Stable Pharmaceutical Articles Containing Dilute Povidone Iodine Formulations

Abstract

The present invention provides a pharmaceutical article that includes a container and a dilute aqueous PVP-I formulation contained in the container, wherein the container is made of polyethylene terephthalate (PET) or polypropylene (PP). The pharmaceutical article provides the aqueous PVP-I formulation with surprisingly enhanced stability over PVP-I-formulations in other pharmaceutical package forms, without the need of a stabilizing agent in the PVP-I formulations.

Claims

1. A pharmaceutical article comprising a container and an aqueous povidone iodine (PVP-I) formulation contained in the container, wherein the container is made of polyethylene terephthalate (PET), polypropylene (PP), or any combination thereof, the PVP-I formulation contains PVP-I at a concentration not greater than 5%, and at least 90% of original available iodine content in the PVP-I formulation remains in the formulation after one month.

2. The pharmaceutical article of claim 1, wherein the container is made of polyethylene terephthalate (PET).

3. The pharmaceutical article of claim 1, wherein the container is made of polypropylene (PP).

4. The pharmaceutical article of claim 1, wherein the aqueous PVP-I formulation is in the form of a solution, suspension, paste, emulsion, cream, gel, or any other liquid or semi-solid form.

5. The pharmaceutical article of claim 1, wherein the PVP-I concentration is in the range of 0.1-5.0% (w/w or w/v), 0.1-2.5% (w/w or w/v), 0.1-1.5% (w/w or w/v), or 0.1-1.0% (w/w or w/v).

6. The pharmaceutical article of claim 5, wherein the PVP-I concentration is in the range of 0.1-1.5% (w/w or w/v) or 0.1-1.0% (w/w or w/v).

7. The pharmaceutical article of claim 5, wherein the PVP-I concentration is about 0.3%, 0.36%, 0.48%, 0.6%, or 1.0% (w/w or w/v).

8. The pharmaceutical article of claim 1, wherein the PVP-I formulation has a pH value in the range of pH 3.5 to pH 7.0.

9. The pharmaceutical article of claim 1, wherein the PVP-I formulation is either buffered or non-buffered.

10. The pharmaceutical article of claim 1, wherein the container further comprises a bottle, a tip, or a dropper, and a cap.

11. The pharmaceutical article of claim 10, wherein the tip or dropper is made of HDPE; or the cap is made of PP or HDPE.

12. The pharmaceutical article of claim 1, wherein the PVP-I formulation is free from a stabilizing agent.

Description

BRIEF DESCRIPTIONS OF THE FIGURES

[0018] FIG. 1 shows the stability data of 0.6% PVP-I formulation (pH 5.5) at 25° C. in borosilicate glass (amber glass), PP, and PET bottles.

[0019] FIG. 2 shows the stability data of 1.0% PVP-I formulation (pH 5.5) at 25° C. in borosilicate glass, PP, and PET bottles.

[0020] FIG. 3 shows the stability data of 0.6% PVP-I formulation (pH 5.5) at 5° C. in borosilicate glass, PP, and PET bottles.

[0021] FIG. 4 shows the stability data of 1.0% PVP-I formulation (pH 5.5) at 5° C. in borosilicate glass, PP, and PET bottles.

[0022] FIG. 5 shows the stress study results of 0.6% PVP-I formulation (pH 5.5) at 40° C. in borosilicate glass, PP, and PET bottles.

[0023] FIG. 6 shows the stability data of 1.0% PVP-I formulation (pH 4.0) at 25° C. in borosilicate glass, PET, HDPE and PP bottles.

[0024] FIG. 7 shows the stability data of 1.0% PVP-I formulation (pH 4.5) at 25° C. in borosilicate glass, PET, HDPE and PP bottles.

[0025] FIG. 8 shows the stability data of 1.0% PVP-I formulation (pH 5.6) at 25° C. in borosilicate glass, PET, HDPE and PP bottles.

[0026] FIG. 9 shows the stability data of 1.0% PVP-I formulations (pH 4.5) at 25° C. in PET and PP bottles.

[0027] FIG. 10 shows the stability data of 1.0% PVP-I formulation (pH 5.0) at 25° C. in PET and PP bottles.

[0028] FIG. 11 shows the stability data of 1.0% PVP-I formulation (pH 5.6) at 25° C. in PET and PP bottles.

