EP2592935A2 - Disinfectant and antiseptic formulation having reduced iodine content - Google Patents

Disinfectant and antiseptic formulation having reduced iodine content

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Publication number
EP2592935A2
EP2592935A2 EP11751629.4A EP11751629A EP2592935A2 EP 2592935 A2 EP2592935 A2 EP 2592935A2 EP 11751629 A EP11751629 A EP 11751629A EP 2592935 A2 EP2592935 A2 EP 2592935A2
Authority
EP
European Patent Office
Prior art keywords
iodine
formulation
siloxane
disinfectant
antiseptic
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Withdrawn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
EP11751629.4A
Other languages
German (de)
French (fr)
Inventor
Endre Mikulásik
Tamás SPAITS
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.)
Egis Pharmaceuticals PLC
Original Assignee
Egis Pharmaceuticals PLC
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 Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Publication of EP2592935A2 publication Critical patent/EP2592935A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/12—Iodine, e.g. iodophors; Compounds thereof
    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/20—Halogens; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
    • A61K8/585—Organosilicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/89—Polysiloxanes
    • A61K8/891—Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention is related to disinfectant and antiseptic formulation having reduced iodine content exhibiting excellent tissue compatibility.
  • the formulation according to the present invention contains iodine in elemental form rather than in ionic or complex form.
  • Further object of the present invention is a method for the preparation of disinfectant and antiseptic formulation according to the invention.
  • a still further object of the invention is the use of the solution of iodine prepared with a siloxane solvent as a disinfectant or antiseptic agent.
  • iodine The disinfective, antiseptic and germicidal activity of iodine has been known for a long time.
  • iodine is the least reactive element.
  • Iodine in elemental state consists of I 2 molecules appearing as a brownish purple, metallic shade solid substance.
  • Liquid state of elemental iodine is also known, while iodine vapour is irritating, violet fume (the name of iodine is originating from the Greek expression professioniodes", which means repayviolet")-
  • Iodine is soluble in organic apolar or dipolar solvents such as chloroform, carbon tetrachloride, carbon disulfide (the colour of the solution is violet); ethanol, diethylether, acetone (the colour of the solution is brownish); benzene (the colour of the solution is brownish-violet).
  • the violet colour shows that iodine is present in elemental form, while in solutions having brownish colour, iodine is transformed partly or completely into ionic or complex form.
  • Iodine is poorly soluble in water and polar solvents resulting in an unstable solution containing ionic and complex forms.
  • Halogen elements especially chlorine and iodine are widely used in their elemental form or in the form of oxy-anions thereof (hypochlorite, hypoiodite etc.) as disinfectants.
  • iodine for the purpose of an antiseptic, only iodine is being used. Elemental iodine is highly efficient, broad spectrum germicide, which in vitro rapidly destroys bacteria, viruses and fungi as well as some protozoons. After the use of iodine preparations known from the prior art, most microorganisms are destroyed in less than one minute; during this period, most damages are brought about in the first 15-30 seconds.
  • iodine destroys Gram-positive and Gram-negative bacteria, viruses and fungi, as well as some protozoons and different developmental stages thereof. Spores of bacteria, fungi and some viruses require longer period of action for inactivation. Different amount of iodine is required for destroying different pathogens. Individual sensitivity of pathogenic strains depends on the form of iodine present in the formulation, concentration thereof, the pH, temperature, period of exposition.
  • the exposition time required for destroying 90 percent of the bacteria is 90 seconds; in the case of a tincture of 7 percent by weight concentration, this exposition time is reduced to 15 seconds.
  • the time period necessary for the inactivation of viruses is between 3 to 20 minutes when applying a iodine solution having the concentration of 1 to 2 percent by weight.
  • Disinfectant and antiseptic efficacy is usually characterized in the state of the art by the MIC value (minimum inhibitory concentration) of the active agent.
  • the MIC value is the concentration of the disinfectant/antiseptic agent, which prevents the visible growth of a given microorganism genus.
  • MIC values measured for polyvinylpyrrolidone-iodine complex were between 0.001 and 0.25 percent by weight (R. S. Traboulsi, P. K. Mukherjee, M. A. Ghannoum: In vitro activity of inexpensive topical alternatives against Candida spp. isolated from the oral cavity of HIV-infected patients. Int. J. Antimicrob.
  • iodine formed with high molecular weight polymers e.g. polyvinylpyrrolidone-iodine
  • various pharmaceutical formulations e.g. solution, suppository, cream, foam, mouth disinfectant tablet
  • Such complexes contain iodine in alcohol-free, soluble form as an ionic-complex.
  • the disinfective and antiseptic effect results from the action of iodine in elemental form released from the complex (approx. 20 mg/1 concentration).
  • the handling of such formulations is more convenient than that of iodine tincture, they are less irritative and usually can be washed away from the skin.
  • iodine complexes formed with high molecular weight polymers are lack of stability, pH dependence, the necessity of using significant amounts of stabilizing excipients and the discomfort resulting from the glutinous film layer of the vehicle polymer remaining on the application area.
  • iodine-containing formulations which contain iodine in form of water-soluble iodide or iodate dispersed in a viscous liquid or elastic solid vehicle.
  • Such products are used for iodine supplementation of drinking water where the iodine content of water does not cover the physiological requirements.
  • the water-soluble iodine-content of such products is released by slowly diffusing out from the hydrophobic, viscous or cross-linked elastomer matrix in an extended period of time.
  • US Patent No. 4384960 discloses a composition suitable for water disinfection, as a wound antiseptic and for iodine supplementation, wherein a receptacle provided with an opening suitable for providing metered dosage and means for retaining solid particles is filled with a iodine-containing liquid formulation.
