HK1187371B - Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors - Google Patents

Description

Novel modified release dosage forms of xanthine oxidoreductase inhibitors or xanthine oxidase inhibitors

Information of related applications

This application claims priority to U.S. provisional application No. 61/355,164, filed on 16/6/2010, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates to novel dosage forms comprising at least one xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor. In addition, the present disclosure also relates to methods of treating certain diseases using the novel dosage forms of the present disclosure.

Background

2- [ 3-cyano-4- (2-methylpropoxy) phenyl ] -4-methylthiazole-5-carboxylic acid (also known as "febuxostat" and "TMX-67") is a potent, non-purine selective inhibitor of xanthine oxidoreductase. Daily (QD)40 and 80mg febuxostat are approved in the united states for long-term care of hyperuricemia in patients with gout. Gout is a disease caused by the deposition of urate crystals in synovial fluid and other tissues when there is an oversaturation of urate in the blood. Febuxostat is a potent selective inhibitor of xanthine oxidoreductase (or xanthine oxidoreductase inhibitor) required for the synthesis of uric acid.

Xanthine oxidoreductase can exist in two different forms (see EnrothC, et al, "Crystal structures of bone mineral dehydrogenase A and bone oxidase:" structure-based biochemical conversion "Proc. Natl. Acad. Sci. USA97 (97) (10723-8 (9/26/2000)). In one form, the xanthine oxidoreductase is synthesized as a xanthine dehydrogenase. This form of enzyme appears to be extremely lowReactivity with oxygen. However, under stress or disease conditions, such as ischemia reperfusion injury and congestive heart failure, xanthine dehydrogenase can undergo intramolecular disulfide bond formation or proteolytic cleavage, which converts the enzyme to the second form, xanthine oxidase. Xanthine oxidase exhibits high reactivity with oxygen. Thus, the synthesis of uric acid from xanthine and hypoxanthine by xanthine oxidoreductase in the form of xanthine oxidase is associated with the production of oxygen radicals, such as superoxide anions and hydrogen peroxide. These free radicals can lead to a number of toxic activities in the body, such as inactivation of proteins, DNA breakdown, lipid peroxidation (which leads to cell membrane disruption) and the increase of pro-inflammatory cytokines.

Many disease states are associated with elevated xanthine oxidoreductase activity, in particular elevated xanthine oxidase activity. Such conditions include, but are not limited to, hyperuricemia, hypertension, metabolic syndrome, diabetes, myocardial ischemia, atherosclerosis, stroke, congestive heart failure, inflammatory bowel disease, progression of renal disease, prostatitis, sleep apnea, and autoimmune diseases. Hyperuricemia is also associated with many disease states, such as renal injury and hypertension.

Allopurinol is used for treating hyperuricemia. Allopurinol has been shown to prevent renal damage and hypertension associated with hyperuricemia by inhibiting xanthine oxidoreductase, thereby lowering uric acid levels. In contrast, it has been found that the degree of protection of subjects with hyperuricemia against renal injury and hypertension is lower in subjects treated with the uricosuric agent benziododazon. Benzydarone does not inhibit xanthine oxidoreductase activity, but rather decreases plasma uric acid levels by increasing uric acid excretion in the kidney (see, Mazzali M, et al, "infectious acid microorganisms blood pressure in the rat by a novel crystal-independentmechanism"Hypertension,38:1101- "Am. J. Physiol Renal Physiol.,282: F991-F997 (2002)). Thus, there is a need in the art for new dosage forms that not only reduce uric acid levels in subjects with hyperuricemia, but are also capable of maintaining a high level (i.e., at least 80%) inhibition of xanthine oxidoreductase activity in the subjects in order to protect subjects receiving these dosage forms from damage by increased concentrations of oxygen radicals throughout their treatment regimen (i.e., typically the 24 hour dosing interval).

As mentioned above, another treatment for hyperuricemia is the use of the compound febuxostat. Extensive pharmacokinetic and pharmacodynamic data have demonstrated that maintaining the concentration of febuxostat in plasma over an extended period of time provides similar efficacy to treatment with high doses of drug. In general, these studies have shown that maintaining a plasma concentration of febuxostat of 100ng/ml is required to provide xanthine oxidase inhibition of 95% or greater. Currently, commercially available febuxostat formulations are only immediate release formulations. There are currently no commercially available extended or delayed release febuxostat formulations. Therefore, febuxostat formulations that maintain drug concentrations above the critical concentration of 100ng/ml over extended periods of time are expected to result in higher drug efficacy and would be a desirable treatment option for controlling hyperuricemia, gout, and many other disease states.

Summary of The Invention

In one embodiment, the present disclosure relates to a modified release dosage form. The modified release dosage form may comprise at least one xanthine oxidoreductase inhibitor or at least one xanthine oxidase inhibitor.

In another embodiment, the modified release dosage form of the present disclosure comprises: a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, wherein said dosage form exhibits at least one of the following characteristics following oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; and

(b) producing a maximum plasma concentration (C) of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in an amount between about 2.5 μ g/mL to about 0.5 μ g/mL in a subject_max)。

Alternatively, the modified release dosage form exhibits the following characteristics after oral administration to a subject in need of treatment thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 1.0 μ g/mL_max)。

Still further alternatively, the modified release dosage form may exhibit each of the following characteristics upon oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.5 μ g/mL to about 0.5 μ g/mL_max)。

In one aspect, the modified release dosage form of the present disclosure may comprise from about 5 to about 240mg of at least one xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof. In another aspect, the modified release dosage form of the present disclosure may comprise from about 40 to about 240mg of at least one xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof.

When administered orally to a subject in need thereofIn particular, the modified release dosage forms of the present disclosure can produce a C of about 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, or about 0.5 μ g/mL of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in a subject_max. In particular, when orally administered to a subject in need of treatment thereof, the modified release dosage forms of the present disclosure can produce from about 2.5 μ g/mL to about 1.0 μ g/mL of the C of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in the subject_max. Even more particularly, the modified release dosage forms of the present disclosure can produce a C of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in a range of about 2.0 μ g/mL to about 1.5 μ g/mL in a subject when administered orally to a subject in need of treatment thereof_max。

In another embodiment, the modified release dosage form of the present disclosure comprises: a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, wherein said dosage form exhibits at least one of the following characteristics following oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; and

(b) producing a maximum plasma concentration (C) of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in an amount between about 2.5 μ g/mL to about 0.050 μ g/mL in a subject_max)。

Alternatively, the modified release dosage form exhibits the following characteristics after oral administration to a subject in need of treatment thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 0.075 μ g/mL_max)。

Still further alternatively, the modified release dosage form may exhibit each of the following characteristics upon oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.5 μ g/mL to about 0.050 μ g/mL_max)。

The modified release dosage forms of the present disclosure may comprise from about 40 to about 240mg of at least one xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof.

When orally administered to a subject in need of treatment thereof, the modified release dosage forms of the present disclosure can produce about 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, about 0.5 μ g/mL, about 0.4 μ g/mL, about 3.3 μ g/mL, about 0.4 μ g/mL, about, About 0.2 μ g/mL, about 0.1 μ g/mL, about 0.099 μ g/mL, about 0.098 μ g/mL, about 0.097 μ g/mL, about 0.096 μ g/mL, about 0.095 μ g/mL, about 0.094 μ g/mL, about 0.093 μ g/mL, about 0.092 μ g/mL, about 0.091 μ g/mL, about 0.090 μ g/mL, about 0.089 μ g/mL, about 0.088 μ g/mL, about 0.087 μ g/mL, about 0.086 μ g/mL, about 0.085 μ g/mL, about 0.084 μ g/mL, about 0.083 μ g/mL, about 0.081 μ g/mL, about 0.086 μ g/mL, about 0.080 μ g/mL, about 0.082 μ g/mLL, about 0.079. mu.g/mL, about 0.078. mu.g/mL, about 0.077. mu.g/mL, about 0.076. mu.g/mL, about 0.075. mu.g/mL, about 0.074. mu.g/mL, about 0.073. mu.g/mL, about 0.072. mu.g/mL, about 0.071. mu.g/mL, about 0.070. mu.g/mL, about 0.069. mu.g/mL, about 0.068. mu.g/mL, about 0.067. mu.g/mL, about 0.066. mu.g/mL, about 0.065. mu.g/mL, about 0.064. mu.g/mL, about 0.063. mu.g/mL, about 0.062. mu.061. mu.g/mL, about 0.060. mu.g/mL, about 0.059. mu.g/mL, about 0.058. mu.057. mu.g/mL, about 0.054. mu.g/mL, about 0.056. mu., C of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in an amount of about 0.053 μ g/mL, about 0.052 μ g/mL, about 0.051 μ g/mL, or about 0.050 μ g/mL_max. In particular, the modified release dosage forms of the present disclosure can produce between about 2.5 μ g/mL to about 0.050 μ g/mL of a C of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in a subject when administered orally to a subject in need thereof_max. Even more particularly, the modified release dosage forms of the present disclosure can produce from about 2.0 μ g/mL to about 0.075 μ g/mL of a C of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in a subject when administered orally to a subject in need thereof_max。

In another embodiment, the modified release dosage form of the present disclosure comprises: a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, wherein said dosage form exhibits at least one of the following characteristics following oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in an amount between about 2.5 μ g/mL to about 0.090 μ g/mL in a subject_max)。

Alternatively, the modified release dosage form exhibits the following characteristics after oral administration to a subject in need of treatment thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 0.095 μ g/mL_max)。

Still further alternatively, the modified release dosage form may exhibit each of the following characteristics upon oral administration to a subject in need thereof:

(a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; and

(b) producing a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.5 μ g/mL to about 0.090 μ g/mL_max)。

The modified release dosage forms of the present disclosure may comprise from about 40 to about 240mg of at least one xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof.

When orally administered to a subject in need of treatment thereof, the modified release dosage forms of the present disclosure can produce about 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, about 0.5 μ g/mL, about 0.4 μ g/mL, about 3.3 μ g/mL, about 0.4 μ g/mL, about, Xanthine oxidoreductase in an amount of about 0.2 μ g/mL, about 0.1 μ g/mL, about 0.099 μ g/mL, about 0.098 μ g/mL, about 0.097 μ g/mL, about 0.096 μ g/mL, about 0.095 μ g/mL, about 0.094 μ g/mL, about 0.093 μ g/mL, about 0.092 μ g/mL, or about 0.091 μ g/mLInhibitor or pharmaceutically acceptable salt thereof C_max. In particular, the modified release dosage forms of the present disclosure can produce from about 2.5 μ g/mL to about 0.090 μ g/mL of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in a subject when administered orally to a subject in need thereof_max. Even more particularly, the modified release dosage forms of the present disclosure can produce from about 2.0 μ g/mL to about 0.095 μ g/mL of the C of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in a subject when administered orally to a subject in need thereof_max。

An example of a xanthine oxidoreductase inhibitor that may be used in the modified release dosage forms of the present disclosure is a xanthine oxidoreductase inhibitor comprising the formula:

wherein R is₁And R₂Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀An alkoxy, unsubstituted or substituted hydroxyalkoxy, phenylsulfinyl or cyano (-CN) group;

wherein R is₃And R₄Each independently hydrogen, or A, B, C or D as shown below:

wherein T is in R₁、R₂、R₃Or R₄Position A, B, C or D is attached to the aromatic ring shown above;

wherein R is₅And R₆Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀Alkoxy radicalA group, unsubstituted or substituted hydroxyalkoxy, COO-glucuronide or COO-sulphate;

wherein R is₇And R₈Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀Alkoxy, unsubstituted or substituted hydroxyalkoxy, COO-glucuronide or COO-sulfate;

wherein R is₉Is unsubstituted pyridyl or substituted pyridyl; and is

Wherein R is₁₀Is hydrogen or lower alkyl, lower alkyl substituted by pivaloyloxy, and in each case R₁₀Attached to one of the nitrogen atoms in the 1,2, 4-triazole ring as shown above.

Examples of compounds having the above formula are: (a) 2- [ 3-cyano-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof; (b) 2- [ 3-cyano-4- (3-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof; (c) 2- [ 3-cyano-4- (2-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof; (d) 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof; (e) 2- [4- (2-carboxypropoxy) -3-cyanophenyl]-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof; (f) 1-3-cyano-4- (2, 2-dimethylpropoxy) phenyl]-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof; (g) pyrazolo [1,5-a]-1,3, 5-triazin-4- (1H) -one, 8- [ 3-methoxy-4- (phenylsulfinyl) phenyl]-sodium salt (±); and (h) 3- (2-methyl-4-pyridyl) -5-cyano-4-isobutoxyphenyl) -1,2, 4-triazole or a pharmaceutically acceptable salt thereof.

Another example of at least one xanthine oxidoreductase inhibitor that may be used in the modified release dosage forms of the present disclosure is a xanthine oxidoreductase inhibitor comprising the formula:

wherein R is₁₁And R₁₂Each independently is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, or R₁₁And R₁₂May form, together with the carbon atoms to which they are attached, a four to eight membered carbocyclic ring;

wherein R is₁₃Is hydrogen or substituted or unsubstituted lower alkyl;

wherein R is₁₄Is one OR two groups selected from hydrogen, halogen, nitro, substituted OR unsubstituted lower alkyl, substituted OR unsubstituted phenyl, - - -OR₁₆and-SO₂NR₁₇R_{17 ’}Wherein R is₁₆Is hydrogen, substituted or unsubstituted lower alkyl, phenyl-substituted lower alkyl, carboxymethyl or ester thereof, hydroxyethyl or ether thereof, or allyl; r₁₇And R_{17 ’}Each independently is hydrogen or substituted or unsubstituted lower alkyl;

wherein R is₁₅Is hydrogen or a pharmaceutically active ester-forming group;

wherein A is a straight or branched hydrocarbon group having 1 to 5 carbon atoms;

wherein B is halogen, oxygen or ethylene dithio (ethidene);

wherein Y is oxygen, sulfur, nitrogen or substituted nitrogen;

wherein Z is oxygen, nitrogen or substituted nitrogen; and is

The dotted line refers to a single bond, a double bond, or two single bonds.

In another embodiment, the disclosure relates to a method of treating a patient suffering from gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, renal injury, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, or congestive heart failure, and in need of treatment thereof. The method comprises the following steps: administering to a subject suffering from gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, renal injury, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, or congestive heart failure and in need of treatment thereof, a therapeutically effective amount of the above modified release dosage form comprising at least one xanthine oxidoreductase inhibitor or at least one xanthine oxidase inhibitor.

In a further embodiment, the present disclosure relates to a pharmaceutical composition comprising a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof, or at least one xanthine oxidase inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer, wherein the pharmaceutical composition comprises at least one of: an immediate release component, a delayed release component, and/or a controlled release component. Examples of xanthine oxidoreductase inhibitors that may be incorporated into the pharmaceutical compositions include all those cited above. Examples of xanthine oxidase inhibitors are oxypurinol (oxypurinol) or allopurinol. In addition, the immediate release component, the delayed release component, and the controlled release component may comprise one or more beads capable of exhibiting a variety of release characteristics. The immediate-release beads release the xanthine oxidoreductase inhibitor immediately upon ingestion, the delayed-release beads release the xanthine oxidoreductase inhibitor upon exposure to an internal environment having a particular pH level, and the controlled-release beads release the xanthine oxidoreductase inhibitor over an extended period of time as compared to the immediate-release beads. Each bead comprises an inert core coated with a xanthine oxidoreductase inhibitor compound and one or more pharmaceutically acceptable polymer layers.

In further embodiments, the present disclosure includes a single pharmaceutical composition comprising immediate release beads and delayed release beads having solubility at a pH level greater than or equal to 6.8. The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 20% to about 40% (w/w) of the total composition weight and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 60% to about 80% (w/w) of the total composition weight released at a pH of 6.8. For example, in one aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 20% (w/w) of the total composition weight and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 80% (w/w) of the total composition weight released at a pH of 6.8. In yet another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 25% (w/w) of the total composition weight and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 75% (w/w) of the total composition weight. In another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 30% (w/w) of the total composition weight and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 70% (w/w) of the total composition weight. In yet another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 40% (w/w) of the total composition weight and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 60% (w/w) of the total composition weight released at a pH of 6.8.

In yet another embodiment of the present disclosure, the pharmaceutical dosage form comprises a single pharmaceutical composition comprising immediate release beads, delayed release beads having solubility at a pH level greater than or equal to 6.0, and delayed release beads having solubility at a pH level greater than or equal to 6.8. The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor bead (in an amount from about 25% to about 35% (w/w) of the total composition weight), a pH6.0 delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 25% to about 35% (w/w) of the total composition weight), and a pH6.8 delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 35% to about 45% (w/w) of the total composition weight).

In other embodiments of the present disclosure, the pharmaceutical composition comprises a single pharmaceutical composition comprising immediate release beads and delayed-controlled release beads, wherein the delayed release beads have a solubility at a pH level of at least 6.8 and the controlled release rate is about four to six hours. The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 20% to about 40% (w/w) of the total composition weight) and a delayed-controlled release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 60% to about 80% (w/w) of the total composition weight) that has solubility at pH levels greater than or equal to 6.8 and provides extended release of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor over a period of about 4 hours to about 6 hours.

In another embodiment of the present disclosure, the pharmaceutical composition comprises a single pharmaceutical composition comprising immediate release beads and controlled release beads capable of active release over about 10 hours to about 12 hours. The pharmaceutical composition of this embodiment generally comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 10% to about 30% (w/w) of the total composition weight) and a controlled release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead (in an amount from about 70% to about 90% (w/w) of the total composition weight) that provides for extended release of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor over a period of from about 10 hours to about 12 hours.

The development of the previously described embodiments resulted from a long-term drug development process. Initially, dose-escalation (dose-evolution), placebo-controlled, double-blind studies were performed on twelve healthy subjects designed to evaluate the safety and maximum tolerated dose of orally administered febuxostat. The study alsoDesigned to evaluate the pharmacokinetic and pharmacodynamic properties of multiple daily oral administrations over a range of doses and ranges, including once daily and twice daily administrations. The results of this study demonstrate valuable pharmacokinetic and pharmacodynamic information regarding the bioavailability of febuxostat in vivo. The results of this study are disclosed in the following documents: rezakhosravan et al,Pharmcokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjectsclinical pharmacy 2006: 45(8): 821-841. In particular, the pharmacokinetic parameters of this study are discussed at page 829 of this document and are shown in table 1 of example 1 contained herein.

In phase 1, multidose, randomized, placebo-controlled, double-blind, single-center, multi-site dose escalation studies involving febuxostat, pharmacokinetics and pharmacodynamics of febuxostat were studied in healthy subjects. In this study, the oral dose of an immediate release dosage form of febuxostat (xanthine oxidoreductase inhibitor) was 10 mg once daily (hereinafter "QD") to 240mg once daily and 30 mg twice daily (hereinafter "BID"). In this study, it was determined that a dose of 30 mg febuxostat administered twice daily (total daily dose of 60 mg) was as effective in reducing uric acid levels as a once daily dose of 120mg febuxostat. In view of these findings, it was determined that maintaining drug levels above a minimum concentration is critical for improved uric acid reduction. By further study and collection of pharmacokinetic data, it was determined that maintaining febuxostat concentrations in vivo at or above 100ng/mL (0.1 μ g/mL) resulted in 80% or greater inhibition of uric acid levels. In view of this surprising determination, the inventors developed an extended release febuxostat formulation that is effective in maximizing the time allotted at minimum critical febuxostat concentrations above 100ng/mL (0.1 μ g/mL).

Subsequently, the pharmacokinetic data obtained in the above-mentioned clinical trials were used to develop estimated plasma properties of various febuxostat formulations, including extended release matrix tablets (matrix tablets), double-pulse (two-pulse) febuxostat formulations, and triple-pulse (three-pulse) febuxostat formulations. The estimated extended release formulation data is based on matrix formulations (matrixformations) including one or more polymers, and the estimated double and triple pulse formulation data is based on formulations including two or more types of beads with different release characteristics. This information and method is discussed in example 2. In addition, as part of the development steps for extended release febuxostat formulations, multiple absorption sites were investigated to determine the optimal physiological site for drug absorption for extended release febuxostat formulations. In early preclinical studies, the absorption of febuxostat from various regions of the gastrointestinal tract was studied in rats. Tests in the rat model showed that febuxostat was absorbed very weakly from the colonic region. To guide the development of dosage forms that provide desirable plasma concentration-time profiles, absorption site studies have been conducted in humans. Data and methods for collecting information are included in example 3. The absorption site data surprisingly show that compared to the absorption properties seen with immediate release, proximal small intestine and intestinal end preparations, the absorption of febuxostat in the colon is only about 40%, which is higher than expected from the rat data.