DETAILED DESCRIPTION OF THE INVENTION

[0029] At low concentrations, PVP-I will degrade quickly and low-concentration PVP-I solutions cannot be effectively maintained during storage. Therefore, dilute PVP-I products (with a PVP-I concentration not greater than 5%, w/w or v/w) generally need to be stored at a lower temperature; yet it still remains a challenge to maintain a reasonable shelf-life of dilute PVP-I solutions. Plastic bottles such as high-density polyethylene (HDPE) have been used as the packaging containers for PVP-I solutions with higher PVP-I concentrations, e.g., greater than 5% (weight/volume or weight/weight). For instance, 10% PVP-I antiseptic solutions (Betadine®) are packaged in HDPE plastic bottles, as do the 5% PVP-I ophthalmic solution for pre-op and post-op ophthalmic surgery disinfection. In other words, packaging material does not appear to have an effect on the stability of PVP-I solution with high concentrations (greater than 5%). However, Applicant unexpectedly discovered that the package material is critical for the stability of dilute PVP-I solutions (with PVP-I concentrations less than 5%). Specifically, it was demonstrated that HDPE did not yield better stability as compared to glass bottle in our previous experiments. Similar effort has been done with low density polyethylene (LDPE) bottles; and it was found that PVP-I formulation has lower stability in LDPE bottles than in HDPE bottles. All LDPE samples showed yellowing at the end of 1 week and there was a noticeable smell associated with samples. Therefore, it has demonstrated that dilute PVP-I solutions were unstable in LDPE bottles. In U.S. Pat. No. 5,126,127, Bhagwat describes stabilizing a dilute 0.3-0.6% PVP-I ophthalmic solution by adding a stabilizing agent (i.e., an alkalinizing agent) to the PVP-I solution, rendering the PVP-I solution stable for three years at room temperature in a non-permeable container, preferably glass bottles, and being nonbuffered.

[0030] The stable dilute compositions in this invention contain povidone Iodine (PVP-I). The concentration of the PVP-I may range from 0.1% to 5% (weight/weight or weight/volume, w/w or w/v), from 0.3% to 1% (w/w or w/v), or from 0.3% to 0.6% (w/w or w/v). The composition may also contain excipients such as pH adjustment agents, viscosity adjustment agents, and osmotic pressure regulator. The packaging container of this composition is made of polyethylene terephthalate (PET), high-density polyethylene (HDPE), or polypropylene (PP) plastic material, which enhances storage stability of the aqueous composition as compared to glass containers. No stabilizer was not required in the compositions in this patent.

[0031] The pH regulator contained in the formulations of this invention can include sodium hydroxide, trishydroxymethylaminomethane (Tromethamine, Tris), or phosphoric acid, resulting in a pH of 3.5 to 7.0 or 4.0 to 6.0.

[0032] The viscosity adjustment agents of this invention can be any ingredients used in prior art.

[0033] The osmotic pressure regulator contained in the formulations of this invention may include sodium chloride, glycerol, polyethylene glycol 400 (PEG400), mannitol, or borate, with a concentration ranging from 0.1 to 0.9% (w/v) or from 0.2 to 0.4% (w/v).

[0034] The stable dilute PVP-I composition can be in the form of aqueous solution, emulsion, suspension, cream, gel, or any other liquid and semi-solid forms.

[0035] The invention is further elucidated with specific examples. It is understood that these examples are only used to describe the invention but not to intend to limit the scope of invention. The experimental methods with no specific conditions in the following examples, are usually prepared under conventional conditions in the literature or according to the conditions suggested by the excipient manufacturer. Unless specifically stated, all percentages, ratios, proportions or fractions disclosed in this invention are calculated by weight by weight. Unless specifically defined in this invention, all professional and scientific terms used herein have the same meaning as well-trained personnel may be familiar with. In addition, any methods and materials similar or equivalent to those recorded in this invention can be applied to this invention. The preferred embodiments and materials described herein are used only for exemplary purposes.

[0036] No stabilizing agent was added in the preparation of the PVP-I solutions or formulations described in the following examples. Unless otherwise stated, the PVP-I concentrations referred to in the following examples are based on w/w.

Example 1

[0037] Dilute aqueous PVP-I solutions of different concentrations and pH values were prepared with a formulation recipe described in U.S. Pat. No. 7,767,217 B2. Briefly, the aqueous solutions contained 0.36-0.60% PVP-I, 0.1% dexamethasone, 0.01% ethylenediaminetetraacetic acid (EDTA), 0.3% sodium chloride, 1.2% sodium sulfate, 0.05% Tyloxapol and 0.25% hydroxyethyl cellulose. The pH values of the solutions were adjusted to 4.0 or 4.5 by sulfuric acid and/or sodium hydroxide. The final dilute aqueous solutions as prepared were packaged in amber glass or HDPE bottles. The stability of these dilute aqueous solutions was evaluated at different temperatures by measuring the amounts of available iodine in these dilute aqueous solutions by titration for 2 weeks. As used herein, the term “available iodine” means the free iodine that can be released from PVP-I complex to exert germicidal action thereof, which can be titrated with a standardized sodium thiosulfate solution as the titrant and starch solution as the indicator.

