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WO1997000076A1 - Compositions contenant des sels de poly(hexamethylene biguanide) et leurs utilisations - Google Patents

Compositions contenant des sels de poly(hexamethylene biguanide) et leurs utilisations Download PDF

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Publication number
WO1997000076A1
WO1997000076A1 PCT/GB1996/001457 GB9601457W WO9700076A1 WO 1997000076 A1 WO1997000076 A1 WO 1997000076A1 GB 9601457 W GB9601457 W GB 9601457W WO 9700076 A1 WO9700076 A1 WO 9700076A1
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Prior art keywords
salt
eye
poly
hexamethylene biguanide
human
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PCT/GB1996/001457
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English (en)
Inventor
Nigel Morlet
Frank Larkin
John Dart
Victor Andrews
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Moorfields Eye Hospital
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Publication date
Application filed by Moorfields Eye Hospital filed Critical Moorfields Eye Hospital
Priority to AU61308/96A priority Critical patent/AU6130896A/en
Publication of WO1997000076A1 publication Critical patent/WO1997000076A1/fr

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    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen

Definitions

  • the present invention relates to poly(hexamethylene biguanide) salts, especially the hydrochloride salt (known as polyhexanide or PHMB) , especially to the use of the salts in the manufacture of medicaments for, and methods of, topical treatment of microbial infections and to their use as antiseptics.
  • poly(hexamethylene biguanide) salts especially the hydrochloride salt (known as polyhexanide or PHMB)
  • PHMB hydrochloride salt
  • Microbial infections such as bacterial, amoebal and fungal infections
  • Microbial infections are common and may be generalised, i.e. throughout the body, or may be localised, i.e. restricted to one area, for example, a wound site or an organ.
  • microbes is taken herein to include bacteria, amoebae, fungi and obligate intracellular organisms.
  • Infections of the eye are relatively common and may be very serious, even sight threatening. At the present time there is a very limited number of agents that have been developed for use in the treatment of infections in the eye.
  • the main antibiotics or antimicrobial agents used in the treatment of the eye are tetracycline, erythromicin, poly ixin, trimethoprim, chloramphenicol, gentamicin, neosporin (a mixture of neomycin and bacitrasin) , fusidic acid, quinolones and anti-fungal agents such as the azole group of agents.
  • Propamidine, an antimicrobial is often used as an over-the-counter (OTC) medication.
  • OTC over-the-counter
  • sulphonamide group and beta-lactam antibiotics e.g. penicillin
  • Polyhexanide is known to be a broad spectrum antibacterial agent. At relatively low concentrations the antibacterial action is biostatic and at higher levels, dependent on particular species of bacteria, it is bactericidal. It is a "membrane-active" antibacterial. Polyhexanide has been found to be active against both Gram- negative and Gram-positive bacteria.
  • Polyhexanide is currently sold as a swimming pool disinfectant, a water system disinfectant and at a concentration of approximately 0.00005%, as a preservative in contact lens solutions. Polyhexanide has been used successfully in the treatment of Acanthamoeba keratitis. an uncommon but blinding amoebal infection of the cornea (the clear front surface of the eye), see, for example, Larkin et al., 1992, Hay et al., 1994, Seal 1994, Elder et al., 1994, and Bacon et al., 1993.
  • the disease has a range of symptoms and resulting conditions including severe pain, ring abscesses, perforated corneas, corneal scarring and intumescent lens requiring keratoplasty, extracapsular lens extraction and posterior chamber lens implant.
  • the infection can be difficult to treat and may be resistant to commonly used agents.
  • polyhexanide was used in its treatment even though very little was known about the penetration of polyhexanide into the eye and what toxicity problems it might cause.
  • polyhexanide In the treatment of Acanthamoeba keratitis polyhexanide has been recommended for use in very low concentrations: up to 0.02 % (w/v).
  • an infection such as Acanthamoeba keratitis some relatively serious side effects of treatment may be acceptable when they would not usually be in the treatment of other, less serious, infections.
  • the present invention is concerned with the use of any physiologically acceptable salt of poly(hexamethylene biguanide) , for example, the hydrochloride, acetate or gluconate salt.
  • the hydrochloride salt which is known as "polyhexanide” or "PHMB”.
  • the invention is not limited to the use of the hydrochloride salt and, unless stated otherwise, references to polyhexanide or PHMB include all other physiologically acceptable salts.