In view of this surprising test data, the present inventors began to develop extended release febuxostat formulations that minimize exposure of febuxostat in the colon and maximize exposure of febuxostat in other areas, including the stomach, proximal small intestine and distal intestine. New febuxostat formulations were developed by preparing febuxostat formulations with an immediate release component, a delayed release component based on pH level, and a continuous release component based on release profile over an extended period of time. Specific formulations are described in examples 4-9. The new febuxostat formulation was then tested in a dog model, as described in example 10. The test results in the dog model are expected to give a recognized limitation of pharmacokinetic testing in the dog model. Regardless of the limitations associated with the length of the gastrointestinal tract in dogs, the delayed release (i.e., pH-dependent) formulations exhibited improved pharmacokinetic parameters compared to the reference immediate release febuxostat formulation. These formulations were then tested in humans in a single dose study as described in example 11.

Specific parameters and ranges for extended release febuxostat formulations are described in more detail in the detailed description.

Brief Description of Drawings

Figure 1 shows the mean febuxostat plasma concentration-time profile of multiple 80mg febuxostat formulations designed to release febuxostat in different parts of the gastrointestinal tract. In particular, figure 1 illustrates the mean plasma febuxostat concentrations over time for dosage forms designed to release febuxostat in the stomach, in the proximal small intestine, in the distal small intestine and in the colon.

Figure 2 shows simulated febuxostat plasma concentration-time profiles for a dosage form containing 80mg of a 3-pulsed febuxostat formulation, where 30% of the febuxostat dose was released immediately (at time = 0 hours) (i.e., pulse 1), 30% of the febuxostat dose was released after 5 hours (i.e., pulse 2), and 40% of the febuxostat formulation was released after 10 hours (i.e., pulse 3). Simulated data were calculated using parameters obtained from the uptake site data referenced and discussed in example 3.

Figure 3 shows simulated febuxostat plasma concentration-time profiles for a dosage form comprising 80mg of a 2-pulsed febuxostat formulation, wherein 20% of the febuxostat dose is released immediately (at time = 0 hours) (i.e., pulse 1), 75% of the febuxostat dose is released after 5 hours, and 5% of the febuxostat formulation is released in the colon after 10 hours (5 and 10 hour releases collectively comprise pulse 2). Simulated data were calculated using parameters obtained from the uptake site data referenced and discussed in example 3.

Figure 4 shows simulated febuxostat plasma concentration-time profiles for dosage forms comprising 80mg of an Extended Release (ER) febuxostat formulation, wherein 90% of the febuxostat dose is absorbed within 6 hours after administration and the remaining 10% of the febuxostat dose is absorbed by the colon. Simulated data were calculated using parameters obtained from the absorption site data discussed in reference to example 3.

Figure 5 shows a table listing the compositions of eight febuxostat modified release matrix tablet formulations.

Figure 6 illustrates the dissolution profile over time of eight different febuxostat modified release matrix tablet formulations. In particular, the dissolution profile was obtained by dissolving 50 mg of the modified release matrix tablet formulation in a solution having a pH of 6.8 and in the presence of 0.5M phosphate buffer.

Figure 7 illustrates the plasma febuxostat concentration-time profiles of various modified release dosage forms tested in a dog model as described in example 10.

Figures 8A and 8B show the mean febuxostat plasma concentration versus time (linear and log c) after administration of a single 80mg oral dose of 4 extended release and IR febuxostat formulations as described in example 11. In fig. 8A and 8B, the formulations are as follows:

formulation a (reference): febuxostat (Uloric) IR 80mg tablets.

Formulation B (test): double pulse prototype (80 mg) febuxostat capsule (TMX-67 XR formulation B).

Formulation C (test): triple pulse prototype (80 mg) febuxostat capsule (TMX-67 XR formulation C).

Formulation D (test): combination of pulsed and continuous release (80 mg) febuxostat capsules (TMX-67 formulation D).

Formulation E (test): continuous release (80 mg) of the prototype febuxostat capsule (TMX-67 XR formulation E).

Figure 9 shows that the dissolution profile of the formulation described in example 12 can vary depending on the ratio of cellulose acetate to polyethylene glycol (PEG).

Figure 10 shows that the formulation described in example 12 can be surface coated with an immediate release layer of the drug (febuxostat) to overcome the time lag.

Figure 11 shows how a multiparticulate formulation according to example 12 can be prepared to have a desired release profile by varying the amount of ethylcellulose coating contained on said formulation.

Detailed description of the disclosure

I.Definition of

The section headings used in this section and the entire disclosure herein are not intended to be limiting.

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The recitation of numerical ranges herein explicitly contemplates each intervening number having the same degree of accuracy. For example, for the range 6-9, numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

The term "about" as used herein is used synonymously with the term "about". Illustratively, use of the term "about" indicates a value slightly outside the referenced value, i.e., plus or minus 10%. Such dosages are therefore encompassed by the scope of the claims referring to the terms "about" and "approximately".

The term "AUC" as used herein refers to the area under the plasma concentration time curve of an active agent and is calculated using the trapezoidal rule. The term "AUC_t"refers to the area under the plasma concentration time curve from 0 hours to 120 hours after administration in units of ng ∙ h/mL, as determined using the trapezoidal rule. The term "AUC ∞" refers to the area under the plasma concentration time curve from 0 hours to infinite time. AUC ∞ is calculated as AUC_t+ LMT/(-beta) where "LMT" is the last measurable plasma concentration and beta is the terminal elimination rate constant. Unless otherwise indicated herein, reported values for AUC areCentral value of AUC. The "central value" of the AUC is the mean AUC ± standard deviation.

The terms "administration", "administering", "administered" or "administration" refer to any manner of providing a drug (e.g., a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof) to a subject or patient. The route of administration can be accomplished by any means known to those skilled in the art. Such means include, but are not limited to, oral, buccal, intravenous, subcutaneous, intramuscular, transdermal, by inhalation, and the like.

The term "active agent" as used herein refers to (1) a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof or (2) a xanthine oxidase inhibitor or a pharmaceutically acceptable salt thereof. The terms "active agent" and "drug" are used interchangeably herein. The solid state form of the active agent used in preparing the dosage forms of the present disclosure is not critical. For example, the active agent used in preparing the modified release dosage forms of the present disclosure may be amorphous or crystalline. The final dosage form contains at least a detectable amount of a crystalline active agent. The crystalline nature of the active agent can be detected using powder X-ray diffraction analysis, by differential scanning calorimetry, or other techniques known in the art.

The term "C_max"refers to the maximum observed plasma concentration of a xanthine oxidoreductase inhibitor or salt thereof produced by ingestion of a dosage form of the present disclosure. Unless otherwise indicated herein, C_maxIs C_maxThe center value of (c). C_maxThe "central value" of (A) is the average C_max± standard deviation.

The term "delayed release" as used herein refers to a modified release type wherein the pharmaceutical dosage form exhibits a time delay between oral administration of the pharmaceutical dosage form and release of the drug from the dosage form. The use of pulsatile release systems (also known as "pulsatile drug release") and enteric coatings, well known to those skilled in the art, are examples of delayed release mechanisms. In general, delayed release dosage forms release little or no active compound for a predetermined time or until a predetermined condition is met, such as exposure to a certain pH level, and then release of the active compound occurs immediately thereafter.

The term "delayed-controlled release" as used herein refers to a modified release type wherein the pharmaceutical dosage form exhibits prolonged drug release over a set period of time and does not begin release until after a certain time delay following ingestion of the dosage form. Generally, a "delayed-controlled release" dosage form releases little or no active compound for a predetermined time or until a predetermined condition is met, such as exposure to a certain pH level, and then release of the active compound occurs for an additional extended period of time.

The term "dosage form" refers to any solid object, semi-solid, or liquid composition designed to contain a specific predetermined amount (i.e., dose) of a certain active agent. Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery or subcutaneous or other implanted drug delivery systems, and the like. Preferably, the dosage forms of the present disclosure are considered to be solid, however, they may comprise liquid or semi-solid components. More preferably, the dosage form is an orally administered system for delivering an active agent to the gastrointestinal tract of a subject. The dosage forms of the present disclosure exhibit improved release of the active agent.

An "effective amount" or "therapeutically effective amount" of an active agent refers to a non-toxic but sufficient amount of the active agent to provide the desired effect. The amount of "effective" active agent will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Therefore, an accurate "effective amount" cannot always be specified. However, in any individual case, an appropriate "effective amount" may be determined by one of skill in the art using routine experimentation.

The term "extended release" as used herein refers to a pharmaceutical formulation that provides a gradual release of a drug over an extended period of time. The term "controlled" release refers to a type of extended release formulation in which the gradual release of the drug is controlled or manipulated over some extended period of time.

The term "immediate release" is used in its conventional sense to refer to a dosage form that provides for release of the active agent immediately after administration of the drug.

The term "modified" as used herein refers to a formulation containing a drug wherein the release of the drug is not immediate (taking part, for example,Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution, Testing and In Vivo Bioequivalence DocumentationU.S. Department of Health and Human Services, food Administration, Center for Drug Evaluation and Research ("CDER"), CMC 8 p.9 1997, page 34, incorporated herein by reference. In the modified formulation, modified release dosage form, or modified dosage form, administration of the formulation or dosage form does not result in immediate release of the drug or active agent into the absorption cell. The term is defined asRemington: The Science and Practice of Pharmacy"non-immediate release" as defined in Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995) is used interchangeably. The term "modified release" as used herein includes extended or controlled release formulations, delayed release formulations and delayed-controlled release formulations.

"pharmaceutically acceptable," such as in the reference to "pharmaceutically acceptable excipient" or "pharmaceutically acceptable additive," means that the material is not biologically or otherwise undesirable, i.e., the material can be included in a pharmaceutical composition administered to a patient without causing any undesirable biological effects.

The term "subject" refers to an animal, preferably a mammal, including a human or a non-human. The terms patient and subject may be used interchangeably herein. The terms "treating" and "treatment" refer to a reduction in the severity and/or frequency of symptoms, elimination of symptoms and/or potential causes, prevention of symptoms and/or potential causes thereof, and amelioration or remediation of injury. Thus, for example, "treating" a patient refers to preventing a particular disorder or adverse physiological event in a susceptible subject by inhibiting the disorder or disease or causing regression of the disorder or disease as well as treating a clinically symptomatic subject.

The term "xanthine oxidoreductase" as used herein refers to at least one form of xanthine oxidoreductase, i.e. xanthine oxidase and/or xanthine dehydrogenase.

The phrase "xanthine oxidoreductase inhibitor" as used herein refers to any compound that (1) is a xanthine oxidoreductase, such as, but not limited to, an inhibitor of xanthine oxidase; and (2) chemically, contain no purine rings in their structure (i.e., are "non-purines"). The phrase "xanthine oxidoreductase inhibitor" as defined herein also includes metabolites, polymorphs, solvates and prodrugs of such compounds, including metabolites, polymorphs, solvates and prodrugs of the compounds described in formula I and formula II below. Examples of xanthine oxidoreductase inhibitors include, but are not limited to, 2- [4- (2-carboxypropoxy) -3-cyanophenyl ] -4-methyl-5-thiazolecarboxylic acid and compounds having the following formula I or formula II:

a compound of formula I:

wherein R is₁And R₂Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀An alkoxy, unsubstituted or substituted hydroxyalkoxy, phenylsulfinyl or cyano (-CN) group;

wherein R is₃And R₄Each independently hydrogen, or A, B, C or D as shown below:

wherein T is in R₁、R_{2 、}R₃Or R₄Where A, B, C or D is attached (connect or attach) to the aromatic ring shown above.

Wherein R is₅And R₆Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀Alkoxy, unsubstituted or substituted hydroxyalkoxy, COO-glucuronide or COO-sulfate;

wherein R is₇And R₈Each independently of the others hydrogen, hydroxy, COOH groups, unsubstituted or substituted C₁-C₁₀Alkyl, unsubstituted or substituted C₁-C₁₀Alkoxy, unsubstituted or substituted hydroxyalkoxy, COO-glucuronide or COO-sulfate;

wherein R is₉Is unsubstituted pyridyl or substituted pyridyl; and is

Wherein R is₁₀Is hydrogen or lower alkyl, lower alkyl substituted by pivaloyloxy, and in each case R₁₀Attached to one of the nitrogen atoms in the 1,2, 4-triazole ring as shown above in formula I.

A compound of formula II:

wherein R is₁₁And R₁₂Each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl (substituted phenyl in formula II refers to phenyl substituted with halogen, lower alkyl, etc. examples include, but are not limited to, p-tolyl and p-chlorophenyl), or R₁₁And R₁₂May form, together with the carbon atoms to which they are attached, a four to eight membered carbocyclic ring;

wherein R is₁₃Is hydrogen or substituted or unsubstituted lower alkyl;

wherein R is₁₄Is one OR two groups selected from hydrogen, halogen, nitro, substituted OR unsubstituted lower alkyl, substituted OR unsubstituted phenyl (the substituted phenyl in formula II means phenyl substituted with halogen OR lower alkyl, etc. - -examples include, but are not limited to, p-tolyl and p-chlorophenyl), - -OR₁₆and-SO₂NR₁₇R_{17 ’}Wherein R is₁₆Is hydrogen, substituted or unsubstituted lower alkyl, lower alkyl substituted by phenyl, carboxymethyl or ester thereof, hydroxyethyl or ether thereof, or allyl; r₁₇And R_{17 ’}Each independently is hydrogen or substituted or unsubstituted lower alkyl;

wherein R is₁₅Is hydrogen or a pharmaceutically active ester-forming group;

wherein A is a straight or branched hydrocarbon group having 1 to 5 carbon atoms;

wherein B is halogen, oxygen or ethylenedithio;

wherein Y is oxygen, sulfur, nitrogen or substituted nitrogen;

wherein Z is oxygen, nitrogen or substituted nitrogen; and is

The dotted line refers to a single bond, a double bond, or two single bonds (e.g., when B is ethylenedithio, the dotted line shown in the ring structure may be two single bonds).

The term "lower alkyl(s)" as used herein means C₁-C₇Alkyl groups including, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl (heptal), and the like.

The term "lower alkoxy" as used herein refers to those groups formed by linking a lower alkyl group to an oxygen atom, which include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, and the like.

The term "lower alkylthio" as used herein refers to those groups formed by linking a lower alkyl group to a sulfur atom.

The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.

The term "substituted pyridyl" as used herein refers to pyridyl which may be substituted by halogen, cyano, lower alkyl, lower alkoxy or lower alkylthio.

The term "four to eight membered carbocyclic ring" as used herein refers to cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The phrase "pharmaceutically active ester-forming group" as used herein refers to a group attached to a carboxyl group through an ester linkage. Such ester forming groups may be selected from the group of carboxy protecting groups commonly used in the preparation of pharmaceutically active substances, especially prodrugs. For the purposes of the present disclosure, the group should be selected from those capable of being linked to a compound having the formula II via an ester linkage, wherein R₁₅Is hydrogen. The resulting ester is effective for increasing the stability, solubility and absorption of the corresponding non-esterified form of the compound having formula II in the gastrointestinal tract, and also for prolonging its effective blood levels. In addition, ester linkages can be readily cleaved at body fluid pH, or by the action of in vivo enzymes, to provide the biologically active form of the compound of formula II. Preferred pharmaceutically active ester-forming groups include, but are not limited to, 1- (oxy-substituted) -C₂To C₁₅Alkyl, e.g. straight-chain, branched, cyclic or partially cyclic alkanoyloxyalkyl, e.g. acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethylEtc. C₃To C₁₅Alkoxycarbonyloxyalkyl such as ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, tert-butoxycarbonyloxyethyl, isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyiisopropyl and the like, C₂To C₈Alkoxyalkyl radicals, e.g. methoxymethyl, methoxyethyl, etc., C₄To C₈2-oxacycloalkyl, e.g. tetrahydropyranyl, tetrahydrofuranyl, etc., substituted C₈To C₁₂Aralkyl radicals, e.g. phenacyl, phthalyl, etc., C₆To C₁₂Aryl, e.g. phenylxylyl, indanyl, etc., C₂To C₁₂Alkenyl groups such as allyl, (2-oxo-1, 3-dioxolyl) methyl and the like, and [4, 5-dihydro-4-oxo-1H-pyrazolo [3,4-d]Pyrimidin-1-yl]Methyl, and the like.

R in formula II₁₆The term "ester" used in the phrase "ester of carboxymethyl group" means a lower alkyl ester such as methyl ester or ethyl ester; and the term "ether" used in the phrase "ether of hydroxyethyl" refers to an ether formed by substituting a hydrogen atom of a hydroxyl group in a hydroxyethyl group with an aliphatic or aromatic alkyl group (e.g., benzyl group).

The carboxylic acid protecting group may be substituted in a variety of ways. Examples of the substituent include a halogen atom, an alkyl group, an alkoxy group, an alkylthio group, and a carboxyl group.

As used herein, the term "straight or branched chain hydrocarbon group" in the definition of a in formula II refers to methylene, ethylene, propylene, methylmethylene, or isopropylene.

The substituent of "substituted nitrogen" in the definitions of Y and Z in formula II above as used herein is hydrogen, lower alkyl or acyl.

The term "phenyl-substituted lower alkyl" as used herein refers to a lower alkyl substituted with a phenyl group, such as benzyl, phenethyl or phenylpropyl.

The term "prodrug" as used herein refers to derivatives of the compounds shown in formulas I and II above, which have chemically or metabolically cleavable groups and become compounds that are pharmaceutically active in vivo by solvolysis or under physiological conditions. Esters of carboxylic acids are examples of prodrugs that may be used in the dosage forms of the present disclosure. Methyl ester prodrugs can be prepared by esterifying a compound having the above formula with an acid or base catalyst (e.g., NaOH, H) in a medium such as methanol₂SO₄) And reacting to prepare the compound. Ethyl ester prodrugs were prepared in a similar manner using ethanol instead of methanol.

Examples of compounds having the above formula I are: 2- [ 3-cyano-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid (also known as "febuxostat"), 2- [ 3-cyano-4- (3-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid, 2- [ 3-cyano-4- (2-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid, 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid, 2- [4- (2-carboxypropoxy) -3-cyanophenyl]-4-methyl-5-thiazolecarboxylic acid, 1- (3-cyano-4- (2, 2-dimethylpropoxy) phenyl) -1H-pyrazole-4-carboxylic acid, 1-3-cyano-4- (2, 2-dimethylpropoxy) phenyl]-1H-pyrazole-4-carboxylic acid, pyrazolo [1,5-a]-1,3, 5-triazin-4- (1H) -one, 8- [ 3-methoxy-4- (phenylsulfinyl) phenyl]-sodium salt (±) or 3- (2-methyl-4-pyridyl) -5-cyano-4-isobutoxyphenyl) -1,2, 4-triazole.

Preferred compounds having the above formula I are: 2- [ 3-cyano-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, 2- [ 3-cyano-4- (3-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid, 2- [ 3-cyano-4- (2-hydroxy-2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid, 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid, 2- [4- (2-carboxypropoxy) -3-cyanophenyl]-4-methyl-5-thiazolecarboxylic acid. These preferred compounds have also been found to have no effect on the activity of any of the following enzymes involved in purine and pyrimidine metabolism in a subject at therapeutically effective amounts: guanine deaminase, hypoxanthine-guanine phosphoribosyl transferase, purine nucleotide phosphorylase, orotic acid phosphate nucleusGlycosyltransferase or orotidine-5-monophosphate decarboxylase (orotidine-5-monophosphonatecarboxylase) (i.e., it means that it is not "selective" for these enzymes involved in purine and pyrimidine metabolism). Assays for determining the activity of each of the above enzymes are described in Yasuhiro Takano, et al,Life Sciences76: 1835-. These preferred compounds have also been described in the literature as non-purine, selective inhibitors of xanthine oxidase (NP/SIXO).

Examples of compounds having formula II above are described in U.S. patent No. 5,268,386 and EP 0415566 a1, and are incorporated herein in their entirety.

With the exception of pyrazolo [1,5-a]-1,3, 5-triazin-4- (1H) -one, 8- [ 3-methoxy-4- (phenylsulfinyl) phenyl]The sodium salt (±), methods of making compounds of formulae I and II that inhibit xanthine oxidoreductase for use in the methods of the present disclosure are known in the art and are described, for example, in U.S. patent nos. 5,268,386, 5,614,520, 6,225,474, 7,074,816 and EP 0415566 a1 and publication Ishibuchi, s. et al.,Bioorg. Med. Chem. Lett11: 879-. Other compounds that inhibit xanthine oxidoreductase can be found using xanthine oxidoreductase and xanthine in assays for determining whether such candidate compounds inhibit the conversion of xanthine to uric acid. Such assays are well known in the art.

Pyrazolo [1,5-a]-1,3, 5-triazin-4- (1H) -one, 8- [ 3-methoxy-4- (phenylsulfinyl) phenyl]The sodium salt (±) is available from Otsuka Pharmaceutical co. ltd. (Tokyo, Japan) and is described in the following publications: uematsu T, et al, "pharmaceutical and pharmacological Properties of a Novel Xanthine oxide Inhibitor, BOF-4272, in health volnters,J. Pharmacology and Experimental Therapeutics,270: 453-.In Purine and Pyrimidine Metabolism in Man,Vol, VII, Part a, ed.: P.A. Harkness, pp.135-138, Plenum Press, New York. Pyrazolo [1,5-a]-1,3, 5-triazines-4- (1H) -one, 8- [ 3-methoxy-4- (phenylsulfinyl) phenyl]The sodium salt (±) may be prepared using conventional techniques known in the art.