[0038] As an example of the titrant or titration method used herein, about 3-10 gram of a PVP-I solution was weighed into a suitable flask and about 10 g of purified water was added in the flask to result in a diluted solution. Titration was performed as soon as the dilute solution became homogenous using a standard sodium thiosulfate solution (e.g., 0.02 mol/L, 0.004 mol/L, or another suitable concentration). When the color became slightly yellow, about 10 drops of starch indicator was added dropwise to titrate the solution slowly. The end point was achieved once the solution became visually colorless. The available iodine in the sample was calculated as follows:

available iodine (mg)=volume titrant (ml)×Titrant Concentration(N)×126.9

[0039] Table 1 lists the percentage of available iodine based on initial content for different solutions under at different storage conditions.

TABLE-US-00001 TABLE 1 PVP-I stability after storage for 2 weeks (available iodine percentage based on initial amounts of available iodine) Container Solutions material 25° C. 30° C. 40° C. 0.6% PVP-I (pH 4.0) Glass 99% 97% 88% HDPE 92% 90% 64% 0.6% PVP-I (pH 4.5) Glass 97% 98% 88% HDPE 92% 83% 65% 0.48% PVP-I (pH 4.0) Glass 103%  100%  87% HDPE 92% 88% 57% 0.48% PVP-I (pH 4.5) Glass 94% 94% 80% HDPE 87% 81% 55% 0.36% PVP-I (pH 4.0) Glass 92% 92% 79% HDPE 82% 74% 40% 0.36% PVP-I (pH 4.5) Glass 87% 91% 76% HDPE 84% 75% not tested

[0040] The data show that the dilute aqueous PVP-I solutions were more stable in amber glass bottles as compared to in HDPE bottles when the pH values of these formulations were either 4 or 4.5. The stability difference between the two types of bottles increased with the decrease in PVP-I concentration. Further, the more dilute the aqueous PVP-I solutions were in both amber glass and HDPE containers, the less stable were the solutions. For 0.6% PVP-I formulation (pH 4.0) at 40° C. after two weeks, the difference in available iodine between in the two different bottles was 24%, while the difference was 30% for 0.48% PVP-I solutions and 39% for 0.36% PVP-I solutions. This trend was not significant for stability at 5° C. as the dilute aqueous PVP-I solutions were more stable at a low temperature. Therefore, the amber glass containers/bottles contributed more stability for these dilute aqueous PVP-I solutions at lower PVP-I concentrations. The dilute PVP-I solutions also showed better stability with a lower pH value.

Example 2

[0041] Two dilute aqueous PVP-I eye drop formulations containing 0.6% PVP-I and 1.0% PVP-I were prepared according to the compositions set forth below in Table 2.

TABLE-US-00002 TABLE 2 PVP-I Eye Drop Formulations Ingredient 0.6% PVP-I Formulation 1.0% PVP-I Formulation PVP-I 0.63 1.  Gellan gum 0.25 0.25 Sodium Chloride 0.25 0.25 Mannitol 3.5  3.3  Tromethamine as needed as needed Distilled water Q.S. Q.S. pH 5.5  5.5 

[0042] The stability of these two dilute low-concentration PVP-I eye drop formulations was investigated after they were filled into amber borosilicate glass bottles, PET bottles, and polypropylene (PP) bottles, respectively. Table 3 and Table 4 below list the results of the stability studies of these dilute aqueous PVP-I solutions after they were stored at different time points at 25° C. The concentration of PVP-I was determined by sodium thiosulfate titration as descripted in Example 1.

