Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2001-08-31
2004-06-15
Tate, Chris (Department: 1654)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S094100, C422S022000
Reexamination Certificate
active
06749851
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for sterilizing preparations of digestive enzymes to reduce the level of one or more active biological contaminants or pathogens therein, such as viruses, bacteria (including inter- and intracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts, molds, fungi, prions or similar agents responsible, alone or in combination, for TSEs and/or single or multicellular parasites. The present invention particularly relates to methods of sterilizing preparations of digestive enzymes, such as trypsin, &agr;-galactosidase and iduronate 2-sulfatase, with irradiation.
BACKGROUND OF THE INVENTION
The principal foods upon which an organism, such as a human, survives can be broadly categorized as carbohydrates, fats and proteins. These substances, however, are useless as nutrients without the process of digestion to break down foods.
Digestion of carbohydrates begins in the mouth and stomach. Saliva contains the enzyme ptyalin (an alpha-amylase), which hydrolyses starch into maltose and other small polymers of glucose. The pancreatic alpha-amylase is similar to the salivary ptyalin, but several times as powerful. Therefore, soon after chyme empties into the duodenum and mixes with pancreatic juice, virtually all of the starches are converted into disaccharides and small glucose polymers. These disaccharides and small glucose polymers are hydrolysed into monosaccharides by intestinal epithelial enzymes.
Digestion of proteins begins in the stomach. The enzyme pepsin, which is produced in the stomach, digests collagen, a major constituent of the intercellular connective tissue of meats. This enzymatic reaction is essential so that other digestive enzymes can penetrate meats and digest the cellular proteins. Consequently, in people who lack peptic activity in the stomach, the ingested meats are not well penetrated by these other digestive enzymes and so are poorly absorbed.
Most protein digestion results from the actions of the pancreatic proteolytic enzymes. Proteins leaving the stomach in the form of proteoses, peptones and large polypeptides are digested into dipeptides, tripeptides and the like by pancreatic proteolytic enzymes or polypeptidases. Trypsin and chymotrypsin split protein molecules into smaller polypeptides at specific peptide linkages, while carboxypolypeptidase cleaves amino acids from the carboxyl ends of polypeptides. Proelastase gives rise to elastase, which in turn digests the elastin fibers that hold together most meat.
Further digestion of polypeptides takes place in the intestinal lumen. Aminopolypeptidase and several polypeptidases split large polypeptides into dipeptides, tripeptides and amino acids, which are transported into the enterocytes that line the intestinal villi. Inside the enterocytes, other polypeptidases split the remaining peptides into their constituent amino acids, which then enter the blood.
Digestion of fats first requires emulsification by bile acids and lecithin, which increase the surface area of the fats up to 1000-fold. Because lipases are water-soluble digestive enzymes that can bind only on the surface of a fat globule, this emulsification process is important for the complete digestion of fat. The most important digestive enzyme in the digestion of triglycerides is pancreatic lipase, which breaks these down into free fatty acids and 2-monoglycerides. After these free fatty acids and monoglycerides enter the enterocytes, they are generally recombined into new triglyerides. A few monoglycerides, however, are further digested by intracellular lipases into free fatty acids.
Digestion therefore continues after the breakdown and uptake of nutrients into the various cells of the body. Intracellular enzymes, such as intracellular lipases, are involved in the uptake, breakdown, transport, storage, release, metabolism and catabolism of nutrients into forms required and useable by the cell(s) of an organism at various places and times. This includes storage of lipids and their metabolism into energy sources as well as their catabolism and synthesis into other useful compounds. Digestion may also occur as a part of an organism's normal process(es) of tissue generation and regeneration or repair of degraded, damaged or abnormal tissue(s) or molecules. It may also be a feature of or result from apoptosis, immune reactions, infections, neoplasms and other abnormal or disease states of an organism.
Preparations of digestive enzymes are therefore often provided therapeutically to humans and animals.
For example, in cases of pancreatitis and lack of pancreatic secretion, preparations of certain pancreatic enzymes, including combinations of lipase, protease and amylase (such as Creon™, Cotazym™, Donnazyme™, Ku-Zyme™ HP, Pancrease™ and Pancrease™ MT, Ultrase™ and Ultrase™ MT, Viokase™, and Zymase™) and combinations of lipase, protease, amylase and cellulase (such as Ku-Zyme™ and Kutrase™), are administered to ensure proper patient nutrition. The digestive enzymes of particular interest, for example in replacement therapy in humans and animals, therefore include pancreatic digestive enzymes, such as trypsin and chymotrypsin, and functional mutants, variants and derivatives thereof.
Trypsin is an enzyme that acts to degrade protein; it is often referred to as a digestive enzyme, or proteinase. In the digestive process, trypsin acts with the other proteinases to break down dietary protein molecules to their component peptides and amino acids. Trypsin continues the process of digestion (begun in the stomach) in the small intestine where a slightly alkaline environment (about pH 8) promotes its maximal enzymatic activity. Trypsin, produced in an inactive form by the pancreas, is remarkably similar in chemical composition and in structure to the other chief pancreatic proteinase, chymotrypsin. Both enzymes also appear to have similar mechanisms of action; residues of histidine and serine are found in the active sites of both. The chief difference between the two molecules seems to be in their specificity, that is, each is active only against the peptide bonds in protein molecules that have carboxyl groups donated by certain amino acids. For trypsin these amino acids are arginine and lysine, for chymotrypsin they are tyrosine, phenylalanine, tryptophan, methionine, and leucine. Trypsin is the most discriminating of all the digestive enzymes in terms of the restricted number of chemical bonds that it will attack.
Preparations of other digestive enzymes, such as glycosidases, are likewise administered therapeutically to human patients. For example, Fabry disease is an X-linked recessive glycolipid storage disorder caused by a deficiency of the lysosomal enzyme &agr;-galactosidase A. Clinical manifestations of Fabry disease included recurrent episodes severe pain and progressive renal, cardiac and cerebrovascular deterioration with death usually occurring in the fourth to sixth decade of life. Enzyme replacement therapy by infusion of a preparation of &agr;-galactosidase A has been tested and found to be a promising potential therapy for this condition (Schiffmann, et al, “Enzyme Replacement Therapy in Fabry Disease: A Randomized Controlled Trial.”
JAMA
, Jun. 6, 2001, Vol. 285, No. 21, pp. 2743-2749.).
Glycogen Storage Disease Type II (also known as Acid Maltase Deficiency or Pompe Disease) is another genetically transmitted storage disorder. In GSD-II, the patient suffers from a deficiency of acid maltase enzyme, which breaks down glycogen in muscle cells. Clinical manifestations of GSD-II include progressive muscle weakness due to a build up of glycogen in muscle tissues, eventually resulting in respiratory and/or cardiac failure. Preparations of glycosidases, or functional mutants or variants or derivatives thereof, are therefore also of particular interest for therapeutic use.
Niemann-Pick Disease is also a genetically transmitted metabolic disorder in which harmful quantities of a fatty substance, sphingomyelin, accumulate in the spleen, liver, lungs, bo
Burgess Wilson
Drohan William N.
Griko Yuri
Macphee Martin J.
Mann David M.
Clearant Inc.
Fleshner & Kim LLP
Tate Chris
Winston Randall
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