DE2537303B2 - Sterile aqueous solution for the delivery or distribution of available iodine and its use - Google Patents

Description

The invention relates to sterile aqueous solutions for the delivery or distribution of available iodine contained in an iodophore is contained at a controlled rate.

The use of iodine as a germicide, to disinfect drinking water or swimming pools, as a therapeutic agent against viruses, bacteria, spores, yeast, mold, protozoa, fungi, worms or nematodes is known. Iodine has a relatively low tissue toxicity, but it is very irritating and a sensitizer. Furthermore, it not only destroys bacterial protein, but to some extent Grade also animal protein, has an unpleasant odor and causes stains.

It is known that iodophores generally increase the bactericidal activity of iodine while they act as the Reduce vapor pressure and odor. They also reduce the staining and irritation caused by bo Iodine and allow strong dilutions with water. The term "iodophor" is used to denote a Designate product in which surface-active agents act as carriers and solubilizing agents for iodine works. These include high molecular weight materials such as starch and various synthetic polymers, such as, for example, polymeric vinyl acetate and high molecular weight alkylene oxide condensates with surface-active substances Properties such as polyvinylpyrrolidone, polyvinylimidazole, Polyvinyl morpholone, polyvinyl caprolactam, polyvinyl alcohol and ethylene and propylene oxide condensates with alcohols, amides and phenols (see DE-OS 19 65307).

An iodophore as an antiseptic is obtained from iodine, potassium iodide and polyvinyl alcohol in an aqueous solution Solution (see Mokhnach "Iodine-High Polymers and Their Use in Medicine and Veterinary Medicine" [Boton. Inst im. Komarova, Leningrad] Iodinol Med. Vet Eksp. KHn. Issled. Akad. Nauk. SS.S.R. Bot inst). These iodophores are effective, but not stable enough and have a limited shelf life

The problem underlying the invention was now to get an aqueous solution that is suitable for the sterilization of contact lenses and for this purpose dispensing iodine at a controlled rate or is able to distribute acts as an antimicrobial protective agent and has good tissue tolerance

The sterile aqueous solutions according to the invention are characterized in that they

a) 0.01 to 5% by weight of sorbic acid or a soluble one Salt of the same and

b) contain 0.01 to 5 wt .-% ethylenediaminetetraacetic acid or a soluble salt thereof.

The remainder of the composition can either consist of water alone or various others Include components that serve special purposes. For example, the solutions can be different Contains alkali and alkaline earth salts of mineral acids to improve the osmotic properties (tonicities) adjust the solutions so that they are better tolerated by living tissue.

The solutions preferably contain 0.1 to 2% by weight of an ammonium, alkali or alkaline earth metal salt of a boroxy acid or boron oxygen acid, which gives the solutions improved stability. They expediently have a surface tension of about 40 to 72 dynes / cm ² .

The aqueous solutions according to the invention are useful for sterilizing prostheses and diagnostic equipment, especially contact lenses. They can be used as contact lens rinsing and cooking solutions or used as eye moisturizing solutions. However, they are particularly suited to the Maintain sterility for long periods of time. They are particularly cheap for sterilization and Disinfect soft, hydrophilic gel lenses. They have high tissue compatibility. Preferably there is the iodophore used in connection with the invention from 0.00005 to 10.0% by weight iodine, 0.0001 to 20.0% by weight of a water-soluble iodide salt and 0.001 to 25.0% by weight of polyvinyl alcohol.

The mechanism of distribution of the available iodine through the solution according to the invention is not known. Sorbic acid or its water-soluble salts and ethylenediaminetetraacetic acid or its water-soluble salts in an aqueous vehicle can imbibe iodine at a predetermined rate Destroy the area from 1 to 300 minutes, depending on the iodine concentration in the added iodophor solution, the concentration of the components in the solution, the pH value and the temperature. The solution can be Have a pH in the range of 2 to 10, with the release or distribution of the available iodine all the more so The higher the pH value, the faster it is. Preferably the pH is adjusted to about 7.0 by

a base, such as NaOH, adds an increase in temperature The rate of distribution or delivery also increases above room temperature. The solution can be conveniently used in amounts of 1 to 1000 parts by weight each Part by weight of available iodine can be used in the iodophor.

