution of the composition can be tested by adding to PBS or MFD solution and stirring to facilitate dissolution. Compositions or methods of drug administration that meet at least one or more concentration criteria in PBS or MFD, or that meet one or more concentration or bioavailability criteria when administered orally into the GI tract of an animal (including mammals, such as humans), are compositions and methods of the present invention.

In one aspect, the compositions of the invention comprising a drug in a solubility-improved form in combination with a concentration-enhancing polymer provide a maximum drug concentration in a use environment that is at least 1.25 times the equilibrium concentration of drug provided in the use environment by a control composition in the absence of the polymer. In addition, the compositions can provide drug concentrations in excess of the equilibrium concentration for longer periods of time than can be provided by conventional control compositions. The conventional or control composition is the drug alone in a solubility-improved form or in combination with an inert diluent in an amount equal to the weight of the drug concentration-enhancing polymer in the composition of the present invention. More preferably, the maximum drug concentration achieved by the composition of the invention is at least 2-fold and more preferably at least 3-fold the equilibrium concentration provided by the control composition.

In scientific terms, the equilibrium concentration of a drug is obtained when the concentration of the drug in solution does not change over time. At this point, the drug has been converted to its lowest energy form, which is susceptible to its particular environment. This form is typically the lowest solubility crystalline form of the drug. In some cases, the rate of formation of the lowest energy, lowest solubility form of a drug from solution in vitro or in vivo can be very slow, requiring days or months. Since the retention time in the GI tract for oral administration is typically only on the order of 24 hours, for the purposes of the present invention, the equilibrium concentration may be designed to be the drug concentration after 20 hours of transport to the use environment. Thus, as used herein and in the claims, "equilibrium concentration" refers to the concentration of drug provided by a control composition after 20 hours in an in vitro dissolution test (e.g., PBS or MFD solution), or the concentration of drug produced by a control composition after 20 hours using an in vivo test, wherein a sufficient amount of drug is present in the control such that the maximum theoretical drug concentration provided by the control composition is greater than the solubility of the drug. Although in some cases the drug concentration may still change after 20 hours, a comparison of the performance of the composition of the invention with the "equilibrium concentration" of a control composition in the use environment measured after 20 hours will allow a determination of whether the composition is within the scope of the invention.

Alternatively, the compositions of the invention provide a dissolution AUC of at least 90 minutes over the course of 1200 minutes immediately upon introduction to a use environment that is 1.25 times the dissolution AUC provided by a control composition containing an equivalent amount of the drug in solubility-improved form but no concentration-enhancing polymer, the dissolution AUC being the integral of the plot of drug concentration versus time over a given time. For the purpose of determining whether a composition or method is part of the present invention, the dissolved AUV is calculated over a period of time as short as 90 minutes, up to 1200 minutes. The time period may be chosen to be any time period between the time of introduction into the use environment (time 0) and 1200 minutes after introduction into the use environment. Therefore, acceptable time periods include, for example, (1) from the time of introduction into the use environment to 90 minutes after introduction into the use environment; (2) from the time of introduction into the use environment to 180 minutes after introduction into the use environment; (3) from 90 minutes after introduction into the use environment to 180 minutes after introduction into the use environment; and (4) from 300 minutes after introduction into the use environment to 1200 minutes after introduction into the use environment. The composition or method is part of the invention if it meets the dissolution AUC criterion for at least one acceptable period of time. In vitro determinations of AUC can be performed by plotting drug concentration versus time after dissolving the drug composition in, for example, PBS or MFD solution. In vivo measurements of AUC where the environment of use is, for example, the GI tract are very complex. This requires the collection of a sample of GI fluid as a function of time and is therefore not preferred compared to in vitro dissolution tests and in vivo relative bioavailability tests.

In a preferred embodiment, the composition comprising the mixture provides a higher relative bioavailability of the drug. Generally, compositions or methods that are evaluated using an in vitro test method and found to be part of the present invention will be tested in vivo. Bioavailability of a drug in a composition or method of the invention can be tested in vivo in animals, such as mammals and humans, using conventional methods for making such assays. A conventional measure of in vivo bioavailability is "relative bioavailability", which is defined as the ratio of the plasma or serum AUC determined from the plasma or serum drug concentration and time curve used to determine the compositions or methods of the invention to the plasma or serum AUC of a control composition or method that does not contain the concentration-enhancing polymer.

The compositions of the present invention achieve a relative bioavailability of at least 1.25. More preferably, the compositions of the present invention provide a relative bioavailability of at least 1.5, more preferably at least 2, and more preferably at least 3.

The compositions or methods of the invention pass one or more in vitro dissolution tests or in vivo relative bioavailability tests or both in vitro and in vivo tests.

The concentration of dissolved drug in a dissolution test is typically determined by taking a sample of the test medium and analyzing the concentration of the dissolved drug. To avoid precipitation of large amounts of drug causing false determinations, the test solution is filtered or centrifuged. "solubilized drug" typically refers to material that can pass through a 0.45 μm syringe filter, or that remains in the supernatant after centrifugation. Filtration can be carried out using a 13mm, 0.45 μm polyvinylidene fluoride (polyvinylidene fluoride) syringe filter, which is sold under the trademark TITAN by Scientific Resources^And (5) selling. Centrifugation is typically performed in polypropylene microcentrifuge tubes at about 13,000G for about 60 seconds. Other similar filtration or centrifugation methods may be employed and useful results obtained. For example, other types of micro-filters may be used than those described aboveHigh or low (+ -10-40%) values, but still allow identification of preferred compositions. It will be understood by those of ordinary skill in the art that this definition of "dissolved drug" includes not only solvated drug molecules, but also a wide variety of species, such as polymeric drug assemblies having submicron dimensions, e.g., drug aggregates, aggregates of polymers and drug mixtures, micelles, polymeric micelles, colloidal particles or nanocrystals, polymer/drug complexes, and other such drug-containing materials, which are present in the filtrate or supernatant in the dissolution test.

Medicine

The present invention is applicable to any drug that can be formulated in a solubility-improved form. The term "drug" is a conventional term and represents a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially a human. The drug need not be poorly soluble to benefit from the present invention, although poorly soluble drugs represent one preferred class for use in the present invention. Although appreciable solubility exists in the desired use environment, the drug may also benefit from the increased solubility/bioavailability produced by the present invention if the addition of a concentration-enhancing polymer can reduce the size of the dose required for therapeutic efficacy or increase the rate of drug absorption in situations where it is desirable to rapidly initiate the effective action of the drug.

The invention analyzes specific utility when the drug is a "low solubility drug" by which is meant that the drug may be "substantially water insoluble" which means that the drug has a minimum aqueous solubility of less than 0.01mg/mL at a physiologically relevant pH (e.g., pH1-8), "poorly soluble" by which is meant a solubility in water of up to about 1-2mg/mL, or even less than the solubility in moderate water, having an aqueous solubility of from about 1mg/mL up to about 20-40 mg/mL. In general, it can be said that the drug has a dose-to-aqueous solubility ratio of greater than 10mL, and more typically greater than 100mL, where the solubility of the drug is the minimum value that can be observed in any physiologically relevant aqueous solution (e.g., those having a pH of between 1 and 8), including USP simulated gastrointestinal buffers.

Preferred classes of drugs include, but are not limited to: antihypertensives, anxiolytics, anticoagulants, anticonvulsants, hypoglycemic agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatory agents, antipsychotic agents, cognitive enhancers, cholesterol-lowering agents, obesity therapeutics, autoimmune diseases drugs, impotence therapeutics, antibacterial and antifungal agents, hypnotics, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, antibiotics, antidepressants, and antiviral agents.

Specific examples of the above and other classes of drugs and therapeutic agents that may be administered by the present invention are described below, but are by way of example only. Each reference to a drug is understood to include the neutral form, pharmaceutically acceptable salts, and prodrugs of the drug. Specific examples of antihypertensive agents include prazosin, nifedipine, tramozosin, and doxazosin; specific examples of anxiolytics are hydroxyzine; specific examples of hypoglycemic agents are glipizide; specific examples of the impotence-treating agent are sildenafil (sildenafil) citrate; specific examples of the antitumor agent include chlorambucil, lomustine, and echinomycin; a specific example of an imidazole-based antineoplastic agent is tobramzole; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, flurbiprofen, and (+) -N- {4- [3- (4-fluorophenoxy) phenoxy ] -2-cyclopenten-1-yl } -N-hydroxyurea; specific examples of barbiturates are phenobarbital; specific examples of antiviral agents include acyclovir, nelfinavir (nelfinavir), and ribavirin; examples of vitamins/nutrients include vitamin a and vitamin E; specific examples of beta blockers include timolol and nadolol; specific examples of emetics are apomorphine; specific examples of diuretics include chlorthalidone and spironolactone; specific examples of anticoagulants are dicoumarins; specific examples of cardiac inotropic agents include digoxin and digitoxin; specific examples of androgens include 17-methyltestosterone and testosterone; specific examples of adrenocortical hormones are deoxycorticosterone; specific examples of steroidal hypnotics/anesthetics are alphaxalone; specific examples of anabolic agents include fluoxymesterone and methandrolone (methanstenone); specific examples of antidepressant drugs include sulpiride, [3, 6-dimethyl-2- (2, 4, 6-trimethyl-phenoxy) -pyridin-4-yl ] - (1-ethylpropyl) -amine, 3, 5-dimethyl-4- (3 '-pentyloxy) -2- (2', 4 ', 6' -trimethylphenoxy) pyridine, pirisidine (pyroxidine), fluoxetine, paroxetine, venlafaxine (venlafaxine), and sertraline; specific examples of antibiotics include ampicillin and penicillin G; specific examples of anti-infective drugs include benzalkonium chloride and chlorhexidine; specific examples of coronary vasodilators include nitroglycerin and mifeprazine; specific examples of hypnotics are etomidate; specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorazol amide (chlorzolamide); specific examples of fungicides include econazole, terconazole, fluconazole, voriconazole (voriconazole), and griseofulvin; specific examples of antiprotozoal agents are metronidazole; specific examples of anthelmintics include thiabendazole and oxfendazole and morantel; specific examples of antihistamines include astemizole, levocabastine, cetirizine, and cinnarizine; specific examples of antipsychotic agents include ziprasidone, fluspirilene, risperidone and pentafluridol; specific examples of gastrointestinal drugs include loperamide and cisapride; specific examples of 5-hydroxytryptamine antagonists include ketanserin and mianserin; specific examples of anesthetics are lidocaine; specific examples of the hypoglycemic agent are acetosulfonyl cyclohexylurea; a specific example of an antiemetic is dimenhydrinate; specific examples of antibacterial agents are cotrimozole (cotrimoxazole); specific examples of dopaminergic agents are L-DOPA; specific examples of anti-alzheimer's disease agents are THA and donepezil (donepezil); specific examples of antiulcer/H2 antagonists are famotidine; specific examples of sedatives/hypnotics include chlordiazepoxide and triazolam; specific examples of vasodilators are alprostadil; specific examples of platelet inhibitors are prostacyclin; specific examples of ACE inhibitors/antihypertensive agents include enalapril acid (enalaprilic acid) and lisinopril; specific examples of tetracycline antibiotics include oxytetracycline and minocycline; specific examples of macrolide antibiotics include erythromycin, azithromycin, clarithromycin, and spiramycin; specific examples of glycogen phosphorylase inhibitors include [ R- (R x S) ] -5-chloro-N- [ 2-hydroxy-3- { methoxymethylamino } -3-oxo-1- (phenylmethyl) propyl-1H-indole-2-carboxamide and 5-chloro-1H-indole-2-carboxylic acid [ (1S) -benzyl- (2R) -hydroxy-3- ((3R, 4S) -dihydroxy-pyrrolidin-1-yl-) -3-oxopropyl ] amide.