  • a iodine-containing preparation such as solid crystalline iodine or a iodine-containing pelleted formulation is added.
  • a small amount of iodine is dissolved and an aqueous iodine solution containing approx. 200-400 mg/1 iodine is formed.
  • iodine is present as elemental iodine, iodide and hypoiodite.
  • the iodine- containing pellets can be formed by dispersing iodine in a silicone cautchouc or silicone elastomer.
  • solubility of iodine in water is low and it is significantly depending on temperature.
  • the rate of dissolution is low, therefore the concentration of the aqeous iodine-containing solution will vary depending on temperature and the time period between subsequent uses when iodine solution is withdrawn from the composition. This effect could make the use of the composition unnecessarily complicated and the disinfection ineffective.
  • solubility of iodine in organic siloxanes and corresponding thermodynamic processes such as the changes in solubility parameter were studied in detail (H. Watanabe, T. Miyauchi, J. Chem. Eng. Japan Vol. 6(2), p. 109-114 [1973]).
  • the solubility decreases by increasing the degree of polymerization. It is well known from the art that although iodine is soluble in many organic solvents and such solutions are stable, however, solvents suitable for dissolving iodine are mostly very toxic to or otherwise incompatible with the living organism.
  • solutions containing a occidentaliodophor wherein iodine is present in ionic or complex form, act by releasing elemental iodine, such solutions must contain iodine in several times or even one to three magnitude higher concentration than the microbiologically effective concentration of free elemental iodine in solution. Since the action mechanism of iodophors rely on releasing free elemental iodine due to the dissociation of the complex, products containing iodophore lack satisfactory stability, decompose unexpectedly depending on temperature, presence or activity of water, skin type, pH and several other factors.
  • iodine complex for reliable disinfective or antiseptic effect, many times more iodine complex must be used to provide the necessary free iodine concentration.
  • iodine present in complex form or released upon the decomposition of the iodophore on the body surface or transferred in the body causes unnecessary exposition, it is environmentally harmful, they cause contamination of the skin, clothing and objects.
  • iodine is well tolerated, its presence on the skin for extended periods of time or in excessive concentration may result in oversensitivity and skin rashes.
  • the disadvantages of the iodine-containing formulations known from the state of the art are the complicated handling due to the risk of contamination of the body and clothing, fast decomposition and short shelf life, often uncertain disinfective and antiseptic effect and environmental harmfulness.
  • iodophors The shelf life of iodophors is inversely correlated with the efficacy thereof. Formulations having greater stability and consequently longer shelf life release significantly smaller amount of iodine, thus exhibit poor efficacy. Formulations releasing their iodine content faster provide for higher elemental iodine concentration and exhibit good efficacy. However, their shelf life is accordingly shorter.
  • the objective of our research-development work was to develop a iodine-containing disinfectant and antiseptic formulation suitable for satisfying the above-mentioned requirements.
  • the objective has been solved by the invention according to the present application.
  • the present invention relies on the surprising recognition that by dissolving elemental iodine in a suitable organic silicone compound, a disinfectant and antiseptic solution can be produced, which exhibits excellent disinfectant and antiseptic effect even in low concentration, stabile, does not cause significant discoloration and contamination and most surprisingly, which is compatible to the living organism and practically does not show any tissue damaging, irritating or oversenzitizing effect.
  • An object of the present invention is the use of the solution of iodine in a silicone-type solvent, preferably in a volatile silicone solvent and optionally with other auxiliary excipients for disinfection and as an antiseptic agent.
  • a suitable silicone type solvent is transferred to the surface such as the skin, utensils or apparatuses to be treated, and if desired, after a suitable 11 000065
  • the solution of iodine prepared in silicone type solvents and optionally containing other ingredients can be transferred to the surface to be treated by spraying or by sweeping with a brush moistened with said solution or the object to be treated can be submerged into said solution according to the invention.
  • the expression represents silicone compounds wherein the silicon atoms in the 0-[SiR 1 R 2 -O] n -Si chain are substituted by R 1 , R 2 alkyl groups.
  • Silicones can be linear (silicone oils and -cautschuks), cyclic, branched (some silicone resins) or cross-linked (silicone resins).
  • the molecular weight of some silicones may exceed 700,000 g/mol.
  • the boiling temperature and viscosity of silicone oils is principally determined by the degree of polymerization. Derivatives having a lower degree of polymerization are volatile and free-flowing; by increasing the degree of polymerization, the boiling temperature and viscosity are increasing. Above a certain limit in the degree of polymerization or by introducing cross-linkage, silicones can be produced in the form of elastic, partly or fully solid silicone cautschuc or silicone gum.
  • Silicones are produced by hydrolyzing alkyl-substituted halogenated silanes or mixtures thereof. For example, according to the method disclosed in published European Patent Application no. 980 885, the mixture of trimethylchlorosilane and dimethyldichlorosilane is hydrolyzed in the presence of aqueous hydrochloric acid solution. In the process, a mixture of silicone polymers is formed which is purified and fractionated by distillation.
  • silicone oils used in the medicine have been formerly set back due to the problems of manufacturing silicone compounds in sufficient purity and at an affordable cost for medicinal purposes.
  • silicone oils used in the ophtalmology were often contaminated with the monomer or oligomers, which impaired product quality and raised health issues as well.
  • Highly volatile silicone oils comprise a group of silicone oils.
  • Highly volatile silicone oils are cosmetical or pharmaceutical excipients which are volatilized from the human skin within a 6-hour period after application to the skin and their quality is suitable for the manufacture of pharmaceutical formulations.
  • silicones having different degree of polymerization during the formulation of cosmetical and pharmaceutical formulations as well as nutrients is known according to the state of the art.
