[go: up one dir, main page]

EP0128205A4 - Enzymes stabilisees et activees utilisees pour guerir des blessures. - Google Patents

Enzymes stabilisees et activees utilisees pour guerir des blessures.

Info

Publication number
EP0128205A4
EP0128205A4 EP19840900247 EP84900247A EP0128205A4 EP 0128205 A4 EP0128205 A4 EP 0128205A4 EP 19840900247 EP19840900247 EP 19840900247 EP 84900247 A EP84900247 A EP 84900247A EP 0128205 A4 EP0128205 A4 EP 0128205A4
Authority
EP
European Patent Office
Prior art keywords
composition
enzymes
amino acids
group
amount
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.)
Withdrawn
Application number
EP19840900247
Other languages
German (de)
English (en)
Other versions
EP0128205A1 (fr
Inventor
Gerald L Bilton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ADVANCED DRUG TECHNOLOGY, INC.
Original Assignee
HAFSTEN RAYMOND J JR
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 HAFSTEN RAYMOND J JR filed Critical HAFSTEN RAYMOND J JR
Publication of EP0128205A1 publication Critical patent/EP0128205A1/fr
Publication of EP0128205A4 publication Critical patent/EP0128205A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/26—Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
    • 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)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • 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)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4826—Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
    • 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)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • wound as used herein is intended to refer to the cellular disruption of mammalian tissue which is either traumatic, as in the case of a burn or cut, or, on the other hand, representative of a degenerative process, such as the gradual accumulation of arterial plaque, which may lead to thrombus formation and strokes. In either case, the sticky cell fragments called platelets are strongly implicated.
  • platelets clump at the wound site, partially sealing the leak.
  • the aggregated platelets activate the protease thrombin, which in turn acts to polymerize circulating plasma fibrinogen to form fibrin.
  • Fibrin "hardens" by forming a series of peptide crosslinks to form the blood gel which becomes a clot.
  • Fibrin formation is also accompanied by an increase in proinflammatory prostaglandins and prostanoids, such as leukotrienes, which cause all the symptoms of inflammation.
  • proinflammatory prostaglandins and prostanoids such as leukotrienes
  • leukotrienes which cause all the symptoms of inflammation.
  • the human body Under normal homeostatic conditions, the human body maintains a natural cleaning and purging mechanism to help alleviate the formation of arterial plaques by destroying the fibrin network which dissolves the plaques or clots.
  • plasmin acts on fibrin and the active peptides formed by fibrin digestion stimulate the biosynthesis of antiinflammatory prostaglandins which inhibit platelet aggregation, relax smooth muscle and increase vascular permeability to nutrients.
  • Circulating lipolytic enzymes also help to dissolve or reduce the lipid component of plaque. This overall process may be termed "wound-healing".
  • bromelain acts to selectively inhibit the biosynthesis of proinflammatory prostaglandins, such as the platelet aggregating thromboxanes.
  • proinflammatory prostaglandins such as the platelet aggregating thromboxanes.
  • the use of bromelain is indicated since the endogenous proteases such as circulating plasmin, trypsin, chymotrypsin, and lipases are inhibited by trauma or exposure to excessive stress. Bromelain also acts on fibrinogen and fibrin to give products similar to those formed by plasmin and which stimulate the biosynthesis of antiinflammatory prostaglandins such as PGI 2 . See S . J . Taussig , Med . Hypth. , 6, 99 (1980), and J. M.
  • proteolytic enzymes such as trypsin and chymotrypsin or alpha-chymotrypsin have been reported to have a favorable influence on the inflammatory process in thromophlebitis.
  • the most common explanation for the antiedema aetion of all the proteolytic enzymes is that they enhance the lysis of soft (unpolymerized or partially polymerized) fibrin present in inflamed tissue. See B. Seligman, Angiology, 20, 22 (1964), and I. Innerfield et al., J. Clin. Invest., 31, 1049 (1952).
  • Pancreatin and Pancrelipase are pancreatic extracts comprising amylase, lipase, and protease which are used to treat patients with cystic fibrosis and with pancreatic insufficiency. See Remington ' s Pharmaceutical Sciences, A. Ossol ed., Mack Pub., Boston, Mass. (16th ed. 1980) , at ch. 53 for a general discussion of the proteolytic enzymes.
  • proteolytic enzymes with or without the use of pancreas-associated digestive enzymes for the alleviation of wound inflammation and the promotion of healing has not been heretofore realized.
