Antibacterial compositions and methods

Abstract

An antibacterial composition comprises: an antimicrobial agent comprising molecular iodine (I2); an iodide salt; a hydroxycarboxylic acid present in a concentration of at least 2% by weight, based on the total weight of the antibacterial composition; and a nonionic surfactant. The antibacterial composition does not contain any amount of anionic surfactant.

Description

Background Art

[0001] Antimicrobial compositions have been discussed, for example, in U.S. Patent No. 7,147,873, U.S. Patent No. 6,838,078, U.S. Patent No. 8,808,722, U.S. Patent No. 10,052,384, U.S. Patent No. 11,259,521, U.S. Patent No. 11,096,958, and German Patent DE10201401069. Detailed Description

[0002] In the industrialized world, it is standard practice to disinfect the skin prior to any invasive procedure such as surgery, catheterization, or needle puncture to reduce the risk of infection. It has also been proposed to decontaminate the oral cavity and nasal cavity to reduce the incidence of infection during cardiac surgery and / or to reduce the spread of methicillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities. These products are commonly referred to as skin preparations, nasal preparations, oral preparations, or simply "preparations".

[0003] Molecular iodine (I2) has proven to be an outstanding antimicrobial agent for such antimicrobial compositions. In many antimicrobial compositions, iodine as an antimicrobial agent is provided in solution in the form of "iodophors", which are complexes of elemental iodine or triiodide with certain carriers. These iodophors not only serve to increase the solubility of iodine, but also to reduce the level of free molecular iodine in the solution and to provide a reservoir for the sustained release of a class of elemental iodine. Among the available iodophors, povidone iodine is particularly useful.

[0004] It has been shown that other components can further enhance the antimicrobial efficacy of molecular iodine. For example, adding hydroxycarboxylic acids as buffers to antimicrobial compositions can advantageously increase the level of bacterial "kill". U.S. Patent No. 7,147,873 (Scholz et al.) reported that high levels of hydroxycarboxylic acids (above 5% weight / weight) can significantly improve antimicrobial efficacy. Therefore, for most antimicrobial compositions, the use of a combination of high levels of hydroxycarboxylic acids with iodophors such as povidone iodine seems to be quite desirable.

[0005] While desirable for higher microbial kill, high levels of hydroxycarboxylic acids can shorten the effective life of the antimicrobial composition. In some cases, hydroxycarboxylic acids tend to ultimately reduce the available free iodine and decrease the stability of the composition.

[0006] A variety of surfactants employed at high concentrations have been used to address the problem of composition instability. For example, mixtures of anionic surfactants, zwitterionic surfactants, and nonionic surfactants have been used to enhance stability. However, many of these surfactants, particularly anionic surfactants, have regulatory issues (US FDA). Thus, components that promote the stability of these compositions containing iodine and hydrocarboxylic acids and that do not have regulatory issues (e.g., are on the list of inactive excipients approved by the US FDA) are desirable.

[0007] In this regard, surprisingly, it has been found that stable compositions can be obtained by increasing the concentration of certain nonionic surfactants even in the absence of the aforementioned anionic surfactants. Further surprisingly, it has been found that such stable compositions can be obtained even at relatively low levels of total iodine (which provides benefits such as reducing skin irritation or blood levels of iodine), where stability is more difficult to control.

[0008] The term "iodine-stable" means that the composition does not suffer a loss of available iodine greater than about 25% weight / weight from the original value (i.e., concentration) when aged at 40 °C for about 6 months in a closed (i.e., sealed and not allowing any components to evaporate) and non-reactive container.

[0009] The terms "tissue antimicrobial composition", "antimicrobial composition", "composition", "skin preparation", and "preparation" herein refer to a composition that is active (i.e., effectively kills and / or inactivates) against at least one bacterium on skin and / or mucosal tissue.

[0010] In the context of the compositions of the present disclosure, the term "available iodine" refers to all species of iodine (including triiodide ions and molecular iodine) that can be titrated with sodium thiosulfate.

[0011] In the context of the compositions of the present disclosure, the term "total iodine" refers to the iodine content present in all forms, including iodine salts and molecular iodine (I2).

[0012] The term "amine oxide" includes compounds, oligomers, and polymers containing one or more amine oxide groups, as well as compounds containing a single amine oxide group.

[0013] As used herein, materials on the list of inactive excipients approved by the US FDA refer to those materials listed in the database of inactive ingredients on the US FDA website (updated as of 10 / 20 / 2022) for nasal or topical or oral use.

[0014] In this document, when these terms appear in the specification and claims, the term "comprising" and its variations do not have a limiting meaning.

[0015] As used herein, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, an antimicrobial composition comprising "an" surfactant can be interpreted to mean that the antimicrobial composition comprises "one or more" surfactants.

[0016] As used herein, unless the context clearly dictates otherwise, the term "or" is generally used in its inclusive sense of "and / or."

[0017] The term "and / or" means one or all of the recited elements or a combination of any two or more of the recited elements (e.g., killing and / or inactivating bacteria means inactivating bacteria, killing bacteria, or both inactivating bacteria and killing bacteria).

[0018] Also herein, a numerical range expressed by endpoints includes all numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0019] The following description more specifically illustrates exemplary embodiments. Throughout the application, guidance is provided by way of lists of examples, which may be used in various combinations. In each case, the recited lists are only used as representative groups and should not be construed as exclusive lists.

[0020] In some embodiments, the present disclosure relates to an antibacterial composition comprising: (i) an antimicrobial agent comprising molecular iodine (I2) (e.g., in the form of povidone iodine); (ii) an iodide salt (e.g., sodium iodide); (iii) a hydroxycarboxylic acid; and (iv) a nonionic surfactant; and does not contain a significant amount of anionic surfactant.

[0021] In some embodiments, the antibacterial composition may comprise an antimicrobial agent that comprises molecular iodine (I2) or is in the form of molecular iodine. In some embodiments, the molecular iodine may be provided in the form of povidone iodine. As in most iodine-containing patient preparations, other iodine-containing substances may be present in addition to iodine. Such substances include, for example, hypoiodous acid (HOI), iodide (I - ), triiodide (I3 - ), iodate (IO3 -), etc. It is widely recognized that molecular iodine is the most active antimicrobial substance. See, e.g., Disinfection, Sterilization, and Preservation by Seymour S. Block, 4th Edition, Chapter 8 "Iodine and Iodine Compounds," Lea & Febiger, Philadelphia, PA., 1991. Small amounts of Br - and / or Cl - .

[0022] In most commercially available iodine disinfectants, the solution is typically buffered to a weak acidity (e.g., 6 or lower, and typically 2 to 6) to prevent the rapid reduction of iodine to iodide. A composition that is too acidic may be irritating. Acidity is generally desired to maintain stability in the iodine solution and to inhibit conversion to other iodine species that are less bactericidal. For example, commercial skin preparations containing iodine typically have a pH value in the range of 3 to 6, which is favorable for the stability of the molecular iodine species. HOI is typically present at very low levels relative to I2, but has been reported as an effective antimicrobial agent and may contribute to killing in some compositions. IO3 - is only an effective oxidant at pH values less than 4, where a large amount of HIO3 will be present.

[0023] As further background for understanding and practicing the present invention, molecular iodine is only slightly soluble in water (0.03 wt% at 25 °C). Alkali metal iodides that combine with iodine to form triiodide (I3 - ) increase this solubility. However, molecular iodine can be very irritating at higher concentrations. For example, Lugol's solution (5% elemental iodine and 10% potassium iodide) and tincture of iodine (an aqueous solution of 45% ethanol containing 2% elemental iodine and 2.4% sodium iodide) have been well demonstrated to be rather irritating to the skin.

[0024] The preparation of "iodophors" has been described in many references. Iodophors are complexes of elemental iodine or triiodides with certain carriers. These iodophors not only serve to increase the solubility of iodine but also to reduce the level of free molecular iodine in solution and to provide a reservoir for the sustained release of a class of elemental iodine. It is known that iodophors use polymeric carriers such as polyvinylpyrrolidone, copolymers of N-vinyl lactams with other unsaturated monomers (such as but not limited to acrylates and acrylamides), various polyether diols (including polyether-containing surfactants such as nonylphenol ethoxylates, etc.), polyvinyl alcohol, polycarboxylic acids (such as polyacrylic acid), polyacrylamides, polysaccharides (such as glucose), etc. and combinations thereof. A suitable combination of iodophors includes polymers such as polyvinylpyrrolidone (PVP), copolymers of N-vinyl lactams, polyether diols (PEG), polyvinyl alcohol, polyacrylamides, polysaccharides, and combinations thereof. Protonated amine oxide surfactants-triiodide complexes, which are also iodophors suitable for the present invention, are also reported in U.S. Patent No. 4,597,975 (Woodward et al.). Various combinations of iodophors can be used in the compositions of the present disclosure.

