Methods for increasing stability of dilute povidone iodine

Abstract

The invention provides methods for increasing long-term stability of dilute povidone iodine compositions, each comprising forming a formulation by mixing povidone iodine, a biocompatible polymer, water and optionally one or more excipients, thereby achieving a higher long-term stability (e.g., over 12 months, 24 months, or 36 months) as compared to formulations without said biocompatible polymer.

Description

[0001] METHODS FOR INCREASING STABILITY OF DILUTE POVIDONE IODINE

[0002] Background of the Invention

[0003] [1] Povidone iodine (PVP-I), also called iodophor, is a complex of polyvinylpyrrolidone and iodine, containing 9-12% effective iodine. It is a powerful disinfectant with broad-spectrum-applications and is effective against viruses, bacteria, fungi, and mold spores. PVP-I products have been used as disinfectants for the inactivation of various bacteria and viruses for years because of their strong bactericidal and antiviral activities. PVP-I is routinely used in ophthalmology and general surgery, as well as in acute and chronic treatment of a variety of other diseases. There have been numerous clinical studies demonstrating the safety of PVP-I in a variety of topical applications in ophthalmology, otology, rhinology and dermatology (see, e.g., US 5,126,127; US 2014 / 0219949; Jaya et al., Arch Otolaryngol Head NeckSurg. 2003,129:10:1098-240; Rooijackers-Lemmens et al., Huisarts Wet. 1995, 28:6:265-71; Rowlands et al., BrJ Gen Pract. 2001, 51:468:533-38; Kavanagh et al., World Articles in Ear Nose & Throat, IT May 2008; and US 2017 / 0266294). It causes little irritation on skin and has low toxicity and lasting effect, and thus can be used safely and easily. The virucidal activity is mainly due to the free iodine released from PVP-I (see, e.g., Wada et al., Biocontrol Sci. 2016, 21:1:21-7). The principle of disinfection by PVP-I is mainly through the release of hydrated iodine, which has bactericidal and virucidal effect. Povidone is hydrophilic and can carry iodine to cell membrane. When the PVP-I complex arrives at the cell wall, iodine is released and then forms complexes with amino acids of bacterial protein to denature and oxidize the active groups of the bacteria's protoplasmic protein at the same time, so that the bacteria would die rapidly. PVP-I is a great bactericidal agent with no antibiotic resistance. In common use, PVP-l's concentration is between 0.1% and 10%. Currently commercially available aqueous PVP-I preparations in with plastic packaging are generally in the forms of gel, suppository, cream, and solution, with PVP-I concentration ranging from 1% to 10%.

[0004] [2] PVP-I eyedrops have been widely used for the treatment of ocular infection, however a concentration of 5% or above may cause toxicity and irritation that cannot be overlooked. Grimesand others have treated infected eyes repeatedly with 0.02% PVP-I eye drops, which has the same germicidal effects as 5.0% PVP-I but without the toxicity and irritation. See, e.g., S.R. Grimes et al., Mil. Med., 1992, 157:111-113. In order to retain the PVP-I eye drops' sterilizing effect, while eliminating or reducing its toxicity to eyes, clinicians have used PVP-I eye drops with a concentration of 0.04% to disinfect eyes with no noticeable toxicity. It has been well documented in literature that PVP-I at concentrations less than 2% (w / w) is in fact tolerable and non-toxic. See, e.g., NC Santos et al. Arq. Bras. Oftalmol., June 2003, 66: 279-298. and J. Wu Jiang et al., Cutaneous and Ocular Toxicology, 2009, 28(3): 119-124. In the placebo-controlled trial of 459 children treated for bacterial, viral, and Chlamydia conjunctivitis with 1.25% PVP-I, there was no reported toxicity by slit-lamp examination and no subjects dropped out of the study due to intolerance of the eye drops. See, e.g., SJ. Isenberg et al. Am J Ophthalmol 2002, 134: 681-68. While tolerability seems to increase as the PVP-I concentration is lowered from 10% to 0.5%, the antimicrobial efficacy increases. This is due to the equilibrium distribution of iodine species in aqueous solutions. See e.g. Gottardi, W. J. Hosp. Infect., 6: (Suppl.) 1985. We have previously reported eye drops with a low concentration PVP-I in combination with dexamethasone, as potential treatment for acute conjunctivitis. See, e.g., US Patent No. 7,767,217 B2. Our US Patent No. 9308173B2 provides a slow-releasing ophthalmic formulation containing PVP-I where PVP-I exists as microspheres formed by PVP-I and sodium alginate and cured by calcium chloride.