  • the individual enzymes are unstable in moist air and in the digestive tract, tending to hydrolyze (self-lyse). Enzyme mixtures become deactivated due to cross reactions and aggregation. Also, many of the proleolytic enzymes are not sufficiently activated to lyse "hardened" fibrin, which is the primary component implicated in persistent thromboembolic disorders.
  • compositions whereby effective wound-healing amounts of proteolytic enzymes may be orally administered to a patient suffering from a fibrinassociated disorder.
  • compositions comprising mixtures of immobilized proteolytic enzymes in combination with a mixture of amino acids, dipeptides, and buffers.
  • the enzymes of the combination are selected from those indicated as effective in wound healing, and the amino acids are selected from those indicated to aid the digestive tract enzyme absorption and for their ability to stimulate enzyme activation in the healing process. Immobilization of the enzymes prevents their selfdeactivation in the digestive tract and allows them to reach the site of the wound in the active state. Buffering agents are optional to protect the enzymes from hydrolysis by gut acid, to correct digestive tract pH imbalance, and to aid in enzyme absorption.
  • the dipeptides employed are those indicated to enhance fibrin reabsorption. Lyophilized raw gland or organ concentrates are also useful in this invention.
  • wound-healing as discussed herein is also intended to include the amelioration and counteraction of deleterious systemic effects which are caused by or which contribute to the wound pathology. Such effects include, but are not limited to, those associated with pancreatic shock, acidosis, and other malfunction. These states may both contribute to thromboembolic pathology such as plaque and clot formation and may inhibit wound-healing processes.
  • pancreatic enzyme production When pancreatic enzyme production is disrupted, the resultant inhibition of fat digestion and absorption reduces the cellular biosynthesis of prostaglandins which are essential to the maintenance of cell wall integrity.
  • the inflammatory processes associated with thrombus formation also enhance the secretion of inflammatory prostaglandins, including those which are known to increase gastric acid secretion.
  • the increased acidity inhibits pancreatic excretion of digestive enzymes and tends to degrade enzyme supplements, thus slowing the wound-healing process.
  • compositions of the present invention are formulated so as to deliver wound-healing amounts of proteolytic enzymes to the traumatized site in conjunction with amino acids and peptides which tend to aid the gut absorption of the wound-healing amino acids and to activate them at the wound site.
  • the enzymes are substantially immobilized by delivering them in conjunction with a starch component so that they are efficiently absorbed in the presence of excess gut acid without being deactivated by self- or cross-lysis or hydrolysis.
  • Buffering salts are also administered via the compositions of the present invention which tend to reduce or stabilize the acidity so as to aid reestablishment of the normal pancreatic function.
  • Supplemental pancreatic enzymes are also components of the present composition. These enzymes act to restore normal lipid metabolism in the small intestine so as to encourage the biosynthesis of antiinflammatory and platelet-declumping prostaglandins, and to assure adequate cell nutrition during the healing period.
  • compositions of the present invention include two or more fibrolytic, proteolytic enzymes.
  • Proteolytic enzymes generally function to hydrolyze or to lyse proteins into their component amino acids, thus providing these essential amino acids in nutritively-adequate ammunts.
  • Fibrolytic enzymes have the added capability to lyse or digest fibrin clots at wound sites, thus restoring free blood flow through the circulatory system and speeding healing, i.e., clot dissolution, at traumatic wound sites.
  • An especially useful class of proteolytic enzymes is the thiol-enzymes, comprising papain, chymopapain, bromelain, cathepsin and ficin.
  • compositions of the present invention will also include one or more of the proteolytic pancreatic enzymes trypsin, alpha-chymotrypsin and chymotrypsin.
  • Trypsins generally act to reduce wound inflammation and edema and also speed healing by the debridement of necrotic wounds and by fibrinolysis. It is postulated that this activity is at least partially due to the inactivation of the normally inactive precursor of collagenase, an enzyme which acts to soften connective tissue. Therefore, it is believed that the chymotrypsin-containing compositions of the present invention will be useful for alleviation of the symptoms of the collagen-vascular diseases such as rheumatoid arthritis, lupus, and other auto-immune disorders.
  • the trypsins are preferably employed in the compositions of the present invention in an amount equal to about 0.110% by weight of the total enzymes present.
  • compositions of the invention will also preferably incorporate an amount of pancreatin, or of the individual primary enzymes incorporated therein, or of mixtures of the individual enzymes with pancreatin.