[0025] In some embodiments, the iodophor can be povidone iodine. Suitable povidone iodine is commercially available as povidone iodine USP, which is believed to be a complex of K30 polyvinylpyrrolidone, iodine, and iodide, wherein available iodine is present at 9 wt% to 12 wt%. As used herein, "available iodine" in a composition can be determined following the method for the determination of available iodine in povidone iodine in the United States Pharmacopeia Official Monographs (United States Pharmacopeia Official Monographs for Povidone-Iodine, Assay for Available Iodine). Certain formulations may contain components that interact with this method, such as other anionic substances. For this reason, appropriate standards must be run to ensure accuracy, and it may be necessary to change the solvent system or reagents to ensure accuracy. Those skilled in the art will understand these considerations.

[0026] In some embodiments, based on the total weight of the antimicrobial composition, the iodophor can be present in the composition at a concentration of at least 1 wt% (wt%), at least 2.5 wt%, at least 4 wt%, or at least 5 wt%. To prevent the dry composition from becoming overly soluble in water and / or to control irritation, iodine toxicity, and off-taste, based on the total weight of the antimicrobial composition, the concentration of the iodophor in the composition used can be present at no more than 15 wt% or no more than 10 wt%.

[0027] Since the amount of available iodine in povidone iodine can vary, it is generally more convenient to describe the concentration in terms of the available iodine level. In the present invention, regardless of whether it is from iodine or povidone iodine or a combination thereof, based on the total weight of the antibacterial composition, the concentration of available iodine can be at least 0.1 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.4 wt% or at least 0.5 wt%. A concentration of available iodine below 0.1 wt% may not be sufficient to kill bacteria and may not reduce the microbial count over a longer period (e.g., 12 hours or 24 hours). In some embodiments, based on the total weight of the antibacterial composition, available iodine can be present at no more than 2 wt%, no more than 1.5 wt% or no more than 1 wt%. A concentration of available iodine above 2 wt% may be too irritating to wounds as well as mucosal tissues and skin.

[0028] In some embodiments, iodide salts can be present in the antibacterial compositions of the present disclosure to promote the stability of iodine-containing solutions. Suitable iodide salts can include sodium iodide (NaI), potassium iodide (KI), calcium iodide (CaI2), and zinc iodide (ZnI2) and combinations thereof. In some embodiments, based on the total weight of the antibacterial composition, the iodide salt can be present at a total concentration of at least 0.25 wt%, at least 0.5 wt%, at least 1 wt%, at least 1.5 wt%, at least 2.0 wt% or at least 2.5 wt%. In certain embodiments, based on the total weight of the antibacterial composition, the iodide salt can be present in the antibacterial composition at a total concentration of no greater than 10 wt%, or no greater than 5 wt%, or no greater than 3%. Compositions containing iodide salts at a total concentration of less than about 0.25 wt% may not be iodine-stable.

[0029] In some embodiments, based on the total weight of the composition, the total iodine present in the compositions of the present disclosure can be

[0030] 0.35 wt% to 3 wt%, 0.8 wt% to 2.7 wt% or 0.8 wt% to 1.5 wt%. Generally, compositions with lower total iodine levels (e.g., less than about 1.5 wt%) that are more difficult to stabilize are less likely to cause irritation to the user.

[0031] In some embodiments, the compositions of the present disclosure can be buffered to prevent pH drift during storage. For example, an iodine-containing system can be maintained at a pH of 2 to 6, or 3 to 5, or 3 to 3.8. When the pH rises above 6, iodine can rapidly convert to iodide, rendering the antimicrobial effectiveness ineffective. If the pH is below 2, the composition may become irritating. In this regard, in some embodiments, in the compositions of the present disclosure, the pH can be adjusted to 3.0 to 4.5. Although conventional compositions already contain various organic and inorganic buffers at concentrations of 0.1 wt% to 2 wt%, in some embodiments, the compositions of the present disclosure can include certain hydroxycarboxylic acid buffers that can be used at much higher buffer concentrations. In some embodiments, based on the total weight of the antimicrobial composition, the hydroxycarboxylic acid buffer can be present in an amount greater than 1 wt%, greater than 2.5 wt%, greater than 3 wt%, greater than 5 wt% or greater than 6 wt%. These compositions (i.e., having a pH adjusted to 3.0 to 3.8 and a relatively high hydroxycarboxylic acid buffer concentration) are substantially non-irritating to tissues (e.g., skin and mucosal tissues).

[0032] In some embodiments, this level of buffering may be desirable for antimicrobial compositions that contain povidone iodine (especially povidone iodine USP) as the antimicrobial agent. In these systems, the level of rapid microbial kill is significantly increased, and for some systems, it increases linearly as the molar concentration of the hydroxycarboxylic acid increases.

[0033] In some embodiments, suitable hydroxycarboxylic acid buffers can include one or more compounds disclosed in U.S. Patent No. 7,147,873 (Scholz et al.) (which is incorporated herein by reference in its entirety) and represented by the formula: R 1 (CR 2 OH) n (CH2) m COOH, where: R 1 and R 2 are each independently H or a (C1-C8) alkyl group (saturated straight-chain, branched or cyclic group), a (C6-C12) aryl or a (C6-C12) aralkyl or alkaryl group (saturated straight-chain, branched or cyclic group), where R 1 and R 2 may optionally be substituted with one or more carboxylic acid groups; m = 0 or 1; and n = 1-3 or n = 1-2.

[0034] In some embodiments, the hydrocarbon-containing buffer and other excipients are saturated or contain low levels of unsaturation to prevent iodine addition, which can consume iodine in the composition and / or produce toxic substances. In some embodiments, the level of unsaturation in the composition is no greater than 50 milliequivalents per liter (meq / L), no greater than 5 meq / L, or no greater than 0.5 meq / L of unsaturation.

[0035] In some embodiments, suitable hydroxycarboxylic acid buffers can include β-hydroxy acids and α-hydroxy acids (β-hydroxy acid (BHA) and α-hydroxy acid (AHA), collectively referred to as hydroxy acids (HA)), their salts, their lactones, and / or their derivatives (preferably, α-hydroxy acids are used). These can include monofunctional carboxylic acids, bifunctional carboxylic acids, and trifunctional carboxylic acids. Suitable HAs can have one or two hydroxy groups and one or two carboxylic acid groups. Suitable HAs include, but are not limited to, lactic acid, malic acid, citric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, mandelic acid, gluconic acid, tartaric acid, salicylic acid, and their derivatives (e.g., compounds substituted with hydroxy, phenyl, hydroxyphenyl, alkyl, halogen, and combinations thereof). Suitable HAs include lactic acid, malic acid, and citric acid. These acids can be in the D, L, or DL form and can exist as free acids, lactones, or their salts. Other suitable HAs are described in U.S. Patent No. 5,665,776 (Yu et al.). In some embodiments, the HAs suitable for use with iodine, particularly with povidone iodine, are lactic acid and malic acid and combinations thereof. If desired, various combinations of hydroxycarboxylic acids can be used.

[0036] It has been found that monocarboxylic acids (e.g., lactic acid) can have excellent stability and good activity while still being effective in formulations without anionic surfactants. The addition of bifunctional and trifunctional carboxylic acids can improve efficacy, but such improvement may come at the expense of chemical degradation and reduced activity (especially when used repeatedly).

[0037] In some embodiments, the hydroxycarboxylic acid buffer can be present at a molar concentration of at least 0.1 mole, at least 0.3 mole, at least 0.45 mole, or at least 0.6 mole. For formulations that are desired to kill microorganisms on the skin very rapidly, the hydroxycarboxylic acid concentration can exceed 0.7 mole.

[0038] It is believed that the antimicrobial efficacy of an antimicrobial composition containing povidone iodine is directly related to the molar concentration of the hydroxycarboxylic acid buffer. Using a high enough level of the hydroxycarboxylic acid buffer, when tested according to ASTM test method E1173-93, the composition containing povidone iodine is capable of reducing the normal skin flora on a dry human skin site (typically, the back or abdomen) by an average of greater than or equal to 2 logs within only 2 minutes after simple application (without scrubbing) and within 30 seconds of scrubbing and after applying the composition to the site three times.

[0039] In some embodiments, based on the total weight of the composition, the hydroxycarboxylic acid buffer concentration by weight percentage of the ready-to-use composition (i.e., the composition that does not need to undergo additional dilution before being applied to the tissue) can be at least 2 wt%, at least 5 wt%, or at least 7 wt%. Based on the weight of the composition, the concentration of the hydroxycarboxylic acid buffer can be no greater than about 15 wt% or no greater than about 10 wt%. Concentrates with much higher hydroxycarboxylic acid buffer concentrations can also be conveniently provided in some applications, but when diluted to the use concentration, they fall within the specified range.

