WO2017093444A1 - Compositions appropriées pour être administrées par voie orale, dans le traitement de maladies intestinales inflammatoires - Google Patents

Compositions appropriées pour être administrées par voie orale, dans le traitement de maladies intestinales inflammatoires Download PDF

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Publication number
WO2017093444A1
WO2017093444A1 PCT/EP2016/079512 EP2016079512W WO2017093444A1 WO 2017093444 A1 WO2017093444 A1 WO 2017093444A1 EP 2016079512 W EP2016079512 W EP 2016079512W WO 2017093444 A1 WO2017093444 A1 WO 2017093444A1
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oral pharmaceutical
tablet
active agent
composition
weight percent
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PCT/EP2016/079512
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English (en)
Inventor
Marie MCNULTY
Francesca Viti
Salvatore Bellinvia
Salvatore Demartis
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Nogra Pharma Limited
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Publication of WO2017093444A1 publication Critical patent/WO2017093444A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • Inflammatory bowel disease can refer to a group of diseases including both Crohn's disease and ulcerative colitis (UC).
  • 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.
  • CT computed tomography
  • 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. UC affects only the large intestine.
  • Inflammation and ulceration in UC 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.
  • the course of both diseases is intermittent, with disease exacerbations followed by periods of remission.
  • UC may be a single event, or continuous with unrelenting symptoms.
  • Oral administration e.g., in the form of a tablet, is usually the easiest way from both a physician and patient's perspective to treat a disorder. However, it remains a challenge to treat disorders such as UC and, e.g., deliver an active ingredient specifically to the targeted site.
  • a pharmaceutical composition suitable for oral administration for treatment of an inflammatory bowel disease comprising: an active compound for treating colitis, such as 3-(4-aminophenyl)-2-methoxypropionic acid (or a pharmaceutically acceptable salt and/or a stereoisomer thereof), a pharmaceutically acceptable excipient, and one or more enteric coatings.
  • an active compound for treating colitis such as 3-(4-aminophenyl)-2-methoxypropionic acid (or a pharmaceutically acceptable salt and/or a stereoisomer thereof)
  • a pharmaceutically acceptable excipient may include about 25% to about 29%, e.g., about 27% to about 29%, by weight of the active compound.
  • Contemplated pharmaceutically acceptable excipients may include micro crystalline cellulose and/or a sugar alcohol, e.g., mannitol.
  • an oral pharmaceutical tablet suitable for the treatment of an inflammatory bowel disease comprising: a) an intragranular component comprising about 26 to about 29 weight percent of an active compound selected from 3-(4- aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt and/or a stereoisomer thereof, and micro crystalline cellulose having an average particle size of about 50 ⁇ ; and b) an extragranular component comprising about 5 to about 14 weight percent of micro crystalline cellulose having an average particle size of about 100 ⁇ .
  • an intragranular component comprising about 26 to about 29 weight percent of an active compound selected from 3-(4- aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt and/or a stereoisomer thereof, and micro crystalline cellulose having an average particle size of about 50 ⁇
  • an extragranular component comprising about 5 to about 14 weight percent of micro crystalline cellulose having an average particle size of about 100 ⁇ .
  • intragranular and/or extragranular component may further include a sugar alcohol such as mannitol.
  • a sugar alcohol such as mannitol.
  • the micro crystalline cellulose of the intragranular component may have an average particle size of about 50 ⁇ and the micro crystalline cellulose of the extragranular component may have an average particle size of about 90 ⁇ .
  • a method of treating active UC in a patient in need thereof comprising orally administering a composition comprising an active agent; wherein the composition releases about 4 percent to about 20 percent of the active agent in the proximal region of the colon at a pH of about 6.8, and at least about 50% of the active agent in the recto-sigmoid region of the colon at a pH of about 6.8, which can permit maximal exposure of the colon to the active agent.
  • an active agent may be (S)-3- (4-aminophenyl)-2-methoxypropionic acid.
  • a method of treating a patient suffering from non-active colitis comprising orally administering a composition comprising an active agent; wherein the composition releases at least about 90 percent of the active agent throughout the colon at a pH of about 7.2.
  • an active agent may be (S)-3-(4-aminophenyl)-2-methoxypropionic acid.
  • a pharmaceutical composition for use as a medicament.
  • a pharmaceutical composition for use in treating an inflammatory bowel disease.
  • compositions comprising an active agent for use in treating active ulcerative colitis by oral administration; wherein the composition releases about 4 percent to about 20 percent of the active agent in the proximal region of the colon at a pH of about 6.8, and at least about 50 percent of the active agent in the recto-sigmoid region of the colon at a pH of about 6.8.
