WO2017046343A1

WO2017046343A1 - Compositions for rectal administration in the treatment of ulcerative colitis and methods of using same

Info

Publication number: WO2017046343A1
Application number: PCT/EP2016/071995
Authority: WO
Inventors: Salvatore Bellinvia; Salvatore Demartis; Francesca Viti
Original assignee: Nogra Pharma Limited
Priority date: 2015-09-17
Filing date: 2016-09-16
Publication date: 2017-03-23

Abstract

Disclosed herein are compositions comprising 3-(4-aminophenyl)-2-methoxypropionic acid or pharmaceutically acceptable salts or stereoisomers thereof useful for treating ulcerative colitis and other inflammatory bowel disorders and suitable for rectal administration. Also disclosed are containers useful for housing and administering such compositions. Also disclosed are kits comprising compositions of the invention as well as, in some embodiments, containers for housing and administering such compositions. Also disclosed are methods of treating inflammatory bowel disease in a patient in need by administering compositions of the invention rectally.

Description

COMPOSITIONS FOR RECTAL ADMINISTRATION IN THE TREATMENT OF ULCERATIVE COLITIS AND METHODS OF USING SAME

CROSS-REFERENCE TO RELATED PATENT APPLICATION

[0001] The present application claims the benefit of priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 62/219,996 filed on September 17, 2015, the content of which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Inflammatory bowel disease can refer to a group of diseases including both Crohn's disease and ulcerative colitis. The two diseases may have similar pathogenesis and clinical manifestations, and the diagnosis of either disease requires imaging studies such as endoscopy (either sigmoidoscopy or colonoscopy), double contrast barium enema, and computed tomography (CT) scan, combined with laboratory tests including complete blood counts to detect elevated leukocyte levels, erythrocyte sedimentation rates and serum albumin concentration.

[0003] Both diseases are chronic, relapsing/remitting inflammatory diseases of the gastrointenstinal (GI) tract. The regions of the GI tract that are most often affected by Crohn's disease are the small intestine and large intestine, also called the colon, including the rectum; however, Crohn's disease can affect the entire GI tract from the mouth to the anus. There may be single or multiple patches of inflammation. Ulcerative colitis affects only the large intestine. Inflammation and ulceration in ulcerative colitis are limited to the mucosal and submucosal layers, the two innermost layers of the four layers of the large intestine. The inflammation and ulceration in Crohn's disease can extend through all layers of the intestinal wall in both the small and large intestines. Common symptoms of the diseases include diarrhea, abdominal pain, rectal bleeding and weight loss. Complications of Crohn's disease include intestinal abscesses, fistula, an abnormal passage leading from one portion of the intestine to another and permitting passage of fluids or secretions, and intestinal obstructions. Typically, the course of both diseases is intermittent, with disease exacerbations followed by periods of remission. However, ulcerative colitis may be a single event, or continuous with unrelenting symptoms. [0004] Rectal administration, e.g., by enema, may be used in treatment of ulcerative colitis as the disease areas are proximal to the rectum. This allows for topical application of a therapeutic agent. Although there are many choices for therapeutic interventions in IBD, many have undesirable side effects that make them less than ideal for treatment of chronic disease. There remains a challenge for development of an active agent that retains topical activity when administered rectally, e.g., by enema.

SUMMARY

[0005] Provided herein are compositions for rectal administration and composition components suitable for reconstituting a dry or powder composition to form a liquid dosage composition having, for example, a compound such as 3-(4-aminophenyl)-2-methoxypropionic acid or N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid. Contemplated composition components may include a dry composition that includes an active compound selected from, for example, 3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof, an anticaking agent, and a lubricant, as well as a liquid composition suitable to reconstitute the dry composition. The disclosure also contemplates kits that include disclosed dry and/or liquid components/compositions. Also provided herein are methods of treating inflammatory bowel disease comprising rectally administering disclosed compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 shows pH of the reconstituted composition, after the addition of the active agent, as a function of the time. The value at time 0 minutes corresponds to the pH of the liquid phase before addition.

[0007] FIG. 2, parts A-D show different components of a disclosed dual-chambered container. Part A shows the body of the dual-chambered container. Part B shows a cannula. Part C shows a cap. Part D shows a separator cap.

[0008] FIG. 3 provides a flow chart of a manufacturing process for formulating disclosed compositions. DETAILED DESCRIPTION

[0009] Provided herein, in an embodiment, is a composition for rectal (e.g., by enema) administration of an active agent for treatment of inflammatory bowel disorders such as, e.g., ulcerative colitis. For example, provided herein is a rectal dosage formulation which is capable of delivering an active agent, e.g., a compound such as N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid or 3-(4-aminophenyl)-2-methoxypropionic acid, or stereoisomers (e.g., racemic mixture or a substantially isolated stereoisomer) and/or pharmaceutically acceptable salts thereof, e.g., (-)-3-(4-aminophenyl)-2-methoxypropionic acid (for example, (5 -3-(4- aminophenyl)-2-methoxypropionic acid), at the colon level. Such disclosed formulations (e.g., enemas) can achieve a topical effect of the drug to treat patients affected by ulcerative colitis.

[0010] For example, provided herein is a set of compositions that may be combined into a single solution for treatment of ulcerative colitis (or other inflammatory bowel disorder), that includes: a solid phase composition comprising (S)-3-(4-aminophenyl)-2-methoxypropionic acid (compound A) and excipients that ease the mixing with liquid phase, and a liquid phase composition that includes viscosity increasing agents and buffering agents, wherein the liquid composition is suitable to reconstitute the dry/solid phase composition. Also provided herein are compositions that may be combined into a single solution for treatment of ulcerative colitis (or other inflammatory bowel disorder), that include: a solid phase composition comprising any of (R)-3-(4-aminophenyl)-2-methoxypropionic acid, a racemic mixture of (S)-3-(4-aminophenyl)-2- methoxypropionic acid and (R)-3-(4-aminophenyl)-2-methoxypropionic acid, N-acetyl-(S)-3-(4- aminophenyl)-2-methoxypropionic acid, N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid, or a racemic mixture of N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic acid and - acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid, and excipients that ease the mixing with liquid phase, and a liquid phase composition that includes viscosity increasing agents and buffering agents, wherein the liquid composition is suitable to reconstitute the dry/solid phase composition. Such disclosed liquid compositions and dry compositions can be combined into a single solution suitable for treatment of ulcerative colitis.

[0011] For example, (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid may be provided as a powder composition; a liquid solvent/composition may also be provided to form a rectal solution to be reconstituted before administration. As contemplated herein in certain embodiments, the drug substance is present in a powder composition. For example, provided herein is a product presented as a single-dose preparation contained in a double chamber powder/liquid bottle. In a particular embodiment, the extractable volume allows administration of 600 mg of drug substance (e.g. compound A) for each dose.

[0012] In another aspect, provided herein in an embodiment is a method for treating ulcerative colitis comprising rectally administering by enema to a patient in need thereof a reconstituted composition wherein the concentration of drug substance (e.g. compound A) in the solution is, e.g., about 0.1 % to about 1.0% (w/w), e.g., about 0.6% (w/w).

