Classifications

• • 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
  • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2103/00—Materials or objects being the target of disinfection or sterilisation
  • A61L2103/05—Living organisms or biological materials

Definitions

• This invention is related to production method of a hydrogel in which antimicrobial effect is enhanced thanks to formation of polyvnylprolydone-iodine (PVP-I) containing nascent iodine in spite of reduced polyvnylprolydone (PVP) ratio as compared to its equivalents containing PVP-I.
• PVP-I polyvnylprolydone-iodine
• PVP polyvnylprolydone-iodine
• iodine was a valuable medicament and superior antimicrobial with its extraordinary effective range. Human body needs this element and iodine deficiency results in goiter disease. Since a long time, iodine solutions are used as wide-spectrum bactericide agents having effect on a wide range of microorganisms such as gram positive and negative bacteria, yeast, viruses and fungi. Iodine forms in certain oxidation situations including wholly degraded iodide ( ⁇ ), oxidation diatomic free element (I 2 ), and certain high oxidation conditions combined with oxygen (for example hypo-iodate (10 ), iodate (IO 3 ) and periodate (I0 4 ⁇ )).
• ⁇ wholly degraded iodide
• I 2 oxidation diatomic free element
• I0 4 ⁇ certain high oxidation conditions combined with oxygen
• iodide forms the efficiently dissolving tri-iodide (I 3 ) balance complex in the form of elemental iodine and in bonded iodine form with no antimicrobial activity.
• I 3 tri-iodide
• iodine It is difficult to process iodine in its free form as it enters into chemical reaction with certain substances in and out of the body. It is also volatile and it sublimates in the atmosphere. Iodine dissolves in pure water only slightly and but if water contains iodide or iodine salt composed of poly-iodine and iodine, iodine will dissolve easier. Iodine must be in dissolved state in order that it can be used for forming useable solutions. There are many dissolution approaches and some of them are given below. First of all, Lugol's solution made in 1829 was a water based solution containing 1-5% iodine and 5-10% potassium iodine.
• Alcoholic solution of elemental iodine in the form of iodine tincture containing 2-7% molecular iodine was accepted as the most effective bactericide combination for a very long time.
• Lugol's solution and iodine tincture fell out of favor in the recent years due to the fact that they tend to cause chemical burns and tissue colorations and because of their relative instabilities, short term effects and characteristic odors. These solutions may cause swelling and bleeding of mucous membrane and they will be highly toxic when they contact with the bruises on the body.
• one 1% iodine tincture solution might release extra 10000 ppm iodine powder. For that reason diluted concentrations are recommended.
• Iodophors are known as products forming through complex formation of iodine with polymers.
• Complex agents used for that purpose are polyvnylprolydone (povidone or PVP), polyvinyl alcohol, polyurethane, cadexomers (recycled carbohydrate polymer complexes mixed with elemental iodine formulated in polyethylene glycol) and polydextrase (non-digestible polysaccarite.
• PVP-I polyvnylprolydone
• PVA-I polyvinyl alcohol
• polyurethane polyurethane
• cadexomers cycled carbohydrate polymer complexes mixed with elemental iodine formulated in polyethylene glycol
• polydextrase non-digestible polysaccarite.
• Iodophors are free complexes of elemental iodine and tri-iodide. They process iodine to add a continuous oscillation to iodine and serve as a polymeric carrier increasing solubility of iodine.
• neutral and water soluble principal commercial polymers containing PVP were used as carrier.
• PVP is an organic polymer characterized with its colloidal features and physical immobility and it is devoid of natural antimicrobial activity, exhibits high molecular change, and it is non- ionic, non-detergent, water soluble, with extraordinary complex ability. Carriers may also exhibit variable degrees of effect increasing surface activity or dampen the solution in which they are used.
• iodophor complexes are in the form of groped mycelium which is dispersed by water or bodily fluids. Until the iodine gets free to form antimicrobial concentrations, the bonding of iodine with polymer gradually weakens.