  • Pancreatin primarily contains amylase, protease and lipase; digestive enzymes which act to break down dietary starch, protein and fat, respectively. Since pancreatic deficiency or overload is implicated in many situations involving wounds, it is believed that a supplemental amount of pancreatin is a beneficial adjunct to the administration of the fibrinolytic and antiinflammatory enzymes. Pancreatin aids in the restoration of normal digestive processes, including the proper metabolism of fats, which is necessary for the achievement of effective plasma levels of anticlotting and antiinflammatory prostaglandins.
  • Pancreatin and/or its component enzymes preferably comprise up to about 90% of the enzyme mixture of the present compositions, most preferably about 15 to about 85%.
  • the total weight percent of the enzymes employed in the compositions of the present invention may be varied over a wide range. For example, 20-80% by weight of the enzymes may preferably be employed.
  • compositions of the present invention will also include an enzyme stabilizing and activating mixture of a plurality of amino acids and dipeptides.
  • the amino acids act as natural buffers and balance the pH of the compositions of the present invention as they dissolve in the gastrointestinal tract, thus protecting them from excess gastric acid. Mixtures of essential and nonessential amino acids have been found to be effective in the practice of the present invention.
  • the amino acid mixture will comprise those which have been implicated in the stimulation of the body's cellular immune response, such as 1-arginine and 1lysine and their salts.
  • the amino acids are selected to substantially exclude those amino acids present in the thiol-enzymes included in the compositions, i.e., cystine, glycine, serine, tryptophan or alanine. Exclusion of these enzymatic amino acids from the present compositions is believed to facilitate the cellular uptake of the wound-healing thiol-enzymes at the wound site. Therefore, an especially preferred amino acid mixture for use in the compositions of the present invention is a mixture of approximately equal weights of 1-arginine.HCl, 1-lysine.HCl, dl-methionine, 1-glutamic acid, 1-leucine and glutathione.
  • the amino acid mixtures useful in the compositions of the present invention will preferably comprise about 0.1-50%, most preferably 0.2-40% by weight of the compositions.
  • compositions of the present invention will also include a minor but effective amount, preferably 0.0015.0% of a dipeptide of such amino acids, e.g., 1arginine-1-glutamate. It is believed that this dimer activates the reactive site of the fibrinolytic enzymes described hereinabove, thus enhancing their ability to cleave linked fibrin chains and dissolve clots.
  • compositions of the present invention will include an amount of starch, preferably wheat or potato starch, effective to physically immobilize the enzymatic components of the compositions and thus inhibit their deactivation. It has been found that the immobilization can be accomplished by mixing the powdered enzymes and amino acids with from about 1 to about 50% by weight of starch based on the weight of the entire composition.
  • Buffers may be incorporated in the compositions of the present invention.
  • the term "buffers” as employed herein includes organic and inorganic acid3 and acid salts, such as alkali metal carbonates, bicarbonates and phosphates, and also compounds which complex organic acids by the process of chelation and esterification.
  • Flavone-containing glycosides may also be incorporated in the compositions of the invention.
  • Preferred glycosides are rutin, melin, eldrin and the like, which act to restore the permeability and flexibility of traumatized capillary walls. These gycosides, when present, may comprise up to about 20% of the composition, and are preferred for compositions adapted for administration in aqueous solutions.
  • Other useful flavinoids and flavinols are disclosed in A. M. Ambrose, et al . , J. Nutr. , 38, 305 (1949), the disclosure of which Is incorporated herein by reference.
  • Preferred buffers include citric acid-citrate and calcium and sodium bicarbonate. It is believed that the buffers both interact with the amino acids to stabilize the enzymes used, counteract the effect of excessive digestive tract acid, and promote the establishment of beneficial intestinal flora.
  • Buffers when used to make up a portion of the present compositions, preferably comprise about 1-10 percent by weight.
  • Various biologically inactive adjuncts may optionally be incorporated into the compositions of the present invention to aid in their compounding, ingestion, tableting, etc.
  • Such adjuvants may include binders, lubricants, food glazes, sugar syrups, colorings and flavorings, which may be applied in amounts and by methods according to established pharmaceutical practices.
  • compositions of the present invention When formulated as tablets, the compositions of the present invention will preferably be enterically coated with standard coating compositions so that they resist solution in gastric fluid but disintegrate in the intestine.
