WO2024119044A2 - Adrulipase compositions - Google Patents

Adrulipase compositions Download PDF

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Publication number
WO2024119044A2
WO2024119044A2 PCT/US2023/082029 US2023082029W WO2024119044A2 WO 2024119044 A2 WO2024119044 A2 WO 2024119044A2 US 2023082029 W US2023082029 W US 2023082029W WO 2024119044 A2 WO2024119044 A2 WO 2024119044A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cellulose acetate
adrulipase
phthalate
succinate
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PCT/US2023/082029
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French (fr)
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WO2024119044A3 (en
Inventor
Ted STOVER
Dinesh SRINIVASAN
Matt BRIEGER
Original Assignee
First Wave BioPharma, Inc.
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Application filed by First Wave BioPharma, Inc. filed Critical First Wave BioPharma, Inc.
Publication of WO2024119044A2 publication Critical patent/WO2024119044A2/en
Publication of WO2024119044A3 publication Critical patent/WO2024119044A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)

Definitions

  • the present invention relates to adrulipase compositions and dosage forms, methods of treatment and methods of preparation.
  • Lipase 2 (Lip2) from Yarrowia lipolytica (i.e., adrulipase) is an autologous yeast recombinant lipase.
  • the targeted indication of adrulipase is the compensation of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis, chronic pancreatitis and other indications the exocrine pancreas is responsible for.
  • EPI exocrine pancreatic insufficiency
  • the symptomatology of EPI is essentially due to pancreatic lipase deficiency, an enzyme that hydrolyses triglycerides into monoglycerides and free fatty acids.
  • Chronic Pancreatitis (CP), the most common cause of EPI, is a long-standing inflammation of the pancreas that alters its normal structure and functions, which is associated with EPI in about 60% of patients.
  • Cystic fibrosis (CF), another frequent aetiology of EPI, is a severe genetic disease associated with chronic morbidity and life-span decrease of most affected individuals. About 80-90% of patients with CF develop EPI.
  • EPI is common after surgical resection of the pancreas, which is usually performed as a result of cancer or complications of CP.
  • EPI Error-like aetiologies include gastric surgery, certain intestinal disorders (e.g., severe celiac disease, small bowel resection, and enteral- artificial nutrition), and pancreatic diseases (e.g., pancreatic trauma, severe acute pancreatitis with pancreatic necrosis, and pancreatic cancer).
  • intestinal disorders e.g., severe celiac disease, small bowel resection, and enteral- artificial nutrition
  • pancreatic diseases e.g., pancreatic trauma, severe acute pancreatitis with pancreatic necrosis, and pancreatic cancer.
  • PPEs porcine pancreatic extracts
  • FDA Food and Drug Administration
  • PPEs porcine pancreatic replacement therapy
  • the dose of PPE that can be given may be limited, especially in CF, due to the risk of fibrosing colonopathy possibly associated with the presence of proteases and/or gastro-protection agents.
  • the present invention is directed to adrulipase dosage forms, methods of treatment and methods of manufacture.
  • the invention is directed to a delayed release oral dosage form comprising adrulipase and an enteric material (e.g., coating or dispersed with the active).
  • the present invention is directed to adrulipase formulations that provide an immediate release dissolution profile in intestinal pH conditions after exposure to stomach pH conditions as well as methods of treatment and methods of manufacture.
  • the formulation is an enteric microgranule formulation.
  • the invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation provides a dissolution of adrulipase of less than 25% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
  • the invention is directed to the adrulipase dosage forms disclosed herein further comprising a second active agent selected from a fat-soluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof.
  • a second active agent selected from a fat-soluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof.
  • the invention is directed to processes for manufacturing the compositions and dosage forms disclosed herein.
  • the invention is directed to methods of treating exocrine pancreatic insufficiency comprising administering a dosage form as disclosed herein.
  • the insufficiency can be caused by one or more of acute or chronic pancreatitis, cystic fibrosis, pancreatectomy (associated with or without cancer such as pancreatic cancer), age related, Shwachman-Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease).
  • the present invention is also directed in certain embodiments to a method of treating a condition (e.g., colon disease or other condition that is treatable by targeted administration of an active agent to the colon) by administering to a subj ect any of the compositions disclosed herein.
  • a condition e.g., colon disease or other condition that is treatable by targeted administration of an active agent to the colon
  • the delivery can be to treat a colon disease or condition and can also be used to treat a systemic condition with adrulipase.
  • the present invention is also directed in certain embodiments to a method of delivering an adrulipase to the colon of a patient by orally administering any of the formulations disclosed herein.
  • at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the adrulipase is delivered to the colon of the patient.
  • composition and formulation as recited herein is interchangeable.
  • Figure 1 shows the results of dissolution studies with a pH 3 hold for 30 minutes.
  • Figure 2 shows the results of dissolution studies with a pH 3 hold for 60 minutes.
  • the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation provides a dissolution of adrulipase of less than 25% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
  • the pharmaceutical formulation provides a dissolution of adrulipase of less than 25%, less than 20%, less than 15%, less than 7%, less than 3%, less than 1% or 0% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm for up to 2 hours, e,g token 15 minutes, 30 minutes, 45 minutes, 60 minutes or 90 minutes.
  • the pharmaceutical formulation provides a dissolution of adrulipase of at least 70% or at least 80% at 45 or 60 minutes after a switch to pH 6.5.
  • the excipient comprises a disintegrant, e.g., selected from sodium starch glycolate, starch, povidone, crospovidone or a mixture thereof.
  • the disintegrant comprises crospovidone.
  • the pharmaceutical formulation comprises less than 8%, less than 7%, less than 5%, less than 3% or 0% sodium starch glycolate.
  • the pharmaceutical formulation comprises from about 0.5% to about 3%, or about 2% sodium starch glycolate.
  • the disintegrant is crospovidone, e.g., less than 20%, less than 15%, or less than 10% crospovidone or about 0.5% to about 20%, about 2% to about 15%, about 5% to about 10% or about 8% crospovidone.
  • the pharmaceutical formulation does not include sodium starch glycolate.
  • crospovidone is the sole disintegrant.
  • the pharmaceutical formulation further comprises a cellulosic polymer, e.g., microcrystalline cellulose.
  • a cellulosic polymer e.g., microcrystalline cellulose.
  • Other embodiments include a lubricant such as magnesium stearate.
  • the pharmaceutical formulation comprises an inner phase (e.g., microgranules) comprising the adrulipase and at least part of the disintegrant and an outer phase comprising an excipient.
  • the outer phase comprising a portion of the disintegrant and does not include adrulipase.
  • the pharmaceutical formulation is contained in a capsule.
  • the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient comprising povidone.
  • the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation does not comprise sodium starch glycolate.
  • the present invention is directed to methods of treating exocrine pancreatic insufficiency with a formulation as disclosed herein.
  • the dosage form comprises an enteric material encompassing or dispersed with the adrulipase.