Compositions

[0013] In an embodiment, a dry composition for the rectal treatment of inflammatory bowel disease is provided comprising an active compound selected from 3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof, an anticaking agent, and a lubricant, wherein the pH of the dry composition is between about pH 3.0 and about pH 5.0. The active compound may be in some embodiments (5 -3-(4-aminophenyl)-

2- methoxypropionic acid. In some embodiments, the active compound may be (i?)-3-(4- aminophenyl)-2-methoxypropionic acid. In yet other embodiments, a dry composition for the rectal treatment of inflammatory bowel disease is provided comprising a racemic mixture of (S)-

3- (4-aminophenyl)-2-methoxypropionic acid and (i?)-3-(4-aminophenyl)-2-methoxypropionic acid, or pharmaceutically acceptable salts thereof, an anticaking agent, and a lubricant, wherein the pH of the dry composition is between about pH 3.0 and about pH 5.0.

[0014] In another embodiment, a dry composition for the rectal treatment of inflammatory bowel disease is provided comprising an active compound selected from -acetyl-3-(4- aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof, an anticaking agent, and a lubricant, wherein the pH of the dry composition is between about pH 3.0 and about pH 5.0. The active compound may be in some embodiments N-acetyl- (5 -3-(4-aminophenyl)-2-methoxypropionic acid. In some embodiments, the active compound may be N-acetyl-(i?)-3-(4-aminophenyl)-2-methoxypropionic acid. In yet other embodiments, a dry composition for the rectal treatment of inflammatory bowel disease is provided comprising a racemic mixture of N-acetyl-(5)-3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-(i?)- 3-(4-aminophenyl)-2-methoxypropionic acid, or pharmaceutically acceptable salts thereof, an anticaking agent, and a lubricant, wherein the pH of the dry composition is between about pH 3.0 and about pH 5.0.

[0015] For example, the dry composition may include about 90% to about 99% by weight of the active compound, e.g., about 97.5% by weight of the active compound. In an embodiment, the dry composition may include 0.5% to about 5% by weight anticaking agent, e.g., about 2% by weight anticaking agent (e.g., colloidal silica anhydrous, for example, selected from

Aerosil® 200 W Pharma, Aerosil® R972 Pharma, Sipernat® 160 PQ, and Syloid® 244 FP). In an embodiment the anticaking agent is Syloid® 244 FP. Contemplated dry compositions may also include 0.10% to about 1.00% by weight lubricant (for example magnesium stearate), e.g., about 0.50% of lubricant by weight.

[0016] A container is contemplated that includes a disclosed dry (or powder) composition having between about 0.60 g and about 0.70 g (e.g., about 0.68 g) of the active compound (e.g., compound A), and may further include between about 0.010 g and about 0.020 g (e.g., about 0.014 g) of an anticaking agent and/or between about 0.0030 g and 0.0040 g (e.g., about 0.0035g) of a lubricant. In other embodiments, the contemplated container may include a disclosed dry (or powder) composition having about 0.10 g, about 0.20 g, about 0.30 g, about 0.40 g, about 0.50 g, about 0.60 g, about 0.70 g, about 0.80 g, about 0.90 g, about 1.00 g, about 1.10 g, about 1.20 g, about 1.30 g, about 1.40 g, about 1.50 g, about 1.60 g, about 1.70 g, or about 1.80 g of the active compound (e.g., compound A), and may further include an anticaking agent and/or a lubricant. In some embodiments, the contemplated container may include a disclosed dry (or powder) composition having between about 0.10 g and about 0.20 g, between about 0.20 g and about 0.30 g, between about 0.30 g and about 0.40 g, between about 0.40 g and about 0.50 g, between about 0.50 g and about 0.60 g, between about 0.60 g and about 0.70 g, between about 0.70 g and about 0.80 g, between about 0.80 g and about 0.90 g, between about 0.90 g and about 1.00 g, between about 1.00 g and about 1.10 g, between about 1.10 g and about 1.20 g, between about 1.20 g and about 1.30 g, between about 1.30 g and about 1.40 g, between about 1.40 g and about 1.50 g, between about 1.50 g and about 1.60 g, between about 1.60 g and about 1.70 g, or between about 1.70 g and about 1.80 g of the active compound (e.g., compound A), and may further include an anticaking agent and/or a lubricant. In some embodiments, the dry (or powder composition) may comprise about 2.00% by weight of an anticaking agent and about 0.50% by weight of a lubricant, where the percent weight refers to the percent of the total weight of the dry composition.

[0017] In another embodiment, provided herein is a liquid composition suitable for reconstituting a disclosed dry or powder composition comprising: a viscosity increasing agent (e.g., selected from the group consisting of povidone, methyl cellulose, and combinations thereof), a buffering agent having a concentration of about 30 mM to about 50 mM (e.g., about 45 mM), a solvent (e.g., water), and optionally, a preservative, wherein the liquid composition has a pH between about 7.2 and about 7.8 (e.g., about pH 7.5). For example, provided herein is a liquid composition comprising about 1.00% to about 3.00% (e.g., about 2.0%) by weight of the viscosity increasing agent and about 90.0% to about 99.0% (e.g., about 96.7%) by weight of the solvent (e.g., water).

[0018] Such liquid compositions may include a buffering agent selected from disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, and combinations thereof, wherein for example, in some embodiments, a disclosed liquid composition may include about 0.75% to about 1.25% (e.g., about 1.04%) by weight of a buffering agent.

[0019] Contemplated liquid compositions may include a preservative selected from the group consisting of sodium propyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, and combinations thereof, and/or may include about 0.01% to about 0.50% (e.g., about 0.22%) by weight of the preservative. In an embodiment, disclosed liquid compositions have a viscosity of less than about 200 cP.

[0020] Also provided herein is a container that includes a disclosed liquid composition, that has, e.g., about 2.00 g and about 2.50 g (e.g., about 2.26 g) of the viscosity increasing agent and may further include between about 1.00 g and 1.25 g of the buffering agent, e.g., about 1.18 g of the buffering agent, and between aboutlOO g and about 120 g of solvent (e.g., about 110 g of water) and optionally about 0.10 g and 0.50 g (for example, about 0.25 g) of the preservative. [0021] In an embodiment, provided herein is a dual-chambered container, wherein one chamber comprises a disclosed dry composition, and a second chamber comprises a disclosed liquid composition suitable to reconstitute the dry composition. Such dual-chamber containers may further comprise a separator cap situated between the two chambers, and a sealing cap, and/or may further comprise a cannula. For example, provided herein is a dual chamber container having about 0.70 g of a disclosed dry composition and about 1 13 g of a disclosed liquid composition.

