EP0288525A1 - Composition contenant une exotoxine bacterienne immunostimulante pour stimuler la cicatrisation, et son emploi - Google Patents

Composition contenant une exotoxine bacterienne immunostimulante pour stimuler la cicatrisation, et son emploi

Info

Publication number
EP0288525A1
EP0288525A1 EP87907259A EP87907259A EP0288525A1 EP 0288525 A1 EP0288525 A1 EP 0288525A1 EP 87907259 A EP87907259 A EP 87907259A EP 87907259 A EP87907259 A EP 87907259A EP 0288525 A1 EP0288525 A1 EP 0288525A1
Authority
EP
European Patent Office
Prior art keywords
healing
exotoxin
wound healing
immunostimulant
composition
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Withdrawn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
EP87907259A
Other languages
German (de)
English (en)
Inventor
Juha Niinikoski
Matti Laato
Bengt Gösta GERDIN
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.)
Pfizer Health AB
Original Assignee
Pharmacia AB
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 Pharmacia AB filed Critical Pharmacia AB
Publication of EP0288525A1 publication Critical patent/EP0288525A1/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Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • composition for the stimulation of wound healing containing an immunostimulant bacterial exotoxin and use thereof
  • the invention relates to a formulation for stimulating the healing of wounds in mammals (including man) , and furthermore relates to a method for using this drug as well as to a method for producing it.
  • stimulating the healing of wounds refers to the taking of steps by means of which wounds showing no tendency to heal are induced to start the healing process, and wounds that have started to heal are induced to heal more quickly; or to the taking of steps which are conducive to a cosmetic improvement of the func ⁇ tional result during the healing or after the completion thereof.
  • Stimulation of wound healing is particularly important when natural healing is slow or is rendered difficult by a number of negative factors like e.g. infection of the wound, impeded blood flow, medical treatments with cell poisons or with steroids of various kinds, or in cases where patients suffer from chronical disorders with concomitant impairment of normal wound healing, e.g.
  • EGF epidermal growth factor
  • PDGF platelet derived growth factor
  • bacterial endo- toxins Hunt et al., Surgery 96:48- , 1984.
  • EGF epidermal growth factor
  • PDGF platelet derived growth factor
  • bacterial endo- toxins Hunt et al., Surgery 96:48- , 1984.
  • the main objects of this invention are to provide improved ways (methods) and means (compositions) for promoting wound healing, especially for local treatment of and administration to wounds.
  • the main object is to obtain an enhanced growth of connective tissue.
  • composition of this invention contains as active sub ⁇ stance an immunostimulant bacterial exotoxin (IBE) (including fragments thereof having this property) in an amount that stimulates the healing of wounds but is non-toxic.
  • IBE immunostimulant bacterial exotoxin
  • the invention involves using IBE for any type of wound healing stimulation.
  • the term employed for the amount as being one that "stimulates the healing of wounds but is non-toxic” means that the amount of IBE is such that the toxic effects are acceptable in their relation to the required wound healing stimulant effect.
  • the exotoxin contemplated exists in substantially pure form with respect to other proteins originating from the source of raw material, i.e. substantially pure from other proteins of the bacteria that produced the exotoxin. Normally, substantially pure means that the exotoxin in question amounts to 90 % (w/w) or more with respect to such proteins.
  • the exotoxins contemplated within the framework of this invention are immunostimulants in that sense that they are capable of inducing the formation of lymphokines in the mammal to be treated, such as gamma-interferon and IL 2 and/or capable of inducing cell division (i.e. are mitogenic) .
  • the formation of lymphokines is essential for the wound healing effect.
  • the preferred exotoxins either are constituted by one polypeptide chain forming a loop by means of an intramolecular disulfide bond, or are composed of two polypeptide chains which are held together by an intermolecular disulfide bond. (In this latter case, the two chains may conceivably have been formed as a consequence of proteolytic cleavage of one or more peptide bonds in the aforesaid loop.)
  • exotoxins such exotoxins as will affect the intestine, i.e. enterotoxins, especially such toxins from Micrococcus bacteria, e.g. Staphylococcal enterotoxins A, B, C, D and E (SEA, SEB, SEC, SED, SEE) and exotoxins stemming from other bacteria and having similar properties, e.g. exotoxins from Streptococci.
  • enterotoxins especially such toxins from Micrococcus bacteria, e.g. Staphylococcal enterotoxins A, B, C, D and E (SEA, SEB, SEC, SED, SEE) and exotoxins stemming from other bacteria and having similar properties, e.g. exotoxins from Streptococci.
  • enterotoxins especially such toxins from Micrococcus bacteria, e.g. Staphylococcal enterotoxins A, B, C, D and E (SEA, SEB, SEC, SED, SEE) and exotoxins stemming from other bacteria and having similar
  • exotoxins can be fragmented and derivatized in a manner such as to give fragments (and derivatives) possessing only the immuno ⁇ stimulant property (see also Spero L and collaborators in J. Immunol. 122:1285-9, 1979 and J. Biol. Chem. 250:5026-32, 1985; and Noskova V P et al.. Int. J. Biochem. 16:201.6, 1984) .
  • the invention because it is based on the concept of obtaining improved wound healing by means of immunostimu- lation, comprises also the immunostimulant fragments and derivatives of the exotoxins.
  • the exotoxin or fragment may be studied in various models adapted for studies of mitogenicity, induction of lymphokines like IL 2 and interferon, and wound healing stimulation.
  • Mitogenicity can be assayed by way of DNA-thymidine uptake in cultured lymphocytes that have been exposed to the exotoxin under ' examination; whereas induction of interferon and IL 2 may be assayed by way of interferon activity and IL 2 activity in the supernatants from cultured lymphocytes similarly exposed.
  • exotoxins that are potentially of importance in the context of the present invention, there are several which are commercially available but are rather expensive.
  • SEA, SEB, SEC, SED and SEE can be purchased from Toxin Technology, Madison, Wi, USA. Possibilities of large-scale production of the toxins and their wound-healing stimulant fragments have been much improved since the introduction of recombinant DNA techniques.
  • the exotoxins as here contemplated are often highly toxic. Therefore, when they are administered within the context of this invention it is imperative that the composition employed is of a type such that the wound can be maintained in contact with the active substance (preferably for a prolonged period of time) without the toxic effects becoming too obtrusive.