II.Dosage forms

The present disclosure relates to modified release solid dosage forms comprising at least one active agent. In particular, the at least one active agent comprised in the modified release solid dosage form of the present disclosure is at least one xanthine oxidoreductase inhibitor or at least one xanthine oxidase inhibitor.

The improved release dosage forms of the present disclosure can achieve any of a number of objectives. First, the modified release dosage forms of the present disclosure, when administered to a subject in need of treatment thereof, are at maximum observed plasma concentrations (i.e., C) significantly lower than those provided by immediate release dosage forms_max) Provide a high percentage of xanthine oxidoreductase inhibition or xanthine oxidase inhibition, the immediate release dosage form comprising at least one xanthine oxidoreductase inhibitor (e.g., an immediate release dosage form containing 40mg, 80mg, 120mg, or 240mg of febuxostat administered to a subject once daily) that is similar to or lower than 2- [ 3-cyano-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid (also referred to as "febuxostat")) or at least one xanthine oxidase inhibitor (e.g., an immediate release dosage form containing 300mg of allopurinol administered to a subject once daily) at the highest dose currently available (i.e., the currently available dose (e.g., 80mg (usa) or 120mg (europe)). Second, because the dosage forms of the present disclosure provide xanthine oxidoreductase inhibition or xanthine oxidase inhibition over extended periods of time (dosing), these solid dosage forms may be used to treat a variety of different conditions or diseases, such as, but not limited to, gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, renal injury, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, congestive heart failure, and other conditions. Third, the modified release agents of the present disclosureThe subject receiving these dosage forms is protected from the increased concentration of oxygen radicals throughout their treatment regimen.

To achieve these benefits, the improved release dosage forms of the present disclosure must achieve certain pharmacokinetic properties when compared to immediate release xanthine oxidoreductase inhibitors or xanthine oxidase inhibitor dosage forms.

In one embodiment, the modified release dosage form of the present disclosure comprising at least one xanthine oxidoreductase inhibitor exhibits at least two of the following characteristics following oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; or (b) produces a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in the subject in an amount between about 2.5 μ g/mL to about 0.5 μ g/mL_max). In another embodiment, the modified release dosage form of the present disclosure exhibits at least two of the following characteristics upon oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; or (b) produces a maximum plasma concentration (Cmax) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 1.0 μ g/mL_max). In yet another embodiment, the modified release dosage forms of the present disclosure exhibit each of the following characteristics upon oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than 0.1 μ g/mL for a period of time from about 5 hours to about 24 hours in a subject; or (b) produces an approximate maximum plasma concentration (Cmax) of the xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in the subject in an amount between about 2.5 μ g/mL to about 0.5 μ g/mL_max)。

As previously mentioned herein, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof greater than about 0.1 μ g/mL in a subject for a period of time from about 5 hours to about 24 hours following oral administration to the subject in need thereof. More specifically, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor, or pharmaceutically acceptable salt thereof, of greater than about 0.1 μ g/mL for a period of time of about 5.0 hours, about 6.0 hours, about 7.0 hours, about 8.0 hours, about 9.0 hours, about 10.0 hours, about 11.0 hours, about 12.0 hours, about 13.0 hours, about 14.0 hours, about 15.0 hours, about 16.0 hours, about 17.0 hours, about 18.0 hours, about 19.0 hours, about 20.0 hours, about 21.0 hours, about 22.0 hours, about 23.0 hours, or about 24.0 hours in a subject following oral administration to a subject in need of treatment thereof.

Also as previously mentioned herein, the improved dosage forms of the present disclosure can yield an amount of between about 2.5 μ g/mL to about 0.5 μ g/mL in a subject (and between, for example, about 2.5 μ g/mL to about 0.6 μ g/mL, about 2.5 μ g/mL to about 0.7 μ g/mL, about 2.5 μ g/mL to about 0.8 μ g/mL, about 2.4 μ g/mL to about 0.5 μ g/mL, about 2.4 μ g/mL to about 0.6 μ g/mL, about 2.3 μ g/mL to about 0.5 μ g/mL, about 2.2 μ g/mL to about 0.5 μ g/mL, about 2.1 μ g/mL to about 0.5 μ g/mL, about 2.0 μ g/mL to about 0.5 μ g/mL, about 2.1 μ g/mL to about 0.5 μ g/mL, about 2.5 μ g/mL to about 0.1 μ g/mL, about 0.5 μ g/mL, about 2 g/mL to about 0.1 μ g/mL, About 1.9 μ g/mL to about 0.5 μ g/mL, about 1.9 μ g/mL to about 1.0 μ g/mL, about 1.8 μ g/mL to about 0.5 μ g/mL, about 1.8 μ g/mL to about 1.0 μ g/mL, about 1.7 μ g/mL to about 0.5 μ g/mL, about 1.7 μ g/mL to about 0.6 μ g/mL, about 1.7 μ g/mL to about 0.7 μ g/mL, about 1.7 μ g/mL to about 0.8 μ g/mL, about 1.7 μ g/mL to about 1.0 μ g/mL, about 1.6 μ g/mL to about 0.5 μ g/mL, about 1.5 μ g/mL to about 1.0 μ g/mL, and the like) of a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof._max). More specifically, the improved dosage forms of the present disclosure can yield about 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, about 2.0 μ g/mL, about 1.9 μ g/mL, about1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, or about 0.5 μ g/mL of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof_max。

The dosage form of the present disclosure may comprise from about 5 mg to about 240mg of at least one xanthine oxidoreductase inhibitor. More specifically, the dosage form may comprise about 5 mg, about 6.25 mg, about 10 mg, about 20mg, about 25 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80mg, about 90 mg, about 100 mg, about 110 mg, about 120mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240mg of the at least one xanthine oxidoreductase inhibitor.

In another embodiment, the modified release dosage form of the present disclosure comprising at least one xanthine oxidoreductase inhibitor exhibits at least two of the following characteristics following oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; or (b) produces a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in the subject in an amount between about 2.5 μ g/mL to about 0.05 μ g/mL_max). In another embodiment, the modified release dosage form of the present disclosure exhibits at least two of the following characteristics upon oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; or (b) produces a maximum plasma concentration (Cmax) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 0.075 μ g/mL_max). In yet another embodiment, the modified release dosage forms of the present disclosure are administered orally to a patient in need of treatment thereofThe subjects exhibited each of the following characteristics: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 16 hours in a subject; or (b) produces a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in the subject in an amount between about 2.5 μ g/mL to about 0.05 μ g/mL_max)。

As previously mentioned herein, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof greater than about 0.1 μ g/mL in a subject for a period of time from about 5 hours to about 16 hours following oral administration to the subject in need thereof. More specifically, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor, or pharmaceutically acceptable salt thereof, of greater than about 0.1 μ g/mL in a subject for a time period of about 5.0 hours, about 6.0 hours, about 7.0 hours, about 8.0 hours, about 9.0 hours, about 10.0 hours, about 11.0 hours, about 12.0 hours, about 13.0 hours, about 14.0 hours, about 15.0 hours, or about 16.0 hours after oral administration to a subject in need of treatment thereof.

Also as previously mentioned herein, the modified release dosage forms of the present disclosure can yield an amount of between about 2.5 μ g/mL to about 0.05 μ g/mL in a subject following oral administration to a subject in need of treatment thereof (as well as amounts of between, for example, about 2.5 μ g/mL to about 0.06 μ g/mL, about 2.5 μ g/mL to about 0.07 μ g/mL, about 2.5 μ g/mL to about 0.08 μ g/mL, about 2.5 μ g/mL to about 0.09 μ g/mL, about 2.5 μ g/mL to about 0.1 μ g/mL, about 2.5 μ g/mL to about 0.2 μ g/mL, about 2.5 μ g/mL to about 0.3 μ g/mL, about 2.5 μ g/mL to about 0.40 μ g/mL, about 2.5 μ g/mL to about 0.5 μ g/mL, About 2.5 μ g/mL to about 0.6 μ g/mL, about 2.5 μ g/mL to about 0.7 μ g/mL, about 2.5 μ g/mL to about 0.8 μ g/mL, about 2.5 μ g/mL to about 0.9 μ g/mL, about 2.5 μ g/mL to about 1.0 μ g/mL, 2.4 μ g/mL to about 0.05 μ g/mL, 2.4 μ g/mL to about 0.06 μ g/mL, about 2.4 μ g/mL to about 0.07 μ g/mL, about 2.4 μ g/mL to about 0.08 μ g/mL, about 2.4 μ g/mL to about 0.09 μ g/mL, about 2.4 μ g/mL to about 0.1 μ g/mL, about 2.4 μ g/mL to about 0.2 μ g/mL, about 2.4 μ g/mL to about 0.3 μ g/mL, about 2.4 μ g/mL to about 0.40 μ g/mL, about 2.4 μ g/mL to about 0.5 μ g/mL, about 2.4 μ g/mL to about 0.6 μ g/mL, about 2.4 μ g/mL to about 0.7 μ g/mL, about 2.4 μ g/mL to about 0.8 μ g/mL, about 2.4 μ g/mL to about 0.9 μ g/mL, 2.4 μ g/mL to about 1.0 μ g/mL, 2.3 μ g/mL to about 0.06 μ g/mL, about 2.3 μ g/mL to about 0.07 μ g/mL, about 2.3 μ g/mL to about 0.08 μ g/mL, about 2.3 μ g/mL to about 0.09 μ g/mL, about 2.4 μ g/mL to about 0.09 μ g/mL, About 2.3 μ g/mL to about 0.1 μ g/mL, about 2.3 μ g/mL to about 0.2 μ g/mL, about 2.3 μ g/mL to about 0.3 μ g/mL, about 2.3 μ g/mL to about 0.40 μ g/mL, about 2.3 μ g/mL to about 0.5 μ g/mL, about 2.3 μ g/mL to about 0.6 μ g/mL, about 2.3 μ g/mL to about 0.7 μ g/mL, about 2.3 μ g/mL to about 0.8 μ g/mL, about 2.3 μ g/mL to about 0.9 μ g/mL, about 2.3 μ g/mL to about 1.0 μ g/mL, 2.2 μ g/mL to about 0.05 μ g/mL, 2.2 μ g/mL to about 0.06 μ g/mL, about 2.3 μ g/mL to about 0.07 μ g/mL, About 2.2 μ g/mL to about 0.08 μ g/mL, about 2.2 μ g/mL to about 0.09 μ g/mL, about 2.2 μ g/mL to about 0.1 μ g/mL, about 2.2 μ g/mL to about 0.2 μ g/mL, about 2.2 μ g/mL to about 0.3 μ g/mL, about 2.2 μ g/mL to about 0.40 μ g/mL, about 2.2 μ g/mL to about 0.5 μ g/mL, about 2.2 μ g/mL to about 0.6 μ g/mL, about 2.4 μ g/mL to about 0.7 μ g/mL, about 2.2 μ g/mL to about 0.8 μ g/mL, about 2.2 μ g/mL to about 0.9 μ g/mL, about 2.2 μ g/mL to about 1.0 μ g/mL, about 2.05 μ g/mL to about 0.05 μ g/mL, 2.1 to about 0.06, about 2.1 to about 0.07, about 2.1 to about 0.08, about 2.1 to about 0.09, about 2.1 to about 0.1, about 2.3, about 2.1 to about 0.40, about 2.1 to about 0.5, about 2.1 to about 0.6, about 2.1 to about 0.7, about 2.1 to about 0.8, about 2.1 to about 0.9, About 2.1 μ g/mL to about 1.0 μ g/mL, 2.0 μ g/mL to about 0.05 μ g/mL, 2.0 μ g/mL to about 0.06 μ g/mL, about 2.0 μ g/mL to about 0.07 μ g/mL, about 2.0 μ g/mL to about 0.08 μ g/mL, about 2.0 μ g/mL to about 0.09 μ g/mL, about 2.0 μ g/mL to about 0.1 μ g/mL, about 2.0 μ g/mL to about 0.2 μ g/mL, about 2.0 μ g/mL to about 0.3 μ g/mL, about 2.0 μ g/mL to about 0.40 μ g/mL, about 2.0 μ g/mL to about 0.5 μ g/mL, about 2.0 μ g/mL to about 0.6 μ g/mL, about 2.0 μ g/mL.0 μ g/mL to about 0.7 μ g/mL, about 2.0 μ g/mL to about 0.8 μ g/mL, about 2.0 μ g/mL to about 0.9 μ g/mL, about 2.0 μ g/mL to about 1.0 μ g/mL, 1.9 μ g/mL to about 0.05 μ g/mL, 1.9 μ g/mL to about 0.06 μ g/mL, about 1.9 μ g/mL to about 0.07 μ g/mL, about 1.9 μ g/mL to about 0.08 μ g/mL, about 1.9 μ g/mL to about 0.09 μ g/mL, about 1.9 μ g/mL to about 0.1 μ g/mL, about 1.9 μ g/mL to about 0.2 μ g/mL, about 1.9 μ g/mL to about 0.3 μ g/mL, about 1.9 μ g/mL to about 0.40 μ g/mL, About 1.9 to about 0.5, about 1.9 to about 0.6, about 1.9 to about 0.7, about 1.9 to about 0.8, about 1.9 to about 0.9, about 1.9 to about 0.05, 1.8 to about 0.06, about 1.8 to about 0.07, about 1.8 to about 0.08, about 1.8 to about 0.09, about 1.8 to about 0.1, about 1.8 to about 2, About 1.8 μ g/mL to about 0.3 μ g/mL, about 1.8 μ g/mL to about 0.40 μ g/mL, about 1.8 μ g/mL to about 0.5 μ g/mL, about 1.8 μ g/mL to about 0.6 μ g/mL, about 1.8 μ g/mL to about 0.7 μ g/mL, about 1.8 μ g/mL to about 0.8 μ g/mL, about 1.8 μ g/mL to about 0.9 μ g/mL, about 1.8 μ g/mL to about 1.0 μ g/mL, 1.7 μ g/mL to about 0.05 μ g/mL, 1.7 μ g/mL to about 0.06 μ g/mL, about 1.7 μ g/mL to about 0.07 μ g/mL, about 1.7 μ g/mL to about 0.08 μ g/mL, about 1.7 μ g/mL to about 0.09 μ g/mL, about 1.8 μ g/mL to about 0.6 μ g/mL, About 1.7 μ g/mL to about 0.1 μ g/mL, about 1.7 μ g/mL to about 0.2 μ g/mL, about 1.7 μ g/mL to about 0.3 μ g/mL, about 1.7 μ g/mL to about 0.40 μ g/mL, about 1.7 μ g/mL to about 0.5 μ g/mL, about 1.7 μ g/mL to about 0.6 μ g/mL, about 1.7 μ g/mL to about 0.7 μ g/mL, about 1.7 μ g/mL to about 0.8 μ g/mL, about 1.7 μ g/mL to about 0.9 μ g/mL, about 1.7 μ g/mL to about 1.0 μ g/mL, 1.6 μ g/mL to about 0.05 μ g/mL, 1.6 μ g/mL to about 0.06 μ g/mL, about 1.6 μ g/mL to about 0.07 μ g/mL, About 1.6 to about 0.08, about 1.6 to about 0.09, about 1.6 to about 0.1, about 1.6 to about 0.2, about 1.6 to about 0.3, about 1.6 to about 0.40, about 1.6 to about 0.5, about 1.6 to about 0.6, about 1.6 to about 0.7, about 1.6 to about 0.8, about 1.6 to about 0.9, about 1.6 to about 1.0g/mL to about 0.05 μ g/mL, 1.5 μ g/mL to about 0.06 μ g/mL, about 1.5 μ g/mL to about 0.07 μ g/mL, about 1.5 μ g/mL to about 0.08 μ g/mL, about 1.5 μ g/mL to about 0.09 μ g/mL, about 1.5 μ g/mL to about 0.1 μ g/mL, about 1.5 μ g/mL to about 0.2 μ g/mL, about 1.5 μ g/mL to about 0.3 μ g/mL, about 1.5 μ g/mL to about 0.40 μ g/mL, about 1.5 μ g/mL to about 0.5 μ g/mL, about 1.5 μ g/mL to about 0.6 μ g/mL, about 1.5 μ g/mL to about 0.7 μ g/mL, about 1.5 μ g/mL to about 0.8 μ g/mL, about 1.5 μ g/mL to about 0.9 μ g/mL, or about 1.5 μ g/mL In any combination in the range between g/mL) of the maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor or of the pharmaceutically acceptable salt thereof_max). More specifically, the improved dosage forms of the present disclosure can yield, upon oral administration to a subject in need of treatment thereof, 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, about 0.5 μ g/mL, about 0.4 μ g/mL, about 3 μ g/mL, about 0.4 μ g/mL, about 3 μ g/mL, about, About 0.2. mu.g/mL, about 0.1. mu.g/mL, about 0.099. mu.g/mL, about 0.098. mu.g/mL, about 0.097. mu.g/mL, about 0.096. mu.g/mL, about 0.095. mu.g/mL, about 0.094. mu.g/mL, about 0.093. mu.g/mL, about 0.092. mu.g/mL, about 0.091. mu.g/mL, about 0.090. mu.g/mL, about 0.089. mu.g/mL, about 0.088. mu.g/mL, about 0.087. mu.g/mL, about 0.086. mu.g/mL, about 0.085. mu.g/mL, about 0.084. mu.g/mL, about 0.083. mu.g/mL, about 0.077. mu.g/mL, about 0.078. mu.g/mL, about 0810.077. mu.g/mL, about 0.078. mu.g/mL, about 0.g/mL, about 081, About 0.075 μ g/mL, about 0.074 μ g/mL, about 0.073 μ g/mL, about 0.072 μ g/mL, about 0.071 μ g/mL, about 0.070 μ g/mL, about 0.069 μ g/mL, about 0.068 μ g/mL, about 0.067 μ g/mL, about 0.066 μ g/mL, about 0.065 μ g/mL, about 0.064 μ g/mL, about 0.063 μ g/mL, a xanthine oxidoreductase inhibitor in an amount of about 0.062, about 0.061, about 0.060, about 0.059, about 0.058, about 0.057, about 0.056, about 0.055, about 0.054, about 0.053, about 0.052, about 0.051, or about 0.050 μ g/mL.C of the formulation or a pharmaceutically acceptable salt thereof_max。

The dosage forms of the present disclosure may contain from about 5 mg to about 240mg of at least one xanthine oxidoreductase inhibitor. More specifically, the dosage form may comprise about 5 mg, about 6.25 mg, about 10 mg, about 20mg, about 25 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80mg, about 90 mg, about 100 mg, about 110 mg, about 120mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240mg of the at least one xanthine oxidoreductase inhibitor.

In another embodiment, the modified release dosage form of the present disclosure comprising at least one xanthine oxidoreductase inhibitor exhibits at least two of the following characteristics following oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; or (b) produces a maximum plasma concentration (C) of the xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in the subject in an amount between about 2.5 μ g/mL to about 0.090 μ g/mL_max). In another embodiment, the modified release dosage form of the present disclosure exhibits at least two of the following characteristics upon oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than about 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; or (b) produces a maximum plasma concentration (Cmax) of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof in the subject of between about 2.0 μ g/mL to about 0.095 μ g/mL_max). In yet another embodiment, the modified release dosage forms of the present disclosure exhibit each of the following characteristics upon oral administration to a subject in need thereof: (a) maintaining a plasma concentration of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, greater than 0.1 μ g/mL for a period of time from about 5 hours to about 14 hours in a subject; or (b) produces in the subject at about 2.5 μ gMaximum plasma concentration (C) of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof in an amount between/mL to about 0.090 μ g/mL_max)。

As previously mentioned herein, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof greater than about 0.1 μ g/mL in a subject for a period of time from about 5 hours to about 14 hours following oral administration to the subject in need thereof. More specifically, the improved dosage forms of the present disclosure can maintain a plasma concentration of the xanthine oxidoreductase inhibitor or pharmaceutically acceptable salt thereof of greater than about 0.1 μ g/mL for a period of time of about 5.0 hours, about 6.0 hours, about 7.0 hours, about 8.0 hours, about 9.0 hours, about 10.0 hours, about 11.0 hours, about 12.0 hours, about 13.0 hours, or about 14.0 hours in a subject following oral administration to a subject in need of treatment thereof.