TABLE-US-00003 TABLE 3 Stability data of 0.6% PVP-I formulations (pH 5.5) at 25° C. Container 0 15 days 1 month 2 months 3 months 6 months Borosilicate amber glass 102.7 79.1 77.9 73.9 71.4 61.0 bottle PET bottle 100.9 98.8 97.8 95.8 94.8 92.8 PP bottle 100.8 93.4 90.6 86.0 83.5 76.7

TABLE-US-00004 TABLE 4 Stability data of 1.0% PVP-I formulations (pH 5.5) at 25° C. Container 0 15 days 1 month 2 months 3 months 6 months Borosilicate amber glass 101.8 90.1 92.4 90.6 88.0 86.8 bottle PET bottle 101.3 99.2 99.5 99.3 98.5 99.1 PP bottle 101.1 94.7 96.0 93.7 91.6 88.2

[0043] FIGS. 1 and 2 show the data from the stability tests of these dilute aqueous formulations of 0.6% PVP-I (pH 5.5) at 25° C. in Borosilicate amber glass, PP, and PET bottles, and of the dilute aqueous formulations of 1.0% PVP-I (pH 5.5) at 25° C. in Borosilicate amber glass, PP, and PET bottles.

[0044] Similar stability study was conducted at 5° C. The results are shown in Tables 5 and 6 and FIGS. 3 and 4.

TABLE-US-00005 TABLE 5 Stability data of 0.6% PVP-I formulations (pH 5.5) at 5° C. Container T0 1 month 50 days 3 months 6 months 9 months Borosilicate amber glass 102.7 90.6 87.7 86 87.3 84.0 bottle PET bottle 100.9 99.6 100 101.4 101 98.9 PP bottle 100.8 96.3 97.2 98.6 97.5 93.4

TABLE-US-00006 TABLE 6 Stability data of 1.0% PVP-I formulations (pH 5.5) at 5° C. Container T0 1 month 50 days 3 months 6 months 9 months Borosilicate amber glass 101.8 98.3 97.9 99.5 98.7 99.3 bottle PET bottle 101.3 102.2 104 103.1 103.8 102.0 PP bottle 101.1 101.5 102 101.5 101.2 99.0

[0045] As shown in Tables 3-6 and FIGS. 1-4, both 0.6% and 1.0% aqueous PVP-I formulations (at pH 5.5) in PET bottles had significantly better stability than those in PP bottles and in amber glass bottles. For 0.6% PVP-I Formulation, PP bottles provide significantly better stability that amber glass bottle. The available iodine was still 92.8% after 6 months at 25° C. for solutions in PET bottles while the available iodine was 76.6% for solutions in PP bottles and 61.0% for solutions in amber glass bottles. For 1.0% formulation, PP bottles provide slightly better stability for the PVP-I solutions than amber glass bottle. The available iodine was 99.1% after 6 months at 25° C. for solutions in PET bottles while the available iodine was 88.2% for solutions in PP bottles and 86.8% for solutions in amber glass bottles. All the dilute PVP-I formulations prepared and studied in this Example had the pH value of 5.5. This is surprisingly contradictory to what were descried in prior arts that plastic bottles, particularly PET bottles and PP bottles, provided better stability for dilute PVP-I solutions than amber glass bottles. Another surprising and unexpected discovery is that the dilute PVP-I solutions or formulations at pH 5.5 exhibited very different stability trends in different packaging containers, as comparing to the same solutions with pH of 4.0 or 4.5.

Example 3

[0046] A 30-day stress study at 40° C. was conducted with the 0.6% aqueous PVP-I formulations, packaged in borosilicate amber glass bottle, PET bottle, and PP bottle. “Stress study” in here, as per FDA guidance “Q1A(R2) Stability Testing of New Drug Substances and Products”, means the storage temperature is above the temperature for accelerated testing temperature (which is 25° C. herein). The stability results are shown in Table 7 and FIG. 5.

TABLE-US-00007 TABLE 7 30-day stress study at 40° C. for 0.6% PVP-I formulation (pH 5.5) Container 0 day 5 days 10 days 15 days 30 days Borosilicate glass bottle 102.7 75.7 67.6 63.3 55.8 PET bottle 100.9 92.0 94.5 91.2 88.8 PP bottle 100.8 80.4 80.9 73.9 63.5

[0047] The results listed in Table 7 and shown in FIG. 5 demonstrate that for the 0.6% aqueous PVP-I formulations of pH 5.5, PET bottles also provided the best stability, significantly better than PP bottles and glass bottles with unexpected stability of available iodine content over 85% after 30 days at 40° C., and PP bottles provide better stability than amber glass bottles.

Example 4

[0048] A heat cycle study was conducted for the 0.6% PVP-I formulation of pH 5.5 and the stability assay result is shown in Table 8. For the heat cycle study in this example, the samples were firstly placed in a −20.sup.˜-10° C. environment for two days and then placed in a 40° C. environment for two days as one cycle. The heat cycle study was performed for 3 cycles with a total of 12 days.

