EP0133438A1 - Onguent enzymatique - Google Patents

Onguent enzymatique

Info

Publication number
EP0133438A1
EP0133438A1 EP19840900913 EP84900913A EP0133438A1 EP 0133438 A1 EP0133438 A1 EP 0133438A1 EP 19840900913 EP19840900913 EP 19840900913 EP 84900913 A EP84900913 A EP 84900913A EP 0133438 A1 EP0133438 A1 EP 0133438A1
Authority
EP
European Patent Office
Prior art keywords
ointment
emollient
skin
ointment according
penetrating
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Withdrawn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
EP19840900913
Other languages
German (de)
English (en)
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 Corp
Original Assignee
ADVANCED DRUG TECHNOLOGY Corp
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 ADVANCED DRUG TECHNOLOGY Corp filed Critical ADVANCED DRUG TECHNOLOGY Corp
Publication of EP0133438A1 publication Critical patent/EP0133438A1/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Withdrawn legal-status Critical Current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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/886—Aloeaceae (Aloe family), e.g. aloe vera
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase
    • 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
    • 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
    • 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)
    • A61K38/49—Urokinase; Tissue plasminogen activator

Definitions

  • prostaglandins i.e. PGE
  • thromboxanes are thought to be synthesized at the trauma site and are believed to be important mediators of the vascular adjustments to be made in the inflammatory response of the body. See, Robbins & Angell, Basic Pathology 38 (2nd ed. 1976).
  • PGE prostaglandin
  • thromboxanes are thought to be synthesized at the trauma site and are believed to be important mediators of the vascular adjustments to be made in the inflammatory response of the body. See, Robbins & Angell, Basic Pathology 38 (2nd ed. 1976).
  • PGE Proliferon filtration
  • thromboxanes are thought to be synthesized at the trauma site and are believed to be important mediators of the vascular adjustments to be made in the inflammatory response of the body. See, Robbins & Angell, Basic Pathology 38 (2nd ed. 1976).
  • clotting factors such as fibrin and thrombin.
  • enzyme blocking factors which prevent fibrin dis
  • necrotic debris which is primarily protein in nature
  • any entrapped bacteria and viruses which are primarily composed of protein and lipids.
  • the accumulation of these substances may be substantial if there is a significant loss of tissue. When this situation occurs, the system is overwhelmed thereby retarding tissue repair.
  • Plasma proteins such as plasminogen and fibrinolysin and the hepatic anticoagulent heparin are usually able to control inflammation during normal homeostasis.
  • Plasma proteins such as plasminogen and fibrinolysin and the hepatic anticoagulent heparin are usually able to control inflammation during normal homeostasis.
  • additional aid is needed by the body to control and alleviate the symptoms of inflammation, since restoration of the damaged tissue cannot be initiated until inflammation is reduced.
  • neutrophils and macrophages contain an abundance of lysosomes containing proteolytic enzymes which are capable of digesting protein matter and bacteria.
  • lysosomes of macrophages are known to contain large quantities of lipases, which are capable of digesting the thick lipid membranes of certain bacteria. See Guyton, Textbook of Medical Physiology 70 (5th ed. 1976).
  • compositions of the present invention are ointments comprising a carrier mixture of penetrating and nonpenetrating emollient oils and a polyhydric alcohol emollient; the proteolytic and other enzymes papain, bromelain, trypsin, chymotrypsin, pancreatin, lipase and amylase; aloe extract; and an organic astringent agent.
  • the carrier mixture, enzymes, aloe extract and the organic astringent agent function synergistically so as to provide an effective wound-healing topical ointment.
  • compositions of the present invention are formulated so as to deliver wound-healing amounts of proteolytic enzymes to the scarred or otherwise traumatized site, in conjunction with reparative quantities of an aloe extract, an organic astringent agent, lipase, amylase, and carrier emollient oils.