Also as previously mentioned herein, the improved dosage forms of the present disclosure can yield an amount of between about 2.5 μ g/mL to about 0.090 μ g/mL in a subject following oral administration to a subject in need of treatment thereof (and in amounts of, for example, about 2.5 μ g/mL to about 0.1 μ g/mL, about 2.5 μ g/mL to about 0.2 μ g/mL, about 2.5 μ g/mL to about 0.3 μ g/mL, about 2.5 μ g/mL to about 0.40 μ g/mL, about 2.5 μ g/mL to about 0.5 μ g/mL, about 2.5 μ g/mL to about 0.6 μ g/mL, about 2.5 μ g/mL to about 0.7 μ g/mL, about 2.5 μ g/mL to about 0.8 μ g/mL, about 2.5 μ g/mL to about 0.9 μ g/mL, About 2.5 μ g/mL to about 1.0 μ g/mL, about 2.4 μ g/mL to about 0.1 μ g/mL, about 2.4 μ g/mL to about 0.2 μ g/mL, about 2.4 μ g/mL to about 0.3 μ g/mL, about 2.4 μ g/mL to about 0.40 μ g/mL, about 2.4 μ g/mL to about 0.5 μ g/mL, about 2.4 μ g/mL to about 0.6 μ g/mL, about 2.4 μ g/mL to about 0.7 μ g/mL, about 2.4 μ g/mL to about 0.8 μ g/mL, about 2.4 μ g/mL to about 0.9 μ g/mL, 2.4 μ g/mL to about 1.0 μ g/mL, about 2.3 μ g/mL to about 1.3 μ g/mL, About 2.3 μ g/mL to about 0.2 μ g/mL, about 2.3 μ g/mL to about 0.3 μ g/mL, about 2.3 μ g/mL to about 0.40 μ g/mL, about 2.3 μ g/mL to about 0.5 μ g/mL, about 2.3 μ g/mL to about 0.6 μ g/mL, about 2.3 μ g/mL to about 0.7 μ g/mL, about 2.3 μ g/mL to about 0.8 μ g/mL, about 2.3 μ g/mLg/mL to about 0.9 μ g/mL, about 2.3 μ g/mL to about 1.0 μ g/mL, about 2.2 μ g/mL to about 0.1 μ g/mL, about 2.2 μ g/mL to about 0.2 μ g/mL, about 2.2 μ g/mL to about 0.3 μ g/mL, about 2.2 μ g/mL to about 0.40 μ g/mL, about 2.2 μ g/mL to about 0.5 μ g/mL, about 2.2 μ g/mL to about 0.6 μ g/mL, about 2.4 μ g/mL to about 0.7 μ g/mL, about 2.2 μ g/mL to about 0.8 μ g/mL, about 2.2 μ g/mL to about 0.9 μ g/mL, about 2.2 μ g/mL to about 1.0 μ g/mL, about 2.1 μ g/mL to about 2.1.0 μ g/mL, about 2 μ g/mL to about 2.9 μ g/mL, About 2.1 μ g/mL to about 0.3 μ g/mL, about 2.1 μ g/mL to about 0.40 μ g/mL, about 2.1 μ g/mL to about 0.5 μ g/mL, about 2.1 μ g/mL to about 0.6 μ g/mL, about 2.1 μ g/mL to about 0.7 μ g/mL, about 2.1 μ g/mL to about 0.8 μ g/mL, about 2.1 μ g/mL to about 0.9 μ g/mL, about 2.1 μ g/mL to about 1.0 μ g/mL, about 2.0 μ g/mL to about 0.1 μ g/mL, about 2.0 μ g/mL to about 0.2 μ g/mL, about 2.0 μ g/mL to about 0.3 μ g/mL, about 2.0 μ g/mL to about 0.40 μ g/mL, about 2.0 μ g/mL to about 5 μ g/mL, About 2.0 μ g/mL to about 0.6 μ g/mL, about 2.0 μ g/mL to about 0.7 μ g/mL, about 2.0 μ g/mL to about 0.8 μ g/mL, about 2.0 μ g/mL to about 0.9 μ g/mL, about 2.0 μ g/mL to about 1.0 μ g/mL, about 1.9 μ g/mL to about 0.1 μ g/mL, about 1.9 μ g/mL to about 0.2 μ g/mL, about 1.9 μ g/mL to about 0.3 μ g/mL, about 1.9 μ g/mL to about 0.40 μ g/mL, about 1.9 μ g/mL to about 0.5 μ g/mL, about 1.9 μ g/mL to about 0.6 μ g/mL, about 1.9 μ g/mL to about 0.7 μ g/mL, about 1.9 μ g/mL to about 0.8 μ g/mL, About 1.9 μ g/mL to about 0.9 μ g/mL, about 1.9 μ g/mL to about 1.0 μ g/mL, about 1.8 μ g/mL to about 0.1 μ g/mL, about 1.8 μ g/mL to about 0.2 μ g/mL, about 1.8 μ g/mL to about 0.3 μ g/mL, about 1.8 μ g/mL to about 0.40 μ g/mL, about 1.8 μ g/mL to about 0.5 μ g/mL, about 1.8 μ g/mL to about 0.6 μ g/mL, about 1.8 μ g/mL to about 0.7 μ g/mL, about 1.8 μ g/mL to about 0.8 μ g/mL, about 1.8 μ g/mL to about 0.9 μ g/mL, about 1.8 μ g/mL to about 1.0 μ g/mL, about 1.7 μ g/mL to about 0.05 μ g/mL, About 1.7 μ g/mL to about 0.1 μ g/mL, about 1.7 μ g/mL to about 0.2 μ g/mL, about 1.7 μ g/mL to about 0.3 μ g/mL, about 1.7 μ g/mL to about 0.40 μ g/mL, about 1.7 μ g/mL to about 0.5 μ g/mL, about 1.7 μ g/mL to about 0.6 μ g/mL, about 1.7 μ g/mL to about 0.7 μ g/mL, about 1.7 μ g/mL to about 0.8 μ g/mL, about 1.7 μ g/mL to about 0.9 μ g/mL, about 1.7 μ g/mL to about 1.0 μ g/mL, 1.6 μ g/mL to about 0.1 μ g/mL, about 1.6 μ g/mLg/mL to about 0.2 μ g/mL, about 1.6 μ g/mL to about 0.3 μ g/mL, about 1.6 μ g/mL to about 0.40 μ g/mL, about 1.6 μ g/mL to about 0.5 μ g/mL, about 1.6 μ g/mL to about 0.6 μ g/mL, about 1.6 μ g/mL to about 0.7 μ g/mL, about 1.6 μ g/mL to about 0.8 μ g/mL, about 1.6 μ g/mL to about 0.9 μ g/mL, about 1.6 μ g/mL to about 1.0 μ g/mL, about 1.5 μ g/mL to about 0.1 μ g/mL, about 1.5 μ g/mL to about 0.2 μ g/mL, about 1.5 μ g/mL to about 0.3 μ g/mL, about 1.5 μ g/mL to about 40 μ g/mL, about 1.5 μ g/mL to about 0.2 μ g/mL, about 1.5 μ g/mL to about 0.3 μ g/mL, about 1.6 μ g/mL to about 0, About 1.5 μ g/mL to about 0.6 μ g/mL, about 1.5 μ g/mL to about 0.7 μ g/mL, about 1.5 μ g/mL to about 0.8 μ g/mL, about 1.5 μ g/mL to about 0.9 μ g/mL, or any combination of ranges between about 1.5 μ g/mL to about 1.0 μ g/mL) of a maximum plasma concentration (Cmax) of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof_max). More specifically, the improved dosage forms of the present disclosure can yield, upon oral administration to a subject in need of treatment thereof, 2.5 μ g/mL, about 2.4 μ g/mL, about 2.3 μ g/mL, about 2.2 μ g/mL, about 2.1 μ g/mL, 2.0 μ g/mL, about 1.9 μ g/mL, about 1.8 μ g/mL, about 1.7 μ g/mL, about 1.6 μ g/mL, about 1.5 μ g/mL, about 1.4 μ g/mL, about 1.3 μ g/mL, about 1.2 μ g/mL, about 1.1 μ g/mL, about 1.0 μ g/mL, about 0.9 μ g/mL, about 0.8 μ g/mL, about 0.7 μ g/mL, about 0.6 μ g/mL, about 0.5 μ g/mL, about 0.4 μ g/mL, about 3 μ g/mL, about 0.4 μ g/mL, about 3 μ g/mL, about, A C of a xanthine oxidoreductase inhibitor, or a pharmaceutically acceptable salt thereof, in an amount of about 0.2. mu.g/mL, about 0.1. mu.g/mL, about 0.099. mu.g/mL, about 0.098. mu.g/mL, about 0.097. mu.g/mL, about 0.096. mu.g/mL, about 0.095. mu.g/mL, about 0.094. mu.g/mL, about 0.093. mu.g/mL, about 0.092. mu.g/mL, about 0.091. mu.g/mL, or about 0.090. mu.g/mL_max。

The dosage forms of the present disclosure may contain from about 5 mg to about 240mg of at least one xanthine oxidoreductase inhibitor. More specifically, the dosage form may comprise about 5 mg, about 6.25 mg, about 10 mg, about 20mg, about 25 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80mg, about 90 mg, about 100 mg, about 110 mg, about 120mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240mg of the at least one xanthine oxidoreductase inhibitor.

C for determining xanthine oxidoreductase inhibitors_maxAnd plasma concentration of xanthine oxidoreductase inhibitors are well known in the art. To determine the percent inhibition of xanthine oxidoreductase exhibited by the dosage forms, the following equation may be used:

percent inhibition of xanthine oxidoreductase activity ("inhibition%"):

wherein C = plasma concentration of xanthine oxidoreductase inhibitor ("XORI"), f in the plasma of the subject_u= free fraction of XORI in plasma, and K_i= xanthine oxidoreductase inhibition constant of XORI.

The plasma concentration of XORI can be determined using techniques known in the art, such as high performance liquid chromatography with fluorescence detection, or validated high performance liquid chromatography tandem mass spectrometry (see Mayer, m. et al,American Journal of Therapeutics,12:22-34 (2005)). A nominal concentration (nominal concentration) of 1 μ g/mL can be used¹⁴In vitro binding of CXORI, determination of f using equilibrium dialysis techniques well known in the art_u. For example, XORI such as f of febuxostat_uCalculated as 0.9 ± 0.2 in normal patients and 1.2 ± 0.2 in patients with severe renal impairment (see Mayer, m. et al.,American Journal of Therapeutics,12:22-34 (2005)). In another study with a larger number of subjects, the percentage of the free fraction of febuxostat in plasma in the male, female, young and elderly groups of subjects was calculated to be 0.7 ± 0.1 (see Khosravan r., oral,Clinic. Pharmacology & Therapeutics,P50 (2005))。

XORI K_iCan be determined using conventional techniques well known in the art. For example, Ki's of XORI such as febuxostat have been usedXanthine oxidase assays, such as those described in osaday, et al,European J. Pharmacology241:183-188 (1993). More specifically, K of febuxostat _i Have been determined to be 0.7nM and 0.6 nM, respectively (see Osada y., et al,European J. Pharmacology241:183-188 (1993) and Takano, Y., et al,Life Sciences, 76:1835-1847(2005))。

in another embodiment, the modified release dosage form of the present disclosure comprises at least one xanthine oxidase inhibitor. These modified release dosage forms comprising at least one xanthine oxidase inhibitor are expected to maintain a critical plasma concentration for a longer duration following oral administration to a subject, thereby inhibiting the target enzyme for an extended period of time, as compared to immediate release formulations comprising allopurinol. Thus, these modified release dosage forms would be advantageous over immediate release tablets because they would reduce inter-patient variability due to variability in the half-lives of oxypurinol and allopurinol, thereby improving therapeutic efficacy.

The dosage form of the present disclosure may contain other drugs in addition to the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor. These additional agents may be selected from any of a variety of types of agents including, but not limited to, non-steroidal anti-inflammatory drugs, analgesics, anesthetics, anti-anginal drugs, antiarthritics, antiarrhythmics, antiasthmatic, antibacterial, anti-BPH, anticancer, anticholinergic, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout, anthelmintics, antihistamines, antihypertensive, anti-inflammatory drugs, antimalarials, antimigraine, antimuscarinics, antimuscarinic, antineoplastic, antiobesity, antipruritic, antipyretics, spasmolytic, antithyroid, antitubercular, antiulcer, anti-enuresis, antiviral, anxiolytic, appetite suppressant, Attention Deficit Disorder (ADD), and attention deficit disorder [ ADHD ] drugs, Calcium channel blockers, inotropic agents, beta-blockers, central nervous system stimulants, cognitive enhancers, corticosteroids, COX-2 inhibitors, decongestants, diuretics, gastrointestinal agents, genetic material, agents for controlling ventilation (e.g., colchicine; uricosuric agents, e.g., probenecid, sulpirtone, pheniododazon; xanthine oxidase inhibitors, e.g., oxypurinol, allopurinol, etc.), histidine receptor antagonists, horonolytics, hypnotics, hypoglycemic agents, immunosuppressive agents, keratolytic agents, leukotriene inhibitors, lipid modulating agents, macrolides, mitotic inhibitors, muscle relaxants, narcotic antagonists, tranquilizers, nicotine, nutritional oils, xanthine derivatives (e.g., but not limited to caffeine and caffeine derivatives), anti-parasympathetic agents, sedatives, sex hormones, sympathomimetic agents, Tranquilizers, vasodilators, vitamins, and combinations thereof. Any of the foregoing agents may also be administered in combination with a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor used in the dosage forms of the present disclosure.

The benefits of the present disclosure are not limited to a single type of dosage form having a particular drug release mechanism. This enhanced pharmacokinetic profile may be obtained with any oral extended release dosage form known in the art, such as, but not limited to, a pulsed release dosage form, an extended release dosage form, or a delayed release dosage form as taught above.

Many different types of oral polymeric modified release dosage forms are known in the art and are contemplated for use in the present disclosure. Examples of three different types of oral polymer modified release dosage forms, such as matrix systems, osmotic pumps or membrane control technologies (also known as depot systems) are described in more detail below. A detailed discussion of these dosage forms can also be found in: (i)Handbook of pharmaceutical controlled release technologyed. D.L. Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Tree on controlled drug delivery, fundamentals, optimization, and applications, ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992), the contents of each of which are hereby incorporated by reference. However, although in more detailThese three oral polymeric modified release dosage forms are described in detail, but other modified release dosage forms known to those skilled in the art are intended to be included within the scope of the present disclosure.

Skeleton system

Skeletal systems are well known in the art. In the matrix system, the drug is homogeneously dispersed in the polymer in combination with conventional excipients. The mixture is compressed, usually under pressure, to produce tablets. The drug is released from the tablet by diffusion and erosion. The aboveWise and KydonieusThe skeletal system is described in detail.

The matrix dosage forms of the present disclosure may comprise a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor and a pharmaceutically acceptable polymer. In one aspect, the xanthine oxidoreductase inhibitor is 2- [ 3-cyano-4-2 (2-methylpropoxy) phenyl ] -4-methylthiazole-5-carboxylic acid. In another aspect, the xanthine oxidase inhibitor is allopurinol.

The pharmaceutically acceptable polymer is a water soluble hydrophilic polymer, or a water insoluble hydrophobic polymer (including waxes). Suitable water-soluble polymers include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, vinyl acetate copolymers, polysaccharides (e.g., alginates, xanthan gum, and the like), polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, and derivatives and mixtures thereof. Examples of suitable water-insoluble polymers include acrylates, cellulose derivatives (e.g. ethyl cellulose or cellulose acetate), polyethylene, methacrylates, acrylic acid copolymers and high molecular weight polyvinyl alcohols. Examples of suitable waxes include fatty acids and glycerin.

In one aspect, the polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, and methylcellulose. In another aspect, the polymer is hydroxypropyl methylcellulose. In yet another aspect, the polymer is a high viscosity hydroxypropyl-methylcellulose having a viscosity of about 4,000 cps to about 100,000 cps. The most preferred high viscosity polymer is hydroxypropyl methylcellulose having a viscosity of about 15,000 cps commercially available from The Dow chemical company under The tradename Methocel @.

The amount of polymer in the dosage form is typically from about 10% to about 70% by weight of the composition.

The dosage forms of the present disclosure will typically comprise a pharmaceutically acceptable excipient. Pharmaceutical excipients are routinely included in solid dosage forms, as is well known to those skilled in the art. This operation is performed to facilitate the handling process and to improve the performance of the dosage form. Common excipients include diluents or bulking agents, lubricants, binders and the like. Such excipients may be used in the dosage forms of the present disclosure.

Diluents or fillers may be added to increase the weight of an individual dose to a size suitable for tablet compression. Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dried starch, sorbitol, and the like.

Lubricants may be included in the dosage form for a variety of reasons. The lubricant reduces the friction between the particles and the die wall during compression and ejection. This prevents the granules from sticking to tablet punches (tabletpunches), facilitates their ejection from tablet punches, and the like. Examples of suitable lubricants that may be used include, but are not limited to, talc, stearic acid, vegetable oils, calcium stearate, zinc stearate, magnesium stearate, and the like.

Glidants may also be included in the dosage form. Glidants improve the flow characteristics of granules. Examples of suitable glidants include, but are not limited to, talc, silicon dioxide, and corn starch.

A binder may be included in the dosage form. If the preparation of the dosage form includes a granulation step, a binder is typically used. Examples of suitable binders include, but are not limited to, pyrrolidone, polyvinylpyrrolidone, xanthan gum, cellulose gums such as carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, gelatin, starch, and pregelatinized starch.

Other excipients that may be included in the dosage form include, but are not limited to, preservatives, antioxidants, or any other excipient commonly used in the pharmaceutical industry, and the like. The amount of excipient used in the dosage form will correspond to the amount typically used in matrix systems. The total amount of excipients, fillers, admixtures, and the like may range from about 10% to about 70% by weight of the dosage form.

Matrix dosage forms are generally prepared using standard techniques well known in the art. Generally, they are prepared by the following method: the polymer, filler, xanthine oxidoreductase inhibitor (e.g. 2- [ 3-cyano-4-2 (2-methylpropoxy) phenyl ] -4-methylthiazole-5-carboxylic acid) or xanthine oxidase inhibitor (e.g. allopurinol and oxypurinol) and other excipients are dry blended, and then the mixture is granulated with alcohol until suitable granules are obtained. Granulation is carried out by methods known in the art. The wet granules are dried in a fluid bed dryer, sieved and ground to the appropriate size. The lubricant is mixed with the dry granules to obtain the final dosage form.

Alternatively, matrix dosage forms may be prepared using direct compression of a powdered, crystalline, or granular composition containing the active agent(s) alone or in admixture with one or more carriers, additives, and the like. Methods of direct compression are well known in the art.

The dosage forms of the present disclosure may be administered orally in the form of tablets, pills, or granules may be loosely filled into capsules. Tablets may be prepared by techniques known in the art and contain a therapeutically effective amount of a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor together with the excipients necessary to form tablets by such techniques. Tablets and pills may additionally be prepared with enteric coatings and other controlled release coatings for the purpose of acid protection, to facilitate swallowing, and the like. The coating may be coloured with a pharmaceutically acceptable dye. The amount of dye and other excipients in the coating liquid may vary and will not affect the performance of the modified release tablet. The coating liquid typically comprises a film forming polymer such as, but not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose esters or ethers (e.g., cellulose acetate or ethyl cellulose), acrylic polymers or mixtures of polymers. The coating solution is typically an aqueous or organic solvent, which also contains propylene glycol, sorbitan monooleate, sorbic acid, fillers such as titanium dioxide, and pharmaceutically acceptable dyes.

Osmotic pump

In an osmotic pump system, a tablet core is surrounded by a semi-permeable membrane having at least one orifice. The semipermeable membrane is permeable to water, but impermeable to the drug. When the system is exposed to body fluids, water will penetrate through the semipermeable membrane into the tablet core containing the osmotic excipients and the active drug. Osmotic pressure builds within the dosage form and the drug is released through the orifice in an attempt to compensate for the pressure.

In more complex pumps, the tablet core contains two internal compartments. The first compartment contains a drug. The second compartment comprises a polymer which swells upon contact with a liquid (swell). Upon ingestion, the polymer swells into the drug-containing compartment at a predetermined rate and pushes the drug from the dosage form at that rate. Such dosage forms are typically used when a zero order release profile is desired.

Osmotic pumps are well known in the art and have been described in the literature. U.S. Pat. Nos. 4,088,864, 4,200,098, and 5,573,776 (both of which are incorporated herein by reference) describe osmotic pumps and methods for their preparation.

As a general guideline, the osmotic pump of the present disclosure may be formed by: tablets of osmotically active drug (or osmotically inert drug and osmotically active agent or osmotic agent (osmagent)) are compressed and then coated with a semipermeable membrane that is permeable to the external water-based fluid but impermeable to passage of the drug and/or osmotic agent. One or more delivery orifices may be drilled through the semi-permeable membrane wall. Alternatively, the aperture(s) through the wall may be formed in situ by including a leachable pore-forming material in the wall. In operation, an external water-based fluid is drawn through the semi-permeable membrane wall and contacts the drug and/or salt to form a solution or suspension of the drug. The drug solution or suspension is then pumped through the orifice as fresh fluid is drawn through the semi-permeable membrane.