  • the invention utilizes spray dried adrulipase lipase as disclosed herein.
  • the invention is directed to dosage form comprising (a) adrulipase formulated as disclosed herein; and (b) a second active agent selected from a fatsoluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non- porcine replacements, or a combination thereof.
  • the vitamin is A, D, E, K or combinations thereof.
  • the second active agent is pancrelipase, liprotamase or a combination thereof.
  • the combination the second active agent is independently immediate release, delayed release or sustained release.
  • the adrulipase can be replaced in whole or in part by one or more of any non-porcine lipase (i) produced from Yarrowia lipolytica, (ii) encoded by the Lip2 gene, (iii) having a molecular weight of about 30 to about 45 kDa or (iv) containing from about 295 to about 310 amino acids.
  • any non-porcine lipase (i) produced from Yarrowia lipolytica, (ii) encoded by the Lip2 gene, (iii) having a molecular weight of about 30 to about 45 kDa or (iv) containing from about 295 to about 310 amino acids.
  • the dosage forms disclosed herein are contained in a capsule wherein the capsule optionally includes an enteric material, e.g., coated over the capsule or dispersed within the capsule.
  • the dosing of the adrulipase is from about 0.01g per day to about 10g per day, about 0.05g per day to 9g per day, from 0.1g per day to about 8g per day, about 2 g per day to about 5 g per day or about 2g per day to about 4g per day. In certain embodiments, the dosing is about 2.2g per day or about 4.4 g per day.
  • the dosage forms disclosed herein comprise a tablet optionally comprising an enteric material, e.g., coated over the tablet or dispersed within the tablet.
  • the adrulipase can be in the form of a powder optionally including an enteric material, e.g., by dry mixing, wet granulation or co-spray dried or cofreeze dried.
  • the formulation is in a liquid form, wherein the adrulipase is in solution or suspension in a medium (e.g., an aqueous, non-aqueous or mixed medium) optionally including an enteric material.
  • a medium e.g., an aqueous, non-aqueous or mixed medium
  • the formulation is a powder or particles and contained in a capsule, sachet or powder paper.
  • the enteric material comprises a naturally occurring material or a non-naturally occurring material.
  • the enteric material comprises a cellulosic material, an acrylic polymer, or a combination thereof.
  • the enteric material comprises hydroxypropylmethylcellulose acetate succinate.
  • the enteric material comprises methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers, polyvinyl acetate phthalate polymers or combinations thereof.
  • the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac or combinations thereof.
  • the enteric material comprises hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate succinate, hydroxypropyl methyl cellulose succinate phthalate, hydroxypropyl methyl cellulose succinate
  • the enteric material does not crack, break or rupture at a pH of less than about 4, less than about 3 or less than about 2.
  • the enteric material is soluble or substantially soluble at a pH of greater than about 5, greater than about 5.5, greater than about 6, greater than about 7 or greater than about 8.
  • the enteric material cracks, breaks or ruptures at a pH of greater than about 5, greater than about 5.5, greater than about 6, greater than about 7 or greater than about 8.
  • the dosage forms disclosed herein target release of the adrulipase in one or more of the jejunum, ileum and duodenum of a patient in need thereof.
  • the adrulipase is prepared by a process comprising drying, such as freeze drying or spray drying.
  • the spray draying utilizes a stabilizer such as an oligosaccharide, e.g., maltodextrin.
  • a stabilizer such as an oligosaccharide, e.g., maltodextrin.
  • the dried adrulipase is in the form of a powder or particles.
  • the particles can have a particle size, e.g. with a D50 of less than 10 micron, from about 1 micron to about 10 micron, about 10 micron to about 50 micron, about 50 micron to about 150 micron, about 60 micron to about 120 micron, about 65 micron to about 85 micron or about 70 micron to about 82 micron.
  • the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, kestose, arginine, glycine, CaCl 2 or mixtures thereof.
  • the ratio of active to stabilizer is about 1 :5 to about 5: 1; about 1 :3 to about 3: 1; about 1 :2 to about 2:1; about 1 : 1 or about 1 :2.
  • the spray drying is performed at a pH of about 3 to about 5, about 2 to about 7, about 4 or about 6.
  • the spray drying is performed at a temperature of greater than about 125°C, greater than about 150°C, or from about 100°C to about 250°C or about 150°C to about 180°C or about 155°C to about 165°C.
  • the spray drying produces the adrulipase at a yield of greater than about 80%, greater than about 90%, greater than about 95% or greater than about 99%.
  • the dosage forms disclosed herein can further comprise a second active agent such as a fat-soluble vitamin (e.g., vitamin A, D, E, K and combinations thereof), a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof.
  • a second active agent such as a fat-soluble vitamin (e.g., vitamin A, D, E, K and combinations thereof), a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof.
  • the second active agent is pancrelipase, liprotamase or a combination thereof.
  • the second active agent is a combination of three enzymes: lipase, protease, and amylase.
  • the invention is directed to a method of treating exocrine pancreatic insufficiency comprising administering a dosage form as disclosed herein.
  • the insufficiency can be caused by one or more of acute or chronic pancreatitis, cystic fibrosis, pancreatectomy (associated with or without cancer such as pancreatic cancer), age related, Shwachman-Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease).
  • the methods of treatment are solely with the adrulipase formulations disclosed herein without the concurrent administration of a second active agent such as a fat-soluble vitamin (e.g., vitamin A, D, E, K and combinations thereof), a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, pancrelipase, liprotamase a combination of three enzymes: lipase, protease, and amylase or a combination thereof.
  • a fat-soluble vitamin e.g., vitamin A, D, E, K and combinations thereof
  • a protease e.g., an amylase
  • a porcine pancreatic enzyme replacement e.g., other non-porcine replacements
  • pancrelipase e.g., liprotamase a combination of three enzymes: lipase, protease, and amylase or a combination thereof.
  • the dosage form is administered by feeding tube in the form of a solution or suspension or sprinkled on food in the form of a powder or administered as an oral dosage form such as a capsule, powder, tablet, liquid or semi-solid.
  • At least a portion of the Adrulipase is delivered to the duodenum of the patient.
  • the portion can be, e.g., at least 50%, at least 60%, at least about 75%, at least about 85%, or at least about 95%.
  • the present formulations and methods provide a CFA% in individual patients or subjects from about 80 to about 99, about 85 to about 95, about 80 to about 92, about 85 to about 92, about 86 to about 92 or about 90 to about 92. [0070] In certain embodiments, the present formulations and methods provide a CNA% in individual patients or subjects from about 90 to about 99, about 92 to about 99, about 95 to about 99 or about 99 to about 99.
  • the present formulations and methods provide a CNA% in a population of patients or subjects from about 90 to about 99, about 92 to about 99, about 95 to about 99 or about 99 to about 99.
