STABILIZED IODINE-CONTAINING GERMICIDAL PREPARATION

Abstract: A stabilized germicidal preparation for use in the presence of a high bio-organic load, for example for sterilizing a urine collection bag, comprises an iodine-­ containing germicide, especially an iodophor such as povi­ done-iodine, together with a stabilizing amount of an acid having a pKa value of less than 2, especially hydrochloric, phosphoric or maleic acid.

Description: STABILIZED IODINE-CONTAINING GERMICIDAL PREPARATION This invention is concerned with improvements in and relating to stabilized iodine-containing germicidal preparations which may be used in the presence of high bioorganic loads. In the course of certain pre-operative and post-operative procedures it is necessary to provide a means for the drainage of body tissue exudates and other organic fluids. Such drainage involves the Insertion of a catheter into the body cavity or replaced after varying periods of time of drainage collection. The length of time during which such drainage catheters are utilized will vary from the indeterminant period for the urinary incontinent patient to the shorttransition interval of the operative period when purulent material is drained. Such drainage materials usually comprise a high bio-organic load which is frequently contaminated with infectious micro-organisms so that microbicidal degening is a necessary procedure to protect both the patient and attending hospital and nursing staff. Unfortunately, the tissue exudates with high blo-organic load present serious problems since germicides are inactivated by the organic matter, enzymes and Inorganic salt content of these drainage systems. The catheterized urinary tract is the most common site for infections while the patient is in a hospital, and urinary tract infections account for approximately 30% of hospital nosocomial infections. While an improvement in the diminution of catheter-associated bacteria has been achieved by the utilization of closed, sterile drainage collection systems, the problem remains of serious concern to the clinician and the patient. It has been found that a significant number of patients with in-dwelling catheters continue to acquire urinary tract infection and the microbial contamination of the urine drainage collection bag has been frequently observed to occur prior to the onset of a bladder bacteremia. The use of suitable germicidal agents which are administered prophylactically to the patient in an effort to delay the onset of bacteria has not been successful in preventing these infections because many of these systemic antimicrobial agents are toxic and therefore may not be used for long-term routine prophylaxis. It has been shown that bacterial contamination of the urine drainage collection bag, which has been established to be a common source of bacteria associated with catheterization, may be eliminated by adding hydrogen peroxide to the collecting container. However, hydrogen peroxide, which is a strong oxidizing agent, enters into secondary chemical reactions with the organic matter of urine and the container. This presents considerable limitations on the routine germicidal use of hydrogen peroxide in such collecting systems. Hydrogen peroxide also has a serious limitation when used as a germicide in the presence of biologic matters containing such enzymes as catalase or peroxidase. These enzymes cause an inactivation of the hydrogen peroxide by releasing gaseous, nascent oxygen into the atmosphere, with the formation of inert water. The urine collected in the course of the post-surgical and/or medical management of genito-urinary pathology frequently contains blood and pus and microbial flora, all of which carry the peroxidase enzymes to render peroxide germicides inert. The use of such germicides consequently requires frequent multiple additions of peroxide agents which not only increases nursing costs, but also presents the patient with the threat of microbicidal failure through enzyme inactivation of the peroxide germicidal systems. Moreover, it has been shown that certain microorganisms may be resistant to hydrogen peroxide germicidal action which consequently provide a still further patient threat as well as new epidemiologic problems. After the surgical intervention for the treatment of gallbladder disease, bile drainage is a frequent necessity. In many instances this drainage fluid is contaminated and presents a toxic hazard for the patient and attending staff. The usual germicides are not satisfactory because of the chemical properties of the bile salts in this drainage fluid which react to degrade the germicidal system. When hydrogen peroxide is used as a germicide for a gallbladder drainage system, the bile salts are highly chemical reactive with peroxides to render the germicidal effect of hydrogen peroxide worthless. Following certain chest procedures drainage catheters are inserted to drain the chest cavity. These chest collection systems involve the common hazard of microbial contamination and also because of reflux of the exudates into the sensitive chest cavity, containing the vital organs, serious patient threat results. The use of antiseptics to degermbuch drainage systems is severely limited because of the inherent toxic nature of the germicide to these sensitive organs, and also because of the presence of the high bio-organic