[0005] [3] However, it is a well-known fact in the industry that the dilute povidone iodine aqueous solution is unstable, especially for long-term storage. As used herein, the term "dilute povidone iodine" refers to an aqueous povidone iodine solution having a low povidone iodine concentration such as less than 5% (e.g., less than 4%, less than 3%, or less than 1.5%) weight / weight. The stability of a dilute povidone iodine aqueous solution is mainly affected by many factors such as temperature, pH, light, concentration and packaging. Among them, povidone iodine will degrade rapidly at low concentration, and it is easy to decompose and sublimate during storage, thus reducing the assay of available iodine and failing to reach the effective bactericidal concentration. Therefore, the dilute povidone iodine solution needs to bestored at a lower temperature to slow down the degradation. However, even if the dilute povidone iodine solution is stored at a lower temperature, it still cannot guarantee its long-term stability, which is still a huge challenge.

[0006] [4] At present, many methods have been reported in the world to increase the stability of dilute povidone iodine aqueous solution, especially the stability of dilute povidone iodine aqueous solution. The stability of dilute povidone-iodine aqueous solution is improved by adding stabilizers, such as iodate disclosed in U.S. Pat. No. 4113857 (Shetty) and China Patent No. CN1965857 (Ceng Jie et al.), and iodide disclosed in U.S. Pat. No. 4996048 (Bhagwat et al.). However, by adding stabilizers to maintain the stability of dilute povidone iodine solution, potassium iodate or potassium iodide may cause potential toxic risks after long-term use in eyes or other parts (such as nose). Choosing the packaging material with low adsorption or low infiltration to povidone iodine as the packaging container of povidone iodine aqueous solution, such as using glass bottles or polyethylene terephthalate (PET) bottles as the packaging container of dilute povidone iodine aqueous solution as disclosed in U.S. Patent No.5, 178, 853. However, it only solves the problem of low adsorption or low infiltration of povidone iodine by packaging materials, and does not solve the problem that povidone iodine solution itself is easy to degrade. Choosing a suitable pH value to solve the stability of dilute povidone-iodine aqueous solution. The research shows that the stability of dilute povidone-iodine aqueous solution can be improved when the pH value is 3.8, but it still does not fundamentally solve the long-term stability problem.

[0007] [5] For dilute povidone-iodine aqueous solution, low-temperature storage is the best way to increase the stability of povidone-iodine aqueous solution, but it still can't guarantee its longterm stability. The invention provides a novel method, which can greatly increase the stability of dilute povidone-iodine aqueous solution, particularly the long-term stability (e.g., for at least 12 months, 24 months, or 36 months), so that the dilute povidone-iodine aqueous solution can be stable for a longer period of time and more suitable for the long-term storage.Brief Summary of the Invention

[0008] [6] This summary is provided to introduce a selection of concepts in a simplified form that is further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[0009] [7] The present invention is based on the unexpected discovery of the applicant that a particular formulation (e.g., an in-situ gel-forming formulation) made with biocompatible polymer and dilute povidone iodine surprisingly achieved advanced long-term stability (e.g., for at least 12 months, or 24 months, or 36 months). Without using any stabilizers (e.g., potassium iodate or potassium iodide), the biocompatible polymer can significantly increase the stability of dilute povidone iodine, and it can ensure the longer-term stability of dilute povidone iodine solutions.