  • the present formulations and methods when combined with a PPE provide a CFA gain relative to mean of about 3% to about 12%, from about 4% to about 10%, about 2% to about 6%, about 3% to about 6%, about 4%, about 5% or about 6%.
  • the present formulations and methods when combined with a PPE provide a maximum individual relative CFA gain from about 5% to about 50%, about 10% to about 45%, about 15% to about 40%, about 20% to about 50%, about 30% to about 40%, about 30%, about 35% or about 40%.
  • the invention is directed to preparing the compositions and formulations disclosed herein.
  • Adrulipase is as follows (SEQ ID NO.l):
  • a pharmaceutical composition comprising adrulipase and a pharmaceutically acceptable excipient, wherein the composition provides a dissolution of adrulipase of less than 25% at 1 hours in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
  • composition of embodiment 1 or 2 wherein the composition provides a dissolution of adrulipase of at least 70% or at least 80% at 45 minutes after a switch to pH 6.5.
  • composition of embodiment 4, wherein the disintegrant is selected from sodium starch glycolate, starch, povidone, crospovidone or a mixture thereof.
  • composition of embodiment 5 comprising less than 8%, less than 7%, less than 5% or less than 3% sodium starch glycolate.
  • composition of embodiment 5 comprising from about 0.5% to about 3%, or about 2% sodium starch glycolate.
  • composition of embodiment 8 comprising less than 20%, less than 15%, or less than 10% crospovidone.
  • composition of embodiment 8 comprising about 0.5% to about 20%, about 2% to about 15%, about 5% to about 10% or about 8% crospovidone.
  • composition of any preceding embodiment further comprising a cellulosic polymer.
  • composition of any of embodiments 4-14 comprising an inner phase comprising the adrulipase and at least part of the disintegrant and an outer phase comprising an excipient.
  • composition of any of embodiments 1-16 comprising a tablet comprising the adrulipase, wherein the tablet is overcoated or dispersed with the enteric material.
  • composition of embodiment 25, wherein the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylatemethacrylic acid copolymers, shellac or combinations thereof.
  • the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylatemethacrylic acid copolymers, shellac or combinations thereof.
  • composition embodiment 25 wherein the enteric material does not crack, break or rupture at a pH of less than about 4.
  • composition of embodiment 36 or 37, wherein the drying forms particles having a D50 of about 50 micron to about 150 micron, about 60 micron to about 120 micron, about 65 micron to about 85 micron or about 70 micron to about 82 micron.
  • composition of embodiment 38, wherein the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, kestose, or mixtures thereof.
  • the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose,
  • composition of any of embodiments 38-41, wherein the ratio of active to stabilizer is about 1 :5 to about 5: 1; about 1 :3 to about 3: 1; about 1 :2 to about 2:1; about 1 :1 or about 1 :2.
  • composition of embodiment 49, wherein the fat-soluble vitamin is selected from vitamin A, D, E, K and combinations thereof.
  • composition of embodiment 48, wherein the second active agent is pancrelipase, liprotamase or a combination thereof.
  • a method of treating exocrine pancreatic insufficiency comprising administering a delayed release dosage form according to any of embodiments 1-51.
  • a method of treating acute or chronic pancreatitis comprising administering a delayed release dosage form according to any of embodiments 1-51.
  • a method of treating cystic fibrosis comprising administering a delayed release dosage form according to any of embodiments 1-51.
  • a process of preparing a pharmaceutical composition comprising combining
  • Adrulipase is a recombinant, non-porcine lipase in development for the treatment of Exocrine Pancreatic Insufficiency (EPI).
  • EPI Exocrine Pancreatic Insufficiency
  • microcrystalline cellulose After sieving all excipients through a 850 pm screen, ’A of microcrystalline cellulose, Adrulipase-SD, ’A Sodium Starch Glycolate or Crospovidone CL (internal), ’A Magnesium Stearate (internal), and the remainder of microcrystalline cellulose are blended for 3 minutes at 10 rpm.
  • Manual capsule filling is performed in a controlled humidity room (30 - 70%) to achieve the desired strength.
  • Vessels are filled with pH 3.0 citrate buffer and set to 37C.
  • Sodium starch glycolate s role as a disintegrant is to accelerate dissolution but it shows a negative disintegrant effect when exposed to low pH over time. This behavior is not suitable for oral products due to the highly variable residence time of solids in the low pH environment of the stomach (15- 120min).
  • the 8% Kollidon® CL formulation quickly achieved the target in both conditions demonstrating no negative disintegrant effect when exposed to low pH over time, making it a superior disintegrant for oral transit.
  • X includes A or B is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances.
  • the articles “a” and “an” as used in this application and the appended claims should generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form.
  • Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.

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Abstract

Disclosed in certain embodiments is a pharmaceutical composition comprising adrulipase and a pharmaceutically acceptable excipient, wherein the composition provides a dissolution of adrulipase of less than 25% at 1 hours in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.

Description

ADRULIPASE COMPOSITIONS
FIELD OF THE INVENTION
[0001] The present invention relates to adrulipase compositions and dosage forms, methods of treatment and methods of preparation.
[0002] Lipase 2 (Lip2) from Yarrowia lipolytica (i.e., adrulipase) is an autologous yeast recombinant lipase. The targeted indication of adrulipase is the compensation of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis, chronic pancreatitis and other indications the exocrine pancreas is responsible for. The symptomatology of EPI is essentially due to pancreatic lipase deficiency, an enzyme that hydrolyses triglycerides into monoglycerides and free fatty acids.
[0003] Chronic Pancreatitis (CP), the most common cause of EPI, is a long-standing inflammation of the pancreas that alters its normal structure and functions, which is associated with EPI in about 60% of patients. Cystic fibrosis (CF), another frequent aetiology of EPI, is a severe genetic disease associated with chronic morbidity and life-span decrease of most affected individuals. About 80-90% of patients with CF develop EPI. In addition, EPI is common after surgical resection of the pancreas, which is usually performed as a result of cancer or complications of CP. Other less common aetiologies of EPI include gastric surgery, certain intestinal disorders (e.g., severe celiac disease, small bowel resection, and enteral- artificial nutrition), and pancreatic diseases (e.g., pancreatic trauma, severe acute pancreatitis with pancreatic necrosis, and pancreatic cancer).
[0004] The compensation of EPI, which classically relies on porcine pancreatic extracts (PPEs, also referred to as porcine pancreatic replacement therapy (PERT)), has been a concern of the Food and Drug Administration (FDA) because of the animal ingredients used for the preparation of PPEs and the related risk of transmission of conventional and non- conventional infectious agents. In addition, the dose of PPE that can be given may be limited, especially in CF, due to the risk of fibrosing colonopathy possibly associated with the presence of proteases and/or gastro-protection agents.
[0005] Accordingly, there continues to be a need in the art for pharmaceutical formulations comprising adrulipase.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to adrulipase dosage forms, methods of treatment and methods of manufacture.