In one embodiment, the tablet comprises two distinct compartments. The first compartment contains the medicament. The second compartment contains an expandable actuation member comprised of a swellable hydrophilic polymer layer that operates to reduce the volume occupied by the drug, thereby delivering the drug from the device at a controlled rate over an extended period of time.

Typical materials for the semipermeable membrane include semipermeable polymers known in the art as osmotic and reverse osmosis membranes, such as cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, acetaldehyde dimethyl acetate (acetaldehydodimethyl acetate), cellulose acetate urethane, polyamides, polyurethanes, sulfonated polystyrene, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethyl acetoacetate, cellulose acetate ethyl carbamate, cellulose acetate chloroacetate (celluloseacetate chloracetate), cellulose dipalmitate, cellulose dioctoate (celluloseadioctarate), cellulose dioctoate (celluloseadicaprylate), cellulose dipentanate (celluloseadipalmitate), cellulose dipentanate (celluloseacetate), Cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, methyl cellulose, cellulose acetate p-toluene sulfonate, cellulose acetate butyrate, such as U.S. patent No. 3,173,876;3,276,586, respectively; 3,541,005, respectively; 3,541,006, respectively; and 3,546,142, semi-permeable polymers formed by co-precipitation of polyanions and polycations, semi-permeable polymers such as disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132, lightly crosslinked polystyrene derivatives such as disclosed in U.S. Pat. No. 4,160,020, crosslinked poly (sodium styrene sulfonate), poly (vinylbenzyltrimethylammonium chloride), cellulose acetate having a degree of substitution of up to 1 and an acetyl content of up to 50%, cellulose diacetate having a degree of substitution of 1-2 and an acetyl content of 21-35%, cellulose triacetate having a degree of substitution of 2-3 and an acetyl content of 35-44.8%.

The osmotic agent present in the pump that can be used when the drug itself is non-osmotically active is an osmotically effective compound that is soluble in the fluid entering the device and exhibits an osmotic pressure gradient across the semipermeable wall relative to the external fluid. Osmotically effective osmotic agents for the present purpose include, but are not limited to, magnesium sulfate, calcium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, hydrophilic polymers such as cellulosic polymers, mixtures thereof, and the like. The osmotic agent is generally present in an excess amount, and it may be in any physical form, such as particles, powders, granules, and the like. The osmotic pressure in an atmosphere suitable for the osmotic agents of the present disclosure will be greater than zero and typically up to about 500atm or more.

The expandable drive member is typically a swellable hydrophilic polymer that interacts with water and aqueous biological fluids and swells or expands to an equilibrium state. The polymer exhibits the ability to swell in water and retains a significant amount of imbibed water within the polymer structure. The polymer swells or expands to a very high degree, typically exhibiting a 2-50 volume increase. The polymer may be non-crosslinked or crosslinked. The swellable hydrophilic polymer may be lightly crosslinked, such crosslinks being formed by covalent ionic or hydrogen bonds. The polymer may be of plant, animal or synthetic origin. Hydrophilic polymers suitable for use in the present disclosure include, but are not limited to, poly (hydroxyalkyl methacrylates) having a molecular weight of 30,000-5,000,000; kappa carrageenan, polyvinylpyrrolidone, with a molecular weight of 10,000-; anionic and cationic hydrogels; a polyelectrolyte complex; poly (vinyl alcohol) having low acetate residue, crosslinked with glyoxal, formaldehyde or glutaraldehyde, and having a degree of polymerization of 200-; a mixture of methylcellulose; cross-linked agar and carboxymethyl cellulose; a water-insoluble water-swellable copolymer made by forming a dispersion of a finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, butylene or isobutylene, the copolymer being crosslinked with from 0.001 to about 0.5 moles of a saturated crosslinking agent per mole of maleic anhydride in the copolymer; water-swellable polymers of N-vinyl lactams, and the like.

The expression "orifice" as used herein includes means and methods suitable for releasing a drug from a system. The expression includes one or more slits or apertures that have been mechanically drilled through a semi-permeable membrane. Alternatively, it may be formed by including an erodible element, such as a gelatin plug, in the semi-permeable membrane. Where the semi-permeable membrane is sufficiently permeable to the drug, the pores in the membrane may be sufficient to release a therapeutically effective amount of the agent/drug. In such cases, the expression "passage" refers to a hole within the membrane wall, even if there is no hole or other orifice that has been drilled through it. Details of permeate passages and the maximum and minimum dimensions of the passages are disclosed in U.S. Pat. nos. 3,845,770 and 3,916,899, the disclosures of which are incorporated herein by reference.

The osmotic pumps of the present disclosure can be prepared by standard techniques. For example, in one embodiment, the drug and other ingredients that may be placed in one region of the compartment adjacent the passageway are compressed into a solid having dimensions corresponding to the internal dimensions of the region of the compartment that the agent will occupy, or the agent and other ingredients and solvent are mixed into a solid or semi-solid formed by conventional means such as ball milling, calendaring, stirring or roller milling, and then compressed into a preselected shape. Next, the two layers surrounded by the hydrophilic polymer layer and the semipermeable wall are brought into contact with the reagent layer in a similar manner. The layering of the reagent formulation and hydrophilic polymer (layering) may be prepared by conventional two-layer compression techniques. The wall may be applied by moulding, spraying or dipping the pressed shape into the wall forming material. Another technique that may be used to apply the walls is the air suspension method (airsuspension procedure). The method consists of suspending and tumbling the compacted agent and the dry hydrophilic polymer in an air stream and wall forming composition until the wall is applied to the agent-hydrophilic polymer composite.The air suspension method is described in U.S. patent nos. 2,799,241;J. Am. Pharm. Assocvol.48, pp. 451-. Other standard preparation methods are described inModern Plastics EncyclopediaVol.46, pp. 62-70 (1969), and published by Mack Publishing Company, Easton, PaPharmaceutical Sciences, RemingtonFourtenanth Edition, pp. 1626-.

Reservoir polymer system

Reservoir systems are well known in the art. This technique is also commonly referred to as microencapsulation, bead technique or coated tablet. Small particles of the drug are encapsulated with a pharmaceutically acceptable polymer(s). The polymer and its relative amounts provide a predetermined resistance to diffusion of the drug from the reservoir to the gastrointestinal tract. Thus, the drug is gradually released from the bead into the gastrointestinal tract and provides the desired controlled release of (1) a xanthine oxidoreductase inhibitor, such as 2- [ 3-cyano-4-2 (2-methylpropoxy) phenyl ] -4-methylthiazole-5-carboxylic acid or (2) a xanthine oxidase inhibitor, such as allopurinol and oxypurinol.

Such dosage forms are well known in the art. U.S. patent nos. 5,286,497 and 5,737,320, both hereby incorporated by reference, describe such formulations and methods of making the same. One skilled in the art, given the teachings of this application and those of the '320 and' 497 patents, can produce bead or pellet based dosage forms that match the pharmacokinetic profiles described above.

However, as a general guideline, beads are formed from an inert core sphere and a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor (optionally in combination with conventional excipients). The core of the bead may optionally comprise any material commonly used for drugs and the material should be selected on the basis of compatibility with the active drug and physicochemical properties of the bead. Other components that may include, but are not limited to, binders, disintegrants, fillers, surfactants, solubilizers, stabilizers, and the like. In addition, the core is then coated with one or more pharmaceutically acceptable polymers capable of imparting different release profiles. Is located inThe core of the core may be prepared by a variety of techniques known in the art. Typically, a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor is bound to the inert core with a conventional binder. The inert core typically comprises starch, sugar or microcrystalline cellulose. One skilled in the art will recognize that a variety of sugars may be included in the bead core and compatibility issues should be considered when selecting the appropriate sugar. Prior to binding the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to the inert core, it is usually mixed with conventional excipients to facilitate its handling and to improve the properties of the final dosage form. These excipients are the same as those described above for the matrix system. The amounts of these excipients may vary widely, but are generally used in conventional amounts. The inert core is then prepared by binding the powdered xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor mixture to a solid support using a binder. This can be accomplished by means known in the art for the preparation of pharmaceutical beads. Suitable means include the use of conventional coating pans, fluid bed processors, extrusion-spheronization (extrusion-spheronization) or rotary granulators (rotogranulators). The preparation of these centrally located cores is described in more detail inPharmaceutical Pelletization TechnologyEd. I. Ghebre-selassie, MarcelDekker, Inc. New York, N.Y. (1989), which is hereby incorporated by reference.

The second major component of the beads is a polymeric coating. As mentioned above, the polymer coating is responsible for imparting a delayed release profile to the beads. The polymeric coating may be applied to the central core using methods and techniques known in the art. Examples of suitable coating equipment include, but are not limited to, fluid bed coaters, pan coaters, and the like. The application techniques are described in more detail in: 1)Aqueous polymeric coatings for pharmaceutical dosage formsed. J.W. McGinity, Marcel Dekker, Inc. New York, N.Y. (1997); and 2)Pharmaceutical Dosage Forms: Tablets Vol. 3Ed. H.A. Lieberman, L.Lachman and J.B.Schwartz, Marcel Dekker, Inc. New York, N.Y. pp. 77-287, (1990), the contents of which are hereby incorporated by reference.

The polymer may be included in the bead by a layer remote from the core which is attached to the pharmaceutically active substance, and may also be provided in a plurality of layers, each of which includes a different polymer, providing different release characteristics in each layer. One such polymer layer comprises a modified release polymer layer. The pharmaceutical active may be released from the modified release polymeric layer such that the active particles are released as the polymer becomes soluble in the surrounding environment. Suitable examples of immediate release polymers that can be used in the immediate release polymer layer include, but are not limited to, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), low density poly (ethylene), poly (propylene), poly (butylene terephthalate, poly (, High density poly (ethylene), poly (propylene), poly (ethylene oxide), poly (vinyl terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride), polyurethane, ethyl cellulose aqueous dispersions (AQUACOAT, SURELASE), poly (butyl methacrylate), poly (2-dimethylaminoethyl methacrylate), methyl methacrylate), poly (methacrylic acid, ethyl acrylate), poly (methyl acrylate, methyl methacrylate, methacrylic acid), poly (ethyl acrylate, methyl methacrylate), poly (ethyl methacrylate, methyl methacrylate), poly (trimethyo methacrylate chloride)), poly (ethyl acrylate, methyl methacrylate), poly (methacrylic acid, ethyl acrylate), type A methacrylic acid copolymer, Type B methacrylic acid copolymer, type C methacrylic acid copolymer, methacrylic acid copolymer dispersion, waterborne acrylic polymer dispersion, (EUDRAGIT compounds), OPADRY @ and the like, and mixtures thereof. In one aspect, the immediate release polymer comprises hydroxypropyl methylcellulose.

Immediately after ingestion by a patient, the polymer layer encapsulating the core becomes soluble and begins to release the active drug. In some cases, it may be beneficial to coat the core with a polymer (to seal the core material and provide a more facile coating of the core).

The beads of the present disclosure may also comprise an enteric coating layer applied over the core with or without a seal coating by conventional coating techniques such as pan coating or fluid bed coating using a solution of the polymer in water or a suitable organic solvent or by using an aqueous polymer dispersion. All commercially available pH-sensitive polymers are included within the scope of the present disclosure. By means of the enteric coating layer, the pharmaceutical active is not released in an acidic gastric environment around, but not limited to, a pH below 4.5. The pharmaceutical active is typically released when the pH-sensitive layer dissolves at a greater pH. Suitable examples of delayed release enteric polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate-1, 2, 4-trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid/methyl methacrylate, materials known for example under the tradenames EUDRAGIT L12.5, L100, EUDRAGIT S12.5, S100, or similar compounds used to obtain enteric coatings. Copolymerized methacrylic acid/methyl methacrylate generally includes three subclasses of compounds: methacrylic acid copolymer type a, methacrylic acid copolymer type B and methacrylic acid copolymer type C. Each type of copolymer represents a compound having a different ratio of methacrylic acid to methyl methacrylate. Thus, the methacrylic acid to methyl methacrylate ratio of the methacrylic acid copolymer of type a is about 1:1, the ratio of type B is about 1:2, and the ratio of type C is similar to type a, but additional components, such as surfactants, may be included. Aqueous colloidal polymer dispersions or redispersions (re-dispersions) may also be used, including polymers sold under the tradenames EUDRAGIT L30D-55, EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT prepatation 4110D (Rohm Pharma), EUDARIT FS 30D, AQUATERIC, AQUACOAT CPD 30(FMC), KOLLICOAT MAE 30D and 30DP (BASF), and EASTACRYL ℃ 30D (Eastman chemical). In one aspect, the delayed release enteric polymer comprises a type a methacrylic acid copolymer. In another aspect, the delayed release enteric polymer comprises a mixture of methacrylic acid copolymer type a and methacrylic acid copolymer type B.

One skilled in the art will recognize that additional components may be added to the delayed release polymer without departing from the scope of the present disclosure. For example, plasticizers may be added to the delayed release enteric polymer to improve the physical characteristics of the delayed release polymer layer. Non-limiting examples of plasticizers include triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, trihexyl citrate, acetyl trihexyl citrate, trioctyl citrate, acetyl trioctyl citrate, butyryl trihexyl citrate, acetyl butyryl trihexyl citrate, trimethyl citrate, acetylated monoglycerides, and phenyl alkyl sulfonates. In another aspect, the plasticizer comprises triethyl citrate.

In addition, the enteric polymers used in the present disclosure may be modified by blending with other known coating products that are not pH sensitive. Examples of such coated products include the natural methacrylates having a small proportion of methacryloyloxyethyl trimethyl ammonium chloride currently sold under the tradenames EUDRAGIT and EUDRAGIT RL; natural ester dispersions sold under the tradenames EUDRAGIT NE30D and EUDRAGIT NE30 which do not contain any functional groups; and other pH dependent coating products.

It is also within the scope of the present disclosure that an additional modifying layer (modifying layer) may be added over the enteric coating layer. The modification layer may comprise a water permeation barrier layer (semipermeable polymer) which may be subsequently enteric coated followed by a coating to reduce the rate of water permeation through the enteric coating layer and thereby increase the time lag for drug release. Controlled release coatings generally known to those skilled in the art can be used for this purpose by conventional coating techniques such as pan coating or fluid bed coating using solutions of the polymers in water or suitable organic solvents or by using aqueous polymer dispersions. For example, the following non-limiting list of controlled release polymers may be used in the present disclosure: cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), low density poly (ethylene), high density poly (ethylene), poly (propylene), poly (ethylene), poly (propylene), poly (butylene), poly (butylene) acrylate), poly (butylene (methacrylate), poly (butylene) acrylate), poly, Poly (ethylene oxide), poly (vinyl terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride), polyurethane, aqueous dispersions of ethylcellulose such as AQUACOAT and SURELEASE, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate), poly (methacrylic acid, ethyl acrylate), poly (methyl acrylate, methyl methacrylate, methacrylic acid), poly (ethyl acrylate, methyl methacrylate, methacryloyl oxyethyltrimethyl ammonium chloride), poly (ethyl acrylate, methyl methacrylate), poly (methacrylic acid, ethyl acrylate), methacrylic acid copolymer type A, methacrylic acid copolymer type B, methacrylic acid copolymer type C, poly (methacrylic acid, co-acrylic acid copolymer type A), poly (vinyl acetate), poly (vinyl chloride), poly (urethane), poly (ethyl cellulose), poly (2-dimethylaminoethyl methacrylate), poly (methacrylic acid, ethyl acrylate), poly (methacrylic acid copolymer type B), poly, Methacrylic acid copolymer dispersion, aqueous acrylic acid polymer dispersion, (EUDRAGIT compounds), OPADRY ®, fatty acids and esters, waxes, corn protein and aqueous polymer dispersion thereof, for example, EUDRAGIT ® RS and RL 30D, EUDRAGIT NE30D, cellulose acetate latex. Also included are combinations of the above polymers and hydrophilic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose (KLUCEL, Hercules Corp.), hydroxypropyl methylcellulose (METHOCEL, Dow chemical Corp.) and polyvinylpyrrolidone. In one aspect, the controlled release polymer comprises ethyl cellulose, hydroxypropyl methylcellulose, and combinations thereof. In another aspect, the controlled release polymer comprises a combination of ethylcellulose and hydroxypropyl methylcellulose, wherein the ratio of ethylcellulose to hydroxypropyl methylcellulose is from about 0.1 to about 10, from about 0.2 to about 5, from about 0.5 to about 3, and from about 1 to about 2. In another aspect, the controlled release polymer comprises a combination of an aqueous dispersion of ethylcellulose and hydroxypropyl methylcellulose, wherein the ratio of the aqueous dispersion of ethylcellulose to hydroxypropyl methylcellulose is from about 0.1 to about 10, from about 0.1 to about 5, from about 0.5 to about 4, and from about 1.5 to about 3.

In one aspect, the pharmaceutical compositions of the present disclosure comprise one or more types of beads, which can be included in a variety of dosage forms, such as capsules, pills, and tablets. Capsules, including hard gelatin capsules, may be prepared according to methods known in the art. In general, a capsule can include the beads discussed herein, and can optionally include the aforementioned additional excipients. The pharmaceutical composition may also be incorporated into tablets. Typically, the method involves including the beads in the aforementioned tablet matrix. Those skilled in the art will recognize that additional components may be added to the formulation to impart desired physical characteristics without departing from the scope of the present disclosure.

Bead type

There are many types of bead formulations included within the scope of the present disclosure, including a variety of polymers according to the foregoing polymers. One skilled in the art can vary the bead formulation to impart specific chemical characteristics. In one aspect, the present disclosure describes four main types of beads. That is, four types of beads can be described as immediate release beads, delayed release beads, controlled release beads, and delayed-controlled release beads. The immediate release beads comprise a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor layered on an inert core, such as sugar spheres or microcrystalline cellulose spheres, by means of a suitable polymeric binder. The polymeric binder functions to create a sealed coating around the inert core material, improving the friability of the inert core. The polymeric binder may comprise any of the immediate release polymers previously described. In one aspect, the polymeric binder comprises hydroxypropyl methylcellulose. For purposes of the various bead compositions described herein, the polymeric binder component will comprise the same material as the immediate release polymer, and the compositional percentage of the immediate release polymer will include the immediate release polymer for the immediate release layer surrounding the inert core and the polymeric binder that provides the inert core with a sealing coating.

The immediate release beads typically comprise from about 5% to about 55% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 20% to about 80% (w/w) inert core, and from about 1% to about 40% (w/w) immediate release polymer. In one aspect, the immediate release bead typically comprises about 25% to about 35% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, about 40% to about 60% (w/w) inert core, and about 10% to about 20% (w/w) immediate release polymer. In another aspect, the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor comprises from about 29% to about 34% (w/w) of the total composition, the inert core comprises from about 50% to about 55% (w/w) of the total composition, and the immediate release polymer comprises from about 14% to about 18% (w/w) of the total composition.

Other types of beads contemplated by the present disclosure are delayed release beads. Delayed release beads are coated beads obtained by coating immediate release beads with a delayed release enteric polymer in an aqueous dispersion or organic solvent. These polymers have a pH dependent solubility that depends on the functional groups on the polymer. For delayed release beads coated with an appropriate amount of delayed release enteric polymer, drug release will not occur in the medium unless the pH of the medium is above the pH at which the polymer dissolves. The delayed release enteric polymers of the present disclosure typically become soluble when the beads are exposed to a pH level that is generally less acidic than the gastric environment. Specifically, the release may be at a pH of greater than or equal to 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.9.6, 9.9.3, 9.9.9.9.9, 9.9.3, 9.4, 9.5, 9.6, 9.9.9.9.9.9.9, 9.9.9.9.9.. In one aspect, the delayed release polymer becomes soluble at pH levels greater than or equal to 5.5, 6.0, and 6.8.

The composition of the immediate release component of the delayed release beads is the same as described above and typically comprises a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor as described above, an inert core and an immediate release polymer. The delayed release beads additionally comprise a pH-sensitive enteric polymer as described above. A non-limiting example of a delayed release bead is one in which the bead has a solubility at a pH level greater than or equal to 6.0. The delayed release pH6.0 beads typically comprise a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor which is about 5% to about 50% (w/w) of the total delayed release beads; an inert core that is about 20% to about 70% (w/w) of the total delayed-release bead, an immediate-release polymer that is about 1% to about 35% (w/w) of the total delayed-release bead, and a delayed-release enteric polymer in an amount that is about 1% to about 35% (w/w) of the total delayed-release bead. In one aspect, the delayed release bead comprises from about 20% to about 30% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 40% to about 50% (w/w) inert core, from about 10% to about 16% (w/w) immediate release polymer, and from about 13% to about 20% (w/w) delayed release polymer. In a further reiteration of this example, the delayed release pH6.0 bead further comprises from about 1% to about 3% (w/w) plasticizer.

