DE2537303C3 - Sterile aqueous solution for the delivery or distribution of available iodine and its use - Google Patents

Description

15th

20th

The invention relates to sterile aqueous solutions for the delivery or distribution of available iodine contained in an iodophor is contained, at a controlled 4, rate.

The use of) od as a germicide, to disinfect drinking water or swimming pools, as a therapeutic agent against viruses, bacteria, spores, yeast, mold, protozoa, fungi, worms w or nematodes is known. Iodine has relatively low tissue toxicity, but it is very irritating and a sensitisafor. Furthermore, it not only destroys bacterial protein, but to some extent Degree also animal protein, has an unpleasant y, Odor and 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 staining and irritation from wi 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 polymeric vinyl lactams and horhmolecular ones Alkylene oxide condensates with surface-active 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 65 307).

An iodophore as an antiseptic is obtained from iodine, Potassium iodide and polyvinyl alcohol in an aqueous solution (see Mokhnach »Iodine-High Polymers and Their Use in Medicine and Veterinary Medicine "[Boton. Inst. In. Komarova, Leningrad] lodinol Med. VeL Eksp. KHn. Issled. Akad. Nauk. S.S.S.R. Bot InsL). 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 salt thereof 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 from 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 faster the higher the pH. Preferably the pH is adjusted to about 7.0 by

a base such as NaOH is added. Raising the temperature above room temperature also increases the rate of distribution or delivery. The solution can conveniently be used in amounts of 1 to 1000 parts by weight per part by weight of available iodine in the iodophore.

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 (H ₃ BO ₃ ), metaboric acid (HBO ₂ ) and pyoboric acid (H ₂ B ₄ O ₇ ). Specific examples of suitable salts are such as

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 (N BO ₂ 4H ₂ O), Potassium metaborate (KBO ₂ ), Potassium tetraborate (K ₂ B ₄ O ₇ · 5 H ₂ OX 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 J ₂ ]

and hydrates of the same,

Calcium tetraborate (CaB ₄ O ₇ ), Magnesium orthoborate (3 MgO · B ₂ O ₃ ), Magnesium metaborate [Mg (BO ₂ J ₂ ■ H ₂ Ol 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 · 5 H 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, / I-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) from about 0.001 to about 25% by weight polyvinyl alcohol and

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

Such iodophor solutions have a broad spectrum of germicidal, fungicidal, virucidal and hygienic agents 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 preferably used iodophores contain from about 0.00005 to 10% by weight and more preferably from about 0.002 to about 5% by weight iodine. The solutions can be made in the form of concentrates and then diluted to the concentration desired for the particular use, typically 5 to 100 ppm available iodine. The dilution can be carried out with purified water or with the solution according to the invention.

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 accordingly the well-known reaction equation

+ r

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. Possibly the boric acid and the polyvinyl alcohol form complexes I ₂ or I ₃ -.

A variety of polyvinyl alcohols in amounts from about 0.001 to 25% by weight, and preferably about 0.1 to 20% by weight can be used in the iodophores. Polyvinyl alcohols are synthetic water-soluble Resins used in the controlled polymerization of vinyl acetate and partial or complete hydrolysis Hydrolysis of the polyvinyl alcohol occurs.

When the polyvinyl alcohols are dissolved in water, they result in solutions with a pH of im Range from 5 to 8. Maximum stability is obtained with an acidic pH. Depending on the concentration and the specially used polyvinyl alcohol can

> o 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:

CH, -

- O
I. OH
ι X Il
0 — C — CH,
I. C-CH,
ι C-CH ₂
j I.
H I.
H

OH

The "X" and "Υ" refer to the relative number of free hydroxyl groups and acetylated groups in the I rzkette. Polymers that are fully hydrolyzed to polymers with about 25.0% acetate groups are in the US Compositions according to the invention are particularly 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 use the Hydrogen ion concentration of the iodophore solutions to the pH range of about 3 to 8 and preferably from 3 to 7, especially from 3.5 to 7.0. A poorly oxidizable acid can be used to adjust the pH, such as H3PO4, HCl, Acetic acid, H2SO4 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% strength aqueous sodium chloride solution are desirable in order to make the aqueous iodophor solution better compatible with living tissue. The osmotic properties can be adjusted by adding suitable amounts of alkali and earth metal salts of mineral acids, such as NaCl, KCl, CaCk, MgCl ₂ and the corresponding phosphates, nitrates and sulfates.

The wetting and cleaning properties of the iodophoric solution can be increased by adding 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. This is shown in the solution Iodine complexes with polyvinyl alcohol and the various compounds, such as the water-soluble ones Salts that at least partially ionize.

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

The solutions according to the invention, in combination with iodophore solutions, are particularly useful for sterilizing contact lenses of all types prior to application to the cornea. Hydrophilic soft gel lenses have particularly severe microbial contamination problems. Were Hydrophilic Gelkontaktlinsen, di ^ made of hydroxyethyl methacrylate or copolymerized with various crosslinking and plasticizing agents · ^1, can absorb up to 80.0% of cold water. These lenses also absorb a large number of low-molecular organ ^is cher molecules from their environment and incorporate it ko ⁿ IPLEX, and such organic molecules can serve as nutrients for microorganisms. Therefore a ^ ^: sterilization is essential.