[0022] In a disclosed aspect, provided herein is a single liquid dose composition having a pH of between about 5.5 and about pH 6.5 (e.g., about pH 6.0) for rectal administration to a patient suffering from inflammatory bowel disease comprising between about 0.60 g and about 0.70 g (e.g., about 0.68 g) of (S)-3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt thereof, about 0.010 g and about 0.020 g (e.g., about 0.014g) of an anticaking agent (e.g., a colloidal silica anhydrous such as Aerosil® 200 W Pharma, Aerosil® R972 Pharma, Sipernat® 160 PQ, and/or Syloid® 244 FP), a lubricant (e.g., about 0.0035 g magnesium stearate) , one or more viscosity increasing agents (e.g., about 1.13 g of an agent selected from povidone, methyl cellulose, and combinations thereof), one or more antimicrobial preservatives (e.g., sodium propyl parahydroxybenzoate and/or sodium methyl

parahydroxybenzoate - for example, about 0.023 g of sodium propyl parahydroxybenzoate and 0.227 g of sodium methyl parahydroxybenzoate), one or more buffering agents (e.g., about 1.18 g, for example about 0.850 g disodium phosphate dodecahydrate and 0.340 g sodium dihydrogen phosphate dihydrate), and a solvent (e.g., water). A contemplated single dose liquid composition may have a viscosity of less than about 200 cP.

[0023] In another disclosed aspect, provided herein is a single liquid dose composition having a pH of between about 5.5 and about pH 6.5 (e.g., about pH 6.0) for rectal administration to a patient suffering from inflammatory bowel disease comprising between about 0.60 g and about 0.70 g (e.g., about 0.68 g) of any of (R)-3-(4-aminophenyl)-2-methoxypropionic acid, a racemic mixture of (S)-3-(4-aminophenyl)-2-methoxypropionic acid and (R)-3-(4-aminophenyl)- 2-methoxypropionic acid, N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid, N-acetyl- (S)-3-(4-aminophenyl)-2-methoxypropionic acid, or a racemic mixture of N-acetyl-(S)-3-(4- aminophenyl)-2-methoxypropionic acid and N-acetyl-(R)-3-(4-aminophenyl)-2- methoxypropionic acid, or a pharmaceutically acceptable salt or pharmaceutically salts thereof, about 0.010 g and about 0.020 g (e.g., about 0.014g) of an anticaking agent (e.g., a colloidal silica anhydrous such as Aerosil® 200 W Pharma, Aerosil® R972 Pharma, Sipernat® 160 PQ, and/or Syloid® 244 FP), a lubricant (e.g., about 0.0035 g magnesium stearate) , one or more viscosity increasing agents (e.g., about 1.13 g of an agent selected from povidone, methyl cellulose, and combinations thereof), one or more antimicrobial preservatives (e.g., sodium propyl parahydroxybenzoate and/or sodium methyl parahydroxybenzoate - for example, about 0.023 g of sodium propyl parahydroxybenzoate and 0.227 g of sodium methyl

parahydroxybenzoate), one or more buffering agents (e.g., about 1.18 g, for example about 0.850 g disodium phosphate dodecahydrate and 0.340 g sodium dihydrogen phosphate dihydrate), and a solvent (e.g., water). A contemplated single dose liquid composition may have a viscosity of less than about 200 cP.

[0024] In a particular embodiment, a single dose liquid composition may include about 0.012% by weight Syloid® 244 FP, and about 1.00% to about 1.25% by weight viscosity increasing agent, about 1.04% by weight buffering agent.

[0025] In a particular embodiment, provided herein is a liquid dosage form for rectal administration by enema, comprising about 0.600% 3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof, or a racemic mixture comprising pharmaceutically acceptable stereoisomers thereof (e.g., a racemic mixture comprising (R)-3-(4- aminophenyl)-2-methoxypropionic acid and (S)-3-(4-aminophenyl)-2-methoxypropionic acid, or pharmaceutically acceptable salts thereof), about 0.012% Syloid® 244 FP, about 0.003% magnesium stearate, about 0.994% povidone,about 0.994% methyl cellulose, about 0.020% sodium propyl parahydroxybenzoate, about 0.199% sodium methyl parahydroxybenzoate, about 0.746% disodium phosphate dodecahydrate, about 0.298% sodium dihydrogen phosphate dihydrate, and about 96.13% water, wherein the percent of each component refers to the percent weight of the total composition; wherein the pH of the composition is about pH 6.0; and wherein the viscosity of the composition is less than about 200 cP.

[0026] In a further embodiment, provided herein is a liquid dosage form for rectal administration by enema, comprising about 0.600% N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof, or a racemic mixture comprising pharmaceutically acceptable stereoisomers thereof (e.g., a racemic mixture comprising N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-(S)- 3-(4-aminophenyl)-2-methoxypropionic acid, or pharmaceutically acceptable salts thereof), about 0.012% Syloid® 244 FP, about 0.003% magnesium stearate, about 0.994%

povidone,about 0.994% methyl cellulose, about 0.020% sodium propyl parahydroxybenzoate, about 0.199% sodium methyl parahydroxybenzoate, about 0.746% disodium phosphate dodecahydrate, about 0.298% sodium dihydrogen phosphate dihydrate, and about 96.13% water, wherein the percent of each component refers to the percent weight of the total composition; wherein the pH of the composition is about pH 6.0; and wherein the viscosity of the composition is less than about 200 cP.

[0027] Disclosed compositions may have minimal impurities, e.g., a contemplated single dose composition may have less than about 0.03 weight percent N-formyl derivative of compound A 9 hours after reconstitution.

Kits

[0028] Provided herein in an embodiment is a kit comprising a disclosed dry composition, and optionally a disclosed liquid composition suitable to reconstitute the dry composition, e.g. to form a reconstituted solution suitable for rectal administration by enema. For example, a contemplated kit may include a dual-chambered container comprising two individual chambers each containing either the dry composition or the liquid composition; and a separator cap situated between said chambers. Such a dual-chambered container may be suitable for combining the dry composition and the liquid composition into a single solution in the container. A dual- chambered container may include, for example, about 0.70 g of a disclosed dry composition in one chamber and about 1 13 g of a disclosed liquid composition in the other chamber.

[0029] Contemplated kits may include a container, e.g., a dual chambered container that includes an outlet suitable for administering said solution rectally to a patient in need thereof, and/or may further include a cannula and/or an outlet suitable for insertion of a cannula. [0030] Such kits may include a suitable dosage form such as those described above and instructions describing the method of using such dosage forms to treat ulcerative colitis. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art, e.g., rectally, for example, by an enema preparation. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (e.g., a disclosed dry composition and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the dry composition is placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the dry composition is sealed in the recesses between the plastic foil and the sheet.

Preferably the strength of the sheet is such that the composition can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess and can then be removed via said opening.

[0031] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the dry compositions whereby the numbers correspond with the days of the regimen which the composition so specified should be administered. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . ." etc. Other variations of memory aids will be readily apparent.

[0032] Methods

[0033] Also provided herein is a method of treating an inflammatory bowel disease comprising dissolving a disclosed dry composition in a disclosed liquid composition, and administering the final dissolved composition rectally by enema (e.g., via cannula) to a patient in need thereof. In some embodiments, the inflammatory bowel disease may be Crohn's disease, ulcerative colitis, indeterminate colitis, collagenous colitis or lymphocytic colitis. In some embodiments, the inflammatory bowel disease may be Crohn's disease or ulcerative colitis. In a preferred embodiment, the inflammatory bowel disease is ulcerative colitis.

