WO2004074470A1 - Pancreatine a haute teneur en protease - Google Patents

Pancreatine a haute teneur en protease Download PDF

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Publication number
WO2004074470A1
WO2004074470A1 PCT/CA2004/000228 CA2004000228W WO2004074470A1 WO 2004074470 A1 WO2004074470 A1 WO 2004074470A1 CA 2004000228 W CA2004000228 W CA 2004000228W WO 2004074470 A1 WO2004074470 A1 WO 2004074470A1
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WO
WIPO (PCT)
Prior art keywords
protease
usp
mixture
pancreatin
isopropanol
Prior art date
Application number
PCT/CA2004/000228
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English (en)
Inventor
Patrick Colin
Francois Martin
Manfred KURFÜRST
Original Assignee
Norax & Company, Limited Partnership
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Norax & Company, Limited Partnership filed Critical Norax & Company, Limited Partnership
Publication of WO2004074470A1 publication Critical patent/WO2004074470A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/94—Pancreatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention concerns a new protease formulation useful in the treatment of pancreatic disorders.
  • Chronic pancreatitis is characterized by episodes of severe epigastric and back pain, which often requires regular doses of narcotics. During these episodes, the pain lasts for hours and occurs every day. Moreover, it recurs periodically for years. Pain is usually epigastric, sometime also felt in the left upper quadrant with radiation to the back between T12 and L2 or to the left shoulder (Pitchumoni 1998). Many patients are chronically debilitated because of the pain. It can be quite frustrating to take care of these patients because they return again and again to the emergency room with severe pain, some of them intoxicated, others denying any ongoing alcoholism, others addicted to narcotics. Excessive alcohol consumption causes about 70% of all cases of chronic pancreatitis while 10-40% is idiopathic (Ectors et al 1997).
  • the gland In chronic pancreatitis, the gland usually undergoes extensive atrophy with fibrosis and inflammatory cell infiltration. Somewhere along the evolution of the atrophy of the gland, there is an increase in protein secretion associated with protein precipitation in the smaller ductules, the formation of protein plugs, and the subsequent blockage of the smaller ductules. As the disease progresses, blockage of the larger ductules and central ducts takes place and stone formation and calcification can occur. Many of these changes probably involve the production of pain, as we know it in the syndrome of chronic pancreatitis.
  • the treatment of chronic pancreatitis is usually influenced by the presence of large or small duct disease. Patients with large duct disease should be referred for an attempt at endoscopic or surgical drainage. On the other hand, small duct disease is often characterized by minimal changes on X-rays, ultrasounds, and CT-scans (Hayakawa 1992, Walsh 1992). The exocrine function may be intact or only partially diminished (Hayakawa 1992). Since there is no effective way to treat these patients, one should proceed from the least invasive to the most invasive approach.
  • the American Gastroenterological Association (AGA 1998) has published guidelines for the treatment of chronic pancreatitis.
  • the first step is to avoid the use of any type of irritant for the pancreas, such as alcohol, and to prescribe a low-fat diet and non-narcotic analgesics, such as acetaminophen.
  • a low-fat diet and non-narcotic analgesics such as acetaminophen.
  • pancreatic enzymes plus acid suppression is advocated.
  • pancreatitis can be managed by the use of large doses of pancreatic enzymes, especially to relieve the pain associated with this condition.
  • the mechanism seems to involve a reduction in the secretion of pancreatic enzymes mediated by the presence of ingested enzymes in the duodenum, a process called negative feedback inhibition.
  • CCK-RP CCK-releasing peptide
  • Trypsin is capable of denaturing this peptide and thereby prevents the release of CCK.
  • basal pancreatic secretion supplies just enough enzyme to denature CCK-RP and thus limits the steady state of release of CCK to small amounts.
  • pancreatitis In chronic pancreatitis, trypsin out-put is diminished. As a result, CCK-RP is not denatured and is available to release excessive amounts of CCK. The pancreas remains under strong stimulation from this hormone and this mechanism is thought to cause pancreatic pain. However, the mechanism remains to be elucidated. Oral enzyme therapy provides increased trypsin within the duodenum and trypsin denatures CCK-RP, thereby reducing CCK release. The result is a decrease in pancreatic stimulation and less pain. Oral enzyme also reduces CCK release in response to food. There are several published studies on the use of pancreatic enzymes for the relief of pain associated with chronic pancreatitis and one meta- analysis. Most of these studies were carried out and suggested that non- coated enzymes preparation should be useful in the treatment of painful chronic pancreatitis.
  • the active component of these preparations is the protease fraction, more specifically trypsin and chymotrypsin, which can denature the CCK releasing peptide. It is then logical to think that enzymes preparations that would contain higher concentration of proteases would be ideal to treat chronic, painful pancreatitis.
  • An object of the present invention is to provide a new process for preparing a formulation having a high content of protease.
  • the process of the present invention comprises the following steps:
  • a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland
  • an autolysis step which comprises mixing the pancreas gland obtained in a) with water, isopropanol, sodium bicarbonate and trypsin, thereby obtaining a first mixture
  • a separation step which comprises pumping the first mixture into a screening kettle thereby separating the insoluble fibers thereby obtaining a filtrate
  • a precipitation step which comprises mixing the filtrate with isopropanol thereby forming a second mixture, and allowing the second mixture to settle thereby obtaining a precipitate;
  • the process being characterized by adjusting the pH to at least 4 after the autolysis step b) or the separation step c).
  • Another object of the present invention is to provide a non-enteric coated formulation having a high content of protease. Accordingly, the formulation comprises protease having at least 100,000 USP U/g of residual protease activity and a pharmaceutically acceptable carrier.
  • a further object of the present invention is the use of the non-enteric formation of the instant invention for the treatment of pancreatic disorders.
  • the formulation of the invention provides a higher ratio of protease/lipase and higher protease residual activity.
  • the process of the present invention allows production of such formulation thanks to the lipase inactivation steps resulting in the pH adjustment.
  • Figure 1 is flowchart illustrating a process for manufacturing a high protease content formulation according to a preferred embodiment of the present invention.