  • compositions comprising an active agent for use in treating non-active colitis by oral administration; wherein the composition releases at least about 90 percent of the active agent throughout the colon at a pH of about 7.2.
  • Such an active agent may be (5)-3-(4-aminophenyl)-2-methoxypropionic acid.
  • FIG. 1 shows the dissolution profiles at pH 6.8 (bottom curve, corresponding to active UC environment - high degree of inflammation) and pH 7.2 (top curve, corresponding to a non-active UC environment) of a disclosed formulation. Results are depicted as the percent of dissolved drug substance (active compound) versus time at stage 3 of dissolution (stage 1, 0.1 N HCL for 2 hours; stage 2, pH 6.4 for 1 hour; and stage 3, pH 6.8 or pH 7.2 for 3 hours).
  • FIG. 2 shows the dissolution profile at pH 6.8 of a disclosed formulation.
  • FIG. 3 shows the dissolution profiles at pH 6.8 (bottom curve, corresponding to active UC environment - high degree of inflammation) and pH 7.2 (top curve, corresponding to a non-active UC environment) of a disclosed formulation. Results are depicted as the percent of dissolved drug substance (active compound) versus time at stage 3 of dissolution (stage 1, 0.1 N HCL for 2 hours; stage 2, pH 6.4 for 1 hour; and stage 3, pH 6.8 or pH 7.2 for 3 hours).
  • the formulations disclosed herein are designed to comply with the specific requirements associated with intestinal pH and transit time and, in particular, are highly specific to the characteristics of motility in an inflamed colon.
  • UC with diarrhea has typically been associated with rapid colonic transit time
  • the gastrointestinal motility disturbances in UC patients demonstrated that whole gut transit of solid markers was no faster in any group of UC patients than in controls, and the distribution of markers showed that patients with active colitis had proximal colonic stasis, whereas transit through the recto sigmoid region was rapid; patients with quiescent colitis had normal distribution of markers.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • Ci_ 6 alkyl is specifically intended to individually disclose Ci, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C 6 , C 1 -C 5 , C1-C4, Ci-C 3 , C1-C2, C2-C6, C2-C5, C2-C4, C2-C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C4-C5, and C 5 -C 6 alkyl.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • phrases "optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.
  • Ci_ 6 alkyl is specifically intended to individually disclose Ci, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C 6 , C 1 -C 5 , C1-C4, Ci-C 3 , C1-C2, C2-C6, C2-C5, C2-C4, C2-C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C4-C5, and C5-C6 alkyl.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • phrases "optionally substituted with 1-5 substituents” is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.
  • compound refers to the compound itself and its pharmaceutically acceptable salts, including its various geometric and stereoisomeric forms, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a pharmaceutically acceptable salt.
  • a compound of the present invention can be 3-(4-aminophenyl)-2-methoxypropionic acid or N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • average particle size of micro crystalline cellulose may be determined as done by the manufacturer and/or supplier of the micro crystalline cellulose.
  • Determination may be by, for example, dry dispersion laser diffraction and/or dynamic image analysis.
  • the average particles size may refer to the mean, median or mode of a distribution of particles sizes (for example, a number distribution) as measured in a sample.
  • compositions for oral administration of an active agent for treatment of inflammatory bowel disorders such as UC.
  • oral dosage formulations which are capable of delivering an active agent, e.g., an active compound such as 3-(4-aminophenyl)-2-methoxypropionic acid, (S)-3-(4-aminophenyl)-2- methoxypropionic acid, and/or N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid, stereoisomers thereof (e.g., as a racemic mixture, a substantially isolated stereoisomer, or a pure stereoisomer) and/or pharmaceutically acceptable salts thereof, to the colon.
  • an active agent e.g., an active compound such as 3-(4-aminophenyl)-2-methoxypropionic acid, (S)-3-(4-aminophenyl)-2- methoxypropionic acid, and/or N-acetyl-3-(4-amin
  • an oral pharmaceutical composition capable of releasing an active agent at pH 6.8 in order to allow drug release at the pH of an inflamed colon.
  • Such a composition is capable of releasing the active ingredient in the proximal region of the colon at pH 6.8 for about 1 hour, reflecting the colonic stasis in the proximal region (e.g., about 40 minutes to about 80 minutes), with a subsequent more rapid release at pH 6.8 in the recto-sigmoid region of the colon for at least one hour (e.g., for one to two hours, or for one to three hours) in patients having active UC.
  • An oral pharmaceutical composition may comprise an intragranular component comprising an active agent (e.g., an agent for the treatment of UC, e.g., (S)-3-(4-aminophenyl)-2-methoxypropionic acid) and at least one pharmaceutically acceptable excipient; and an extragranular component comprising at least one pharmaceutically acceptable excipient.