  • wound-healing as used herein is intended to refer to the process of tissue repair and to the reduction of symptoms of inflammation present due to the body's response to the cellular disruption of skinsurface 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 an ulcer.
  • compositions of the present invention include a plurality of proteolytic enzymes, which generally function to hydrolyze or to lyse proteins into their component amino acids, thereby providing these essential amino acids in nutritionally adequate amounts.
  • Fibrolytic, proteolytic enzymes possess the added capacity to lyse or digest fibrin clots at wound sites. This action tends to restore the free flow of blood through the circulatory system thereby accelerating the healing process at wound sites and minimizing the development of scar tissue.
  • compositions of the invention will comprise one or more of the proteolytic enzymes streptokinase, urokinase, trypsin, chymotrypsin, papain, bromelain and pancreatin. In a preferred embodiment, all of these enzymes except streptokinase and urokinase are contained in the composition.
  • Trypsin and chymotrypsin have been demonstrated to be successful in the dissolution of the clotting factor fibrin, necrotic tissue and proteinaceous exudates. When applied topically to post-thrombotic leg ulcers, they have shown remarkable success in accelerating the healing process. See, Gordon, The Use of Topical Proteolytic Enzymes in the Treatment of Post-thrombotic Leg Ulcers, Brit. J. Clin. Prac. , 29, 143 (1975). Moreover, trypsin and chymotrypsin are thought to have a favorable influence on the inflammatory process in thromophlebitis. It is expected that streptokinase and urokinase would exhibit similar actions when applied topically in an active form, and may be used in addition to, or as replacements for, the trypsins.
  • trypsin and chymotrypsin are often used in combination for the prevention and treatment of inflammation from injury, each may be used in the formulation of the present invention without the other.
  • trypsin will make up about .025-2.5% by weight and chymotrypsin about .001-1% by weight of the compositions of the present invention and most preferably, about .05-1% and .002-.1%, respectively.
  • Papain has been reported to achieve excellent results in promoting the healing of wounds. See, Hwang & Ivy, A Review of the Literature on the Potential Therapeutic Significance of Papain, Annals N.Y. Acad. Science, 54, 161 (1951-52). Indeed, papain has demonstrated clinical efficacy as a local agent to debride or solubilize collections of proteinaceous materials in an antiinflammatory role. See, Emele et al., The AnalgesicAnti-Inflammatory activity of Papain, Arch. Int.
  • Papain is considered to be clinically efficacious in a topical application in removing clotted blood, purulent exudate and necrotic tissue from skin-surface wounds and ulcers.
  • papain will make up about .05-5% by weight of the compositions according to the invention and most preferably, about .1-2%.
  • bromelain acts to selectively inhibit the biosynthesis of proinflammatory prostaglandins, such as the platelet-aggregating thromboxanes.
  • proinflammatory prostaglandins such as the platelet-aggregating thromboxanes.
  • 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 yield products similar to those formed by plasmin and which stimulate the biosynthesis of anti-inflamatory prostaglandins such as PGI 2 .
  • bromelain will make up about .05-5% by weight of the total enzyme component of the composition according to the invention and most preferably, about .1-2%.
  • 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 anti-inflammatory 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 .1-10% by weight of the compositions of the present invention, most preferably about .2-2%.
  • the compositions of the present invention will also preferably include topically wound-cleansing amounts of pancreatic digestive enzymes such as lipases and/or amylases, which are thought to effect the fats and carbohydrates contained in the structure of bacteria and viruses. For instance, many types of viruses possess an outer cell envelope composed of protein, lipid and carbohydrate constituents.
  • Amylase and/or lipase in conjunction with the proteolytic enzymes of the present invention, are thought to act synergistically to degrade the cell envelope and protein and lipid components of the virus particle so as to inactivate the pathenogicity of viruses contained in or entering the wound.