Another non-limiting example of a delayed release bead is one in which the bead has a solubility at a pH level greater than or equal to 6.8. The delayed release pH6.8 beads typically comprise a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor which is about 5% to about 50% (w/w) of the total delayed release beads; an inert core that is about 20% to about 70% (w/w) of the total delayed release bead; an immediate release polymer that is about 1% to about 35% (w/w) of the total delayed release bead; and a delayed release enteric polymer in an amount of about 1% to about 35% (w/w) of the total delayed release beads. In one aspect, the delayed release pH6.8 bead comprises about 20% to about 30% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, about 40% to about 50% (w/w) inert core, about 10% to about 16% (w/w) immediate release polymer, and about 13% to about 20% (w/w) delayed release polymer. In one aspect, the delayed release pH6.8 beads comprise about 23% to about 27% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, about 40.5% to about 43% (w/w) inert core, about 12% to about 14% (w/w) immediate release polymer, and about 17% to about 19% (w/w) of one or more delayed release enteric polymers. In a further reiteration of this example, the delayed release pH6.8 bead further comprises from about 1% to about 3% (w/w) plasticizer.

Other types of beads contemplated by the present disclosure are controlled release beads. Controlled release beads are coated beads obtained by coating immediate release beads with a controlled release polymer according to methods currently known in the art. Typically, the controlled release beads include one or more polymers that reduce the release rate of the drug from the bead, such that the drug is released over an extended period of time. Controlled release beads differ from delayed release beads in that release from the controlled release beads is continuous over an extended period of time after exposure to the dissolution medium, whereas release from the delayed release beads is extremely rapid once the beads are exposed to a pH greater than that at which the delayed release enteric polymer is soluble. In general, the composition of the controlled release polymeric layer can be varied such that release is possible over a period of about 1 hour to about 24 hours. In particular, controlled release formulations can release the active drug over a period of 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours.

In one embodiment of the present disclosure, the controlled release beads comprise a composition capable of releasing the active compound over a period of about 4 hours to about 6 hours. The controlled release beads of this embodiment typically comprise from about 5% to about 40% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 20% to about 50% (w/w) inert core, from about 5% to about 25% (w/w) immediate release polymer, and from about 10% to about 50% (w/w) controlled release polymer. In one aspect, the controlled release bead comprises from about 20% to about 24% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 30% to about 40% (w/w) inert core, from about 9% to about 13% (w/w) immediate release polymer, from about 25% to about 35% (w/w) controlled release polymer. In one aspect, the controlled release bead comprises from about 25% to about 35% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 40% to about 60% (w/w) inert core, from about 12% to about 18% (w/w) immediate release polymer, from about 3% to about 9% (w/w) controlled release polymer.

In another embodiment, the controlled release beads comprise a composition capable of releasing the active compound over a period of about 10 hours to about 12 hours. The controlled release beads of this embodiment typically comprise from about 10% to about 50% (w/w) of a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 30% to about 70% (w/w) of an inert core, from about 5% to about 25% (w/w) of an immediate release polymer, and from about 1% to about 15% (w/w) of a controlled release polymer. In one aspect, the controlled release bead comprises from about 25% to about 35% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 40% to about 60% (w/w) inert core, from about 12% to about 18% (w/w) immediate release polymer, and from about 3% to about 9% (w/w) controlled release polymer. In one aspect, the controlled release bead comprises from about 28% to about 31% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 47% to about 51% (w/w) inert core, from about 14% to about 16% (w/w) immediate release polymer, and from about 5% to about 7% (w/w) controlled release polymer.

Other types of beads contemplated by the present disclosure are delayed-controlled release beads. Delayed-controlled release beads the delayed release beads described above and the controlled release beads described above are mixed in features intended to delay drug release until the beads are exposed to a pH greater than the pH at which the polymer dissolves, and then to extend drug release over an extended period of time. To illustrate, a single administration of controlled release beads will generally release the active ingredient over an extended period of time, which begins to release immediately after ingestion. Delayed release beads administered alone will not begin to release the active until the environment meets the minimum pH level. For example, the pH level in the intestine is higher than the pH level in the stomach, and thus the delayed release bead may be designed to release the active ingredient once it reaches the pH level found in the intestine, without releasing any active ingredient in the region where the pH level is lower, e.g. the stomach. However, once the pH level is initiated, drug release is usually rapid.

In this embodiment, the delayed-release polymer layer encapsulates the controlled-release polymer layer such that the extended release of the active ingredient by the controlled-release polymer will not begin until the delayed-controlled-release bead is exposed to the minimum pH level. Thus, one skilled in the art will recognize that the characteristics of the delayed-controlled release beads may be varied such that the delayed release polymer does not become soluble until the beads are exposed to the aforementioned pH levels, which are typically from about 5 to about 10. In addition, the delayed-controlled release beads can be designed to release the active ingredient over a period of about 1 hour to about 24 hours as previously described.

In one embodiment of the present disclosure, the delayed-controlled release beads comprise a delayed release enteric polymer having a solubility of pH level greater than or equal to 6.8 and a controlled release polymer that allows for extended delivery of the active compound within 4-6 hours. The delayed-controlled release beads of this embodiment typically comprise from about 5% to about 35% (w/w) of a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 20% to about 50% (w/w) of an inert core, from about 5% to about 20% (w/w) of an immediate release polymer, from about 5% to about 20% (w/w) of a controlled release polymer, and from about 5% to about 35% (w/w) of a delayed release enteric polymer. In one aspect, the delayed-controlled release bead comprises from about 15% to about 25% (w/w) xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 30% to about 40% (w/w) inert core, from about 8% to about 14% (w/w) immediate release polymer, from about 8% to about 15% (w/w) controlled release polymer, and from about 13% to about 22% (w/w) delayed release enteric polymer. In another aspect, the delayed-controlled release bead comprises from about 20% to about 23% (w/w) of a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor, from about 34% to about 37% (w/w) of an inert core, from about 10% to about 12% (w/w) of an immediate release polymer, from about 11% to about 13% (w/w) of a controlled release polymer, and from about 17% to about 20% (w/w) of a delayed release enteric polymer.

One skilled in the art will recognize that the various improved release beads of the present disclosure may be prepared by any means known in the art. Examples of non-limiting methods of preparing beads include fluid bed processing, centrifugal granulation, extrusion-spheronization, high shear granulation, melt extrusion, and solution or suspension layering. In fluid bed processing, the immediate release polymer is dissolved in water and the micronized drug is suspended in the immediate release polymer solution. The suspension is then sprayed onto inert spherical carrier beads (e.g., sugar spheres or microcrystalline cellulose spheres). Alternatively, the non-micronized drug may be suspended in an immediate release polymer solution, and the suspension may be passed through a mill. In the centrifugal granulation process, inert beads are placed on a turntable at the bottom of the granulator in the granulator. The micronized drug was introduced into the granulator and simultaneously sprayed with an immediate release polymer solution. Extrusion and spheronization are another method of preparation of immediate release beads, in which the drug is mixed with dry excipients and subjected to wet aggregation (wet-mass) by the addition of a binder solution and extruded to form pasta-like strands. The extrudate was then chopped and converted to dense spherical beads using a spheronizer. Another method of preparing beads includes high shear granulation. High shear granulation involves dry blending the active and other ingredients. The mixture is then wetted in a high shear granulator/mixer by adding a binder solution. After wetting by the combined action of mixing and milling, the granules are kneaded. The resulting granules or pellets are then dried and sieved. Another method includes melt extrusion or melt granulation. The process generally involves melting a generally solid hydrophobic binder material, such as a wax or the like, and adding a powdered drug thereto. To achieve a controlled or extended release dosage form, additional hydrophobic release materials, such as ethylcellulose or water-insoluble acrylic polymers, may be included in the molten waxy hydrophobic binder material. Furthermore, solution or suspension layering involves the following process: whereby the active ingredient solution or suspension, with or without binder, is sprayed onto starting seeds (startingseeds) of a certain particle size in a fluid bed processor or other suitable equipment. The drug is thus coated on the surface of the starting seed. Drug loaded pellets were dried for other applications.

Pharmaceutical dosage form

One skilled in the art will appreciate that the various types of beads described herein having different active release characteristics may be mixed in a single or multiple pharmaceutical dosage forms to provide pulsatile drug delivery of the xanthine oxidoreductase inhibitors or xanthine oxidase inhibitors described herein. Various combinations of immediate release beads, delayed release beads, controlled release beads, and delayed-controlled release beads can be used to impart different release characteristics. It is to be understood that any potential combination of immediate release, delayed release, controlled release, and delayed-controlled release beads for dispensing the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor described herein are within the scope of the present disclosure.

In one embodiment, the present disclosure includes a single pharmaceutical composition comprising both immediate release beads and delayed release beads having solubility at a pH level greater than or equal to 6.8. The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 20% to about 40% (w/w) by weight of the total composition, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead at pH6.8 in an amount from about 60% to about 80% (w/w) by weight of the total composition.

The immediate release beads comprise: a.) an inert core in an amount of about 50% to about 55% (w/w) of the weight of the immediate release bead; and b.) an immediate release layer encapsulating the inert core, comprising a mixture of a xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor and a binder (e.g., hydroxypropyl methylcellulose or hydroxypropyl cellulose) in an amount of from about 45% to about 50% (w/w) by weight of the immediate release bead, the ratio of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to hydroxypropyl methylcellulose being from about 1.5 to about 3. Insoluble disintegrants such as low substituted hydroxypropyl cellulose (L-HPC) may be added to the rate release of the active.

ph6.8 delayed release beads comprise a.) an inert core in an amount of about 40.5% to about 43% (w/w) of the weight of the delayed release beads; b.) an immediate release layer encapsulating the inert core (as described above) in an amount of about 35% to about 40% (w/w) by weight of the delayed release bead, the ratio of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to hydroxypropyl methylcellulose being about 1.5 to about 3; c.) a delayed release enteric polymer layer encapsulating the immediate release layer, comprising a delayed release enteric polymer in an amount of about 17% to about 20% (w/w) of the delayed release bead, the delayed release enteric polymer comprising a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B in a ratio of about 0.1 to about 0.5; and d.) a plasticizer in an amount of about 1% to about 3% (w/w) of the weight of the delayed-controlled release bead. In one aspect of the pharmaceutical composition, the xanthine oxidoreductase inhibitor comprises febuxostat and the plasticizer comprises triethyl citrate. In another aspect, the xanthine oxidase inhibitor in the pharmaceutical composition comprises allopurinol and the plasticizer comprises triethyl citrate.

In another embodiment of the present disclosure, a pharmaceutical dosage form comprises a single pharmaceutical composition comprising immediate release beads, delayed release beads having a solubility at a pH level of greater than or equal to 6.0, and delayed release beads having a solubility at a pH level of greater than or equal to 6.8. The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 25% to about 35% (w/w) by weight of the total composition, a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead at pH6.0 in an amount from about 25% to about 35% (w/w) by weight of the total composition, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead at pH6.8 in an amount from about 35% to about 45% (w/w) by weight of the total composition.

The immediate release bead comprises a.) an inert core in an amount of about 50% to about 55% (w/w) of the weight of the immediate release bead; and b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 45% to about 50% (w/w) by weight of the immediate release bead, the ratio of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to the hydroxypropylmethylcellulose ranging from about 1.5 to about 3.

The delayed release pH6.0 beads comprise a.) an inert core in an amount of about 40.5% to about 43% (w/w) of the weight of the delayed release pH6.0 beads; b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount of from about 35% to about 40% (w/w) by weight of the delayed release ph6.0 bead, the ratio of the xanthine oxidoreductase inhibitor or the xanthine oxidase inhibitor to the hydroxypropylmethylcellulose being from about 1.5 to about 3; c.) a delayed release pH6.0 enteric polymer layer encapsulating the immediate release layer, comprising a delayed release enteric polymer in an amount of about 17% to about 19% (w/w) of the delayed release bead, the delayed release pH6.0 enteric polymer comprising methacrylic acid copolymer type a; and d.) a plasticizer in an amount of about 1% to about 3% (w/w) of the weight of the delayed-controlled release bead.

For convenience, the two types of beads, i.e., immediate release and pH6.0 delayed release beads, can be mixed together into a single bead by applying an immediate release coating over the pH6.0 delayed release coating. The resulting composition comprises a.) an inert core in an amount of about 25% to about 35% (w/w) of the weight of the mixed immediate release-delayed release pH6.0 beads; b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount of about 25% to about 31% (w/w) of the weight of the mixed beads; c.) a delayed release pH6.0 enteric polymer layer encapsulating the immediate release layer, comprising a delayed release enteric polymer in an amount of about 11% to about 15% (w/w) of the delayed release bead, the delayed release pH6.0 enteric polymer comprising methacrylic acid copolymer type a; d.) a plasticizer in an amount of about 1% to about 3% (w/w) of the weight of the delayed-controlled release bead; and e.) an immediate release outer coating layer comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropyl methylcellulose in an amount of about 23% to about 29% (w/w) of the weight of the mixed beads.

Delayed release pH6.8 beads comprise a.) an inert core in an amount of about 40.5% to about 43% (w/w) of the weight of the delayed release beads; b.) an immediate release layer encapsulating an inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 35% to about 40% (w/w) by weight of the delayed release bead, the ratio of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to hydroxypropylmethylcellulose ranging from about 1.5 to about 3; c.) a delayed release pH6.8 enteric polymer layer encapsulating the immediate release layer, comprising a delayed release enteric polymer in an amount of about 17% to about 20% (w/w) of the delayed release pH6.8 beads, the delayed release enteric polymer comprising a mixture of methacrylic acid copolymer type a and methacrylic acid copolymer type B in a ratio of about 0.1 to about 0.5; and d.) a plasticizer in an amount of about 1% to about 3% (w/w) by weight of the delayed-controlled release bead, said plasticizer comprising triethyl citrate. In another aspect of the pharmaceutical composition, the xanthine oxidoreductase inhibitor comprises febuxostat and the plasticizer comprises triethyl citrate. In yet another aspect of the pharmaceutical composition, the xanthine oxidase inhibitor comprises allopurinol and the plasticizer comprises triethyl citrate.

In other embodiments of the present disclosure, the pharmaceutical composition comprises a single pharmaceutical composition comprising immediate release beads and delayed-controlled release beads (which have a delayed release polymer with solubility at a pH level of at least 6.8 and a controlled release rate of about 4-6 hours). The pharmaceutical composition of this embodiment comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 20% to about 40% (w/w) by weight of the total composition, and a delayed-controlled release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead having a solubility at a pH level greater than or equal to 6.8 and providing an extended release of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor over a period of from about 4 hours to about 6 hours in an amount from about 60% to about 80% (w/w) by weight of the total composition. For example, in one aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 20% (w/w) of the total composition weight, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 80% (w/w) of the total composition weight. In another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 25% (w/w) by weight of the total composition, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 75% (w/w) by weight of the total composition. In another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 30% (w/w) by weight of the total composition, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 70% (w/w) by weight of the total composition. In another aspect, the pharmaceutical composition comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount of about 40% (w/w) by weight of the total composition, and a delayed release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead released at a pH of 6.8 in an amount of about 60% (w/w) by weight of the total composition.

The immediate release bead comprises a.) an inert core in an amount of about 50% to about 55% (w/w) of the weight of the immediate release bead; and b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 45% to about 50% (w/w) by weight of the immediate release bead, the ratio of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to the hydroxypropylmethylcellulose ranging from about 1.5 to about 3.

The delayed-controlled release beads comprise a.) an inert core in an amount of about 34% to about 37% (w/w) of the weight of the delayed-controlled release beads; b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 31% to about 34% (w/w) by weight of the delayed-controlled release bead, the ratio of the xanthine oxidoreductase inhibitor or the xanthine oxidase inhibitor to the hydroxypropylmethylcellulose ranging from about 1.5 to about 2.5; c.) a controlled release layer encapsulating the immediate release layer, comprising a controlled release polymer in an amount of about 10% to about 14% (w/w) by weight of the delayed-controlled release beads, the controlled release polymer comprising a mixture of an aqueous ethylcellulose dispersion and hydroxypropyl methylcellulose in a ratio of ethylcellulose dispersion to hydroxypropyl methylcellulose of about 1.5 to about 3; d.) a delayed release pH6.8 layer encapsulating the controlled release layer, comprising a delayed release pH6.8 polymer in an amount of about 17.5% to about 20% (w/w) of the weight of the delayed-controlled release bead, the delayed release pH6.8 polymer comprising a mixture of methacrylic copolymer type a and methacrylic copolymer type B, the ratio of copolymer type a to copolymer type B being about 0.1 to about 0.5; and e.) a plasticizer in an amount of about 1% to about 3% (w/w) by weight of the delayed-controlled release bead, said plasticizer comprising triethyl citrate. In one aspect of the pharmaceutical composition, the xanthine oxidoreductase inhibitor comprises febuxostat and the plasticizer comprises triethyl citrate. In yet another aspect of the pharmaceutical composition, the xanthine oxidase inhibitor comprises allopurinol and the plasticizer comprises triethyl citrate.

In yet another embodiment of the present disclosure, the pharmaceutical composition comprises a single pharmaceutical composition comprising immediate release beads and controlled release beads capable of active release over about 10 hours to about 12 hours. The pharmaceutical composition of this embodiment generally comprises an immediate release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead in an amount from about 10% to about 30% (w/w) by weight of the total composition, and a controlled release xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor bead which provides for extended release of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor over a period of from about 10 hours to about 12 hours in an amount from about 70% to about 90% (w/w) by weight of the total composition.

The immediate release bead comprises a.) an inert core in an amount of about 50% to about 55% (w/w) of the weight of the immediate release bead; and b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 45% to about 50% (w/w) by weight of the immediate release bead, the ratio of the xanthine oxidoreductase inhibitor or xanthine oxidase inhibitor to the hydroxypropylmethylcellulose ranging from about 1.5 to about 3.

10-12 hour controlled release beads comprising: a.) an inert core in an amount of about 47% to about 51% (w/w) of the weight of the controlled release bead; b.) an immediate release layer encapsulating the inert core, comprising a xanthine oxidoreductase inhibitor or a mixture of a xanthine oxidase inhibitor and hydroxypropylmethylcellulose in an amount ranging from about 42% to about 48% (w/w) by weight of the controlled release bead, the ratio of the xanthine oxidoreductase inhibitor or the xanthine oxidase inhibitor to the hydroxypropylmethylcellulose ranging from about 1.5 to about 2.5; and c.) a controlled release layer encapsulating the immediate release layer, comprising a controlled release polymer comprising a mixture of ethylcellulose and hydroxypropyl methylcellulose in an amount of about 4% to about 8% (w/w) by weight of the controlled release bead, the ratio of ethylcellulose to hydroxypropyl methylcellulose being about 1 to about 2. In one aspect of the pharmaceutical composition, the xanthine oxidoreductase inhibitor comprises febuxostat. In yet another aspect of the pharmaceutical composition, the xanthine oxidase inhibitor comprises allopurinol.

One skilled in the art will recognize that the various embodiments and dosage forms described herein may include any dosage form known in the art. In one aspect, the dosage forms include pills, tablets, and capsules. In addition, the pharmaceutical composition may have a total composition weight of about 5 mg to about 240 mg. In one aspect, the total pharmaceutical composition weight (total weight) comprises about 60 mg to about 100 mg. In another aspect, the total pharmaceutical composition weight is about 80 mg.

Method of treatment

The dosage forms of the present disclosure are useful for treating a number of disease states. When the dosage form of the present disclosure comprises febuxostat, such dosage forms may be used to treat a disease state such as, but not limited to, gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, renal injury, chronic kidney disease, metabolic syndrome (also referred to as "syndrome X" and including at least one of abdominal obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance, prothrombotic state, or proinflammatory state (propflumimatic state)), diabetes, diabetic nephropathy, congestive heart failure, and the like. A subject suffering from one of the above-described disease states and in need of treatment thereof can be administered an effective amount (or therapeutically effective amount) of a dosage form of the present disclosure to treat the disease state.

When the dosage forms of the present disclosure contain allopurinol or oxypurinol, such dosage forms may be used to treat disease states such as, but not limited to, gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, renal injury, chronic kidney disease, metabolic syndrome (also referred to as "syndrome X" and including at least one of abdominal obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance, prothrombotic state or proinflammatory state), diabetes, diabetic nephropathy, congestive heart failure, and the like. A subject suffering from one of the above-described disease states and in need of treatment thereof can be administered an effective amount (or therapeutically effective amount) of a dosage form of the present disclosure to treat the disease state.

Embodiments of the present disclosure will now be presented by way of illustration, not limitation.