The solutions according to the invention preferably contain about 0.1 to 2% of an ammonium, alkali or alkaline earth metal salt of a boroxy acid or boron oxygen acid. Suitable salts are those of boric acid (H3BO3), metaboric acid (HBO ₂ ) and pyoboric acid (H ₂ B ₄ O ₇ ). Specific examples of suitable salts are, for example, borax (Na ₂ B ₄ O ₇ · 1 OH ₂ O),

Sodium tetraborate (Na ₂ B ₄ O ₇ ),

Sodium tetraborate pentahydrate

(Na ₂ B ₄ O ₇ · 5H ₂ O),

Sodium metaborate (NBO ₂ 4H ₂ O),

Potassium metaborate (KBO ₂ ),

Potassium tetraborate (K ₂ B ₄ O ₇ · 5 H ₂ O),

Lithium metaborate dihydrate (LiBO ₂ 2 H ₂ O),

Lithium tetraborate (Li ₂ B ₄ O ₇ · 5 H ₂ O),

Calcium metaborate [Ca (BO ₂ ) ₂ ]

and hydrates of the same,

Calcium tetraborate (CaB ₄ O ₇ ),

Magnesium orthoborate (3MgO · B ₂ O ₃ ),

Magnesium metaborate [Mg (BO ₂ J ₂ · H ₂ O],

Magnesium Pyroborate (Mg ₂ B ₂ Os H ₂ O),

Lithium metaborate (LiBO ₂ 8 H ₂ O),

Lithium tetraborate (Li ₂ B ₄ O ₇ · 5H ₂ O),

Ammonium tetraborate [(NH ₄ J ₂ B ₄ O ₇ · 4 H ₂ O] and

Ammonium pentaborate [(NH ₄ ) ₂ BioOi6 · 8H ₂ O].
Sodium borates are preferred. It should of course be noted that the hydrates identified above do not exist as hydrates in solution.

It is often desirable to add up to about 2.0% by weight of a water-soluble alkali or alkaline earth metal salt of a mineral acid to the solution in order to adjust the osmotic properties (tonicities) of the solutions and thus to make the solutions more compatible with living tissues. Salts of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid are useful, such as NaCl, KCl, CaCl ₂ , MgCl ₂ and the corresponding phosphates, nitrates and sulfates.

Solutions according to the invention are suitable for use with a variety of iodophores. Typical examples of commercially available iodophores that can be used here are polyvinylpyrrolidone / Iodine, nonylphenol ethoxylate / iodine, soluble starch / iodine, jJ-cyclodextrin / iodine, polyoxyethylene polyoxypropylene condensate / iodine or ethoxylated linear alcohol / iodine. Iodophores derived from an aqueous one are suitable antiseptic solution consist of that

a) about 0.00005 to about 10% by weight iodine,

b) about 0.0001 to about 20% by weight of a water soluble Iodide salt,

c) about 0.001 to about 25 weight percent polyvinyl alcohol; and

d) contains from about 0.001 to about 10% by weight boric acid.

Such iodophor solutions have a broad spectrum of germicidal, fungicidal, virucidal and hygienic ones Properties combined with a high degree of stability. It turned out, however, that such Solutions have greater germicide, fungicide, virucide and sanitizing properties if the Boric acid is omitted from the solutions. The resulting slight loss of stability is compensated by the solutions according to the invention

Accordingly, the solutions according to the invention are preferably used in connection with iodophores, which do not contain boric acid.

The preferred iodophores used contain about 0.00005 to 10 wt%, and more preferably about 0.002 to about 5 weight percent iodine. The solutions can be prepared and subsequently in the form of concentrates be diluted to the concentration desired for the particular use, typically 5 up to 100 ppm available iodine. The dilution can be done with purified water or with the inventive Solution take place.

The iodophor compositions, in dilutions of up to 1: 200,000 available iodine, destroy all vegetative forms of bacteria within 15 minutes.
Preferably, the aqueous iodophoric antiseptic solutions also contain from about 0.0001 to 20% by weight, and more preferably from about 0.004 to about 10% by weight of a water-soluble iodide salt. Potassium iodide is preferred, but any other known soluble iodine salts such as sodium iodide or hydriodic acid can also be used. The iodide salt supports the initial solubilization of the iodine and simplifies the production of the finished solutions.

In solution, the iodide ion reacts with the iodine according to the known reaction equation

I ₂ + r - » K-

The resulting triiodide ion is water-soluble and leads to the use of the solution according to the present invention

J5 Invention of free iodine. Maybe that make Boric acid and the polyvinyl alcohol complexes I2 or Ij-.

A variety of polyvinyl alcohols in amounts from about 0.001 to 25 weight percent, and preferably about

0.1 to 20% by weight can be used in the iodophores will. Polyvinyl alcohols are synthetic water-soluble resins that are used in controlled polymerization of vinyl acetate and the partial or complete hydrolysis of the polyvinyl alcohol.