  • the present invention provides the use of a poly (hexamethylene biguanide) salt, especially of poly (hexamethylene biguanide) hydrochloride, for the manufacture of a medicament for the topical treatment of microbial infection of the human or animal body, excluding amoebal infection of the eye.
  • the present invention especially provides the use of a poly(hexamethylene biguanide) salt, especially of poly (hexamethylene biguanide) hydrochloride, for the manufacture of a medicament for the topical treatment of microbial infection of the eye, excluding amoebal infection of the eye.
  • the present invention further provides use of a poly (hexamethylene biguanide) salt for the manufacture of a medicament for the topical treatment of microbial infection of the human or animal body, including infection of the eye, the salt being present in a concentration of at least 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations) .
  • infection does not imply the presence of a particular number of microbes; infection may be said to be present even if a relatively small number of microbes is present.
  • the virulence of the organism, the host response and many intrinsic and environmental factors are all important factors.
  • the present invention also provides the use of a poly(hexamethylene biguanide) salt, especially poly (hexamethylene biguanide) hydrochloride, for the manufacture of an antiseptic for topical use on the human or animal body, including use on the eye.
  • a poly(hexamethylene biguanide) salt especially poly (hexamethylene biguanide) hydrochloride
  • antiseptic generally accepted, is used herein to have its generally accepted meaning of a preparation which is used for disinfecting, i.e. cleaning or sterilising, rather than for the treatment of infection.
  • an antiseptic may be used to clean the skin or the surface of the eye before surgery or may be used to clean a wound, made in surgery or in an accident, to prevent infection.
  • Antiseptic preparations may be used in order to eradicate or prevent the spread of bacteria, amoeba or fungi or other microbes such as free obligate intracellular organisms.
  • Polyhexanide when used as an antiseptic may also be able to kill certain free viruses (i.e. those coated in a cell membrane - enveloped viruses) even though it may not be a therapeutic antiviral agent.
  • Antiseptic preparations in accordance with the invention may also comprise further compounds having antimicrobial properties.
  • the present invention further provides a pharmaceutical preparation comprising a physiologically acceptable amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, in a form suitable for topical administration in or on the human or animal body, excluding administration on the eye. That is to say, the invention provides preparations of a type suitable for use in or on the body which are not suitable for application on the eye. Such preparation may, for example, comprise carriers or diluents which may not be used on the eye.
  • the present invention also provides a pharmaceutical preparation comprising a physiologically acceptable amount of a poly(hexamethylene biguanide) salt in a form suitable for topical administration in or on the human or animal body, including on the eye, the salt being present in a concentration of at least 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations) .
  • the present invention further provides an antiseptic preparation, comprising a physiologically acceptable amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, in a form suitable for topical administration in or on the human or animal body, including use on the eye.
  • an antiseptic preparation comprising a physiologically acceptable amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, in a form suitable for topical administration in or on the human or animal body, including use on the eye.
  • an antiseptic preparation comprises the poly(hexamethylene biguanide) salt in a concentration of at least 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations) .
  • the invention further provides a method of treating microbial infection, other than amoebal infection on the eye, comprising administering a therapeutically effective amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, topically to the human or animal body.
  • the invention especially provides a method of treating microbial infection of the eye, other then an amoebal infection on the eye, comprising administering a therapeutically effective amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, topically to the eye.
  • the invention also provides a method of treating a microbial infection comprising administering a therapeutically effective amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, topically to the human or animal body, including to the eye, the salt being present in a concentration of at least 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations) .