[0040] For effective killing on skin and mucosal tissues, the compositions of the present disclosure can include one or more surfactants. The surfactant can be compatible with the antimicrobial agent, iodide salt, hydroxycarboxylic acid buffer, and any other components of the composition. When formulated with a film-forming polymer, it may be desirable to include one or more surfactants to enhance the solubility and stability of the polymer in the composition. In addition, the surfactant can help the composition wet the skin and ensure a smooth and uniform coating. It may be desirable to provide a coating with complete coverage to ensure easy and error-free application. On tissues that are difficult to visualize, such as most mucosal surfaces, it may be desirable to use a surfactant to help wet and ensure that the antimicrobial agent will be distributed on the tissue by diffusion and / or capillary action. On the skin, a thin, relatively uniform coating can be applied that will dry quickly. In addition, certain surfactants can increase antimicrobial activity.

[0041] In some embodiments, suitable surfactants for the compositions of the present disclosure include nonionic surfactants. It has been found that polyalkoxylated (and especially polyethoxylated) nonionic surfactants can stabilize film-forming polymers particularly well in aqueous solutions. Generally, useful polyalkoxylated nonionic surfactants can have a hydrophilic / lipophilic balance (HLB) of at least 12, at least 14, or at least 16. Useful polyalkoxylated nonionic surfactants can have an HLB of no greater than 20. When using a combination of nonionic surfactants, the weighted average HLB is used to determine the HLB of the nonionic surfactant system. As used herein, HLB is defined as one-fifth of the weight percentage of the ethylene oxide chain segment in the surfactant molecule.

[0042] Non-ionic

[0043] Available nonionic surfactants include:

[0044] 1. Polyalkoxylated alkanols. Surfactants having an HLB of at least about 14, such as those commercially available under the trade name BRIJ from ICI Specialty Chemicals, Wilmington, DE, have been shown to be useful. Specifically, stearyl alcohol ethoxylates BRIJ 78 and BRIJ 700, having 20 moles and 100 moles of polyethylene oxide, respectively, have been shown to be very useful. Cetearyl alcohol polyether 55 is also useful and is commercially available under the trade name PLURAFAC A-39 from BASF Corp., Performance Chemicals Div., Mt. Olive, NJ. Other surfactants may include stearyl polyoxyethylene ether-100 (Hetoxyl STA-100), stearyl polyoxyethylene ether-40 (Ethal SA-40), and cetearyl alcohol polyether-25 (C-25), sold by Ethox Chemicals, Greenville, SC.

[0045] 2. Polyalkoxylated alkylphenols. Useful surfactants of this type include polyethoxylated octyl or nonyl phenols having an HLB value of at least 14, which are commercially available under the trade names ICONOL and TRITON from BASF Corp., Performance Chemicals Div., Mt. Olive, NJ, and Union Carbide Corp., Danbury, CN, respectively. Examples include TRITON X100 (octylphenol having 15 moles of ethylene oxide, commercially available from Union Carbide Corp., Danbury, CN) and ICONOL NP70 and NP40 (nonylphenols having 40 moles and 70 moles of ethylene oxide units, respectively, commercially available from BASF Corp., Performance Chemicals Div., Mt. Olive, NJ). Sulfated and phosphated derivatives of these surfactants are also useful. Examples of such derivatives include ammonium nonylphenol polyether-4-sulfate, which is commercially available under the trade name RHODAPEX CO-436 from Rhodia, Dayton, NJ.

[0046] 3. Polyethylene oxide. Surfactants based on polymers of ethylene oxide (EO) can be useful. Polyethylene oxide having a molecular weight greater than 300 can also be used.

[0047] 4. Poloxamers. Surfactants that are block copolymers of ethylene oxide (EO) and propylene oxide (PO) have been shown to be effective in stabilizing film-forming polymers and provide good wetting. As long as the HLB is at least 14, preferably at least 16, both EO-PO-EO blocks and PO-EO-PO blocks are expected to function well. Such surfactants are commercially available under the trade names PLURONIC and TETRONIC from the High Performance Chemicals Division of BASF Corporation, Mount Olive, New Jersey. Note that the reported HLB values for PLURONIC surfactants from BASF are calculated differently than those above. In such cases, the HLB values reported by BASF should be used. For example, preferred PLURONIC surfactants are L-64 and F-127, which have HLB values of 15 and 22, respectively. Although PLURONIC surfactants are very effective in stabilizing the compositions of the present invention and are very effective with iodine as the active agent, they may reduce the antimicrobial activity of compositions using povidone iodine as the active agent.

[0048] 5. Polyalkoxylated esters. Polyalkoxylated diols such as ethylene glycol, propylene glycol, glycerol, etc. can be partially or fully esterified, i.e., one or more alcohols can be esterified with (C8-C22) alkyl carboxylic acids. Such polyalkoxylated esters having an HLB of at least 14, preferably at least 16, are suitable for the compositions of the present invention.

[0049] 6. Alkyl polyglucosides. Alkyl polyglucosides, such as those described starting at column 9, line 44 in U.S. Patent No. 5,951,993 (Scholz et al.), are compatible with film-forming polymers and may contribute to polymer stability. Examples include glucopon 425, which has a (C8-C16) alkyl chain length with an average chain length of 10.3 carbons and 1-4 glucose units.

[0050] 7. Polyethylene oxide-extended sorbitan monoalkyl esters (i.e., polysorbates). Specifically, a useful surfactant of this type can be polysorbate 20, commercially available as NIKKOL TL-10 (from Barret Products).

[0051] Zwitterionic

[0052] In some embodiments, suitable surfactants for the compositions of the present disclosure may optionally include zwitterionic surfactants. Zwitterionic surfactants include surfactants having a protonatable tertiary amine group and quaternary amine-containing zwitterionic surfactants, and they are on the inactive excipient list of the U.S. FDA. Suitable zwitterionic surfactants may include:

[0053] 1. Oxidized amines. Such surfactants can be represented by the following formula:

[0054] R 1 R 2 R 3 -N + -O -

[0055] wherein at least one of R 1 , R 2 and R 3 is a (C8-C22) alkyl group. Preferably, the oxidized amine is an oxidized amine that is commercially available from McIntyre Group Ltd., University Park, IL as MACKAM LO (where R 1 is a C12 alkyl group and R 1 and R 2 are hydrogen).

[0056] It has been reported that amine oxides are complexed with molecular iodine and / or triiodide to stabilize some iodine solutions. In this regard, in some embodiments, the compositions of the present disclosure may optionally include one or more amine oxides. An amine oxide can be a compound, oligomer, or polymer containing one or more amine oxide groups, or a compound containing a single amine oxide group. Suitable amine oxides are acceptable for topical pharmaceutical formulations, i.e., pharmaceutical formulations that do not cause significant irritation or toxicity to skin or mucosal tissues. Examples of suitable amine oxides for use in the compositions of the present invention are those having surface activity (surfactants), and are generally characterized by having at least one alkyl group with a weight average chain length greater than 6 carbon atoms, greater than 8 carbon atoms, or greater than 10 carbon atoms. Also included are amine oxides of aromatic tertiary amines and tertiary amines containing alkaryl groups, such as dimethylbenzylamine oxide. Trialkylamine oxides (e.g., lauryldimethylamine oxide) have at least one C6-C22 alkyl group, wherein the one or more alkyl groups may optionally be substituted with N, O, or S in the chain or on the chain. Alkaryldialkylamine oxides have at least one alkaryl group having 7 carbon atoms and a C1-C22 alkyl group optionally substituted with N, O, or S in the chain or on the chain. Particularly useful are myristamine oxides such as myristamidopropyldimethylamine oxide, laurylamine oxides such as lauramidopropyldialkylamine oxide, dihydroxyethyldodecylamine oxide, and mixtures thereof. Other amine oxides suitable for use in the compositions of the present invention include those commercially available under the trade names AMMONYX LO, LMDO, and CO, which are lauryldimethylamine oxide, lauramidopropyldimethylamine oxide, and cetylamine oxide, all from Stepan Co. (Northfield, IL), and N-oxides of ethoxylated tertiary amines, such as those having the structure R2-N(AO)2, R-N(AO)2, or R-N(AO)-R’N(AO)2, or R-N(AO)-R’N(AO), where AO = polyalkylene oxide having 1-100 moles of ethylene oxide or propylene oxide residues and R = a C1-C22, preferably C8-C18 aliphatic hydrocarbon optionally substituted with N, O, or S. R’ is a linking group and is most preferably a C2-C10 alkylene group.Examples include Ethomeen obtained from Akzo Nobel and alkoxylated Duomeen tertiary amines. Other examples of suitable amine oxides include: N,N-dimethylbenzylamine oxide; N-ethyl, N-laurylbenzylamine oxide; N-methyl N-ethylbenzylamine oxide; 4-alkylpyridine N-oxide, 3-alkylpyridine N-oxide, 2-alkylpyridine N-oxide; alkylpyrazine N-oxide; alkylpyrazine N,N'-dioxide; N-alkylpiperidine N-oxide; N,N'-alkylpiperazine N-oxide; N,N'-dialkylpiperazine N,N'-dioxide; N-alkylmorpholine N-oxide; alkyl-substituted quinoline N-oxide; N,N-dialkylcyclohexylamine N-oxide; N,N-dialkylaniline N-oxide, etc. and mixtures thereof.