  • Oils as well as cautschucs of high molecular weigh are used as a vehicle or a film- forming agent.
  • Silicone oils are applied as dispersing or stabilizing agents.
  • antiseptic or disinfectant formulations which contains elemental iodine and siloxane vehicle as well as optionally further active agents or excipients.
  • the disinfectant and antiseptic iodine-containing formulations may appear mainly in three forms.
  • Rapidly evaporating formulations e.g. aerosol, tincture, solution, foam
  • the iodine-containing solution acts within seconds and evaporates from the surface within 1 minute.
  • Such formulations can be presented, for example, in the form of aerosol, tincture, solution or foam, which are suitable for the antiseptic or disinfective treatment of easily or less easily accessible surfaces (e.g. aerosol, tincture, solution) or cavities (aerosol, foam).
  • the formulations according to the present invention are used as an antiseptic for the treatment of an injury of the body surface or treatment of body cavities.
  • Such rapidly evaporating formulations are suitable as a medicinal antiseptic, antiseptic for first aid and for treating small injuries. These formulations evaporate from the skin rapidly and without staining the body or the clothing.
  • Formulations having medium-term permanent effect are characterized by releasing iodine to the surface at least for the period of one minute but not longer than 1 hours. After releasing iodine, the formulation is evaporated from the surface or, if desired, it can be washed away. These formulations are effective within few minutes.
  • Formulations having sustained effect are effective for a period longer than one hour and can be removed from the site of the antiseptic or disinfectant treatment by washing.
  • the solution of iodine in a siloxane solvent according to the present invention is stabile for indefinite period of time unlike the ionic and complex forms wherein elemental iodine responsible for disinfectant and antiseptic effect is formed during decomposition.
  • the stability of the formulation according to the present invention is limited by the evaporation through the packaging material, unlike the iodine-containing formulations known from the prior art which are heat sensitive and due to their instability, they loose their efficacy soon.
  • the formulation according to the present invention does not cause any stinging, irritating sensation, tissue damaging effect or any other discomfort.
  • the formulation can be easily applied, the use of the formulation according to the present invention prevents sticking wound-treating materials into the wound.
  • Formulations according to the present invention are sterile per se (due to the disinfectant and antiseptic effect of iodine) and preserve sterility in suitable packaging for an infinite period of time.
  • the formulation according to the present invention in its simplest form consists of iodine dissolved in a suitable siloxane.
  • the formulation can contain further excipients or pharmaceutically active agents.
  • a film-forming agent preventing the access of air and environmental effects to the treated area, thus decreasing the risk of repeated infection.
  • film-forming agents include but are not limited to lipophil polymers, preferably a silicone oil, such as dimethicone or a suitable silicone elastomer or organic compounds of higher molecular weight.
  • the formulation can contain a further antiseptic of disinfectant agent, an antibiotic, antiviral or antifungal agent, a cosmetic agent or pharmaceutically active ingredient suitable for the treatment of sound or injured skin surface, e.g.
  • siloxane an agent facilitating tissue regeneration or wound healing.
  • the properties or composition of the siloxane or the mixture of siloxanes used as vehicle there is no limitation with regard to the properties or composition of the siloxane or the mixture of siloxanes used as vehicle.
  • Siloxane products with different degree of polymerization are available for cosmetical or pharmaceutical use. Such individual compounds, products or mixtures thereof can be used in the preparation of formulation according to the present invention.
  • the rate of evaporation of a formulation according to the present invention depends on the composition of the vehicle, most importantly on the concentration and degree of polimerization of the volatile silicone component. Siloxane derivatives having higher degree of polimerization evaporate slowly and at the same time, act as a film-forming agent providing a iodine-containing film on the treated surface.
  • Preferable siloxane oligomers are hexamethyldisiloxane, octamethyltrisiloxane and decamethylcyclopentasiloxane.
  • the antiseptic and disinfectant formulation according to the present invention comprising iodine dissolved in a siloxane is effective at 0.001 percent by weight iodine concentration against certain microorganisms.
  • the iodine concentration can be chosen according to the intended use between 0.001 percent by weight and the saturation concentration of iodine in the siloxane solvent used. This saturation concentration is in the range of 0.5-0.8 percent by weight for low molecular weight volatile siloxanes and significantly decreases with the increasing molecular weight and degree of polymerization of the siloxane at constant temperature.
  • formulations according to the present invention having 0.2-0.3 percent by weight iodine concentration show antiseptic effect against all test organisms ⁇ Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis) within 0.25-1 minute exposure at room temperature. Consequently, the formulation according to the most preferable embodiment of the present invention contains 0.1-0.5 percent by weight, most typically 0.25 percent by weight iodine. In case of rapidly evaporating formulations, it is advantageous to set the iodine concentration in the higher region of the range due to the shorter exposition time. When a formulation according to the present invention with intermediate or long-lasting effect is intended, it is advantageous to set the iodine concentration in the lower region of the concentration range, taking the longer exposition into account.
  • the formulations according to the present invention can be produced according to known methods of pharmaceutical technology. Usually iodine and optional other active ingredients or excipients are dispersed or dissolved in the lowest molecular weight siloxane component with continous stirring and the mixture thus obtained is homogenized with the other components of the formulation.
  • Example 1 iodine and optional other active ingredients or excipients are dispersed or dissolved in the lowest molecular weight siloxane component with continous stirring and the mixture thus obtained is homogenized with the other components of the formulation.
  • Iodine is dissolved in hexamethyldisiloxane at room temperature with stirring. Thereafter octamethyltrisiloxane is added. The solution thus obtained is filled into aerosol bottles equipped with a dosing pump and closure.