• r> When the polyvinyl alcohols dissolved in water they result in solutions with a pH value in the range from 5 to 8. Maximum stability is obtained with an acidic pH. Depending on the concentration and the specific polyvinyl alcohol used, the

μ Viscosities of the iodophor solutions in the range of 1.1 can be varied up to 10,000 cp at 20 ° C.

Polyvinyl alcohols can be represented as follows:

OH

CH ₃ -C-CH ₂
H

Il

0-C-CH ₃

C-CH ₂

"OH

The "X" and "Y" refer to the relative number of free hydroxyl groups and acetylated groups in the ii5 resin chain. Polymers that are completely polymeric with about 25.0% acetate groups hydrolyzed are particular in the compositions of the invention suitable.

A particularly suitable polyvinyl alcohol is 88.0 to 90.0% hydrolyzed and has a volatile content Components of up to 5.0%. A 4.0% solution of these materials in water has a viscosity of 5 cp at 20 ° C

In order to improve the stability, it is desirable to adjust the hydrogen ion concentration of the iodophore solutions to the pH range from about 3 to 8 and preferably from 3 to 7, especially from 3.5 to 7.0. Any poorly oxidizable acid can be used to adjust the pH, such as H ₃ PO ₄ , HCl, acetic acid, H ₂ SO _4, or nitric acid.

In certain applications it is desirable to adjust the osmotic properties of the iodophor solution. Tonicities corresponding to 0.1% to 5.0% aqueous sodium chloride solution are desirable in order to make the aqueous iodophor solution better compatible with living tissues. The osmotic properties can be adjusted by adding suitable amounts of alkali and alkaline earth salts of mineral acids, such as NaCl, KCl, CaCl ₂ , MgCl ₂ and the corresponding phosphates, nitrates and sulfates.

The wetting and cleaning properties of the iodophor solution can be increased by the addition of conventional neutral anionic, cationic and nonionic detergents are improved. Numerous Examples of suitable detergents are known in the art. Detergents can be used in amounts of up to 25.0% by weight can be added. In the solution, the iodine forms complexes with the polyvinyl alcohol and the various compounds, such as the water-soluble salts, which at least partially ionize.

The iodine availability and stability of the iodophor solutions can be adjusted by direct titration with Sodium thiosulphate solutions are determined. This classic redox reaction is known to those skilled in the art Field of Jcdchemie known.

The solutions according to the invention are particularly useful in combination with iodophor solutions Sterilizing all types of contact lenses prior to application to the cornea of Hydrophilic soft gel lenses have particularly severe microbial contamination problems. Hydrophilic gel contact lenses, those made from hydroxyethyl methacrylate or with various crosslinking and plasticizing agents Agents that have been co-polymerized can absorb up to 80.0% cold water. These lenses also absorb and bind a large number of low molecular weight organic molecules from their environment they complex, and such organic molecules can serve as nutrients for microorganisms. Because of this sterilization is essential.

Chemical sterilization of hydroxyethyl methacrylate lenses with conventional sterilization solutions resulted in big problems. Namely, such lenses form complexes with most of the conventional ones Sterilizers such as benzalkonium chloride, chlorhexidine gluconate, thimerosal sodium, chlorobutanol, and Phenyl mercury acetate. The possibility of chemical burns to the cornea with lenses made with treated with these conventional preservatives practically precluded their use. The cooking such lentils is not a satisfactory method of sterilization because it is insufficient before cooking removed eye mucus in the lens is denatured, resulting in loss of lens clarity, causing discomfort and possibly leads to the destruction of the lens. Autoclaving of the lenses is also disadvantageous, as this leads to some physical change in lens geometry and lens porosity An aqueous solution that is particularly suitable for the sterility of prostheses such as contact lenses, to maintain, can be prepared by adding 1 to about 10 wt .-% of an aqueous iodophoric acid, like the aqueous iodine-iodized salt-polyvinyl alcohol-iodophor solution described above, with about 90 to about 99

ίο% by weight of the sterile aqueous solution mixed according to the invention Prostheses, such as contact lenses, can be sterilized by first treating them with the iodophor and then adding the sterile aqueous solution according to the invention. The available iodine in the iodophoric solution sterilizes the prostheses. After sterilization by releasing the available iodine, a solution is obtained that maintains the sterility of the treated prostheses. The lenses are expediently washed with water and 4 to 6 drops of an iodine-potassium iodide-polyvinyl alcohol iodophore and placed in a lens container. 6 ml of the solution according to the invention are added to the container and the container is shaken. In about 15 minutes the solution in the lens container loses its distinct iodine color. The iodine is consumed by the lenses within 1 to 2 hours, a maximum of 6 to 8 hours, and the lenses can then be rinsed and reinserted into the eyes. Lenses treated in this way were found to be sterile.