[0057] In some embodiments, the amine oxide in the antimicrobial composition is present in an amount such that the ratio of the total moles of amine oxide to the total moles of available iodine is less than about 2. In some embodiments, based on the total weight of the antimicrobial composition, the total amine oxide present in the compositions of the present disclosure can be at least 0.25 wt%, at least 0.50 wt% or at least 1 wt%.

[0058] In some embodiments, the amine oxide (if present) is on the list of FDA-approved inactive excipients in the United States.

[0059] 2. Ammonium carboxylate zwitterionic surfactants. Such surfactants can be represented by the following formula:

[0060] R 3 -(C(O)-NH) a -R 5 -N + (R 4 )2-R 6 -COO -

[0061] Where: a = 0 or 1; R 3 is a (C7-C21) alkyl group (saturated straight-chain, branched or cyclic group), a (C6-C22) aryl group or a (C6-C22) aralkyl or alkaryl group (saturated straight-chain, branched or cyclic alkyl), where R 3 may optionally be substituted with one or more N, O or S atoms, or substituted with one or more hydroxyl, carboxyl, amide or amine groups; R 4 is H or a (C1-C8) alkyl group (saturated straight-chain, branched or cyclic group), where R 4 may optionally be substituted with one or more N, O or S atoms, or substituted with one or more hydroxyl, carboxyl, amine groups, a (C6-C9) aryl group or a (C6-C9) aralkyl or alkaryl group; and R5 and R 6 are each independently a (C1-C10) alkylene group, which may be the same or different and may optionally be substituted with one or more N, O or S atoms, or with one or more hydroxyl or amine groups.

[0062] In some embodiments, in the formula of the above ammonium carboxylate zwitterionic surfactant, R 3 is a (C1-C16) alkyl group and R 4 is a (C1-C2) alkyl group preferably substituted with a methyl or benzyl group. When R 4 is H, it should be understood that the surfactant at higher pH values can exist in the form of a tertiary amine together with a cationic counterion such as Na, K, Li or in the form of a quaternary amine group.

[0063] Examples of such zwitterionic surfactants include, but are not limited to: certain betaines such as coco betaine and cocamidopropyl betaine (which are commercially available from McIntyre Group, Ltd., University Park, Illinois under the trade names MACKAM LO, MACKAM CB-35 and MACKAM L); monoacetates such as sodium lauroamphoacetate; diacetates such as disodium lauroamphodiacetate; amino and alkylaminopropionic acids such as lauroaminopropionic acid (commercially available from McIntyre Group, Ltd. under the trade names MACKAM 1L, MACKAM 2L and MACKAM 151L respectively).

[0064] 3. Ammonium sulfonate zwitterionic surfactants. Such zwitterionic surfactants are commonly referred to as "sultaine" or "sulfobetaine" and can be represented by the following formula:

[0065] R 3 -(C(O)-NH) a -R 5 -N + (R 4 )2-R 6 -SO3 -

[0066] wherein R 3 -R 6 and "a" are as defined above for the ammonium carboxylate zwitterionic surfactant. Examples include cocoamidopropyl hydroxysultaine and lauramidopropyl hydroxysultaine (commercially available from McIntyre Group, Ltd. under the trade name MACKAM 50-SB).

[0067] 4. Phospholipid zwitterionic surfactants. These surfactants are characterized by having at least one anionic phosphate group, one cationic ammonium group (protonated or quaternized), and at least one alkyl, alkenyl, aralkyl, or aralkenyl group having at least 8 carbon atoms. Many of these surfactants can be represented by the following formula:

[0068] R 7 -OP - (O)2O-CH2CH2N + (R 4 )3

[0069] wherein R 4 is as defined above for ammonium carboxylate zwitterionic surfactants, and R 7 is R 3 (as defined above for ammonium carboxylate zwitterionic surfactants), provided that R 7 may also contain multiple R 3 groups, such as in the case where R 7 is a glyceride derivative, for example in phosphatidylcholine. Examples include lecithin, phosphatidylcholine, and phosphatidylethanolamine. So-called "reverse phospholipids" having a quaternary ammonium group in the chain and a terminal phosphate group are also possible, such as those sold by Uniqema / Croda under the trade names Arlasilk Phospholipid CDM (coconut PG-dimonium chloride phosphate), Arlasilk Phospholipid EFA (linolenamidopropyl PG-dimonium chloride phosphate), etc.

[0070] In some embodiments, the composition may be free (or substantially free) of anionic surfactants. As discussed above, while anionic surfactants can be used to stabilize compositions containing iodine and hydrocarboxylic acids, known anionic surfactants have undesirable regulatory issues. In this regard, in some embodiments, based on the total weight of the composition, the composition of the present disclosure may contain less than 1 wt%, less than 0.5 wt%, less than 0.1 wt%, less than 0.01 wt%, or 0 wt% of anionic surfactant; or based on the total weight of the composition, may contain less than 1 wt%, less than 0.5 wt%, less than 0.1 wt%, less than 0.01 wt%, or 0 wt% of surfactants not on the list of inactive excipients approved by the US FDA.

[0071] In some embodiments, based on the total weight of the composition, surfactants (e.g., nonionic surfactants and optionally zwitterionic surfactants) may be present in the antimicrobial compositions of the present disclosure in a total amount of at least 0.25 wt%, at least 0.5 wt%, or at least 1 wt%. In some embodiments, based on the total weight of the composition, surfactants may be present in the composition in a total amount of no greater than 10 wt%, no greater than 7 wt%, no greater than 5 wt%, or no greater than about 3 wt%. For embodiments in which a zwitterionic surfactant such as lauryldimethylamine oxide is added, lower levels of nonionic surfactant may be required to prevent formulation degradation (i.e., adding a high level of lauryldimethylamine oxide (0.75%) can result in stronger chemical degradation). Too little surfactant can result in an unstable composition (especially when exposed to high temperatures) and / or reduced antimicrobial efficacy on tissue. Too much surfactant can disrupt the affinity of the dry composition on the skin and cause tissue irritation.

[0072] In some embodiments, when the composition contains povidone iodine, certain types of nonionic surfactants may be used based on the concentration of povidone iodine. Specifically, when the concentration of povidone iodine is relatively high, nonionic surfactants with a lower HLB and higher hydroxyl value such as cetostearyl alcohol polyether-25 can provide the strongest physical stability, while when used with a relatively low content of povidone iodine, surfactants with a higher HLB and lower hydroxyl value such as stearyl polyoxyethylene ether-100 can provide the strongest physical stability. In this regard, in some embodiments, when the concentration of povidone iodine based on the total weight of the composition is greater than 3 wt%, greater than 4 wt%, or greater than 5 wt%, the nonionic surfactant may have an HLB value between 10 and 17, between 12 and 17, or between 16 and 17 and a hydroxyl value (-OH value (mg KOH / g)) between 30 and 50, between 35 and 45, or between 40 and 45. In some embodiments, when the concentration of povidone iodine based on the total weight of the composition is less than 3 wt% or less than 2.5 wt%, the nonionic surfactant may have an HLB value between 17 and 20, between 18 and 20, or between 18 and 19 and a hydroxyl value (-OH value (mg KOH / g)) between 10 and 25, between 12 and 20, or between 12 and 15.

[0073] In some embodiments, based on the total weight of the composition, the nonionic surfactant may be present in the antimicrobial compositions of the present disclosure in an amount between 0.25 wt% and 10 wt%, between 0.5 wt% and 7 wt%, or between 0.5 wt% and 3 wt%. Surprisingly, using these relatively high concentrations of nonionic surfactant, the iodine-containing compositions can be stable in the absence of charged surfactants (and even in the presence of charged substances / charged complexes such as anionic iodides and cationic thickeners).

