CA2419572A1 - High dosage protease formulation - Google Patents
High dosage protease formulation Download PDFInfo
- Publication number
- CA2419572A1 CA2419572A1 CA002419572A CA2419572A CA2419572A1 CA 2419572 A1 CA2419572 A1 CA 2419572A1 CA 002419572 A CA002419572 A CA 002419572A CA 2419572 A CA2419572 A CA 2419572A CA 2419572 A1 CA2419572 A1 CA 2419572A1
- Authority
- CA
- Canada
- Prior art keywords
- protease
- uusp
- pharmaceutical composition
- pancreatin
- formulation
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
HIGH DOSE PROTEASE FORMULATION
FIELD OF THE INVENTION
The invention concerns a new protease formulation useful in the treatment of pancreatic disorders.
BACKGROUND OF THE INVENTION
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 199$). 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 only prospective study on the incidence and prevalence of chronic pancreatitis was performed in Copenhagen in 1978 and 1979. ft showed an incidence of 8.2 new cases/100,000 inhabitants per year and a prevalence of 26.4 cases/100,000 inhabitants. Alcohol consumption is considered to be a major factor in the development of chronic pancreatitis.
Japan has traditionally had a very low alcohol intake, which may well explain the low incidence (rate) of chronic pancreatitis. Environmental or hereditary factors may influence the susceptibility to alcohol-induced pancreatitis. Alternatively, this may be related to regional differences in diagnostic criteria for chronic pancreatitis. Thus, the figures for frequency of chronic pancreatitis differ markedly from one center to another. Most likely, this does not reflect a real difference in frequency but point strongly to regional differences in patient selection and diagnostic criteria. Valid and comparable figures for incidence and prevalence of chronic pancreatitis are pending for careful prospective epidemiologic studies based on uniformly accepted diagnostic criteria.
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. Secondly, when the patient suffers from refractory pains, the use of high dose pancreatic enzymes plus acid suppression is advocated.
These new guidelines confirm the increasing evidences that chronic 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. The ability of ingested enzymes to initiate changes in pancreatic exocrine secretion, and therefore, possibly modify pain, appears to involve a peptide in the mucosa of the small intestine, called CGK-releasing peptide (CCK-RP), that releases CCK into the circulation.
Trypsin is capable of denaturing this peptide and thereby prevents the release of CCK.
In the fasting state, basal pancreatic secretion supplies just enough enzyme to denature CCK-RP and thus limits the steady state of release of CCK to small amounts.
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.
FIELD OF THE INVENTION
The invention concerns a new protease formulation useful in the treatment of pancreatic disorders.
BACKGROUND OF THE INVENTION
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 199$). 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 only prospective study on the incidence and prevalence of chronic pancreatitis was performed in Copenhagen in 1978 and 1979. ft showed an incidence of 8.2 new cases/100,000 inhabitants per year and a prevalence of 26.4 cases/100,000 inhabitants. Alcohol consumption is considered to be a major factor in the development of chronic pancreatitis.
Japan has traditionally had a very low alcohol intake, which may well explain the low incidence (rate) of chronic pancreatitis. Environmental or hereditary factors may influence the susceptibility to alcohol-induced pancreatitis. Alternatively, this may be related to regional differences in diagnostic criteria for chronic pancreatitis. Thus, the figures for frequency of chronic pancreatitis differ markedly from one center to another. Most likely, this does not reflect a real difference in frequency but point strongly to regional differences in patient selection and diagnostic criteria. Valid and comparable figures for incidence and prevalence of chronic pancreatitis are pending for careful prospective epidemiologic studies based on uniformly accepted diagnostic criteria.
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. Secondly, when the patient suffers from refractory pains, the use of high dose pancreatic enzymes plus acid suppression is advocated.
These new guidelines confirm the increasing evidences that chronic 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. The ability of ingested enzymes to initiate changes in pancreatic exocrine secretion, and therefore, possibly modify pain, appears to involve a peptide in the mucosa of the small intestine, called CGK-releasing peptide (CCK-RP), that releases CCK into the circulation.
Trypsin is capable of denaturing this peptide and thereby prevents the release of CCK.