  • an active agent e.g., an agent for the treatment of UC, e.g., (S)-3-(4-aminophenyl)-2-methoxypropionic acid
  • an extragranular component comprising at least one pharmaceutically acceptable excipient.
  • Such a composition may release, after administration to a patient, (e.g., at pH of about 6.8, e.g., wherein the release is substantially in the proximal region of the colon where, for example, the patient is suffering from active colitis), about 4 percent to about 20 percent (e.g., about 5 percent to about 21 percent, or about 7 percent to about 19 percent, or about 10 percent to about 18 percent, e.g., about 10 percent to about 25 percent) of the active agent in the first hour after reaching or being exposed to an environment of pH 6.8.
  • a patient e.g., at pH of about 6.8, e.g., wherein the release is substantially in the proximal region of the colon where, for example, the patient is suffering from active colitis
  • about 4 percent to about 20 percent e.g., about 5 percent to about 21 percent, or about 7 percent to about 19 percent, or about 10 percent to about 18 percent, e.g., about 10 percent to about 25 percent
  • composition can then release about 50% or, at least about 50%, of the active agent between the first and second hour in an environment of pH 6.8 (e.g., more rapidly in the recto-sigmoid region of the colon than in the proximal region of the colon), and/or releasing substantially all the active agent within about 3 hours to about 5 hours or 6 hours after reaching or being exposed to an environment of pH 6.8.
  • pH 6.8 e.g., more rapidly in the recto-sigmoid region of the colon than in the proximal region of the colon
  • an oral pharmaceutical composition capable of releasing an active agent at pH 6.8 in order to reflect the pH of an inflamed colon.
  • Such a composition is capable of releasing the active agent in the proximal region of the colon at pH 6.8 for about
  • the pharmaceutical composition can comprise (i) an intragranular component comprising an active agent (e.g., an agent for the treatment of UC, e.g., (S)-3-(4-aminophenyl)-2-methoxypropionic acid) and at least one pharmaceutically acceptable excipient; and (ii) an extragranular component comprising at least one pharmaceutically acceptable excipient.
  • an active agent e.g., an agent for the treatment of UC, e.g., (S)-3-(4-aminophenyl)-2-methoxypropionic acid
  • an extragranular component comprising at least one pharmaceutically acceptable excipient.
  • Such a composition can release, after administration to a patient, (e.g., at a pH of about 6.8, e.g., wherein the release is substantially in the proximal region of the colon where, for example, the patient is suffering from active colitis), about 4 percent to about 20 percent (e.g., about 5 percent to about 21 percent, or about 7 percent to about 19 percent, or about 10 percent to about 18 percent, or e.g., about 10 percent to about 25 percent) of the active agent after the composition reaches an environment of pH 6.8.
  • a patient e.g., at a pH of about 6.8, e.g., wherein the release is substantially in the proximal region of the colon where, for example, the patient is suffering from active colitis
  • about 4 percent to about 20 percent e.g., about 5 percent to about 21 percent, or about 7 percent to about 19 percent, or about 10 percent to about 18 percent, or e.g., about 10 percent to about 25 percent
  • composition can then release about 50%, or at least about 50%, of the active agent between the first and third hours after reaching an environment of pH 6.8 (e.g., more rapidly in the recto-sigmoid region of the colon), and/or releasing substantially all the active agent within about 3 hours to about 6 hours after reaching an environment of pH 6.8.
  • an environment of pH 6.8 e.g., more rapidly in the recto-sigmoid region of the colon
  • Such disclosed oral pharmaceutical compositions upon administration, e.g., to a patient in, e.g., remission from colitis (where the proximal colon has a pH of about 7.2), are capable of releasing substantially all of the active agent at pH 7.2 (e.g., by rapidly traversing the proximal and the recto-sigmoid region of the colon, and releasing substantially all the active within about 2 hours to about 5 hours after encountering an environment of pH 7.2).
  • compositions suitable for oral administration for treatment of inflammatory bowel disorders e.g., UC.
  • the compositions can include an active compound selected from 3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt and/or a stereoisomer thereof, a pharmaceutically acceptably excipient, and an enteric coating.
  • compositions suitable for oral administration for treatment of an inflammatory bowel disease where the pharmaceutical composition includes a tablet core, a seal coating, and an enteric coating, where the tablet core includes a pharmaceutically acceptable excipient and an active compound selected from 3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt or a stereoisomer thereof, where the active compound is present in an amount of from about 25 weight percent to about 29 weight percent of the total weight of the tablet core.
  • an active compound selected from 3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid or a pharmaceutically acceptable salt or a stereoisomer thereof, where the active compound is present in an amount of from about 25 weight percent to about 29 weight percent of the total weight of the tablet core.