[0074] In some embodiments, the compositions of the present disclosure may include monosaccharides or sugar alcohols. Suitable monosaccharides for use in the compositions described herein have the chemical formula (CH2O) n + m , and its chemical structure is H(CHOH) n C=O(CHOH) m H. If n or m is 0, it is an aldehyde and is called an aldose, otherwise it is a ketone and is called a ketose. Monosaccharides contain a ketone or aldehyde functional group, as well as hydroxyl groups on most or all of the non-carbonyl carbon atoms. Monosaccharides can be compounds of 5 or 6 carbon atoms (n + m = 5 or 6). They can exist in D-form, L-form, or a combination thereof. Most preferred monosaccharides are xylose, xylulose, lyxose, mannose, maltose, sorbose, erythrose, glucose (dextrose), fructose, galactose, and ribose.

[0075] The term "sugar alcohol" should be understood to mean a monosaccharide or disaccharide in which the aldehyde group of the first carbon atom is reduced to a primary alcohol. They include the following sugar alcohols: xylitol, sorbitol, mannitol, maltitol, erythritol, lactitol, and arabinitol or combinations thereof. The sugar alcohols can be those derived from monosaccharides (i.e., alcohols of monosaccharides), including xylitol, mannitol, or combinations thereof. The sugar alcohol can be xylitol. As used herein, the term "alcohol of monosaccharide" should be understood to mean a monosaccharide in which the aldehyde group of the first carbon atom is reduced to a primary alcohol.

[0076] It has been found that these monosaccharides and / or sugar alcohols further enhance the efficacy of the iodine-containing compositions (i.e., the rate and / or extent of bacteria killing). (See, for example, U.S. Application Publication No. 2009 / 0169647 (Scholz)).

[0077] Based on the total weight of the composition, the monosaccharides and / or sugar alcohols may be present at a concentration of at least 0.25 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 4 wt%, or at least 5 wt%. The concentration can be adjusted to ensure improved antimicrobial performance and / or improved taste of the composition (if it is applied to the oral cavity, esophageal lumen, nasal passages, or anterior nares). The upper limit can be determined by the solubility limit of the monosaccharides and / or sugar alcohols.

[0078] In some embodiments, it may be desirable to add one or more thickeners to the antimicrobial composition, such as polymeric thickeners (which may be film-forming polymers) and / or film-forming polymers, to improve affinity (e.g., resistance to being washed off by nasal mucus secretions, blood, and body fluids exposure), improve the adhesion of PSA-coated products, increase viscosity to prevent dripping, etc., reduce the tackiness of the composition, and / or reduce the loss of available iodine during storage. Suitable polymeric thickeners and / or film-forming polymers for the antimicrobial compositions of the present disclosure are affinity and resistant to being removed by prolonged exposure to fluids such as water, saline, and body fluids, yet can be easily and gently removed without the need for organic solvents.

[0079] Certain skin antimicrobial compositions of the present disclosure resist removal particularly well after they dry. These compositions generally have a low viscosity (e.g., less than 1000 cps), preferably greater than 10 cps, and polymers having generally low molecular weights (e.g., less than 200,000 daltons).

[0080] However, on wounds and mucosal tissues, such as in the nose and anterior nares, antimicrobial compositions used may have a higher viscosity in order to keep the composition on the tissue (which is usually wet) for a longer time and prevent dripping and mess. These compositions may have a viscosity greater than 100 cps, greater than 500 cps, greater than 1000 cps, greater than 2000 cps, greater than 5000 cps, or greater than 8000 cps. These compositions can be thickened with one or more of the following:

[0081] a. Polymeric thickeners

[0082] b. Hydrophobically modified polymeric thickeners

[0083] c. Polymer / surfactant combinations

[0084] d. Emulsifiers (including waxes)

[0085] e. Inorganic colloid thickeners

[0086] In some embodiments, suitable polymeric thickeners (which may be film-forming agents) may have both hydrophilic and hydrophobic moieties. The polymeric thickeners may include relatively high levels of total hydrophobic monomers. The polymer may be relatively hydrophobic to provide good affinity and long-term adhesion of PSA-coated products. Based on the total weight of the polymerizable composition (or based on the total weight of the polymer), a hydrophobic monomer level of at least 50 wt% and typically up to 80 wt% can be used to form the polymer. If desired, various combinations of hydrophobic monomers can be used.

[0087] Polymeric thickeners, which can be film-forming polymers, can be nonionic, anionic, cationic, or zwitterionic. In some embodiments, the polymeric thickener can be cationic, as it has surprisingly been found that such thickeners can be used to form stable, long-lasting compositions. Specifically, cationic thickeners allow viscous formulations (1000 cp - 15000 cp) to have anti-elution properties and to remain in place for an extended period of time to be effective in the decolonization of skin and mucosal surfaces.

[0088] In certain embodiments, the polymeric thickener can be a cationic polymer, such as those including pendant functional amine groups, which can be film-forming polymers. Examples of such groups include protonated tertiary amines, quaternary amines, amine oxides, and combinations thereof.

[0089] In some embodiments, the polymeric thickener can be a vinyl polymer prepared from amine-containing monomers. The vinyl polymer can have a Tg of at least 30 °C, or at least 50 °C. One method of measuring the Tg of a polymer can include using a differential scanning calorimeter (DSC, e.g., PYRIS 7-series thermal analyzer, Perkin-Elmer, Shelton, CN) in the range of -100 °C to +100 °C at a rate of 20 °C per minute.

[0090] For certain polymeric thickeners, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer), the amine-containing monomer can be used in an amount of at least 15 wt%, at least 20 wt%, even at least 25 wt% or at least 30 wt% to prepare the polymer. The equivalent weight of the amine groups contained in the polymer can be at least 300 g, at least 350 g, at least 400 g or at least 500 g of polymer per equivalent of amine group. The equivalent weight of the amine groups contained in the polymer can be no greater than 3000 g, no greater than 1500 g, no greater than 1200 g or no greater than 950 g of polymer per equivalent of amine group.

[0091] Examples of polymeric thickeners that are film-forming polymers and are PSAs at room temperature include those based on combinations of pendant functional amine group monomers with long-chain alkyl acrylate polymers and optionally other hydrophilic monomers.

[0092] In certain embodiments, based on the total weight of the antimicrobial composition, one or more polymeric thickeners and / or film-forming polymers (preferably affinity film-forming polymeric thickeners) can be present in the antimicrobial composition in a total amount of at least 2 wt%, at least 3 wt% or at least 5 wt%. In certain embodiments, based on the total weight of the antimicrobial composition, one or more polymeric thickeners and / or film-forming polymers (preferably affinity film-forming polymeric thickeners) can be present in the antimicrobial composition in a total amount of no greater than 10 wt%, or no greater than 8 wt%.

[0093] It may be desirable to include one or more other (second) antimicrobial agents in combination with iodine as a preservative and / or active ingredient. Other active ingredients may include cationic surfactants such as polyhexamethylene biguanide (PHMB, Arch Biocide from Arch Biocides Limited), chlorhexidine salts such as chlorhexidine gluconate, chlorhexidine acetate, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, octenidine, cetylpyridinium chloride, etc., and other cationic antibacterial agents disclosed in U.S. Patent Application Publication No. 2006 / 0051384. Natural oil antimicrobial agents may be added, such as those disclosed in U.S. Patent Application Publication No. 2006 / 0051384. In addition, it may be desirable to add antimicrobial lipids, such as those described in U.S. Patent Application Publication No. 2005 / 0089539, but in certain embodiments, the compositions of the present invention do not include antimicrobial lipids. Phenolic antimicrobial agents may also be useful, such as triclosan, parachlorometaxylenol, and other antimicrobial agents disclosed in U.S. Patent Application Publication No. 2006 / 0052452.

[0094] It may also be desirable to add preservatives such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben, 2-phenoxyethanol, hydantoin, imidazolidinyl urea, etc.

[0095] The compositions of the present disclosure may additionally employ auxiliary components conventionally found in pharmaceutical compositions in a manner and at a level determined in the art. Thus, for example, the compositions may contain additional compatible pharmaceutical active substances for combination therapy (such as supplementary antimicrobial agents, antiparasitic agents, antipruritics, astringents, local anesthetics, or anti-inflammatory agents), or may contain substances that can be used to physically formulate the various dosage forms of the present invention, such as excipients, dyes, fragrances, lubricants, stabilizers, skin penetration enhancers, preservatives or antioxidants, edible flavors, taste masking agents, odor masking agents, anti-inflammatory agents, antioxidants, vitamins, enzymes, enzyme inhibitors, growth factors, and sensates that cause a cool or warm sensation such as menthol, etc.