[0007] In certain embodiments, the invention is directed to a delayed release oral dosage form comprising adrulipase and an enteric material (e.g., coating or dispersed with the active).
[0008] In certain embodiments, the present invention is directed to adrulipase formulations that provide an immediate release dissolution profile in intestinal pH conditions after exposure to stomach pH conditions as well as methods of treatment and methods of manufacture. In certain embodiments, the formulation is an enteric microgranule formulation.
[0009] In certain embodiments, the invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation provides a dissolution of adrulipase of less than 25% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
[0010] In certain embodiments, the invention is directed to the adrulipase dosage forms disclosed herein further comprising a second active agent selected from a fat-soluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof. [0011] In certain embodiments, the invention is directed to processes for manufacturing the compositions and dosage forms disclosed herein.
[0012] In certain embodiments, the invention is directed to methods of treating exocrine pancreatic insufficiency comprising administering a dosage form as disclosed herein. In certain embodiments the insufficiency can be caused by one or more of acute or chronic pancreatitis, cystic fibrosis, pancreatectomy (associated with or without cancer such as pancreatic cancer), age related, Shwachman-Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease).
[0013] The present invention is also directed in certain embodiments to a method of treating a condition (e.g., colon disease or other condition that is treatable by targeted administration of an active agent to the colon) by administering to a subj ect any of the compositions disclosed herein. The delivery can be to treat a colon disease or condition and can also be used to treat a systemic condition with adrulipase.
[0014] The present invention is also directed in certain embodiments to a method of delivering an adrulipase to the colon of a patient by orally administering any of the formulations disclosed herein. In certain embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the adrulipase is delivered to the colon of the patient.
[0015] The term composition and formulation as recited herein is interchangeable.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 shows the results of dissolution studies with a pH 3 hold for 30 minutes.
[0017] Figure 2 shows the results of dissolution studies with a pH 3 hold for 60 minutes. DETAILED DESCRIPTION
[0018] In certain embodiments, the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation provides a dissolution of adrulipase of less than 25% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
[0019] In certain embodiments, the pharmaceutical formulation provides a dissolution of adrulipase of less than 25%, less than 20%, less than 15%, less than 7%, less than 3%, less than 1% or 0% in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm for up to 2 hours, e,g„ 15 minutes, 30 minutes, 45 minutes, 60 minutes or 90 minutes.
[0020] In certain embodiments, the pharmaceutical formulation provides a dissolution of adrulipase of at least 70% or at least 80% at 45 or 60 minutes after a switch to pH 6.5.
[0021] In certain embodiments, the excipient comprises a disintegrant, e.g., selected from sodium starch glycolate, starch, povidone, crospovidone or a mixture thereof. In a particular embodiment, the disintegrant comprises crospovidone.
[0022] In certain embodiments, the pharmaceutical formulation comprises less than 8%, less than 7%, less than 5%, less than 3% or 0% sodium starch glycolate.
[0023] In certain embodiments, the pharmaceutical formulation comprises from about 0.5% to about 3%, or about 2% sodium starch glycolate.
[0024] In certain embodiments, the disintegrant is crospovidone, e.g., less than 20%, less than 15%, or less than 10% crospovidone or about 0.5% to about 20%, about 2% to about 15%, about 5% to about 10% or about 8% crospovidone.
[0025] In certain embodiments, the pharmaceutical formulation does not include sodium starch glycolate. [0026] In certain embodiments, crospovidone is the sole disintegrant.
[0027] In certain embodiments, the pharmaceutical formulation further comprises a cellulosic polymer, e.g., microcrystalline cellulose. Other embodiments include a lubricant such as magnesium stearate.
[0028] In certain embodiments, the pharmaceutical formulation comprises an inner phase (e.g., microgranules) comprising the adrulipase and at least part of the disintegrant and an outer phase comprising an excipient. In certain embodiments, the outer phase comprising a portion of the disintegrant and does not include adrulipase.
[0029] In certain embodiments the pharmaceutical formulation is contained in a capsule.
[0030] In certain embodiments, the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient comprising povidone.
[0031] In certain embodiments, the present invention is directed to a pharmaceutical formulation comprising adrulipase and a pharmaceutically acceptable excipient, wherein the formulation does not comprise sodium starch glycolate.
[0032] In certain embodiments, the present invention is directed to methods of treating exocrine pancreatic insufficiency with a formulation as disclosed herein.
[0033] In certain embodiments, the dosage form comprises an enteric material encompassing or dispersed with the adrulipase.
[0034] In certain embodiments, the invention utilizes spray dried adrulipase lipase as disclosed herein.
[0035] In certain embodiments, the invention is directed to dosage form comprising (a) adrulipase formulated as disclosed herein; and (b) a second active agent selected from a fatsoluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non- porcine replacements, or a combination thereof. In certain embodiments, the vitamin is A, D, E, K or combinations thereof. In other embodiments, the second active agent is pancrelipase, liprotamase or a combination thereof.
[0036] In certain embodiments, the combination the second active agent is independently immediate release, delayed release or sustained release.
[0037] In certain embodiments, the adrulipase can be replaced in whole or in part by one or more of any non-porcine lipase (i) produced from Yarrowia lipolytica, (ii) encoded by the Lip2 gene, (iii) having a molecular weight of about 30 to about 45 kDa or (iv) containing from about 295 to about 310 amino acids.
[0038] In certain embodiments, the dosage forms disclosed herein are contained in a capsule wherein the capsule optionally includes an enteric material, e.g., coated over the capsule or dispersed within the capsule.
[0039] In certain embodiments, the dosing of the adrulipase is from about 0.01g per day to about 10g per day, about 0.05g per day to 9g per day, from 0.1g per day to about 8g per day, about 2 g per day to about 5 g per day or about 2g per day to about 4g per day. In certain embodiments, the dosing is about 2.2g per day or about 4.4 g per day.
[0040] In certain embodiments, the dosage forms disclosed herein comprise a tablet optionally comprising an enteric material, e.g., coated over the tablet or dispersed within the tablet.
[0041] In certain embodiments, the adrulipase can be in the form of a powder optionally including an enteric material, e.g., by dry mixing, wet granulation or co-spray dried or cofreeze dried.
[0042] In certain embodiments, the formulation is in a liquid form, wherein the adrulipase is in solution or suspension in a medium (e.g., an aqueous, non-aqueous or mixed medium) optionally including an enteric material. [0043] In certain embodiments, the formulation is a powder or particles and contained in a capsule, sachet or powder paper.
[0044] In certain embodiments, the enteric material comprises a naturally occurring material or a non-naturally occurring material.
[0045] In certain embodiments, the enteric material comprises a cellulosic material, an acrylic polymer, or a combination thereof.
[0046] In certain embodiments, the enteric material comprises hydroxypropylmethylcellulose acetate succinate.