  • the active compound also referred to herein as the active ingredient or the active agent
  • a stereoisomer e.g., a substantially isolated or a pure stereoisomer, e.g., (5)-3-(4-aminophenyl)-2-methoxypropionic acid or N- acetyl-(5)-3-(
  • a tablet core of a disclosed composition comprises about 26.5% by weight of the active compound, e.g., 3-(4-aminophenyl)-2-methoxypropionic acid. In some embodiments, a disclosed composition comprises about 28.5%> by weight of the active compound.
  • a tablet core of a disclosed composition comprises about 20%, about 21%, about 22%, about 23%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 27%, about 27.5%, about 28%, about 29%, about 29.5%, about 30%), about 31%>, about 32%>, about 33%>, about 34%>, or about 35%> by weight of the active compound, e.g., 3-(4-aminophenyl)-2-methoxypropionic acid.
  • the active compound e.g., 3-(4-aminophenyl)-2-methoxypropionic acid.
  • a tablet core of a disclosed composition comprises about 25%> to about 29%>, about 26%> to about 29%, about 27% to about 29%, about 25% to about 30%, or about 24% to about 30% by weight of the active compound.
  • the tablet core of a pharmaceutical formulation may include about 25% to about 29% by weight of 3-(4'-aminophenyl)-2- methoxypropionic acid or N-acetyl-(5)-3-(4-aminophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the tablet core of the pharmaceutical formulation may include about 27% to about 29% by weight of 3- (4'-aminophenyl)-2-methoxypropionic acid or N-acetyl-(5)-3-(4-aminophenyl)-2- methoxypropionic acid, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • a disclosed composition ⁇ e.g., a tablet) or a tablet core of a disclosed composition may include about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, or about 320 mg of an active compound such as (5)-3-(4-aminophenyl)-2-methoxypropionic acid.
  • an active compound such as (5)-3-(4-aminophenyl)-2-methoxypropionic acid.
  • a disclosed composition can include a pharmaceutically acceptable excipient such as a sugar alcohol.
  • a pharmaceutically acceptable excipient such as a sugar alcohol.
  • disclosed compositions may include an intragranular component and an extragranular component, where one or both components may include a sugar alcohol such as mannitol.
  • Exemplary sugar alcohols include arabitol, erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol.
  • a disclosed composition or a tablet core of a disclosed composition comprises about 10% to about 30%>, e.g., about 25% or about 15%, by weight of a sugar alcohol such as mannitol.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 10%>, about 11%, about 12%, about 13%, about 13.5%, about 14%, about 14.5%, about 15.5%, about 16%, about 16.5%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 23.5%, about 24%, about 24.5%, about 25.5%, about 26%, about 26.5%, about 27%, about 28%, about 29%, or about 30% by weight of a sugar alcohol such as mannitol.
  • a sugar alcohol such as mannitol
  • an oral pharmaceutical tablet suitable for the treatment of an inflammatory bowel disease comprising: an intragranular component comprising about 26 percent by weight to about 29 percent by weight (of a disclosed oral pharmaceutical tablet or a tablet core of a disclosed oral pharmaceutical tablet) of an active compound ⁇ e.g., about 25, 26, 27, 28, or 29 percent by weight) selected from 3-(4- aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt and/or a stereoisomer thereof, and micro crystalline cellulose having an average particle size of about 50 ⁇ ; and an extragranular component comprising about 5 percent by weight to about 14 percent by weight (of a disclosed oral pharmaceutical tablet or a tablet core of a disclosed oral pharmaceutical tablet) of micro crystalline cellulose having an average particle size of about 100 ⁇ .
  • the intragranular component and/or the extra granular component of a disclosed tablet may further comprise a sugar alcohol, e.g., mannitol.
  • a disclosed oral pharmaceutical tablet or a tablet core of a disclosed oral pharmaceutical tablet has an extragranular component that further includes about 1 to about 6 weight percent, or about 3 to about 6 weight percent, or about 1 to about 3 weight percent (e.g., about 1, about 2, about 3, about 4, about 5, about 6, e.g., or about 4-6 weight percent) of a sugar alcohol such as mannitol.
  • a disclosed oral pharmaceutical tablet or a tablet core of a disclosed oral pharmaceutical tablet may include an intragranular component that includes about 19 to about 22 weight percent of a sugar alcohol, e.g., mannitol (e.g., about 19, about 20, about 21, or about 22 weight percent sugar alcohol, e.g., mannitol).
  • the intragranular component of a disclosed tablet or a tablet core of a disclosed tablet comprises about 9 to about 12 weight percent of a sugar alcohol, e.g., mannitol (e.g., about 10, about 11 weight percent, e.g., about 10 to about 11 weight percent).