[0010] [8] The gel formulation of dilute povidone iodine can be applied to the drug treatment of diseases related to body cavities such as ophthalmology, rhinology and gynecology. The dosage forms include ophthalmic formulation and nasal formulation, etc.

[0011] [9] The gel-forming formulation of dilute povidone iodine of the invention also includes other excipients that needed for the ophthalmic formulation and nasal formulation, etc.

[0012]

[0010] In particular, according to the present invention, an aqueous gel-forming formulation containing dilute povidone iodine may form a solution state by shaking during or prior to use, while forming or substantially maintaining a semi-solid state during storage time and achieve great benefits for prolonging its shelf life. For instance, the switching of the state between semisolid and solution may reduce the movement speed of molecules, thereby limitingthe movement of molecules or particles in solution during long-term storage. It also may reduce the chance of effective collision between molecules, and thus reduce the reaction speed of iodine decomposition and the escape speed of iodine sublimation, particularly for long-term storage.

[0013]

[0011] One aspect of the present invention provides a method for increasing long-term stability of dilute povidone iodine composition, which comprises forming a formulation by mixing povidone iodine, a biocompatible polymer, water and optionally one or more excipients, thereby achievinga higher long-term stability (e.g., over 36 months) as compared to a comparable formulation without said biocompatible polymer. For instance, the formulation may be an aqueous, ophthalmic or nasal solution.

[0014]

[0012] In some embodiments, the formulation is able to exhibit a long-term stability of over 85% available iodine assay for at least 12 months, 24 months, or 36 months under 2-8 °C.

[0015]

[0013] In some embodiments, the step of forming the formulation further comprises adding a sufficient amount of the biocompatible polymer to allow the formulation to form and substantially maintain a semi-solid state during storage.

[0016]

[0014] In some embodiments, the formulation is able to return to the state of solution by shaking prior to use, and form a gel in situ at physiological temperature with instant viscosity increase upon instillation of the formulation onto a body cavity of a subject.

[0017]

[0015] In some embodiments the biocompatible polymer comprises gellan gum (DGG), xanthan gum, sodium alginate, carrageenan, poloxamer or a combination thereof.

[0018]

[0016] In some embodiments, povidone iodine is present in the formulation at a concentration in the range of 0.1% (w / w) to 5.0% (w / w), 0.1% (w / w) to 2.5% (w / w), 0.1% (w / w) to 2.0% (w / w), 0.1% (w / w) to 1.5% (w / w), 0.1% (w / w) to 1.0% (w / w) , or 0.1% (w / w) to 0.5% (w / w).

[0019]

[0017] In some embodiments, the biocompatible polymer is present in the formulation at a concentration in the range from about 0.1% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.6%(w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.2% (w / w).

[0020]

[0018] In some embodiments, the biocompatible polymer is present in the formulation at a concentration in the range from about 0.1% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.6%(w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.2% (w / w).

[0021]

[0019] In some embodiments, the one or more excipients comprise a pH regulator, an osmoticpressure regulator, a viscosity regulator.

[0022]

[0020] Examples of the pH regulator include, but are not limited to, sodium hydroxide, tromethamine, and hydrochloric acid. In some embodiments, the resulting pH of the formulation ranges from 4.0 to 9.0 or from 4.0 to 6.0

[0023]

[0021] Examples of the osmotic pressure regulator include, but not limited to, sodium chloride, mannitol, and glycerol. In some embodiments, the osmotic pressure regulator is present in the formulation at a concentration ranging from about 0.01% (w / w) to about 5% (w / w).

[0024]

[0022] Examples of the viscosity regulator include but not limited to sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, and povidone. In some embodiments, the formulation has a desired viscosity, such as a viscosity ranging from 25 to 100 mpa.s. In some further embodiments, the formulation has a viscosity of about 100, 75, 50, 40, 30, 25 mpa.s.

[0025]

[0023] In some embodiments, the formulation does not include a stabilizer, such as potassium iodate and potassium iodide.

[0026]

[0024] In some embodiments, the formulation has a dosage form comprising aqueous solution, emulsion, suspension, suppository or any other liquid or semi-solid form.