  • Iodine tincture prepared with a siloxane solvent containing 0.1 percent by weight iodine (intermediate effective period)
  • Iodine 0.25 g Iodine is dissolved in octamethyltrisiloxane at room temperature with stirring. Thereafter dimethicone is added and dissolved. The solution thus obtained is filled into bottles with a spreading or dropping accessory and closure.
  • Iodine is dissolved in octamethyltrisiloxane at room temperature with stirring. The solution is admixed to the gel base and homogenized at room temperature. The gel thus obtained is filled into plastic tubes or jars and closed.
  • the bacteriostatic efficacy test of the formulations according to the present invention was carried out in a mixed culture of Escherichia coli (ATCC 8739, American Type Culture Collections, Manassas, Virginia, USA) Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538) and Bacillus subtilis (ATCC 6633) strains.
  • the mixture of the culture of the strains after 24 hours incubation was used in the tests (incubation temperature: 36 °C). Experiments were carried out aseptically.
  • Subcultures were incubated at the temperature of 36 °C for 72 hours. Subcultures wherein the propagation of the bacteria was observed, were inoculated for the second time into fresh medium of the same composition and results were read after 48 hours.
  • a disinfectant solution corresponding to the test (Betadine) was used as a control solution. Bacterium cultures were checked by inoculating portions of the medium containing the neutralizing component but prepared without test or control disinfectant.
  • the antiseptic and/or disinfectant effect was deemed to be satisfactory if the proliferation of the bacteria could neither be observed in the primary nor in the secondary cultures.
  • the antiseptic/disinfectant test formulation is judged to be suitable if the bactericide effect occurs after the identical or a shorter incubation period than that observed in the case of the control disinfectant (Betadine).
  • Sterile contact plates are prepared using the medium of the following composition:
  • 3 plates were incubated at the temperature of 36 °C.
  • 3-3 plates are treated with 0.2-ml aliquots of the test formulation according to the invention and further 3 plates were treated with the same volume of Betadin solution. All aliqouts were dispersed evenly on the surface of the plate. Plates were incubated for 72 hours at the temperature of 36 °C.
  • the number of colonies were counted on each plate treated with the test preparation and the results were compared to those obtained with that obtained from the plate treated with Betadine solution.
  • the initial colony number is calculated as the average of the number of colonies obtained with the positive control. If the number of the colonies can not be counted due to formation of continuous layer of bacteria, the test is repeated using a diluted bacterial culture.

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Abstract

The invention is related to the use of the solution of elemental iodine prepared in an organosiloxane solvent as antiseptic or disinfectant agent and formulations suitable for such use.

Description

DISINFECTANT AND ANTISEPTIC
FORMULATION HAVING REDUCED IODINE
CONTENT
Technical field of the invention
The present invention is related to disinfectant and antiseptic formulation having reduced iodine content exhibiting excellent tissue compatibility. The formulation according to the present invention contains iodine in elemental form rather than in ionic or complex form. Further object of the present invention is a method for the preparation of disinfectant and antiseptic formulation according to the invention. A still further object of the invention is the use of the solution of iodine prepared with a siloxane solvent as a disinfectant or antiseptic agent.
Technical background of the invention
The disinfective, antiseptic and germicidal activity of iodine has been known for a long time. Among the halogen elements used for disinfection, iodine is the least reactive element. Iodine in elemental state consists of I2 molecules appearing as a brownish purple, metallic shade solid substance. Liquid state of elemental iodine is also known, while iodine vapour is irritating, violet fume (the name of iodine is originating from the Greek expression„iodes", which means„violet")- Iodine is soluble in organic apolar or dipolar solvents such as chloroform, carbon tetrachloride, carbon disulfide (the colour of the solution is violet); ethanol, diethylether, acetone (the colour of the solution is brownish); benzene (the colour of the solution is brownish-violet). In solution, the violet colour shows that iodine is present in elemental form, while in solutions having brownish colour, iodine is transformed partly or completely into ionic or complex form. Iodine is poorly soluble in water and polar solvents resulting in an unstable solution containing ionic and complex forms.
Halogen elements, especially chlorine and iodine are widely used in their elemental form or in the form of oxy-anions thereof (hypochlorite, hypoiodite etc.) as disinfectants. However, for the purpose of an antiseptic, only iodine is being used. Elemental iodine is highly efficient, broad spectrum germicide, which in vitro rapidly destroys bacteria, viruses and fungi as well as some protozoons. After the use of iodine preparations known from the prior art, most microorganisms are destroyed in less than one minute; during this period, most damages are brought about in the first 15-30 seconds. Resistance to iodine is not known, it is effective against a wide range of pathogens since iodine destroys Gram-positive and Gram-negative bacteria, viruses and fungi, as well as some protozoons and different developmental stages thereof. Spores of bacteria, fungi and some viruses require longer period of action for inactivation. Different amount of iodine is required for destroying different pathogens. Individual sensitivity of pathogenic strains depends on the form of iodine present in the formulation, concentration thereof, the pH, temperature, period of exposition. Thus, when using iodine tincture of 1 percent by weight concentration, the exposition time required for destroying 90 percent of the bacteria is 90 seconds; in the case of a tincture of 7 percent by weight concentration, this exposition time is reduced to 15 seconds. The time period necessary for the inactivation of viruses is between 3 to 20 minutes when applying a iodine solution having the concentration of 1 to 2 percent by weight.