  • the intragranular component of a disclosed tablet or a tablet core of a disclosed tablet may further include about 24 to about 29 weight percent (e.g., about 25, about 26, about 27, about 28, or about 29 weight percent) of micro crystalline cellulose having an average particle size of about 50 ⁇ .
  • the extragranular component of a disclosed tablet or a tablet core of a disclosed tablet may include about 5 to about 8 weight percent of micro crystalline cellulose having an average particle size of about 100 ⁇ .
  • the extragranular component can include about 11 to about 15 weight percent (of a disclosed tablet or a tablet core of a disclosed tablet) of micro crystalline cellulose having an average particle size of about 100 ⁇ .
  • the extragranular component of a disclosed tablet or a tablet core of a disclosed tablet may include about 5 to about 8 weight percent or about 11 to about 15 weight percent of micro crystalline cellulose having an average particle size of about 90 ⁇ .
  • compositions the tablet core of disclosed compositions include pharmaceutically acceptable excipients such as micro crystalline cellulose, for example, micro crystalline cellulose having an average particle size of, e.g., about 50 to about 100 ⁇ , for example, about 50 ⁇ or about 90 ⁇ , or, for example, 100 ⁇ .
  • pharmaceutically acceptable excipients such as micro crystalline cellulose, for example, micro crystalline cellulose having an average particle size of, e.g., about 50 to about 100 ⁇ , for example, about 50 ⁇ or about 90 ⁇ , or, for example, 100 ⁇ .
  • Micro crystalline cellulose in the disclosed compositions may have a moisture content of less than or equal to about 5% by weight. Both the intragranular phase and extragranular phase of the composition may include micro crystalline cellulose. In certain embodiments, a disclosed composition or a tablet core of a disclosed composition comprises about 35% by weight micro crystalline cellulose. In certain embodiments, a disclosed composition or a tablet core of a disclosed composition comprises about 39% by weight micro crystalline cellulose.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 30%, about 31%, about 32%, about 33%, about 33.5%, about 34%, about 34.5%, about 35.5%), about 36%, about 36.5%, about 37%, about 37.5%, about 38%, about 38.5%, about 39.5%, about 40%, about 40.5%, about 41%, about 42%, about 43%, about 44%, or about 45% by weight micro crystalline cellulose.
  • Exemplary, micro crystalline celluloses are Avicel PH 101 and Avicel PH 102.
  • a disclosed tablet further includes one or more pharmaceutically acceptable excipients such as a surfactant, a disintegrant, a lubricant, and/or a binder.
  • a disclosed tablet may include one or more excipients such as povidone, sodium lauryl sulphate, sodium starch glycollate, L-HPC, sodium citrate (or another salt of citrate) and/or magnesium stearate.
  • excipients may be part of either the intragranular phase and/or extragranular phase of the composition.
  • a disclosed composition or a tablet core of a disclosed composition comprises about 6% by weight of an excipient such as povidone.
  • a disclosed composition or a tablet core of a disclosed composition can comprise about 1%, about 2%, about 3%, about 4%, about 4.5%), about 5%, about 5.5%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%), about 9%), about 10%, or about 11% by weight of an excipient such as povidone.
  • a disclosed composition comprises a surfactant, e.g., sodium lauryl sulphate, for example, about 0.8% by weight of a surfactant such as sodium lauryl sulphate.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, or about 1.6% by weight of a surfactant such as sodium lauryl sulphate.
  • compositions or a tablet core of a disclosed composition comprises about 1.7% by weight of a disintegrant such as sodium starch glycolate.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 0.5%, about 0.75%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.8%, about 1.9%, about 2.0%, about 2.1%), about 2.2%, about 2.3%, about 2.4%, or about 2.5% by weight of a disintegrant such as sodium starch glycolate.
  • An exemplary sodium starch glycolate is Glycolys Type A.
  • Disclosed tablets may include a dry binder, e.g., low-substituted hydro xypropyl ether of cellulose (L-HPC).
  • a disclosed composition or a tablet core of a disclosed composition comprises about 3.5% by weight of a binder such as L-HPC.
  • a disclosed composition or a tablet core of a disclosed composition comprises about 6.5%> by weight of a binder such as L-HPC.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 1%, about 1.5%, about 2%), about 2.5%, about 3%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 7%o, about 7.5%, about 8%, about 8.5%, about 9%, about 10%, or about 1 1% by weight of a binder such as L-HPC.
  • a binder such as L-HPC.
  • Magnesium stearate is a lubricant that is used commonly as a pharmaceutically acceptable excipient.