TABLE-US-00008 TABLE 8 Heat cycle study result for 0.6% PVP-I formulation (pH 5.5) Borosilicate amber glass bottle PET bottle PP bottle 12-day 12-day 12-day 0 day cycle 0 day cycle 0 day cycle Available 102.7 69.8 100.9 91.6 100.8 79.9 Iodine %

[0049] It can be seen that PET bottles provide the best stability in the heat cycle study, with over 90% available iodine content after the 5-day heat cycle, and PET bottles provided significantly better stability of dilute PVP-I solutions than PP bottles and glass bottles. PP bottles provide significant better stability than glass bottles for 0.6% PVP-I formulation (pH 5.5).

Example 5

[0050] 1.0% aqueous PVP-I formulations of pH 4.0, pH 4.5 and pH 5.6 were prepared with the compositions listed in Table 9.

TABLE-US-00009 TABLE 9 1.0% PVP-I Formulations with different pH values 1.0% PVP-I, 1.0% PVP-I, 1.0% PVP-I, Ingredient pH 4.0 pH 4.5 pH 5.6 PVP-I 1.05 1.05 1.05 Gellan gum 0.25 0.25 0.25 Sodium Chloride 0.20 0.20 0.20 Mannitol 3.3  3.3  3.3  Tromethamine as needed as needed as needed Distilled water Q.S. Q.S. Q.S. pH 4.0  4.5  5.6 

[0051] The 1.0% PVP-I formulations were filled in amber glass bottles, PET bottles 1, PET bottles 2, HDPE bottles and PP bottles and their stability was evaluated at 25° C. and 60% relative humidity. Tables 10-12 list the PVP-I stability test results after storing at different time points at 25° C. The available iodine content was determined by titration with sodium thiosulfate.

[0052] Table 10-12 and FIGS. 6-8 show the data obtained from the stability of these 1.0% aqueous PVP-I formulations.

TABLE-US-00010 TABLE 10 Stability data of 1.0% PVP-I, pH 4.0 formulations at 25° C. Packaging T = 0 1 month 2 months 3 months Borosilicate amber glass bottle 99.4 86.0 83.0 75.5 PET bottle 1 92.7 93.4 92.5 PET bottle 2 97.3 90.3 86.9 HDPE bottle 83.8 78.4 72.0 PP bottle 82.1 80.1 73.5

[0053] Specifically, Table 10 and FIG. 6 show the surprising stability of the 1.0% PVP-I formulations (pH 4.0) over three months at 25° C. in Borosilicate amber glass, PET, HDPE and PP bottles. PE bottles show surprisingly stabling effect on the PVP-I formulations, with 89.55% of available iodine on average remaining in the 1.0% PVP-I formulations after 3 months, much higher than amber glass, HDPE, or PP bottles.

TABLE-US-00011 TABLE 11 Stability data of 1.0% PVP-I, pH 4.5 formulations at 25° C. Packaging T = 0 1 month 2 months 3 months Borosilicate amber glass bottle 96.5 88.1 83.6 77.9 PET bottle 1 88.8 92.2 89.0 PET bottle 2 91.0 92.3 88.9 HDPE bottle 84.3 77.6 71.3 PP bottle 82.4 77.9 72.0

[0054] Table 11 and FIG. 7 show the similarly surprising stabilizing effect of PET bottles on the 1.0% PVP-I formulations (pH 4.5) at 25° C., which kept at least 89% of available iodine on average remaining in the 1.0% PVP-I formulations after 3 months, also much higher than amber glass, HDPE or PP bottles.

TABLE-US-00012 TABLE 12 Stability data of 1.0% PVP-I, pH 5.6 formulations at 25° C. Packaging T = 0 1 month 2 months 3 months Borosilicate amber glass bottle 93.5 86.4 82.2 74.0 PET bottle 1 91.9 92.1 90.8 PET bottle 2 92.0 94.9 89.2 HDPE bottle 86.9 80.2 76.9 PP bottle 86.2 82.7 77.1

[0055] Lastly, Table 12 and FIG. 8 also show the similarly surprising effect of PET bottles on stabilizing the 1.0% PVP-I formulations (pH 5.6) at 25° C., which kept at least 90% of available iodine on average remaining in the 1.0% PVP-I formulations after 3 months, also much higher than amber glass, HDPE or PP bottles.