[0047] In certain embodiments, the enteric material comprises methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers, polyvinyl acetate phthalate polymers or combinations thereof.
[0048] In certain embodiments, the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac or combinations thereof.
[0049] In certain embodiments, the enteric material comprises hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate or combinations thereof. [0050] In certain embodiments, the enteric material is insoluble or substantially insoluble at a pH of less than about 4, less than about 3 or less than about 2.
[0051] In certain embodiments, the enteric material does not crack, break or rupture at a pH of less than about 4, less than about 3 or less than about 2.
[0052] In certain embodiments, the enteric material is soluble or substantially soluble at a pH of greater than about 5, greater than about 5.5, greater than about 6, greater than about 7 or greater than about 8.
[0053] In certain embodiments, the enteric material cracks, breaks or ruptures at a pH of greater than about 5, greater than about 5.5, greater than about 6, greater than about 7 or greater than about 8.
[0054] In certain embodiments, the dosage forms disclosed herein target release of the adrulipase in one or more of the jejunum, ileum and duodenum of a patient in need thereof. [0055] In certain embodiments, the adrulipase is prepared by a process comprising drying, such as freeze drying or spray drying.
[0056] In certain embodiments, the spray draying utilizes a stabilizer such as an oligosaccharide, e.g., maltodextrin.
[0057] In certain embodiments, the dried adrulipase is in the form of a powder or particles. The particles can have a particle size, e.g. with a D50 of less than 10 micron, from about 1 micron to about 10 micron, about 10 micron to about 50 micron, about 50 micron to about 150 micron, about 60 micron to about 120 micron, about 65 micron to about 85 micron or about 70 micron to about 82 micron.
[0058] In certain embodiments, the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, kestose, arginine, glycine, CaCl2 or mixtures thereof.
[0059] In certain embodiments, the ratio of active to stabilizer is about 1 :5 to about 5: 1; about 1 :3 to about 3: 1; about 1 :2 to about 2:1; about 1 : 1 or about 1 :2.
[0060] In certain embodiments, the spray drying is performed at a pH of about 3 to about 5, about 2 to about 7, about 4 or about 6.
[0061] In certain embodiments, the spray drying is performed at a temperature of greater than about 125°C, greater than about 150°C, or from about 100°C to about 250°C or about 150°C to about 180°C or about 155°C to about 165°C.
[0062] In certain embodiments, the spray drying produces the adrulipase at a yield of greater than about 80%, greater than about 90%, greater than about 95% or greater than about 99%.
[0063] In certain embodiments, the dosage forms disclosed herein can further comprise a second active agent such as a fat-soluble vitamin (e.g., vitamin A, D, E, K and combinations thereof), a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof. In alternative embodiments, the second active agent is pancrelipase, liprotamase or a combination thereof. In a certain embodiment, the second active agent is a combination of three enzymes: lipase, protease, and amylase.
[0064] In certain embodiments, the invention is directed to a method of treating exocrine pancreatic insufficiency comprising administering a dosage form as disclosed herein.
[0065] In certain embodiments the insufficiency can be caused by one or more of acute or chronic pancreatitis, cystic fibrosis, pancreatectomy (associated with or without cancer such as pancreatic cancer), age related, Shwachman-Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease).
[0066] In certain embodiments, the methods of treatment are solely with the adrulipase formulations disclosed herein without the concurrent administration of a second active agent such as a fat-soluble vitamin (e.g., vitamin A, D, E, K and combinations thereof), a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, pancrelipase, liprotamase a combination of three enzymes: lipase, protease, and amylase or a combination thereof.
[0067] In certain embodiments, the dosage form is administered by feeding tube in the form of a solution or suspension or sprinkled on food in the form of a powder or administered as an oral dosage form such as a capsule, powder, tablet, liquid or semi-solid.
[0068] In certain methods disclosed herein, at least a portion of the Adrulipase is delivered to the duodenum of the patient. The portion can be, e.g., at least 50%, at least 60%, at least about 75%, at least about 85%, or at least about 95%.
[0069] In certain embodiments, the present formulations and methods provide a CFA% in individual patients or subjects from about 80 to about 99, about 85 to about 95, about 80 to about 92, about 85 to about 92, about 86 to about 92 or about 90 to about 92. [0070] In certain embodiments, the present formulations and methods provide a CNA% in individual patients or subjects from about 90 to about 99, about 92 to about 99, about 95 to about 99 or about 99 to about 99.
[0071] In certain embodiments, the present formulations and methods provide a CNA% in a population of patients or subjects from about 90 to about 99, about 92 to about 99, about 95 to about 99 or about 99 to about 99.
[0072] In certain embodiments, the present formulations and methods when combined with a PPE provide a CFA gain relative to mean of about 3% to about 12%, from about 4% to about 10%, about 2% to about 6%, about 3% to about 6%, about 4%, about 5% or about 6%. [0073] In certain embodiments, the present formulations and methods when combined with a PPE provide a maximum individual relative CFA gain from about 5% to about 50%, about 10% to about 45%, about 15% to about 40%, about 20% to about 50%, about 30% to about 40%, about 30%, about 35% or about 40%.
[0074] In certain embodiments, the invention is directed to preparing the compositions and formulations disclosed herein.
[0075] The sequence of Adrulipase is as follows (SEQ ID NO.l):
[0076] VYTSTETSHIDQESYNFFEKYARLANIGYCVGPGTKIFKPFNCGLQCAHFPN VELIEEFHDPRLIFDVSGYLAVDHASKQIYLVIRGTHSLEDVITDIRIMQAPLTNFDLA ANISSTATCDDCLVHNGFIQSYNNTYNQIGPKLDSVIEQYPDYQIAVTGHSLGGAAA LLFGINLKVNGHDPLVVTLGQPIVGNAGFANWVDKLFFGQENPDVSKVSKDRKLY RITHRGDIVPQVPFWDGYQHCSGEVFIDWPLIHPPLSNVVMCQGQSNKQCSAGNTL LQQVNVIGNHLQYFVTEGVCGI.
[0077] LIST OF CERTAIN EMBODIMENTS
1. A pharmaceutical composition comprising adrulipase and a pharmaceutically acceptable excipient, wherein the composition provides a dissolution of adrulipase of less than 25% at 1 hours in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
2. The pharmaceutical composition of embodiment 1, wherein the composition provides a dissolution of adrulipase of less than 20% or less than 15% at 1 hour in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm.
3. The pharmaceutical composition of embodiment 1 or 2, wherein the composition provides a dissolution of adrulipase of at least 70% or at least 80% at 45 minutes after a switch to pH 6.5.
4. The pharmaceutical composition of any of embodiments 1-3, wherein the excipient comprises a disintegrant.
5. The pharmaceutical composition of embodiment 4, wherein the disintegrant is selected from sodium starch glycolate, starch, povidone, crospovidone or a mixture thereof.
6. The pharmaceutical composition of embodiment 5, comprising less than 8%, less than 7%, less than 5% or less than 3% sodium starch glycolate.