Chorus sterilization of hydroxyethyl methacrylate lenses has posed major problems with conventional sterilizing solutions. Namely, such lenses form Complexes with most of the conventional sterilants, such as benzalkonium chloride, chlorhexidine gluconate, Thimerosal sodium, chlorobutanol, and phenyl mercury acetate. The possibility of chemical Corneal burn 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 ocular mucus in the lens is denatured, resulting in loss of lens integrity, causing discomfort and possibly leads to the destruction of the lens. Autoclaving 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-iodine salt-polyvinyl alcohol-iodophor solution described above, with about 90 to about 99 wt .-% of the sterile aqueous solution after Invention mixed prostheses, like contact lenses, can be sterilized by using them first Treated the iodophore and then add the sterile aqueous solution according to the invention The available iodine

The prostheses are sterilized in the iodophore solution. After sterilization by dispensing the available Iodine gives you a solution 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 washed and placed in a lens case. 6 ml of the solution according to the invention added to the container and the container is shaken. In about 15 minutes, the solution loses in its distinct iodine color in the lens case. This will be done within 1 to 2 hours, a maximum of 6 to 8 hours Iodine is consumed by the lenses and the lenses can then be rinsed and reinserted into the eyes will. Lenses treated in this way were found to be sterile.

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

example 1

J5 The following solution A is an example of an iodophor composition:

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

The above composition can be produced 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 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 The pH is then adjusted and the remaining water is added.

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

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 7.4% Purified water, q.s. to 100%

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 included in the transfer signal of the

Contact lens cleaning and storage devices according to the US-PS 35 19 005 and 36 45 284 inserted. 4th ml of solution B was added to each part. 3 to 6 drops of Solution A were added to each part, and the contact lenses were immersed in the solution for disinfection. Some of the lenses initially turned yellow due to their ability to concentrate the available iodine. In these cases, bring lower Contents (3 to 4 drops) of solution A keep the initial uptake of iodine to a minimum. I all Cases, the iodine was consumed by the resulting solution in 1 to 6 hours. At the end of that time were no visual or measurable adverse effects on the lenses were observed. The attempt was made several times repeated 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 purposely made with actively growing cultures of Staphylococcus aureus. Streptococcus pyogenes. Escherichia coli, 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 that were adapted to the human cornea, were treated with solutions A and B and resulted in initial concentrations of available iodine im Range from 0.003 to 0.01% over a period of 2 hours to 12 hours. These lenses were subsequently worn by test persons without any adverse effects occurring.

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 prepared following the procedure of the example table
Disinfecting efficacy of solution C in solution D 1, with the exception that the step of dissolving boric acid prior to dissolving de: polyvinyl alcohol was omitted. Then hydrochloric acid was added to the solution in order 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, a.s. to 100%

Suspensions of the test organisms listed in the table below were prepared and adjusted so that they contained a final population of about 1 × 10 ⁵ cells per milliliter of the final liquid volume. 7 drops of Solution C were added to sterile contact lens cases, and hydrophilic soft gel lenses were placed in the cases. Vio ml of inoculum was then added to the housings. 7 ml of solution D were added to the housings, which were then closed and shaken over a circular arc of 30 cm for 60 seconds and exposed to normal room light for 6C minutes. After this, most of the iodine color had disappeared from the solution. It was inoculated and treated as above, with the exception that physiological saline solution was used in place of solutions C and D.

The experiments on each organism were carried out in triplicate. After the 60 minutes during the When exposed to normal room light, the entire contents of the housing were aseptically in 40 ml tryptic soy broth (TSB) or thioglycolate broth (THIO), which contained neutralizing agents, and incubated for 14 days at the optimal growth temperature of the test organism. Sterile blood was added to the culture media used for growing N genorrhea, Heamophilus influencae. Moraxella sp. and jj hemolytic streptococci were used These cultures were subcultured on blood agar media after 1, 2. 7 and 14 days of incubation time transferred to the status of organism viability to be determined, since the growth in the broth media could not be determined by the added blood.

The results of these tests are summarized in the table below. As can be seen, is the solution C in the solution D is effective / lüiii 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 10 ^) 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 Bacillus cereus (Spores) 1.7 TSB ³ ) 1 NG NG Bacillus subtilis (veg.) 2.57 TH 10 2 Bacillus subtilis (Spores) 2.8 TSB 1 Escherichia coli 1.8 TH 10 NG

continuation

10

TeslorganisiiHis Vaccine / rush Miles ium Days after of vaccination if d; 3 is first ml (x I (Γι growth was observed NG Try Ni r. NG Positive I. 2 NG control Proteus mirabilis 1.41 do ίο NG NG NG 1 Proteus vulgaris 1.8 TlI 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 Stiiphylococcus aureus 3.28 TH 10 NG NG NG 1 Staphylococcus epidermidis 6.57 TH 10 NG NG NG 1 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 Candida parapsilosis 3.57 TSB NG NG NG 1 Neisseria gonorrhea 3.93 TH 10 / B ⁴ ) NG NG NG 2 Propionibacterium acnes 1.27 TH 10 NG NG NG 3 Haemophilus influenzae 1.85 TH 10 / B NG NG 2 Moraxella species 3.42 TH 10 / B NG NG 1 / 7-hemolytic streptococci 1.53 TH 10 / B NG NG 2

) NG = no growth after half an incubation.

-) TH 10 = thioglycolate broth.

) TSB = tryptic soy broth.

') TU 10 / B = thioglycolate 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 wt .-% 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 water-soluble iodide salt and 0.001 to 25% by weight of polyvinyl alcohol and b) 90 to 99 wt .-% of a sterile aqueous solution with 0.01 to 5 wt .-% sorbic acid or a soluble salt thereof, 0.01 to 5 wt .-% ethylenediaminetetraacetic acid or a soluble salt thereof and 0.1 to about 2 wt .-% of an ammonium, alkali or Alkaline earth salt of a boroxy acid or boron oxygen acid. 6. Use of a solution according to claim 5 for the sterilization of contact lenses. 10