[0027]

[0025] In some embodiments, the formulation is used for treating a disease (e.g., an infection or inflammation) related to a body cavity (e.g., ophthalmology, rhinology and gynecology).

[0028]

[0026] In some embodiments, the biocompatible polymer particularly comprises deacetylated gellan gum. In some embodiments, the povidone iodine has good chemical compatibility with deacetylated gellan gum

[0029]

[0027] In some embodiments, under that storage condition of 2-8°C, the gel-forming dilute povidone iodine solutions can be stable for at least 12 months, or 24 months, or 36 months, and available iodine assay is not less than 85%. This greatly increases the shelf-life of dilute povidone iodine solution.

[0030]

[0028] In some embodiments, under the storage condition of 25°C, the gel-forming formulation of dilute povidone-iodine solutions can be stable for at least 2 months, and available iodine assay isnot lower than 85%, so that it can be used conveniently at room temperature.

[0031]

[0029] As used herein, a "dilute" povidone iodine solution or formulation contains povidone iodine at the concentration not greater than 5%, measured either by weight / weight (w / w) or by weight / volume (w / v).

[0032]

[0030] As used herein, the term "available iodine" or "available iodine assay" refers to the free iodine that can be released from PVP-I complex to exert germicidal action.

[0033]

[0031] As used herein, the term "in-situ gel" or "Gel-forming" refers to a system which is applied as a solution and is capable of undergoing rapid sol-to-gel transformation triggered by external stimulus (such as temperature, pH, ion strength etc.) on instillation or spray, etc.

[0034]

[0032] As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0035]

[0033] As used herein, the terms "include", "includes" and "including" are meant to be non-limiting.

[0036]

[0034] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0037]

[0035] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. Other terms are defined herein within the description of the various aspects of the invention.Brief Descriptions of the Drawings

[0038]

[0036] The following figures illustrate by way of example and not limitation. For the sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers.

[0039]

[0037] Fig.l shows the stability data of 0.6% povidone iodine solution, 0.6% povidone iodine gelforming solution including DGG, 1.0% povidone iodine solution, 1.0% povidone iodine gelforming solution including DGG at 5 °C.

[0040]

[0038] Fig.2 shows the stability data of 0.6% povidone iodine solution, 0.6% povidone iodine gelforming solution including DGG, 1.0% povidone iodine solution, 1.0% povidone iodine gelforming solution including DGG at 25 °C.

[0041]

[0039] Fig. 3 shows the stability data comparison diagrams of Example 4 (25 °C).

[0042]

[0040] Fig. 4 shows the state of solution by shaking during use (A) and the state of semi-solid formed during storage (B).

[0043] Detailed Description of the Invention

[0044]

[0041] Reference will now be made in detail to the preferred embodiments of the invention, examples of which are further illustrated. While the invention will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the invention to these embodiments. To the contrary, the invention is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the claims. Furthermore, in the detailed description of the present invention, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be obvious to one of ordinary skill in the art that the present invention may be practiced without these specific details. In other instances, well known methods, procedures, components, and other features have not been described in detail as not tounnecessarily obscure aspects of the present invention.

[0045]

[0042] Generally speaking, various embodiments of the present invention provide for a novel method for increasing long-term stability and prolonging shelf life of dilute povidone iodine composition (e.g., aqueous, ophthalmic or nasal, dilute PVP-I solution). In particular, the method includes mixing dilute povidone iodine, a biocompatible polymer (e.g., DGG, at a concentration such as 0.2%-0.4%), water and optionally one or more excipients, thereby forming a formulation without conventional stabilizers (e.g., potassium iodate and potassium iodide), which unsurprisingly achieved great long-term stability. The long-term stability of the present invention is much higher than a comparable formulation without said biocompatible polymer.