[0096] In some embodiments, the antimicrobial compositions of the present disclosure can have one or more of the following characteristics: a relatively high level of bacteria killing; a relatively rapid rate and / or length of bactericidal activity; less likely to produce bacterial resistance; capable of delivering iodine (I2) over a period of time; suitable for sensitive tissues such as mucosal tissues, including vaginal, oral, esophageal, and nasal tissues; relatively non-irritating to most patients; an acceptable odor; an acceptable taste in cases where some compositions are intentionally used in the oral or esophageal cavity or if the composition is placed intranasally and migrates up and down the nasal passages to the throat; good adhesion to skin and / or mucosal tissues when wet and dry; a viscosity high enough to provide an affinity for mucosal tissues such that the residence time in the nose or other mucosal tissues (e.g., mouth, vagina, or esophagus) is increased compared to an unthickened formulation; preferably good adhesion of pressure-sensitive adhesive (PSA)-coated products such as incision drapes, tapes, wound dressings, etc. to dry preparations on the skin (preferably, for an extended period of time, such as several hours to several days); resistance to peeling of PSA-coated products from dry preparations on the skin when under the stresses typically occurring during surgical retraction; can be removed relatively easily, preferably without the need for an organic solvent-based remover, and does not lose more than 20% weight / weight iodine (and preferably no more than 10% weight / weight iodine) during the shelf life of the product.

[0097] In some embodiments, the antimicrobial compositions of the present disclosure have many or all of the above characteristics. Significantly, they can provide rapid broad-spectrum microbial killing (bacteria, viruses, molds, yeasts, etc.), with a very low or no chance of microbial resistance, are well tolerated on mucosal tissues, and have an acceptable odor and taste. In addition, they can be gentle on tissues and can be removed with a water-soaked or soap-and-water-soaked fabric (such as a towel or simple gauze).

[0098] In some embodiments, having an unthickened solution may be useful, so it can be used as an easily administered spray. These compositions without any thickeners can be useful, especially if they have similar efficacy and can reduce the microbial count on tissues over an extended period of time compared to thickened compositions.

[0099] In some embodiments, the compositions can be iodine-stable at the relatively high iodine concentrations used in "ready-to-use" compositions because they are characterized by having more available iodine (and thus higher antimicrobial efficacy) after a significant storage period than certain other iodine-containing antiseptic compositions that include elevated levels of hydroxycarboxylic acids. When aged at 40 °C for about 6 months in a closed, non-reactive container, certain embodiments do not suffer a loss of available iodine from an original weight percentage greater than about 15%, greater than about 10%, or greater than about 5%. As used herein, "ready-to-use" refers to compositions intended to be administered without dilution (e.g., administered to skin or mucosal tissue).

[0100] In some embodiments, the compositions of the present disclosure are also physically stable because they do not show signs of visible gross phase separation (e.g., precipitation, phase splitting, sedimentation) after storage at about 50 °C for 4 - 7 days. Although certain embodied compositions may separate into two portions having different viscosities, sometimes the lower portion appears to be gel-like. The absence of gross precipitation and / or sedimentation means that these samples can be considered physically stable. Other compositions of the present disclosure do not show visible changes. Moreover, certain compositions of the present disclosure can be thickened with emulsifier systems that form emulsions and dispersions. These systems are considered physically stable if there is no syneresis and if the viscosity does not drop to less than half of the initial viscosity when aged at 40 °C for 30 days and allowed to equilibrate at 23 °C for 24 hours.

[0101] In some embodiments, samples tested after freeze-thaw testing (as described in the examples) may also separate into two portions having different viscosities (sometimes the lower portion appears to be gel-like).

[0102] In some embodiments, the compositions of the present disclosure are generally also compatible, and can be compatible even when in a moist environment such as the nose, anterior nares, and vaginal vault, and remain on any of these tissues for a longer time than typical antiseptics such as BETADINE 10% povidone iodine solution (Purdue Frederick, Norwalk, CN).

[0103] An "affinity" composition is a composition that, when placed in the anterior nares, remains visible iodine in most subjects for 30 minutes (min) after instilling 0.25 milliliters (mL) with a cotton swab and gently massaging the nares for 30 seconds to ensure even distribution (as long as the patient does not expel or intentionally or inadvertently wipe away the product). In some embodiments, the affinity composition remains in the anterior nares for 45 minutes or 60 minutes after instillation. This is conveniently determined by gently wiping the inside of the anterior nares with white tissue paper such as KLEENEX tissue paper or by imparting color to the composition (e.g., containing a small amount of a dye or colored active substance such as povidone iodine at a sufficient concentration such that the presence or absence of a relatively dark color can be easily seen on the skin).

[0104] Many compositions of the present disclosure can also be "skin-affinitive", and thus, when tested as described in the "affinity test" as described in U.S. Patent No. 7,147,873 (Scholz et al.), the applied and dried composition resists removal from the skin for at least 15 seconds. For use on the skin, the composition can be even more affinitive and resist removal for at least 30 seconds, at least 45 seconds, or at least 60 seconds under the same conditions. This is conveniently determined by imparting color to the composition (e.g., containing a small amount of a dye or colored active substance such as povidone iodine at a sufficient concentration such that the presence or absence of a relatively dark color can be easily seen on the skin).

[0105] The dry films of certain antibacterial compositions of the present disclosure that include a film-forming polymer are generally flexible and durable. That is, they do not crack or flake like brittle films. Significantly, the film-forming polymer helps to achieve a delicate balance between low tack and flexibility.

[0106] Although the antibacterial compositions of the present disclosure can have a wide variety of viscosities, in some embodiments, the composition has a viscosity that ensures easy travel of the formulation and, in particular, the formation of an affinity film on moist tissues such as mucosal tissues. The Brookfield viscosity of the composition can be greater than 100 centipoise (cps), greater than 500 cps, greater than 1000 cps, greater than 2000 cps, or greater than 5000 cps. Certain skin antibacterial compositions of the present disclosure can resist removal particularly well after they dry. These compositions generally have a lower viscosity (e.g., less than 1000 cps). The viscosities herein are measured at 23 °C using a Brookfield LVT viscometer and the procedures described in the Examples section.

[0107] A relatively low viscosity ensures that the composition can be applied effortlessly in the form of a uniform film that dries quickly onto the skin or mucosal tissue. Thus, the viscosity of the composition for use on intact skin in the present disclosure may be no greater than 500,000 cps, no greater than 200,000 cps, no greater than 50,000 cps, no greater than 10,000 cps, or no greater than 5,000 cps. For use on the skin, the composition may have a viscosity of less than 100 cps. For use on a wound or mucosal tissue, such as in the nasal cavity or vagina, the viscosity may be relatively high to minimize drainage and mess, but may be no greater than 20,000 cps. On wounds and mucosal tissue, the composition may not dry during use. Thus, a high viscosity helps to retain the composition at the site of application for an extended period to improve microbicidal killing.

[0108] This rapid and high antimicrobial activity is provided by the use of iodine, for example, iodine delivered as povidone-iodine to reduce the irritation potential and as the active antimicrobial agent. The compositions of the present disclosure may also contain one or more hydroxycarboxylic acid buffers at particularly high use concentrations. The elevated hydroxycarboxylic acid concentration in the composition significantly promotes an increase in bacterial killing. By comparison, the compositions of the present disclosure reduce the normal skin flora by at least 0.5 log more than the same composition without the hydroxycarboxylic acid buffer. This "same" composition contains additional water instead of the hydroxycarboxylic acid buffer and is adjusted to the same pH as the composition having these components using an inorganic acid or inorganic base (such as hydrochloric acid or sodium hydroxide) that does not compromise the stability of the composition. A placebo composition (i.e., a composition without an antimicrobial agent but still containing the hydroxycarboxylic acid buffer) is relatively inactive. In contrast, when tested on a dry human skin site (e.g., the back or abdomen) according to ASTM test method E1173-93, the compositions of the present disclosure reduce the normal skin flora by at least 0.5 log more than the same composition without iodine or povidone-iodine, which is measured 2 minutes after a 30-second scrub with a gauze soaked in the composition using moderate pressure.

[0109] Typically, an antimicrobial composition is applied to the tissue (usually the skin), allowed to dry, and kept in place for at least 2 minutes and typically for several hours to several days. Significantly, many of the compositions of the present disclosure maintain a very low bacterial count on the tissue (usually the skin) for an extended period, for example, typically up to 6 hours and even up to 24 hours.

[0110] In some embodiments, the compositions of the present disclosure may be provided at ready-to-use concentrations (i.e., may be applied directly to the tissue). The compositions may also be prepared as concentrates to be diluted prior to use. For example, concentrates are contemplated that require a dilution ratio of 0.5:1 to 3:1 parts water:concentrate. The upper limit of the concentrate is limited by the solubility and compatibility of the various components at higher concentrations.