7. The pharmaceutical composition of embodiment 5, comprising from about 0.5% to about 3%, or about 2% sodium starch glycolate.
8. The pharmaceutical composition of embodiment 5, wherein the disintegrant is crospovidone.
9. The pharmaceutical composition of embodiment 8, comprising less than 20%, less than 15%, or less than 10% crospovidone.
10. The pharmaceutical composition of embodiment 8, comprising about 0.5% to about 20%, about 2% to about 15%, about 5% to about 10% or about 8% crospovidone.
11. The pharmaceutical composition of any preceding embodiment that does not include sodium starch glycolate. 12. The pharmaceutical composition of embodiment 4, comprising crospovidone as the sole disintegrant.
13. The pharmaceutical composition of any preceding embodiment, further comprising a cellulosic polymer.
14. The pharmaceutical composition of embodiment 13, wherein the cellulosic polymer is microcrystalline cellulose.
15. The pharmaceutical composition of any of embodiments 4-14, comprising an inner phase comprising the adrulipase and at least part of the disintegrant and an outer phase comprising an excipient.
16. The pharmaceutical composition of embodiment 15, wherein the outer phase comprising a portion of the disintegrant and does not include adrulipase.
17. The pharmaceutical composition of any preceding embodiment contained in a capsule.
18. The pharmaceutical composition of embodiment 17 wherein the capsule is a hard capsule.
19. The pharmaceutical composition of embodiment 17 wherein the capsule is a soft capsule.
20. The pharmaceutical composition of any of embodiments 17-19, wherein the capsule comprising an enteric material (e.g., as a coating or dispersed within the capsule).
21. The pharmaceutical composition of any of embodiments 1-16, comprising a tablet comprising the adrulipase, wherein the tablet is overcoated or dispersed with the enteric material.
22. The pharmaceutical composition of any of embodiments 1-21, wherein the adrulipase is combined with an enteric material in a solution and freeze dried or spray dried to form a powder. 23. The pharmaceutical composition of any of embodiments 1-21, wherein the adrulipase is in solution or suspension in a medium.
24. The pharmaceutical composition of embodiment 22, wherein the powder is contained in a capsule, sachet or powder paper.
25. The pharmaceutical composition of any preceding embodiment, wherein the enteric material comprises a naturally occurring material or a non-naturally occurring material.
26. The pharmaceutical composition of embodiment 25, wherein the enteric material comprises a cellulosic material, an acrylic polymer, or a combination thereof.
27. The pharmaceutical composition of embodiment 25, wherein the enteric material comprises hydroxypropylmethylcellulose acetate succinate.
28. The pharmaceutical composition of embodiment 25, wherein the enteric material comprises methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers, polyvinyl acetate phthalate polymers or combinations thereof.
29. The pharmaceutical composition of embodiment 25, wherein the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylatemethacrylic acid copolymers, shellac or combinations thereof.
30. The pharmaceutical composition of embodiment 25, wherein the enteric material comprises hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxy ethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate or combinations thereof.
31. The pharmaceutical composition of embodiment 25, wherein the enteric material is insoluble or substantially insoluble at a pH of less than about 4.
32. The pharmaceutical composition embodiment 25, wherein the enteric material does not crack, break or rupture at a pH of less than about 4.
33. The pharmaceutical composition of embodiment 25, wherein the enteric material is soluble or substantially soluble at a pH of greater than about 5.
34. The pharmaceutical composition of embodiment 25, wherein the enteric material cracks, breaks or ruptures at a pH of greater than about 5.
35. The pharmaceutical composition of any preceding embodiment, that targets release of the adrulipase in the duodenum of a patient in need thereof.
36. The pharmaceutical composition of any preceding embodiment, wherein the adrulipase is prepared by freeze drying. 37. The pharmaceutical composition of any preceding embodiment, wherein the adrulipase is prepared by spray drying.
38. The pharmaceutical composition of embodiment 35, wherein the spray draying utilizes a stabilizer.
39. The pharmaceutical composition of embodiment 38, wherein the stabilizer is an oligosaccharide.
40. The pharmaceutical composition of embodiment 36 or 37, wherein the drying forms particles having a D50 of about 50 micron to about 150 micron, about 60 micron to about 120 micron, about 65 micron to about 85 micron or about 70 micron to about 82 micron.
41. The pharmaceutical composition of embodiment 38, wherein the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, kestose, or mixtures thereof.
42. The pharmaceutical composition of any of embodiments 38-41, wherein the ratio of active to stabilizer is about 1 :5 to about 5: 1; about 1 :3 to about 3: 1; about 1 :2 to about 2:1; about 1 :1 or about 1 :2.
43. The pharmaceutical composition of any of embodiments 37-42, wherein the spray drying is performed at a pH of about 3 to about 5, about 2 to about 7 or about 6.
44. The pharmaceutical composition of any of embodiments 37-43, wherein the spray drying is performed at a pH of about 4.
45. The pharmaceutical composition of any of embodiments 37-44, wherein the spray drying is performed at a temperature of greater than about 125°C or from about 100°C to about 250°C or about 150°C to about 180°C or about 155°C to about 165°C or about 162°C. 46. The pharmaceutical composition of any of embodiments 37-45, wherein the spray drying is performed at a temperature of greater than about 150°C.
47. The pharmaceutical composition of any of embodiments 37-46, wherein the spray drying produces the adrulipase at a yield of greater than about 80%, greater than about 90%, greater than about 95% or greater than about 99%.
48. The pharmaceutical composition of any preceding embodiments, further comprising a second active agent.
49. The pharmaceutical composition of embodiment 48, wherein the second active agent is a fat-soluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non-porcine replacements, or a combination thereof.
50. The pharmaceutical composition of embodiment 49, wherein the fat-soluble vitamin is selected from vitamin A, D, E, K and combinations thereof.
51. The pharmaceutical composition of embodiment 48, wherein the second active agent is pancrelipase, liprotamase or a combination thereof.
52. A method of treating exocrine pancreatic insufficiency comprising administering a delayed release dosage form according to any of embodiments 1-51.
53. A method of treating acute or chronic pancreatitis comprising administering a delayed release dosage form according to any of embodiments 1-51.
54. A method of treating cystic fibrosis comprising administering a delayed release dosage form according to any of embodiments 1-51.
55. The method of embodiment 52, wherein the insufficiency is caused by pancreatectomy such as due to pancreatic cancer.
56. The method of embodiment 52, wherein the insufficiency is age related or due to Schachman-Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease). 57. The method of any of embodiments 52-56, wherein the dosage form is administered by feeding tube in the form of a solution or suspension or sparkled on food in the form of a powder.
58. The method of any of embodiments 52-57, that delivers at least a portion of the adrulipase to the duodenum of the patient.