  • the invention further provides a method of disinfecting (asepticizing) a part of the human or animal body comprising topical administration of an effective amount of a poly(hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, to the human or animal body, including to the eye.
  • a poly(hexamethylene biguanide) salt especially poly(hexamethylene biguanide) hydrochloride
  • the salt is present in a concentration of at least 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations)
  • the invention further provides for the use of a poly (hexamethylene biguanide) salt, especially poly
  • (hexamethylene biguanide) hydrochloride as a disinfectant for surfaces and for surface disinfectants which comprise a poly(hexamethylene biguanide) salt.
  • a disinfectant may be used to disinfect medical equipment and medical and household surfaces.
  • Disinfectants will usually comprise the salt in the form of an aqueous solution.
  • the concentration of polyhexanide in a disinfectant will usually be relatively high and may be as high as 20 %. Preferably the concentration will be greater than 0.1 % w/v or w/w (w/v for solutions, w/w for other formulations) .
  • the antiseptic preparation, pharmaceutical preparation or method of treatment is in a form suitable for use on the skin; on or in a wound; on a mucosal surface, for example, in the nasal passages, the throat, in the bladder or in the vagina; as a colonic enema or lavage prior to or during surgery; in an ear cavity; in the mouth, for example, on the gums or on the teeth; on the scalp or on the hair.
  • the preparation may take the form of an aqueous formulation, an oily formulation, an oil-in-water emulsion or a water-in-oil emulsion, a liposomal formulation or a gel formulation.
  • the preparation may take the form of a mouth wash, a gargle, a slowly dissolving pastille or lozenge or a mouth, throat or nasal spray.
  • a gel formulation may be, for example, suitable for application to the gums and both gel and paste formulations are suitable for use as toothpastes.
  • a liquid formulation such a preparation may be used in bladder irrigation to eradicate or prevent the spread of infection.
  • shampoo or soap formulations of polyhexanide may be especially useful.
  • the treatment of microbial infections may be carried out in order to eradicate the bacteria, amoeba, fungi or other microbe completely or may be used to restrict or prevent the growth or spread of the bacteria, amoeba, fungi or other microbe.
  • Microbial infections which may be treated with polyhexanide include the common organisms which cause infection of the' external eye and other parts of the body, such as, Gram positive cocci and rods, for example, Staphylococci species, Corvnebacteria species and
  • Steptococci species Gram negative cocci and rods, for example, Haemophilus species, Pseudomonas species, Enterobacter species and Bacillus species, yeast forming fungi, for example, Candida, filamentary fungi, for example, Aspergillus and Fusarium.
  • amoebae for example, Acanthamoeba species, and obligate intracellular organisms, for example, Chlamydia species.
  • blepharitis which is an infection of the eyelids and eyelid margins
  • conj nctivitis which is an infection of the conjunctiva and the conjunctival sac
  • keratitis which is an infection of the clear cornea. In some cases a patient may suffer from all three infections at the same time.
  • eye is used herein to include not only the eyeball itself but also associated structures such as the eyelids, conjunctiva and conjunctival sac.
  • Administration of polyhexanide to the eye is to be topical administration.
  • Use of the terms administration "to the eye” and “on the eye” are used to mean administration to the external surfaces of the eye. It is not intended that the polyhexanide be administered to internal tissues of the eye by means such as injection into the eye.
  • the invention also provides the use of a poly (hexamethylene biguanide) salt, especially poly(hexamethylene biguanide) hydrochloride, as a preservative in liquid formulations, for example, eye drops and contact lens solutions, for use on the eye, the polyhexanide being present in a concentration of greater than 0.01 %, preferably in the range of greater than 0.01 % to 2.0 % and more preferably in the range of greater than 0.01 % to 0.02 % w/v or w/w (w/v for solutions, w/w for other formulations; lg per 100 ml of solution i ⁇ 1% w/v) .
  • a poly (hexamethylene biguanide) salt especially poly(hexamethylene biguanide) hydrochloride
  • polyhexanide When used therapeutically as an antimicrobial, polyhexanide will preferably be used in a concentration of at least 0.02 % and more preferably at least 0.1 %. Preferably the concentration will be in the range 0.02 % to 2.0 % and still more preferably in the range 0.1 % to 1.0 %. (Concentrations are calculated as w/v or w/w, w/v for solutions, w/w for other formulations.) When used as an antiseptic polyhexanide may be used in similar concentrations but will generally be used in higher concentration formulations.