[0034] In a preferred embodiment, a method of treating an inflammatory bowel disease is also provided comprising rectally administering about 600 mg of (S)-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt thereof to a patient (e.g., a human patient) in need thereof. In other embodiments, a method of treating an inflammatory bowel disease is provided comprising rectally administering about 600 mg of (R)-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt thereof, or 600 mg of a racemic mixture of (S)-3-(4-aminophenyl)-2-methoxypropionic acid and (R)-3-(4-aminophenyl)-2- methoxypropionic acid or pharmaceutically acceptable salts thereof, to a patient (e.g., a human patient) in need thereof. In yet further embodiments, a method of treating an inflammatory bowel disease is provided comprising rectally administering about 600 mg of N-acetyl-(S)-3-(4- aminophenyl)-2-methoxypropionic acid, about 600 mg of N-acetyl-(R)-3-(4-aminophenyl)-2- methoxypropionic acid, or about 600 mg of a racemic mixture comprised of N-acetyl-(S)-3-(4- aminophenyl)-2-methoxypropionic acid and N-acetyl-(R)-3-(4-aminophenyl)-2- methoxypropionic acid or pharmaceutically acceptable salts thereof to a patient (e.g., a human patient) in need thereof. In other embodiments, a method of treating inflammatory bowel disease is provided comprising rectally administering about 0.10 g, about 0.20 g, about 0.30 g, about 0.40 g, about 0.50 g, about 0.55 g, about 0.65 g, about 0.70 g, about 0.80 g, about 0.90 g, about 1.00 g, about 1.10 g, about 1.20 g, about 1.30 g, about 1.40 g, about 1.50 g, about 1.60 g, about 1.70 g, or about 1.80 g of 3-(4-aminophenyl)-2-methoxypropionic acid, N-acetyl-3-(4- aminophenyl)-2-methoxypropionic acid, or stereoisomers (including racemic mixtures) or pharmaceutically acceptable salts thereof, to a patient in need thereof. In some embodiments, a method of treating inflammatory bowel disease is provided comprising rectally administering between about 0.10 g and about 0.20 g, between about 0.20 g and about 0.30 g, between about 0.30 g and about 0.40 g, between about 0.40 g and about 0.50 g, between about 0.50 g and about 0.60 g, between about 0.60 g and about 0.70 g, between about 0.70 g and about 0.80 g, between about 0.80 g and about 0.90 g, between about 0.90 g and about 1.00 g, between about 1.00 g and about 1.10 g, between about 1.10 g and about 1.20 g, between about 1.20 g and about 1.30 g, between about 1.30 g and about 1.40 g, between about 1.40 g and about 1.50 g, between about 1.50 g and about 1.60 g, between about 1.60 g and about 1.70 g, or between about 1.70 g and about 1.80 g of 3-(4-aminophenyl)-2-methoxypropionic acid, N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid, or stereoisomers (including racemic mixtures) or pharmaceutically acceptable salts thereof, to a patient in need thereof. Such rectal administration may be in the form of an enema.

[0035] Contemplated methods may include administering a disclosed composition once per week, twice per week, three times per week, four times per week, five times per week, six times per week, once per month, twice per month, three times per month, four times per month, five times per month, once per day, two times per day, three times per day, four times per day, five times per day, or more. For example, a composition may be administered once per day.

EXAMPLES

Example 1: Formulation of the liquid phase/liquid composition

[0036] The components listed in Table 1 were selected for use in the liquid phase of the final formulation for treating ulcerative colitis.

[0037] Table 1. Components selected for liquid phase formulation

[0038] Parahydroxybenzoate sodium salts were selected as antimicrobial preservatives for the liquid phase due to their high activity at pH 7.5 and because they readily dissolve in aqueous media.

[0039] The liquid phase was formulated with a target viscosity of less than 200 cP to promote both easy dissolution of the active pharmaceutical ingredient and ease of administration. Povidone and methylcellulose were selected as thickening agents in order to achieve the desired viscosity. Five different formulations of the liquid phase containing from 0.84% to 1.75% by weight of each viscosity agent. Formulations containing 1.00% and 1.25% by weight each of povidone and methyl cellulose fell within the desired viscosity range. The formulation containing 1.00% by weight each of povidone and methyl cellulose was selected for the final liquid phase formulation.

[0040] The liquid phase was formulated to have a final pH of 7.5. This pH value was selected in order to achieve a final pH in the range of pH 5.5 and pH 6.5 - suitable for administration to the rectum and distal colon in patients affected by IBD - upon dissolution of the dry composition containing the active pharmaceutical ingredient (API). A pH of 7.5 was also selected for the liquid phase in order to allow maintain activity of the preservatives, which is optimal in the range of pH 4 to pH 8. A target pH value above pH 6 was also selected to avoid the need for excess buffering reagents and formation of phosphate salts.

[0041] Disodium phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate were selected as buffers for the liquid phase formulation. To determine the optimal buffer concentration, 4 formulations of the liquid phase with total phosphate buffer concentrations of 33 mM, 38 mM, 45 mM, or 51 mM, all at pH 7.5, were prepared. The pH of solutions containing each formulation were measured before and after addition of the API (i.e., (S)-3-(4- aminophenyl)-2-methoxypropionic acid). As shown in Table 2, lower phosphate buffer concentrations resulted in lower the pH solution values following addition of the API. A final phosphate buffer concentration of 45 mM was chosen for the liquid phase in order to achieve a final pH value of 6.0 upon dissolution of the API.

[0042] Table 2. Relationship between liquid phase phosphate buffer concentration and final dissolved API formulation pH.

[0043] The pH of each preparation of the liquid phase containing different phosphate buffer concentrations was also measured as a function of time in order to determine the kinetics of the pH change in the dissolved solution and to determine whether the final dissolved solution is stable with respect to pH. As seen in FIG. 1 , about 4 minutes after addition of the API to the liquid phase test formulations, the pH of most of the solutions, including the 45 mM phosphate buffer solution, stabilized. This demonstrates that the 45 mM solution quickly reached a stable pH in the desired range after API addition.

[0044] The final formulation of the liquid phase composition is shown in Table 3. [0045] Table 3: Final liquid phase formulation

Example 2: Formulation of the solid phase/dry composition

[0046] The components listed in Table 3 were selected for use in the solid phase of the final formulation for treating ulcerative colitis. [0047] Table 3. Components selected for solid phase formulation.

[0048] Solid phase formulation components were selected to facilitate mobility between chambers within the administration device, to avoid clogging within the device, and to prevent formation of lumps. To achieve these properties, the solid phase was formulated to include a lubricant (magnesium stearate) and an anticaking agent (colloidal silica). Solid phase components were also selected for inertness and because they displayed no effect on pH following dissolution in the liquid phase.