Other examples of drugs which can be administered by the present invention are the hypoglycemic drugs chlorpropamide, the antifungal agent fluconazole, the antihypercholesterolemic agent atorvastatin (calcium), the antipsychotic agent tiotropium hydrochloride, the anxiolytic therapeutic agents hydroxyzine hydrochloride and doxepin hydrochloride, the antihypertensive drugs amlodipine sulfonate, the anti-inflammatory agents piroxicam, valdicoxib, carprofen and celecoxib, and the antibiotics carpinin sodium, palmicin hydrochloride, oleandomycin acetate and doxycycline hydrochloride.

The drug is in a solubility-improved form, as described in the summary of the invention. However, other test media may be used to determine whether a drug is in a solubility-improved form, with the media suitable varying from drug to drug. Generally, the solubility-improved drug form will provide a maximum concentration within the test medium that is greater than the equilibrium concentration provided by the low solubility form of the drug in the same test medium. Furthermore, since the maximum concentration provided by a drug in a test medium is always greater than or equal to the equilibrium concentration provided by the same drug in the same test medium, a drug is considered to be a solubility-improved form if the maximum concentration provided by the drug in the test medium is greater than the maximum concentration provided by a low-solubility form of the drug.

Care must be taken when conducting a test to determine whether a drug is in a solubility-improved form because, as noted above, the rate at which a solubility-improved drug is converted to its lowest energy state (e.g., a low solubility form) will vary greatly from drug to drug and from test medium to test medium. As noted above, the rate at which a solubility-improved form of a drug is converted to its lowest energy form will vary greatly from drug to drug, and will be highly dependent on the environment in which the drug form is evaluated for use. Therefore, it is desirable to assess the solubility improvement of a particular drug form in an in vitro test, wherein the use environment can be carefully controlled. The solubility-improved form of the drug will provide, at least temporarily, a dissolved drug concentration in an in vitro test medium, such as distilled water, or a PBS or MFD solution having a physiologically relevant pH (e.g., 1-8), that is greater than the equilibrium concentration provided by the low-solubility form of the drug. Distilled water at 37 c has been found to be a routine use environment for testing the solubility improvement of a drug form to determine whether the drug form is a solubility-improved form.

In one aspect of the invention, the solubility-improved form of the drug is crystalline and a very soluble salt form of the drug. As used herein, "highly soluble salt form" means that the drug is a salt form that provides a maximum concentration of drug in at least one in vitro test medium that is greater than the equilibrium concentration provided by the lowest solubility form of the drug. The drug may be in the form of any pharmaceutically acceptable salt of a basic, acidic or zwitterionic drug meeting this criteria. Examples of salt forms of the basic drug include hydrochloride, hydrobromide, chloride, bromide, acetate, iodide, mesylate, phosphate, maleate, citrate, sulfate, tartrate, lactate, and the like. Examples of salt forms of acidic drugs include sodium, calcium, potassium, zinc, magnesium, lithium, aluminum, meglumine, diethanolamine, benzathine (benzathine), choline, and procaine salts and the like. These salts can also be used in zwitterionic drugs.

While virtually any salt form of a particular basic drug may provide a higher concentration of drug in the use environment than known low solubility salt forms, it is generally the fact that the free base or hydrochloride salt form of the basic drug has lower aqueous solubility than other salt forms of the same drug. In addition, in the environment of use of the GI tract of a mammal, the free base and hydrochloride salt forms of the basic drug are typically drug forms that are in equilibrium with the solubilized drug. Therefore, when the solubility-improved form of the drug consists solely of the basic drug, the solubility-improved form must provide an increased concentration of the drug in the use environment over the free base and hydrochloride forms of the drug.

Preferred highly soluble salt forms are those salt forms that have a solubility in water that is at least 1.25 times, preferably at least 2 times, and more preferably at least 5 times the solubility in water of the more soluble crystalline free base and crystalline hydrochloride salt forms. However, as described below, when the solubility-improved form consists of a drug in combination with a solubilizing agent, a low solubility salt form or even a free base form of the drug may be employed.

It should also be noted that for low solubility alkaline drugs, they generally have a higher solubility in the low pH gastric environment than in the intestinal or colon, which typically has a pH of about 6-8. Thus, even administration of the lowest solubility known drug forms of such drugs to the gastric environment can produce high concentrations of the dissolved drug, and such compositions and methods do not form part of the present invention.

More preferably, when the solubility-improved form of the drug consists solely of the crystalline salt form of the basic drug, the solubility-improved form of the drug provides a drug concentration in gastric fluid or simulated gastric fluid that is greater than the maximum drug concentration provided by the free base or hydrochloride salt form of the drug in the same fluid. Furthermore, when the solubility-improved form of the drug consists solely of a crystalline basic drug, which is solubilized in the presence of gastric fluid (i.e., more soluble in gastric fluid than in intestinal fluid), compositions containing the solubility-improved form of the basic drug and the concentration-enhancing polymer preferably provide improved relative bioavailability compared to controls containing an equivalent amount of the same drug but in a low solubility form (e.g., the hydrochloride salt form) and an equivalent amount of the concentration-enhancing polymer.

An example of a basic drug having a crystalline very easily soluble salt form is sertraline. At pH3, sertraline lactate has a solubility in distilled water of 256mg/mL (expressed as the free base), whereas the HCl salt form has a solubility of only 3mg/mL, expressed as the free base. When sertraline lactate is administered into simulated or actual gastric fluid, the drug exchanges the lactate counterion with the chloride ions present in the gastric fluid and precipitates or crystallizes out the chloride salt and/or free base until an equilibrium concentration is reached. The equilibrium concentration is lower than the maximum concentration provided by sertraline lactate. Drug solubility also decreases with increasing pH of the surrounding liquid because of the enhanced conversion of the drug to the free base form, which has a solubility of 0.2mg/mL at pH 7, which is lower than the solubility of the chloride salt form. Thus, crystalline sertraline lactate is a solubility-improved form relative to the crystalline hydrochloride and crystalline free base forms of sertraline.

It should be noted that while distilled water may be used as a test medium to assess whether a drug is in a solubility-improved form, it is generally not suitable for use as an in vitro use environment because its pH and chloride content do not reflect typical in vivo use environments. Thus, the solubility-improved form is suitable for providing higher than equilibrium concentrations of drug in an in vitro use environment having a chloride content close to the intended in vivo use environment and a pH between about 6 and 8.

Alternatively, in another aspect of the invention, the drug is present in a high energy crystalline form that has increased solubility over a low energy crystalline form. It is known that some drugs can crystallize into one of several different crystalline forms. Such crystalline forms are often referred to as "polymorphs". As used herein, "high energy crystalline form" means that the drug is in a crystalline form that provides at least a maximum concentration of the drug in an in vitro test medium that is greater than the equilibrium concentration of the drug provided by another low energy crystalline form.

An example of such a drug is 5-chloro-1H-indole-2-carboxylic acid [ (1S) -benzyl-3- ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl ] amide in the form "A1", which has a solubility of about 480. mu.g/mL in PBS, whereas the form "A2" has a solubility of only 87. mu.g/mL in PBS.

In another aspect of the invention, the drug may be capable of existing in amorphous or crystalline form, but in another aspect of the inventionIn the composition it is in amorphous form. The drug in its amorphous form provides a maximum concentration of the drug in at least the in vitro test medium that is greater than the equilibrium concentration of the drug provided by the drug in crystalline form. An example of such a drug is 5-chloro-1H-indole-2-carboxylic acid [ (1S) -benzyl-3- ((3R, 4S) -dihydroxypyrrolidin-1-yl-) (2R) -hydroxy-3-oxopropyl]Amides of C in amorphous form_maxIs 270. mu.g/mL, and its crystalline form is C_maxOnly 160. mu.g/mL, both results were determined in MFD solution at pH 6.5.

In another aspect of the invention, the solubility-improved form of the drug is a mixture of the drug and a solubilizing agent. The drug/solubilizing agent mixture provides, at least temporarily, in at least an in vitro test medium, a maximum concentration of the drug that is greater than the equilibrium concentration of the drug provided by the drug without the solubilizing agent. An example of such a drug/solubilizing agent mixture is sertraline hydrochloride mixed with citric acid, the equilibrium solubility of which is 28mg/mL compared to 3mg/mL of sertraline hydrochloride, both measured at pH3.

Examples of the solubilizer include: a surfactant; pH control agents such as buffers, organic acids, organic acid salts, organic and inorganic bases, and organic and inorganic base salts; a glyceride; partial glycerides; a glyceride derivative; polyoxyethylene and polyoxypropylene ethers and copolymers thereof; sorbitan esters; polyoxyethylene sorbitan esters; a carbonate salt; alkyl sulfonates; and a cyclodextrin. In this regard, both the drug and the solubilizing agent are preferably solids.

Various factors need to be considered when selecting an appropriate solubilizing agent for a drug. The solubilizing agent should not interact adversely with the drug. Furthermore, the solubilizing agent should be very effective and only small amounts are required to produce improved solubility. It is also desirable that the solubilizing agent have high solubility in the environment of use. Organic acids and organic acid salts, organic and inorganic bases, and organic and inorganic base salts are known to be effective solubilizing agents for acidic, basic, and zwitterionic drugs. It is generally desirable that these compounds have a high number of equivalents of acid or base per gram. In addition, it is generally desirable to select acid or base solubilizing agents so that the ionic form of the drug has high solubility with the salt formed from the corresponding conjugate acid or base salt of the solubilizing agent. The choice of solubilizer is therefore highly dependent on the nature of the drug.