  • Figure 2 is a table summarizing the pH values that may be used in the process of Figure 1.
  • pancreatin formulation according to the present invention may be prepared by a process comprising:
  • a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland
  • an autolysis step which comprises mixing the pancreas gland obtained in a) with water, isopropanol, sodium bicarbonate and trypsin, thereby obtaining a first mixture;
  • a separation step which comprises pumping the first mixture into a screening kettle thereby separating the insoluble fibers thereby obtaining a filtrate
  • a precipitation step which comprises mixing the filtrate with isopropanol thereby forming a second mixture, and allowing the second mixture to settle thereby obtaining a precipitate;
  • step b) or c the process of the instant invention is characterized by a pH adjustment after step b) or c). It has been discovered that the pH adjustment allows inactivation of lipase.
  • the pH must be at least 4. In a preferred embodiment, the pH may range between 4 and 7. Such conditions give rise to a composition having a residual lipase activity which varies from 20,000 to 100,000 USP U/g; a residual amylase activity which is greater than 75,000 USP U/g; and a residual protease activity which varies from 100,000 to 300,000 USP U/g.
  • the present invention is also concerned with a pancreatin, pancrealipase or pharmaceutical formulation comprising protease which has a residual protease activity of at least 100,000 USP U/g.
  • a pancreatin, pancrealipase or pharmaceutical formulation comprising protease which has a residual protease activity of at least 100,000 USP U/g.
  • such formulation has a residual protease activity ranging from about 150,000 USP U/g to 300,000 USP U/g.
  • the formulation according to the present invention may also contain amylase and lipase.
  • the feasible ratio of protease/lipase is around 3 to 15 in the final product.
  • the lipase will then be between 25,000 to 35,000 USP U/g.
  • the residual lipase activity is about 2,000 USP U/g for pancreatin and for pancrealipase, 24,000 USP U/g.
  • the lipase inactivation may be carried out for up to 60 minutes, and preferably for 30 minutes.
  • pancreatin or pharmaceutical formulation according to the present invention may be used for the treatment of digestive deficiencies and pancreatic disorders such as chronic pancreatitis and non-ulcerous dyspepsia.
  • Dyspepsia is a common clinical symptom, associated with a potentially profound impact on health care resource utilization and patient quality of life.
  • There are many possible causes for dyspepsia including acid-related disease, motility disturbances, abnormal visceral sensitivity, and neoplastic disorders of the esophagus, stomach, and duodenum.
  • the majority of patients with dyspepsia have no identifiable upper gastrointestinal pathology after standard test (1-8).
  • symptoms persist in >50% patients despite treatment with potent acid suppressants, prokinetics, drugs affecting visceral pain thresholds, and/or antibiotics against H. pylori.
  • Biliary tract disease may account for symptoms in some patients with dyspepsia, but it is well known that cholecystectomy and/or biliary sphincterotomy often fail to relieve symptoms in patients without classic biliary colic or objective evidence of biliary obstruction.
  • pancreatic disease in dyspepsia The role of pancreatic disease in dyspepsia is unclear. A number of studies have documented abnormal pancreatic function in patients with dyspepsia. Lundh meal tests were abnormal in 20/72 (28%) uninvestigated dyspeptics studied by Schulze et al. (11) and in 159/460 (35%) studied by Anderson et al. (12) Smith et al. also found significantly reduced mean tryptic activity after a Lundh test meal in 6/27 (27%) patients with endoscopically confirmed non ulcer dyspepsia (13) and Skude et al. found abnormal serum pancreatic isoamylase levels in 7/36 (19%) consecutive males seeking primary care for dyspepsia (14).
  • Batch size is 470 to 740 Kg after addition of two sub-batches of this size to step 8 shredding.
  • Step 1 Mincing
  • the minced material is pumped with 500 L of drinking water to a stirred mixture of 300 L (250 to 350 L) of Isopropanol 88%, 150 L (100 to 250 L) of drinking water and 32.5 kg (25 to 40 kg) of Sodium bicarbonate in a autolysis kettle. Then 40 to 80 million FIP trypsin units and 0 to 1.2 kg of Simethicone emulsion (if foaming occurs) are added.
  • Step 3 Separation The mixture is pumped into the screening kettle and insoluble fibers are separated by sieving.
  • the filtrate is charged to 7,000 L (6,500 to 7,500 L) of isopropanol 88% (v/v) in the precipitation kettle and stirred for a minimum of 30 minutes.
  • the precipitate is allowed to settle during a minimum of 30 minutes and the upper layer of solvent is removed.
  • This solvent is distilled to recycle isopropanol.
  • the purified product is isolated by filtration on a filter press.
  • the wet filter cake of two autolysis sub-batches, produced as described above, are combined and shredded in a screw-type extruder.
  • Step 9 Drying The sized product is dried in a vacuum double-cone dryer.
  • the drying of pancreatin is performed in vacuum at temperatures between 0 and 85°C over a period of minimum 16 h, at least 1 h with a minimum temperature of 60°C.
  • the dried product is milled in a cylinder mill and sieved.
  • Step 11 Sifting
  • the material is sieved on a 0.6 mm sifting system.
  • the material Before taking samples for analysis the material is collected in an aluminum container and homogenized with the container mixer.
  • the drug substance is stored in aluminum containers until released by Quality Control.
  • the digestive power of the drug substance can be standardized to customer requirements by blending material in a container mixer with a higher digestive power with material of a lower digestive power.
  • Step 14 Packaging and Labelling Pancreatin / Pancrealipase is weighed into PE bags, sealed up tightly together with a desiccant in an Al-laminated foil and packaged in a corrugated cardboard box.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
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  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de préparation d'une formulation à haute concentration de protéase, ce procédé comprenant les étapes suivantes: a) broyage d'une glande pancréatique congelée, b) autolyse de la glande pancréatique broyée à l'étape a); c) séparation des fibres non solubles pour l'obtention d'un filtrat; d) mélange du filtrat avec de l'isopropanol pour l'obtention d'un précipité; e) purification du précipité par lavage avec de l'isopropanol; et f) isolation du précipité obtenu à l'étape e) par filtration. Ce procédé permet de préparer une formulation dont la teneur en protéase présente une activité protéasique résiduelle d'au moins 100 000 USP U/g. Cette formulation peut être utilisée pour le traitement de troubles pancréatiques.
PCT/CA2004/000228 2003-02-18 2004-02-18 Pancreatine a haute teneur en protease WO2004074470A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA002419572A CA2419572A1 (fr) 2003-02-18 2003-02-18 Preparation a forte concentration de protease
CA2,419,572 2003-02-18

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WO2004074470A1 true WO2004074470A1 (fr) 2004-09-02

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015069677A1 (fr) * 2013-11-05 2015-05-14 Aptalis Pharma Ltd. Compositions pharmaceutiques de pancréatine de haute puissance
US9259393B2 (en) 2000-11-15 2016-02-16 Aptalis Pharma S.R.L. Microspheres of pancreatic enzymes with high stability and production method thereof
US9976171B2 (en) 2011-08-08 2018-05-22 Allergan Pharmaceuticals International Limited Method for dissolution testing of solid compositions containing digestive enzymes
US10087493B2 (en) 2008-03-07 2018-10-02 Aptalis Pharma Canada Ulc Method for detecting infectious parvovirus in pharmaceutical preparations
US10184121B2 (en) 2013-06-28 2019-01-22 Allergan Pharmaceuticals International Limited Methods for removing viral contaminants from pancreatic extracts
US10206882B2 (en) 2007-02-20 2019-02-19 Allergan Pharmaceuticals International Limited Stable digestive enzyme compositions
CN112080487A (zh) * 2019-06-14 2020-12-15 苏州融析生物科技有限公司 一种羊胰酶制备方法
US10993996B2 (en) 2013-08-09 2021-05-04 Allergan Pharmaceuticals International Limited Digestive enzyme composition suitable for enteral administration
US11364205B2 (en) 2010-10-01 2022-06-21 Societe Des Produits Nestle S.A. Stable low digestive enzyme content formulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016527247A (ja) * 2013-07-22 2016-09-08 アラガン ファーマシューティカルズ インターナショナル リミテッド 高力価パンクレアチン医薬組成物