load of these exudates which serves to neutralize and destroy the conventional germicides. When the above drainage fluids comprise blood and other tissue exudates, the incidence of infection is materially increased since such organic composition of these fluids is an excellent medium for microbial growth. Of the antiseptic agents utilized for environmental degerming, iodine is considered to be one of the best antimicrobial agents because of its broad spectrum rapid microbicidal action against every species of microorganism. However, elemental iodine Is a strong, corrosive, oxidizing halogen which interacts with many substances. Elemental iodine stains skin and natural fibres as well as most surface materials. The tissue irritative properties of elemental iodine presents another serious threat to its use with patients. Because iodine has a high vapour pressure, it poses the problem of refluxing iodine vapours from a urine collecting bag into the genito-urinary system to cause local tissue damage. The development of iodophor germicidal preparations eliminated many of the noxious toxic chemical properties of elemental iodine without affecting its germicidal efficacy. The class of organic iodophor compounds consists of two distinct groups; the first is the non-detergent, iodine containing organic germicidal preparations of which polyvinylpyrrolidone-iodine (hereinafter for convenience referred to as "povidone-iodine" or "PVPI") is the only member and the second group consists of compounds prepared from a variety of detergent, surface-active agents and iodine. This latter group of detergent iodophor compounds are useful for environmental degerming such as occurs in urine collecting bags. This group of germicidal compounds includes such iodophor detergent compounds as nonyl phenoxypoly-( ethyl eneoxy)-ethanol iodine and undecoylium chloride iodine. Detergent-lodophor compounds may be formed by combining iodine with an anionic, cationic or nonionic detergent compound. An example of nonionic detergent suitable for forming an iodophor compound is a polyglycol ether-type, surface active compound, well known in the art. (See United States Patents Nos. 1,970,578 and 2,213,447). Other nonionic surfactants that may be used to prepare lodophors are disclosed in United States Patent No. 2,674,619. Anionic detergents also form iodophor compounds, and surface-active agents such as alkanoyl taurates and alkylaryl sulphonates, such as for example alkyl benzene sodium sulphonates and alkyl naphthyl sodium sulphonates, may be combined with iodine to form such anionic iodophors. When a cationic detergent is desired to be used as an iodide carrier, then well known cationic surfactant compounds, such as for example the quaternary ammonium salts such formed by the alkylation of fatty amines and straight chain fatty amine salts having from 8 to 18 carbon atoms in chain length (e.g.octadecyl amine; amino amides and imidazolines), may be used. The detergent lodophor group possesses common disadvantages for use in urine collection systems in that the surface tension reduction, because of the detergent content, gives rise to massive foam formation which tend to clog catheters. While germicidal activity is satisfactory for these surfactant lodophors, this physical property of foam formation make these agents somewhat less preferred. Of the general class of iodophor germicidal preparations, povidone-iodine is the preferred degerming compound because this organic iodine germicide has a low systemic toxicity and it is essentially non-irritating to mammalian tissues while acting as a broad-spectrum germicidal agent with nonselective antimicrobial activity. It is effective in dilute solutions and has been established to be active against bacteria, fungi, virus, spores, amoeba and nematodes. However, it is known that all iodophor preparations are not stable in the alkaline pH range solutions of povidoneiodine described in compendial literature all carry the caution that the pH of such solutions must not exceed pH 6. This inactivation of iodophor germicidal activity in the alkaline pH range is especially important to the use of these agents in urine collection systems because the microbial action on urea liberates ammonia to result in a strong alkaline chemical reaction. It is a primary object of the present invention to provide for the stabilization of iodine-containing germicidal preparations even in the presence of large amounts of bioorganic matter. It is another object of the present invention to provide for the stabilization of iodophor compositions so that the same can be used in connection with in-dwelling catheters and gallbladder drainage collection vessels. It is another object of the present invention to provide for the stabilization of iodophor compositions so that the same can be used in connection with catheters inserted to provide a drainage system to the chest cavity and abdominal cavity. It is another object of the present invention to provide for the stabilization of iodophor compositions so that the same can be used in connection with in-dwelling catheters for body cavity, wherein the drainage fluid comprises blood, tissue exudate and other serous materials, to degerm the collected fluids. It is another object of the present invention to provide for stabilized aqueous iodine-coating solutions which retain germicidal