In another aspect of the invention, the solubility-improved form of the drug is a solution or suspension of the drug substantially dissolved or suspended in a liquid at a concentration at least 10 times greater than the equilibrium concentration of the drug in the environment of use. Examples of solubility-improved forms suitable for such drugs include: water-immiscible triglyceride vegetable oils such as safflower oil, sesame oil, corn oil, castor oil, coconut oil, cottonseed oil, soybean oil, olive oil, etc.; water-immiscible refined and synthetic and semi-synthetic oils, e.g. mineral oils, known as MIGLYOL^Triglycerides of (a), including caprylic/capric triglycerides and caprylic/capric/linoleic triglycerides, long chain triglyceride oils, such as triolein, other mixed chain triglycerides that are liquid at room temperature, monoglycerides, diglycerides, and mixtures of mono-, di-, and triglycerides; fatty acids and esters; water-miscible alcohols, glycerol and propylene glycol; and water-miscible polyethylene glycols (PEGs) that are liquids at the temperature of the environment of use (which is typically about 35-40 ℃), such as PEG-400. Examples of such commercially available materials include corn oil, propylene glycol, CREMOPHOR RH-40 (polyoxyl) -40 hydrogenated castor oil), LABRAFIL M2125 (linoleoyl) polyoxyl-6 glycerides), and 1944 (oleoyl polyoxyl-6 glycerides), ethanol, PEG 400, tween 80, glycerol, peppermint oil, soybean oil (long chain triglycerides), sesame oil (long chain triglycerides), propylene carbonate, and tocopheryl TPGS. Other key commercial materials include MIGLYOL 812 (caprylic/capric triglycerides), oleic acid, olive oil (long chain triglycerides), CAPMUL MCM (medium chain monoglycerides), CAPMUL PG-8 (propylene glycol caprylyl glycerol mono-and diesters), CREMOPHOR EL (polyoxyl 35 castor oil), LABRASOL (caprylocaproyl polyoxyl-8 glycerides), triacetin (acetyl triglycerides), MAISINE 35-1 (glyceryl monooleate), OLICINE (glyceryl monooleate/linoleate), PECEOL (glycerol monooleate), TRANSCUTOL P (diethylene glycol monoethyl ether), PLUROL Oleique CC (polyglyceryl-6 dioleate), LAUROGLYCOL 90 (propylene glycol monolaurate), capriyol 90 (propylene glycol monocaprylate), myvaces (acetylated monoglycerides), arlaces (sorbitan fatty acid ester), PLURONICS (copolymer of propylene oxide and ethylene oxide), BRIJ30 (polyoxyethylene 4 lauryl ether), GELUCIRE 44/14 (lauroyl polyoxyl-32 glycerides), and GELUCIRE 33/01 (glycerides of fatty acids). Mixtures of these and other related materials are acceptable provided that they are liquid at the temperature of their use environment, which is typically about 35-40 ℃.

Concentration enhancing polymers

Concentration-enhancing polymers suitable for use in the various aspects of the invention should be inert, i.e., they should not chemically react with the drug in an adverse manner, and should have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1-8). Almost any neutral or ionizable polymer having a solubility of at least 0.1mg/mL over at least a portion of the pH range of 1-8 is suitable.

Preferred classes of concentration-enhancing polymers include ionizable and non-ionizable cellulosic polymers (including those polymers and copolymers thereof bearing ether or ester or mixtures of ester and ether substituents, including so-called "enteric" and "non-enteric" polymers); and copolymers of vinyl polymers and substituents having hydroxyl, alkanoyloxy, and cyclic amido groups. It is also preferred that the concentration-enhancing polymer is "amphiphilic" in nature, meaning that the polymer has both hydrophobic and hydrophilic portions.

Amphiphilic and/or ionizable polymers are preferred because it is believed that such polymers tend to have strong interactions with the drug and may facilitate the formation of a variety of the above-described polymer/drug assemblies. In addition, the repulsion between like charges of the ionized groups of such polymers can serve to limit the size dimension of the polymer/drug assembly to the nanometer or submicron scale. For example, while not wishing to be bound by a particular theory, such a polymer/drug assembly may contain hydrophobic drug clusters surrounded by a concentration-enhancing polymer, the hydrophobic region of the polymer turning inward toward the drug while the hydrophilic region of the polymer turns outward toward the aqueous environment. Alternatively, depending on the particular chemical nature of the drug, the ionized functional groups of the polymer may be associated with ionic or polar groups of the drug, for example, via ion-pairing or hydrogen bonding. In the case of ionizable polymers, the hydrophilic regions of the polymer should contain ionizing functional groups. Such drug/concentration-enhancing polymer assemblies can be very similar charged polymeric micelle-like structures in solution. In any case, regardless of the mechanism of action, the inventors have observed that such amphiphilic polymers, in particular ionizable cellulosic polymers, such as those listed below, have shown interaction with the drug, thereby inhibiting its crystallization.

Amphiphilic celluloses can be prepared by substituting any or all of the 3 hydroxyl substituents present on each saccharide repeat unit with at least one relatively hydrophobic group. The hydrophobic substituent can be essentially any substituent that can render the cellulosic polymer substantially water insoluble if it is substituted to a sufficiently high level or degree of substitution. Hydrophilic regions of the polymer can be those portions that are relatively unsubstituted, since unsubstituted hydroxyl groups are themselves relatively hydrophilic, or those regions that are substituted with hydrophilic substituents. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, and the like; or ester-linked alkyl groups such as acetate, propionate, butyrate, and the like; and ether-and/or ester-linked aryl groups, such as phenyl, benzoate or phenyl ether. Hydrophilic groups include ether-or ester-linked non-ionizing groups such as hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkylether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those ether-or ester-linked celluloses, the following substitutions having ionizable groups such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates. Specific substituents include succinic acid, citric acid, phthalic acid, 1, 2, 4-trimellitic acid, hydroxyphenoxy, aminoethoxy, thiosuccinic acid, diethylaminoethoxy, trimethylaminoethoxy, sulfoethoxy (sulfonate ethoxy) and phosphoethoxy (phosphate ethoxy).

It should be noted that polymer names such as "cellulose acetate phthalate" (CAP) refer to any member of the cellulose polymer family having acetate and phthalate groups attached via ester groups to a significant fraction of the cellulose polymer hydroxyl groups. In general, the degree of substitution of each substituent may be in the range of 0.1 to 2.9, as long as other criteria of the polymer are met. By "degree of substitution" is meant the average number of 3 hydroxyl groups substituted per saccharide repeat unit on the cellulose chain. For example, if all of the hydroxyl groups of the cellulose chain are substituted with phthalic acid, the degree of substitution of phthalic acid is 3. Also included in each polymer family type are cellulosic polymers having a relatively small number of additional substituents that do not substantially alter the properties of the polymer.

It should be noted that in the polymer nomenclature herein, the ether-linked substituents are described before "cellulose" as the moiety linked to an ether group; for example, "ethyl cellulose benzoate" has an ethoxybenzoic acid substituent. Likewise, ester-linked substituents are described after "cellulose" as carboxylic acid esters; one carboxylic acid of each phthalate, e.g., "cellulose phthalate", is attached to the polymer via an ester bond and the remaining carboxylic acids are unreacted.

Specific examples of cellulosic polymers having hydrophilic and hydrophobic regions that meet the definition of amphiphilicity include polymers such as CAP and cellulose acetate 1, 2, 4-trimellitate (CAT), where cellulosic repeat units having one or more acetate substituents are hydrophobic relative to those having no acetate substituents or having one or more ionized phthalate or 1, 2, 4-trimellitate substituents; and polymers such as Hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose acetate (HPCA) in which a cellulose repeat unit having a higher number of methoxy or acetic acid substituents than unsubstituted hydroxy or hydroxypropyl substituents constitutes a hydrophobic region relative to other repeat units of the polymer.

Non-cellulosic polymers that meet the definition of amphiphilicity are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include acrylate and methacrylate copolymers. Examples of commercially available grades of such copolymers include EUDRAGITS, which is a copolymer of methacrylate and acrylate esters, produced by Rohm Tech inc.

Examples of ionizable polymers that can be used as concentration-enhancing polymers that at least partially ionize at physiologically relevant pH include: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose and carboxylic acid functionalized polymethacrylates.

Polymers that can be used as non-ionizing polymers of the concentration-enhancing polymer include: hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol having at least a portion of its repeating units in unhydrolyzed (vinyl acetate) form, polyvinyl alcohol-polyvinyl acetate copolymers, polyethylene glycol-polypropylene glycol copolymers, polyvinyl pyrrolidone and polyethylene-polyvinyl alcohol copolymers, and chitan.

One class of polymers that meets the requirements of the present invention includes: a cellulosic polymer having ester-or ether-linked aromatic substituents, wherein the polymer has a degree of substitution of at least 0.1. Examples of aromatic substituents include benzoate, phenoxy and ethoxyphenyl. In order for the aromatic-substituted polymer to also have the necessary solubility in water, it is also desirable that sufficient hydrophilic groups, such as hydroxypropyl or carboxylic acid functional groups, be attached to the polymer. Such carboxylic acid groups may be ether-linked to the polymer, which may be, for example, carboxyethyl groups, or they may be linked via ester groups, such as succinate groups. The carboxylic acid and aromatic group may be combined as a substituent, which may be, for example, a carboxylic acid substituted aromatic group, which may be linked via an ester group, including phthalate esters, 1, 2, 4-trimellitate esters, different isomers of pyridine dicarboxylic acids, terephthalate esters, isophthalate esters and alkyl substituted derivatives of these groups. Examples of carboxylic acid-substituted aromatic groups that may be attached via an ether group include salicylic acid, alkoxybenzoic acids, such as ethoxybenzoic acid or propoxybenzoic acid, different isomers of alkoxyphthalic acids, such as ethoxyphthalic acid and ethoxyisophthalic acid, and different isomers of alkoxynicotinic acid, such as ethoxynicotinic acid and ethoxypicolinic acid.