Example 1: method for obtaining high level of xanthine oxidase inhibition-comparative example

In healthy human subjectsMost orally administered febuxostat absorbs within about 1 hour (i.e., T;)_maxAbout 1 hour). In addition, the oral clearance of febuxostat from plasma is about 7.3-15.1L/hr with an effective half-life of about six (6) hours. In fact, the drug is highly bound to albumin in the blood (-99.3%) and appears to have a low to moderate apparent volume of distribution of about 0.7L/kg.

Despite the short effective half-life of febuxostat, clinical studies have shown that once daily administration with an immediate release formulation containing as little as 10 mg of febuxostat reduced uric acid concentrations with minimal fluctuations in serum uric acid concentrations in healthy subjects. This is due to the nature of the Pharmacokinetic (PK) -Pharmacodynamic (PD) relationship between plasma (PK markers) and serum uric acid concentrations (PD markers) of febuxostat. For gout patients with low serum uric acid concentrations (i.e., 7 mg/dL), once-daily administration of an immediate release dosage form containing as little as 10 mg of febuxostat is expected to effectively reduce and maintain serum uric acid concentrations at therapeutic targets (i.e., <6 mg/dL); however, these dosage forms do not maintain high inhibition, i.e., at least 80% inhibition of xanthine oxidase during the dosing interval (i.e., 24 hours), even after multiple dosing.

Table 1 below shows the results from a multiple-dose, randomized, placebo-controlled, double-blind, single-center, multi-site dose escalation study involving phase 1 of febuxostat. This study evaluated the pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. In this study, the oral dose of the febuxostat immediate release dosage form ranged from 10 mg once daily (hereinafter "QD") to 240mg once daily and 30 mg twice daily (hereinafter "BID"). Plasma, serum and urine samples were collected for determination of febuxostat and metabolite, uric acid, xanthine and hypoxanthine concentrations. Samples were analyzed by high performance liquid chromatography.

Watch (A) 1: Pharmacokinetics and pharmacodynamics of multiple dose febuxostat administration with multiple release profiles

a AUC means day 1 (QD) respectively&BID), day 14 (QD) and day 14 (BID) AUC_∞、AUC₂₄And AUC₁₂；

b arithmetic mean (harmonic mean).

In addition, the percentage inhibition of xanthine oxidase at 12, 16 and 24 hours (after administration) after multiple administrations in healthy subjects using an immediate release dosage form containing 70 mg and 120mg of febuxostat was calculated using equation 1 below. The results of this calculation are incorporated into equation 2, discussed below, and the results of equation 2 are listed in table 2 below.

Equation 1-percent inhibition of xanthine oxidase ("XOD") (% inhibition ")

Wherein C = plasma concentration of febuxostat in plasma, f_u= free fraction of febuxostat in plasma, and K_i= xanthine oxidase inhibition constant of febuxostat.

Plasma concentrations of febuxostat can be determined using validated high performance liquid chromatography with fluorescence detection (see figureBiopharmaceutics Coordinating Committee in the Center for Drug Evaluation and Research (CDER) 。 Guidance for industry: bioanalytical method validation.May2001 and Mayer, M. et al.,American Journal of Therapeutics12:22-34(2005), each incorporated herein by reference). For febuxostat, the lower limit of quantitation for 0.5mL plasma samples was 0.01 μ g/mL.

At a nominal concentration of 1 mug/mL may be used¹⁴In vitro binding of C febuxostat, f was determined using equilibrium dialysis techniques well known in the art_u. For example, f of febuxostat_uThe percentage has been calculated to be 0.9 ± 0.2 in normal patients and 1.2 ± 0.2 in patients with severe renal impairment (see Mayer, m. etal,American Journal of Therapeutics12:22-34(2005), incorporated herein by reference). In another study with a larger number of subjects, the percentage of the free fraction of febuxostat in plasma in the male, female, young and elderly groups of subjects was calculated to be 0.7 ± 0.1 (see Khosravan r., oral,Clinic. Pharmacology & Therapeutics,p50 (2005), incorporated herein by reference).

Osada y, et al, has been used, for example, as described in incorporated herein by reference,European J. Pharmacologydetermination of K of febuxostat by xanthine oxidase assay in 241:183-188 (1993)_i. More specifically, K of febuxostat_iHave been determined to be 0.7nM and 0.6 nM, respectively (see Osada y., et al,European J. Pharmacology241:183-188 (1993) and Takano, Y., et al,Life Sciences, 76:1835-1847(2005)). K of febuxostat is known in the art_iAt 0.6 nM (see Takano, y., et.,Life Sciences76: 1835-.

In addition, the concentrations of febuxostat exhibiting 50%, 60%, 70%, 80%, 90%, 95%, and 99% inhibition of xanthine oxidase activity were calculated using equation 2 below (based on the calculation performed above using equation 1). The results of this calculation for all dosage regimens are listed below in table 2.

Equation 2-

Wherein C = plasma concentration of febuxostat in plasma, f_u= free fraction of febuxostat in plasma, and K_i= xanthine oxidase inhibition constant of febuxostat.

Watch (A) 2 : administration of drugs IR After preparationPercent inhibition

80mg data are the result of the simulated data used to calculate the percent simulated inhibition.

As shown in table 2, the subject failed to provide at least 80% xanthine oxidase inhibition for greater than sixteen (16) hours, even when receiving a high dose of febuxostat (120 mg). In addition, other studies involving 120mg immediate release dosage forms of febuxostat demonstrated that such dosage forms provided about 3.9 and about 4.2 μ g/mL of C_maxAnd exhibits at least 80% xanthine oxidase inhibition for about fourteen (14) hours. Further studies involving 240mg immediate release dosage forms of febuxostat demonstrated that such dosage forms provide 10.2 μ g/mL of C_maxAnd exhibits at least 80% xanthine oxidase inhibition for about 22 hours. Thus, in view of these results, the inventors contemplate the improved release dosage forms of the present disclosure. These dosage forms exhibit high levels (at least 80%) of xanthine oxidase inhibition for periods greater than sixteen (16) hours without compromising patient compliance. The dosage forms of the present disclosure maintain high levels of xanthine oxidase inhibition at similar or lower total plasma exposure levels compared to high doses of febuxostat (i.e., 120mg and 240mg QD).

Example 2: estimated plasma properties of extended release febuxostat formulations

In view of the pharmacokinetic data on the immediate release febuxostat formulation included in example 1, the inventors developed estimated plasma profiles for various extended release formulations. Specifically, the inventors developed estimated plasma properties for three types of formulations: delayed release formulations, double pulse formulations and triple pulse formulations. The plasma profile information for extended release formulations is based on formulations with a polymeric component that provides febuxostat release at a constant rate over time and may incorporate techniques such as matrix formulations. The estimated double-pulse formulation data is based on a febuxostat formulation with beads that released febuxostat immediately and after about 5 hours. The estimated tripulsatile formulation data is based on febuxostat formulations with immediate release beads, beads that release febuxostat after about 5 hours, and beads that release febuxostat after about 10 hours. The estimated plasma properties of the various formulations are listed in table 3. It should be noted that the plasma profile information for the immediate release formulation listed in table 3 represents actual data obtained in clinical trials.

Watch (A) 3 : estimated plasma properties of extended release febuxostat formulations

Preparation	Dosing regimens	Tmax (h)	Cmax (μg/mL	Cmin (μg/mL)	AUC∞ (μg.h/mL)	Duration concentration > 0.1 μg/mL ( Hour(s) )
IR*	80 QD	0.5	3.06	0.0159	7.99	8
							SR	80 QD	2.5	0.99	0.020	7.32	13.75
2PS-5 h	80 QD	5.75	1.69	0.025	7.46	15
3PS-5 h	80 QD	5.5	0.77	0.028	5.95	17.25

Plasma properties of the immediate release formulations represent actual data and are not estimates.

Example 3: bioavailability of febuxostat released in various locations of gastrointestinal tract

The inventors tested the relative bioavailability of 80mg of febuxostat released in the proximal small intestine, distal small intestine and colon of 12 healthy male subjects compared to the bioavailability of an immediate release dosage form.

Subjects were randomly assigned in equal numbers into one of four protocol orders as shown in table 4. According to a random schedule, subjects received the regimen in a crossover manner. Additional cycles (up to 2/subject) were added when subject dose release issues required a repeat regimen. There is a wash-out period of at least 7 days between administration in one cycle and a second administration in the next cycle.

Watch (A) 4 : subjects and schedule for febuxostat administration

Sequence of	# subject	Period 1	Period 2	Period 3	Period 4
						1	3	Scheme A	Scheme B	Scheme C	Scheme D
2	3	Scheme B	Scheme A	Scheme D	Scheme C
						3	3	Scheme C	Scheme D	Scheme A	Scheme B
4	3	Scheme D	Scheme C	Scheme B	Scheme A

Scheme A febuxostat 80mg immediate release tablet (reference)

InteliSite capsules containing 80mg febuxostat drug released in the proximal small intestine

InteliSite capsules containing 80mg febuxostat drug released in the distal small intestine

InteliSite capsules containing 80mg of febuxostat drug for release in the colon.

Blood samples were obtained prior to dosing on day 1 of each cycle (0 hours) (for regimens B, C and D, prior to release of the study product from intelsisite capsules (0 hour pre-adaptation)) and 0.25, 0.5, 1, 1.5, 2, 3,4, 6,8, 10, 12, 16, 24, 30 and 36 hours after tablet dosing or febuxostat release in selected segments of the gastrointestinal tract. Plasma concentrations of febuxostat were determined from EDTA-treated samples using a validated liquid chromatography assay (Richmond, VA) with mass spectrometry detection (using cationic electrospray ionization at PPD). The method uses protein precipitation (with 100- µ L aliquots of acetonitrile in plasma) with a lower detection limit of 10.0 ng/mL.

Pharmacokinetic parameters of febuxostat were estimated using standard non-compartmental methods. Calculations were performed using WinNonlin Pro version 5.2 (Mountain View, CA, USA). Descriptive statistics of estimates of pharmacokinetic parameters were calculated. In febuxostat T_maxAnd C_maxAnalysis of variance (ANOVA) (factors of order, in order of groups (nested) subjects, cycles, and protocol) were performed on the natural logarithms of AUC (0-tlqc) and AUC (0-inf). Febuxostat C through scheme B and scheme A, scheme C and scheme A, and scheme D and scheme A respectively_maxAnd the ratio of the central value of AUC and the 90% confidence interval evaluate the effect of release in the proximal small intestine, distal small intestine and colon on the bioavailability of febuxostat. After the end of its scheduled sequence, subjects with inappropriate capsule release were repeated for up to two additional cycles. For ANOVA purposes, the period originally planned using the protocol replaces missing or incomplete data from periods with improper capsule release with data from the corresponding repetition period.

The mean plasma febuxostat concentration-time characteristics (linear and log-linear forms) and absorption sites for each protocol are depicted in figure 1. A summary of the mean pharmacokinetic parameter estimates for all four cycles of febuxostat after a single dose of 80mg of febuxostat is shown in table 5. All febuxostat plasma concentrations from each subject were used for pharmacokinetic parameter estimation; however, subject 017-JDF (rand 112) had significantly less plasma exposure (C)_maxAnd AUC) because the drug product is directed to the small intestine when compared to all othersA significant delay (about 3 hours) in the release of the distal part of (protocol C). Subjects 017-JDF distal small intestine Release provided 5-13% febuxostat C_maxValues, and AUC values of 12-28% for all other distal releases. Thus, data from distal small intestine release from this subject is not included in the statistical analysis.

Watch (A) 5 : in a single administration of febuxostat 80 mg Mean pharmacokinetic parameter estimates of later febuxostat

Scheme A80 mg febuxostat immediate release reference

Regimen B80 mg febuxostat proximal small intestine Release

Scheme C, 80mg febuxostat distal small intestine release

Scheme D80 mg febuxostat released in the colon.

After administration of febuxostat 80mg released in the proximal small intestine (regimen B) or in the distal small intestine (regimen C), the mean T when compared to the immediate release tablet (regimen A)_maxValues were 65% and shorter 49%, respectively (46%, excluding subjects 017-JDF). In the colon (scheme D), mean T_maxMore than twice as much as the immediate release tablet (regimen a). When febuxostat was released in the proximal small intestine (regimen B) or the distal small intestine (regimen C) (without consideration of subject 017-JDF), the average C of the two_maxThe value is approximately equal to the average C obtained from immediate release tablets (scheme A)_maxA value; however, mean C of febuxostat for colonic release (protocol D)_maxThe value is the average C from an immediate release tablet (protocol A)_maxThe value was 14%. Mean febuxostat AUC values were generally similar in the proximal (regimen B) small intestine and after release from the immediate release tablet (regimen a); however, for the distal (regimen C) release, the mean AUC value was reduced to that of the immediate release tablet (regimen A) when compared to that of the immediate release tablet (regimen A)75% (81%, when subjects 017-JDF were excluded). After febuxostat was released in the colon (regimen D), the mean AUC values were about 35% of those from the immediate release tablets (regimen a).

Through C_maxStatistical evaluation of the bioavailability of febuxostat relative to dosing of febuxostat immediate release (regimen a) (regimens B, C and D) was evaluated with point estimates and 90% confidence intervals for ratios of central values of AUC (0-tlqc) and AUC (0-inf) and summarized in table 6 (excluding distal small intestine release data of subjects 017-JDF).

Watch (A) 6 : and scheme A Comparison, scheme B 、 C And D is a statistical evaluation of the bioavailability of

。

Based on data from 12 subjects (11 for distal small intestine release-regimen C), febuxostat C with a 90% confidence interval of the ratio of the central values not between 0.80 and 1.25 relative to the administration of the immediate release tablet (regimen a) when febuxostat 80mg is administered in the proximal small intestine, distal small intestine or colon (regimens B, C or D, respectively)_maxAUC (0-tlqc) or AUC (0-inf). Febuxostat C released at proximal (B) and distal (scheme C)_maxCenter values were respectively compared to C after immediate release tablet (protocol A)_maxThe central values were about 7% and 6% higher. The AUC center values for proximal release (regimen B) or distal release (regimen C) were reduced by about 3% and 16%, respectively, when compared to those after the immediate release tablet (regimen a). Febuxostat C for colonic delivery (protocol D)_maxThe central values of AUC (0-tlqc) and AUC (0-inf) were 14%, 35% and 37% of those after immediate release tablet (protocol A), respectively.

Thus, it was observed that following a single oral administration of febuxostat 80mg in a single dose released in the proximal small intestine, distal small intestine or colon (protocol B, C or D) in 12 healthy male subjects (for distal small intestine release, subject 017-JDF excluded), systemic exposure to febuxostat was not bioequivalent to those obtained following administration of febuxostat 80mg immediate release tablet (a).

In addition, the inventors plotted FIGS. 2-4 using the estimated data included in tables 3,4, and 5. The inventors calculated estimated pharmacokinetic values for the absorption of febuxostat in various parts of the gastrointestinal tract (i.e., the stomach, proximal small intestine, distal small intestine and colon) and used these parameters to plot log-linear plots of the febuxostat plasma concentrations over time for various dosage forms including 80mg 3-pulsed febuxostat formulation, 80mg 2-pulsed febuxostat formulation and 80mg Extended Release (ER) febuxostat formulation.

Example 4: improved release matrix tablet formulations

A modified release dosage form for the continuous release of a xanthine oxidoreductase inhibitor (i.e., febuxostat) was prepared as a matrix tablet containing the ingredients shown in figure 5 (the ingredients are shown in weight percent). More specifically, the tablets were prepared by wet granulation using Black & Decker hand Chopper. The order of addition of the ingredients is not critical. A V-blender (Blend Master Lab, LC 9292659) was used to prepare the final mixture. Tablets were compressed into round shapes by using an a-2308 tool or an oval (a-2253) device on an engraved tablet press (carver press). For each dosage form shown in fig. 5, the drug release profile was determined and the resulting dissolution profile is shown in fig. 6. More specifically, regarding drug release characteristics and dissolution profiles, the dissolution of an oral dosage form of febuxostat described herein and comprising the ingredients shown in figure 5 was evaluated using the slurry method (USP Apparatus 2) at 50 rpm in 900 mL of 0.5M phosphate buffer (pH 6.8) equilibrated at 37 ℃ ± 0.5 ℃. Aliquots of the samples were withdrawn at different time intervals and analyzed by high performance liquid chromatography. The composition shown in figure 5 represents an extended release febuxostat formulation.

Example 5: three-phase dosage form

A three-phase dosage form that releases a xanthine oxidoreductase inhibitor such as febuxostat can be prepared containing the ingredients listed in table 7 below (shown in weight percent). These dosage forms include three (3) groups of particles. Particle a is designed to release the active agent in the stomach. Particles B are designed to release the active agent in the jejunum. Granule C is designed to release the active agent in the distal part of the ileum and ascending colon.

More specifically, the active agent loading layer may be deposited by spraying an aqueous suspension of the active agent onto a plurality of neutral cores so as to obtain a plurality of drug particles. These drug particles are defined as "particle a". A first portion of the particles A were removed and then coated with an active agent-containing methacrylic copolymer dispersion (e.g., Eudragit L30D-55 or Eudragit L100-55). The methacrylic copolymer dispersion may be applied to particles a by spraying the aqueous dispersion directly onto particles a. The methacrylic acid copolymer coated particles a are now referred to as "particles B". A second portion of the particles A were removed and coated with an aqueous dispersion of a mixture of type A methacrylic acid copolymer (e.g., Eudragit L100 and Eudragit L12.5) and type B methacrylic acid copolymer (e.g., Eudragit S100 and Eudragit S12.5) and an active agent. The aqueous dispersion comprising a mixture of methacrylic acid copolymer type a and methacrylic acid copolymer type B can be applied to particles a by spraying the mixture directly onto particles a. This coated granule a is now referred to as "granule C". Next, the remaining granule a was then mixed together with granules B and C and filled into hard gelatin size 0 capsules.

Watch (A) 7: Febuxostat modified release preparation

Components	Granules A	Granules B	Granules C
				Febuxostat	20.0	20.0	80.0
Microcrystalline cellulose spheres	20.0	20.0	80.0
				Citric acid	7.0	7.0	15.0
Sucrose	25.0	25.0	50.0
				Low-substituted hydroxypropyl cellulose	5.0	5.0	20.0
				Eudragit L30D-55		15.0
Polyethylene glycol		2.0
				Titanium dioxide		1.0
Talc		2.0
				Methacrylic acid copolymer of type B			30.0
Methacrylic acid copolymer of type A			45.0
				Citric acid triethyl ester			6

Figure 2 shows the estimated plasma properties of a dosage form having three types of particles (3 pulses) as shown in table 7 above (including all three particles). Specifically, figure 2 shows the estimated plasma febuxostat concentration-time profile after multiple dosing with a febuxostat controlled release (3-bead, IR = 24 mg, CR = 24 mg released at 5.0 hours, CR = 32 mg released at 10 hours) dosage form using human pharmacokinetic data from examples 1-3 and other studies and a two-compartment model with first order absorption and comparing the estimated plasma profile to an 80mg immediate release formulation.

Example 6: composition with 30% immediate release febuxostat beads and 70% delayed release 6.8 febuxostat beads

The following composition was developed as a double-pulse drug delivery system, wherein a single capsule comprises two types of febuxostat beads. The first pulse consisted of 24 mg of immediate release febuxostat beads, wherein the febuxostat was released immediately after ingestion by the patient. The second pulse consisted of 56 mg of delayed release 6.8 febuxostat beads, wherein the febuxostat was released upon exposure of the beads to a pH level of at least 6.8. Tables 8 and 9 below list the composition of the immediate release and delayed release 6.8 beads.

Watch (A) 8.Composition of immediate release febuxostat beads

Composition (I)	Content (wt.) %
		Febuxostat	31.5
Sugar ball	52.25
		Hydroxypropyl methylcellulose	16.25

Watch (A) 9. Delayed release 6.8 Composition of febuxostat beads

Composition (I)	Content (wt.) %
		Febuxostat	25.2
Sugar ball	41.8
		Hydroxypropyl methylcellulose	13.0
Methacrylic acid copolymer of type A	4.5
		Methacrylic acid copolymer of type B	13.7
Citric acid triethyl ester	1.8

Example 7: composition with 30% immediate release febuxostat beads, 30% delayed release 6.0 febuxostat and 40% delayed release febuxostat beads

The following composition was developed into a tripulsatile drug delivery system in which a single capsule included three types of febuxostat beads. The first pulse consisted of 24 mg of immediate release febuxostat beads, wherein the febuxostat was released immediately after ingestion by the patient. The second pulse consisted of 24 mg delayed release 6.0 febuxostat beads, wherein the febuxostat is released upon exposure of the beads to a pH level of at least 6.0. The third pulse consisted of 42 mg delayed release 6.8 febuxostat beads, wherein the febuxostat was released upon exposure of the beads to a pH level of at least 6.8. The compositions of the immediate release febuxostat beads and the delayed release 6.8 febuxostat beads are listed in tables 8 and 9, respectively, above. The composition of the delayed release 6.0 beads is listed in table 10 below.