In the fasting state, basal pancreatic secretion supplies just enough enzyme to denature CCK-RP and thus limits the steady state of release of CCK to small amounts.
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.
Moreover, 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 only proteases would be ideal to treat chronic, painful pancreatitis.
Thus; there is a need to develop a new non-enteric coated formulation having a high content of protease.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a formulation having a high content of protease.
Another object of the invention is to provide a non-enteric coated formulation having a high content of protease.
A further object of the present invention is the use of the above-mentioned new formulation for the treatment of pancreatic disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is flowchart illustrating a process for manufacturing a high protease content formulation according to a preferred embodiment of the present invention;
Moreover, 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 only proteases would be ideal to treat chronic, painful pancreatitis.
Thus; there is a need to develop a new non-enteric coated formulation having a high content of protease.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a formulation having a high content of protease.
Another object of the invention is to provide a non-enteric coated formulation having a high content of protease.
A further object of the present invention is the use of the above-mentioned new formulation for the treatment of pancreatic disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is flowchart illustrating a process for manufacturing a high protease content formulation according to a preferred embodiment of the present invention;
5 Figure 2 is a table summarizing the pH values that may be used in the process of Figure 1.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with a pancreatin or pharmaceutical formulation comprising protease which has a residual protease activity of at least 100 000 Uusp/g. Preferably, such formulation has a residual protease activity ranging from about 150 000 Uusp/g to 300 000 Uusp/g.
The formulation according to the present invention may also contain amylase and lipase. The feasible ratio of protease/lipase is around 3 to 10 in the final product. The lipase will then be between 25,000 to 35,000 Uusp/g. The residual lipase activity is about 2,000 Uusp/g for pancreatine and for pancrelipase, 24,000 Uusp/g.
The pH shift between 5 and 6, between 0 and 60 minutes. The residual lipase activity varies from 20,000 to 40,000 Uusp/g. The residual amylase activity is greater than 75,000 Uusp/g. The residual protease activity varies from 150,000 to 300,000 Uusp/g.
The pancreatin formulation according to the present invention may be prepared by a process comprising:
a) a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland;
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with a pancreatin or pharmaceutical formulation comprising protease which has a residual protease activity of at least 100 000 Uusp/g. Preferably, such formulation has a residual protease activity ranging from about 150 000 Uusp/g to 300 000 Uusp/g.
The formulation according to the present invention may also contain amylase and lipase. The feasible ratio of protease/lipase is around 3 to 10 in the final product. The lipase will then be between 25,000 to 35,000 Uusp/g. The residual lipase activity is about 2,000 Uusp/g for pancreatine and for pancrelipase, 24,000 Uusp/g.
The pH shift between 5 and 6, between 0 and 60 minutes. The residual lipase activity varies from 20,000 to 40,000 Uusp/g. The residual amylase activity is greater than 75,000 Uusp/g. The residual protease activity varies from 150,000 to 300,000 Uusp/g.
The pancreatin formulation according to the present invention may be prepared by a process comprising:
a) a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland;
b) an autolysis step which comprises mixing the pancreas gland obtained in a) with water, isopropanol, sodium bicarbonate and trypsin, thereby obtaining a first mixture;
c) a separation step which comprises pumping the first mixture into a screening kettle thereby seperating the insoluble fibers thereby obtaining a filtrate;
d) 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;
e) a purification step which comprises washing the precipitate with isopropanol; and f) an isolation step which comprises isolating the precipitate obtained in e) by filtration.
The 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. However, the majority of patients with dyspepsia have no identifiable upper gastrointestinal pathology after standard test (1-8). Furthermore, whether or not structural or functional abnormalities are documented, symptoms persist in >50% patients despite treatment with potent acid suppressants, prokinetics, drugs affecting visceral pain thresholds, and/or antibiotics against H, pyroli. (9-10) 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.
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 6127 (27°/A) 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).
Mild pancreatic disease is difficult to diagnose since duodenal intubation tests may be impractical to perform outside of referral centers and because endoscopic retrograde pancreatography may be considered too invasive.
Some authors have suggested that mild pancreatic disease may present as dyspepsia (15) and abnormal pancreatic function has been found in up to 35% of patients with dyspepsia (11-14). 'There are no published data on pancreatographic finding in patients classified prospectively as suffering from dyspepsia.