[0056] In summary, the stability of dilute PVP-I solutions in containers of different materials varied depending on the solutions' pH values. Yet, it was surprisingly discovered that for formulations at all pH values, PET bottles provided the best stability compared to amber glass bottles, HDPE bottles, and PP bottles, particularly the amber glass bottles which have been widely used for over a century. For 1.0% aqueous PVP-I formulations of pH 4.0 and pH 4.5, glass bottles provided better stability than HDPE bottles and PP bottles. While for pH 5.6 formulations, HDPE bottles and PP bottles provided slightly better stability than glass bottles up to 3 months. The two PET bottles from two different sources did not result in significant difference.

Example 6

[0057] Additional aqueous 1.0% PVP-I formulations at different pH (pH 4.5, pH 5.0 and pH 5.6) were prepared to have the formulae listed in Table 13.

TABLE-US-00013 TABLE 13 1.0% PVP-I Formulations of different pH 1.0% PVP-I, 1.0% PVP-I, 1.0% PVP-I, Ingredient pH 4.5 pH 5.0 pH 5.6 PVP-I 1.05 1.05 1.05 Gellan gum 0.25 0.25 0.25 Sodium Chloride 0.20 0.20 0.20 Mannitol 3.3  3.3  3.3  Tromethamine As needed As needed As needed Distilled water Q.S. Q.S. Q.S. pH 4.5  5.0  5.6 

[0058] The stability of these PVP-I formulations was evaluated at 25° C. with 60% relative humidity (RH) by determining the concentrations of available PVP-I by sodium thiosulfate titration, after the formulations were filled in PET bottles, PET bottles and PP bottles. Tables 14-16 and FIGS. 9-11 show the results from the stability tests after the formulations were stored at different time points at 25° C.

TABLE-US-00014 TABLE 14 Stability data of 1.0% PVP-I, pH 4.5 formulations at 25° C. and 60% RH Packaging T = 0 1 month 2 months 3 months PET bottle 1 99.6 94.6 93.3 96.7 PET bottle 2 93.5 92.4 93.2 PET bottle 3 92.6 93.1 92.1 PP bottle 87.0 82.1 79.0

[0059] Table 14 and FIG. 9 show that the 1.0% PVP-I formulations (pH 4.5) were surprisingly much more stable in PET bottles over a three-month period when they were stored at 25° C. and 60% relative humidity (RH), with 95% (on average) of the PVP-I still available after three months in PET bottles, compared to under 80% in PP bottles.

TABLE-US-00015 TABLE 15 Stability result of 1.0% PVP-I, pH 5.0 formulation at 25° C. and 60% RH Packaging T = 0 1 month 2 months 3 months PET bottle 1 99.6 95.0 95.9 91.0 PET bottle 2 94.9 93.7 91.6 PET bottle 3 93.3 92.5 91.4 PP bottle 87.5 83.7 79.3

[0060] Similarly, Table 15 and FIG. 10 show that the 1.0% PVP-I formulations (pH 5.0) were surprisingly much more stable in PET bottles over a three-month period when they were stored at 25° C. and 60% relative humidity (RH), with at least 91% of the PVP-I still available after three months in PET bottles, compared to under 80% in PP bottles.

TABLE-US-00016 TABLE 16 Stability data of 1.0% PVP-I, pH 5.6 formulations at 25° C. and 60% RH Packaging T = 0 1 month 2 months 3 months PET bottle 1 97.5 93.1 93.5 92.6 PET bottle 2 94.1 91.3 92.7 PET bottle 3 93.5 89.7 90.2 PP bottle 90.2 83.9 76.7

[0061] Lastly, Table 16 and FIG. 11 also show that the 1.0% PVP-I formulations (pH 5.6) were surprisingly much more stable in PET bottles over a three-month period when they were stored at 25° C. and 60% relative humidity (RH), with at least 91% (on average) of the PVP-I still available after three months in PET bottles, compared to well under 80% in PP bottles.

[0062] It was surprisingly discovered that for 1.0% aqueous PVP-I formulations of various pH values, PET bottles provided the best stability and was significantly better than PP bottles. For the three PET bottles from different sources, there is no significant difference.

[0063] In summary, dilute PVP-I formulations in PET bottles provide the best stability than those in amber glass bottles, HDPE bottles and PP bottles. Amber glass bottles provided better stability for dilute PVP-I solutions than HDPE bottles and PP bottles at lower pH (pH 4.0 and pH 4.5) did. PP bottles and HDPE bottles provided better stability for dilute PVP-I solutions than amber glass bottle at higher pH (e.g., pH 5.5), especially for lower PVP-I concentration (e.g. 0.6%).