[0046]

[0043] The addition of the biocompatible polymer (e.g., DGG), along with other ingredients, into a PVP-I dilute solution enables the formulation form and substantially maintain a semi-solid state during storage, while being able to return to the state of solution by shaking prior to use, and form a gel in situ at physiological temperature with instant viscosity increase upon instillation of the formulation onto a body cavity of a subject. More importantly, such particular state-switching feature surprisingly improves the long-term stability and prolongs the product's shelf life. For instance, under that storage condition of 2-8°C, the dilute povidone iodine solution according to the present invention can be stable for at least 12 months, 24 months or 36 months, and available iodine assay is not less than 85%. This greatly increases the shelf-life of dilute povidone iodine solution. Also, even under the storage condition of 25°C, the dilute povidone-iodine solutions according to the present invention can be stable for at least 2 months, and available iodine assay is not lower than 85%, so that it can be used conveniently at room temperature.

[0047]

[0044] Examples of the biocompatible polymers according to the present invention include, but are not limited to, gellan gum (DGG), xanthan gum, sodium alginate, carrageenan, poloxamer and a combination thereof. In some embodiments, the biocompatible polymer is particularly DGG. It was found that the povidone iodine has good chemical compatibility with deacetylated gellan gum, and DGG is able to significantly improve the long-term stability of the dilute PVP-I solutions.

[0048]

[0045] The formulation may include other suitable excipients such as a pH regulator, an osmoticpressure regulator, and / or a viscosity regulator.

[0049]

[0046] Examples of the pH regulator include but are not limited to sodium hydroxide, tromethamine, and hydrochloric acid. For instance, the resulting pH of the formulation may range from 4.0 to 9.0 or from 4.0 to 6.0

[0050]

[0047] Examples of the osmotic pressure regulator include, but not limited to, sodium chloride, mannitol, and glycerol. In some embodiments, its concentration may range from about 0.01% (w / w) to about 5% (w / w).

[0051]

[0048] Examples of the viscosity regulator include, but not limited to, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, and povidone.

[0052]

[0049] For instance, an exemplary formulation according to the present invention may include PVP-I (e.g., 1.0 %), DGG (e.g., 0.25%) and NaCI (e.g., 0.2%). The formulation according to the present invention may achieve a desired viscosity (e.g., about 100, 75, 50, 40, 30, or 25 mpa.s).

[0053]

[0050] The formulation according to the present invention can be applied to the treatment of diseases (e.g., an infection or inflammation) related to body cavities such as ophthalmology, rhinology and gynecology. The dosage forms may include ophthalmic formulation and nasal formulation, etc.

[0054]

[0051] The present invention is further elucidated with specific examples. It is understood that these examples are only used to describe the invention but not 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 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.Example 1: Screening of biocompatible polymer.

[0055]

[0052] Different kinds of biocompatible polymer were screened by the determination of gel strength and gel phase change ability. See Table 1-4 for the basic formula and viscosity measurement results.

[0056] Table 1: DGG

[0057]

[0058] Table 2. Xanthan gum

[0059]

[0060] Table 3. Carrageenin

[0061]

[0062]

[0063] Table 4. Sodium alginate

[0064]

[0065]

[0053] The results in Table 1-4 show that all the biocompatible polymer screened by the inventors can show certain gel strength and in-situ gel characteristics. Especially DGG, it shows strong gel strength and remarkable in-situ gel characteristics.

[0066] Example 2: Study on chemical compatibility between DGG and povidone iodine.

[0067]

[0054] The povidone iodine, DGG, sodium chloride, mannitol, tromethamine and water for injection are used. Samples of formulas 1 to 5 were prepared as described in Table 5. Take samples on the 0 day, 5 day, 10 day and 30 day to investigate the stability of samples under 25°C. The detection items are: assay.

[0068] Table 5

[0069]

[0070]

[0055] The results are shown in Table 6 below.

[0071] Table 6

[0072]

[0073]

[0074]

[0056] From the results in Table 6, it can be seen that under the condition of keeping samples for 30 days from Fl to F5, the assay changes did not exceed 5%, and there was no significant difference. This shows that the selected excipients have good chemical compatibility with povidone iodine, and povidone iodine has good chemical compatibility with DGG. This further indicates that biocompatible polymer has good chemical compatibility with povidone iodine. Example 3: Stability of dilute povidone-iodine aqueous solutions with different concentrations under storage conditions of 5 °C and 25 °C.