iodine even in the presence of large amounts of urine, blood, bile and other tissue exudates. According to the present invention there Is provided a germicidal composition for use in the presence of blo-organic matter and comprising an iodine-containing germicide together with a stabilizing amount of one or more acids having a pKa. value of less than 2; especially hydrochloric acid, phosphoric acid and or maleic acid; particularly maleic acid alone or in admixture with hydrochloric or phosphoric and; the pH of the system preferably not exceeding about 3. While It is known that iodophor preparations are not stable in the alkaline pH range, attempts to avoid the lack of stability thereof when used in connection with urine collecting bags by the acidification of the bag contents for the purpose of controlling the developing alkalinity in the body exudate collecting container were not successful in attempting to avoid the loss of iodine potency of the iodophor solution at alkaline pH. Thus, for example, the acidification of the urine with strong acids has been found to cause the formation of precipitates when the iodophor is added thereto. Accordingly, this cannot be used as a means of avoiding the loss of iodine potency of iodophor solutions in urine collection bags and the like systems with a high bio-organic load. We have attempted to avoid the problem of loss of iodine potency of iodophor solutions at alkaline pH by the addition of an acid to the aqueous iodine solutions prior to the mixing thereof with the drained body exudate. However, quite surprisingly it was found that the addition of the acid to the aqueous iodine solutions is effective only in the case of hydrochloric acid, maleic acid, or phosphoric acid, or mixtures thereof. Thus, aqueous iodine solutions were prepared to contain about 2.0% titratable iodine and strong acids, such as for example, acetic acid, citric acid, hydrochloric acid, lactic acid, maleic acid, phosphoric acid, succinic acid and tartaric acid. Urine which is a common body drainage fluid and typifies the high bio-organic load of such drainage fluids-was used as a representative test material to demonstrate the value of the present invention. Exactly 400 ml. of pooled urine was mixed with 30 ml. of the resulting iodophor solutions, agitated thoroughly to obtain a homogeneous mixture and assayed for available iodine content. The urine-iodophor-acid mixture was permitted to stand for at least 8 hours and was reassayed for physical appearance, pH and iodine content. The values obtained after standing were then compared with the initial data (see Table e 1 below). All of the acids used, except hydrochloric acid, phosphoric acid and maleic acid caused a marked drop.in the initial iodine value immediately after the addition of the iodophor compound. These acids have a pKa value of less than 2 whereas the other strong acids have a pKa value greater than 2. Within a matter of 5 to 10 minutes a loss of approximately 50 mg. to 150 mg. of available iodine was observed. The iodine levels for hydrochloric acid alone or in admixture with phosphoric acid were virtually unchanged, whereas only a small iodine loss was observed for the maleic acid systems. There was a strong iodine odor with the hydrochloric acid mixture to reflect the formation of elemental iodine with high vapour pressure which was not present in the other preparations. The values obtained with the various acids which were tested are set forth in Table 1 below. TABLE 1 The effectiveness of acidulants as stabilizers for povidone-iodine solutions in the presence of an organic urine biologic load EMI12.1 <tb> <SEP> Initial <SEP> Test <SEP> Data <tb> <SEP> Test <SEP> Total <SEP> pH <tb> <SEP> Mixture <SEP> Available <SEP> at <SEP> Appearance <tb> <SEP> Iodine/mg <SEP> 25"0 <SEP> <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 345.0 <SEP> 2.5 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> HC1 <SEP> with <SEP> precipitate <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 347.0 <SEP> 3.7 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> H3P04 <SEP> with <SEP> precipitate <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 315.0 <SEP> 3.9 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> maleic <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 297.0 <SEP> 3.9 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3X <SEP> tartaric <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 252.0 <SEP> 4.1 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> citric <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 252.0 <SEP> 4.1 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> lactic <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 233.0 <SEP> 4.2 <SEP> dark <SEP> brown <SEP> solution <tb> + <SEP> 3% <SEP> succinic <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 197.0 <SEP> 4.3 <SEP> dark <SEP> brown <SEP> soution <tb> + <SEP> 3% <SEP> acetic <SEP> acid <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 22% <SEP> PVP-I <SEP> 74.0 <SEP> 4.8 <SEP> reddish <SEP> brown <tb> (no <SEP> acid <SEP> added) <SEP> (control) <SEP> . <SEP> <SEP> solution <tb> 400 <SEP> ml <SEP> urine <SEP> 0.0 <SEP> 5.9 <SEP> pale <SEP> yellow <SEP> solution <tb> (control) <tb> TABLE 1 (Contd.) Test Data after 8 hours at room temperature EMI13.1 <tb> <SEP> Total <SEP> pH <tb> Available <SEP> at <SEP> Appearance <tb> Iodine/mg <SEP> 250 <SEP> C <SEP> <tb> <SEP> 345.0 <SEP> 2.3 <SEP> dark <SEP> brown <SEP> solution <SEP> with <tb> <SEP> precipitate <tb> <SEP> 58.9 <SEP> 3.3 <SEP> reddish <SEP> brown <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 43.7 <SEP> 3.5 <SEP> reddish <SEP> brown <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 3.6 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 3.7 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 3.8 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 4.0 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 4.0 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 4.6 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> <SEP> 0.0 <SEP> 5.8 <SEP> pale <SEP> yellow <SEP> solution; <SEP> free <SEP> of <tb> <SEP> precipitate <tb> Acidification with hydrochloric acid and phosphoric acid caused a copious precipitate to develop immediately after mixing. The presence of insoluble material limits the use of hydrochloric acid as an acidifying preservative for germicidal iodine since the separated insoluble matter may not only clog the catheter but could adsorb urine biocomponents to interfere with laboratory diagnostic testing. The precipitate formed with phosphoric acid dispersed and returned to solution on standing. There was no precipitate with the maleic acid preservative. After incubation for 8 hours (at room temperature) only the hydrochloric acid, phosphoric acid and maleic acid systems still retained iodine in the solution. The remaining acidulated preparations were virtually colourless and without iodine content. Unexpectedly, the analysis of this test data established that strong acids with a pKa value of less than 2 stabilized the iodophor preparation in the presence of an organic urine biologic load; whereas those strong acids with a pKa value greater than 2 failed to maintain an effective iodine level in the presence of high organic urine biologic load. Thus, only the hydrochloric acid, phosphoric acid and maleic acid preparations were useful as stabilizing acidulants for an iodine-containing germicide in the presence of high organic urine bio-loads, with phosphoric acid being particularly useful for open systems. The preservative activity of strong acids was also explored with other iodophor preparations, as for example, the detergent-iodophor system, nonoxynol-l0 iodine complex, which is known In the trade as Biopal R and marketed by the GAF Corporation, New York City, New York, and Lugol's Solution which is an aqueous solution of elemental iodine, prepared in accord with the monograph for Strong Iodine Solution of USP XX. Lugol's Solution, or Strong Iodine Solution, is an aqueous solution of elemental Iodine which is prepared by dissolving one part by weight of iodine and two parts by weight of potassium iodide in 100 ml. of water and then adding sufficient water to bring the volume to one litre. When 400 ml. of urine was mixed with 11% (w/v) of Biopal, plus 3% (w/v) of the following acids, hydrochloric acid, phosphoric acid, maleic acid, tartaric acid and citric acid, a precipitate was immediately observed to form in the preparations containing hydrochloric acid, tartaric acid and citric acid. While there was initial transient precipitation after the addition of the phosphoric acid, this was soon reversed and it went into solution on standing. After the 8 hours of incubation, the Blopal-tartaric acid and the Biopal-citric acid preparations had virtually no detectable iodine-content, whereas the iodine content for Biopal preparations acidified with hydrochloric acid, phosphoric acid and maleic acid ranged from low to moderate amounts to indicate that effective germicidal activity was present despite the high urine bio-load (see Table II below). When the Lugol's Solution (iodide-iodine aqueous solution) was studied by adding 400 mi. of urine to a sufficient volume of aqueous iodine-iodide solution to provide 2.2S equivalent of titratable iodine and 3% (w/v) of a strong acid selected from the group of hydrochloric acid, phosphoric acid, maleic acid, tartaric acid and citric acid, only the 4 hydrochloric acid-Lugol's Solution preparation was found to have moderate iodine content after 8 hours of incubation, although it did have a'formed precipitate. The remaining other acid preparations had virtually no iodine content and no precipitate material (Table II). Thus, maleic acid which is useful to preserve organic iodophor germicides is not suitable to stabilize elemental inorganic iodine products. This response may be due to the iodination of the unsaturated bonds of maleic acid. TABLE II Effectiveness of acidulants as stabilizers for two iodophors in the presence of an organic urine biologic load EMI17.1 <tb> <SEP> Inactivity <SEP> as <tb> <SEP> Test <SEP> Preparation <SEP> Measured <SEP> bq <SEP> Physical <tb> <SEP> Stability <tb> <SEP> 12 <SEP> color* <tb> BIOPAL <SEP> SERIESa <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 11% <SEP> Biopal <SEP> + <SEP> 3% <SEP> HCl <SEP> ++ <SEP> <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 11% <SEP> <SEP> Biopal <SEP> + <SEP> 3% <SEP> H3PO4 <SEP> + <SEP> no <SEP> ppt. <SEP> <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 11% <SEP> Biopal <SEP> + <SEP> 3% <SEP> maleic <tb> acid <SEP> + <SEP> no <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 11% <SEP> Biopal <SEP> + <SEP> 3% <SEP> tartaric <tb> acid <SEP> -- <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 11% <SEP> Biopal <SEP> + <SEP> citric <SEP> acid <SEP> -- <SEP> ppt. <tb> IODIDE-IODINE <SEP> SERIES <SEP> (Lugol's <SEP> Sol.) <SEP> <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 2.2X <SEP> iodine <SEP> + <SEP> 3% <SEP> HC1 <SEP> ++ <SEP> <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 2.2% <SEP> iodine <SEP> + <SEP> 3% <SEP> H3P04 <SEP> -- <SEP> no <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 2.2% <SEP> iodine <SEP> + <SEP> 3 <SEP> maleic <tb> acid <SEP> -- <SEP> no <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 2.2% <SEP> iodine <SEP> + <SEP> 3% <SEP> tartaric <tb> acid <SEP> -- <SEP> no <SEP> ppt. <tb> 400 <SEP> ml <SEP> urine <SEP> + <SEP> 2.2% <SEP> iodine <SEP> + <SEP> 3% <SEP> citric <tb> acid <SEP> -- <SEP> no <SEP> ppt. <tb> * ++ moderate, + low, - nil (pale yellow) (a) nonoxynol-l0 iodophor series Thus, it was unexpectedly found that preferred useful stabilizers for iodine containing germicides in the presence of high urine bio-loads are maleic acid, hydrochloric acid, phosphoric acid and mixtures of these. Hydrochloric acid was unexpectedly found to be an excellent stabilizer of germicidal iodine activity in the presence of a high urine bio-burden but the presence of a precipitate limited its use to those systems used for urine drainage collection wherein such formed precipitated matter does not interfere with the catheter urine drainage. Further examination of the general utility of strong acids as stabilizing agents for iodine-containing germicides in the presence of a urine load indicated that while other inorganic acids such as nitric acid and sulphuric acid may possess a stabilizing tole to the available iodine content, these inorganic acids present other limitations which so seriously interfere with their use in urine-collection systems as to render these acids useless. Thus, for example, there is a strong vapour of elemental iodine present when nitric and sulphuric acids are used. The iodine vapours are apparent and iodine may reflux into the kidney from the urine collection system to be a potential source of injury as well as to injure the surrounding surfaces. When hydrochloric acid was used the known volatility of hydrochloric acid presented a problem of its own volatilization to render such use a problem in the closed system while preserving the iodine content. However, hydrochloric acid is of value in the open collection system wherein refluxing of halogen vapours does not occur and the strong acid properties of hydrochloric acid is not an environmental problem. We have further found that maleic acid and phosphoric acid have preferred properties and can be used to stabilize the germicidal iodine content in the presence of a high urine biologic load even over periods as long as 8 hours, which is the maximum period before changing the urine collection bag when an in-dwelling catheter is used. Furthermore, we have found that hydrochloric acid is useful for certain systems as well as for inorganic iodine germicide. Other organic acids such as acetic acid, citric acid, lactic acid, succinic acid and tartaric acid failed to stabilize the iodine content of the different iodine-containing germicides and therefore although closely related in chemical structure and chemical properties to maleic acid, these are essentially of no value. In order to demonstrate the scope of utility for maleic acid as a stabilizing preservative for iodophor preparations used in degerming body exudate urine drainage collection bags, a series of solutions of maleic acid were prepared and mixed with 400 ml. of urine and a sufficient amount of povidone-iodine solution to provide 2% available iodine; the amount of maleic acid used was from 2% to 6% (w/v). The pH of these preparations was measured and the observations were made of the length of time wherein the iodine content was found to be present. The results of this study are shown in Table III. The results of this test confirm that the addition of at least 2E maleic acid to an iodophor preparation Is sufficiently capable of preserving iodine germicidal activity even when large amounts of urine are present to maintain an essentially germ-free sanitized urine pool. A concentration of 3% maleic acid is preferred and the use of additional amounts of maleic acid above 3% (w/v) does not improve the effective degerming properties of the product. However, larger amounts of maleic acid may be found useful for special use conditions as for example when genito-urinary infection is present or significant bleeding occurs. TABLE III The range of efficacy of maleic acid in preserving iodophor potency in the presence of high urine bio-load EMI21.1 <tb> Volume <SEP> Amount <SEP> Amount <SEP> Initial <SEP> Residual <tb> Human <SEP> + <SEP> <SEP> Iodine <SEP> maleic <SEP> Observation <SEP> Available <SEP> available <SEP> iodin <tb> Urine <SEP> Solution <SEP> acid <SEP> added <SEP> iodine <SEP> content <SEP> after <SEP> 24 <tb> <SEP> % <SEP> (w/v) <SEP> content <SEP> hr. <SEP> study <SEP> period <tb> 400 <SEP> ml <SEP> + <SEP> 60 <SEP> ml <SEP> none <SEP> No <SEP> iodine <SEP> colour <SEP> 1.3 <SEP> mg/ml <SEP> Nil <tb> <SEP> (control) <SEP> after <SEP> 24 <SEP> hrs. <tb> 400 <SEP> ml <SEP> + <SEP> 45 <SEP> ml <SEP> none <SEP> No <SEP> iodine <SEP> colour <SEP> 1.35 <SEP> mg/ml <SEP> Nil <tb> <SEP> (control) <SEP> after <SEP> 12 <SEP> hrs. <tb> <SEP> (pH <SEP> 3.55) <tb> 400 <SEP> ml <SEP> + <SEP> 30 <SEP> ml <SEP> none <SEP> No <SEP> iodine <SEP> colour <SEP> 1.40 <SEP> mg/ml <SEP> Nil <tb> <SEP> (control) <SEP> after <SEP> 8 <SEP> hrs. <tb> 400 <SEP> ml <SEP> + <SEP> 30 <SEP> ml <SEP> 2X <SEP> 1 <SEP> Slight <SEP> iodine <SEP> 1.40 <SEP> mg/ml <SEP> < 0.1 <SEP> mg/ml <tb> <SEP> colour <SEP> after <SEP> 24 <tb> <SEP> hrs. <SEP> (pH <SEP> 2.95) <tb> 400 <SEP> ml <SEP> + <SEP> 30 <SEP> ml <SEP> 3% <SEP> Good <SEP> iodine <SEP> 1.40 <SEP> mg/ml <SEP> 0.5 <SEP> mg/ml <tb> <SEP> colour <SEP> after <SEP> 24 <tb> <SEP> hrs. <SEP> (pH <SEP> 2.85) <tb> 400 <SEP> ml <SEP> + <SEP> 30 <SEP> ml <SEP> 4% <SEP> Good <SEP> iodine <SEP> 1.40 <SEP> mg/ml <SEP> 0.5 <SEP> mg/ml <tb> <SEP> colour <SEP> after <SEP> 24 <tb> <SEP> hrs. <SEP> (pH <SEP> 2.65) <tb> 400 <SEP> ml <SEP> + <SEP> 30 <SEP> ml <SEP> 6% <SEP> Good <SEP> iodine <SEP> 1.40 <SEP> mg/ml <SEP> 0.5 <SEP> mg/ml <tb> <SEP> colour <SEP> after <SEP> 24 <tb> <SEP> hrs. <SEP> (pH <SEP> 2.45) <tb> The impact of precipitate formation was explored and it was found that when phosphoric acid and/or hydrochloric acid is combined with the maleic acid, so that an effective concentration of these acids is equivalent to at least 2% by weight/volume of the combined acids, then immediate precipitation was avoided and effective iodine stabilization occurred. When it is desired to stabilize an iodine-containing germicide solution in the presence of a high urine bio-load in order to sanitize the urine collected in the catheter drainage collection bag, then a germicidal solution may be prepared by dissolving 30 gm. of povidone-iodine USP in 80 gm. of purified water, adding 3 gm. of maleic acid and bringing the volume to 100 ml. Approximately 30 ml. of this solution is added to the empty urine drainage collection bag and connected into the system. When urine samples are removed to determine the presence of microorganisms to demonstrate the efficacy of the system, even prior to emptying the bag after 8 hours of drainage, the urine will be found to be essentially sterile. Over the usual 8 hour period that urine drains into the collection bag, the volume of fluid increases so that the stabilized iodophor germicide solution, as described herein, is at full iodine strength at the time the drainage period starts, but may be diluted to 4% of the original strength after 8 hours since the mean urine volume in the collection system after 8 hours is approximately 840 ml. (average). The mean and standard deviation of urine volumes determined for 253 urine collection bags was 840 ml. + 450 ml. with an average iodophor iodine germicide concentration after 8 hours of 30/840 x 100 or 4% or original strength. The results of a controlled study of the microbicidal efficacy of an iodophor-maleic acid preserved collection system in 21 patients is reported in Table IV. The average volume of urine collected from the patients was 840 ml. with a range of from 100 ml. to 3430 ml. The microbial and pH testing of the collected urine was conducted in the usual manner and demonstrated the acid pH present throughout and that the available iodine content was preserved and was sufficient to maintain a virtually sterile urine collection environment during the entire catheterization and urine drainage period. The pH of the urine in the collection bag averaged pH 3.6 with a range of from pH 2.2 to pH 4.3 over the entire study period, while the pH of the bladder urine was found to average pH 6.2 with a range of from pH 5.8 to pH 7.1 for the same period. Thus the maintenance of the acid pH reflects the excellent stabilizing properties of the new preparations. Results are reported in Table IV. The microbiological testing conducted in accord with the methods known in the art, established that the urine samples taken from the urine collecting bags treated with the new preparations during 8 hours of urine drainage were essentially sterile in contrast to the presence of microorganisms such as yeast cells, E. Coli and Pseudomonas aeruginosa present in the control group where no stabilized iodine germicidal solution was added to the collection bag. When a sample of bladder urine was obtained and microbiologically studied, two of the subjects Nos. 6 and 12, were found to have E. Coli present and Pseudomonas mirabilis in the bladder urine samples because of an upper urinary tract infection both these organisms were destroyed in the treated urine bag collecting system. TABLE IV Efficacy of stabilized iodine solution in maintaining a sterile environment in the urine collecting bag of 21 patients Random Bag urine-vol. Assignment at each 8 hr. pH bag pH bladder Subject bag drainage urine urine Number (ml) TEST GROUP - 30 ML STABILIZED PVP-I SOLUTION ADDED TO BAG 1 300 - 640 2.2 5.8 2 1120 - 1350 3.9 5.9 3 300 - 750 3.4 7.1 6 100 - 1050 3.8 6.3 7 500 - 1000 3.8 5.9 10 240 - 1000 3.4 5.9 - 11 500 - 800 4.3 5.8 12 260 - 1500 3.0 6.5 14 450 - 650 3.2 6.3 15 230 - 2020 3.7 6.2 17 240 - 1040 3.2 6.4 19 400 - 3430 4.0 6.5 21 360 - 1400 3.2 6.4 Average: 3.6 6.2 CONTROL GROUP - NO PVP-I SOLUTION ADDED TO BAG 4 550 - 2400 5.8 5.9 5 250 - 910 6.2 6.3 8 . 