  • Medicaments according to the present invention are provided in a pharmaceutical preparation form suitable for topical administration, for example, an emulsion, suspension, solution, cream, lotion, ointment, drops, foam, gel, a liposomal preparation, an aerosol or spray.
  • a pharmaceutical preparation form suitable for topical administration for example, an emulsion, suspension, solution, cream, lotion, ointment, drops, foam, gel, a liposomal preparation, an aerosol or spray.
  • Such preparations are generally conventional formulations, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia or Martindale The Extra Pharmacopoeia.
  • Preparations for the treatment of eye infections may be in the form of aqueous formulations, oily formulations, liposomal formulations, gels or ointments.
  • the polyhexanide may be mixed with other polymeric compounds such as polyacrylic acid.
  • the pH of liposomal, aqueous and gel formulations may be adjusted to a pH in the range 6 to 8.5.
  • Acid or alkali compounds may be used to adjust the pH, preferably with a buffer, especially a boric acid/borate buffer, a phosphate buffer or an acetic acid/acetate buffer.
  • Preparations for treatment of the eye may also comprise sodium chloride or another excipient to adjust the tonicity of the medicament.
  • Preparations especially for treatment of the eye, may also comprise polyvinyl alcohol or another excipient, for example, hypromellose, to adjust the viscosity of the medicament.
  • Ointments especially for treatment of the eye, may also comprise polyethylglycol, paraffin oils or other excipients to adjust the volume and viscosity of the medicament.
  • Liposomal preparation ⁇ especially for treatment of the eye, may comprise phosphatidylglycerol, phosphatidylcholine and/or chloresterol dissolved in chloroform.
  • Gel formulations may compri ⁇ e carbomer (polyacrylic acid) 940.
  • Antiseptic preparations according to the invention may take any of the forms discussed above.
  • antiseptic preparations may take the form of wipes, medicated plasters and other such forms which are commonly used for antiseptics.
  • Polyhexanide may be administered, for example, as a solution in physiological saline or in an artificial tear complex.
  • An example of a ⁇ olution which i ⁇ ⁇ uitable for use in the eye is one comprising polyhexanide and 0.3% hypromellose, 0.45% NaCl, 0.37% KCI, 0.19% borax (sodium tetraborate decahydrate) and 0.19% boric acid (% are w/v). Further examples of formulations which may be used in accordance with the present invention are given in Examples 7 to 14.
  • the medicaments, and methods described herein may also compri ⁇ e further pharmaceutically active ⁇ ubstances, for example, steroids, such as Dexamethasone, antivirals, such as aciclovir and other compounds having antimicrobial activity, such as bacitacin and trimethoprin (currently used in PolytrimTM drops) .
  • the polyhexanide may be u ⁇ ed in combination with other pharmaceutically active agent ⁇ either in the same formulation or they may be applied in separate formulations.
  • the appropriate dose and frequency of treatment will be dependent on the symptoms and phy ⁇ ical condition of the individual patient.
  • the optimal concentration and frequency of treatment samples of the infecting agent may be taken and grown in culture and those cultures subjected to sensitivity testing. Examples of such tests are described in Elder et al. 1994, Larkin et al. 1992 and Hay et al. 1994.
  • Medicaments administered to the eye are usually diluted by tears. It may therefore be advantageous to use relatively high concentrations of polyhexanide when treating the eye. In that way a therapeutically effective concentration of polyhexanide may remain in the eye for longer.
  • Polyhexanide is suitable for general use as a first line therapy for external ocular infections such as blepharitis, conjunctivitis and keratitis. It may be used to replace chloramphenicol, for which there are few alternatives, and may be especially useful in the U.S.A. where chloramphenicol is not used because of the rare, but fatal, complication of aplastic anaemia with which its use has been linked. It is cheap to manufacture and may therefore be extremely valuable in treatment of patients in the Third World where corneal blindness from infection is prevalent. Apart from 5% BetadineTM (providone iodine) there are no ocular antiseptics currently available commercially.
  • Polyhexanide is composed of a mixture of polymeric compounds with the structure:
  • n is generally in the range 2 to 30 inclusive with a mean value of 5.5. If desired fractionation may be used to produce polyhexanide with a specific composition or mean value of n.
  • the biguanide groups exist in the form of their ⁇ alts so polyhexanide is es ⁇ entially a polyelectrolyte.
  • polyhexanide comprising a mixture of short and long polymer chains is used (see Gilbert et al.) .