Disinfectant and antiseptic efficacy is usually characterized in the state of the art by the MIC value (minimum inhibitory concentration) of the active agent. The MIC value is the concentration of the disinfectant/antiseptic agent, which prevents the visible growth of a given microorganism genus. For example, in the case of yeasts belonging to the genus Candida, MIC values measured for polyvinylpyrrolidone-iodine complex were between 0.001 and 0.25 percent by weight (R. S. Traboulsi, P. K. Mukherjee, M. A. Ghannoum: In vitro activity of inexpensive topical alternatives against Candida spp. isolated from the oral cavity of HIV-infected patients. Int. J. Antimicrob. Agents 31 (2008) p. 272-276). Solutions of iodine prepared in different solvents are being used for centuries as disinfectants or antiseptics. Most widely, the alcoholic solution of elemental iodine and potassium iodide is used, wherein elemental iodine is present in form of complexes with potassium iodide. The active disinfecting agent is elemental iodine released from the ionic form and the complex, respectively. The compendial iodine tincture produced in this way is, however, unstably, rapidly dries, intensively discolours the objects contacted with, corrosive and highly irritates the tissues. Thus, the use of iodine tincture is presently declining.
Recently water-soluble complexes of iodine formed with high molecular weight polymers, e.g. polyvinylpyrrolidone-iodine are used in various pharmaceutical formulations (e.g. solution, suppository, cream, foam, mouth disinfectant tablet) instead of iodine tincture. Such complexes contain iodine in alcohol-free, soluble form as an ionic-complex. The disinfective and antiseptic effect results from the action of iodine in elemental form released from the complex (approx. 20 mg/1 concentration). The handling of such formulations is more convenient than that of iodine tincture, they are less irritative and usually can be washed away from the skin. The disadvantages of iodine complexes formed with high molecular weight polymers are lack of stability, pH dependence, the necessity of using significant amounts of stabilizing excipients and the discomfort resulting from the glutinous film layer of the vehicle polymer remaining on the application area. According to the state of the art, there are known iodine-containing formulations which contain iodine in form of water-soluble iodide or iodate dispersed in a viscous liquid or elastic solid vehicle. Such products are used for iodine supplementation of drinking water where the iodine content of water does not cover the physiological requirements. The water-soluble iodine-content of such products is released by slowly diffusing out from the hydrophobic, viscous or cross-linked elastomer matrix in an extended period of time.
Such formulations wherein the water-soluble iodine compound is embedded into an organic siloxane elastomer or dispersed in viscous silicone oil have been disclosed in published European Patent Nos. 283407, 283408, 284521, 285525, 357519 and 402275.
US Patent No. 4384960 discloses a composition suitable for water disinfection, as a wound antiseptic and for iodine supplementation, wherein a receptacle provided with an opening suitable for providing metered dosage and means for retaining solid particles is filled with a iodine-containing liquid formulation. During use, the receptacle is filled with water and a iodine-containing preparation, such as solid crystalline iodine or a iodine-containing pelleted formulation is added. In this way, a small amount of iodine is dissolved and an aqueous iodine solution containing approx. 200-400 mg/1 iodine is formed. In this solution, iodine is present as elemental iodine, iodide and hypoiodite. The iodine- containing pellets can be formed by dispersing iodine in a silicone cautchouc or silicone elastomer. The drawback of this composition resides in that solubility of iodine in water is low and it is significantly depending on temperature. Thus, the rate of dissolution is low, therefore the concentration of the aqeous iodine-containing solution will vary depending on temperature and the time period between subsequent uses when iodine solution is withdrawn from the composition. This effect could make the use of the composition unnecessarily complicated and the disinfection ineffective.
Diffusion and membrane permeability of iodine and iodine complexes between two compartments separated by a silicone membrane has been studied in order to optimize extended release iodine-containing formulations (K. Takikawa, M.Nakano, T. Arita, Chem. Pharm. Bull. 26(3) p- 874-879 [1978]). It has been found that iodine complexes exhibit significantly lower permeability than elemental iodine.
The solubility of iodine in organic siloxanes and corresponding thermodynamic processes such as the changes in solubility parameter were studied in detail (H. Watanabe, T. Miyauchi, J. Chem. Eng. Japan Vol. 6(2), p. 109-114 [1973]). The researchers found that the solubility of iodine in organic polysiloxanes is approximately 5-7 g/1 (0.5-0.7 percent by weight) at room temperature. The solubility decreases by increasing the degree of polymerization. It is well known from the art that although iodine is soluble in many organic solvents and such solutions are stable, however, solvents suitable for dissolving iodine are mostly very toxic to or otherwise incompatible with the living organism. Therefore such solutions can not be used as disinfectants or antiseptics. Since solutions containing a „iodophor" wherein iodine is present in ionic or complex form, act by releasing elemental iodine, such solutions must contain iodine in several times or even one to three magnitude higher concentration than the microbiologically effective concentration of free elemental iodine in solution. Since the action mechanism of iodophors rely on releasing free elemental iodine due to the dissociation of the complex, products containing iodophore lack satisfactory stability, decompose unexpectedly depending on temperature, presence or activity of water, skin type, pH and several other factors. Thus, for reliable disinfective or antiseptic effect, many times more iodine complex must be used to provide the necessary free iodine concentration. In this way, iodine present in complex form or released upon the decomposition of the iodophore on the body surface or transferred in the body causes unnecessary exposition, it is environmentally harmful, they cause contamination of the skin, clothing and objects. Although iodine is well tolerated, its presence on the skin for extended periods of time or in excessive concentration may result in oversensitivity and skin rashes.
In summary, the disadvantages of the iodine-containing formulations known from the state of the art are the complicated handling due to the risk of contamination of the body and clothing, fast decomposition and short shelf life, often uncertain disinfective and antiseptic effect and environmental harmfulness.