EXAMPLES
1.0) Manufacturing process for pancreatin formula for 235 to 370 kg*
Material I Mass ~ Addition Pancreas glands2,000-3,000 at step 1 Mincing: frozen kg material is minced Sodium 25-40 kg at step 2 Autolysis: as buffer bicarbonate substance Simethicone 0-12 kg at step 2 Autolysis: in case of foaming emulsion Pancreatin for 40-80 Mio at step 2 Autolysis: to activate FIP- Trypsin starting Units for autolysis Isopropanol 250-350 L at step 2 Autolysis (start) 88% to reduce (vw) microbiological contamination ' at step 2 Autolysis (end) to dissolve fat 1,500-1,700 L r ci itate i ti t it t t p p on o p e rec a s ep a ' pancreatin 6,500-7,500 L i II; at step 5 Purification to wash 4,000-6,000 L
i pancreatin and to reduce microbiological contamination I
Drinking water 600-750 L at step 2 Autolysis: to dissolve buffer and pancreas glands I
* Batch size is 470 to 740 Kg after addition of two sub-batches of this size to step 8 shredding.
1 1 ) Detailed description of the process Step 1: Mincing 2,500 kg (2,000 to 3,000 kg) of deep frozen Porcine Pancreas Glands are minced with a meat grinder.
Step 2: Autolysis 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.
This mixture is heated in stages to a maximum of 25°C, while stirring.
Samples are taken to determine the end of autolysis. To stop the autolysis (after 12 to 96 h) 1,600 L (1,500 to 1,700 L) of Isopropanol 88% (v/v) is added, while stirring.
Step 3: Separation The mixture is pumped into the screening kettle and insoluble fibers are separated by sieving.
Step 4: Precipitation 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.
Step 5: Purification The remaining precipitate is stirred with 4,000 to 6,000 L of isopropanol 88% (v/v) at a maximum temperature of 25°C for a minimum of 60 minutes.
Step 6: Isolation 5 The purified product is isolated by filtration on a filter press.
Step 7: Cold storage In a cold storage room the product is stored in closed containers at a max temperature of 0°C.
Step 8: Shredding 10 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.
Step 10: Milling The dried product is milled in a cylinder mill and sieved.
Step 11: Sifting To remove residual fibers the material is sieved on a 0.6 mm sifting system.
c) a separation step which comprises pumping the first mixture into a screening kettle thereby seperating the insoluble fibers thereby obtaining a filtrate;
d) 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;
e) a purification step which comprises washing the precipitate with isopropanol; and f) an isolation step which comprises isolating the precipitate obtained in e) by filtration.
The 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. However, the majority of patients with dyspepsia have no identifiable upper gastrointestinal pathology after standard test (1-8). Furthermore, whether or not structural or functional abnormalities are documented, symptoms persist in >50% patients despite treatment with potent acid suppressants, prokinetics, drugs affecting visceral pain thresholds, and/or antibiotics against H, pyroli. (9-10) 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.
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 6127 (27°/A) 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).
Mild pancreatic disease is difficult to diagnose since duodenal intubation tests may be impractical to perform outside of referral centers and because endoscopic retrograde pancreatography may be considered too invasive.
Some authors have suggested that mild pancreatic disease may present as dyspepsia (15) and abnormal pancreatic function has been found in up to 35% of patients with dyspepsia (11-14). 'There are no published data on pancreatographic finding in patients classified prospectively as suffering from dyspepsia.
EXAMPLES
1.0) Manufacturing process for pancreatin formula for 235 to 370 kg*
Material I Mass ~ Addition Pancreas glands2,000-3,000 at step 1 Mincing: frozen kg material is minced Sodium 25-40 kg at step 2 Autolysis: as buffer bicarbonate substance Simethicone 0-12 kg at step 2 Autolysis: in case of foaming emulsion Pancreatin for 40-80 Mio at step 2 Autolysis: to activate FIP- Trypsin starting Units for autolysis Isopropanol 250-350 L at step 2 Autolysis (start) 88% to reduce (vw) microbiological contamination ' at step 2 Autolysis (end) to dissolve fat 1,500-1,700 L r ci itate i ti t it t t p p on o p e rec a s ep a ' pancreatin 6,500-7,500 L i II; at step 5 Purification to wash 4,000-6,000 L
i pancreatin and to reduce microbiological contamination I
Drinking water 600-750 L at step 2 Autolysis: to dissolve buffer and pancreas glands I
* Batch size is 470 to 740 Kg after addition of two sub-batches of this size to step 8 shredding.