  • polyhexanide may overcome the drug resi ⁇ tance in bacterial infection ⁇ ⁇ ince it seems unlikely that resi ⁇ tance to polyhexanide will develop, it will broaden the limited spectrum of currently used antibiotics and cause fewer side effects.
  • the primary u ⁇ e of the pre ⁇ ent invention is in the field of human medicine, it may also be desirable to treat other animals, especially mammals, for microbial infections, and the present invention therefore also includes u ⁇ e ⁇ of the de ⁇ cribed medicament ⁇ and preparations for the treatment of animals other than humans and further includes preparations and medicament ⁇ de ⁇ cribed above that are suitable for the treatment of non-human animals.
  • Examples 1 and 2 illustrate the efficacy of polyhexanide (PHMB) a ⁇ an anti-microbial.
  • Examples 3 to 6 illustrate the effect of polyhexanide (PHMB) on the ocular surface of the eye and confirm that it is safe for use at the proposed concentrations.
  • Examples 7 to 14 show a number of different formulations which are suitable forms in which to administer polyhexanide.
  • the polyhexanide used wa ⁇ the hydrochloride salt.
  • the formulation ⁇ exemplified may comprise any physiologically acceptable salt of poly(hexamethylene biguanide) but preferably comprise the hydrochloride ⁇ alt.
  • Figure 1 is a diagrammatic representation of the results of experiments described in Example 2. It is a graph showing the colony forming units/mL of a Pseudomona ⁇ aeruginosa clinical isolate in a test sample over time for a number of different treatment regimes with polyhexanide.
  • Figure 2 is a diagrammatic representation of the results of experiments described in Example 2. It is a graph showing the colony forming units/mL of NCTC 10662, a laboratory ⁇ train of P ⁇ eudomona ⁇ aeruginosa. over time for a number of different treatment regimes with polyhexanide.
  • Figure 3 is a diagrammatic representation of the results of experiments described in Example 4. It is a graph showing corneal thicknes ⁇ over time for a number of different experimental regimes.
  • the "A criteria” express the recommended efficacy to be achieved. In ju ⁇ tified ca ⁇ e ⁇ where the "A criteria" cannot be attained, for example, for reasons of an increased risk of adverse reaction ⁇ , the "B criteria" (also set out above) must be satisfied.
  • Example 2 Efficacy against a wide range of microorganisms
  • the minimum inhibitory concentration (MIC) of polyhexanide was found for a broad range of microbes. Those microbes, listed below with the MIC values, are all known ocular pathogens and may also be found on or in other parts of the body.
  • the experimental procedure used was the standard one used for calculating MIC values. The procedure i ⁇ ⁇ et out in the Clinical Microbiology Procedure ⁇ Handbook (I ⁇ enberg 1992a) .
  • microbes used in the tests were all stored clinical isolates. All MIC values are concentrations given in parts per million.
  • Figures 1 and 2 show the kill time for a range of concentrations of polyhexanide against two isolates of
  • Pseudomonas aeruginosa One isolate is a clinical isolate taken from a patient ( Figure 1) and the other, NCTC 10662, is a standard laboratory strain. The figures show plots of colony forming units/mL (cfu/mL) against time for microbe populations treated with polyhexanide at the concentrations shown. The experimental procedure followed was the standard one used for kill time experiments, see the Clinical Microbiology Procedure ⁇ Handbook (Isenberg, 1992b). (The control ⁇ u ⁇ ed culture broth alone.) MIC for the pseudomonas aeruginosa strain in Figure 1 is 30 ppm and for NCTC 10662 in Figure 2 is 7 ppm of PHMB.
  • Figures 1 and 2 show that PHMB has a very rapid antimicrobial action.
  • the corneal thickness was remeasured then the corneal scleral buttons were dissected from the eye.
  • the buttons were then weighed (weight 1) and placed epithelial surface down, covered with medium 199 (Sigma) and incubated at 37°C for four to six hour ⁇ . After incubation, the cornea ⁇ were re-weighed (weight 2) , air dried at room temperature for 24 to 48 hour ⁇ and re-weighed dry (weight 3) . That was Experiment Set A.
  • the experiments were also performed using eyes that had the epithelium completely removed prior to exposure to the te ⁇ t ⁇ olution, Experiment Set B.
  • Control ⁇ were expo ⁇ ed to balanced salt solution (BSS (Alcon Laboratories)) only (BSS control).
  • Test ⁇ olutions were made up from 20% stock solution (aqueou ⁇ ) of PHMB diluted with BSS.
  • the percentage change in weight was calculated by ⁇ ubtracting the dry weight (weight 3) from each of the wet weights (weights 1 and 2) to give a pre ⁇ incubation net weight (weight 1 - weight 3) and a post- incubation net weight (weight 2 - weight 3) and dividing the post-incubation net weight by the pre-incubation net weight then multiplying by 100.