[0049] In order to determine the optimal concentration of anticaking agent and lubricant to include in the final solid phase formulation, experiments were performed to measure angle of repose and flowability through a funnel. Formulations containing different amounts of magnesium stearate and colloidal silica were produced. Final concentrations of 0.50%.

magnesium stearate and 2.00% colloidal silica by weight were selected for the solid phase formulation based on the results of these tests.

[0050] Solid phase formulations containing different types of colloidal silica were also tested in order to determine whether colloidal silica could be employed as an inert diluent and to test homogeneity and flow properties of the different formulations. Solid phase formulations containing up to 0.684 g were produced in order to mimic the API concentration in the final dissolved liquid formulation (i.e., 49.75%). Each formulation contained one of four types of silica: Aerosil 200 W Pharma, Aerosil R972 Pharma, Sipernat 160 PQ, and Syloid 244 FP. Additionally, formulations containing either 49.75% or 2.00% silica were generated and tested. Homogeneity of each formulation was analyzed by taking samples from the top and the bottom of a vessel following production of each test formulation and performing high performance liquid chromatography (HPLC) to determine the makeup of each sample. Additionally, the flowability of each test formulation was analyzed by passing a sample through a 10 mm diameter funnel and measuring the formation of clogs and the amount of material adhering to the funnel wall. The results of these tests are shown in Table 4. [0051] Table 4. Solid phase test formulation homogeneity and flow properties

DS = Drug Substance

[0052] As indicated in Table 4, formulations 4 and 6, each containing 1 : 1 ratios of APLsilica displayed poor flow properties. These results demonstrated that the formulations containing 2.0% silica displayed optimal homogeneity and flow properties.

[0053] Solid phase formulations containing different types of silica at 2.0% or 49.75% of the solid phase by weight were also generated in order to analyze API recovery following dissolution in liquid phase formulations. The average recovery results from three samples of each formulation are shown in Table 5. As indicated in Table 5, high concentration silica formulations displayed clogging formation. The results also demonstrated that formulations containing 2.0% Sipernat or Syloid silicas provided the highest API recovery rates.

[0054] Table 5. Percentage of API recovery after reconstitution.

(*) Clog formation was observed. Results are the average value of three replications.

[0055] The final formulation of the solid phase composition is shown in Table 6.

[0056] Table 6: Final solid phase formulation

Example 3: Reconstituted Solution

[0057] The final dry powder composition formulation containing the API was dissolved in the final liquid phase composition formulation containing buffers, preservatives, solvent, and viscosity increasing agents. Following dissolution, the final composition was clear and colorless; it had a density of 1.005 kg/L; it had a pH of 6.0; and it had a viscosity of 5 cP. These results are documented in Table 6. The composition of the final formulation for administration is shown in Table 7. [0058] Table 6. Properties of the final reconstituted composition

[0059] Table 7. Final reconstituted formulation

Example 4: Dual-chambered container and Drug Extrusion

[0060] A suitable dual-chambered container with separate chambers for the final dry composition formulation and the final liquid composition formulation was produced. The dual- chambered container was also designed to allow mixture and dissolution of the dry composition in the liquid composition prior to administration. The final container included the following components: a double chamber flask made of low-density polyethylene (LDPE), a separator cap made of high-density polyethylene (HDPE); a cap made of polyethylene (PE); and a cannula made of PE (FIG. 2A-D). LDPE was selected as the material for the container body in order to ensure the container could be easily compressed during administration. The container was designed to include a separator cap in order to ensure that the dry and liquid compositions are isolated during storage.

[0061] Tests were performed to determine the optimal volume of solid phase and liquid phase formulations that should be loaded into the container in order to ensure that 600 mg of API dissolved in a final volume of 100 ml (with a final density of 1.00 g/ml) was administered upon extrusion of the dissolved solution from the container. Containers were loaded with between 1 12 g and 115 g of the reconstituted final formulation. A cannula was inserted into each container and the solution was extruded by squeezing. The mass of liquid successfully extruded from each container and the mass left in the containers following extrusion were measured. This analysis was performed in replicate between 5 to 10 times per tested volume. The results in Table 8 demonstrate that filling the container with 114 g of solution resulted in successful extrusion of approximately 100 g of the solution.

[0062] Table 8. Extruded liquid mass as a function of total liquid mass per container

Example 5: Batch Formulation Manufacturing for Clinical Trial Use and Quality Control

Assays

Manufacturing

[0063] 1400 bottles containing (S)-3-(4-aminophenyl)-2-methoxypropionic acid

(Compound A) in dry composition and liquid composition (at a final concentration of 6 mg Compound A per 1 g total dry and liquid composition) were manufactured. Compound A drug product was manufactured in compliance with cGMP guidelines. FIG. 3 provides a flow chart of the manufacturing process.

[0064] The liquid phase composition was prepared in the following manner: in a suitable vessel, purified water was transferred and stirred. The following components were then added to the water until the liquid solution reached a pH of 7.5: sodium propylparaben, sodium

methylparaben, sodium phosphate dibasic dodecahydrate, and sodium phosphate monobasic dihydrate. This solution was then stirred for 3 minutes. Povidone and methylcellulose which had been previously mixed together, were then added to the solution, which was mixed for an additional 20 minutes. The final liquid composition was then transferred into a storage vessel prior to filling dual-chambered containers with the solution.

[0065] The solid phase composition was prepared in the following manner. First, all solid phase components (Compound A, magnesium stearate, and silica) were accurately weighed. Compound A powder was transferred into a plastic drum mixer. Magnesium stearate was sieved using a 0.5 mm stainless steel sieve and added to Compound A. Colloidal silica anhydrous was also then sieved using a 0.5 mm stainless steel sieve and added to the other components. The plastic drum containing the sieved components was closed and components were mixed in the drum for 20 minutes using a rotating mixer. The mixed powder was transferred into a storage vessel prior to filling dual- chambered containers with the powder.

[0066] Dual-chambered containers were manually filled with the liquid and solid phase compositions. First, approximately 113 g of the liquid solution was weighed and added to the container, taking care not to allow liquid to enter the upper chamber designated for the dry composition. Following addition of the liquid solution to the lower chamber, a separator cap was inserted below the upper chamber and fixed in place. A funnel was then used to add

approximately 0.700 g of the dry powder composition to the upper chamber. The sealing cap was then added to the top of the bottle.

Dry composition/Solid phase quality analysis

[0067] The following procedures were utilized to analyze the quality of the solid phase composition. The powder was visually inspected to ensure that the final composition was white to off-white powder. Water content of the powder was analyzed by weighing the powder and using the Karl Fischer titration method in accordance with the European Pharmacopoeia (Ph. Eur.) 2.5.12. pH was determined according to the Ph. Eur. 2.2.3 methodology in a 1% (w/w) water solution. The percent of active Compound A was determined using an external reference standard (one point calibration).