A particularly preferred collection of cellulosic ionizable polymers are those having carboxylic acid functional aromatic substituents and alkylated substituents. Exemplary polymers include: cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate 1, 2, 4-trimellitate, methyl cellulose acetate 1, 2, 4-trimellitate, ethyl cellulose acetate 1, 2, 4-trimellitate, hydroxypropyl methyl cellulose acetate 1, 2, 4-trimellitate, hydroxypropyl cellulose acetate 1, 2, 4-trimellitate succinate, hydroxypropyl cellulose acetate phthalate succinate, Cellulose propionate 1, 2, 4-trimellitate, cellulose butyrate 1, 2, 4-trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose salicylate acetate, hydroxypropyl cellulose salicylate acetate, ethyl benzoate cellulose acetate, hydroxypropyl ethyl benzoate cellulose acetate, ethyl phthalate cellulose acetate, ethyl nicotinate cellulose acetate, and ethyl picolinate cellulose acetate.

Another particularly preferred collection of cellulosic ionizable polymers are those having a non-aromatic carboxylate substituent. Exemplary polymers include: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, and hydroxyethyl cellulose acetate succinate.

More preferred polymers are hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate 1, 2, 4-trimellitate, cellulose acetate terephthalate and cellulose acetate isophthalate. The most preferred polymers are hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and cellulose acetate 1, 2, 4-trimellitate.

While specific polymers have been discussed as being suitable for use in the blends of the present invention, blends of such polymers are also suitable. The term "concentration-enhancing polymer" therefore includes mixtures of said polymers in addition to a single species of said polymer.

Preparation of the composition

The compositions of the present invention may be prepared by dry-or wet-mixing the drug or drug mixture with the concentration-enhancing polymer to form the composition. Mixing methods include physical processing as well as wet granulation and coating methods. Any conventional mixing method that does not substantially convert the drug and polymer into a molecular dispersion may be used.

For example, mixing methods include convective mixing, shear mixing, or diffusion mixing. Convective mixing involves moving a relatively large amount of material from one part of the powder bed to another by means of vanes or paddles, rotating a screw, or inverting the powder bed. Shear mixing is performed when a slip plane is formed in the materials being mixed. Diffusive mixing involves the exchange of the positions of individual particles. These mixing processes can be accomplished using batch or continuous type equipment. A drum mixer (e.g., double shell) is a common device for batch processing. Continuous mixing can be used to improve the homogeneity of the composition.

Milling may also be used to prepare the compositions of the present invention. Milling is a mechanical processing method (comminution) that reduces the particle size of solids. Since milling can in some cases alter the crystalline structure and cause chemical changes in some materials, the milling conditions are chosen so as not to alter the physical form of the drug, i.e., the drug and polymer do not mix at the molecular level to form a dispersion of polymer and drug. The most common grinding devices are rotary shears, hammers, rollers and fluid energy mills. The choice of device depends on the nature of the components in the pharmaceutical form (e.g. soft, abrasive or friable). Wet-or dry-milling techniques may also be selected for several of these methods, again depending on the characteristics of the components (e.g. stability of the drug in the solvent). The grinding process can be performed simultaneously with the mixing process if the material dosed is not uniform. Conventional mixing and milling methods suitable for use in The present invention are discussed fully in Lachman, et al, The Theory and Practice of Industrial Pharmacy (3d Ed, 1986). The components of the compositions of the present invention may also be combined by dry-or wet-granulation methods, provided that the granulation conditions are selected so as not to convert a substantial portion of the drug into a molecular dispersion of polymer and drug.

In addition to the physical mixtures described above, the compositions of the present invention may constitute any device (device) or collection of devices that can accomplish the goal of delivering both the solubility-improved form of the drug and the concentration-enhancing polymer to the environment of use. Thus, in the case of oral administration to a mammal, the dosage form may constitute a layered tablet, wherein one or more layers contain a solubility-improved form of the drug and one or more other layers contain the concentration-enhancing polymer. Alternatively, the dosage form may be a coated tablet wherein the core comprises said solubility-improved drug form and the coating comprises said concentration-enhancing polymer. Furthermore, the solubility-improved drug form and concentration-enhancing polymer may even be present in different dosage forms, such as tablets or beads, and may be administered simultaneously or separately, so long as both the solubility-improved drug form and concentration-enhancing polymer are administered in such a manner that the drug and polymer come into contact in the environment of use. When the solubility-improved drug form and the concentration-enhancing polymer are administered separately, it is generally preferred that the polymer is administered prior to the drug.

The amount of concentration-enhancing polymer relative to the amount of drug present in the mixture of the invention depends on the drug and concentration-enhancing polymer, and may be in the range of 0.01 to 5 drug: the polymer weight ratio may vary within a range. However, in most cases, the drug is preferred: the ratio of polymers is greater than 0.05 and less than 2.5, and the increase in drug concentration or relative bioavailability is often found in drug: the proportion of the polymer is 1 or less than 1. Even equal to 0.2 or less than 0.2 for some drugs. The minimum drug to polymer ratio that produces satisfactory results varies from drug to drug and is best determined in vitro and/or in vivo dissolution tests.

Generally, to maximize the drug concentration or relative bioavailability of the drug, it is preferred to reduce the drug to polymer ratio. At low drug: at the polymer ratio, there is sufficient concentration-enhancing polymer available in the solution to ensure that precipitation or crystallization of the drug from the solution is inhibited, whereby the average concentration of the drug is very high. For high drug/polymer ratios, there is not enough concentration-enhancing polymer in solution, and precipitation or crystallization of the drug can occur more readily. However, the amount of concentration-enhancing polymer that can be used in a dosage form is often limited by the overall quantity of the dosage form. For example, when oral administration to humans is desired, at low drug/polymer ratios, the total amount of drug and polymer in a single tablet or capsule may be unacceptably large for the intended dose administered. Therefore, it is often desirable to use a lower than optimal drug/polymer ratio in a particular dosage form to provide a sufficient dosage of drug in the dosage form that is small enough to facilitate transport to the environment of use.

Excipients and dosage forms

Although the key ingredients in the compositions of the present invention are only the drug and concentration-enhancing polymer administered in their solubility-improved form, other excipients may be included in the compositions. These excipients can be used with the drug/polymer mixture to formulate the mixture into tablets, capsules, suspensions, powders for suspensions, creams, transdermal patches, depot formulations, and the like. The drug and concentration-enhancing polymer may be added to the other dosage form components in any manner that does not substantially alter the drug. Furthermore, as mentioned above, the drug in its solubility-improved form and the concentration-enhancing polymer may each be mixed with excipients to form different beads, or layers, or coatings, or cores or even separate dosage forms.

One very useful excipient is a surfactant. Suitable surfactants include fatty acids and alkyl sulfonates; commercially available surfactants such as benzalkonium chloride (HYAMINE)^1622, available from Lonza, inc., Fairlawn, n.j.); DOCUSATE SODIUM (available from Mallinckrodt spec. chem., st. louis, MO); polyoxyethylene sorbitan fatty acid ester (TWEEN)^(ii) a Available from ICI Americas inc, Wilmington, DE); LIPOSORB^P-20 (available from Lipochem Inc., Patterson NJ); CAPMUL^POE-0 (available from Abitec Corp., Janesville, Wis.); and natural surfactants such as sodium taurocholate, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and other phospholipidsCompounds and mono-and diglycerides of glycerol. Such substances may be advantageously used to increase the rate of dissolution by promoting wetting, thereby increasing the maximum dissolved concentration, and may also inhibit crystallization or precipitation of the drug through interaction with the dissolved drug by mechanisms such as complexation, formation of inclusion complexes, formation of micelles, or adsorption onto solid drug, crystalline or amorphous surfaces. These surfactants may constitute up to 5% by weight of the composition.

It may also be beneficial to add a pH modifier, such as an acid, base or buffer, which delays the dissolution of the composition (e.g., an acid such as citric acid or succinic acid when the polymer is anionic) or increases the dissolution rate of the composition (e.g., a base such as sodium acetate or an amine compound when the polymer is anionic).

Conventional matrix materials, complexing agents, solubilizers, fillers, disintegrants or binders may also be added as an integral part of the composition itself, or by wet or mechanical granulation or other means. These materials may constitute up to 90% by weight of the composition.

Examples of matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, dibasic calcium diphosphate and starch.

Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose and croscarmellose sodium.

Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums, such as guar gum and tragacanth.

Examples of lubricants include magnesium stearate and calcium stearate.

Other excipients in conventional forms may be used in the compositions of the invention, including those well known in the art. In general, excipients such as pigments, lubricants, flavoring agents, and the like may be used for conventional purposes and in typical amounts that do not detract from the characteristics of the compositions of the invention. The compositions can be formulated using such excipients as tablets, capsules, suspensions, powders for suspensions, creams, transdermal patches, and the like.

The compositions of the present invention may be used in a variety of dosage forms for administration. Examples of dosage forms are powders or granules which can be taken orally, either dry or reconstituted by addition of water to form a paste, slurry, suspension or solution; a tablet; a capsule; composite microparticles; and pills. Various additives may be mixed, milled or granulated with the compositions of the present invention to form materials suitable for the dosage forms described above.

In some cases, the overall dosage form or the microparticles, granules or beads that make up the dosage form may have superior performance if coated with an enteric polymer to prevent or delay dissolution until the dosage form leaves the stomach. Examples of enteric coating materials include HPMCAS, HPMCP, CAP, CAT, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.

The compositions of the present invention may be administered in a controlled release dosage form. In one such dosage form, the combination of the drug in a solubility-improved form and the concentration-enhancing polymer is blended in an erodible polymer matrix device. By erodable matrix is meant water-erodable or water-swellable or water-soluble, i.e. erodable or swellable or soluble in pure water, or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution. Upon contact with an aqueous use environment, the erodible polymeric matrix absorbs water and forms a water-swollen gel or "matrix" that can entrap the mixture of the solubility-improved drug and the concentration-enhancing polymer. The water-swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of use, thereby controlling the release of the drug mixture to the environment of use.

Alternatively, the compositions of the present invention may be administered or mixed in a non-eroding matrix device.

Alternatively, the pharmaceutical mixtures of the present invention may be administered using a coated osmotic controlled release dosage form. This dosage form has two components: (a) a core containing an osmotic agent and a solubility-improved form of the drug and a concentration-enhancing polymer, either mixed or in separate regions of the core; and (b) a non-dissolving and non-eroding coating surrounding the core, the coating controlling the flow of water from the aqueous environment of use to the core, whereby compression of some or all of the core triggers release of the drug into the environment of use. The osmotic agent contained in the core of such a device may be a water-swellable hydrophilic polymer, a zymogen, or osmagent. The coating is preferably polymeric, water permeable, and has at least one transport outlet (port).