• Betadine is available in Swiss market. Contrary to iso-Betadine, Braunol and Betadine are stabilized with NaI0 3. For that reason, hereinafter Betadine will be referred to as standardized Betadine. And on the contrary, iso-Betadine will be referred to as non- standardized iso-Betadine. Lugol's solution contains 170 mg/L free iodine and non- standardized iso-Betadine is concentrated 85,17 and 8,5 times more then standardized Betadine and Braunol respectively.
• these iodine complexes in aqueous solution is less concentrated and can mix better with bodily fluids and disperse relatively faster and as they highly reduce tissue irritation, bad odor, tissue coloring and corrosion on metal surfaces of medical materials, they are preferred to Lugol's solution and iodine tincture.
• Braunol contains 7,5% PVP and 0.75% iodine
• Betadine and iso-Betadine contains approximately 90% water, 8,5-9% PVP and 1% iodine. Since it I not possible with the available production methods to dissolve more elementary iodine iside PVP, PVP/iodine ratio in all of these products remained fixed as 1/10. Severe toxicological restrictions caused by PVP-I complexes when they are used widely on the body can be attributed to high iodine content in their combination since they are absorbed by the body and result in concentrations in the thyroid glands.
• Quantities of iodine and PVP in iodine containing commercial bactericides are a necessary parameter to ensure legal compliance and effect and acceptance by the consumers.
• Primary element in the cost of iodine containing commercial bactericides is costs of iodine and PVP. Since iodine based antiseptics are special chemicals, the cost is critical in terms of product acceptability.
• Nascent iodine production has been investigated in order to resolve the problems inherent in PVP-I complexes.
• the patent document published in 2009 describes a method in which some current was applied between two electrodes placed in a glass container put into an electrolyte bath by using a certain amount of iodine. This effect allowing iodine atom to receive stimulation energy from the magnetic area caused a diatomic bond destroying the iodine molecules.
• the simplest method to produce iodine by nascent reaction is to prepare iodine tincture.
• iodine solution in weight inside ethyl alcohol is immersed in an electrolyte bath composed of copper sulfate, sulfuric acid and zinc chips and copper and nickel alloy anode on which AC current is connected is placed at both surfaces of the glass container.
• an electrolyte bath composed of copper sulfate, sulfuric acid and zinc chips and copper and nickel alloy anode on which AC current is connected is placed at both surfaces of the glass container.
• nano-iodine synthesis was investigated by using chemical design in back-bone structure that can dissolve in nature and allows production of minimum two populations of nano-iodine containing chemical compounds.
• First population of the particles might contain one pH buffer, additional compounds containing iodate (IO 3- " ) and iodide ( ⁇ ).
• Second population of particles might contain those components that would create a micro-frame in the range of 5 ⁇ pH ⁇ 6 which surrounds the first population of particles immediately.
• a and B particles populations are maintained in dry condition. Particles are dispersed evenly and they do not contact with each other in dry state. In tile antimicrobial medium is achieved while I 2 is created.
• This dressing product could be applied only to single or double layered stupe and it activated when it start to touch wound fluid. For that reason, this process may be applied only on antibacterial stupe and cannot be produced in liquid or gel form which restricts its application.
• Purpose of the invention is to find a production method for iodophor based antimicrobial hydrogel where polyvinylprolydone (povidone) and iodine complex in nascent and/or nano form.
• polyvinylprolydone povidone
• iodine complex in nascent and/or nano form.
• Another purpose of the invention is to find a production method for an iodophor based antimicrobial hydrogel that reduces skin irritation thanks to its lower iodine and PVP content as compared to the traditional antimicrobial iodophors.
• Another purpose of the invention is to find a production method for an iodophor based antimicrobial hydrogel that exhibits better and longer antimicrobial effect as compared to the traditional PVP-I complexes thanks to the use of iodine in nascent form in spite of its low PVP and iodine content.