  • the percentage change represents the change in hydration of the eye ti ⁇ ues and gives an indication of changes in endothelial function, as does the change in corneal thicknes ⁇ .
  • Po ⁇ itive controls were performed in which the endothelial cells of the eye were destroyed after exposure to the test solutions thereby causing complete dysfunction of the endothelium. These are shown below as " + control”. For Experiment Set A only one positive control was carried out and that eye was treated with the BSS control solution. For Experiment Set B a positive control was performed with each of the four te ⁇ t ⁇ olution ⁇ and with BSS control solution.
  • the corneal thicknes ⁇ diminishes slightly after treatment with PHMB rather than thickening slightly as with the control. There was no evident endothelial damage, the percentage change in weight wa ⁇ not significantly different from that observed for the control test solution, and no significant dose effect was discernible.
  • Set B - epithelium removed The corneal ⁇ welling ob ⁇ erved with the control test solution was les ⁇ than that ob ⁇ erved with the polyhexanide (PHMB) test ⁇ olution, but no ⁇ ignificant do ⁇ e effect was discernible. There was no evidence of endothelial damage.
  • Fre ⁇ h unscalded pig eyes were dis ⁇ ected within 4 hours of slaughter.
  • the corneal scleral button wa ⁇ mounted on an artificial anterior chamber and the endothelial ⁇ urface wa ⁇ perfu ⁇ ed with BSS Plus (Alcon Laboratories) at 23 cm H 2 0, 37°C, with the anterior chamber volume replaced every 1/2 hour.
  • Serial mea ⁇ urements of corneal thickness were made with an ultrasonic pachymeter.
  • the epithelial surface was kept moistened with BSS and was not allowed to dehydrate.
  • the test ⁇ olution was used to bathe the epithelial surface continuously for 1 hour. (Perfusion of the endothelium with BSS Plus was continued throughout) .
  • the test solution wa ⁇ made up from 20% ⁇ tock ⁇ olution (aqueou ⁇ ) of PHMB diluted with BSS .
  • Positive controls were produced by exposing the endothelium to 70% alcohol for 1 to 2 minutes and then continuing perfusion with BSS Plus.
  • the po ⁇ itive controls show the re ⁇ ults which would be obtained if complete dysfunction of the endothelium were to have been caused by the test solutions.
  • control cornea which were continuously perfused with BSS Plus for the full six hours and had their epithelial ⁇ urfaces kept moistened with BSS. They received no other treatment.
  • Measurements for a positive control are shown ("+" control) . That cornea was treated as a normal control but the endothelial surface was expo ⁇ ed to 70% alcohol for 1 to 2 minute ⁇ after 120 minutes of the test period had pas ⁇ ed.
  • Mea ⁇ urement ⁇ for a cornea which had the epithelial surface bathed in 0.2% PHMB solution are shown (0.2% PHMB). Exposure to PHMB took place between minutes 120 and 180 of the experiment.
  • the endothelium was perfused with BSS Plus for the entire six hour period. Measurements were also taken for a cornea receiving exposure of the epithelial surface to 0.2% PHMB ⁇ olution for 1 hour followed by expo ⁇ ure of the endothelium to 70% alcohol for 1 to 2 minute ⁇ . This is shown as "0.2%' PHMB "+" control" on Figure 3.
  • the 2.0% polyhexanide solution produced obvious dehydration of the epithelial cells with a large loss of cell volume and flattening of the cells, but no disruption of the cell membranes.
  • the 0.2% polyhexanide solution produced an irregular but less complete los ⁇ of cell volume, producing an irregular appearance of the epithelial surface but not disruption of the cell membranes.
  • the 0.02% polyhexanide solution produced changes that were similar but less pronounced than those produced by the 0.2% solution.
  • PHMB Polyhexanide
  • polyhexanide may be ⁇ afely u ⁇ ed on the external eye and other epithelial surfaces of the body such as the skin and mucous membranes, at concentrations ⁇ howing antimicrobial activity.
  • Composition ⁇ are given a ⁇ % w/v. (7) Phosphate buffered: polyhexanide 0.1 to 2.0 % hypromellose 0.3 % sodium chloride 0.42 % sodium acid 0.075 % phosphate (2H 2 0) magnesium chloride (6H 2 0) 0.03 % sodium acetate (3H 2 0) 0.39 % acetic acid 0.001 % citric acid 0.00001465 % purified water to 100 %
  • Acetate/citrate buffered polyhexanide 0.1 to 2.0 % hypromellose 0.3 % sodium chloride 0.49 % potas ⁇ ium chloride 0.075 % calcium chloride (2H 2 0) 0.048 % magnesium chloride (6H 2 0) 0.03 % sodium acetate (3H 2 0) 0.39 % acetic acid 0.001 % citric acid 0.00001465 % purified water to 100 %
  • Bicarbonate buffered polyhexanide 0.1 to 2.0 % hypromellose 0.25 % sodium chloride 0.6 % - sodium bicarbonate 0.45 % purified water to 100 %
  • Composition ⁇ are given a ⁇ % w/w.
  • Example 13 Gel formulation Compositions are given as % w/v. polyhexanide 0.1 to 2.0 % carbomer 940 polymer 0.2 % mannitol 5.0 % hydrochloric acid/ qs pH 7.4 sodium hydroxide purified water to 100 %
  • Example 14 Liposomal formulation
  • compositions are given as % w/v