[0075]

[0057] Preparation of povidone iodine solutions: accurately weigh povidone iodine solid powder 20 g, 15 g, 10 g, 5 g and 2.5 g, respectively, add pure water to 1000 mL, and put them in 100 mL glass bottles with concentrations of 2.0%, 1.5%, 1.0%, 0.5% and 0.25%, respectively. Store at 5 °C and 25 °C. The percentage decrease of available iodine assay in 2 months and 5 months was investigated.

[0076]

[0058] The results of stability of the percentage decrease of available iodine assay are shown in Table 7.

[0077] Table 7

[0078]

[0079]

[0059] The results in Table 7 show that: 1) Dilute povidone-iodine aqueous solutions are unstable stored at 5°C or 25°C at either 2-month or 5-month. 2) With the increase of povidone iodine concentration, the dilute povidone iodine aqueous solution becomes more stable. 3) The lower the storage temperature, the higher the stability. 4) With the extension of storage time, the assay decreased continuously. 5) The above results are also consistent with information in the published literature. From the results in Table 7, it was also found that even if a dilute povidone-iodine aqueous solution was stored at 5°C, it still did not have a long-term shelf life, and its assay still decreased significantly over time.

[0080] Example 4: Comparative Study on the Stability of Dilute Povidone-iodine Aqueous Solution and Dilute Povidone-iodine Gel-Forming Solution at 25°C

[0081]

[0060] Table 8 shows the key formulation of dilute povidone iodine aqueous solution and dilute povidone iodine gel-forming solution.

[0082] Table 8

[0083]

[0084]

[0061] Prepare sample solution according to the formulation in Table 8 and put it in bottles. Store at 25 °C. Investigate the available iodine assay at 0 day, 1 month, 2 months, 3 months.

[0085]

[0062] The results of stability of the available iodine assay are shown in Table 9.Table 9

[0086]

[0087]

[0063] From the data in Table 9 (Fl vs F5, F2 vs F6, F3 vs F7, F4 vs F8), the long-term stability of dilute povidone-iodine gel-forming solution is much higher than that of dilute povidone-iodine aqueous solution. This result suggests that DGG can significantly increase the long-term stability of dilute povidone iodine in water, and further suggests that biocompatible polymer can significantly increase the long-term stability of dilute povidone iodine in water. This is an unexpected result and has never been reported in any published literature.

[0088] Example 5: Study on the stability of 0.6% povidone iodine gel-forming aqueous solution containing DGG at 5°C and 25°C.

[0089]

[0064] Table 10 shows the formulation of 0.6% povidone iodine aqueous solution containing DGG.

[0090] Table 10

[0091]

[0092]

[0093]

[0065] Prepared sample solutions according to the formulations in Table 10 and put them in PET bottles. Stored at 5 °C and 25 °C. Investigate the percentage decrease of available iodine assay at 1 month, 2 months, 3 months, 6 months and 9 months.

[0094]

[0066] The results of stability of the percentage decrease of available iodine assay are shown in Table 11.

[0095] Table 11

[0096]

[0097]

[0067] The results in Table 11 show that: 1) Compared with the research results shown in Example 3, although the assay of the sample solutions in this example also decreased, the overall downward trend was significantly slowed down, and the povidone iodine solution was more stable. 2) Comparing with the stability results of Example 3, it is surprisingly discovered that the sample solutions of this example are more stable, which is an unexpected discovery of this invention. It shows that gellan gum has played a role in stabilizing dilute povidone iodine (e.g., over a number of months), which is unexpected and has never been described in any published literature.

[0098] Example 6: Study on the stability of 1.0% povidone iodine gel-forming aqueous solution containing DGG at 5 °C and 25 °C.