Unless otherwise indicated in the following examples, all percentages are percentages by weight.

example 1

The following solution A is an example of an iodophor composition:

The above composition can be prepared in such a way that the boric acid is about 85% of the total water content dissolves. The polyvinyl alcohol is dissolved in the boric acid solution, whereby one the dissolution is assisted by heating and stirring, and the resulting solution is allowed to cool. The iodine and potassium iodide are in 5 to 10% by weight of the total water content dissolved and added to the cooled polyvinyl alcohol-boric acid solution. Of the The pH is then adjusted and the remaining water is added.

A second solution B was made according to the following recipe:

Solution B was sterilized by heating. Eight different hydrophilic soft gel lenses, a pair of flexible silicone lenses and 2 pairs of conventional polymethyl methacrylate lenses from contact lens manufacturers were in the transfer signal of the

iodine 0.1% Kaiium iodide 0.2% Polyvinyl alcohol 2.5% Boric acid 0.5% Purified water, q.s. to 100%

Sorbic acid 0.1% Trisodium edetate 0.1% Sodium chloride 0.75% Potassium chloride 0.20% 5% sodium hydroxide solution to the to adjust the pH value 7.4O / o Purified water, q.s. to 100%

Contact lens cleaning and storage devices according to the US-PS 35 19 005 and 36 45 284 inserted. 4 ml of solution B was added to each part. 3 to 6 Drops of Solution A were added to each part and the test lenses were placed in the solution to disinfect submerged. Some of the lenses initially turned yellow due to their ability to use up the available iodine focus. In these cases lower levels (3 to 4 drops) of solution A bring the Initial iodine intake to a minimum. In all cases the iodine was removed from the resulting solution in 1 consumed up to 6 hours. At the end of this time there were no visual or measurable adverse effects noted on the lenses. The experiment was repeated several times with practically the same results.

Representative contact lenses were attached to rabbit corneas after changing them long (1 minute to 8 hours) mixtures of solutions A and B in the above proportions had been exposed. There were no adverse effects. Solution A was taken directly into rabbit eyes dropped without any adverse effects being found.

Representative lenses were deliberately mixed with actively growing cultures of Staphylococcus aureus, Streptococcus pyogenes, Escherichia coil, Pseudomonas aeroginosa and Candida albicans contaminated before they Mixtures of solutions A and B were exposed for different times. As little as 3 Drops of solution A added to solution B (resulting in a concentration of available iodine equivalent of about 0.003 wt%) resulted in complete kill within 30 minutes.

Representative soft hydrophilic gel lenses, conventional polymethyl methacrylate lenses and silicone lenses, which were adapted to the human cornea were treated with solutions A and B and resulted in initial levels of available iodine ranging from 0.003 to 0.01% for a period of 2 Hours to 12 hours. These lenses were then worn by test subjects without any adverse effects occurred.

Example 2
The following iodophor solution C was prepared:

Iodine 0.1%

Potassium iodide 0.3%

Polyvinyl alcohol 2.0%

Sodium chloride 0.7%

Purified water, q.s. to 100%

The solution was made following the procedure of the example

Tabel

Disinfecting effectiveness of solution C in solution D 1 established, but with the exception that the step (of dissolving boric acid before dissolving the polyvinyl alcohol was omitted. Then, hydrochloric acid was added to the solution to adjust the pH to 4.

A second solution D was made according to the following recipe:

Sorbic acid 0.1% Disodium edetate 0.1% Sodium chloride 0.6% Potassium chloride 0.2% Sodium borate 0.2% Purified water, q.s. to 100%

Suspensions of the test organisms, which are listed in the table below, were Herge and adjusted so that they contained an end population of about 1 10 ⁵ cells per milliliter of the end liquid volume. 7 drops of solution C were added to sterile contact lens cases, and hydrophilic soft gel lenses were placed in the cones. > 10 ml of inoculum was then added to the housings. 7 ml of solution D were the housing! added, which were then closed and shaken over an arc of 30 cm for 60 seconds and exposed to normal room for 6 minutes. Most of the iodine color had disappeared from the solution. It was inoculated and treated as above, with the exception that it was physiological

jo saline solution was used in place of solutions C and E.