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Abstract

Utilisations de sels de poly(héxaméthylène biguanide), en particulier le sel d'hydrochlorure, dans la fabrication de médicaments pour le traitement local des infections microbiennes, et méthodes de traitement afférentes. L'invention a également trait à des préparations pharmaceutiques, des antiseptiques, des désinfectants et des formulations liquides renfermant un sel de poly(hexaméthylène biguanide).
PCT/GB1996/001457 1995-06-16 1996-06-17 Compositions contenant des sels de poly(hexamethylene biguanide) et leurs utilisations WO1997000076A1 (fr)

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Application Number Priority Date Filing Date Title
AU61308/96A AU6130896A (en) 1995-06-16 1996-06-17 Compositions containing poly(hexamethylene biguanide) salts and uses thereof

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GBGB9512290.9A GB9512290D0 (en) 1995-06-16 1995-06-16 Uses of polyhexanide
GB9512290.9 1995-06-16

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WO1997000076A1 true WO1997000076A1 (fr) 1997-01-03

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WO (1) WO1997000076A1 (fr)

Cited By (20)

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EP0788797A1 (fr) * 1996-02-08 1997-08-13 Fresenius AG L'usage de PHMB pour le traitement des infections causées par germes qui se propagent intracellulairement
GB2323279A (en) * 1997-03-20 1998-09-23 Medeva Europ Ltd Polybiguanide Preservative
WO2000018442A1 (fr) * 1998-09-25 2000-04-06 Becton, Dickinson And Company Solution de rinçage de catheter et procede d'utilisation associe
WO2001062237A3 (fr) * 2000-02-23 2002-06-13 Orentreich Foundation For The Methodes et compositions de traitement de l'alopecie et d'autres troubles de l'appareil pilosebace
WO2003037356A1 (fr) * 2001-10-26 2003-05-08 Fresenius Kabi Deutschland Gmbh Composition pharmaceutique contenant un facteur de croissance et/ou une cytokine et un biguanide antiseptique
WO2004093545A1 (fr) * 2003-04-11 2004-11-04 Bausch & Lomb Incorporated Solutions desinfectantes efficaces contre les endospores bacteriennes
WO2006066752A1 (fr) * 2004-12-21 2006-06-29 Bayer Innovation Gmbh Mousses polyurethane resistantes a l'infection, leur procede de production et leur utilisation dans des pansements a action antiseptique
EP2165701A1 (fr) * 2008-09-18 2010-03-24 Croma-Pharma Gesellschaft m.b.H. Composition active antimicrobienne et antivirale
WO2010031096A1 (fr) * 2008-09-18 2010-03-25 Croma-Pharma Gesellschaft M.B.H. Composition à action antimicrobienne et antivirale
AU2005282377B2 (en) * 2004-09-07 2011-07-28 3M Innovative Properties Company Cationic antiseptic compositions and methods of use
US8198326B2 (en) 2004-09-07 2012-06-12 3M Innovative Properties Company Phenolic antiseptic compositions and methods of use
US8338491B2 (en) 2006-10-27 2012-12-25 3M Innovative Properties Company Antimicrobial compositions
WO2013152838A1 (fr) 2012-04-11 2013-10-17 Merz Pharma Gmbh & Co. Kgaa Préparation pour application locale sur les muqueuses, contenant un polyhexanide comme substance active
US8623935B2 (en) 2007-12-31 2014-01-07 3M Innovative Properties Company Antimicrobial compositions
CN104398534A (zh) * 2014-11-04 2015-03-11 卫国刚 聚六亚甲基胍滴眼液
US9826770B2 (en) 2005-03-10 2017-11-28 3M Innovative Properties Company Antimicrobial compositions comprising esters of hydroxycarboxylic acids
US9848604B2 (en) * 2014-07-11 2017-12-26 Medtronic Xomed, Inc. Antimicrobial wash
US10471036B2 (en) 2003-09-09 2019-11-12 3M Innovative Properties Company Antimicrobial compositions and methods
WO2020069007A1 (fr) * 2018-09-25 2020-04-02 Global Health Solutions Llc Procédés et compositions de soin oculaire
US10918618B2 (en) 2005-03-10 2021-02-16 3M Innovative Properties Company Methods of reducing microbial contamination