Alternatively, the pharmaceutical mixture of the present invention may be administered in a coated hydrogel controlled release dosage form having three components: (a) a composition comprising the drug in said solubility-improved form, (b) a water-swellable composition, wherein the water-swellable composition is in discrete regions within a core formed from the drug-containing composition and the water-swellable composition, and (c) a coating surrounding the core which is water-permeable, water-soluble, and has at least one transport outlet. In use, the core imbibes water through the coating, the water-swellable composition swells and increases the pressure within the core, fluidizing the drug-containing composition. With the coating intact, the drug-containing composition is extruded from the delivery outlet into the environment of use. The concentration-enhancing polymer may be administered in a separate dosage form, may be contained in a drug-containing composition, or may form all or part of a coating used in the dosage form.

When the solubility-improved pharmaceutical form is a solution or suspension of the drug in water or an organic liquid, the composition can be administered via a soft gelatin or hard gelatin capsule, as is known and readily understood in the art. These dosage forms comprise a water-soluble soft or hard gelatin shell encapsulating a carrier in which the drug has been dissolved and/or suspended. Examples of vectors suitable for this purpose are described above. The concentration-enhancing polymer can be dissolved or suspended in water or an organic liquid. Alternatively, the soft or hard gelatin shell may be coated with or made of a concentration-enhancing polymer.

Alternatively, the compositions of the present invention may be administered in combination, meaning that the drug in a solubility-improved form may be administered separately from the concentration-enhancing polymer, but administration is carried out in the same general time frame. Thus, a drug in a solubility-improved form can be administered, for example, in its own dosage form at about the same time as the concentration-enhancing polymer, which is in a separate dosage form. If administered separately, it is generally preferred to administer the drug in a solubility-improved form and the concentration-enhancing polymer at 60 minute intervals so that both are present together in the environment of use. When not administered simultaneously, the concentration-enhancing polymer is preferably administered prior to the solubility-improved form of the drug.

In addition to the above additives or excipients, the compositions of the present invention may be used to prepare suitable dosage forms using any conventional materials and methods known to those skilled in the art.

Other features and embodiments of the invention will become more apparent from the following examples, which illustrate the invention but do not limit its scope.

Examples 1 to 3

These examples demonstrate compositions containing a mixture of an amorphous drug and a concentration-enhancing polymer, as well as in vitro dissolution testing, known as the "microcentrifuge" method. This method was used to test the dissolution of MF grade hydroxypropyl methylcellulose acetate succinate mixture (HPMCAS-MF, containing 23.4% methoxy, 7.2% hydroxypropoxy, 9.4% acetyl, 11.0% succinyl; average molecular weight 10,000-]Amide (a glycogen phosphorylase inhibitor) (drug 1). Maximum concentration C of drug 1_maxFor the presence in the pH 6.5 MFD solutionIs 270. mu.g/mL, while the crystalline form of C_maxBut 160. mu.g/mL.

An amorphous drug (here in a solubility-improved form) was prepared by adding 10g of drug 1 to 118g of acetone and 6.2g of water. The solvent in this solution was rapidly removed by spray drying. In the Spray drying process, the drug solution is placed in a pressurized container that delivers the drug solution at a controlled rate to a commercially available Spray Dryer (Mobile mineral Hi-Tecnno-Aqueous Feed Spray Dryer, manufactured by Niro A/S, Soburg, Denmark). The Niro spray dryer consists of a two-fluid nozzle atomizer, which is fixed to the top of the drying chamber. The nitrogen nebulant was delivered to the nozzle at 2.7bar and the drug solution at a flow rate of 197 g/min. The drying gas (nitrogen heated to 197 c) was delivered to the drying chamber through an inlet duct surrounding the two-fluid nozzle. The spray-dried material present in the chamber passes through the transfer duct together with the drying gas and into the cyclone. At the top of the cyclone, a vent vented vent discharges the nitrogen and evaporates to allow the solvent to escape. The spray dried material was collected in a jar. The material was a dry, white, substantially amorphous powder. The yield of amorphous drug was 43%.

3.6mg of amorphous drug 1 was accurately weighed into 8 empty microcentrifuge tubes (polypropylene, Sorenson Bioscience, Inc.) in a 37 ℃ temperature controlled box. The theoretical maximum supersaturation concentration of this compound in solution was 2000. mu.g/mL (3.6mg drug [ 1000. mu.g/1 mg]2000g/mL to 1.8 mL). (abbreviated as theory C)_maxThe theoretical maximum supersaturation concentration of (b) is the concentration if all of the compound is dissolved in the solvent). The tests were performed in duplicate.

Control 1, consisting of amorphous drug 1 alone, was present in tubes 1 and 2. For example 1, 1.2mg of HPMCAS-MF was added to tubes 3 and 4. For example 2, 3.6mg of HPMCAS-MF was added to tubes 5 and 6. For example 3, 10.8mg of HPMCAS-MF was added to tubes 7 and 8. The four groups of samples represent control 1 and compositions 1, 2 and 3 of amorphous drug 1 with drug to polymer ratios of 3: 1, 1: 1 and 1: 3, respectively.

When the time is equal to 0, 1.8mL of 37 ℃ PBS solution (8.2mM NaCl, 1.1mM Na)₂HPO₄，4.7mM KH₂PO₄pH 6.5, 290mOsm/kg) was added to each tube. The centrifuge tube was closed and timing was started. The centrifuge tubes were then mixed continuously for 60 seconds at the highest speed of the Fisher Vortex Genie 2 mixer. The tubes were removed and transferred to a centrifuge (Marathon, Model Micro A) followed by centrifugation at 13,000G for 60 seconds. At 4 minutes, 50 μ L of sample was pipetted from the solids-free supernatant in the centrifuge tube. The solids were resuspended in the centrifuge tube by continuously mixing the sample in a vortex mixer for 30 seconds. The centrifuge tube was placed again in the centrifuge and left to stand until the next sample was collected. The individual samples were centrifuged, sampled and resuspended as described above. Each sample was diluted by adding 50. mu.L of the supernatant to 250. mu.L of methanol, and the concentration of the compound was determined by High Performance Liquid Chromatography (HPLC) (Hewlett Packard 1100, Zorbax SB C18 column, 35% Acetonitrile (ACN)/65% H₂O, absorbance was measured at 297nm with a diode array spectrophotometer (diode arraypectrophotometer).

Samples were taken after 4, 10, 20, 40, 90, 180 and 1200 minutes as described above, analyzed, and the concentration of the compound calculated. The data are summarized in table 1.1. Examples 1-3 each continued to provide a drug concentration in solution above the equilibrium concentration provided by control 1 for a period of time in excess of 20 hours (1200 minutes).

TABLE 1.1

Time (minutes)	[ medicine)Object 1](μg/mL)
					Control 1 (drug alone)	1 (3: 1 drugs 1: HPMCAS-MF)	2 (1: 1 medicine 1: HPMCAS-MF)	3 (1: 3 drugs 1: HPMCAS-MF)
	4	574	714	754					998
10					507	736	739	1032
	20	286	695	835					1064
40					217	690	845	1132
	90	187	728	897					1184
180					208	683	917	1301
	1200	203	440	626					1377

To obtain the maximum concentration of the drug (C)_max) The area under dissolution (AUC) from 0 to 90 minutes under the curve plotted against time for drug 1 was calculated and listed in table 1.2₉₀) And concentration after 20 hours or 1200 minutes (C)₁₂₀₀) And theory C_max. Theory C_maxIs the drug concentration that would be obtained if all of drug 1 were dissolved. That is, the total amount of active drug in μ g added to the test solution is divided by the total volume of the test solution in mL. It is clear that C of examples 1, 2 and 3_maxC for amorphous drug alone (control 1) respectively_max1.28-fold, 1.6-fold, and 2.4-fold, whereas the AUC of examples 1, 2, and 3 is 2.7-fold, 3.0-fold, and 4.2-fold that of amorphous alone (control 1).

TABLE 1.2

Examples	Cmax(μg/ml)	AUC90(minutes. mu.g/ml)	C1200(μg/ml)	Theory Cmax(μg/ml)
					Control 1 (drug 1 single use)	574	23,500	203	2000
1 (3: 1 drugs 1: HPMCAS-MF)	736	62,200	440	2000
					2 (1: 1 medicine 1: HPMCAS-MF)	917	74,200	626	2000
3 (1: 3 drugs 1: HPMCAS-MF)	1377	98,400	1377	2000

Example 4

This example demonstrates another composition of amorphous drug 1 and concentration-enhancing polymer. Amorphous drug 1 was prepared as described in example 1 and the dissolution of Oral Powder for Construction (OPC) suspensions was determined in an in vitro test called "gastric buffer to PBS transfer test". This test mimics oral administration of OPC dosage forms by contact with a small volume of acid (gastric buffer) for 30 minutes followed by PBS solution (intestinal buffer).

To perform these tests, 40mL of gastric buffer (0.084M HCl, 0.058 MNaCl, 7.0atm, pH 1.2) was added to a 500mL disoette flask at 37 ℃. Control 2 consisted of 0.6g of amorphous drug 1. Example 4 consisted of 0.6g of amorphous drug 1 and 1.8g of HPMCAS-MF. The components of control 2 and example 4 were weighed into OPC bottles, respectively, and 15mL of 2% by weight Tween 80 was added to each bottle. The solutions were mixed for 2 minutes. Deionized water (105mL) was added to each OPC bottle, each bottle was inverted 2 times, and the contents were added to each disoette flask. Rinse each OPC bottle 2 times into the corresponding disoette flask with 60mL of deionized water each time. Each dissoette flask was stirred at 100rpm for 30 minutes; samples were taken from each vial after 25 minutes. After stirring for 30 minutes, 0.55mL of 10% NaOH and 200mL of 2.5 XPBS (PBS solution with 2.5 fold standard buffer salt concentration) were added to each disoette vial. The pH of the solution in each vial was adjusted to 6.5 with 10% NaOH.

After adjusting the pH to 6.5, samples were taken at 4, 10, 20, 40, 90, 180 and 1200 minutes. This was done by removing 4 drops from each disoette flask and placing the drops in respective microcentrifuge tubes. The samples were centrifuged at 13,000G for 1 min. The supernatant (50. mu.l) was taken and added to 250. mu.l of methanol present in the HPLC vial. The concentration of the drug was determined by HPLC. The results are shown in Table 2.1.