  • compositions of the invention are thought to act on the cell wall and membrane of the bacterial cell leading to the lysing of the microorganism with a consequent loss of virulence. In this manner, wound-healing is aided by the control of infectious microorganisms.
  • the pancreatic digestive enzymes such as lipase and amylase will each make up about .01-5% of the compositions of the present invention and most preferably, about .05-1%.
  • compositions according to the invention may also include an aloe extract and an organic astringent agent.
  • aloe extract which is preferably incorporated as an aloe concentrate, e.g. aloe vera or aloe perryi concentrate, is thought to promote healing and has been applied as a soothing cream to skin-surface wounds, burns and scar tissue.
  • the aloe extract contains enzymes which promote the removal of dead skin while stimulating the normal growth of living tissue.
  • aloe extract refers to the inspissated juice of the aloe plant as well as to its dried concentrates which contain aloe-emodin, aloin or other active anthraquinone principles.
  • the preferable organic astringent agent is witch hazel, a herb substance which has demonstrated effectiveness as an astringent for the treatment of itching, skin irritations and burns. This compound acts to inhibit the pathological transcapillary movement of plasma protein thereby reducing inflammation, edema and exudation.
  • Witch hazel has been used in an antiseptic capacity for the healing of wounds and for cleansing the skin surface.
  • compositions of the present invention may also include one or more of a mixture of carrier emollients of a penetrating emollient oil, a non-penetrating emollient oil and a polyhydric alcohol emollient.
  • the penetrating emollient oil will be ethoxylated lanolin.
  • lanolin is known to be effective as a moisturizer and lubricant. The substance penetrates into the skin surface quickly and is quite beneficial when applied to skin-surface wounds since it acts to prevent a dressing from sticking to the wound. This effective penetrator also acts to replenish valuable lipids in the wound area.
  • Other characteristics of lanolin are disclosed in U.S. Patent No. 2,478,820, the disclosure of which is incorporated herein by reference. Useful compounds of this type are formed by the condensation of about 10-80 moles of ethylene oxide per mole of lanolin or by the linking of sorbitol and lanolin with a polyoxyethylene chain containing 10-80 moles of ethylene oxide.
  • Atlas ® G-1790 (20 moles of ethylene oxide/mole of lanolin)
  • Atlas ® G-1441 40 moles of ethylene oxide linking sorbitol and lanolin
  • Atlas ® G-1471 75 moles of ethylene oxide linking sorbitol and lanolin
  • the preferred non-penetrating emollient oil is petrolatum, which is known to aid in restoring the natural texture of the skin surface.
  • petrolatum is a non-penetrating moisturizer and lubricant for the skin surface and as such, acts to aid in the topical action of the composition of the present invention.
  • the preferred polyhydric alcohol emollient is glycerin. Its main utility is in moisturizing the skin and providing a medium solvent. It is also reported to possess therapeutic uses such as its application to reduce corneal edema. See, Remington's Pharmaceutical Sciences, A. Ossol ed, Mack Pub., Boston, Mass. (16th ed. 1980) at page 1255.
  • the weight percent of the carrier emollients is substantially greater than that of any of the other components of the invention.
  • the carrier emollients comprise about 85-99% of the total weight of the compositions of the present invention and most preferably, about 93-97%.
  • compositions of the present invention may also include one or more antibacterial preservatives, preferably from the C 1 -C 4 lower alkyl benzoates such as methyl and propyl paraben, each with a total weight percent in the compositions of about .025-1.5%, preferably.
  • antibacterial preservatives preferably from the C 1 -C 4 lower alkyl benzoates such as methyl and propyl paraben, each with a total weight percent in the compositions of about .025-1.5%, preferably.
  • the total weight percent of the components of the compositions of the present invention may be varied over a wide range.
  • the weight percent of all of the enzymes in the compositions is preferably about .2- 20% and of just the proteolytic enzymes, about .2-15%.