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0788797A1 (fr) * 1996-02-08 1997-08-13 Fresenius AG L'usage de PHMB pour le traitement des infections causées par germes qui se propagent intracellulairement
GB2323279A (en) * 1997-03-20 1998-09-23 Medeva Europ Ltd Polybiguanide Preservative
WO1998042373A1 (fr) * 1997-03-20 1998-10-01 Medeva Europe Limited Methode de preservation de vaccins mettant en oeuvre un polybiguanide
GB2323279B (en) * 1997-03-20 2001-02-07 Medeva Europ Ltd A method of preservation
US6403363B1 (en) 1997-03-20 2002-06-11 Medeva Europe Limited Method of preservation of vaccines with polybiguanide
WO2000018442A1 (fr) * 1998-09-25 2000-04-06 Becton, Dickinson And Company Solution de rinçage de catheter et procede d'utilisation associe
US7105573B2 (en) 2000-02-23 2006-09-12 Orentreich Foundation For The Advancement Of Science, Inc. Methods and compositions for the treatment of alopecia and other disorders of the pilosebaceous apparatus
WO2001062237A3 (fr) * 2000-02-23 2002-06-13 Orentreich Foundation For The Methodes et compositions de traitement de l'alopecie et d'autres troubles de l'appareil pilosebace
AU2001239826B2 (en) * 2000-02-23 2006-06-15 Orentreich Foundation For The Advancement Of Science, Inc. Methods and compositions for the treatment of alopecia and other disorders of the pilosebaceous apparatus
WO2003037356A1 (fr) * 2001-10-26 2003-05-08 Fresenius Kabi Deutschland Gmbh Composition pharmaceutique contenant un facteur de croissance et/ou une cytokine et un biguanide antiseptique
WO2004093545A1 (fr) * 2003-04-11 2004-11-04 Bausch & Lomb Incorporated Solutions desinfectantes efficaces contre les endospores bacteriennes
US10471036B2 (en) 2003-09-09 2019-11-12 3M Innovative Properties Company Antimicrobial compositions and methods
US10016501B2 (en) 2004-09-07 2018-07-10 3M Innovative Properties Company Cationic antiseptic compositions and methods of use
US9028852B2 (en) 2004-09-07 2015-05-12 3M Innovative Properties Company Cationic antiseptic compositions and methods of use
US8198326B2 (en) 2004-09-07 2012-06-12 3M Innovative Properties Company Phenolic antiseptic compositions and methods of use
AU2005282377B2 (en) * 2004-09-07 2011-07-28 3M Innovative Properties Company Cationic antiseptic compositions and methods of use
US8147857B2 (en) 2004-12-21 2012-04-03 Bayer Innovation Gmbh Infection-resistant polyurethane foams, method for producing the same and use thereof in antiseptic wound dressings
AU2005318512B2 (en) * 2004-12-21 2009-09-24 Bayer Innovation Gmbh Infection-resistant polyurethane foams, method for producing the same and use thereof in antiseptic wound dressings
EA016503B1 (ru) * 2004-12-21 2012-05-30 Байер Инновейшн Гмбх Ячеистый гидрофильный полиуретановый гель, способ его получения и применение этого ячеистого гидрофильного полиуретанового геля для изготовления изделия медицинского назначения и повязка на рану, содержащая этот ячеистый гидрофильный полиуретановый гель
WO2006066752A1 (fr) * 2004-12-21 2006-06-29 Bayer Innovation Gmbh Mousses polyurethane resistantes a l'infection, leur procede de production et leur utilisation dans des pansements a action antiseptique
US10918618B2 (en) 2005-03-10 2021-02-16 3M Innovative Properties Company Methods of reducing microbial contamination
US9826770B2 (en) 2005-03-10 2017-11-28 3M Innovative Properties Company Antimicrobial compositions comprising esters of hydroxycarboxylic acids
US8338491B2 (en) 2006-10-27 2012-12-25 3M Innovative Properties Company Antimicrobial compositions
US8569384B2 (en) 2006-10-27 2013-10-29 3M Innovative Properties Company Antimicrobial compositions
US8623935B2 (en) 2007-12-31 2014-01-07 3M Innovative Properties Company Antimicrobial compositions
WO2010031096A1 (fr) * 2008-09-18 2010-03-25 Croma-Pharma Gesellschaft M.B.H. Composition à action antimicrobienne et antivirale
EP2165701A1 (fr) * 2008-09-18 2010-03-24 Croma-Pharma Gesellschaft m.b.H. Composition active antimicrobienne et antivirale
DE102012007212A1 (de) * 2012-04-11 2013-10-17 Merz Pharma Gmbh & Co. Kgaa Zubereitung zur topischen Anwendung auf Schleimhäuten mit Polyhexanid als Wirkstoff
EP2836196B1 (fr) 2012-04-11 2019-06-12 Merz Pharma GmbH & Co. KGaA Préparation pour application locale sur les muqueuses, contenant un polyhexanide comme substance active
WO2013152838A1 (fr) 2012-04-11 2013-10-17 Merz Pharma Gmbh & Co. Kgaa Préparation pour application locale sur les muqueuses, contenant un polyhexanide comme substance active
US9848604B2 (en) * 2014-07-11 2017-12-26 Medtronic Xomed, Inc. Antimicrobial wash
US10681910B2 (en) 2014-07-11 2020-06-16 Medtronic Xomed, Inc. Antimicrobial wash
CN104398534A (zh) * 2014-11-04 2015-03-11 卫国刚 聚六亚甲基胍滴眼液
WO2020069007A1 (fr) * 2018-09-25 2020-04-02 Global Health Solutions Llc Procédés et compositions de soin oculaire
EP3856157A4 (fr) * 2018-09-25 2022-07-06 Global Health Solutions, LLC Procédés et compositions de soin oculaire

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GB9512290D0 (en) 1995-08-16

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