  • enteric coating methods useful in the practice of the present invention, see Remington's Pharmaceutical Sciences at pages 1590-1591, the disclosure of which is incorporated herein by reference.
  • a preferred powdered composition will be formulated so as to contain about 30-80% of enzymes of which about 10-70% will be thiol-enzymes, about 0.1-10% will be trypsins and about 15-85% will be pancreatin or its component enzymes.
  • About 0.1-30% amino acids will be incorporated in the compositions, along with about 0.002-2% dipeptide, about 1-50% starch and about 0-10% of organic or inorganic buffers. The above weight percentages do not include the additional binders used in the tableting process.
  • compositions of the present invention a dry mix of the powdered glandular extracts (thymus, spleen, or lung), the amino acids and the dimer is prepared in a ribbon-type mixer and then the enzymes are sequentially added with continuous spraying with an alcohol soluble refined glaze under conditions of low atmospheric humidity. After the mixing of the enzymes and amino acids is complete, the mixture contains about 5-10% by weight of glaze solids. The spray is discontinued and the buffers and starch are added to the stirred powder to form the final composition.
  • the composition may be packages or encapsulated at this point for administration via an aqueous enema, douche or capsule suppository.
  • the powdered composition may be tableted, for example, into 1000 mg or 450 mg tablets by any of the commercially-available dry tablet presses.
  • the resultant tablets may be enterically coated, and then further coated with refined food glaze, talc, dusting powder, sugar syrup and dye, according to standard practice.
  • compositions were prepared with the following ingredients.
  • Thymus Substance (Armour 1.5 3.9 0.06
  • compositions of Ex's IA and IB were formulated by dry mixing the ingredients of Part A under conditions of low humidity (less than 30%) and then sequentially adding the ingredients of Part B while lightly spraying 7.4 grams of a solution of 24.0 ml of refined food glaze in 16.7 ml of isopropanol. The ingredients of Part C are then added with continued mixing. The powdered composition is then pressed into 333,000 450 mg tablets on a Stoke's BB-2 tablet press using a 7/16 inch punch. The composition of Ex IB is similarly punched into 400,000 450 mg tablets using a 3/8 inch punch.
  • the tablets of Ex's IA and IB are then enterically coated and finish coated by sequentially applying to each batch a total of 8.0 1 of food glaze, 6.0 kg of talc, 7.9 1 of suspension coating solution, 3.7 kg of dusting powder, 2.0 1 of sugar syrup and 2.2 kg of Opalux pink AS1408 dye in 3, 6, 25, 10, 2 and 1 coatings, respectively, to yield the final tablets.
  • the enteric coated tablet preferably comprises about 50-90% enzymes, about 2-15% starch (although greater amounts may be used as a tablet filler), about 5-15% amino acids, and about 3-15% gland or organ extracts, wherein the percentages are by weight based on the ingredients listed.
  • the tablets may alsoccontain about 0.05-10% of a calcium or sodium acid salt buffer, although the fillers may also exhibit some buffering effect.
  • composition of Ex IC was formulated as a powder by dry mixing the ingredients in the order listed, and then packaging the resultant powder in 1 g foil packets.
  • the resultant formulations when ingrested orally (as in the case of the tablets), or when dissolved in water (as in the case of the powder) and administered as an enema or douche, will effectively deliver wound-healing amounts of enzymes to wound sites such as bruises, cuts, burns, arterial clots, arthritic sites and the like.
  • the invention has general applicability as a technique for preparing compositions comprising a mixture of enzymes in which the enzymes are inhibited from adverse interaction and provision is made for an appropriate environment and activation to facilitate maximum utilization of the enzymes.
  • Combinations of conventionally-available enzymes are adaptable to the present invention, as are combinations of enzymes with other types of therapeutic agents.
  • this invention comprises a mixture of enzymes as the major active ingredient which is susceptible to potential adverse interactions, a stabilizing long-chain molecule having available active sites, such as hydroxyl sites on starch, and a plurality of amino acids (including those provided by raw organ concentrates) to create the proper environment and activation for the enzymes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Compositions contenant une pluralité d'enzymes, de l'amidon, une pluralité d'acides aminés, ainsi que des extraits de glandes ou d'organes pour le traitement d'affections associées à la fibrine.
EP19840900247 1982-12-09 1983-12-07 Enzymes stabilisees et activees utilisees pour guerir des blessures. Withdrawn EP0128205A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44815482A 1982-12-09 1982-12-09
US448154 1982-12-09