TABLE 2.1

	[ drug 1](μg/mL)
			Time (minutes)	Control 2: (drug only 1)	Example 4 (1: 2 drug 1: HPMCAS-MF)
0	720	427
			4	359	857
10	357	880
			20	325	893
40	291	886
			90	263	923
180	251	765
			1200	237	528

C_max、AUC₁₈₀(AUC calculated from 0 to 180 min), the C₁₂₀₀And theory C_maxAs shown in table 2.2.

TABLE 2.2

Examples	Cmax(μg/ml)	AUC180(minutes. mu.g/ml)	C1200(μg/ml)	Theory Cmax(μg/ml)
					Control 2 (drug only 1)	720	50,800	237	1250
Example 4 (1: 2 drug: HPMCAS-MF)	923	155,600	528	1250

As the data show, C of example 4, consisting of amorphous drug and HPMCAS-MF polymer_max1.28 times that of control 2 consisting of amorphous drug alone, while the AUC of example 4₁₈₀Is AUC of control 2₁₈₀3 times of the total weight of the product.

Examples 5 to 9

These examples demonstrate compositions of amorphous drug 1 mixed with varying proportions of concentration-enhancing polymers. Amorphous drug 1(15mg) was added to microcentrifuge tubes containing 1.5mL of PBS solution and varying concentrations of HPMCAS-MF. The dissolution performance was determined at 37 ℃ using the microcentrifugation method described in example 1. Drug concentrations were determined at 1.5 hours and 20 hours for each polymer concentration. The results are shown in Table 3.

TABLE 3

Examples	Medicine 1: HPMCAS-MF ratio (w: w)	[ drugs)]1.5 hours (μ g/ml)	[ drugs)]20 hours (μ g/ml)
				Control 3	HPMCAS-MF-free	224	196
5	20∶1	447	289
				6	10∶1	487	293
7	5∶1	4928	1550
				8	1∶1	7453	5431
9	1∶2	8099	7451

The data in table 3 show that a certain concentration-increasing effect can be observed even at low polymer concentrations. However, this effect increases as the weight ratio of drug to polymer decreases. This indicates that a sufficient amount of polymer must be present in the composition to maximize the concentration-raising effect.

Examples 10 to 11

These examples demonstrate the combination of a drug in a highly soluble salt form (solubility-improved form) and a concentration-enhancing polymer. As discussed in the drug section describing the solubility improvement, sertraline lactate (drug 2) is a soluble salt of the antidepressant drug sertraline. The solubility of sertraline lactate was 256mg/mL (calculated from the molecular weight of the free base, 306 g/mol), while the solubility of its hydrochloride salt was only 3mg/mL (calculated from the molecular weight of the free base), both determined at pH3.

To perform these tests, 1.8mg of sertraline lactate was added to 0.9mL of HPLC water present in each tube of 6 microcentrifuge tubes, and for control 4, 0.9mL of 2 XPBS (PBS solution with 2 fold standard buffer salt concentration) adjusted to pH 8.0 was added to tubes 1 and 2. For example 10, 0.9mL of 2 XPBS (pH 8.0) containing 3.6mg of HPMCAS-MF was added to tubes 3 and 4. For example 11, 0.9mL of 2 XPBS (pH 8.0) containing 3.6mg of CAT was added to tubes 5 and 6. Control 4 contained no concentration-enhancing polymer.

The dissolution properties were measured at 37 ℃ using the microcentrifugation method described in example 1. Samples were taken after 4, 10, 20, 40, 90 and 180 minutes as described in example 1. Samples were at 35% H₂Diluted in O/65% ACN (vol/vol) and analyzed by HPLC. The mobile phase was 35% by volume of 0.025M triethylamine in HPLC water with 0.05M acetic acid in ACN. The analytical column used was Phenomenex ODS 20 and the drug concentration was measured at 230nm using a diode array. The results of the microcentrifuge test are shown in Table 4.1.

TABLE 4.1

	[ drug 2](μg/mL)
				Time (minutes)	Control 4 (drug 2 only)	Example 10 (1: 2 drug 2: HPMCAS-MF)	Example 11 (1: 2 drugs 2: CAT)
4	101	617	456
				10	89	550	376
20	72	459	321
				40	67	413	286
90	63	373	283
				180	60	341	245

These data show that for the composition containing the concentration-enhancing polymer, the maximum concentration of drug 2 is 4.5-6.1 times the maximum concentration of control 4.

TABLE 4.2

Examples	Cmax(μg/ml)	AUC180(minutes. mu.g/ml)	Theory Cmax(μg/ml)
				Control 4 (drug 2 only)	101	11,700	1000
10 (1: 2 medicine 2: HPMCAS-MP)	617	70,300	1000
				11 (1: 1 drugs 2: CAT)	456	50,900	1000

Table 4.2 shows AUC for HPMCAS-MF containing compositions₁₈₀AUC of CAT-containing composition 6.0-fold higher than control 4₁₈₀4.4 times that of control 4.

Examples 12 to 14

These examples demonstrate compositions containing a drug in a highly soluble salt form (here, a solubility-improved form) and a concentration-enhancing polymer. Ziprasidone mesylate (drug 3) is a soluble salt form of the antipsychotic agent, Ziprasidone. To perform these tests, 0.5mg of the drug was added to each of 8 microcentrifuge tubes. For control 5, no concentration-enhancing polymer was added to tubes 1 and 2. For example 12, 1.0mg of CAT was added to tubes 3 and 4. For example 13, 1.0mg of CAP (NF grade, available from Eastman Fine Chemical of Kingsport, Tennessee) was added to tubes 5 and 6. For example 14, 1.0mg of HPMCP (NF grade, available from Eastman chemical company) was added to tubes 7 and 8.

The dissolution properties were measured at 37 ℃ using the microcentrifugation method described in example 1. For each test, 0.616mg of drug 3 was added to the microcentrifuge tube. At time 0, 1.8ml of PBS was added to each centrifuge tube. The drug concentration was measured by HPLC, while the mobile phase was 60% (by volume) of 0. O2M KH in ACN₂PO₄pH 3.0, detected at 254nm with a diode array. The results of the dissolution test are shown in table 5.1.

TABLE 5.1

	[ drug 3 ]](μg/mL)
					Time (minutes)	Control 5 (drug only 3)	Example 12 (1: 2 drugs 3: CAT)	Example 13 (1: 2 drug 3: CAP)	Example 14 (1: 2 drugs 3: HPMCP)
10	3	23	18	22
					20	11	23	21	18
40	6	11	22	6
					90	7	6	25	6
180	1	5	23	12

Table 5.2 reports C_max、AUC₁₈₀And theory C_max. C of examples 12 to 14_max2.0-2.3 times of control 5, while AUC of examples 12-13₁₈₀1.6-4.0 times of control 5.

TABLE 5.2

Examples	Cmax(μg/ml)	AUC180(minutes. mu.g/ml)	Theory Cmax(μg/ml)
				Control 5 (drug only 3)	11	1000	342
12 (1: 2 medicine 3: CAT)	23	1600	342
				13 (1: 2 drugs 3: CAP)	25	4000	342
14 (1: 2 drugs 3: HPMCP)	22	1600	342

Examples 15 to 16

These examples demonstrate the combination of a drug in a high energy crystalline state (here, a solubility-improved form) and a concentration-enhancing polymer. Multiple polymorphic forms of the mesylate salt of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK inhibitor) [6, 7-bis (2-methoxy-ethoxy) -quinazolin-4-yl ] - (3-ethynyl-phenyl) amine (drug 4) have been isolated with varying solubilities. For example, the "A" form has a solubility in water of 102 μ gA/mL, while the "C" form has a solubility of 28 μ gA/mL. These polymorphs are metastable states that can rapidly interconvert into more stable forms, reaching lower equilibrium concentrations in the use environment. In these examples, the "a" polymorph was studied.

To perform these tests, 2.5mg of polymorph "a" was added to each of 6 microcentrifuge tubes. For control 6, no strength-enhancing polymer was added to tubes 1 and 2, and for example 15, 1.2mg of HPMCAS-MF was added to tubes 3 and 4. For example 16, 1.2mg of HPMCP was added to tubes 5 and 6.

The dissolution properties were measured at 37 ℃ using the microcentrifugation method described in example 1. At time 0, 1.8mL of PBS was added to tubes 1-6. Drug concentration was determined by HPLC. The mobile phase was a 55/45(v/v) mixture of 0.2% by weight trifluoroacetic acid (adjusted to pH 3.0) and ammonium hydroxide in HPLC water and 85/15(v/v) acetonitrile/isopropanol. The analytical column used was Inertsil C8 and the drug concentration was determined by diode array detection at 252 nm. The results of the dissolution test are shown in table 6.1.

TABLE 6.1

	[ drug 4 ]](μg/mL)
				Time (minutes)	Control 6 (drug only 4)	Example 152.1: 1 (drug 4: HPMCAS-MF)	Example 162.1: 1 (drug 4: HPMCP)
4	17	287	164
				10	18	113	41
20	21	34	32
				40	14	36	44
90	18	29	49
				1200	10	32	121

Table 6.2 shows C for compositions containing HPMCAS-MF (example 15)_maxIs C of control 6_max13.7 times of (D), while its AUC₉₀3.2 times that of control 6. C of HPMCP-containing composition (example 16)_max7.8 times higher than control 6, and AUC thereof₉₀2.9 times that of control 6.

TABLE 6.2

Examples	Cmax(μg/ml)	AUC90(minutes. mu.g/ml)	C1200(μg/ml)	Theory Cmax(μg/ml)
					Control 6 (drug only 4)	21	1500	10	1391
15 (2.1: 1 drugs 4: HPMCAS-MF)	287	4800	32	1391
					16 (2.1: 1 medicine 4: HPMCP)	164	4400	121	1391

Example 17

This example demonstrates a solubilizing agent mixed with a drug in a solubility-improved form of the drug. The solubility of sertraline HCl (drug 5) was determined in saturated citric acid at 37 ℃ and pH3.1 water (adjusted to pH3.1 with acetic acid) and at the same pH. As shown in table 7.1, the solubility of drug 5 was significantly increased in the presence of citric acid, giving a solubility improvement factor of 9.3. Therefore, citric acid is an excellent solubilizer for drug 5.

TABLE 7.1

Pharmaceutical forms	Sertraline HCl (mg/ml)
		Medicine 5	3
Drug 5 in saturated citric acid	28

For example 17, a solution containing 1,000. mu.g/mL drug 5, 500. mu.g/mL citric acid, and 1,000. mu.g/ML HPMCAS-MF was prepared in sulfate buffer (pH 7.9). For control 7, a solution containing no concentration-enhancing polymer was prepared.