1 1 ) Detailed description of the process Step 1: Mincing 2,500 kg (2,000 to 3,000 kg) of deep frozen Porcine Pancreas Glands are minced with a meat grinder.
Step 2: Autolysis 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.
This mixture is heated in stages to a maximum of 25°C, while stirring.
Samples are taken to determine the end of autolysis. To stop the autolysis (after 12 to 96 h) 1,600 L (1,500 to 1,700 L) of Isopropanol 88% (v/v) is added, while stirring.
Step 3: Separation The mixture is pumped into the screening kettle and insoluble fibers are separated by sieving.
Step 4: Precipitation 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.
Step 5: Purification The remaining precipitate is stirred with 4,000 to 6,000 L of isopropanol 88% (v/v) at a maximum temperature of 25°C for a minimum of 60 minutes.
Step 6: Isolation 5 The purified product is isolated by filtration on a filter press.
Step 7: Cold storage In a cold storage room the product is stored in closed containers at a max temperature of 0°C.
Step 8: Shredding 10 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.
Step 10: Milling The dried product is milled in a cylinder mill and sieved.
Step 11: Sifting To remove residual fibers the material is sieved on a 0.6 mm sifting system.
Step 12: Homogenizing Before taking samples for analysis the material is collected in an aluminum container and homogenized with the container mixer.
Step 13: Quarantine Storage The drug substance is stored in aluminum containers until released by Quality Control.
Optional: Standardizing 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 / Pancrelipase is weighed into PE bags, sealed up tightly together with a desiccant in an AI-laminated foil and packaged in a corrugated cardboard box.
REFERENCES
1. Jebbink HJ, Smout AJ, van Bergc-H~enegouwen GP. Pathophysiology and treatment of functional dysp~psia.w] [80 refs]. Scandinavian [I~ev e Journal of Gastroenterology - Supplement -14.
1993;2006 2. Agreus l-, Svardsudd K, Nyren O, Ti blin G. Irritable bowel syndrome and dyspepsia in the general population;lap and lack of stability ov r over time [see comments]. Gastroenterology 1-680, 1995;109:6 3. Bytzer P, Schaffalitzky dMO.
Prediction ofi major pathologic conditions in dyspeptjc patients referred for endoscopy, A pro~spect(ve validation study of a scoring system. Scandinavian Journal terology 1992;27:987-992.
of Gastroe 4. Edenholm M, Gustavsson R, Jansspn, Lingfors H, Nilsson O, Soderlind, T, Tltusson L, Thulin A. Endoscopics in patients with ulcer-like fiindin dyspepsia.
Scandinavian Journal of Gastroenterology- Supplement 1985;109:163-167.
5. Heikkinen M, Pikkarainen P, Takala J,~Rasanen H, Julkunen R. Etiology of dyspepsia: four hundred unselected co secutive patients in general practice.
Scandinavian Journal of Gastroenterologyi1995;30:519-523.
6, Johnson R, Bernersen B, StraumeForde OH, Bostad L, Burhol B' PG.
Prevalences of endoscopic and histologiC~a! findings in subjects with and without dyspepsia. BMJ 1991;302:749-752.j 7. Kahn KL, Greenfield S, The efficacy~oscopy in the evaluation of en of dyspepsia.
A review ofi the literature and developmentiof a sound strategy. [Review] [138 refs], Journal of Clinical Gastroenterology 19B6'~:346-358.
8, Williams B, Luckas M, Ellingham JH, pam A, Wicks AC. Do young patienfs with x ;2:1349-1351.
dyspepsia need investigation?