[0099]

[0068] Table 12 shows the formulation of 1.0% povidone iodine aqueous solution containing DGG.Table 12

[0100]

[0101]

[0069] Prepared sample solutions according to the formulation in Table 12 and put them in glass bottles. Stored at 5 °C and 25 °C. Investigated the percentage decrease of available iodine assay at 1 month, 3 months, 6 months and 9 months.

[0102]

[0070] The results of stability of the percentage decrease of available iodine assay are shown in Table 13.

[0103] Table 13

[0104]

[0105]

[0071] The results in Table 13 show that: 1) Comparing with the 1.0% povidone iodine research results shown in Example 3, the available iodine content of the sample solution in this example did not decrease under the storage condition of 5°C, which is very stable. This is completely different from the changing trend that the available iodine content of the sample solutions in Example 3 which has been decreasing under the storage condition of 5°C. 2) Comparing with the research results of 1.0% povidone iodine shown in Example 3, although the available iodine content of the sample solutions in this example also decreased under the storage condition of 25°C, the overall downward trend was significantly slowed down and the povidone iodine solution was more stable. 3) Comparing with the stability results of Example 3, it is surprisingly discovered that the sample s of this example is more stable, which is an unexpected discovery of this invention. Under the storage condition of 5°C, the available iodine content did not decreaseat all. This suggests that DGG has played a key role in stabilizing dilute povidone iodine solution (e.g., over a number of months), which is unexpected discovery and has never been mentioned in any published literature.

[0106] Example 7: Further Long-term Stability of 1.0% povidone iodine ophthalmic gel-forming formulation containing DGG at 5 °C.

[0107]

[0072] Table 12 shows the formulation of 1.0% povidone iodine ophthalmic gel-forming formulation containing DGG.

[0108]

[0073] According to the formulation described in Table 12, the sample solution was prepared under GMP condition and put in PP eye drops. Store at 5°C. The available iodine assay was detected at 1 month, 3 month, 6 month, 9 month, 12 month, 18 month, 24 month, 30 month and 36 month. The stability results are provided in Table 14 .

[0109] Table 14

[0110]

[0111]

[0074] From the results in Table 14, it can be seen that available iodine assay of the formulation of the invention is above 85.0% when it is stored at 5°C for 36 months, which shows that the formulation of the invention can guarantee the 3-year shelf-life period of the dilute povidone iodine aqueous solution at least for 36 months at 5°C. This is a surprising result and an unexpected discovery, which has never been reported.

[0112]

[0075] In order to understand the clear picture of significantly improved stability of dilute povidone-iodine aqueous solutions, the inventors made the stability data comparison diagrams of 0.6% povidone-iodine aqueous solution, 0.6% povidone-iodine aqueous solution containing DGG, 1.0% povidone-iodine aqueous solution and 1.0% povidone-iodine aqueous solution containing DGG under the storage conditions of 5°C and 25°C, as shown in Fig. 1 and Fig. 2. The inventors also made the stability data comparison diagrams of Example 4, as shown in Fig. 3.

[0076] The aqueous gel-forming formulation containing dilute povidone iodine according to the present invention can form a solution state by shaking during use and is easy to use, but it can form a semi-solid state during storage. The inventor speculated that it was the switching of the state between semi-solid and solution that reduced the movement speed of molecules, thus limiting the movement of molecules or particles in solution, reducing the chance of effective collision between molecules, and thus reducing the reaction speed of iodine decomposition and the escape speed of iodine sublimation. Fig. 4 shows the state of solution by shaking during use (A) and the state of semi-solid formed during storage (B) .

[0113]

[0077] The description of the above embodiments is only for helping to understand the method of the invention. It should be pointed out that for those skilled in the art, without departing from the principle of the invention, several improvements and modifications can be made to the invention, and these improvements and modifications also fall within the scope of protection of the claims of the invention.

Claims

WHAT IS CLAIMED IS:

1. A method for increasing long-term stability of dilute povidone iodine composition comprising: forming a formulation by mixing povidone iodine, a biocompatible polymer, water and optionally one or more excipients, thereby achieving a higher long-term stability as compared to a comparable formulation without said biocompatible polymer.