The dissolution properties were measured at 37 ℃ using the microcentrifugation method described in example 1. Samples were taken at 15, 30, 60, 120 and 240 minutes as described in example 1 and drug 5 was analyzed in the same manner as in example 10. The results of these tests are shown in table 7.2, with a number of calculated values given in table 7.3.

TABLE 7.2

Examples	Time (minutes)	[ drug 5 ]](μg/ml)
			17	15	106
30	94
		60		55
120	59
		240		58
Control 7	5
		15	64
	30			52
		60	55
	120			52
		240	39

TABLE 7.3

Examples	Cmax(μg/ml)	AUC120(minutes. mu.g/ml)	Theory Cmax(μg/ml)
				Example 17	106	8700	1000
Control 7	64	6500	1000

These data show that the addition of concentration-enhancing polymer HPMCAS results in C of example 17_max1.7 times that of control 7. In addition, AUC thereof₁₂₀1.3 times that of control 7.

Example 18

This example demonstrates the in vivo application of the present invention. The soluble drug form and the concentration-enhancing polymer in aqueous solution are administered to dogs. The solubility-improved drug form is the mesylate (drug 6) salt of the drug 4- [3- [4- (2-methylimidazol-1-yl) phenylthio ] phenyl-3, 4, 5, 6-tetrahydro-2H-pyran-4-carboxamide hemifumarate. For this drug, the solubility of the hydrochloride salt was 0.37mgA/mL at pH 4, while the solubility of the mesylate salt (the solubility-improved form of the drug) was 3.7mgA/mL at pH 4. The solubility of both of these pharmaceutical forms decreases with increasing pH. At pH 7, the solubility of the hydrochloride salt was 0.0009mgA/mL and the solubility of the mesylate salt was 0.0042 mgA/mL. Ideally, the higher solubility of the solubility-improved drug form should be maintained in gastric fluid, and also the drug concentration should be able to be maintained in intestinal fluid at elevated pH.

Example 18A suspension containing 15mgA of drug 6 was prepared wherein the physical mixture of drug 6/HPMCAS-LF was 1: 10 (w/w). Control 8 contained no HPMCAS. The suspension compositions of example 18 and control 8 are shown in table 8.1.

TABLE 8.1

Components	Example 18(g)	Control 8(g)
			Medicine 6(0.814 potency)	0.246	0.246
HPMCAS	2.000	-
			Sterile water	40	40
pH	2.9	4.1

After an overnight fast, the dogs were administered 20mL of the suspension, immediately followed by a 10cc air purge through a surgically placed inlet, directly into the ascending colon. Blood samples (5ml) were collected from the jugular vein before and at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing.

Plasma concentrations of drug 6 in the standards, controls and study samples were determined by LC/MS analysis. 100 μ L aliquots of plasma from the sample, standard and control were added to appropriate wells of a 96 well plate followed by 5 μ L of Internal Standard (IS), 4- [ 5-fluoro-3- [4- (2-methylimidazole-1-yl) benzyloxy group]Phenyl radical]-3, 4, 5, 6-tetrahydro-2H-pyran-4-carboxamide (10 μ g/mL in 50/50 acetonitrile/water); then 100. mu.L of acetonitrile was added to each well. After vortexing and centrifugation (5 min at 1730G), the supernatants from each well were transferred to new wells of a 96-well plate and 20 μ L was injected into the LC/MS system. Reverse phase HPLC System from Waters C18 Symmetry^The composition of the column (2.1 mm. times.150 mm) was analyzed. The mobile phase solvent is: solvent a ═ 5mM ammonium acetate, 1% isopropanol per 1L of mobile phase; and solvent B ═ acetonitrile, containing 1% isopropanol per 1L of mobile phase. The gradient was from 100% A to 0% A at 0-3.0 min, and the transition was back to 100% A at 3.1 min at a flow rate of 0.5 mL/min. The retention times for drug 6 and IS were both about 2.6 minutes. Detection was performed by a SCIEX PE API-150 mass spectrometer equipped with a Turbo IonSpray interface. Cation was monitored for quantitative analysis of drug 6(m/z 394.1) and IS (m/z 410.3), respectively. The ratio of peak area response of drug 6 relative to that of the internal standard was used to construct a standard curve using linear least squares regression and 1/x2 weighting. The lower limit of quantitation (LLOQ) and the upper limit of quantitation (ULOQ) for plasma assays were 0.01 and 5. mu.g/mL, respectively. The performance of the assay was monitored by using quality control samples prepared in dog plasma.

Pharmacokinetic data are shown in Table 8.2, where C_maxIs the maximum observed plasma drug 6 concentration, averaged from the values for dogs administered the various forms of the drug. AUC₁₂₀₀Is the average area under the curve of plasma drug 6 concentration versus time from 0 to 24 hours (1200 minutes).

TABLE 8.2

Examples	Dosage form1(mg)	n2	Cmax(μg/ml)	AUC1200(μ g-hr/ml)
					Example 18	50	1	1.41	9.63
Control 8	50	2	0.28	3.12

¹The average weight of the dogs used in this test was about 9kg²Number of dogs studied

These data demonstrate that the physical mixture of HPMCAS and drug 6 results in higher systemic drug 6 exposure when administered to beagle dogs than that obtained with drug 6 alone. HPMCAS form C_maxAnd AUC₁₂₀₀5.0-fold and 3.1-fold of the control, respectively. These data demonstrate the effectiveness of the present invention in delivering compounds to the colon.

Example 19

Example 19 demonstrates a composition similar to that used in example 18, which was tested in vitro as follows. Example 19 was prepared by first adding 20mL of deionized water to a small glass beaker and then adjusting the pH to within 1-2 with 10M HCl. Subsequently, 100mg of drug 6 was dissolved in the solution by stirring for 5 minutes. During this time, the pH was maintained in the range of 1-2, resulting in a final concentration of drug 6 of 5 mg/mL.

The mixture of drug 6 was then aliquoted into two small glass beakers, each containing a magnetic stir bar. A10 mg sample of HPMCAS-LF was added to one flask (example 19) and no concentration-enhancing polymer was added to the second flask (control 9). Therefore, the drug/polymer ratio was 1: 4 (weight: weight) in this test. The pH of both was then adjusted to pH 6.8 with 0.1M and 0.01M NaOH. Cover the beaker and stir the mixture.

Samples (. apprxeq.1 ml) were collected at 60, 120, 180, 240 and 1440 minutes using a glass Pasteur pipette. Each sample was transferred to a 1.0mL plastic syringe connected to a Gelman Acrodisc 1.2 μm syringe filter. The sample was then drained through the filter into a glass HPLC injection vial, capped, immediately analyzed by HPLC, and the concentration of the compound calculated. Samples were analyzed on a Zorbax C8 Reverse Phase, 5 μm, 4.6X 150mm column with detection at 264 nm.

The results of these tests are shown in tables 9.1 and 9.2. They show that C of example 19_max2.5 times that of control 9. Furthermore, AUC of example 19₁₈₀3.7 times that of control 9. These data agree well with the in vivo test described in example 18.

TABLE 9.1

	[ drug 6 ]](μg/ml)
			Time (minutes)	Example 19 (1: 4 drugs 6: HPMCAS-LF)	Control 9: (Only the medicine 6)
60	46	21
			120	52	7
180	47	9
			240	51	6
1440	36	4

TABLE 9.2

Sample (I)	Cmax(μg/ml)	AUC180(minutes. mu.g/ml)	Theory Cmax(μg/ml)
				Example 19 (1: 4 drugs 6: HPMCAS-LF)	52	7290	250
Control 9 (drug only 6)	21	1950	250

Example 20

Dynamic light scattering analysis was used to demonstrate the formation of polymer/drug aggregates in solution. Different amounts of amorphous drug 1 and HPMCAS-MF were added to PBS and light scattering was measured with a PSS-NICOMP 380 Submicron particle sizer. For these tests, 0.1, 1.0, 10.0, 25.0, or 50.0mg of solid amorphous drug 1 was added to a mortar containing 200mg of HPMCAS-MF and mixed with a spatula. The various drug/polymer mixtures were then added to 50mL PBS equilibrated at 37 ℃ for 2 hours. Table 10 gives the final polymer and drug concentrations present in the solution. After 2 hours, 1mL of the solution was transferred and centrifuged at 13,000rpm for 5 minutes. Dynamic light scattering (based on the diffusion of the microparticles) was measured for the supernatant of each centrifuged solution and the particle size of any drug and polymer microparticles in the solution was calculated. The concentrations of drug and polymer in solution and the corresponding average particle size of the plurality of microparticles in solution are shown in table 10. It should be noted that the values reported for solutions 5 and 6 are average values, with about 85% of the particle volume being within about 30% of the average particle size.

Watch 10

Number of solution	Drug 1 concentration (mg/ml)	HPMCAS-MF concentration (mg/mL)	Particle size (nm)
				1	0	2.0	12
2	0.002	2.0	18
				3	0.02	2.0	16
4	0.2	2.0	14
				5	0.5	2.0	84
6	1.0	2.0	83

When no drug is present (solution No. 1), small particles of about 10-20nm in size are present, due to aggregation of the polymer (HPMCAS-MF), which appears to be a result of its amphiphilicity. At low concentrations of amorphous drug 1 (0.002-0.2mg/mL), light scattering indicated only small particles (about 10-20nm in size) in solution due to the presence of the polymer alone. At higher concentrations of amorphous drug 1 (. gtoreq.0.5 mg/mL), which are higher than the solubility of amorphous drug 1 (about 0.2-0.4mg/mL), the microparticles are present at an average particle size of about 80-85 nm. This demonstrates the formation of polymer/drug aggregates in solution and shows that the amount of drug required for aggregate formation is about equal to or about the solubility of the amorphous drug.

The concentration-enhancing effect provided by these polymer/drug aggregates has been shown to cause drug 1 concentrations to be higher than those shown in table 10 (higher than the solubility of the amorphous drug). For the dissolution test described in example 9, 10.0mg/mL amorphous drug 1 was added to PBS containing 20mg/mL HPMCAS-MF at 37 ℃. The control of example 9 was amorphous drug alone. The concentration of drug 1 determined at 1.5 hours was 224 μ g/mL for amorphous drug alone and 8,099 μ g/mL for example 9. The ratio of drug to polymer in example 9 was relative to the ratio used in solution No. 6 above (table 10). The formation of drug/polymer aggregates in solution enables drug 1 to be maintained in solution at a concentration much greater than its amorphous solubility.

