EP1135116A1 - Utilisation de poly (hexamethylene) biguanide pour produire un agent destine a favoriser la guerison de blessures non infectees - Google Patents

Utilisation de poly (hexamethylene) biguanide pour produire un agent destine a favoriser la guerison de blessures non infectees

Info

Publication number
EP1135116A1
EP1135116A1 EP99963370A EP99963370A EP1135116A1 EP 1135116 A1 EP1135116 A1 EP 1135116A1 EP 99963370 A EP99963370 A EP 99963370A EP 99963370 A EP99963370 A EP 99963370A EP 1135116 A1 EP1135116 A1 EP 1135116A1
Authority
EP
European Patent Office
Prior art keywords
phmb
solution
hexamethylene
biguanide
poly
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.)
Ceased
Application number
EP99963370A
Other languages
German (de)
English (en)
Inventor
Frank Jethon
Ulrich Kirschner
Katja SCHÖN-HÖLZ
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.)
Fresenius Kabi Deutschland GmbH
Original Assignee
Fresenius Kabi Deutschland GmbH
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 Fresenius Kabi Deutschland GmbH filed Critical Fresenius Kabi Deutschland GmbH
Publication of EP1135116A1 publication Critical patent/EP1135116A1/fr
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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

  • the invention relates to the use of poly (hexamethylene) biguanide as an agent for promoting healing or for treating wound healing disorders in wounds which are free of infection, and to the use of poly (hexamethylene) biguanide for producing an agent for promoting wound healing that are infection free.
  • wound healing disorders such as, for. B. with severe soft tissue defects, difficult to heal wounds and chronic wounds.
  • Wound healing disorders are also caused by the size of a wound and local infections. Infection of a wound requires antiseptic treatment.
  • antisepsis was first coined in 1772 by Pringle (J. Pringle, Observations on the Diseases of the Army, translated by AE Brande, Richterische Buch Kunststoff, Altenburg, 1772) in connection with means that can prevent rotting.
  • Pringle J. Pringle, Observations on the Diseases of the Army, translated by AE Brande, Richterische Buchmaschine, Altenburg, 1772
  • the development of locally applied antiseptics then went from carbolic dressing, the use of chlorozinc solution, to chlorine-containing solutions, sublimate (Robert Koch) and iodoform (Billroth) to azo dyes and sulfonamides.
  • every new development is based on the fundamental striving for optimal microbicidal activity with the best possible tolerance for the organism.
  • PHMB poly (hexamethylene) biguanide
  • an anti-infective agent based on PHMB with an average molecular weight of M w of 2,900 to 15,000 is described, which is in the form of a wound antiseptic and / or a wound treatment agent.
  • This PHMB can be used with PEG in the ratio of PHMB to PEG from 6: 1 to 24: 1.
  • the agents are used as local antiseptics in many areas of medicine, the use for soft tissue infections being mentioned as an example.
  • PHMB salts for example the hydrochloride salt
  • the concentration of the PHMB is different for the individual purposes and, when used therapeutically as an antimicrobial, is preferably at least 0.02% and in particular at least 0.1%.
  • EP 0 450 117 describes a Ringer's solution and its use as a local wound treatment medicament having a bactericidal action, the lactate-free Ringer's solution additionally containing 0.1% to 0.2% of a concentrate in solution which consists of a 20% aqueous poly (hexamethylene) biguanide - There is a hydrochloride solution in which 1 g of polyethylene glycol with a molecular weight of about 4,000 is dissolved per 100 ml.
  • the product sold under the trademark Vantocil ® IB by ICI is also described as suitable as PHMB.
  • Lavasept ® an antiseptic for topical use is known, wherein the Lavasept concentrate is an aqueous solution of 20 wt .-% PHMB and 1 weight polyethylene glycol 4,000 and the PHMB is the commercial product Vantocil IB ® ICI.
  • iodophores in surgery have become particularly popular for antiseptic wound treatment. Because of known side effects (Hernandez-Richter H. J., Struck, H.: Wound Healing, Georg-Thieme-Verlag, Stuttgart, 1970) the use of iodophores is limited.
  • the object of the present invention is to provide an agent with which wound healing in wounds which are free of infection can be effectively promoted or with which wound healing disorders in wounds which are free of infection can be effectively treated.
  • PHMB poly (hexamethylene) biguanide
  • PHMB has granulation-promoting properties and thus itself promotes wound healing.
  • the use of PHMB according to the invention achieves earlier and improved granulation and epithelialization of the wound, that is to say improved blood flow to the wound surface and the formation of new healthy tissue in connection with the wound healing process, and thus the healing process is improved and accelerated.
  • infection-free is understood to mean wounds that are not infected, that is to say have no signs of infection (eg redness, smell, secretion formation, pus) and therefore do not need to be treated or no longer need to be treated antiseptically.
  • the PHMB used according to the invention suitably has a medium one
  • M w Molecular weight distribution up to 15,000 and preferably from 1,000 to 8,000.
  • Preferred is a poly (hexamethylene) biguanide with an average molecular weight distribution of 1,500 to 5,000, particularly preferably a PHMB with an average molecular weight distribution of 2,000 to 4,000 and in particular from 2,800 to 4,000, for example with an average molecular weight M w of 2,600, 2,800. 3,500, 4,000 or 4,500.
  • the molecular weight is determined by a viscometric method.
  • the poly (hexamethylene) biguanide used according to the invention is produced in a manner known per se, for example as described in DE-PS 16 20 938 or GB-PS 1,202,495, the disclosure of which is hereby incorporated in its entirety.
  • an undesired molecular weight fraction can be separated off from the poly (hexamethylene) biguanide obtained, for example by dialysis, molecular filtration, HPLC, gel permeation chromatography (GPC), fractional precipitation and the like (see, for example, EP - PS 0 700 249).