360 - 1000 6.8 6.7 9 240 - 1480 6.0 6.1 13 120 - 1240 6.0 6.0 16 100 - 780 5.3 5.2 18 450 - 2400 6.3 6.2 20 1780 - 2740 6.1 6.1 Average: 390 - 1290 6.0 6.0 TABLE IV (Contd.) EMI26.1 <tb> Bag <SEP> urine <SEP> Bladder <SEP> urine <tb> <SEP> Max. <SEP> No. <SEP> Cells/ml <SEP> contaminant <SEP> Max. <SEP> No. <SEP> Cells/ml <SEP> contaminant <tb> TEST GROUP - 30 ML STABILIZED PVP-I SOLUTION ADDED TO BAG Sterile Sterile Sterile Sterile Sterile Sterile Sterile 103E. Coli.* Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Sterile Average: 0/13 2/13* CONTROL GROUP - NO PVP-I SOLUTION ADDED TO BAG 10 Yeast Sterile Sterile Sterile 10 E. Coli 10 E. Coli Sterile Sterile 10êP. Aeruginosa Sterile 105E. Coli 10 E. Coli 108P-. Aeruginosa 105P. Aeruginosa Sterile Sterile Average: 5/8 3/8 * Patient had 10 cells/ml in bladder at time of initial catherization For the control group E. coli and Pseudomonas aeruginosa were found in bladder urine but no yeast cells; all of these were found in the urine collecting bag. This study clearly demonstrates that an iodine germicidal preparation stabilized with maleic acid is capable of rendering the urine in the catheter drainage collection bag germ-free thereby reducing the chance for Infection during and after in-dwelling catheterization. In a similar manner, the degerming of the fluid exudate drained post-operatively after surgical intervention in gallbladder disease is accomplished by adding to the container vessel a volume of from 10 ml. to 40 ml. of a stock iodophor germicidal solution prepared by dissolving 30 gm. of povidoneiodine USP in 80 gm. of purified water and adding thereto from 1 gm. to 4 gms of maleic acid and the volume brought to 100 ml. In place of the povidone-iodine USP there may be substituted a sufficient quantity of the surfactant iodophor preparation nonoxynol iodine complex, in an amount sufficient to provide 2% (w/v) of titratable iodine or povidone iodine aqueous solution to provide 2% titratable iodine (w/v). For the preparation of all of these stock solutions, the concentration of maleic acid used will range from 1% to 4% (w/v) depending on the anticipated volume and bio-organic load of the particular exudate drainage fluid being collected. The exact volume of the iodophor germicidal stock solution to be added to the fluid drainage vessel will depend on the bio-organic load and the volume of fluid to be degermed. If the volume is small and the organic load light, then a volume of about 10 ml. of the selected stock solution is used, but when the drainage volume is large and the organic load high, then 40 ml. of the stock solution is used to achieve degerming over an 8 hour period. The fluid volume of the drainage solution, as well as the degree of bio-organic load present is readily discernible to one trained in the art upon inspection of the vessel contents and detection of odour. When the contents of the chest cavity drainage collection vessel is intended to be degermed, then a volume of between 20 ml. and 40 ml. of the iodophor germicidal stock solution prepared, as described above, is used. The presence of blood serous exudate and microbial contaminents will direct that the higher volume of 40 ml. of the germicidal stock solution to be added to the container while lesser degrees of organic material evident in the drainage fluid will require the smaller amounts of stock solution. While generally the same amounts of the lodophor maleic acid containing stock solution are used, as described above for urine bag degerming to degerm the contents of the vessel receiving the exudate from the gallbladder drainage systems and chest cavity drainage systems, it will be found that smaller amounts of the detergentlodophor active substance will be required. However, a preferred stock solution is one that is prepared to provide 2% (w/v) titratable iodine and to contain 3% of maleic acid (w/v) with a preferred volume of the stock solution to be added will be 30 cc. added directly to the drainage fluid container to achieve an 8 hour effective degerming. The following examples are given by way of illustration only. EXAMPLE 1 In a suitable glass container were placed 80 gms of purified water and 20 gms of povidone-iodine USP. The mixture was stirred until a solution was achieved and 3 gms of maleic acid were added. When the maleic acid had dissolved, sufficient water was added to bring the volume to 100 ml. thus forming a 20% solution of the iodophor germicide, povidone-iodine (w/v) and maleic acid 3% (w/v). Thirty (30) c.c. of this solution is then added to the body exudate drainage collection container in order to render the collection vessel contents virtually sterile over the common collection period of about 8 hours. EXAMPLE 2 In place of the povidone-iodine used in Example 1, there is added a sufficient quantity of a povidone-iodine aqueous solution to provide the equivalent amount of titratable iodine to the drainage collection vessel and 2% (w/v) of maleic acid are added to the povidone-iodine solution. The samples of the drainage contents obtained after 8 hours of drainage are virtually sterile. EXAMPLE 3 In place of the iodophor germicide used in Examples 1 and 2 above , there is substituted a sufficient quantity of the aqueous iodine solution described in the U.S. Pharmacopeia (20th Edition, page 406), and which is known as Iodine Topical Solution or Strong Iodine Solution, to provide an equivalent iodine content to that obtained from the iodophor used in Examples 1 and 2 above. A volume of the iodine solution, sufficient to provide at least 2% (w/v) of available or titratable iodine and from 2% to 3% (w/v) of maleic acid is then added to the urine collection bag. Samples of the drainage fluids taken over appropriate periods will be found to be virtually free of microorganisms. EXAMPLE 4 When a surfactant iodophor preparation is desired to be used to render germ-free the contents of the urine collection bag then the detergent iodophor, nonoxynol-iodine complex may be mixed with a sufficient amount of maleic acid to provide at least 2% (w/v) and the whole is dissolved in sufficient distilled water to provide 2% (w/v) titratable iodine. About 30 ml. of this solution will be found sufficient to degerm the urine collected in the catheter drainage bags. EXAMPLE 5 When an iodophor germicidal preparation is desired to be used to degerm the contents of a urine collection bag, then 20 gm. of povidone-iodine USP are dissolved in about 90 gm. of purified water and 3 gm. of maleic acid added to this solution. Sufficient water is then added to bring the volume to 100 ml. thus forming a 20% solution of the non-surfactant i odophor germicide povidone- iodine (w/v) and maleic acid 3% (w/v). In place of the povidone-iodine USP described above there may be added a sufficient quantity of povidone-iodine aqueous solution to provide an equivalent amount of titratable iodine (2% w/v) to the urine drainage collection bag and 2% (w/v) of maleic acid is added to the povidone-iodine solution before adding to the urine drainage collection bag. The urine samples obtained after 8 hours of urine drainage are virtually sterile when either povidone-iodine USP and maleic acid stock solution or povidone-iodine aqueous solution and maleic acid are used. In place of the iodophor germicide povidone-iodine used to prepare the stock solution as described above, there is substituted a sufficient quantity of aqueous iodine solution which is described in the U.S. Pharmacopeia as Iodine Topical Solution or Strong Iodine Solution, to provide an equivalent Iodine content to that obtained from the iodophor compound. An equivalent volume of the iodine stock solution to provide at least 2% titratable iodine and containing from 2% to 3% of maleic acid is added to the urine collection bag. When 30 cc. of this stock solution is added to the urine drainage collection bag, the contents of the collection bag remain virtually sterile over a common continuous collection period of about 8 hours. EXAMPLE 6 When it is desired to degerm the contents of a gallbladder drainage collection vessel, then between 10 cc. and 40 cc. of an iodine containing germicidal stock solution is prepared to contain 20% (w/v) of povidone-iodine USP nonoxynol-iodine complex, which is known in the art as Biopal, to provide at least 2% (w/v) of titratable iodine and from 1% to 4% of maleic acid (w/v). The aqueous solution described in the U.S. Pharmacopela as Iodine Topical Solution may be used in place of the iodophor to prepare the stock solution and is used in an amount to provide at least 2% (w/v) of titratable Iodine and to contain from 2% to 4% by weight of maleic acid is prepared. An amount of from 10 ml. to 30 ml. of this stock solution will be found to be sufficient to degerm the gallbladder exudate collection vessel over a period of from 6 to 12 hours. EXAMPLE 7 When it is desired to degerm the contents of the chest cavity drainage collection vessel then any of the germidical stock solutions prepared as described in Examples 1 through 6 above containing either a non-surfactant or a surfactant or an aqueous iodine solution and maleic acid may be used. When the drainage exudate fluid contains a large proportion of blood then approximately 30 ml. to 40 ml. of the stock solution is used to degerm the drainage collection vessel contents but in the absence of a large amount of serous and bio-organic exudate, smaller amounts such as 20 ml. of the iodine containing germicide stock solution will provide adequate degerming of the contents of the chest cavity drainage collection vessel. EXAMPLE 8 In place of the maleic acid used in Examples 1 7 above, there may be substituted, in part or in whole, hydrochloric acid and/or phosphoric acid in sufficient amounts such that the total amount of combined acids or the hydrochloric and/or the phosphoric acid used alone, and which is present in the iodophor solution, Is not less than least 2% (w/v).

Claims: CLAIMS 1. A germicidal composition for use in the presence of bio-organic matter and comprising an iodine-containing germicide, characterized in that it contains a stabilizing amount of one or more acids having a pKa value of less than 2. 2. A composition as claimed in claim 1 characterized in that the acid is hydrochloric acid, phosphoric acid and/or maleic acid. 3. A composition as claimed in claim 1 or claim 2 characterized in that it is in the form of an aqueous solution. 4. A composition as claimed in any one of the preceding claims characterized in that the acid is present in an amount of at least 2% weight to volume. 5. A composition as claimed in claim 4 characterized in that the acid is present in an amount of from 2 to 6% weight to volume

Inventors: INY, OLIVER, NASH, ROBERT ARNOLD
Applicants: EUROCELTIQUE SA
Application year: 1982
Main classification: A01N59
IPC codes: A01N59