[0111] The compositions of the present disclosure can be applied to the skin or mucosal surfaces (such as nostrils, urethra, vagina, etc.) in any suitable manner. Generally, a type of absorbent material such as gauze, foam sponge, non-woven fabric, cotton fabric, cotton swab or cotton ball, etc. is soaked with the composition, and the absorbent material is used to wipe the composition onto the intended site. For very highly active compositions with excellent wetting properties (e.g., formulations with a higher alcohol content), a single-stroke formulation may be all that is necessary. However, in most cases, it is believed to be helpful to wipe the soaked absorbent material on the skin several times, preferably in various directions, in order to thoroughly wet the skin and ensure good coverage of the finer details of the skin. However, generally speaking, extensive scrubbing as recommended by prior art products is not required because the high concentration of the organic buffer results in enhanced activity. For example, the manufacturer of BETADINE Surgical Scrub (Purdue Frederick Company, Norwalk, Connecticut) specifies that the user scrub thoroughly for 5 minutes. The compositions of the present disclosure may require scrubbing for less than about 60 seconds, less than about 45 seconds or less than about 30 seconds, followed by waiting for 2 minutes without soaking.

[0112] In some embodiments, it may be necessary to reduce the microbial count on the nostrils such that the reduction is maintained for at least 12 hours. In other cases, it may be necessary to add it repeatedly, twice a day or once a day, for up to 21 days.

[0113] To maintain strict sterility, the applicator of the preoperative patient skin preparation can start at the recommended incision site and work outward, thus preventing the "dirty" applicator from returning to the incision site. When the user works outward, certain compositions of the present disclosure can be wiped on the skin in a simple overlapping motion, carefully covering each spot at least two or three times such that essentially no scrubbing is required.

[0114] Example

[0115] These examples are for illustrative purposes only and are not intended to limit the scope of the appended claims. Unless otherwise indicated, all parts, percentages, ratios, etc. in the examples and the rest of the specification are by weight. The materials used in the examples and their sources are provided in Table 1. Unless otherwise indicated, the solvents and other reagents used are available from MilliporeSigma, St. Louis, Missouri.

[0116] Table 1: Materials and Suppliers 。

[0117]

[0118] Test Method

[0119] Stability Data

[0120] Freeze-thaw and centrifuge: Centrifugation studies were performed using an Allegra 6R centrifuge from Beckman Coulter. All samples were tested at a force of 1620G for 10 to 15 minutes. Each composition was placed in a centrifuge tube and then centrifuged at ambient temperature, followed by freezing overnight at below -12°C and then thawing at above 17°C for at least 4 to 5 hours. A freeze-thaw protocol was performed two to three times, and then the freeze-thaw stability was evaluated by performing viscosity measurements.

[0121] Brookfield Viscosity Measurement

[0122] The viscosity of each composition was measured at ambient pressure at approximately 22°C - 24°C using a Brookfield LVDV-I+ viscometer equipped with a D-type Brookfield heliopath and an LV spindle. The spindle and speed were selected for each sample such that the viscometer operated in the middle of its range. All samples were equilibrated at approximately 22°C - 24°C for 24 hours before measurement. Viscosity measurements were performed at the lowest possible spindle speed while maintaining the viscosity reading within 30% - 70% of the viscometer range. Viscosity measurements were performed at 22°C - 24°C using 20 mL glass vials and an S4 spindle size. At other times, the vials were placed in an oven at 52°C for 4 days before measuring the viscosity.

[0123] Total Iodine Titration

[0124] Chemical stability was measured by iodometric titration. The total iodine was determined by transferring approximately 3 g - 4 g of the accurately weighed (accurate to 0.0001 g) composition to a 100 mL polypropylene beaker. A magnetic stir bar, 50 mL of deionized water, and 12 - 15 drops of 6N sulfuric acid were added to each sample. The sample was stirred until dissolved. Then, using a Metrohm 751 automatic titrator and a combined platinum electrode, titration was performed with a 0.1000 ± 0.0002N sodium thiosulfate titrant. The samples were run in duplicate. The average value of the total iodine measurements was recorded in Table 2.

[0125] Porcine Mucosal Model (PMM) Efficacy Determination Protocol

[0126] Tissue Preparation

[0127] Wash and rinse the porcine vaginal mucosal tissue with tap water. Then, produce biopsy explants with a diameter of 5 mm, transfer them to RPMI 1640 medium + 2% penicillin / streptomycin (P / S), trim them, and sonicate for 2.0 ± 0.1 minutes. Incubate the tissue explants in RPMI 1640 medium + 2% P / S for 15 minutes. Replace the medium with RPMI 1640 medium without antibiotics and wash 3 times. Incubate the explants in RPMI 1640 medium without antibiotics for 15 minutes. Fill the wells of a 6-well plate with 2.0 ± 0.1 mL RPMI 1640 medium (without antibiotics, without fetal bovine serum) and transwell inserts. Transfer the tissue explants to the transwells with the epidermal side facing up (3 explants / well).

[0128] Infection (MRSA Xen30)

[0129] Within one week of the experiment, streak fresh Petri plates directly with the bacterial test organism (MRSA Xen30) from the frozen stock. Inoculate multiple colonies into a culture tube containing 5 mL Todd Hewitt (TH) broth and place it in an orbital shaker incubator (37 °C, 200 rpm) late in the afternoon of the day before the experiment. In the morning of the experiment, transfer 20 ± 5 microliters (µL) of the bacteria to 2 mL of fresh TH broth and allow it to grow for 3 ± 1 hours. Measure the optical density of the culture at 600 nm, and a reading of 0.6 corresponds to approximately 5×10 8 colony-forming units (CFU) / mL. Prepare dilutions in RPMI 1640 medium such that 1 mL contains approximately 5×10 8 CFU. Transfer the bacteria (2 ± 1 µL) to each explant and return the explants to the incubator for infection for 2 ± 0.25 hours.

[0130] Treatment

[0131] Apply a fixed volume (100 µL) of each treatment solution (pH 3.2) to the tissue to provide an excess of the treatment solution on the tissue. Incubate the treated and inoculated bacteria explants at 37 ± 2 °C for 1 hour, then gently rinse with 1 mL of 2% mucin solution (using a repeat pipette to dispense 330 µL / explant at the set loading speed). Aspirate the mucin solution from around each explant and replace it with fresh medium. Incubate the explants at 37 ± 2 °C for 1 hour and 24 hours.

[0132] Sampling / Counting

[0133] Remove the explants from the transwell and place them in a microcentrifuge tube containing 1 mL of 2X DE broth neutralizer. Release the bacteria using a vortex / ultrasound / vortex protocol (30 ± 5 seconds of vortexing, 2 ± 0.5 minutes of sonication, 30 ± 5 seconds of vortexing). Inoculate the bacterial plates (using a spiral plater) onto MSA plates (dilute in PBS if necessary). Incubate the plates overnight at 37 °C in ambient CO2. Perform the sample tests in triplicate and express the data as the mean log10 recovery of bacteria ± standard deviation.

[0134] Example 1: Formulation 。

[0135] Prepare the formulations according to Table 2. In a typical experiment, weigh water to a total of 100 wt% of each formulation into a vial, then sequentially add povidone iodine, lactic acid, and nonionic surfactant, and mix using a magnetic stirrer or a blade mixer. After mixing for 30 minutes, add xylitol, sodium iodide, and sodium hydroxide and mix. Finally, add celquat and stir with a blade mixer to thicken for at least 30 minutes or stir overnight with a magnetic stirrer. Measure the pH of the sample and adjust to 3.1 - 3.4 if necessary.

[0136] Example 2: Physical Stability of the Composition 。

[0137] Evaluate the physical stability by subjecting each formulation to freeze-thaw experiments according to the test method described earlier. In this example, all compositions contain PVP-I, lactic acid, sodium iodide, xylitol, and Celquat. Composition 1 shows that a composition containing PVP-I and lactic acid can be stabilized by a relatively high concentration of nonionic surfactant (Tables 2 and 3). Using a relatively low concentration of nonionic surfactant renders Compositions 2 and 3 unstable, and the results for Compositions 5 and 6 show that zwitterionic surfactants produce good stability.

[0138] Composition 7 is stabilized with stearyl polyoxyethylene ether 100 containing half the level of povidone iodine. The solution is stabilized with a lower level of sodium iodide. Compositions 8, 9, and 10 containing stearyl polyoxyethylene ether 100 are physically unstable.