  • the weight percent of aloe extract preferably ranges from about .05-3% and the weight percent of the organic astringent agent preferably ranges from about .06-3% .
  • the respective weight percents would be as follows: enzymes, .2-20%; aloe extract, 0.02-10%, or preferably .05-3%; organic astringent agent, .025-8%, or preferably .06-3%; petrolatum, 40-80%; ethoxylated lanolin, 5-30%; glycerine 5-30%, and preservatives .05-3%.
  • compositions of the present invention will be formulated such that the total enzyme component will comprise, by weight, papain, about 15-40%; trypsin, about 5-15%; chymotrypsin, about .2-.6%; bromelain, about 10-30%; pancreatin, about 30-50%; lipase, about 2-8%; and amylase, about 2-8%.
  • the total enzyme component will comprise, by weight, papain, about 15-40%; trypsin, about 5-15%; chymotrypsin, about .2-.6%; bromelain, about 10-30%; pancreatin, about 30-50%; lipase, about 2-8%; and amylase, about 2-8%.
  • the wound-healing, reparative quality of the ointment may be effectuated by means of the method according to the present invention.
  • the method comprises the topical administration of an effective amount of the hereinabove discussed compositions to traumatic or degenerative skin-surface wounds.
  • the ointments are typically prepared by first mixing the carrier emollients. A second homogeneous mixture of enzymes and aloe extract is then slowly incorporated into a small amount of the carrier emollient mixture. The resultant paste is then added to the remainder of the carrier emollient mixture while mixing in a mixer. A second homogeneous paste, composed of the organic astringent agent and a small quantity of the carrier emollient mixture is then added to the mixer and mixing of all the components is continued until the composition begins to solidify. At this time, the composition is poured into a tube filling apparatus, pressure is applied and the ointment is tubed.
  • a melt of 15,162 g of petrolatum, 4,364 g of ethoxylated lanolin and 3,509 g of glycerin was prepared in a stainless steel container.
  • Small amounts of a second homogeneous mixture of 252 g of pancreatin, 153 g papain, 113 g of bromelain, 25 g of lipase, 25 g of amylase, 60 g of trypsin, 2.5 g of chymotrypsin and 42 g of aloe vera powder extract were added to small quantities of the melt in a 2 gallon stainless steel container.
  • the resultant paste was added to a larger quantity of the melt while mixing until homogeneous in a "J.H. Day" mixer.
  • a second paste was made of 84 g of witch hazel extract and a small amount of melt.
  • the paste was homogeneous, it was added to the first paste with mixing.
  • the homogeneous mixture began to solidify, it was poured Into a "Colton" tube filling machine and one ounce tubes were filled under 30 lbs. pressure.
  • the ointment of this invention has been used in the treatment of superficial wounds and bruises and has been reported as effective for such applications in providing symptomatic relief.
  • the recommended mode of application is to apply a thin layer of the ointment to the afflicted area and optionally cover with a sterile gauze dressing.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Biomedical Technology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Onguent topique pour des blessures de la surface de la peau contenant des quantités thérapeutiques de papaïne, de bromelaïne, de trypsine, de chromotrypsine, de pancréatine, de lipase, d'amylase, d'extraits d'aloès, ainsi qu'un agent astringent organique formulé dans un mélange porteur d'huiles émollientes pénétrantes et non pénétrantes et d'un émollient d'alcool polyhydrique. L'onguent réduit l'inflammation à l'endroit des blessures de la surface de la peau et provoque l'accroissement des activités anti-inflammatoires normales du corps.
EP19840900913 1983-01-21 1984-01-18 Onguent enzymatique Withdrawn EP0133438A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US46002383A 1983-01-21 1983-01-21
US460023 1999-12-13

Publications (1)

Publication Number Publication Date
EP0133438A1 true EP0133438A1 (fr) 1985-02-27

Family

ID=23827108

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840900913 Withdrawn EP0133438A1 (fr) 1983-01-21 1984-01-18 Onguent enzymatique

Country Status (3)

Country Link
EP (1) EP0133438A1 (fr)
CA (1) CA1222453A (fr)
WO (1) WO1984002846A1 (fr)

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