  • suitable commercially available PHMB such as Vantocil IB ® or Arlagard ® E or other commercial products.
  • the PHMB used according to the invention is in free form or in the form of a water-soluble salt, for example as hydrochloride, as a powder (for example freeze-dried) in a 100% concentration or in aqueous solution. It is in concentrations up to 40% by weight, for example 2 to 40% by weight, preferably 3 to 30% by weight, in particular 4 to 20% by weight, for example 4% by weight, 4.5% by weight .-%, 5 wt .-%, 6 wt .-- available in aqueous solution (ie as a concentrate).
  • a water-soluble salt for example as hydrochloride
  • PHMB here means both the poly (hexamethylene) biguanide and the poly (hexamethylene) biguanide in the form of a water-soluble salt.
  • the concentration at which the PHMB used according to the invention or the aqueous solution of the PHMB for the treatment of wound healing disorders or for the promotion of Wound healing depends on the intended use.
  • Suitable concentrations are generally in the range from 0.0001 to 0.1% by weight, preferably in the range from 0.0005 to 0.06% by weight, in particular in the range from 0.001 to 0.04% by weight, for example 0.04% by weight (based on PHMB).
  • the PHMB can be used, for example, in water, in Ringer's solution, preferably lactate-free Ringer's solution, or in saline in the concentrations mentioned.
  • the PHMB used in accordance with the invention can be used together with surfactants which reduce the surface tension, such as, for example, polyethylene glycol.
  • surfactants which reduce the surface tension
  • polyethylene glycol Preferably polyethylene glycol with a molecular weight of 1,500 to 6,000 and in particular such a polyethylene glycol with a molecular weight of 4,000, as it is sold under the trademark Lutrol ® E 4000 by BASF AG, is used.
  • the ratio of PHMB to the surfactant is suitably in the range from 6: 1 to 24: 1, preferably in the range from 12: 1 to 22: 1 and is in particular 20: 1.
  • the commercial product Lavasept ® after appropriate dilution are employed to the use concentration.
  • PHMB is used in various ways, for example locally or systemically, orally, rectally, on the eye or vaginally. It is used in animals and humans, preferably in humans.
  • the PHMB can, according to the invention, be in various forms of use or pharmaceutical preparation, for example in the form of aqueous solutions (optionally containing lactate-free Ringer's solution or saline, preferably lactate-free Ringer's solution), emulsions, suspensions, gels, ointments or Creams, tablets, capsules, dragees, suppositories and the like.
  • aqueous solutions optionally containing lactate-free Ringer's solution or saline, preferably lactate-free Ringer's solution
  • emulsions suspensions, gels, ointments or Creams
  • tablets, capsules, dragees, suppositories and the like also contain the usual auxiliaries and additives necessary for the preparation of the respective preparation form.
  • the saline solution can be as 0.4 to 1.2 wt .-% solution can be used. However, physiological, ie 0.9% saline solution is preferably used.
  • they can be used in the form of wound irrigation solutions, in the form of tamponades soaked with the solution used according to the invention (for example in dental surgery), compresses or longuettes (for example for covering wounds left open postoperatively) and the like.
  • irrigation-suction drainage can also be used internally for irrigation.
  • PHMB can be used to promote wound healing in wound healing disorders in many areas of medicine, such as wounds of soft tissues or wounds on bones (skeleton).
  • PHMB is preferably used for soft tissue sores.
  • PHMB can sore soft tissue, such as surgical wounds after appendectomy or abdominal surgery or skin and subcutis and deeper soft tissue abscesses, after accidents in which, for example, the soft parts of the upper and lower extremities, including the hand and foot, as well as the thorax and abdomen and / or back are affected.
  • the PHMB can be used particularly in the case of wound healing disorders such as those which occur in the case of severe soft tissue defects, in wounds which are difficult to heal and in chronic wounds.
  • the use is suitable in aseptic bone surgery, for the treatment of wounds that correspond to wound types 2-4 according to Hierholzer (Der Chirurg, 1991, Vol. 62, pages 861-865), from leg ulcers, pressure ulcers, diabetic feet, from severely and severely burn injured, in seriously injured patients and in wounds in the area of the nose and throat, such as the oral cavity, and in wounds in the area of the eyes.
  • PHMB can be used both for already infected wounds and for fresh wounds (for example type 2 wounds).
  • Figure 1 shows the course of healing in freshly contaminated, non-infected (i.e., infection-free) soft tissue wounds with treatment with either 0.04% PHMB solution or Ringer's solution (see Example 4). 1 shows a clear difference in the time course of wound healing between the two treatments. A significantly accelerated healing process can be seen using the PHMB-containing solution.
  • Vantocil ® IB or Arlagard ® E is an aqueous solution that contains 20% poly (hexamethylene) biguanide hydrochloride as active ingredient.
  • Example 1 was repeated to prepare a further solution for the use according to the invention, with the exception that the corresponding PHMB was used instead of the PHMB hydrochloride.
  • PHMB with an average molecular weight distribution (M w ) of 2,800 and lactate-free Ringer's solution a solution containing PHMB to be used according to the invention with a final concentration of 0.04% by weight of PHMB was prepared by mixing these components.
  • the wounds were treated openly moist (wet wound treatment). Open, infected soft tissue wounds were rinsed by means of a cannula from drain points or via inserted rinsing drains. Wounds were covered antiseptically with longuettes or compresses (10 cm x 10 cm) that were soaked with the PHMB-containing solution or with the placebo (Ringer's solution). The masking material was moistened twice a day.
  • the maximum duration of treatment was 15 days.