The shelf life of iodophors is inversely correlated with the efficacy thereof. Formulations having greater stability and consequently longer shelf life release significantly smaller amount of iodine, thus exhibit poor efficacy. Formulations releasing their iodine content faster provide for higher elemental iodine concentration and exhibit good efficacy. However, their shelf life is accordingly shorter.
Consequently there is a significant need for a stabile, efficient, instantly effective and optionally long-acting disinfectant and antiseptic iodine formulation suitable for industrial production, wherein iodine is used in low concentration in a form different from a complex thereof, said formulation can be used with a minimum risk of contamination and irritation and it is suitable for minimizing the tissue damage due to antiseptic treatment in those areas where the tissue damage is already present (e.g. wounds).
The objective of our research-development work was to develop a iodine-containing disinfectant and antiseptic formulation suitable for satisfying the above-mentioned requirements. The objective has been solved by the invention according to the present application.
The present invention relies on the surprising recognition that by dissolving elemental iodine in a suitable organic silicone compound, a disinfectant and antiseptic solution can be produced, which exhibits excellent disinfectant and antiseptic effect even in low concentration, stabile, does not cause significant discoloration and contamination and most surprisingly, which is compatible to the living organism and practically does not show any tissue damaging, irritating or oversenzitizing effect.
The state of the art is silent about the use of a solution of iodine prepared in an organic silicone compound or a siloxane type solvent as antiseptic or disinfectant.
Summary of the invention
An object of the present invention is the use of the solution of iodine in a silicone-type solvent, preferably in a volatile silicone solvent and optionally with other auxiliary excipients for disinfection and as an antiseptic agent. To achieve this objective, the solution of iodine in a suitable silicone type solvent is transferred to the surface such as the skin, utensils or apparatuses to be treated, and if desired, after a suitable 11 000065
10
treatment period, it is removed from said surface. Surprisingly, we have found that the solution of iodine prepared in silicone type solvents optionally containing other excipients is fully compatible with biological tissues, mucous membranes and the animal or human skin; it is practically without any tissue-damaging effects or irritation in those cases when said solution is applied to wounds. Further object of the present invention is a formulation containing elemental iodine in a siloxan-type vehicle.
Detailed description of the invention
During the use according to the present invention, the solution of iodine prepared in silicone type solvents and optionally containing other ingredients can be transferred to the surface to be treated by spraying or by sweeping with a brush moistened with said solution or the object to be treated can be submerged into said solution according to the invention.
In the present description, the expression „silicone" or „siloxane" represents silicone compounds wherein the silicon atoms in the 0-[SiR1R2-O]n-Si chain are substituted by R1, R2 alkyl groups.
Silicones can be linear (silicone oils and -cautschuks), cyclic, branched (some silicone resins) or cross-linked (silicone resins). The molecular weight of some silicones may exceed 700,000 g/mol. The boiling temperature and viscosity of silicone oils is principally determined by the degree of polymerization. Derivatives having a lower degree of polymerization are volatile and free-flowing; by increasing the degree of polymerization, the boiling temperature and viscosity are increasing. Above a certain limit in the degree of polymerization or by introducing cross-linkage, silicones can be produced in the form of elastic, partly or fully solid silicone cautschuc or silicone gum.
Silicones are produced by hydrolyzing alkyl-substituted halogenated silanes or mixtures thereof. For example, according to the method disclosed in published European Patent Application no. 980 885, the mixture of trimethylchlorosilane and dimethyldichlorosilane is hydrolyzed in the presence of aqueous hydrochloric acid solution. In the process, a mixture of silicone polymers is formed which is purified and fractionated by distillation.
The use of silicones in the medicine has been formerly set back due to the problems of manufacturing silicone compounds in sufficient purity and at an affordable cost for medicinal purposes. For example, silicone oils used in the ophtalmology were often contaminated with the monomer or oligomers, which impaired product quality and raised health issues as well. Highly volatile silicone oils comprise a group of silicone oils. Highly volatile silicone oils are cosmetical or pharmaceutical excipients which are volatilized from the human skin within a 6-hour period after application to the skin and their quality is suitable for the manufacture of pharmaceutical formulations.
The use of silicones having different degree of polymerization during the formulation of cosmetical and pharmaceutical formulations as well as nutrients is known according to the state of the art. Oils as well as cautschucs of high molecular weigh are used as a vehicle or a film- forming agent. Silicone oils are applied as dispersing or stabilizing agents.
According to the present invention, there are provided antiseptic or disinfectant formulations, which contains elemental iodine and siloxane vehicle as well as optionally further active agents or excipients. The disinfectant and antiseptic iodine-containing formulations may appear mainly in three forms.
Rapidly evaporating formulations (e.g. aerosol, tincture, solution, foam) has the common feature that the iodine-containing solution acts within seconds and evaporates from the surface within 1 minute. Such formulations can be presented, for example, in the form of aerosol, tincture, solution or foam, which are suitable for the antiseptic or disinfective treatment of easily or less easily accessible surfaces (e.g. aerosol, tincture, solution) or cavities (aerosol, foam). Preferably, the formulations according to the present invention are used as an antiseptic for the treatment of an injury of the body surface or treatment of body cavities. Such rapidly evaporating formulations are suitable as a medicinal antiseptic, antiseptic for first aid and for treating small injuries. These formulations evaporate from the skin rapidly and without staining the body or the clothing.
Formulations having medium-term permanent effect are characterized by releasing iodine to the surface at least for the period of one minute but not longer than 1 hours. After releasing iodine, the formulation is evaporated from the surface or, if desired, it can be washed away. These formulations are effective within few minutes.
Formulations having sustained effect (solution, tincture, cream, gel, ointment, paste, powder, suppository, stick etc.) are effective for a period longer than one hour and can be removed from the site of the antiseptic or disinfectant treatment by washing.