59. The method of embodiment 58, wherein the portion is at least about 75%.
60. The method of embodiment 58, wherein the portion is at least about 85%
61. The method of embodiment 58, wherein the portion is at least about 95%.
62. A process of preparing a pharmaceutical composition comprising combining
Adrulipase and one or more excipients as disclosed herein to form a dosage form according to any of embodiments 1-51.
[0078] The following examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
Examples
[0079] Adrulipase is a recombinant, non-porcine lipase in development for the treatment of Exocrine Pancreatic Insufficiency (EPI). In the present study, the effect of typical fed pH conditions on common disintegrants was evaluated as part of the reformulation of adrulipase for oral dosing.
Methods:
[0080] Manufacture: drug substance containing an enteric polymer is blended with excipients and one of two disintegrants (sodium starch glycolate or Kollidon® CL); then dry granulated to produce microgranules of particle size D90<0.5mm and filled into hypromellose capsules.
Figure imgf000022_0001
A general procedure is set forth below:
1. After sieving all excipients through a 850 pm screen, ’A of microcrystalline cellulose, Adrulipase-SD, ’A Sodium Starch Glycolate or Crospovidone CL (internal), ’A Magnesium Stearate (internal), and the remainder of microcrystalline cellulose are blended for 3 minutes at 10 rpm.
2. After sieving through a 1,200 pm screen the blend is passed through a Shenzhen / Mini-DC roller compactor set with 1.0 mm milling screen.
3. After compaction, the granules are combined with the remainder of Sodium Starch Glycolate or Crospovidone CL and magnesium stearate (previously sieved through a 850 pm screen) are added. Blending is performed at 10 rpm for 3 minutes.
4. Manual capsule filling is performed in a controlled humidity room (30 - 70%) to achieve the desired strength.
[0081] General Transitional Dissolution testing: 1 capsule was added to 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm. At 30 or 60 minutes a 5mL sample was removed and 24mL of IN NaOH was added to shift the pH to 6.5, then samples were taken at 15, 30, 45 and 60 minutes. The paddle speed was increased to 250rpm for 15 minutes and the final (Inf) sample taken. Samples from each time point were immediately filtered and analyzed via a Bradford assay to determine free lipase.
More specifics of the dissolution with a Distek dissolution tester, model 2500 USP Apparatus
2 (paddle) is set forth below:
1) Vessels are filled with pH 3.0 citrate buffer and set to 37C.
2) One capsule is added to each vessel, held in place with sinker.
3) Stir at 75 RPM for 30 minutes, sample. a. LONG pH3 study was stirred for 60 minutes before sampling.
4) Adjust pH for 6.5 in each vessel.
5) Sample after 15, 30, 45, 60 minutes.
6) Increase stir speed to 250 RPM, sample. a. Note: All samples are immediately filtered through a 10 pm PE membrane prior to analysis. 7) Analyze total protein of each sample via Bradford assay.
Results:
[0082] All adrulipase formulations showed similar transitional dissolution profiles during the Normal low pH hold condition (pH 3 for 30 min) as shown in Figure 1. The enteric polymer in the drug substance protects the lipase at pH 3 and very little drug is released (<15%) until the pH is adjusted to >5.5 and the enteric polymer rapidly releases the drug, which was observed by all formulations achieving the target of >75% dissolution at 45 min. However, the Long low pH hold condition (pH3 for 60 min) showed substantially slower drug release in the 8% sodium starch glycolate formulation, only achieving 64% at 45min, as shown in Figure 2. When sodium starch glycolate was reduced to 2% the target was achieved (86% at 45 min). Sodium starch glycolate’s role as a disintegrant is to accelerate dissolution but it shows a negative disintegrant effect when exposed to low pH over time. This behavior is not suitable for oral products due to the highly variable residence time of solids in the low pH environment of the stomach (15- 120min). The 8% Kollidon® CL formulation quickly achieved the target in both conditions demonstrating no negative disintegrant effect when exposed to low pH over time, making it a superior disintegrant for oral transit.
Conclusion:
[0083] The effect of stomach pH conditions on two common disintegrants was evaluated to achieve an optimal adrulipase delayed release profile for low pH protection during oral dosing. Sodium starch glycolate showed a significantly delayed dissolution profile when exposed to low pH over time. A formulation with Kollidon® CL as the disintegrant surpassed the target dissolution in all conditions tested indicating that Kollidon® CL is better suited to the low pH transit times that may result during oral dosing. [0084] For simplicity of explanation, the embodiments of the methods of this disclosure are depicted and described as a series of acts. However, acts in accordance with this disclosure can occur in various orders and/or concurrently, and with other acts not presented and described herein. Furthermore, not all illustrated acts may be required to implement the methods in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that the methods could alternatively be represented as a series of interrelated states via a state diagram or events.
[0085] In the foregoing description, numerous specific details are set forth, such as specific materials, dimensions, processes parameters, etc., to provide a thorough understanding of the present invention. The particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words “example” or “exemplary” are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “example” or “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, use of the words “example” or “exemplary” is intended to present concepts in a concrete fashion. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or”. That is, unless specified otherwise, or clear from context, “X includes A or B” is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances. In addition, the articles “a” and “an” as used in this application and the appended claims should generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form. Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.
[0086] Reference throughout this specification to numerical ranges should not be construed as limiting and should be understood as encompassing the outer limits of the range as well as each number and/or narrower range within the enumerated numerical range.
[0087] The present invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

What is claimed is:
1. A pharmaceutical composition comprising adrulipase and a pharmaceutically acceptable excipient, wherein the composition provides a dissolution of adrulipase of less than 25% at 1 hours in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm and thereafter provides a dissolution of adrulipase of at least 70% at 45 minutes after a switch to pH 6.5.
2. The pharmaceutical composition of claim 1, wherein the composition provides a dissolution of adrulipase of less than 20% or less than 15% at 1 hour in 500 mL of 20mM citrate buffer pH 3.0 at 37°C in a type II dissolution apparatus, paddle speed 75rpm.
3. The pharmaceutical composition of claim 1, wherein the composition provides a dissolution of adrulipase of at least 70% or at least 80% at 45 minutes after a switch to pH 6.5.
4. The pharmaceutical composition of claim 1, wherein the excipient comprises a disintegrant.
5. The pharmaceutical composition of claim 4, wherein the disintegrant is selected from sodium starch glycolate, starch, povidone, crospovidone or a mixture thereof.
6. The pharmaceutical composition of claim 5, comprising less than 8%, less than 7%, less than 5% or less than 3% sodium starch glycolate.
7. The pharmaceutical composition of claim 5, comprising from about 0.5% to about 3%, or about 2% sodium starch glycolate.
8. The pharmaceutical composition of claim 5, wherein the disintegrant is crospovidone.
9. The pharmaceutical composition of claim 8, comprising less than 20%, less than 15%, or less than 10% crospovidone.
10. The pharmaceutical composition of claim 8, comprising about 0.5% to about 20%, about 2% to about 15%, about 5% to about 10% or about 8% crospovidone.