  • the effectiveness was assessed on the basis of a wound score which was composed of a wound base index and a wound edge index, the wound base index and wound edge index being graded as follows:
  • the wound granulation, the wound base index, the efficacy and tolerance assessment as well as the germ colonization of the wounds were examined on the basis of microbiological accompanying examinations, microbiological examinations for the type and number of germs and number (semi-quantitative) were carried out on treatment days 0, 2. Wounds that had the microbiologically "no germs detectable” result, but were classified as "infected", “greasy” or “necrotic” when assessing the wound bed, were classified as infected. Otherwise the assessment was based on the germs actually found. The safety assessment was based on the logging of adverse events and control of laboratory parameters as well as the subjective tolerance assessment by investigators.
  • FIG. 1 shows the course of the wound healing examined in the study in the case of contaminated, non-infected, fresh soft tissue wounds both under treatment with the solution containing PHBM and under treatment with Ringer's solution, with the wound score consisting of the evaluation on the y-axis the healing process of the wound base and the wound edge on the days indicated on the x-axis according to the formula
  • the wound healing-promoting effect of the PHMB-containing solution is therefore not based solely on the microbicidal activity and the compatibility, which is equally good compared to Ringer's solution, but was caused by PHMB itself.
  • Example 3 was repeated with the exception that instead of the PHMB used there with an average molecular weight distribution (M w ) of 2,800, PHMB with an average molecular weight distribution (M w ) of 4,000 was used.
  • the solution thus produced with a final concentration of PHMB (M w 4,000) of 0.04% by weight, was used successfully, like the solution of Example 3, to promote wound healing or to treat wound healing disorders in soft tissue wounds.
  • the PHMB used was separated in a known manner by fractional filtration from the commercially available PHMB product Vantocil IB ® or Arlagard ® E ICI (see. EP 0700249 Bl).
  • Example 1 was repeated with the exception that a PHMB with an average molecular weight (M w ) of 2,800 was used instead of the PHMB with an average molecular weight (M w ) of 2,600 used there.
  • the solution thus prepared can, after suitable dilution with water, lactate-free
  • Ringer's solution or saline as well as the solution from Example 3 can be successfully used to treat wound healing disorders in soft tissue wounds.
  • Example 1 was repeated with the exception that instead of the PHMB used there with an average molecular weight distribution (M w ) of 2,600, a PHMB with an average molecular weight distribution (M w ) of 4,000 was used.
  • the solution thus prepared was successfully used to promote wound healing in soft tissue wounds.
  • the PHMB used was prepared in the manner described in Example 5.
  • a solution of the following composition was prepared from PHMB with an average molecular weight (M w ) of 3,500, polyethylene glycol 4,000 and water by mixing the constituents:
  • the solution thus prepared can be successfully used to promote wound healing in soft tissue wounds or bone wounds.
  • Another solution containing PHMB to be used according to the invention was prepared from PHMB with an average molecular weight distribution (M w ) of 3,500 and lactate-free Ringer's solution by mixing the same to a final concentration of PHMB of 0.04% by weight. This solution has been used successfully to promote wound healing in soft tissue wounds.
  • M w average molecular weight distribution
  • the PHMB used was obtained in the manner described in Example 5.
  • a solution of the following composition was prepared from PHMB with an average molecular weight (M w ) 4,500, polyethylene glycol 4,000 and water by mixing the constituents:
  • the solution thus prepared was used after appropriate dilution with water, lactate-free Ringer's solution or saline to application concentration to promote wound healing in soft tissue wounds.
  • the PHMB used was obtained in the manner described in Example 5.
  • Wound healing can be used for soft tissue wounds.
  • the PHMB used was obtained in the manner described in Example 5.
  • a solution of the following composition was prepared from PHMB with an average molecular weight distribution (M w ) of 4,000 and water by mixing the same:
  • the solution thus prepared was used after appropriate dilution with water, lactate-free Ringer's solution or saline to application concentration to promote wound healing in soft tissue wounds.
  • the PHMB used was prepared in the manner described in Example 5.
  • a solution of the following composition was prepared from PHMB with an average molecular weight distribution (M w ) of 3,500 and water by mixing the same:
  • the PHMB used was prepared as described in Example 5.
  • a solution of the following composition was prepared from PHMB with an average molecular weight (M w ) of 2,800, polyethylene glycol 4,000 and water by mixing the constituents:
  • a gel of the following composition to be used according to the invention was prepared using 2.0 g of the solution thus prepared and the following constituents:
  • DAB Hydroxyethyl cellulose
  • the gel thus produced has been successfully used to treat wound healing disorders in soft tissue wounds.
  • Example 14 was repeated to produce a further gel to be used according to the invention, with the exception that instead of the PHMB with an average molecular weight of 2,800 used there, a PHMB with an average molecular weight (M w ) of 3,500 was used.
  • the PHMB used was produced in the manner described in Example 5.
  • the gel thus produced was successfully used to promote wound healing in soft tissue wounds.
  • DAB Hydroxyethyl cellulose
  • the PHMB used was obtained in the manner described in Example 5.
  • the gel thus produced was successfully used to promote wound healing in soft tissue wounds.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Organic Chemistry (AREA)
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Abstract