2. The method of claim 1, wherein the formulation is able to exhibit a long-term stability of over 85% available iodine assay for at least 12 months, 24 months, or 36 months at 2-8 °C.

3. The method of claim 1 or 2, wherein the formulation is an aqueous, ophthalmic or nasal solution.

4. The method of any one of claims 1 to 3, wherein the step of forming the formulation further comprises adding a sufficient amount of the biocompatible polymer to allow the formulation to form and substantially maintain a semi-solid state during storage.

5. The method of any one of claims 1 to 4, wherein the formulation is able to return to the state of solution by shaking prior to use, and form a gel in situ at physiological temperature with instant viscosity increase upon instillation of the formulation onto a body cavity of a subject.

6. The method of any one of claims 1 to 5 , wherein the biocompatible polymer comprises ge Ila n gum (DGG), xanthan gum, sodium alginate, carrageenan, poloxamer or a combination thereof.

7. The method of any one of claims 1 to 6, wherein the povidone iodine is present in the formulation at a concentration in the range of 0.1% (w / w) to 5.0% (w / w), 0.1% (w / w) to 2.5% (w / w), 0.1% (w / w) to 2.0% (w / w), 0.1% (w / w) to 1.5% (w / w), 0.1% (w / w) to 1.0% (w / w) , or 0.1% (w / w) to 0.5% (w / w).

8. The method of any one of claims 1 to 7, wherein the biocompatible polymer is present in the formulation at a concentration in the range from about 0.1% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.6%(w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.2% (w / w).

9. The method of any one of claims 1 to 8, wherein the biocompatible polymer is present in theformulation at a concentration in the range from about 0.1% (w / w) to about 10% (w / w), from about 0.1% (w / w) to about 5% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% (w / w) to about 1% (w / w), from about 0.1% (w / w) to about 0.6%(w / w), from about 0.1% (w / w) to about 0.4% (w / w), from about 0.1% (w / w) to about 0.2% (w / w).

10. The method of any one of claims 1 to 9, wherein the one or more excipients comprise a pH regulator, an osmotic pressure regulator, a viscosity regulator.

11. The method of claim 10, wherein the step of forming the formulation further comprises adding the PH regulator to obtain a pH ranging from 4.0 to 9.0 or from 4.0 to 6.0, wherein the pH regulator comprises sodium hydroxide, tromethamine, or hydrochloric acid.

12. The method of claim 10 or 11, wherein the step of forming the formulation further comprises adding the osmotic pressure regulator, said osmotic pressure regulator comprising sodium chloride, mannitol, or glycerol.

13. The method of claim 12, wherein the osmotic pressure regulator is present in the formulation at a concentration ranging from about 0.01% (w / w) to about 5% (w / w).

14. The method of any of claims 10 to 13, wherein the step of forming the formulation further comprises adding the viscosity regulator, said regulator comprising sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, or povidone.

15. The method of any one of claims 1 to 13, wherein the formulation has a viscosity ranging from 25 to 100 mpa.s.

16. The method of any one of claims 1 to 15, wherein the formulation does not comprise a stabilizer.

17. The method of claim 16, wherein the stabilizer is selected from the group consisting of potassium iodate and potassium iodide.

18. The method of any one of claims 1 to 17, wherein the formulation has a dosage form comprising an aqueous solution, emulsion, suspension, suppository or any other liquid or semisolid form.

19. The method of any one of claims 1 to 18, wherein the formulation is used for treating a disease related to a body cavity.

20. The method of any one of claims 1 to 19, wherein the dilute povidone iodine composition contains povidone iodine at a concentration less than 5%, less than 4%, less than 3%, less than 1.5%, or less than 1% (weight / weight).

21. The method of any one of claims 1 to 20, wherein the dilute povidone iodine composition contains povidone iodine at a concentration less than 1.5% or less than 1% (weight / weight).

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