Lancet 198 9. Ta(ley NJ. Drug treatment of functio al ~ dyspepsia. [Reviews [115 refs], Scandinavian Journal of Gastroenterology , Supplement 1991;182:47-60, 10. Talley NJ, McNeil D, Hoyden A, Coireavy C, Piper DW. Prognosis of chronic unexplained dyspepsia. Gastroenterology 11 8?;92:1060-1066.
11. Schulze S, Thorsgaard PN, Jorgensen MJ~, Mollmann KM, Rune SJ, Association between duodenal bulb ulcerationced exocrine pancreatic function.
and red Gut 1983;24:781-783.
Step 13: Quarantine Storage The drug substance is stored in aluminum containers until released by Quality Control.
Optional: Standardizing 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 / Pancrelipase is weighed into PE bags, sealed up tightly together with a desiccant in an AI-laminated foil and packaged in a corrugated cardboard box.
REFERENCES
1. Jebbink HJ, Smout AJ, van Bergc-H~enegouwen GP. Pathophysiology and treatment of functional dysp~psia.w] [80 refs]. Scandinavian [I~ev e Journal of Gastroenterology - Supplement -14.
1993;2006 2. Agreus l-, Svardsudd K, Nyren O, Ti blin G. Irritable bowel syndrome and dyspepsia in the general population;lap and lack of stability ov r over time [see comments]. Gastroenterology 1-680, 1995;109:6 3. Bytzer P, Schaffalitzky dMO.
Prediction ofi major pathologic conditions in dyspeptjc patients referred for endoscopy, A pro~spect(ve validation study of a scoring system. Scandinavian Journal terology 1992;27:987-992.
of Gastroe 4. Edenholm M, Gustavsson R, Jansspn, Lingfors H, Nilsson O, Soderlind, T, Tltusson L, Thulin A. Endoscopics in patients with ulcer-like fiindin dyspepsia.
Scandinavian Journal of Gastroenterology- Supplement 1985;109:163-167.
5. Heikkinen M, Pikkarainen P, Takala J,~Rasanen H, Julkunen R. Etiology of dyspepsia: four hundred unselected co secutive patients in general practice.
Scandinavian Journal of Gastroenterologyi1995;30:519-523.
6, Johnson R, Bernersen B, StraumeForde OH, Bostad L, Burhol B' PG.
Prevalences of endoscopic and histologiC~a! findings in subjects with and without dyspepsia. BMJ 1991;302:749-752.j 7. Kahn KL, Greenfield S, The efficacy~oscopy in the evaluation of en of dyspepsia.
A review ofi the literature and developmentiof a sound strategy. [Review] [138 refs], Journal of Clinical Gastroenterology 19B6'~:346-358.
8, Williams B, Luckas M, Ellingham JH, pam A, Wicks AC. Do young patienfs with x ;2:1349-1351.
dyspepsia need investigation?
Lancet 198 9. Ta(ley NJ. Drug treatment of functio al ~ dyspepsia. [Reviews [115 refs], Scandinavian Journal of Gastroenterology , Supplement 1991;182:47-60, 10. Talley NJ, McNeil D, Hoyden A, Coireavy C, Piper DW. Prognosis of chronic unexplained dyspepsia. Gastroenterology 11 8?;92:1060-1066.
11. Schulze S, Thorsgaard PN, Jorgensen MJ~, Mollmann KM, Rune SJ, Association between duodenal bulb ulcerationced exocrine pancreatic function.
and red Gut 1983;24:781-783.
12, Andersen BN, Scheel J, Rune SJ, WQrning H. Exocrine pancreatic function in patients with dyspepsia. Hepato-Gastroenterology 1982;29:35-37.
13. Smith RC, Talley NJ, Dent OF, Jones M.'.Waller SL.. Exocrine pancreatic function and chronic unexplained dyspepsia. A case-contra! study. International Journal of Pancreatoiogy 1991;8:253-262.
14. Skude G, Andren P, Haliert C, Kalin S, Lorentzson S, Petersson BG, Sassner P, Pancreatic disease in dy5pepsla. pigestion 1987;37 Suppl 1.14-17.
15. Toskes Pt'. Medical management of chronic pancreatitis. Scandinavian Journal of Gastroenterology - Supplement '! 995;208:74-8a.