11. The pharmaceutical composition of claim 1 that does not include sodium starch glycolate.
12. The pharmaceutical composition of claim 4, comprising crospovidone as the sole disintegrant.
13. The pharmaceutical composition of claim 1, further comprising a cellulosic polymer.
14. The pharmaceutical composition of claim 13, wherein the cellulosic polymer is microcrystalline cellulose.
15. The pharmaceutical composition of claim 4, comprising an inner phase comprising the adrulipase and at least part of the disintegrant and an outer phase comprising an excipient.
16. The pharmaceutical composition of claim 15, wherein the outer phase comprising a portion of the disintegrant and does not include adrulipase.
17. The pharmaceutical composition of claim 1 contained in a capsule.
18. The pharmaceutical composition of claim 17 wherein the capsule is a hard capsule.
19. The pharmaceutical composition of claim 17 wherein the capsule is a soft capsule.
20. The pharmaceutical composition of claim 17, wherein the capsule comprising an enteric material (e.g., as a coating or dispersed within the capsule).
21. The pharmaceutical composition of claim 1, comprising a tablet comprising the adrulipase, wherein the tablet is overcoated or dispersed with the enteric material.
22. The pharmaceutical composition of claim 1, wherein the adrulipase is combined with an enteric material in a solution and freeze dried or spray dried to form a powder.
23. The pharmaceutical composition of claim 1, wherein the adrulipase is in solution or suspension in a medium.
24. The pharmaceutical composition of claim 22, wherein the powder is contained in a capsule, sachet or powder paper.
25. The pharmaceutical composition of any preceding claim, wherein the enteric material comprises a naturally occurring material or a non-naturally occurring material.
26. The pharmaceutical composition of claim 25, wherein the enteric material comprises a cellulosic material, an acrylic polymer, or a combination thereof.
27. The pharmaceutical composition of claim 25, wherein the enteric material comprises hydroxypropylmethylcellulose acetate succinate.
28. The pharmaceutical composition of claim 25, wherein the enteric material comprises methacrylic acid polymers, cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose acetate succinate polymers, hydroxypropylmethyl cellulose phthalate polymers, polyvinyl acetate phthalate polymers or combinations thereof.
29. The pharmaceutical composition of claim 25, wherein the enteric material comprises methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac or combinations thereof.
30. The pharmaceutical composition of claim 25, wherein the enteric material comprises hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate or combinations thereof.
31. The pharmaceutical composition of claim 25, wherein the enteric material is insoluble or substantially insoluble at a pH of less than about 4.
32. The pharmaceutical composition of claim 25, wherein the enteric material does not crack, break or rupture at a pH of less than about 4.
33. The pharmaceutical composition of claim 25, wherein the enteric material is soluble or substantially soluble at a pH of greater than about 5.
34. The pharmaceutical composition of claim 25, wherein the enteric material cracks, breaks or ruptures at a pH of greater than about 5.
35. The pharmaceutical composition of claim 1, that targets release of the adrulipase in the duodenum of a patient in need thereof.
36. The pharmaceutical composition of claim 1, wherein the adrulipase is prepared by freeze drying.
37. The pharmaceutical composition of claim 1, wherein the adrulipase is prepared by spray drying.
38. The pharmaceutical composition of claim 35, wherein the spray draying utilizes a stabilizer.
39. The pharmaceutical composition of claim 38, wherein the stabilizer is an oligosaccharide.
40. The pharmaceutical composition of claim 36, wherein the drying forms particles having a D50 of about 50 micron to about 150 micron, about 60 micron to about 120 micron, about 65 micron to about 85 micron or about 70 micron to about 82 micron.
41. The pharmaceutical composition of claim 38, wherein the stabilizer is maltodextrin, xylan, mannan, fucoidan, galactomannan, chitosan, raffinose, stachyose, pectin, inulin, levan, graminan, and amylopectin, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, kestose, or mixtures thereof.
42. The pharmaceutical composition of any of claims 38-41, wherein the ratio of active to stabilizer is about 1 :5 to about 5: 1; about 1 :3 to about 3:1; about 1 :2 to about 2: 1; about 1 : 1 or about 1 :2.
43. The pharmaceutical composition of any of claims 37-42, wherein the spray drying is performed at a pH of about 3 to about 5, about 2 to about 7 or about 6.
44. The pharmaceutical composition of any of claims 37-43, wherein the spray drying is performed at a pH of about 4.
45. The pharmaceutical composition of any of claims 37-44, wherein the spray drying is performed at a temperature of greater than about 125°C or from about 100°C to about 250°C or about 150°C to about 180°C or about 155°C to about 165°C or about 162°C.
46. The pharmaceutical composition of any of claims 37-45, wherein the spray drying is performed at a temperature of greater than about 150°C.
47. The pharmaceutical composition of any of claims 37-46, wherein the spray drying produces the adrulipase at a yield of greater than about 80%, greater than about 90%, greater than about 95% or greater than about 99%.
48. The pharmaceutical composition of any preceding claims, further comprising a second active agent.
49. The pharmaceutical composition of claim 48, wherein the second active agent is a fatsoluble vitamin, a protease, an amylase, a porcine pancreatic enzyme replacement, other non- porcine replacements, or a combination thereof.
50. The pharmaceutical composition of claim 49, wherein the fat-soluble vitamin is selected from vitamin A, D, E, K and combinations thereof.
51. The pharmaceutical composition of claim 48, wherein the second active agent is pancrelipase, liprotamase or a combination thereof.
52. A method of treating exocrine pancreatic insufficiency comprising administering a delayed release dosage form according to any of claims 1-51.
53. A method of treating acute or chronic pancreatitis comprising administering a delayed release dosage form according to any of claims 1-51.
54. A method of treating cystic fibrosis comprising administering a delayed release dosage form according to any of claims 1-51.
55. The method of claim 52, wherein the insufficiency is caused by pancreatectomy such as due to pancreatic cancer.
56. The method of claim 52, wherein the insufficiency is age related or due to Schachman- Diamond Syndrome, diabetes type 1, diabetes type 2, HIV, celiac disease, or inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease).
57. The method of any of claims 52-56, wherein the dosage form is administered by feeding tube in the form of a solution or suspension or sparkled on food in the form of a powder.
58. The method of any of claims 52-57, that delivers at least a portion of the adrulipase to the duodenum of the patient.
59. The method of claim 58, wherein the portion is at least about 75%.
60. The method of claim 58, wherein the portion is at least about 85%
61. The method of claim 58, wherein the portion is at least about 95%.
62. A process of preparing a pharmaceutical composition comprising combining
Adrulipase and one or more excipients as disclosed herein to form a dosage form according to any of claims 1-51.
PCT/US2023/082029 2022-12-01 2023-12-01 Adrulipase compositions WO2024119044A2 (en)

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