We have surprisingly found that the solution of iodine in a siloxane solvent according to the present invention is stabile for indefinite period of time unlike the ionic and complex forms wherein elemental iodine responsible for disinfectant and antiseptic effect is formed during decomposition. The stability of the formulation according to the present invention is limited by the evaporation through the packaging material, unlike the iodine-containing formulations known from the prior art which are heat sensitive and due to their instability, they loose their efficacy soon. We have furthermore surprisingly experienced that the formulation according to the present invention does not cause any stinging, irritating sensation, tissue damaging effect or any other discomfort. The formulation can be easily applied, the use of the formulation according to the present invention prevents sticking wound-treating materials into the wound. Formulations according to the present invention are sterile per se (due to the disinfectant and antiseptic effect of iodine) and preserve sterility in suitable packaging for an infinite period of time.
The formulation according to the present invention in its simplest form consists of iodine dissolved in a suitable siloxane. However, if desired, the formulation can contain further excipients or pharmaceutically active agents. As an excipient, a film-forming agent preventing the access of air and environmental effects to the treated area, thus decreasing the risk of repeated infection. Such film-forming agents include but are not limited to lipophil polymers, preferably a silicone oil, such as dimethicone or a suitable silicone elastomer or organic compounds of higher molecular weight. The formulation can contain a further antiseptic of disinfectant agent, an antibiotic, antiviral or antifungal agent, a cosmetic agent or pharmaceutically active ingredient suitable for the treatment of sound or injured skin surface, e.g. an agent facilitating tissue regeneration or wound healing. Practically there is no limitation with regard to the properties or composition of the siloxane or the mixture of siloxanes used as vehicle. Siloxane products with different degree of polymerization are available for cosmetical or pharmaceutical use. Such individual compounds, products or mixtures thereof can be used in the preparation of formulation according to the present invention.
The rate of evaporation of a formulation according to the present invention depends on the composition of the vehicle, most importantly on the concentration and degree of polimerization of the volatile silicone component. Siloxane derivatives having higher degree of polimerization evaporate slowly and at the same time, act as a film-forming agent providing a iodine-containing film on the treated surface.
Preferable siloxane oligomers are hexamethyldisiloxane, octamethyltrisiloxane and decamethylcyclopentasiloxane.
We have found that the antiseptic and disinfectant formulation according to the present invention comprising iodine dissolved in a siloxane is effective at 0.001 percent by weight iodine concentration against certain microorganisms. The iodine concentration can be chosen according to the intended use between 0.001 percent by weight and the saturation concentration of iodine in the siloxane solvent used. This saturation concentration is in the range of 0.5-0.8 percent by weight for low molecular weight volatile siloxanes and significantly decreases with the increasing molecular weight and degree of polymerization of the siloxane at constant temperature. We have found that formulations according to the present invention having 0.2-0.3 percent by weight iodine concentration show antiseptic effect against all test organisms {Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis) within 0.25-1 minute exposure at room temperature. Consequently, the formulation according to the most preferable embodiment of the present invention contains 0.1-0.5 percent by weight, most typically 0.25 percent by weight iodine. In case of rapidly evaporating formulations, it is advantageous to set the iodine concentration in the higher region of the range due to the shorter exposition time. When a formulation according to the present invention with intermediate or long-lasting effect is intended, it is advantageous to set the iodine concentration in the lower region of the concentration range, taking the longer exposition into account.
The formulations according to the present invention can be produced according to known methods of pharmaceutical technology. Usually iodine and optional other active ingredients or excipients are dispersed or dissolved in the lowest molecular weight siloxane component with continous stirring and the mixture thus obtained is homogenized with the other components of the formulation. Example 1
Fast-acting aerosol formulation containing 0.1 percent by weight iodine dissolved in a siloxanes
Composition
Hexamethyldisiloxane 79.85 g
Octamethyltrisiloxane 19.9 g
Iodine 0.25 g
Iodine is dissolved in hexamethyldisiloxane at room temperature with stirring. Thereafter octamethyltrisiloxane is added. The solution thus obtained is filled into aerosol bottles equipped with a dosing pump and closure.
Example 2
Iodine tincture prepared with a siloxane solvent containing 0.1 percent by weight iodine (intermediate effective period)
Composition
Octamethyl-trisiloxane 98.75 g
Dimethicon 1.0 g
Iodine 0.25 g Iodine is dissolved in octamethyltrisiloxane at room temperature with stirring. Thereafter dimethicone is added and dissolved. The solution thus obtained is filled into bottles with a spreading or dropping accessory and closure.
Example 3
Lipogel containing 0.1 percent by weight iodine in siloxane
(prolonged effect)
Composition
Octamethyltrisiloxane 9.75 g
Mixture of silicone elastomer and
Decamethylcyclopentasiloxane
(e.g. Dow Corning ST Elastomer 10) 90.0 g
Iodine 0.25 g
Iodine is dissolved in octamethyltrisiloxane at room temperature with stirring. The solution is admixed to the gel base and homogenized at room temperature. The gel thus obtained is filled into plastic tubes or jars and closed.
Example 4
Test of bacteriostatic efficacy
The bacteriostatic efficacy test of the formulations according to the present invention was carried out in a mixed culture of Escherichia coli (ATCC 8739, American Type Culture Collections, Manassas, Virginia, USA) Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538) and Bacillus subtilis (ATCC 6633) strains. The mixture of the culture of the strains after 24 hours incubation was used in the tests (incubation temperature: 36 °C). Experiments were carried out aseptically. 5-ml aliquots of the test (formulation according to the present invention having 0.05-0.5 percent by weight iodine content), and control preparation (Betadine solution containing 100 mg/ml povidone-iodine having 10 mg/ml iodine concentration) were transferred into 3-3 sterile test tubes using sterilized pipettes.