Claims (11)
1. A pancreatin formulation comprising protease having a residual protease activity of at least 100 000 Uusp/g.
2. The pancreatin formulation according to claim 1, wherein the protease has a residual activity ranging from about 150 000 Uusp/g to 300 000 Uusp/g.
3. The pancreatin formulation according to claim 1 or 2, having a protease/lipase ratio ranging from about 3 to 10.
4. A pancreatin formulation obtained from a process for preparing a high density protease pancreatin formulation, the process comprising:
a) a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland;
b) an autolysis step which comprises mixing the pancreas gland obtained in a) with water, isopropanol, sodium bicarbonate and trypsin, thereby obtaining a first mixture;
c) a seperation step which comprises pumping the first mixture into a screening kettle and seperating the insoluble fibers thereby obtaining a filtrate;
d) 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;
e) a purification step which comprises washing the precipitate with isopropanol; and g) an isolation step which comprises isolating the precipitate obtained in f) by filtration.
a) a grinding step which comprises grinding a predetermined amount of a frozen pancreas gland;
b) an autolysis step which comprises mixing the pancreas gland obtained in a) with water, isopropanol, sodium bicarbonate and trypsin, thereby obtaining a first mixture;
c) a seperation step which comprises pumping the first mixture into a screening kettle and seperating the insoluble fibers thereby obtaining a filtrate;
d) 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;
e) a purification step which comprises washing the precipitate with isopropanol; and g) an isolation step which comprises isolating the precipitate obtained in f) by filtration.
5. A pharmaceutical composition comprising protease having at least 100 000 Uusp/g of residual protease acivity, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to claim 5, wherein the protease has a residual activity of ranging from about 150 000 to 300 000 Uusp/g.
7. The pharmaceutical composition according to claim 5 or 6, having a protease/lipase ratio ranging from about 3 to 10.
8. Use of a pancreatin formulation as defined in any one of claims 1 to 4, for the treatment of digestive deficiencies and pancreatic disorders.
9. Use of a pancreatin formulation as defined in any one of claims 1 to 4, for the treatment of non-ulcerous dyspepsia or chronic pancreatitis.
10. Use of a pharmaceutical composition as defined in any one of claims 5 to 7, for the treatment of digestive deficiencies and pancreatic disorders.
11. Use of a pharmaceutical composition as defined in any one of claims 5 to 7, for the treatment of non-ulcerous dyspepsia or chronic pancreatitis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002419572A CA2419572A1 (en) | 2003-02-18 | 2003-02-18 | High dosage protease formulation |
| PCT/CA2004/000228 WO2004074470A1 (en) | 2003-02-18 | 2004-02-18 | High protease content pancreatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002419572A CA2419572A1 (en) | 2003-02-18 | 2003-02-18 | High dosage protease formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2419572A1 true CA2419572A1 (en) | 2004-08-18 |
Family
ID=32855086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002419572A Abandoned CA2419572A1 (en) | 2003-02-18 | 2003-02-18 | High dosage protease formulation |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2419572A1 (en) |
| WO (1) | WO2004074470A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015019198A3 (en) * | 2013-07-22 | 2015-05-28 | Aptalis Pharma Ltd. | High potency pancreatin pharmaceutical compositions |
| 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 |
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106659773A (en) * | 2013-11-05 | 2017-05-10 | 阿勒根制药国际有限公司 | High potency pancreatin pharmaceutical compositions |
| CN112080487B (en) * | 2019-06-14 | 2024-03-26 | 苏州融析生物科技有限公司 | Sheep pancreatin preparation method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3248588A1 (en) * | 1982-12-30 | 1984-07-12 | Nordmark-Werke Gmbh, 2000 Hamburg | Process for obtaining pancreatin with high apparent density |