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US4623624A (en) * 1982-12-30 1986-11-18 Basf Aktiengesellschaft Isolation of pancreatin
DE4203315A1 (de) * 1991-02-14 1992-08-20 Kali Chemie Pharma Gmbh Verfahren zur gewinnung von pankreatin
WO1998038292A1 (fr) * 1997-02-24 1998-09-03 Biozymes Inc. Procede de preparation de pancreatine contenant de faibles quantites de solvant organique residuel et produit obtenu selon ledit procede

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
DE3248588A1 (de) * 1982-12-30 1984-07-12 Nordmark-Werke Gmbh, 2000 Hamburg Verfahren zur gewinnung von pankreatin von hohem schuettgewicht
US4623624A (en) * 1982-12-30 1986-11-18 Basf Aktiengesellschaft Isolation of pancreatin
DE4203315A1 (de) * 1991-02-14 1992-08-20 Kali Chemie Pharma Gmbh Verfahren zur gewinnung von pankreatin
WO1998038292A1 (fr) * 1997-02-24 1998-09-03 Biozymes Inc. Procede de preparation de pancreatine contenant de faibles quantites de solvant organique residuel et produit obtenu selon ledit procede

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NEOPTOLEMOS J P ET AL: "Treatment of pancreatic exocrine insufficiency after pancreatic resection. Results of a randomized, double-blind, placebo-controlled, crossover study of high vs standard dose pancreatin.", INTERNATIONAL JOURNAL OF PANCREATOLOGY: OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION OF PANCREATOLOGY. UNITED STATES JUN 1999, vol. 25, no. 3, June 1999 (1999-06-01), pages 171 - 180, XP009033038, ISSN: 0169-4197 *
O'KEEFE S J ET AL: "The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis.", JOURNAL OF CLINICAL GASTROENTEROLOGY. UNITED STATES APR 2001, vol. 32, no. 4, April 2001 (2001-04-01), pages 319 - 323, XP009033039, ISSN: 0192-0790 *
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TOSKES P P: "Update on diagnosis and management of chronic pancreatitis.", CURRENT GASTROENTEROLOGY REPORTS. UNITED STATES APR 1999, vol. 1, no. 2, April 1999 (1999-04-01), pages 145 - 153, XP009033138, ISSN: 1522-8037 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9259393B2 (en) 2000-11-15 2016-02-16 Aptalis Pharma S.R.L. Microspheres of pancreatic enzymes with high stability and production method thereof
US9884025B2 (en) 2000-11-15 2018-02-06 Aptalis Pharma S.R.L. Microspheres of pancreatic enzymes with high stability and production method thereof
US10206882B2 (en) 2007-02-20 2019-02-19 Allergan Pharmaceuticals International Limited Stable digestive enzyme compositions
US10087493B2 (en) 2008-03-07 2018-10-02 Aptalis Pharma Canada Ulc Method for detecting infectious parvovirus in pharmaceutical preparations
US11364205B2 (en) 2010-10-01 2022-06-21 Societe Des Produits Nestle S.A. Stable low digestive enzyme content formulation
US9976171B2 (en) 2011-08-08 2018-05-22 Allergan Pharmaceuticals International Limited Method for dissolution testing of solid compositions containing digestive enzymes
US10184121B2 (en) 2013-06-28 2019-01-22 Allergan Pharmaceuticals International Limited Methods for removing viral contaminants from pancreatic extracts
US10993996B2 (en) 2013-08-09 2021-05-04 Allergan Pharmaceuticals International Limited Digestive enzyme composition suitable for enteral administration
WO2015069677A1 (fr) * 2013-11-05 2015-05-14 Aptalis Pharma Ltd. Compositions pharmaceutiques de pancréatine de haute puissance
EP3613429A1 (fr) * 2013-11-05 2020-02-26 Allergan Pharmaceuticals International Limited Compositions pharmaceutiques de pancréatine de haute puissance
JP2017500885A (ja) * 2013-11-05 2017-01-12 アラガン ファーマシューティカルズ インターナショナル リミテッド 高力価パンクレアチン医薬組成物
CN112080487A (zh) * 2019-06-14 2020-12-15 苏州融析生物科技有限公司 一种羊胰酶制备方法
CN112080487B (zh) * 2019-06-14 2024-03-26 苏州融析生物科技有限公司 一种羊胰酶制备方法

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