[0068] The presence and content of impurities in the solution relative to the amount of Compound A were determined using HPLC. The amount of the impurity N-formyl-Compound A was quantified using an external reference standard (one point calibration). Other unknown impurities were quantified using (S)-3-(4-aminophenyl)-2-methoxypropanoic acid (one point calibration) as the reference. An Agilent 1100/1200 or equivalent high performance liquid chromatographic system equipped with a gradient pump, diode array detector, and

polytetrafluoroethylene (PTFE) 0.45 μ filters was used for HPLC analysis. Column: PFP (pentalfluorophenyl propyl), 5μηι, 4.6x250 mm or equivalent. Mobile phase A was potassium phosphate buffer/acetonitrile (97.5/2.5 v/v) (Solution A), and mobile phase B was acetonitrile. The following settings were used: flow rate of 2.0 ml/min, column temperature of 55°C, injection volume of 50μ1, detection wavelength of 210 nm, and a run time of 20 minutes. The gradient in Table 9 was used.

[0069] Table 9. HPLC Gradient Program.

[0070] A diluting solvent (solution A) was produced by mixing purified water and acetonitrile at a ratio of 1 : 1 by volume.

[0071] For preparation of the Compound A standard (solution B), 10 mg of Compound A was dissolved in water at a concentration of 10 mg/100 ml. For preparation of the N-formyl- Compound A impurity standard (solution C), 10 mg of N-formyl- Compound A was dissolved in solution A at 10 mg/100 ml. A related substance reference solution (solution D) was produced by dissolving 1 ml of each of solutions B and C in mobile phase A at a final concentration of 0.1 mg/lOOml of each diluted reference molecule (or 0.2% by weight of the final solution, for each molecule). A second reference solution (solution E) was produced by diluting 10 ml of solution B in 90 ml of mobile phase A to yield a final concentration of 1 mg/ 100 ml.

[0072] To prepare solid phase preparations for analysis (solution F), 50 mg samples of solid phase preparations were each dissolved in 80 ml of mobile phase A by stirring for 10 minutes, adding mobile phase A to a volume of 100 ml, and filtering the final 50 mg/ 100 ml solution through a 0.45 μηι filter. 2ml of this solution was diluted in mobile phase A at a final concentration of 1 mg/ 100 ml (to produce solution H). Mobile phase A was used as a blank for HPLC analysis (solution J).

[0073] To prepare the final reconstituted formulation for analysis (solution G), 8000 mg samples of the reconstituted composition were each dissolved in mobile phase A at a total volume of 100 ml, and filtered through a 0.45 μηι filter. The final concentration of the solution was 8000 mg/ 100 ml. 2 ml of this solution was dissolved in mobile phase A at a final concentration of 160 mg/ 100 ml (to produce solution I). A blank solution was produced by diluting 5 ml of the liquid composition (i.e., no solid phase components) in mobile phase A at a total volume of 100 ml (solution K).

[0074] Analyses of the solid phase and reconstituted solution samples were performed by injecting reference and sample solution volumes into the HPLC system, as shown in Table 10.

[0075] Table 10. HPLC injection volume and number of injections by sample.

[0076] Tests were performed to detect the total aerobic microbial count and the total combined yeast and mould count in the manufactured formulations using current Ph. Eur. 5.1.4. Tests were performed on the reconstituted phase in order to determine whether either of the solid phase or liquid phase contained microbial contaminants.

Liquid composition/Liquid phase quality analysis

[0077] The following assays were performed to analyze the quality of the manufactured liquid composition. Appearance of the composition was inspected visually by looking for a clear to slightly yellow color. pH of the solution was tested using Ph. Eur. 2.2.3, with a desired range of pH 7.2-7.8.

[0078] Viscosity of the liquid composition was determined in accord with Ph. Eur. 2.2.10. A viscosity of less than 200 cP is preferred.

[0079] HPLC was also used to analyze the antimicrobial preservatives used in the liquid composition. An Agilent 1 100/1200 or equivalent high performance liquid chromatographic system equipped with a gradient pump, diode array detector, and polytetrafluoroethylene (PTFE) 0.45 μ filters was used for HPLC analysis. Column: PFP (pentalfluorophenyl propyl), 5μηι, 4.6x250 mm or equivalent. Mobile phase A was potassium phosphate buffer/acetonitrile (97.5/2.5 v/v) (Solution A), and mobile phase B was acetonitrile. The following settings were used: flow rate of 2.0 ml/min, column temperature of 55°C, injection volume of 20μ1, detection wavelength of 210 nm, and a run time of 20 minutes. The gradient in Table 1 1 was used.

[0080] Table 1 1. HPLC Gradient Program.

[0081] A sodium methyl parahydroxybenzoate stock standard (solution B) was prepared by dissolving 20 mg of sodium methyl parabenzoate in water at a final concentration of 200 mg/100 ml. A sodium propyl parahydroxybenzoate stock standard (solution C) was prepared by dissolving 10 mg of sodium propyl parabenzoate in water at a final concentration of 20 mg/100 ml. A p-hydroxybenzoic acid stock standard (solution D) was produced by dissolving 10 mg of p-hydroxybenzoic acid in water at a concentration of 20 mg/100 ml. A reference solution was prepared by dissolving 1 ml each of solutions B, C, and D in mobile phase A at a total volume of 100 ml (final concentrations: sodium methyl parahydroxybenzoate^ mg/100 ml; sodium propyl parahydroxybenzoate, 0.2 mg/100 ml; p-hydroxybenzoic acid, 0.2 mg/100 ml). The sample solution was prepared by dissolving 1000 mg of sample in mobile phase at a total volume of 100 ml and filtering through a 0.45 μηι filter (final concentration of 1000 mg/100 ml). Mobile phase A was used as a blank solution.

[0082] Analysis was performed by injecting reference and sample solution volumes into the HPLC system, as shown in Table 12. [0083] Table 12. HPLC injection volume and number of injections by sample.

Reconstituted composition quality analysis

[0084] The following assays were performed to analyze the quality of the reconstituted composition. Appearance of the reconstituted composition was inspected visually by looking for a clear to slightly yellow color. pH of the solution was tested using Ph. Eur. 2.2.3, with a desired pH in the range of pH 5.5-6.5.

[0085] Viscosity of the reconstituted composition was determined in accord with Ph. Eur. 2.2.10. A viscosity of less than 200 cP is desired.

[0086] HPLC analysis was used to detect the purity of the reconstituted phase. A protocol similar to the solid phase protocol was used.

Test batch quality analysis

[0087] Three pilot batches of 100 containers of dry composition and liquid composition each were manufactured for analysis according to the protocols described herein. The analysis results for these batches are shown in Table 13. [0088] Table 13. Quality control analysis of test batches.

[0089] No impurities were detected in the manufactured test batch. [0090] The stability of the test batch was also analyzed. Specifically, the manufactured compositions packaged in 160 ml dual-chambered containers with a screw tap were placed at storage conditions in compliance with the (ICH) guidelines (25°C/60% RH, 30°C/65%RH, 40°C/75% RH and 5°C).

[0091] The stability results confirmed that the manufactured product was stable.