  • the active substance is usually incorporated, and thus diluted, in a suitable vehicle.
  • This vehicle may be in the form of for instance a physiological aqueous solution buffered to a pH that is suitable for the wound healing process; that is, pH 4.5-8, preferably pH 5-8.0.
  • the active substance may also be incorporated in a vehicle that is soluble or insoluble in water.
  • Suitable vehicles of this type are e.g. various hydrophilic macromolecular materials which are capable of absorbing water. Examples are gauze bandages, compresses and various water-absorbing types of layers useful and used for treating injured tissues (see e.g. GB-A-2,048,292) .
  • a type of very suitable materials are water-insoluble macro ⁇ molecular compounds in a particulate form which when contacted with water become capable of a limited degree of swelling so as to form discrete gel particles.
  • These types of materials have been employed earlier not only for wound dressing (GB-A-1,454,055) but also as carrier phases in gel and affinity chromatography.
  • These hydrophilic particles consist usually of an a ine- and/or hydroxyl-containing polymer, for example a polysaccharide in an insoluble form such as an insoluble dextran derivative, cellulose, starch, agarose etc; a polymerized mono-, di-, or oligosaccharide in an insoluble form; or a sugar alcohol similarly polymerized.
  • the polymer may be crosslinked or be provided with covalently bound ion-exchanging or hydrophobic or hydrophilic groups.
  • a type of derivatization may be effective for bestowing on a given basal polymer some particular physical and chemical properties that are desirable for the purpose contemplated.
  • the active substance may also be incorporated in a liposomal form.
  • vehicles of special interest may be mentioned vehicles based on water- soluble polymers, like for example hyaluronic acid, which form highly viscous solutions with water.
  • the insoluble vehicle employed may be one permitting the toxin to be released slowly or in a delayed mode.
  • the toxin thus may be bound covalently to the vehicle via bonds that are capable of being cleaved by means of enzymes present in the wound, e.g. hydrolases.
  • Some types of insoluble vehicles are resorbable, for example those that are composed of polylactate, polyglycolate and starch, so as to slowly release bound toxin as a result of such resorption,
  • the active substance may be enclosed physically in a manner such that its diffusion from the vehicle is thwarted.
  • crosslinking or other suitable types of derivatizations of insoluble polymers are well-known ex ⁇ pedients for achieving a decreased diffusion of a substance occluded within the polymer.
  • compositions employed in accordance with the invention may be in a dry state, for example in the form of a dry free-flowing powder, dry sponge or dry compress.
  • Particulate vehicles may be suspended in various known per se suspension- type ointment bases (for example oil-in-water, water-in-oil and fatty ointments) .
  • compositions of the invention are always sterile. Sterility is obtainable either by manufacturing the compo ⁇ sition aseptically from sterile starting materials or by sterilizing it after manufacture.
  • the IBE is mixed with, bound to, enclosed within, or in some other manner incorporated into one of the aforesaid vehicles, whereupon the resultant product is if required transformed into a suitable form as set forth above.
  • an important feature in the context of this invention may reside in an ability of the composition to present the active substance (IBE) in a soluble form to the immune system of the patient.
  • the amount of IBE in the composition of the invention may vary with the particular IBE employed and with the type of wound for which it is to be used. Two important properties to be taken into consideration are (1) the wound-healing potency of the IBE - for as a rule high potency implies that lower concentrations can be used - and (2) the toxicity of the IBE - inasmuch as a high degree of toxicity of course means that only small amounts can be used and such highly toxic IBEs therefore must be present in a very diluted state in the composition or in a form of very well-defined release. Normally the composition of the invention contains a healing stimulant IBE in a concentration that is lower than about 5 % (w/w) .
  • the wound is contacted in a manner known per se with an effective amount of the par ⁇ ticular IBE chosen, the IBE being preferably incorporated in a vehicle of the aforesaid type that is suitable for the purpose contemplated, whereupon after a sufficient period of time excess amounts of IBE (plus residual vehicle) are removed.
  • the treatment may be repeated if required.
  • the solution may be divided into minor aliquot portions but can also be used as a stock solution.
  • Cellulose sponge was employed as an inductive matrix for repaired tissue.
  • the material was cut into cylindrical pieces of 40 mm length and 10 mm diameter, a tunnel of 3 mm diameter then being made through the center of the sponge.
  • Discs of silicone rubber having a diameter of 10 mm and a thickness of 2 mm were sewn onto both ends of the sponge to create a stable void volume.
  • the cylinders were sterilized by being boiled for 30 minutes in physiological saline, and subcutaneous implants were made using a strictly aseptic technique.
  • Male Sprague- Dwaley rats weighing 230-250 g were anesthesized with ether, and a 4 cm incision was made on the lower back portion in the central line thereof.
  • Each rat received a sponge cylinder which was implanted longitudinally under the skin. All in all 24 rats were studied which were divided into 4 groups.
  • a control group which was only given solvent (0.1 % bovine serum albumin in phosphate buffered saline, 0.05 ml/day in the central tunnel) ; one group was given 50 ng of Staphylococcal enteoroxin A in the same solvent; one group was given 10 ng of Staphylococcal enterotoxin A per day; and one group was given 2 ng of Staphylococcal enterotoxin A per day. Seven days after the implantation the rats were sacrificed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition stimulant la cicatrisation de plaies et contenant une quantité cicatrisante efficace d'une exotoxine bactérienne immunostimulante sous forme pratiquement pure. Les exotoxines préférées sont les entérotoxines staphylococciques. Sont également décrites des méthodes pour stimuler la cicatrisation et pour produire la composition.
EP87907259A 1986-10-28 1987-10-28 Composition contenant une exotoxine bacterienne immunostimulante pour stimuler la cicatrisation, et son emploi Withdrawn EP0288525A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8604587A SE8604587D0 (sv) 1986-10-28 1986-10-28 Lekemedelssats for sarlekningsstimulering samt sett att anvenda och tillverka satsen
SE8604587 1986-10-28