The experiments on each organism were carried out in triplicate. After the 60 minutes while dei was exposed to normal room light, the entire contents of the housing were aseptically in 40 m tryptic soy broth (TSB) or thioglycolate broth (THlO), which contained neutralizing agents, and sterile blood was incubated for 14 days at the optimal growth temperature of the test organism added to the culture media used for growing N genorrhea, Heamophilus influencae, Moraxella sp. and / Miemolytic streptococci were used These cultures were subcultured on blood agar media after 1, 2, 7 and 14 days of incubation transferred to determine the status of organism viability as the growth in the broth media was not detectable by the added blood.

The results of these experiments are shown below Table compiled As can be seen, solution C in solution D is very effective Disinfect soft contact lenses. Bacterial spores survived the exposure.

Test organism Vaccine cells medium Days after of vaccination when 2 3 the first ml (X ΙΟ ⁵ ) growth was observed NG ¹ ) NG Attempt no. 1 1 Positive 1 2 2 control Bacillus cereus (veg.) 2.8 TH 10 ² ) 2 1 1 1 Bacillus cereus (Spores) 1.7 TSB ³ ) 1 NG NG 1 Bacillus subtilis (veg.) 2.57 THlO 2 1 Bacillus subtilis (Spores) 2.8 TSB 1 1 Escherichia coli 1.8 THlO NG 1

continuation

10

Tistorgjnismus Vaccine cells medium Days after of vaccination when 7th 3 the first ml (x 10 ¹ ) growth was observed NG NG Attempt no. NG NG Positive I. NG NG control Proteus mirabilis 1.41 TH 10 NG NG NG 1 Proteus vulgaris 1.8 TH 10 NG NG NG 1 Pseudomonas aeroginosa 1.5 TH 10 NG NG NG 1 Serratia marcescens 2.2 TH 10 NG NG NG 1 Staphylococcus aureus 3.28 TH 10 NG NG NG 1 Staphylococcus epidermidis 6.5? TH 10 NG NG NG i Aspergillus niger 2.14 TSB NG NG NG 5 Fusarium solanti 3.28 TSB NG NG NG 3 Candida albicans 6.92 TSB NG NG NG 1 f.hn'in \ a parapsilosis 3.57 TSB NG NG NG 1 NtiSi'jria gonorrhea 3.93 TH 10 / B ") NG NG NG 2 f'ropionibactcrium acncs 1.27 TH 10 NG NG NG 3 Haemophilus influenz ^ e 1.85 TH 10 / B NG 2 Moraxclla species 3.42 TH 10 / B NG 1 Λ-hemolytic streptococci 1.53 TH 10 / B NG 2

') NG = no growth after incubation for 1 days.

² ) TH 10 = thiogiycolate broth.

³ ) TSB = tryptic soy series.

⁴ ) TH 10 / B = thiogiycolate broth supplemented with blood.

Claims (6)

Patent claims: 1. Sterile aqueous solution for the delivery or distribution of available iodine, which in a Iodophor is contained at a controlled rate, characterized that they a) 0.01 to 5 wt .-% sorbic acid or a soluble salt thereof and b) 0.01 to 5% by weight of ethylenediaminetetraacetic acid or a soluble salt thereof 2. Solution according to claim 1, characterized in that it contains 0.1 to 2 wt .-% of an ammonium, Contains alkali or alkaline earth metal salt of a boroxy acid or boron oxygen acid 3. Solution according to claim 2, characterized in that it contains sodium borate as the salt 4. Solution according to claim 2 and 3, characterized in that it contains up to 2 wt .-% of one contains water-soluble alkali or alkaline earth salt of a mineral acid 5. Solution according to claim 1 to 4, characterized in that it is a mixture a) from 1 to 10 wt .-% of an aqueous iodophor solution with 0.00005 to 10 wt .-% iodine, 0.0001 to 20% by weight of the water-soluble iodide salt and 0.001 up to 25 wt .-% polyvinyl alcohol and b) 90 to 99 wt .-% of a sterile aqueous solution with 0.01 to 5 wt .-% sorbic acid or jo of a soluble salt thereof, 0.01 to 5 wt .-% ethylenediaminetetraacetic acid or a soluble salt thereof and 0.1 to about 2 wt ° / o of an ammonium, alkali metal or alkaline earth metal salt of an η Boroxysäure or Borsau- erstoffsäure comprises 6. Use of a solution according to claim 5 for the sterilization of contact lenses.