  • a disclosed composition or a tablet core of a disclosed composition comprises about 1.0% by weight of a lubricant such as magnesium stearate.
  • a disclosed composition or a tablet core of a disclosed composition may comprise about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.4%, or about 1.5% by weight of a lubricant such as magnesium stearate.
  • a lubricant such as magnesium stearate.
  • a disclosed pharmaceutical composition or a tablet core of a disclosed composition comprises about 6% by weight povidone, about 0.8% sodium lauryl sulphate, about 1.7% sodium starch glycolate, about 3.5% by weight L-HPC, and about 1% by weight magnesium stearate.
  • Methocel K 4M includes water- soluble methylcellulose and hydroxypropyl methylcellulose (hypromellose) polymers used for controlled release formulations.
  • a disclosed pharmaceutical composition or a tablet core of a disclosed composition comprises about 10% by weight methocel K 4M.
  • a disclosed pharmaceutical composition or a tablet core of a disclosed composition may comprise about 1%, about 2.5%, about 5%, about 6%, about 7%, about 8%o, about 9%, about 1 1%, about 12%, about 13%, about 14%, or about 15% by weight methocel K 4M.
  • a disclosed composition or a tablet core of a disclosed composition comprises about 6% by weight L-HPC, about 10% by weight methocel
  • an enteric coating can be cellulose acetate phthalate, hdroxypropyl methylcellulose (HPMC), and/or an acrylate polymer such as a Eudragit grade enteric coating.
  • an enteric coating includes Eudragit S 100 and/or Eudragit L 100.
  • Eudragit S 100 is an anionic copolymer based on methacrylic acid and methyl methacrylate, which dissolves at pH 7.0.
  • Eudragit L 100 is an anionic copolymer based on methacrylic acid and methyl methacrylate, which dissolves at pH 6.0.
  • Eudragit grades are commonly used in pH- or time-dependent controlled release formulations.
  • the weight-to-weight ratio of Eudragit S 100 to Eudragit L 100 is about 6 to 4, about 65 to 35, about 75 to 25, or about 8 to 2.
  • the weight-to- weight ratio of Eudragit S 100 to Eudragit L 100 is about 10 to 90, about 20 to 80, about 25 to 75, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40, about 70 to 30, about 80 to 20, or about 90 to 10.
  • the weight-to -weight ratio of Eudragit S 100 to Eudragit L 100 is from about 30 to 70 to about 70 to 30.
  • an enteric coating may be present in an amount of about 1% to about 5%, about 5% to about 10%, about 5% to about 15%, about 10% to about 12%, about 9% to about 13%, about 9% to about 26%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 20% to about 25%, about 10% to about 30%, about 15%) to about 25%, about 20%> to about 30%>, or about 20%> to about 40%>, e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%o, about 24%, or about 25% by weight based on the total weight of the tablet core and the seal coating.
  • the enteric may be present in an amount of about 1% to
  • a disclosed pharmaceutical composition or a tablet core may further comprise a sealing or seal coating, which can be initially applied to the pharmaceutical tablet to prevent moisture penetration into the tablet core.
  • a seal coating can include polymers and/or other materials that can create a pharmaceutically acceptable barrier to moisture.
  • Exemplary seal coatings include poly(vinyl alcohol)-based coatings and formulations such as Opadry materials of various grades, e.g., Opadry 85F and Opadry 85F White.
  • a disclosed pharmaceutical composition is a pharmaceutical composition that is suitable for oral administration for treatment of an inflammatory bowel disease, where the pharmaceutical composition includes a tablet core that includes an active compound, and the composition also includes a pharmaceutically acceptable excipient, and an enteric coating.
  • the pharmaceutical composition or the tablet core of the pharmaceutical composition includes about 10 percent to about 40 percent by weight of the active compound or active ingredient which is selected from 3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • a disclosed pharmaceutical composition is suitable for oral administration for treatment of an inflammatory bowel disease, where the pharmaceutical composition includes a tablet core, a seal coating, and an enteric coating, where the tablet core includes a pharmaceutically acceptable excipient and an active compound selected from 3-(4-aminophenyl)-2-methoxypropionic acid and N-acetyl-3-(4-aminophenyl)-2- methoxypropionic acid, or a pharmaceutically acceptable salt or a stereoisomer thereof, where the active compound is present in an amount of from about 25% to about 29% by weight of the total weight of the tablet core (for example, about 27% to about 29% by weight of the total weight of the tablet core).
  • the seal coating is about 3% by weight of the total weight of the tablet core.
  • the seal coating will be about 3 mg.
  • the seal coating is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, between about 0.1% to about 3%), between about 1% to about 3%, between about 1% to about 5%, between about 2% to about 4%, or between about 2% to about 3% by weight of the total weight of the tablet core.