Utilisation de poly (hexaméthylène) biguanide en tant qu'agent destiné à favoriser la guérison ou à traiter les troubles de la guérison de plaies non infectées, et plus précisément utilisation de poly (hexaméthylène) biguanide pour préparer un tel agent. Le poly (hexaméthylène) biguanide qui convient pour la préparation d'un tel agent possède une répartition du poids moléculaire moyen (Mw) allant jusqu'à 15.000. De préférence, le poly (hexaméthylène) biguanide possède une répartition du poids moléculaire moyen de 1.000 à 8.000, plus préférablement de 1.500 à 5.000 et idéalement de 2.000 à 4.000. Le poly (hexaméthylène) biguanide peut éventuellement être employé avec un tensioactif abaissant la tension de surface et/ou éventuellement dans de l'eau, une solution de Ringer exempte de lactate ou une solution de chlorure de sodium, et il est utilisé de préférence pour des blessures de tissus mous.
EP99963370A 1998-12-05 1999-12-02 Utilisation de poly (hexamethylene) biguanide pour produire un agent destine a favoriser la guerison de blessures non infectees Ceased EP1135116A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19856153 1998-12-05
DE19856153 1998-12-05
PCT/EP1999/009426 WO2000033829A1 (fr) 1998-12-05 1999-12-02 Utilisation de poly (hexamethylene) biguanide pour produire un agent destine a favoriser la guerison de blessures non infectees