To determine the drug/polymer aggregate composition, solutions No. 4, 5 and 6 (table 10) were re-prepared and analyzed by HPLC and NMR. Drugs and polymers were added to PBS at 37 ℃. Centrifugation (5 min at 13,000 rpm) was performed 2 hours after addition of drug and polymer samples. The concentration of free drug and free polymer in the supernatant was determined by NMR. The total amount of dissolved drug in the supernatant, consisting of "free" (solvated) drug and drug in the polymer/drug aggregates, was determined by HPLC after centrifugation. The centrifuged pellet was dissolved in DMSO and analyzed by NMR to give the concentration of drug and polymer. The amount of drug contained in the drug/polymer aggregate is determined by subtracting the concentration of free drug in the supernatant from the total amount of dissolved drug. The amount of polymer contained in the drug/polymer aggregate was determined by subtracting the polymer in free and precipitated form from the total amount of polymer used. The results are shown in Table 11.

TABLE 11

Number of solution	Total drug concentration 1(μ g/ml)	HPMCAS-MF concentration (μ g/ml)	Concentration of free drug in solution 1(μ g/ml)	Concentration of free Polymer in solution (. mu.g/ml)	Total dissolved drug 1(μ g/ml)	Precipitated drug 1(μ g/ml)	Precipitated Polymer (μ g/ml)	In aggregatesMedicine 1 (mug/ml)	Polymer in aggregate (μ g/ml)
										4	200	2000	166	1770	198	0	0	32	230
5	500	2000	265	1367	462	47	88	197	545
										6	1000	2000	301	1004	542	377	535	241	461

The data in table 11 show that for drug concentrations above the solubility limit (solutions No.5 and No. 6), a significant portion of the total dissolved drug is contained within the drug-polymer aggregates. Furthermore, the free drug concentration of solution No. 6 is about 3.8 times the solubility of crystalline drug 1 (80. mu.g/mL) and about 1.5 times the solubility of amorphous drug 1 (200. mu.g/mL).

The terms and expressions which have been employed in the foregoing specification are used therein as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding equivalents of the features shown and described or portions thereof, it being recognized that the scope of the invention is defined and limited only by the claims which follow.

Claims (33)

1. A composition comprising:

(a) a pharmaceutically acceptable solubility-improved form of the drug; and

(b) a concentration-enhancing polymer associated with said solubility-improved form in an amount sufficient such that, upon introduction of the composition to a use environment, the composition provides a maximum concentration of the drug in said use environment that is at least 1.25 times greater than the equilibrium concentration of the drug in said use environment, and the concentration of the drug in said use environment that exceeds said equilibrium concentration is maintained for a longer period of time than the concentration of the drug in said use environment that exceeds the equilibrium concentration provided by a control composition that does not contain said concentration-enhancing polymer and that contains an equivalent amount of the drug in the solubility-improved form.

2. The composition of claim 1, wherein the drug in the solubility-improved form is a crystalline, highly soluble salt form of the drug.

3. The composition of claim 1, wherein the drug in the solubility-improved form is a high energy crystalline form of the drug.

4. The composition of claim 1, wherein said drug in said solubility-improved form is amorphous.

5. The composition of claim 1 wherein said drug in said solubility-improved form is a composition comprising a mixture of said drug and a solubilizing agent.

6. The composition of claim 1, wherein said solubility-improved form of said drug is a solution of the drug substantially dissolved in a liquid at a concentration at least 10 times the equilibrium concentration of the drug in said use environment.

7. The composition of claim 1 wherein said concentration-enhancing polymer has a hydrophobic portion and a hydrophilic portion.

8. The composition of claim 1 wherein said concentration-enhancing polymer is a cellulosic ionizable polymer that is soluble in said use environment when ionized.

9. The composition of claim 8 wherein said polymer is selected from the group consisting of cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate 1, 2, 4-trimellitate, methyl cellulose acetate 1, 2, 4-trimellitate, ethyl cellulose acetate 1, 2, 4-trimellitate, hydroxypropyl methyl cellulose acetate 1, 2, 4-trimellitate, hydroxypropyl cellulose acetate 1, 2, 4-trimellitate succinate, cellulose propionate 1, 2, 4-trimellitate, cellulose butyrate 1, 2, 4-trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose salicylate acetate, hydroxypropyl cellulose salicylate acetate, ethyl cellulose benzoate acetate, hydroxypropyl ethyl cellulose benzoate acetate, ethyl cellulose phthalate acetate, ethyl cellulose nicotinate acetate, and ethyl cellulose picolinate acetate.

10. The composition of claim 8 wherein said polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate 1, 2, 4-trimellitate.

11. The composition of claim 1, wherein the polymer is a non-ionized cellulose polymer.

12. The composition of claim 11 wherein said polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose.

13. The composition of claim 1, wherein said polymer is an ionizable non-cellulosic polymer.

14. The composition of claim 1, wherein the polymer is a non-ionized, non-cellulosic polymer.

15. The composition of claim 1, wherein the composition provides a dissolution area under the concentration-time curve for a time of at least 90 minutes in the use environment that is at least 1.25 times the corresponding area under the curve provided by the control composition over the course of 1200 minutes immediately after introduction to the use environment.

16. A composition comprising:

(a) a pharmaceutically acceptable solubility-improved form of the drug; and

(b) a concentration-enhancing polymer associated with said drug in an amount sufficient to provide a dissolution area under a concentration-time curve in said use environment for a time of at least 90 minutes which is at least 1.25 times the corresponding area under the curve provided by said control composition during 1200 minutes from introduction of the composition to the use environment, wherein said control composition does not contain said concentration-enhancing polymer and contains an equivalent amount of the drug in a solubility-improved form.

17. A composition comprising:

(a) a pharmaceutically acceptable solubility-improved form of the drug; and

(b) a concentration-enhancing polymer associated with the drug in an amount sufficient to provide a relative bioavailability of the composition of at least 1.25 after introduction to a use environment.

18. A method of administering a drug, the method comprising co-administering to a patient in need of said drug:

(a) a pharmaceutically acceptable solubility-improved form of the drug; and

(b) a concentration-enhancing polymer; wherein the concentration-enhancing polymer is administered in combination with a sufficient amount of the drug in the solubility-improved form to provide, upon introduction to a use environment, a maximum concentration of the drug in the use environment that is at least 1.25-fold the equilibrium concentration of the drug in the use environment provided by the control composition;

and wherein the drug concentration in the use environment in excess of the equilibrium concentration is provided for a longer period of time than the drug concentration in excess of the equilibrium concentration provided by a control composition in the use environment;

wherein said control composition does not contain said concentration-enhancing polymer and contains an equivalent amount of said drug in a solubility-improved form.

19. The method of claim 18 wherein said drug is administered separately from said concentration-enhancing polymer.

20. The method of claim 19, wherein said drug and said concentration-enhancing polymer are administered substantially simultaneously.

21. The method of claim 18, wherein said drug is administered in a composition further comprising said concentration-enhancing polymer.

22. A method of administration comprising co-administering to a patient in need of said medicament:

(a) a drug in a solubility-improved form; and

(b) a concentration-enhancing polymer; wherein the concentration-enhancing polymer is administered in combination with the drug in an amount sufficient to provide a dissolution area under the concentration-time curve for a time of at least 90 minutes in the use environment during 1200 minutes immediately after introduction into the use environment that is at least 1.25 times the corresponding area under the curve provided by the control composition;

wherein said control composition does not contain said concentration-enhancing polymer and contains an equivalent amount of said drug in a solubility-improved form.

23. A method of administration comprising co-administering to a patient in need of said medicament:

(a) a drug in a solubility-improved form; and

(b) a concentration-enhancing polymer; wherein said concentration-enhancing polymer is administered in combination with said drug in an amount sufficient to provide, upon introduction to a use environment, a relative bioavailability that is at least 1.25-fold greater than that provided by a control composition that does not contain said concentration-enhancing polymer and that contains an equivalent amount of the drug in a solubility-improved form.

24. An aqueous solution formed by administering a solubility-improved form of a solid drug and a concentration-enhancing polymer to an environment of use, comprising:

(a) one of each of said drug and said concentration-enhancing polymer at least partially dissolved in said solution;

(b) at least a portion of said dissolved drug associated with at least a portion of said polymer in an assembly of a plurality of drugs and polymers, said assembly having a size of about 10-1000 nanometers; and is

(c) Said solution having a maximum concentration of said drug that is at least 1.25 times the equilibrium concentration of the drug in said use environment and a concentration above said equilibrium concentration that is greater than the concentration of the drug above the equilibrium concentration in said use environment for a longer period of time than provided by a control composition that does not contain said concentration-enhancing polymer and that contains an equivalent amount of the drug in a solubility-improved form.

25. The solution of claim 24 wherein said drug in said solubility-improved form is a highly soluble salt form of the drug crystals.

26. The solution of claim 24 wherein said drug in said solubility-improved form is a high energy crystalline form of the drug.

27. The solution of claim 24 wherein said drug in said solubility-improved form is amorphous.

28. The solution of claim 24 wherein said drug in said solubility-improved form is a composition comprising a mixture of said drug and a solid solubilizing agent.

29. The solution of claim 24 wherein said environment of use is in vivo.

30. The solution of claim 29 wherein the use environment is selected from the group consisting of the GI tract, the subcutaneous space, the vagina, the pulmonary tract, arterial and venous blood vessels, and intramuscular tissues of an animal.

31. The solution of claim 24, wherein said use environment is in vitro.

32. The solution of claim 24 wherein said concentration-enhancing polymer has a hydrophobic portion and a hydrophilic portion.

33. An aqueous solution formed by administering a solubility-improved form of a drug and a concentration-enhancing polymer to an environment of use, comprising:

(a) one of each of said drug and said concentration-enhancing polymer at least partially dissolved in said solution;

(b) at least a portion of said dissolved drug associated with at least a portion of said polymer in an assembly of a plurality of drugs and polymers, said assembly having a size of about 10-1000 nanometers; and is

(c) The polymer is selected from hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl cellulose ethyl acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate 1, 2, 4-trimellitic acid, cellulose acetate terephthalate, and cellulose acetate isophthalic acid; and

(d) said solution having a maximum concentration of said drug that is at least 1.25 times the equilibrium concentration of the drug in said use environment and a concentration above said equilibrium concentration that is greater than the concentration of the drug above the equilibrium concentration in said use environment for a longer period of time than provided by a control composition that does not contain said concentration-enhancing polymer and that contains an equivalent amount of the drug in a solubility-improved form.