• Another purpose of the invention is to find a production method for an iodophor based antimicrobial hydrogel that that could be used also as a solution with the addition of alcohol in it.
• Figure- 1 Flow chart of the invented method
• Figure-2 The table indicating the ratio of the components of the samples prepared by the invented method.
• Figure-3 The table comparing antibacterial efficiencies of the main samples prepared by the invented method and control samples.
• PVP polyvinylpyrrolidone
• the acid solution prepared in this manner is added preferably drop by drop into the PVP and iodine containing mixture and is mixed at the same time (104). Mixing process is done by using magnetic mixer and mixing process is continued until viscosity of the solution increases to such level that it would be difficult to mix it. Reactions occurring one after the other in this step are as follows.
• hydrogel composed of PVP and nascent iodine complex (PVP-I) is obtained (105).
• Optimum components of the antimicrobial hydrogel produced by the invented production method (100) will be 1,2% iodine and 4.4% PVP.
• Low pH medium, i.e. abundance of H + ions in the medium has great importance for continuous movement of A reaction toward right. For that reason, preferred pH is between 4 and 6. If pH gets higher in the medium, H + ions are consumed faster and as a result, the reaction is slowed down.
• acid quantity in step 104 might be used in excess up to 40% of stoichiometric need.
• Acid quantity must be kept optimum because making the medium more acidic would not greatly enhance antimicrobial activity of the end product and besides, excessively acidic medium would cause skin irritation.
• a and B reactions stay in balance during the production phase and during the shelf life of the product produced by the invented method (100).
• quantity of KI0 3 used in step 101 must exceed stoichiometric need by minimum 10% and PVP quantity must be as low as possible so that it could cover all surface of iodine that will be released during the reaction. In this manner, the compound can be produced economically and retains its consistency as viscous gel.
• ratios of stoichiometric component required so that antimicrobial hydrogel prepared by the invented method (100) would contain 1.2% nascent iodine would be 0.33% KIO 3 , 1,3% KI and 1,8% acid in weight.
• maximum 2.5% citric acid and 0,36% KIO 3 in weight are used in order to ensure continuity of A and B reactions.
• Hydrogel product obtained by the invented method (100) could be diluted by alcohol in 1: 1 ratio and used as a solution containing 2.2% PVP and 0.6% iodine. The tests run showed that even if the invented hydrogel is diluted with alcohol and used as a solution, it would exhibit better and longer antimicrobial activity as compared to the equivalent products.
• the same procedure is started dissolving citric acid by water and later added PVP to this solution. Finally, the solution contains 0,36 g of KIO 3 , 1,3 g of KI and 10 g of water added to the PVP, citric acid mixture. Mixing is continued by magnetic mixer until the increasing of viscosity of hydrogel has stopped.
• control samples were also compared with another group of samples prepared by molecular iodine and PVP dissolved in water in ratios given in Figure 4 (Al and A7) in terms of antimicrobial activity.
• Al and A7 the results of this comparison are given on a table in Figure 5.
• Agar diffusion method was used to determine antimicrobial activities.
• Each bacterium was infused to nutrient liquid media and yeast was infused to malt extract media and then they were diluted to contain 10 6 -10 7 kob/ml (unit producing colony per millimeter) microorganisms.
• Each bacterium was infused 250 ml into the medium in Erlenmeyer with a temperature of 43-45°C which contained 25 ml of sterile medium (for bacteria, Mueller Hinton agar and for yeast, malt extract agar).
• Agars that were infused with microorganism culture were poured into Petri dishes of 9 cm and after solidification, they were waited for 1 hour in 4°C.

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• 2016
  • 2016-04-27 WO PCT/TR2016/050127 patent/WO2016175727A1/en not_active Ceased
  • 2016-04-27 EP EP16729403.2A patent/EP3341029A1/de not_active Withdrawn

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