| DE3377506D1 (en) * | 1982-12-30 | 1988-09-01 | Nordmark Arzneimittel Gmbh | Process for obtaining pancreatin |
| DE4203315A1 (en) * | 1991-02-14 | 1992-08-20 | Kali Chemie Pharma Gmbh | Recovery of pancreatin from aq. pancreas tissue suspension autolysate(s) - by cross-current ultrafiltration to give retentate enriched in amylase, lipase and protease which is then spray dried |
| US5861291A (en) * | 1997-02-24 | 1999-01-19 | Biozymes Inc. | Method for producing pancreatin which contains low amounts of residual organic solvent and product thereof |
-
2003
- 2003-02-18 CA CA002419572A patent/CA2419572A1/en not_active Abandoned
-
2004
- 2004-02-18 WO PCT/CA2004/000228 patent/WO2004074470A1/en active Search and Examination
Cited By (11)
| 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 |
| WO2015019198A3 (en) * | 2013-07-22 | 2015-05-28 | Aptalis Pharma Ltd. | High potency pancreatin pharmaceutical compositions |
| CN105392496A (en) * | 2013-07-22 | 2016-03-09 | 阿普塔利斯制药有限公司 | High potency pancreatin pharmaceutical compositions |
| RU2686460C2 (en) * | 2013-07-22 | 2019-04-26 | Апталис Фарма Лтд. | High potency pancreatin pharmaceutical compositions |
| US10993996B2 (en) | 2013-08-09 | 2021-05-04 | Allergan Pharmaceuticals International Limited | Digestive enzyme composition suitable for enteral administration |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004074470A1 (en) | 2004-09-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101333664B1 (en) | Compositions containing lipase, protease and amylase for treating pancreatic insufficiency | |
| US7122357B2 (en) | Method for the treatment of diabetes | |
| Ferrone et al. | Pancreatic enzyme pharmacotherapy | |
| US4485095A (en) | Pronase used for the treatment of diseases of the liver and kidneys in humans and animals | |
| US20100196344A1 (en) | Compositions and methods for treating pancreatic insufficiency | |
| Jiang et al. | The impact of micronized purified flavonoid fraction on the treatment of acute haemorrhoidal episodes | |
| CA2419572A1 (en) | High dosage protease formulation | |
| US20180104317A1 (en) | Methods and pharmaceutical compositions for treating celiac disease and gluten intolerance | |
| Kulthanan et al. | Angioedema: clinical and etiological aspects | |
| JP5199919B2 (en) | Glucose level rise inhibitor comprising star decollagen peptide as active ingredient and method for producing dedecollagen peptide | |
| Keller et al. | Pancreatic enzyme supplementation therapy | |
| Pedersen et al. | LongoVital in the treatment of Sjögren’s syndrome | |
| US6013680A (en) | Digestive enzyme-containing medicament | |
| US20130039999A1 (en) | Use of clays for treating coeliac disease | |
| JP2023530742A (en) | Non-porcine formulations and methods thereof | |
| Ruseler-van Embden et al. | Increased proteolysis and leucine aminopeptidase activity in faeces of patients with Crohn’s disease | |
| Huang et al. | AB0379 IS MYCOPHENOLATE SODIUM (MYFORTIC) SIMILARLY EFFECTIVE AS MYCOPHENOLATE MOFETIL (CELLCEPT) IN TREATMENT OF LUPUS NEPHRITIS? EXPERIENCE FROM NON-MEDICAL SWITCHING REAL WORLD DATA IN TAIWAN | |
| Huang et al. | AB0380 THERAPEUTIC CHOICES AND OUTCOMES IN CHINESE PATIENTS WITH SEROLOGICALLY ACTIVE CLINICALLY QUIESCENT SYSTEMIC LUPUS ERYTHEMATOSUS | |
| RU2171688C2 (en) | Method for treating infantine reactive pancreatitis | |
| Sato et al. | Case of an elderly man with associated Henoch-Schönlein purpura during treatment of acute pancreatitis | |
| Sulikowska et al. | IgA Nephropathy–selected problems including older patients Nefropatia IgA–wybrane zagadnienia z uwzględnieniem chorych w wieku starszym | |
| Saito et al. | Lysosomal enzyme activities in rat kidney treated with DOCA, especially with reference to renin, cathepsin and β-glucuronidase | |
| Cornell et al. | Enzyme therapy for coeliac disease: Is it ready for prime time? | |
| CN114761015A (en) | Use of inhibitors of neutrophil elastase in pulmonary diseases | |
| JPS61293928A (en) | Remedy for renal nephrosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |