Pharmaceutical iodine compositions

Abstract: A pharmaceutical composition comprising an aqueous solution of elemental iodine and at least one organic substance which reacts with iodine, whereby iodine loss is controlled by providing a source of iodate loss sufficient to provide from 0.01% to 0.04% by weight iodate ions, preferably from 0.02% to 0.03% by weight iodate ions.

Description: This invention relates to pharmaceutical iodine compositions, to processes for their preparation and to their medical use. In particular the invention relates to stable germicidal iodine compositions in which the elemental iodine concentration level is maintained by the addition of iodate ion. It is recognised in the art that in aqueous iodine compositions wherein the iodine is formulated with organic substances with which it reacts, such as water soluble organic solvents, iodine complexing polymers or surface active agents, the elemental iodine concentration decreases on storage leading to decreased germicidal effectiveness and lack of reproducibility of results. One method of overcoming the problem of elemental iodine stability which has been suggested involves adding iodate or iodide ions to the aqueous solution. For example UK Specification No. 2060385 describes aqueous germicidal iodine compositions comprising an aqueous solution of elemental iodine and at least one organic substance which slowly reacts with iodine wherein iodine loss on storage due to reaction with the organic substance is controlled by providing balanced sources of iodide ion in the range of about 0.025% to 0.5% and iodate ion in the range of about 0.005% to 0.2% and controlling the pH within the range of pH 5 to 7. In this way, iodine loss in the iodine composition is balanced by iodine formed from reacting iodate, iodide and hydrogen ions, the rate of formation of iodine being governed by the pH selected. We have now found that by adding iodate ions in the range of 0.01% to 0.04% by weight to aqueous iodine compositions stable compositions with unexpectedly reduced irritancy are obtained. Thus the present invention provides a pharmaceutical composition comprising an aqueous solution of elemental iodine and at least one organic substance which is an iodine complexing polymer, such a polyvinylpyrrolidone or a non-ionic, cationic or anionic detergent carrier or surface active agent (such as nonoxynol or sodium lauryl sulphate), whereby iodine loss is controlled by providing a source of iodate ions sufficient to provide from 0.01% to 0.04% by weight iodate ions, preferably from 0.02% to 0.03% by weight iodate ions. According to the invention, elemental iodine is present in the range of 0.75 to 1.25% by weight. Conveniently the composition according to the invention comprises an aqueous solution of a complex iodine with an organic iodine-complexing agent, preferably a polyvinylpyrrolidone-iodine complex. Where polyvinylpyrrolidine-iodine is used this is preferably present in the range of from 1% to 12% by weight to give from 0.1% to 1.4% of available iodine in solution. The pH range of compositions according to the present invention is desirably maintained within the range from pH 3 to 7, preferably pH 4 to 6. The pH is conveniently maintained in the desired range by addition of a conventional buffer such as a citrate or phosphate buffer. Compositions according to the present invention may be formulated for administration by any convenient route conventional in the art. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients. Compositions according to the present invention are conveniently formulated for topical or mucosal administration in the form of solution, soaps, ointments, gels or paints. In a further aspect there is provided a process for preparing a pharmaceutical iodine composition according to the invention comprising forming a solution of iodine and at least one organic substance with which iodine reacts and adding iodate ions in the range of from 0.01% to 0.05% by weight. In an alternative aspect there is provided a method for the germicidal treatment of a mammal, including man, comprising administering a composition as defined above. It will be appreciated that reference to treatment is intended to include prophylaxis. In order that the invention may be well understood the following examples are given by way of illustration only. Example The following iodine compositions were prepared. Constituent I % w/w II (Comparative) % w/w III (Comparative) % w/w Povidone-iodine 10.00 10.00 10.00 (Overage %) (0) (20) (0) Glycerol 1.0 1.0 1.0 Nonoxynol 9 0.25 0.25 0.25 Potassium iodate 0.03 - 0.225 Citrate/phosphate buffer (Approx. 1.11 0.20 1.1 Sodium hydroxide q.s. q.s. q.s. Purified water to 100.00 to 100.00 to 100.00 A portion of the purified water (60%) was placed in a suitable vessel. Glycerol was added and mixed until the solution was uniform. Povidone-iodine was added and mixed until dissolved. Pottasium iodate was dissolved in a separate small quantity of purified water and added to the povidone-iodine solution. The citrate/phosphate were dissolved in water and added to the solution with mixing followed by the addition of Nonoxynol 9. The solution was made up with the remaining purified water and the pH adjusted to within the desired range. The cutaneous irritancy of the three compositions was assessed in a panel of 12 normal volunteer subjects. Each subject received 7 applications of each material under occlusive patches to separate sites on the back. The treatments were applied to 21 sites on the lower and upper parts of the back using 12mm aluminium Finn chambers on Scanpor tape with filter paper inserts. 50mcl of the solution was pipetted onto the filter paper. The chamber and filter paper was then applied to one of the sites on the back and the procedure repeated for all 21 sites. One chamber per treatment was removed after 1, 2, 3, 4, 5, 6 and 8 hours following application and the skin assessed. Assessments were performed 30 minutes after removal of the chambers to allow for any erythema due to chamber removal to subside. Following removal of the chambers, irritancy was assessed using three procedures. Sites were assessed for erythema/oedema using the following categorical scale: 0 - No reaction 0.5 - Slight patch erythema 1 - Slight uniform erythema 2 - Moderate erythema 3 - Strong erythema 4 - Strong erythema, spreading outside patch 5 - Strong erythema, spreading outside patch with either swelling or vesiculation 6 - Severe reaction with erosion When at any time point a site was scored as Grade 3 (strong erythema) or more, then the applications were removed from all remaining sites of that solution on that subject. In this situation, the sites were assessed at the same time points as originally scheduled as if no severe reactions had occurred. Erythema was also assessed using an Erythema Meter. Cutaneous blood flow was measured using a Laser Doppler blood flow device (Periflux blood flow meter, Perimed, Sweden). Method of Analysis In the clinical study the data was either non-parametric in nature or not normally distributed or not of equal variances. Therefore, it was decided that a non-parametric method of analysis was the most suitable. As the data is based on within subject comparison (each subject receiving all three treatments) the Friedman non-parametric analysis of variance was considered appropriate. Comparisons were made between treatments at t=1, t=2, t=3 and t=4 hours for the three parameters measured. If a significant value for the test statistic was found, then a multiple comparison procedure was carried out in order to determine individual treatment difference. The threshold value for significance was set at 5%. Analysis was not carried out at the later time points as in some subject the treatments had been removed. Results The results (means and standard deviations) for visual erythema assessment, erythema meter readings and blood flow measurements as shown in Figures 1-3. The results for all three methods of assessment show a clear difference in the irritancy potential of the three solutions. From the results it can be seen that composition III is the most irritant, producing the greatest rate of increase of parameters assessed as well as the highest mean values. II produced the second highest values whilst I produced the least irritancy. Statistical analysis confirmed these differences at the 2, 3 and 4 hour time points. It will be appreciated that these time periods are important in the clinical situation of an operation. An in-vitro study to compare the bactericidal activity of solutions I, II and III using standard microbiological dilution techniques against a test bacterial organism, Staphylococcus aureus NCTC 29213 showed no difference in the bactericidal activity of the three solutions.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LU, LI, NL, SE A pharmaceutical composition comprising an aqueous solution of from 0.75 to 1.25% by weight of elemental iodine and at least one iodine complexing polymer, or nonionic, anionic or cationic detergent carrier or surface active agent, whereby iodine loss is controlled by providing a source of iodate ions sufficient to provide from 0.01% to 0.04% by weight of iodate ions. A composition according to Claim 1 wherein the amount of iodate ions is within the rage of 0.02% to 0.03% by weight. A composition according to claim 1 or claim 2 wherein the iodine complexing agent comprises polyvinylpyrrolidone. A composition according to Claim 3 wherein the amount of polyvinylpyrrolidone is within the range of 1% to 12% by weight. A process for preparing a composition according to Claim 1 which comprises forming a solution of iodine and at least one iodine complexing polymer or nonionic, anionic or cationic detergent carrier or surface active agent and adding iodate ions in the range of from 0.01% to 0.04% by weight. Claims for the following Contracting States : ES, GR A process for preparing a pharmaceutical composition comprising an aqueous solution of from 0.75 to 1.25% by weight of elemental iodine and at least one organic component with which iodine reacts and which is an iodine complexing polymer, or nonionic, anionic or cationic detergent carrier or surface active agent whereby iodine loss is controlled by providing a source of iodate ions sufficient to provide from 0.01% to 0.04% by weight of iodate ions which comprise forming a solution of iodine and the at least one organic substance with which iodine reacts and adding iodate ions in the range of from 0.01% to 0.04% by weight. A process according to Claim 1 wherein the amount of iodate ions is within the range of 0.02% to 0.03% by weight. A process according to claim or claim 2 wherein the complexing polymer comprises polyvinylpyrrolidone. A process according to Claim 3 wherein the amount of polyvinylpyrrolidone is within the range of 1% to 12% by weight.

Inventors: BUXTON IAN RICHARD, LESLIE STEWART THOMAS, MALKOWSKA SANDRA THERESE ANTOI, MILLER ALLAN JOHN, MILLER RONALD BROWN, PRATER DEREK ALLAN, BUXTON, IAN RICHARD, LESLIE, STEWART THOMAS, MALKOWSKA, SANDRA THERESE ANTOINETTE, MILLER, ALLAN JOHN, MILLER, RONALD BROWN, PRATER, DEREK ALLAN
Applicants: EURO CELTIQUE SA, LADENBURG BV, EUROCELTIQUE S.A., LADENBURG B.V.
Application year: 1991
Main classification: A61K33
IPC codes: A61K9, A61L2, A61P31, A61K47, A61K33