[0139] Thus, the examples demonstrate the ability to use nonionic surfactants in stabilizing antibacterial compositions containing PVP-I and lactic acid. The use of relatively safe nonionic surfactants in stabilizing PVP-I compositions containing hydroxycarboxylic acids (such as lactic acid) should improve the safety of such compositions for use on sensitive tissues.

[0140]

[0141]

[0142] Table 3: Non-ionic Surfactants 。

[0143]

[0144] At a higher concentration of povidone iodine (5%), stable formulations were obtained with cetostearyl alcohol polyether-25 in the absence of anionic surfactants. The addition of lauryldimethylamine oxide contributed to an increase in the chemical stability of the cetostearyl alcohol polyether-25 formulations. Stearyl polyoxyethylene ether-100 did not seem to have good physical stability in higher povidone iodine formulations. However, stearyl polyoxyethylene ether 100 seemed to stabilize the formulations at lower povidone iodine levels.

[0145] Example 3: Addition of a Thickener to Stabilize a Formulation Containing Povidone Iodine and a Monofunctional Acid 。

[0146] Formulations were prepared using the above method according to Table 4 and their properties were evaluated as described above.

[0147] Table 4: Formulations 。

[0148]

[0149]

[0150] The data in Table 4 demonstrate that nonionic and anionic thickeners are less effective than cationic thickeners in increasing viscosity and maintaining formulation stability.

[0151] Example 4: Efficacy and Persistence of 2.5% Povidone Iodine Formulation Relative to 5% Povidone Iodine Formulation 。

[0152] At 1 hour with an inoculum of 5.42 Log 10 CFU / explant, formulations 1, 5, 6, and 7 in Table 2 were treated once and no detectable growth was observed, while the recovery of betadine (10% povidone iodine solution) was close to 7 log, and formulations 1, 5, 6, and 7 continued to have no recovery at the 24-hour time point.

[0153] Therefore, the 5% formulation has similar activity to 2.5% povidone iodine in the short term and long term (1 hour and 24 hours).

[0154] Example 5 :

[0155] PMM MTT viability assay: (Test simulating more than one application of the formulation)

[0156] To determine the viability of the formulation:

[0157] Viability

[0158] Vitality in a Repeated Dose Explant Tissue Model

[0159] RPMI 1640 = Roswell Park Memorial Institute medium

[0160] ABX = 2% Penicillin / Streptomycin

[0161] FCS = Fetal Calf Serum

[0162] A. Tissue Preparation :

[0163] Scrub and rinse porcine mucosal model (PMM) tissue sections with tap water. Generate biopsy explants with a 5 mm diameter, transfer to RPMI 1640 + 2% ABX, trim, and wash three times in RPMI without antibiotics. Incubate the explants for at least 30 minutes (ABX rinse). Add 2.0 ± 0.1 mL of RPMI (without ABX, without FCS) per well to each well of a 6-well plate and add transwell inserts. Transfer the explants with the lumen side up to the inserts (3 explants / well).

[0164] B. Treatment :

[0165] Evaluate Formulations 1, 5, 6, 7, and 11 (Table 2). Administer 10 μL of the formulation to each explant. Incubate the explants at 37 ± 2 °C for 1 hour, then gently rinse each well with 1 mL of 2% mucin solution. For each explant, dispense 330 μL of 2% mucin using a repeat pipette at a dispense rate of 4. Aspirate the mucin from around each explant. Aspirate the medium and replace it with fresh medium under the transwell. Incubate the explants at 37 ± 2 °C for 24 hours. Administer 10 μL of the formulation to each explant again and wash the explants with mucin after 1 hour. Aspirate the mucin and replace the medium as above. Incubate the explants at 37 ± 2 °C for 24 hours.

[0166] C. MTT Assay

[0167] Wash the explants by vortexing three times in 200 ± 20 µL PBS (three separate wells, each containing 200 ± 20 µL PBS). Transfer the explants to a 96-well plate with 100 ± 10 µL RPMI and 10 ± 1 µL MTT substrate per well. Incubate the explants in the plate submerged in the MTT substrate at 37 °C + 7% CO2 for 3 hours. Transfer the explants to a 96-well plate containing 100 ± 10 µL decolorization solution per well and seal with a plate film (one explant per well). Incubate the sealed plate overnight at 4 °C. Remove the explants from the wells. Read the plate at 570 nm and 690 nm and calculate the percentage viability using the following formula: % viability = 100 × [OD (sample) / OD (negative control)]

[0168] Results: Formulations 1, 5, 6, and 7 in Table 2 each had a viability greater than 30%, while formulation 11 had a viability less than 30% after two administrations and was measured at the 48-hour time point.

Claims

1. An antibacterial composition, the antibacterial composition comprising: an antimicrobial agent comprising molecular iodine (I2), an iodide salt; a hydroxycarboxylic acid present at a concentration of at least 2% by weight based on the total weight of the antibacterial composition; and a nonionic surfactant; wherein the antibacterial composition does not contain any amount of anionic surfactant.

2. The antibacterial composition according to claim 1, wherein the hydroxycarboxylic acid comprises a monocarboxylic acid.

3. The antibacterial composition according to any one of the preceding claims, wherein the nonionic surfactant has an HLB value between 12 and 20.

4. The antibacterial composition according to any one of the preceding claims, wherein any surfactant present in the antibacterial composition is included in the list of inactive excipients approved by the US FDA.

5. The antibacterial composition according to any one of the preceding claims, the antibacterial composition further comprising an amphoteric surfactant.

6. The antibacterial composition according to any one of the preceding claims, wherein the composition is iodine-stable.

7. The antibacterial composition according to any one of the preceding claims, wherein the composition is physically stable.

8. The antibacterial composition according to any one of the preceding claims, wherein the hydroxycarboxylic acid is present in an amount between 2% and 10% by weight based on the total weight of the antibacterial composition.

9. The antibacterial composition according to any one of the preceding claims, the antibacterial composition further comprising an amine oxide.

10. The antibacterial composition according to claim 8, wherein the amine oxide is present at a concentration of 0.25% to 1.5% by weight based on the total weight of the antibacterial composition.

11. The antibacterial composition according to any one of claims 1 to 9, wherein the iodide salt is present in an amount between 0.25% and 5% by weight based on the total weight of the antibacterial composition.

12. The antibacterial composition according to any one of claims 1 to 11, wherein the antimicrobial agent comprises an iodophor.

13. The antibacterial composition according to claim 12, wherein the iodophor is povidone iodine.

14. The antibacterial composition according to claim 13, wherein the concentration of povidone iodine is greater than 3% by weight based on the total weight of the composition, and wherein the nonionic surfactant has an HLB value between 12 and 17 and a hydroxyl value (mg KOH / g) between 35 and 45.

15. The antibacterial composition according to claim 13, wherein the concentration of povidone iodine is less than 3% by weight based on the total weight of the composition, and wherein the nonionic surfactant has an HLB value between 18 and 20 and a hydroxyl value (mg KOH / g) between 12 and 20.

16. The antibacterial composition according to any one of the preceding claims, the antibacterial composition further comprising a monosaccharide, a sugar alcohol, or a combination thereof.

17. The antimicrobial composition according to claim 16, wherein the monosaccharide, sugar alcohol, or combination thereof is present at a concentration greater than 5% by weight based on the total weight of the antimicrobial composition.

18. The antimicrobial composition according to any one of the preceding claims, wherein the total iodine level in the composition is less than 2.7% by weight based on the total weight of the antimicrobial composition.

19. The antimicrobial composition according to any one of the preceding claims, wherein the antimicrobial composition further comprises a thickener containing a cationic polymer.

20. A method for decolonizing or disinfecting the nasal passages of a subject, the method comprising administering a composition according to any one of claims 1 to 19 to the nasal passages of the subject.

21. A method for disinfecting the tissue of a subject, the method comprising administering a composition according to any one of claims 1 to 19 to the nasal passages of the subject.

22. A method for forming a stable antimicrobial composition comprising povidone iodine and a hydroxycarboxylic acid, the method comprising: providing an antimicrobial agent comprising molecular iodine (I2); providing a hydroxycarboxylic acid; providing an iodide salt; and providing a nonionic surfactant; and mixing the antimicrobial agent, hydroxycarboxylic acid, iodide salt, and nonionic surfactant to form a stabilized composition; wherein the antimicrobial composition does not contain any amount of anionic surfactant.

23. An antimicrobial composition, the antimicrobial composition comprising: an antimicrobial agent comprising povidone iodine; an iodide salt; a hydroxycarboxylic acid present at a concentration of at least 2% by weight based on the total weight of the antimicrobial composition; and a nonionic surfactant in an amount of at least 1% by weight based on the total weight of the antimicrobial composition, wherein the nonionic surfactant has an HLB value between 12 and 20.

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