Example 6: Reconstitution of Drug Product in the Container and Administration

[0092] Dissolution of the dry powder composition in the liquid formulation in the dual- chambered container can be achieved in the following manner. One should first depress the top of the container, displacing the separator cap, and opening a channel between the two chambers. With the container positioned horizontally, one should shake the bottle to promote dissolution of the dry composition in the liquid composition containing the solvent. The tip on the upper cap should then be removed, and the anal cannula inserted. The cannula should be inserted into the anal cavity and dissolved API formulation extruded by placing pressure on the container.

Example 7: Local Tolerability Study of a Rectal Composition in Rabbits

[0093] A study to test the local tolerance of the rectal formulation (the components of the solid phase are shown in Table 14 and the pH of the final solution was adjusted to 6.2) was performed in New Zealand white rabbits. The purpose of the study was to ascertain tolerability of the medicinal product (both active substance and excipients) at the site of administration for four weeks as per EMA guideline CPMP/SWP/2145 and to evaluate reversal of possible side effects over two weeks. The study was designed based on CPMP/SWP/2145/00, 2001. "Note for guidance on non-clinical local tolerance testing of medicinal products."

[0094] Table 14. Components of the solid phase for the rectal formulation

Formulations were prepared on a weekly basis and stored at + 4°C. All the formulations were returned to room temperature before daily utilization.

Experimentals

[0095] The study was conducted according to the experimental scheme of Table 15. Three groups of five male rabbits and three groups of five female rabbits were given a repeated rectal application of the formulation as enema once daily for 28 days (4 consecutive weeks) at concentrations of 0 (vehicle, Group 1), 6 (Group 2), or 18 (Group 3) mg/mL of (S)-3-(4- aminophenyl)-2-methoxypropionic acid in the fixed volume of 5 mL. At the end of the treatment period, theree rabits per group were sacrificed and the remaining rabbits were allowed a two- week recovery period.

[0096] Table 15. Experimental Scheme

[0097] - INCORPORATION BY REFERENCE

[0098] The entire disclosure of each of the patent documents and scientific articles cited herein is incorporated by reference for all purposes.

EQUIVALENTS

[0099] The invention can be embodied in other specific forms with departing from the essential characteristics thereof. The foregoing embodiments therefore are to be considered illustrative rather than limiting on the invention described herein. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

WHAT IS CLAIMED:

1. A dry composition for the rectal treatment of inflammatory bowel disease comprising:

an active compound selected from 3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof,

an anticaking agent, and

a lubricant, wherein the pH of the dry composition is between about pH 3.0 and about pH 5.0.

2. The dry composition of claim 1 , wherein the active compound is (5 -3-(4-aminophenyl)-2- methoxypropionic acid.

3. The dry composition of claim 1 or 2, wherein the composition comprises about 90% to about 99% by weight of the active compound.

4. The dry composition of any one of claims 1-3, wherein the composition comprises about 97.5% by weight of the active compound.

5. The dry composition of any one of claims 1-4, wherein the composition comprises about 0.5% to about 5% by weight anticaking agent.

6. The dry composition of any one of claims 1-5, wherein the composition comprises about 2% by weight anticaking agent.

7. The dry composition of any one of claims 1-6, wherein the anticaking agent is colloidal silica anhydrous.

8. The dry composition of claim 7, wherein the colloidal silica anhydrous is selected from Aerosil® 200 W Pharma, Aerosil® R972 Pharma, Sipernat® 160 PQ, and Syloid® 244 FP.

9. The dry composition of any one of claims 1-8, wherein the anticaking agent is Syloid® 244 FP.

10. The dry composition of any one of claims 1-9, wherein the lubricant is magnesium stearate.

11. The dry composition of any one of claims 1-10, wherein the composition comprises about 0.10% to about 1% by weight lubricant.

12. The dry composition of any one of claims 1-11 , wherein the composition comprises about 0.50% of lubricant by weight.

13. A container comprising the dry composition of any one of claims 1-12, wherein the composition has between about 0.60 g and about 0.70 g of the active compound.

14. The container of claim 13, wherein the composition has about 0.68 g of the active compound.

15. The container of claim 13 or 14, wherein the composition further has between about 0.010 g and about 0.020 g of the anticaking agent.

16. The container of claim 15, wherein the composition has about 0.014 g of the anticaking agent.

17. The container of any one of claims 13-16, wherein the composition further has between about 0.0030 g and 0.0040 g of the lubricant.

18. The container of claim 17, wherein the composition has about .0035 g of the lubricant.

19. A liquid composition suitable for reconstituting the dry composition of any one of claims 1- 12, comprising:

a viscosity increasing agent,

a buffering agent having a concentration of about 30 mM to about 50 mM,

a solvent, and optionally, a preservative, wherein the liquid composition has a pH between about 7.2 and about 7.8.

20. The liquid composition of claim 19, wherein the viscosity increasing agent is selected from the group consisting of povidone, methyl cellulose, and combinations thereof.

21. The liquid composition of claim 19 or 20, wherein the composition comprises about 1.00% to about 3.00% by weight of the viscosity increasing agent.

22. The liquid composition of any one of claims 19-21, wherein the composition comprises about 2.00% by weight of the viscosity increasing agent.

23. The liquid composition of any one of claims 19-22, wherein the buffering agent is selected from disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, and combinations thereof.

24. The liquid composition of any one of claims 19-23, wherein the composition comprises about 0.75% to about 1.25% by weight of the buffering agent.

25. The liquid composition of any one of claims 19-24, wherein the composition comprises about 1.04% by weight of the buffering agent.

26. The liquid composition of any one of claims 19-25, wherein the buffering agentis at a concentration of about 45 mM.

27. The liquid composition of any one of claims 19-26, wherein the solvent is water.

28. The liquid composition of any one of claims 19-27, wherein the composition comprises about 90.0% to about 99.0% by weight of the solvent.

29. The liquid composition of any one of claims 19-28, wherein the composition comprises about 96.7% by weight of the solvent.

30. The liquid composition of any one of claims 19-29, wherein the preservative is selected from the group consisting of sodium propyl parahydroxybenzoate, sodium methyl

parahydroxybenzoate, and combinations thereof.

31. The liquid composition of any one of claims 19-30, wherein the composition comprises about 0.01% to about 0.50% by weight of the preservative.

32. The liquid composition of any one of claims 19-31, wherein the composition comprises about 0.22% by weight of the preservative.

33. The liquid composition of any one of claims 19-32, wherein the pH of the composition is about pH 7.5.

34. The liquid composition of any one of claims 19-33, wherein the viscosity of the solution is less than about 200 cP.

35. A container comprising the liquid composition of any one of claims 19-34, wherein the composition has between about 2.00 g and about 2.50 g of the viscosity increasing agent.

36. The container of claim 35, wherein the composition has about 2.26 g of the viscosity increasing agent.

37. The container of claim 35 or 36, wherein the composition further has between about 1.00 g and 1.25 g of the buffering agent.

38. The container of claim 37, wherein the composition has about 1.18 g of the buffering agent.

39. The container of any one of claims 35-38, wherein the composition further has between about 100 g and 120 g of solvent.