Publications (2)

Publication Number Publication Date
EP0128205A1 EP0128205A1 (fr) 1984-12-19
EP0128205A4 true EP0128205A4 (fr) 1987-01-10

Family

ID=23779212

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840900247 Withdrawn EP0128205A4 (fr) 1982-12-09 1983-12-07 Enzymes stabilisees et activees utilisees pour guerir des blessures.

Country Status (3)

Country Link
EP (1) EP0128205A4 (fr)
JP (1) JPS61500431A (fr)
WO (1) WO1984002274A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU209955B (en) * 1987-07-01 1994-12-28 Genentech Inc Process for producing pharmaceutical compositions containing tissue- -plasminogen-activator of poor solubility for inhibiting production and regeneration of deformities
EP0498532A1 (fr) * 1991-01-10 1992-08-12 E.R. SQUIBB & SONS, INC. Poudre pour le débridement des tissus nécropés contenant une enzyme protéolytique
EP1100529B2 (fr) 1998-07-30 2010-08-25 The Government of the United States of America, as repres. by the Secretary of Health and Human Services, Nat. Inst. of Health Amelioration de la guerison des blessures par la thymosine beta 4
EG24184A (en) 2001-06-15 2008-10-08 Otsuka Pharma Co Ltd Dry powder inhalation system for transpulmonary
US9056087B2 (en) 2001-08-29 2015-06-16 Regenerx Biopharmaceuticals, Inc. Methods of healing or preventing inflammation, damage and other changes that occur prior to, during or immediately after a myocardial event with thymosin beta 4, analogues, isoforms and other derivatives
CA2665689C (fr) * 2006-10-04 2015-12-01 Kyowa Hakko Bio Co., Ltd. Preparation de glutathion et procede de production de celui-ci

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE636817A (fr) * 1962-08-31
US3297480A (en) * 1962-09-11 1967-01-10 Nagase & Co Ltd Method for preparing starch having improved amylase adsorptive capacity
US3395222A (en) * 1966-03-11 1968-07-30 Armour Pharma Prolongation of clotting time of blood
US3841971A (en) * 1973-02-16 1974-10-15 Corning Glass Works Synergistic enzymes adsorbed within porous inorganic carriers
US4307081A (en) * 1974-01-08 1981-12-22 Gerold K. V. Klein Enzyme mixture
US4361551A (en) * 1979-11-05 1982-11-30 Riker Laboratories, Inc. Method of enzymatic debridement

Also Published As

Publication number Publication date
EP0128205A1 (fr) 1984-12-19
WO1984002274A1 (fr) 1984-06-21
JPS61500431A (ja) 1986-03-13

Similar Documents

Publication Publication Date Title
Maurer Bromelain: biochemistry, pharmacology and medical use
KR0127754B1 (ko) 항응고제
US5002766A (en) Use of catabolic enzymes for controlling the acquired immune deficiency syndrome (AIDS) and its precursors (LAS, ARC)
Matthews Protein absorption
EP0115974B1 (fr) Préparation à activité collagénolytique ayant une activité élevée et compositions pharmaceutiques la contenant
EP0838213B1 (fr) Utilisation d'enzymes de krill dans le traitement de la plaque dentaire
US4695457A (en) Enzyme composition acting as a digestion promoter on various levels in the alimentary tract, and a method for facilitating digestion
US5945102A (en) Crustacean and fish derived multifunctional enzyme
Rudenskaya et al. Preparation of proteolytic enzymes from Kamchatka crab Paralithodes camchatica hepatopancreas and their application
JPH0680015B2 (ja) 医薬組成物
US3860702A (en) Anti-inflammatory compositions
US5387422A (en) Proteolytic fungal enzyme food supplement composition
JPS63317083A (ja) 組織プラスミノーゲンアクチベーター活性を有するタンパク質の高濃度溶液
CA2176771C (fr) Preparation pharmaceutique avec effet modulatoire sur les tumeurs malignes; son utilisation
WO1984002274A1 (fr) Enzymes stabilisees et activees utilisees pour guerir des blessures
JP6319592B2 (ja) 静脈血栓状態の予防および治療のための、ブロメラインとナットウキナーゼとを含む線維素溶解組成物
CA3055116A1 (fr) Comprime dispersible contenant de la burlulipase et composition pharmaceutique obtenue a partir de ce comprime
Erickson et al. Rat intestinal angiotensin-converting enzyme: purification, properties, expression, and function
WO2001012795A1 (fr) COMPOSITION ET PROCEDE DE TRAITEMENT DE MALADIES PAR AUGMENTATION DE α2 MACROGLOBULINE DANS LE SANG ET TISSU EXTRAVASCULAIRE
Forrester et al. Enhancement of vitreous clot lysis by urokinase: mode of action
JP2010024165A (ja) オキアミタンパク質由来アンジオテンシン変換酵素阻害剤
US7947270B2 (en) Removing dental plaque with krill enzymes
Markland Fibrin (ogen) olytic enzymes from snake venoms
US20060134641A1 (en) Treating viral infections with krill enzymes
CN106215176A (zh) 一种高效抗炎多酶组合物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB LI LU NL SE

17P Request for examination filed

Effective date: 19850221

A4 Supplementary search report drawn up and despatched

Effective date: 19870110

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ADVANCED DRUG TECHNOLOGY, INC.

17Q First examination report despatched

Effective date: 19880915

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19890527

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BILTON, GERALD, L.