Watch (A) 10. Delayed release 6.0 Composition of beads

Composition (I)	Content (wt.) %
		Febuxostat	25.2
Sugar ball	41.8
		Hydroxypropyl methylcellulose	13.0
Methacrylic acid copolymer of type A	18.0
		Citric acid triethyl ester	2.0

Example 8: composition with 30% immediate release febuxostat beads and 70% delayed-controlled release febuxostat beads

The following compositions were developed into monopulse and delayed controlled release drug delivery systems, where a single capsule comprised two types of febuxostat beads. The first pulse consisted of 24 mg of immediate release febuxostat beads, wherein the febuxostat was released immediately after ingestion by the patient. The remainder of the capsule comprises 56 mg of delayed controlled release beads whereby the outermost delayed release layer becomes soluble at a pH level of 6.8 or greater and the controlled release layer releases febuxostat for an extended period of 4-6 hours after the outermost layer has dissolved. The composition of the immediate release febuxostat beads is listed in table 8 above. The composition of the delayed-controlled release beads is shown in table 11 below.

Watch (A) 11. Delay - Composition of controlled release febuxostat beads

Composition (I)	Content (wt.) %
		Febuxostat	21.4
Sugar ball	35.5
		Hydroxypropyl methylcellulose (in IR beads)	11.1
Surelease E-7-19010 (solid content)	8.4
		Hydroxypropyl methylcellulose (in CR coating)	3.6
Methacrylic acid copolymer of type A	4.6
		Methacrylic acid copolymer of type B	13.6
Citric acid triethyl ester	1.8

Example 9: composition with 20% immediate release febuxostat beads and 80% controlled release beads for 10-12 hours

The following compositions were developed as monopulse and controlled release drug delivery systems, where a single capsule comprised two types of febuxostat beads. One pulse consisted of 16 mg of immediate release febuxostat beads, wherein febuxostat was released immediately after ingestion by the patient. The remainder of the capsule comprises 64 mg controlled release febuxostat beads, whereby febuxostat is released over an extended period of 10-12 hours (starting immediately after ingestion by the patient). The composition of the immediate release febuxostat beads is listed in table 8 above. The composition of the beads for 10-12 hours of controlled release is shown in Table 12 below.

Watch (A) 12. Controlled release 10-12 Composition of Houfebuxostat beads

Composition (I)	Content%
		Febuxostat	29.6
Sugar ball	49.1
		Hydroxypropyl methylcellulose (in IR beads)	15.3
Ethyl cellulose	3.6
		Hydroxypropyl methylcellulose (in CR coating)	2.4

Example 10: febuxostat modified release pharmacokinetic data in dogs

A study was conducted in which eight different febuxostat formulations were administered to 6 dogs in a staggered fashion, and plasma concentrations (ng/ml) were measured in the dogs at 0.25, 0.5, 1,2, 3,4, 5,6, 8, 12, 18, and 24 hours post-administration. This test was performed to determine how various formulations were absorbed in the dog model, as well as to determine plasma concentration profiles over time. Specifically, six male inbred beagle dogs were used in this study, with each of the eight test formulations administered to six dogs in the same group. The dogs were housed individually and were left out of mixed (pooled) for at least 24 hours after dosing to allow monitoring of any test article related effects. The test formulations were administered in the form of oral dosage forms comprising capsules or tablets. Dogs were fasted overnight by approximately 4 hours post-dose. Individual doses were calculated from body weights collected on each dosing day. Approximately 1 hour prior to administration of the test formulation, an intramuscular dose of 6 μ g/kg (0.048mL/kg) of pentagastrin was administered to each dog. The mean plasma febuxostat concentration was measured by blood samples (about 2 mL) collected from the jugular vein by syringe and needle to contain K at the time intervals listed above₂EDTA anticoagulant predose in tubes. The plasma sample is then transported off-site for analysis. The dog model was chosen because of prior experience with delayed release beads for administration of other drugs in dogs and the relationship of dog data to human data. In previous studies, delayed release of T from beads_maxDelay (with observed T in dogs of about 2 hours)_max) T which has resulted in a delay of up to 8 hours in humans_max。

All eight febuxostat formulations included a total dose of 80mg of febuxostat, with different compositions of immediate release, delayed release, controlled release and delayed-controlled release beads. The eight febuxostat preparations comprise:

(1) 80mg of an immediate release tablet (reference formulation) (referred to as "phase 1");

(2) 80mg delayed release 5.5 beads having a solubility at a pH level of at least 5.5 (referred to as "phase 2");

(3) 24 mg of immediate release beads and 56 mg of delayed release pH6.0 beads (referred to as "phase 3");

(4) 24 mg of immediate release beads and 56 mg of delayed release pH6.8 beads (referred to as "phase 4");

(5) 24 mg of immediate release beads, 24 mg of delayed release pH6.0 beads and 32 mg of delayed release pH6.8 beads (referred to as "phase 5");

(6) 24 mg of immediate release beads and 56 mg of controlled release 4-6 hour beads (referred to as "phase 6");

(7) 24 mg of immediate release beads and 56 mg of delayed-controlled release beads, wherein the delayed release layer is soluble at a pH level of at least 6.0 and the controlled release layer releases febuxostat over a period of 4-6 hours (referred to as "phase 7"); and

(8) 24 mg of immediate release beads and 56 mg of controlled release beads for 10-12 hours (referred to as "phase 8").

The plasma concentrations of the individual dosage forms are shown in figure 7. Specifically, fig. 7 illustrates a linear plot for each formulation disclosing the mean febuxostat plasma concentration for each formulation over a period of 6 hours after ingestion of the dosage form. Although plasma samples were collected for up to 24 hours, very low plasma concentrations were measured over 6-8 hours for most animals. This is consistent with literature reports indicating that dogs have a shorter gastrointestinal tract length than humans. Thus, the solid dosage form migrates (transitions) through the gastrointestinal tract of dogs more rapidly than humans. Thus, a delayed release formulation designed to release febuxostat rapidly at a specific pH initiator is absorbed much better than a controlled release formulation that releases the drug over a period of time.

In addition, comparisons of all eight formulations were made, examining mean plasma concentrations of febuxostat for each phase of the study at four, five and six hours post-dose. The results are generally expected to include controlThe bead-releasing formulations did not achieve significantly higher plasma febuxostat concentrations than the formulations containing only immediate release beads. To reiterate, the results are expected to be much shorter in the gastrointestinal tract of dogs than humans. This physiological result, which is relevant to pharmacokinetic testing in dog models, is discussed in more detail in the following documents: the process is carried out by StephenC, Sutton,Companion animal physiology and dosage form performanceadvanced Drug Delivery Reviews, 2004, vol.56, pp. 1383-,Comparison of Canine and Human Gastrointestinal Physiologypharmaceutical Research, 1986, vol. 3, No. 3, pp. 123-. Thus, controlled release formulations that do not completely release the active ingredient until 4-6 hours or 10-12 hours after ingestion may have passed through most, if not all, of the dog's gastrointestinal tract before the time at which release of the active begins and are not capable of achieving high plasma concentrations. A summary of these results is included in table 13 below.

Watch (A) 13: Mean plasma concentration of febuxostat formulation in dogs

。

The mean plasma concentration of the phase 1 formulation containing 80mg of immediate release beads was 289.8 ng/ml at 4 hours post-administration. This value is significantly lower than the mean plasma concentration of the dosage forms containing delayed release beads, as the 2-, 3-, 4-and 5-phase formulations showed mean concentrations of 632.6 ng/ml, 785.2ng/ml, 448.3 ng/ml and 827.9 ng/ml, respectively. The pH levels in the gastrointestinal tract of dogs are similar to those found in humans, so delayed release beads are not affected by the length of the gastrointestinal tract of dogs, as observed by controlled release beads. As expected, dosage forms comprising a combination of immediate release beads and controlled release beads typically exhibit mean plasma concentrations similar to phase 1. Mean plasma concentrations of 319.0 ng/ml, 329.8 ng/ml and 86.2ng/ml were observed for the 6-, 7-and 8-phase formulations, respectively. In these cases, only a small amount of febuxostat in the controlled release beads may be released, as plasma concentrations depend, at least in part, on the immediate release beads found in the 6-, 7-and 8-phase formulations.

Note the mean concentration at 5 hours post-administration, the mean plasma concentration of the phase 1 formulation was 73.2 ng/ml. In comparison, the delayed release formulations of phase 2, phase 3, phase 4 and phase 5 showed higher mean plasma concentrations of 207.8ng/ml, 283.7 ng/ml, 151.3 ng/ml and 249.1ng/ml, respectively. The phase 6, 7 and 8 controlled release formulations showed mean plasma concentrations of 124.2 ng/ml, 95.5 ng/ml and 50.2ng/ml, respectively.

Furthermore, the mean plasma concentrations at 6 hours post-administration showed comparable data to those at 4 and 5 hours post-administration. The mean plasma concentration of the phase 1 formulation was 53.8 ng/ml. Similar to the data for 4 and 5 hours, the delayed release formulations of phase 2, phase 3, phase 4 and phase 5 showed higher mean plasma concentrations of 79.1 ng/ml, 105.3 ng/ml, 69.3ng/ml and 104.9 ng/ml, respectively. The phase 6, 7 and 8 controlled release formulations showed mean plasma concentrations of 64.2 ng/ml, 44.3 ng/ml and 25.6ng/ml, respectively.

Thus, even though the collection of plasma concentrations in a dog model is inherently limited by the shorter length of the dog's gastrointestinal tract compared to the human gastrointestinal tract, the results of the comparison support improved plasma concentrations of febuxostat for the modified release formulation compared to the immediate release formulation. All formulations for the 2-, 3-, 4-and 5-phase delayed release formulations showed higher mean plasma concentrations at 4,5 and 6 hours after administration compared to the reference immediate release formulation. The phase 6 and phase 7 controlled release formulations (both including 4-6 hour controlled release beads) showed improved mean plasma concentrations at 4,5 and 6 hours (except for the mean concentration of phase 7 at 6 hours), although to a lesser extent than observed for the delayed release formulations. These results may be due to the fact that the 6 and 7 phase controlled release components are designed to release the active within 4-6 hours, which means that the formulation may only release a portion of the febuxostat before the formulation passes through the full length of the gastrointestinal tract. The phase 8 controlled release formulation (including 10-12 hour controlled release beads) showed the lowest mean plasma concentration, lower than the reference immediate release formulation. As previously discussed, this result was not unexpected, as it was possible to control the release of the 10-12 hour beads (including 70% formulation) to release only a small fraction of febuxostat prior to passage through the gastrointestinal tract of the dog.

Example 11: results of a 1-phase, single dose study in humans of four extended release formulations of febuxostat and one immediate release formulation of febuxostat

This example describes a phase 1, single-centered, signature-published, randomized, 5-way cross-over study (5-way crossover study). 35 well-conditioned adult male and female subjects 18-55 years of age (inclusive) were selected for participation in the study. Subjects were randomly assigned in equal numbers to one of 5 formulation order groups as shown in table 14.

Watch (A) 14 Order of preparation group

Formulation A (reference) febuxostat (Uloric)^®) IR 80mg tablet.

Formulation B (test) double-pulsed prototype (80 mg) febuxostat capsule (TMX-67 XR formulation B).

Formulation C (test) triple pulse prototype (80 mg) febuxostat capsule (TMX-67 XR formulation C).

Formulation D (test) pulsed and continuous release combination (80 mg) febuxostat capsule (TMX-67 formulation D).

Formulation E (test) continuous release (80 mg) prototype febuxostat capsule (TMX-67 XR formulation E).

All subjects in this study received 5 febuxostat formulations (IR, 2-pulse, 3-pulse, combination of pulse and continuous release) in a staggered fashion according to a randomized protocol. A schematic of the study design is shown in table 15.

Watch (A) 15 Design of research Schematic diagram of

。

Pharmacokinetic sample collection

In cycles 1-5, blood samples (4 mL) for determination of plasma febuxostat concentration were collected at the indicated time points for 48 hours after administration of 80mg of febuxostat. The febuxostat plasma concentration was quantified using a validated liquid chromatography/tandem mass spectrometry (LC \ MS) assay.

Pharmacokinetic results

A summary of the estimated mean pharmacokinetic parameters of febuxostat after administration of five different 80mg febuxostat formulations is summarized in table 16. The mean plasma concentration-time profiles (linear and log-linear forms) of febuxostat are shown in figures 8A and 8B after oral administration of a single 80mg dose of febuxostat immediate release tablet and four extended release 80mg capsule formulations. In all subjects, febuxostat was detected in plasma immediately after oral administration without absorption lag. At approximately 16 hours post-administration following administration of the extended release formulations (formulations B-E), the plasma febuxostat concentration decreased below the target concentration of 100 ng/mL.

Watch (A) 16 In a single oral administration 80 mg Dosage of febuxostat immediate release tablets and four 80 mg Summary of plasma pharmacokinetic parameters of febuxostat following extended release formulation

A = febuxostat 80mg IR tablet

B = febuxostat 80mg extended release (double pulse) capsule formulation

C = febuxostat 80mg extended release (triple pulse) capsule formulation

D = febuxostat 80mg extended release (combination pulsed and continuous) capsule formulation

E = febuxostat 80mg extended release (continuous release) capsule formulation.

Example 12: osmotic pump tablet of febuxostat

Osmotic pump tablet formulations were prepared using the expandable core technique. Tablets consist of a drug layer and a swellable polymer layer. The bilayer tablet is coated with a semipermeable membrane comprising cellulose acetate and polyethylene glycol. The upper surface of the tablet is drilled with a laser. The semipermeable membrane allows water to be absorbed into the substrate, but does not allow diffusion of any other substances across the membrane. The swellable polymer layer swells as it absorbs water and pushes the drug out of the laser drilled orifice. The composition of the swellable polymer layer and the thickness of the semipermeable membrane affect the release of the drug. The tablet compositions for the various tablet formulations are shown in table 17 below. Formulation 1 was designed to provide a longer release duration because it contained a smaller amount of zymogen (osmogen) NaCl. Higher amounts of zymogen in formulation 2 are expected to result in faster polymer swelling.

Watch (A) 17:

。

Formulation 3 was coated with a semipermeable coating consisting of Cellulose Acetate (CA) and PEG 3350. The ratio of CA to PEG may vary. For example, the ratio of CA to PEG can be from 5:5 to 9: 1. As shown in fig. 9, the CA to PEG ratio of 6:4 resulted in faster release from the tablet compared to the ratio of 7: 3. The amount of coating can be varied to adjust the desired dissolution profile using conventional techniques known in the art.

The osmotic pump tablets may be coated with an immediate release layer of the drug (febuxostat) to overcome the lag time shown in fig. 10. In this figure 10, 60 mg of febuxostat tablet (formulation 2 above) was overcoated with 20mg of febuxostat, which is expected to be immediately released and thus converted to be available for absorption.

Osmotic multiparticulates (osmatic multiparticulates) are prepared by layering febuxostat on microcrystalline cellulose spheres using techniques conventional in the art. Drug layered beads (drug layered beads) are coated with a disintegrant layer (e.g., croscarmellose sodium, crospovidone, etc.) and then coated in vitro with an aqueous dispersion of ethylcellulose. As shown in fig. 11, it is possible to obtain multiparticulates of the desired release profile by varying the amount of ethylcellulose coating. The ruptured multiparticulates can be mixed with uncoated beads to provide a 2-pulse formulation system, similar to the other 2-pulse systems described herein.

Those skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. Those skilled in the art will readily recognize various substitutions and modifications that may be made to the disclosure herein without departing from the scope and spirit of the disclosure. All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be substituted by two other terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification and variation of the disclosure herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims.

In addition, where a feature or aspect of the disclosure is described in terms of a markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the markush group. For example, if X is described as being selected from the group consisting of bromine, chlorine, and iodine, then the claims to X as bromine and chlorine are all described.

Claims (7)

1. A modified release pharmaceutical composition comprising immediate release febuxostat beads in an amount of 20% to 40% (w/w) of the total composition weight and delayed release febuxostat beads having solubility at a pH level of greater than or equal to 6.8 in an amount of 60% to 80% (w/w) of the total composition weight, wherein the beads are comprised in an oral dosage form selected from the group consisting of pills, tablets and capsules,

wherein the immediate release bead comprises

(a) An inert core in an amount of 50% to 55% (w/w) of the weight of the immediate release bead, and

(b) an immediate release layer encapsulating an inert core comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 45% to 50% (w/w) of the weight of the immediate release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 3; and is

Wherein the delayed release bead comprises

(a) An inert core in an amount of 40.5% to 43% (w/w) of the weight of the delayed release beads,

(b) an immediate release layer encapsulating an inert core comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 35% to 40% (w/w) of the weight of the delayed release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 3,

(c) a delayed release enteric polymer layer encapsulating the immediate release layer, comprising a delayed release enteric polymer in an amount of 1% to 20% (w/w) of the delayed release bead, the delayed release enteric polymer comprising a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B in a ratio of 0.1 to 0.5, and

(d) a plasticizer in an amount of 1% to 3% (w/w) of the weight of the delayed-controlled release bead, the plasticizer comprising triethyl citrate.

2. The modified release pharmaceutical composition of claim 1 wherein the total amount of febuxostat contained in the composition is 80 mg.

3. A modified release pharmaceutical composition comprising immediate release febuxostat beads in an amount of 20% to 40% (w/w) of the total composition weight, and delayed-controlled release febuxostat beads having solubility at a pH level of greater than or equal to 6.8 and providing prolonged release of febuxostat over a period of 4 to 6 hours in an amount of 60% to 80% (w/w) of the total composition weight, wherein the beads are comprised in an oral dosage form selected from the group consisting of pills, tablets and capsules,

wherein the immediate release bead comprises

(a) An inert core in an amount of 50% to 55% (w/w) of the weight of the immediate release bead, and

(b) an immediate release layer encapsulating an inert core comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 45% to 50% (w/w) of the weight of the immediate release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 3; and is

Wherein the delayed-controlled release bead comprises

(a) An inert core in an amount of 34% to 37% (w/w) of the weight of the delayed-controlled release beads,

(b) an immediate release layer encapsulating an inert core, comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 31% to 34% (w/w) of the weight of the delayed-controlled release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 2.5,

(c) a controlled release layer encapsulating the immediate release layer, comprising a controlled release polymer in an amount of 10% to 14% (w/w) of the weight of the delayed-controlled release bead, the controlled release polymer comprising a mixture of an aqueous dispersion of ethyl cellulose and hydroxypropyl methylcellulose, the ratio of the aqueous dispersion of ethyl cellulose to hydroxypropyl methylcellulose being 1.5 to 3,

(d) a delayed release pH6.8 layer encapsulating the controlled release layer, comprising a delayed release pH6.8 polymer in an amount of 1% to 20% (w/w) of the weight of the delayed-controlled release bead, the delayed release pH6.8 polymer comprising a mixture of methacrylic acid copolymer type a and methacrylic acid copolymer type B, the ratio of copolymer type a to copolymer type B being 0.1 to 0.5, and

(e) a plasticizer in an amount of 1% to 3% (w/w) of the weight of the delayed-controlled release bead, said plasticizer comprising triethyl citrate.

4. The modified release pharmaceutical composition of claim 3 wherein the total amount of febuxostat contained in the composition is 80 mg.

5. A modified release pharmaceutical composition comprising immediate release febuxostat beads in an amount of 10% to 30% (w/w) of the total composition weight, and controlled release febuxostat beads providing prolonged release of febuxostat over a period of 10 hours to 12 hours in an amount of 70% to 90% (w/w) of the total composition weight, wherein the beads are comprised in an oral dosage form selected from the group consisting of pills, tablets and capsules,

wherein the immediate release bead comprises

(a) An inert core in an amount of 50% to 55% (w/w) of the weight of the immediate release bead, and

(b) an immediate release layer encapsulating an inert core comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 45% to 50% (w/w) of the weight of the immediate release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 3; and is

Wherein the controlled release bead comprises

(a) An inert core in an amount of 47% to 51% (w/w) of the weight of the controlled release beads,

(b) an immediate release layer encapsulating an inert core comprising a mixture of febuxostat and hydroxypropyl methylcellulose in an amount of 42% to 48% (w/w) of the weight of the controlled release bead, the ratio of febuxostat to hydroxypropyl methylcellulose being 1.5 to 2.5, and

(c) a controlled release layer encapsulating the immediate release layer comprising a controlled release polymer comprising a mixture of ethylcellulose and hydroxypropyl methylcellulose in an amount of 4% to 8% (w/w) by weight of the controlled release bead, the ratio of ethylcellulose to hydroxypropyl methylcellulose being 1 to 2.

6. The modified release pharmaceutical composition of claim 5 wherein the total amount of febuxostat contained in the composition is 80 mg.

7. Use of a therapeutically effective amount of the modified release pharmaceutical composition of claim 1,3 or 5 in the manufacture of a medicament for treating a patient suffering from gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, congestive heart failure.