  • the enteric coating is between about 9% and about 26% by weight based on the total weight of the tablet core and the seal coating. For example, if the enteric coating is about 10% by weight based on the total weight of the tablet core and the seal coating, and the weight of the tablet core and the seal coating is 103 mg, the enteric coating would be about 10.3 mg.
  • the enteric coating is between about 1%) and about 5%, about 5% and about 10%, about 10% and about 15%, about 15% and about 20%), about 20% and about 25%, about 25% and about 30%, about 30% and about 35%, about 5%) and about 15%, about 10%> and about 20%>, about 15% and about 25%, about 20%o and about 30%>, about 25% and about 35%, about 5%, about 6%, about 7%, about 9%, about 10%o, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%o, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%o, about 33%o, about 34%, or about 35% by weight based on the total weight of the tablet core and the seal coating.
  • Methods of treating an inflammatory bowel disease generally include orally administering a disclosed pharmaceutical composition to a patient in need thereof.
  • the inflammatory bowel disease may be Crohn's disease, Crohn's colitis, Crohn's ileo-colitis, diverticulitis, UC, indeterminate colitis, collagenous colitis, or lymphocytic colitis.
  • the inflammatory bowel disease may be Crohn's disease or UC.
  • the inflammatory bowel disease may be UC.
  • a method of treating an inflammatory bowel disease comprises orally administering about 80 mg, about 160 mg, or about 320 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.
  • a method of treating an inflammatory bowel disease comprises orally administering about 80 mg of (R)-3-(4- aminophenyl)-2-methoxypropionic acid or a pharmaceutically acceptable salt thereof, or about 80 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.
  • a patient e.g., a human patient
  • a method of treating an inflammatory bowel disease comprises orally administering about 80 mg of N-acetyl-(S)-3-(4-aminophenyl)-2- methoxypropionic acid, about 80 mg of N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid, or about 80 mg of a racemic mixture comprising 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.
  • a patient e.g., a human patient
  • a method of treating inflammatory bowel disease comprises orally administering about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 72.5 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 88.5 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 320 mg of 3-(4-aminophenyl)-2-methoxypropionic acid, N-acetyl-3-(4-aminophenyl)- 2-methoxypropionic acid, or stereoisomers thereof (including racemic mixtures) and/or pharmaceutically acceptable salts thereof, to a patient in need thereof.
  • a method of treating inflammatory bowel disease comprises orally administering between about 10 mg to about 20 mg, between about 20 mg to about 30 mg, between about 30 mg to about 40 mg, between about 40 mg to about 50 mg, between about 50 mg to about 60 mg, between about 60 mg to about 65 mg, between about 65 mg to about 70 mg, between about 70 mg to about 75 mg, between about 75 mg to about 80 mg, between about 80 mg to about 85 mg, between about 85 mg to about 90 mg, between about 90 mg to about 100 mg, between about 100 mg to about 1 10 mg, between about 1 10 mg to about 120 mg, between about 120 mg to about 130 mg, between about 130 mg to about 140 mg, between about 140 mg to about 150 mg, or between about 150 mg to about 160 mg of 3-(4-aminophenyl)-2- methoxypropionic acid, N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid, one or more stereoisomers thereof (including racemic mixtures) and/or one or more
  • Such oral administration may be in the form of a tablet.
  • the disclosed 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.
  • a composition may be administered once per day.
  • a method of treating an inflammatory bowel disease (such as UC) is provided, comprising orally administering a disclosed pharmaceutical composition to a patient in need thereof.
  • compositions such as disclosed herein, comprising an active agent, wherein about 4 percent to about 20 percent of the active agent is released in the proximal region of the colon at a pH of about 6.8, and at least about 50% of the active agent is released in the recto-sigmoid region of the colon at a pH of about 6.8, and substantially all of the remaining active agent is then released at a pH of about 6.8, which can permit maximal exposure of the colon to the active agent.
  • an active agent may be 3-(4-aminophenyl)-2-methoxypropionic acid, or one or more stereoisomers
  • the method can comprise orally administering a composition such as disclosed herein, comprising an active agent, wherein about 4 percent to about 20 percent of the active agent is released in the proximal region of the colon at a pH of about 6.8 between about 0 hours to about 1 hour after encountering an environment of about pH 6.8 following administration ⁇ e.g., within about 1 hour after encountering an environment of about pH 6.8 following administration), and at least about 50% of the active agent is released in the rectosigmoid region of the colon at a pH of about 6.8 between about 1 hour and 2 hours after encountering an environment of about pH 6.8 following administration ⁇ e.g., after about 1 hour after encountering an environment of about pH 6.8 following administration, between about 1 hour to about 2 hours after encountering an environment of about pH 6.8 following administration, and substantially all of the remaining active agent is then released at a pH of about 6.8 between about 3 hours to about 5 hours after encountering an environment of about pH
  • Such a release profile can permit maximal exposure of the colon to the active agent.