100-μ1 portions of the mixed culture of the bacteria were added to each test tubes. The suspension thus obtained was thoroughly mixed. The measurement of exposition time was started, and a portion of each bacterium suspension treated with a disinfectant test and control preparation were inoculated after 1, 3, 5, 7, 10, 15, 20, 25 and 30-min exposition time into Caso Broth medium (MAST) containing neutralizing component. During the preparation of subcultures, 10-ml portions of Caso Broth medium were used, which are supplemented by 1 ml of 20 percent by weight sodium thiosulfate solution as a neutralizing component (in order to stop the bacteriostatic effect of the tested disinfectant).
Subcultures were incubated at the temperature of 36 °C for 72 hours. Subcultures wherein the propagation of the bacteria was observed, were inoculated for the second time into fresh medium of the same composition and results were read after 48 hours.
As a control solution, a disinfectant solution corresponding to the test (Betadine) was used. Bacterium cultures were checked by inoculating portions of the medium containing the neutralizing component but prepared without test or control disinfectant.
The antiseptic and/or disinfectant effect was deemed to be satisfactory if the proliferation of the bacteria could neither be observed in the primary nor in the secondary cultures. The antiseptic/disinfectant test formulation is judged to be suitable if the bactericide effect occurs after the identical or a shorter incubation period than that observed in the case of the control disinfectant (Betadine).
Example 5
Test of bactericide effect using contact plate method
5.1. Composition of the medium used with contact plates
Sterile contact plates are prepared using the medium of the following composition:
Casein digested with pancreatine 15.0 g
Soybean peptone 5.0 g
Sodium chloride 5.0 g
Agar 17.0 g
Lecithin 0.7 g
L-histidine 1.0 g
S orbitan-monooleate 5.0 g
Tween 80 2.0 ml pH: 7.3±0.2
5.2. Test method
0.1 -ml portions of the mixed bacterial culture according to Example 4 (after 24-hours incubation time) were transferred onto 3-3 contact plate and were allowed to dry.
As positive control, 3 plates were incubated at the temperature of 36 °C. 3-3 plates are treated with 0.2-ml aliquots of the test formulation according to the invention and further 3 plates were treated with the same volume of Betadin solution. All aliqouts were dispersed evenly on the surface of the plate. Plates were incubated for 72 hours at the temperature of 36 °C.
5.3. Evaluation
After the incubation period, the number of colonies were counted on each plate treated with the test preparation and the results were compared to those obtained with that obtained from the plate treated with Betadine solution. The initial colony number is calculated as the average of the number of colonies obtained with the positive control. If the number of the colonies can not be counted due to formation of continuous layer of bacteria, the test is repeated using a diluted bacterial culture.

Claims

What we claim is:
1. Use of the solution of elemental iodine prepared with an organic siloxane-type vehicle and optionally containing further excipients or pharmaceutically active ingredients as disinfectant or as antiseptic agent.
2. Use of the solution of elemental iodine prepared with an organic siloxane-type vehicle for the manufacture of disinfectant or antiseptic pharmaceutical preparations.
3. Disinfectant or antiseptic pharmaceutical formulation, which comprises elemental iodine as active agent and a siloxane or a mixture of siloxanes as vehicle optionally in admixture with further pharmaceutically active ingredients or excipients.
4. Formulation according to claim 3, characterized in that the vehicle is a volatile siloxane or a mixture of such compounds.
5. Formulation according to claim 3, characterized in that the vehicle comprises a volatile siloxane or mixture of such compounds, a silicone oil or a silicone elastomer component or a mixture thereof.
6. The use according to claim 1, characterized in that the elemental iodine concentration in the solution thereof prepared with a siloxane-type solvent is 0.001-0.8 percent by weight, preferably 0.1-0.5 percent by weight, the most advantageously 0.2-0.3 percent by weight.
7. A formulation according to any of claims 3 to 5, characterized in that the concentration of elemental iodine in the formulation is 0.001-0.8 percent by weight, preferably 0.1-0.5 percent by weight, the most advantageously 0.2-0.3 percent by weight.
8. A formulation according to any of claims 3 to 5, characterized in that the siloxane vehicle is hexamethyldisiloxane, octamethyltrisiloxane, decamethylcyclopentasiloxane or a mixture thereof.
9. A formulation according to any of claims 3 to 5 in a form of aerosol, solution, gel, tincture, cream or foam.
10. A formulation according to any of claims 3 to 5, characterized in that the formulation contains further excipients.
11. A formulation according to claim 10 comprising as a further ingredient a film-forming agent, preferably silicone oil or silicone elastomer, preferably dimethicone.
12. Formulation according to any of claims 3 to 5, characterized in that the formulation contains further pharmaceutically active ingredients, preferably a further antiseptic or disinfectant agent, an antibiotic, a cosmetic agent suitable for the treatment of healthy or injured skin, a pharmaceutical active ingredient, preferably a tissue regenerating or an agent facilitating wound healing.
13. Method for the preparation of formulations according to any of claims 3 to 5, which comprises dispersing or dissolving elemental iodine in the siloxane component of the lowest molecular weight used in the formulation and homogenizing the mixture thus obtained with the further ingredients of the pharmaceutical formulation.
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WO2012007776A3 (en) 2012-06-07
HUP1000362A2 (en) 2012-11-28
UA109144C2 (en) 2015-07-27
EA201390090A1 (en) 2013-05-30
HU1000362D0 (en) 2010-10-28

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