40. The container of claim 39, wherein the composition has about 110 g of water.

41. The container of any one of claims 35-40, wherein the composition further has between about 0.10 g and 0.50 g of the preservative.

42. The container of claim 41, wherein the composition has about 0.25 g of the preservative.

43. A single liquid dose composition having a pH of between about 5.5 and about pH 6.5 for rectal administration to a patient suffering from inflammatory bowel disease comprising:

between about 0.60 g and about 0.70 g of (S)-3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt thereof,

an anticaking agent, a lubricant, one or more viscosity increasing agents, one or more antimicrobial preservatives, one or more buffering agents, and a solvent.

44. The composition of claim 43, comprising about 0.68 g of (S)-3-(4-aminophenyl)-2- methoxypropionic acid.

45. The composition of claim 43 or 44, wherein the anticaking agent is colloidal silica anhydrus.

46. The composition of claim 45, wherein the colloidal silica anhydrus is selected from Aerosil® 200 W Pharma, Aerosil® R972 Pharma, Sipernat® 160 PQ, and Syloid® 244 FP.

47. The composition of any one of claims 43-46, comprising between about 0.010 g and about 0.020 g of the anticaking agent.

48. The composition of any one of claims 43-47, comprising about 0.014 g of the anticaking agent.

49. The composition of any one of claims 43-48, wherein the anticaking agent comprises about 0.012% of the composition by weight.

50. The composition of claim any one of claims 43-49, wherein the anticaking agent is Syloid® 244 FP.

51. The composition of any one of claims 43-50, wherein the lubricant is magnesium stearate.

52. The composition of any one of claims 43-51, wherein the lubricant comprises about 0.003% of the composition by weight.

53. The composition of any one of claims 43-52, comprising about 0.0035 g of the lubricant.

54. The composition of any one of claims 43-53, wherein the one or more viscosity increasing agents are selected from the group consisting of povidone, methyl cellulose, and combinations thereof.

55. The composition of any one of claims 43-54, comprising about 1.00% to about 3.00% by weight one or more viscosity increasing agents.

56. The composition of any one of claims 43-55, comprising about 1.13 g of each of the one or more viscosity increasing agents.

57. The composition of any one of claims 43-56, comprising about 2.26 g in total of the one or more viscosity increasing agents.

58. The composition of any one of claims 43-57, comprising about 1.04% by weight one or more buffering agents.

59. The composition of any one of claims 43-58, comprising about 1.18 g of the one or more buffering agents.

60. The composition of any one of claims 43-59, wherein the one or more buffering agents comprise about 0.850g disodium phosphate dodecahydrate and 0.340 g sodium dihydrogen phosphate dihydrate.

61. The composition of any one of claims 43-60, wherein the solvent is water.

62. The composition of any one of claims 43-61, comprising about 110 g of water.

63. The composition of any one of claims 43-62, comprising about 96.13% solvent by weight.

64. The composition of any one of claims 43-63, wherein the one or more antimicrobial preservatives are selected from sodium propyl parahydroxybenzoate and sodium methyl parahydroxybenzo ate .

65. The composition of any one of claims 43-64, wherein the one or more antimicrobial preservatives are sodium propyl parahydroxybenzoate and sodium methyl parahydroxybenzoate.

66. The composition of any one of claims 43-65, comprising about 0.22% by weight antimicrobial preservatives.

67. The composition of any one of claims 43-66, comprising about 0.25 g of the one or more antimicrobial preservatives.

68. The composition of any one of claims 43-67, wherein the one or more antimicrobial preservatives comprise about 0.023 g of sodium propyl parahydroxybenzoate and 0.227 g of sodium methyl parahydroxybenzoate.

69. The composition of any one of claims 43-68, wherein the pH of the composition is about pH 6.0.

70. The composition of any one of claims 43-69, wherein the viscosity of the composition is less than about 200 cP.

71. A composition for treatment of ulcerative colitis suitable for rectal administration comprising

about 0.600% 3-(4-aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt or stereoisomer thereof,

about 0.012% Syloid® 244 FP,

about 0.003% magnesium stearate,

about 0.994% povidone,

about 0.994% methyl cellulose,

about 0.020% sodium propyl parahydroxybenzoate,

about 0.199% sodium methyl parahydroxybenzoate,

about 0.746% disodium phosphate dodecahydrate,

about 0.298% sodium dihydrogen phosphate dihydrate, and

about 96.13% water,

wherein the percent of each component refers to the percent weight of the total composition; wherein the pH of the composition is about pH 6.0; and

wherein the viscosity of the composition is less than about 200 cP.

72. A dual-chambered container, wherein one chamber comprises the dry composition of any one of claims 1-12, and a second chamber comprises the liquid composition of any one of claims 19-34.

73. The container of claim 72, further comprising a separator cap situated between the two chambers, and a sealing cap.

74. The container of claim 72 or 73, further comprising a cannula.

75. The container of any one of claims 72-74, comprising about 0.70 g of said dry composition and about 1 13 g of said liquid composition.

76. A kit comprising components

i) a dry composition of any one of claims 1-12 ii) a liquid composition suitable to reconstitute the dry composition, wherein said liquid composition and said dry composition can be combined into a single solution suitable for treatment of ulcerative colitis.

77. The kit of claim 76, further comprising a dual chambered container comprising

two individual chambers each containing either the dry composition or the liquid composition; and

a separator cap situated between said chambers.

78. The kit of claim 77, wherein said dual chambered container is suitable for combining the dry composition and the liquid composition into a single solution in the container.

79. The kit of claim 77 or 78, wherein said dual-chambered container comprises about 0.70 g of said dry composition and about 113 g of said liquid composition.

80. The kit of any one of claims 77-79, wherein said dual chambered container further comprises an outlet suitable for administering said solution rectally to a patient in need thereof.

81. The kit of any one of claims 77-80, wherein said dual chambered container further comprises an outlet suitable for insertion of a cannula.

82. The kit of any one of claims 77-81, further comprising a cannula.

83. A method of treating an inflammatory bowel disease comprising the steps of: dissolving the dry composition of any one of claims 1-12 in the liquid composition of any one of claims 19-34, and administering the final dissolved composition rectally to a patient in need thereof.

84. A method of treating an inflammatory bowel disease, wherein the composition of any one of claims 43-70 is administered rectally to a patient in need thereof.

85. The method of claim 84, wherein the composition is administered in the form of an enema.

86. The method of claim 84, wherein the composition is administered via a cannula.

87. The method of claim 83 or 84, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

88. The method of claim 87, wherein the inflammatory bowel disease is ulcerative colitis.

89. The method of claim 83 or 84, wherein about 600 mg of (S)-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt thereof is administered to the patient with each dose.

90. The method of claim 83 or 84, wherein the patient is a human patient.

91. The method of claim 83 or 84, wherein the composition is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, once per month, twice per month, three times per month, four times per month, five times per month, once per day, two times per day, three times per day, four times per day, five times per day, or more.

92. The method of claim 83 or 84, wherein the composition is administered once per day.