Publications (1)

Publication Number Publication Date
EP1135116A1 true EP1135116A1 (fr) 2001-09-26

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99963370A Ceased EP1135116A1 (fr) 1998-12-05 1999-12-02 Utilisation de poly (hexamethylene) biguanide pour produire un agent destine a favoriser la guerison de blessures non infectees

Country Status (3)

Country Link
EP (1) EP1135116A1 (fr)
AU (1) AU1969500A (fr)
WO (1) WO2000033829A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2809310B1 (fr) 2000-05-26 2004-02-13 Centre Nat Rech Scient Utilisation de derives de biguanide pour fabriquer un medicament ayant un effet cicatrisant
DE10132817A1 (de) * 2001-07-06 2003-01-30 Prontomed Gmbh Wundbehandlungsmittel
DE102004022645A1 (de) 2004-05-07 2005-12-15 Resorba Wundversorgung Gmbh & Co. Kg Bioresorbierbares Material auf Kollagen-Basis
DE102004024140A1 (de) * 2004-05-14 2005-12-08 Fresenius Medical Care Deutschland Gmbh Konservierungsmittel für medizinische Vorrichtungen
DE102009008919A1 (de) * 2009-02-13 2010-08-26 Nawa-Heilmittel Gmbh Behandlungslösung für die Behandlung von Wunden, insbesondere für die liquide Wundbehandlung
DE102012007212A1 (de) 2012-04-11 2013-10-17 Merz Pharma Gmbh & Co. Kgaa Zubereitung zur topischen Anwendung auf Schleimhäuten mit Polyhexanid als Wirkstoff
EP2896396A1 (fr) 2014-01-20 2015-07-22 Abem Kimya Tibbi Malzemeler Yönetim Danismanligi Temizlik Servis Hizmetleri Sanayi Ve Dis Ticaret Limited Sirketi Formulation à base de plantes médicinales topiques pour le traitement des plaies topiques
DE102020107665A1 (de) 2020-03-19 2021-09-23 Nawa-Heilmittel Gmbh Verwendung einer wässrigen Lösung zur keimreduzierenden Reinigung von Oberflächen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3537627C2 (de) * 1984-11-03 1995-01-26 Infectless S A Desinfektionsmittel und seine Verwendung
CA2163791C (fr) * 1993-05-26 2003-12-30 Ulrich Kirschner Produits anti-infectieux
DE29611266U1 (de) * 1996-07-01 1996-09-19 Bakhtiari, Cyrus, Dr.med., 48165 Münster Antiseptikum

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0033829A1 *

Also Published As

Publication number Publication date
AU1969500A (en) 2000-06-26
WO2000033829A1 (fr) 2000-06-15

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