Publications (1)

Publication Number Publication Date
EP0288525A1 true EP0288525A1 (fr) 1988-11-02

Family

ID=20366091

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87907259A Withdrawn EP0288525A1 (fr) 1986-10-28 1987-10-28 Composition contenant une exotoxine bacterienne immunostimulante pour stimuler la cicatrisation, et son emploi

Country Status (4)

Country Link
EP (1) EP0288525A1 (fr)
JP (1) JPH01501065A (fr)
SE (1) SE8604587D0 (fr)
WO (1) WO1988003029A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2648350B1 (fr) * 1989-06-20 1994-07-01 Roussel Uclaf Utilisation de lipopolysaccharides extraits de bacteries gram(-) pour la fabrication d'un medicament facilitant la cicatrisation de la peau
RU2098109C1 (ru) * 1996-09-26 1997-12-10 Александр Григорьевич Чучалин Противоаллергическое, противовоспалительное средство, способ его получения, лечебное и косметическое средства с его использованием
US5736508A (en) * 1997-03-04 1998-04-07 Milkhaus Laboratory, Inc. Methods for treatment of scar tissue

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE229131C (fr) *
US3882233A (en) * 1973-07-27 1975-05-06 American Home Prod Methods of increasing production of pituitary hormones
US4285931A (en) * 1978-01-30 1981-08-25 Merck & Co., Inc. E. coli enterotoxin vaccine for veterinary and human use
JPS6028999A (ja) * 1983-06-30 1985-02-14 Maruho Kk 細胞増殖促進作用を有するたんぱく質、その組成物と製造方法
US4615884A (en) * 1985-04-09 1986-10-07 Vanderbilt University Method and vaccine for treatment of demyelinating diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8803029A1 *

Also Published As

Publication number Publication date
JPH01501065A (ja) 1989-04-13
WO1988003029A1 (fr) 1988-05-05
SE8604587D0 (sv) 1986-10-28

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