  • an active agent may be 3-(4-aminophenyl)-2- methoxypropionic acid, or one or more stereoisomers (including a racemic mixture) and/or one or more pharmaceutically acceptable salts thereof, e.g., (S)-3-(4-aminophenyl)-2- methoxypropionic acid.
  • Also provided herein is a method of treating active UC in a patient in need thereof, where the method can comprise orally administering a composition such as disclosed herein, comprising an active agent, wherein about 4 percent to about 20 percent of the active agent is released in the proximal region of the colon at a pH of about 6.8 about 0 hours to about 1 hour after encountering an environment of about pH 6.8 following administration (e.g., within about 1 hour after encountering an environment of about pH 6.8 following administration), and at least about 50% of the active agent is released in the recto-sigmoid region of the colon at a pH of about 6.8 between about 1 hour and 3 hours after encountering an environment of about pH 6.8 following administration (e.g., about 1 hour after
  • a method of treating a patient suffering from non-active colitis comprises orally administering a composition comprising an active agent (such as disclosed herein) to a patient in need thereof; wherein the active agent releases at least about 90 percent of the active agent throughout the colon at a pH of about 7.2.
  • an active agent such as disclosed herein
  • FIG. 1 shows the dissolution profile at pH 6.8 and pH 7.2 of formulation (A).
  • Dissolution tests were performed using a USP apparatus II. A three stage dissolution test was performed:
  • Figure 1 shows the dissolution test results as the percent of dissolved drug substance versus time at the 3 rd stage of dissolution.
  • the bottom curve shows dissolution at pH 6.8 ( corresponding to an active UC environment— high degree of inflammation).
  • the top curve shows dissolution at pH 7.2 ( corresponding to a non-active UC environment).
  • FIG. 2 shows the dissolution profile at pH 6.8 of a tablet of formulation A.
  • Dissolution tests were performed using a USP apparatus II, and demonstrated the segmented release profile of the formulation in line with a UC gut.
  • a three stage dissolution test was performed:
  • Example 2 Formulation of a tablet
  • Example 4 Formulation of a tablet
  • Example 5 In vitro dissolution test of a clinical batch preparation
  • FIG. 3 shows the dissolution profile of tablets produced from a clinical batch of tablets of Formula A at pH 6.8 and 7.2. Dissolution tests were performed using a USP apparatus II. A three stage dissolution test was performed: Dissolution test a:
  • Figure 3 shows the dissolution test results as the percent of dissolved drug substance versus time at the 3 rd stage of dissolution.
  • the bottom curve shows dissolution at pH 6.8 (corresponding to active UC environment - high degree of inflammation).
  • the top curve shows dissolution at pH 7.2 (corresponding to a non-active UC environment).
  • the dissolution profile revealed that tablets produced from the clinical batch of Formula A released substantially all drug substance after about 3 to 6 hours at pH 6.8.

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Abstract

L'invention concerne des compositions pharmaceutiques, appropriées pour être administrées par voie orale, comprenant de l'acide 3-(4-aminophényl)-2-méthoxypropionique, ou des sels ou stéréoisomères pharmaceutiquement acceptables de celui-ci, utiles dans le traitement de la colite ulcéreuse et d'autres troubles intestinaux inflammatoires.
PCT/EP2016/079512 2015-12-01 2016-12-01 Compositions appropriées pour être administrées par voie orale, dans le traitement de maladies intestinales inflammatoires WO2017093444A1 (fr)

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US10398667B2 (en) 2009-02-16 2019-09-03 Nogra Pharma Limited Methods of treating hair related conditions
US11046641B2 (en) 2012-02-09 2021-06-29 Nogra Pharma Limited Methods of treating fibrosis
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10398667B2 (en) 2009-02-16 2019-09-03 Nogra Pharma Limited Methods of treating hair related conditions
US10959970B2 (en) 2009-02-16 2021-03-30 Nogra Pharma Limited Methods of treating hair related conditions
US11046641B2 (en) 2012-02-09 2021-06-29 Nogra Pharma Limited Methods of treating fibrosis
US11753365B2 (en) 2012-02-09 2023-09-12 Nogra Pharma Limited Methods of treating fibrosis
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof
WO2021174024A1 (fr) 2020-02-28 2021-09-02 First Wave Bio, Inc. Méthodes de traitement de la colite auto-immune iatrogène

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