Cationic antiseptic compositions and methods of use

The use of antibacterial agents plays an important role in recent drug therapies. This is especially true in the field of dermatology and even skin and wound disinfection, where it is most effective for treating skin or mucous membranes suffering from bacterial, fungal, viral or lesioned infections. Methods often include the use of topical antibacterial agents, such as antibiotics. For many years, the medical community has relied primarily on antibiotics in its commitment to systemic and even local infections.

Antibiotics are organic molecules produced by microorganisms that disrupt or inhibit the growth of bacteria and other microorganisms in dilute solutions (eg, solutions <10 μg / mL, often less than 1 μg / mL). Has the ability. Antibiotics are generally effective at very low levels, have very low side effects, if any, and are often safe. The antibacterial activity spectrum of antibiotics is generally narrow. In addition, antibiotics often act on highly specific sites on cell membranes or on highly specific metabolic pathways. This tends to make it relatively easy for bacteria to develop resistance to their antibiotics (ie, genetically acquire the ability to tolerate higher concentrations of antibiotics). By natural selection, by transmission of plasmid coding resistance, by mutation, or by other means. Tolerance not only eliminates the possibility of drug therapy to treat the disease, but also puts the patient at additional risk, especially if the antibiotic is systemically used on a daily basis. There is a possibility of incurring.

Over the last few decades, colonization of the anterior nares with Staphylococcus aureus (SA) has been well documented to cause a number of problems. The medical community has also relied primarily on antibiotics for nasal decolonization. For example, bacitracin, neomycin sulfate, polymyxin B sulfate, gentamicin, flameicetin-gramicidin, lithostafin, methicillin, rifampin, tobramycin, nystatin, mupirocin, and combinations thereof have been used for nasal decolonization with varying effects. Was there.

For example, nasal colonization with SA in preoperative patients has resulted in higher infection rates and higher rates of other nosocomial infections such as catheter infections. Nasal colonization by SA in hemodialysis patients has resulted in a significantly higher incidence of bloodstream infections. In addition, because the anterior nares are an environmentally suitable place for SA colonization, the epidemic of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals or other medical facilities can be seen in patients and healthcare. It is well documented that it can be suppressed by decorating the anterior nares of the worker.

Bactroban by Glaxo Smith Kline Mupirocin, marketed as a calcium salt in Nasal), is the only antibiotic approved by the Food and Drug Administration for nasal decolonization applications in the United States. For example, there are many reports of resistance to mupirocin when used as a nasal decolonizing agent. It has been reported that the resistance rate reaches as high as 25% and even as high as 50% (for example, E. Perez-Roth et al., Diag.Micro.Infect.Dis., 43. See: 123 ~ 128 (2002) and H. Watanabe et al., J. Clin. Micro., 39 (10): 3775 ~ 3777 (2001)). Preoperative decolonization of the anterior nostril with mupirocin has been shown to reduce the risk of infection at the surgical site from 1/2 to 1/10 (T. Perl). Et al., Ann. Pharmacaother., 32: S7 ~ S16 (1998)), which have a high resistance rate to this antibiotic, making it unsuitable for routine use.

Disinfectants, on the other hand, are synthetic molecules that destroy or inhibit microorganisms and viruses by inhibiting metabolic pathways, altering cell envelopes, or both. They tend to have a broader antibacterial activity spectrum and often act by non-specific means such as cell membrane disruption, oxidation of cellular components, and denaturation of proteins. Such non-specific activity makes it difficult for microorganisms to develop clinical resistance to disinfectants. For example, there are few reports of clinical resistance to disinfectants such as iodine, lower alcohols (ethanol, propanol, etc.), chlorhexidine, quaternary amine surfactants, chlorinated phenols and the like. However, some of these compounds should be used at concentrations that often result in irritation and tissue damage, especially when used repeatedly. Moreover, unlike antibiotics, many disinfectants are inactive in the presence of high levels of organic compounds. For example, formulations containing iodine or quaternary ammonium compounds have been reported to be inactivated by the presence of nasal or vaginal secretions and possibly organic substances such as those present on the skin.

Many disinfectant compounds are considered irritants. For example, it has been reported that compositions containing iodine and / or chlorhexidine caused irritation to skin and mucosal tissues. This means that some otherwise healthy individuals, as well as individuals with infections such as chronic sinusitis, may have high levels of microbial colonization, anterior nares, nasal and esophageal cavities. This is especially true for sensitive mucosal tissues such as. In addition, because of its irritation, many of these compounds are stimulated or infected to treat skin conditions such as lesions caused by impetigo or shingles. It may be inappropriate for application to scabbed skin tissue.

In addition, the composition is colorless or almost colorless, odorless or almost odorless, and has an acceptable taste, for certain uses, especially when applied to the nose and mouth. Is particularly desirable. Many disinfectants have undesired properties, such as iodine and iodophore, which are orange to brown in concentrations typically used for disinfection and have a strong odor.

It has been proposed to use chlorhexidine gluconate (combined with neomycin sulphate) for nasal decolonization, but with little success. For example, Naseptin is an antibiotic emulsifying cream containing neomycin sulfate (3250 units / g) and chlorhexidine gluconate (0.1 wt%), the combination of which destroys bacteria. The formulation further comprises peanut oil, cetostearyl alcohol / ethylene oxide concentrate, and setostearyl alcohol in an aqueous substrate. The formulation must be used at a frequency of 4 times / day over a 10-day period to eradicate staphylococci from the nasal pathway. In addition, US Pat. No. 6,214,866 discloses the use of chlorhexidine in combination with the antibiotic mupirocin.

Povidone-iodine has also been proposed for use in nasal decoronization (RL Hill and MW Casewell, Journal of Hospital Infection, 2000, Vol. 45, pp. 198-205). Betadine Cream (5 wt% povidone iodine) was found to kill methicillin-resistant Staphylococcus aureus in vitro in enrichment culture techniques. The addition of nasal discharge reduces the activity of povidone-iodine by as much as 80-90% due to the reaction of free iodine with organic loads. Other drawbacks of using 5% povidone-iodine in patients include 1) extremely dark brown color, 2) irritation due to low pH, and 3) strong iodine odor. Can be mentioned.

The composition of the ingredients can affect the performance of the antibacterial agent and the likelihood of irritation. For example, many commonly used antibacterial compositions are too viscous and / or inherently hydrophilic, resulting in moist tissue such as the anterior nares, openness, exudation, or Alternatively, it cannot retain sufficient substantivity and persistence to impart sufficient antibacterial activity in the infected lesion. It has been reported that the presence of solvents can reduce antibacterial activity in many disinfectants. Furthermore, it has been reported that many surfactants may reduce the effectiveness of the disinfectant by confining the disinfectant in the micelles. (HB Costenbauer, Disinfection, Sterilization, and Preservation, First Addition, Chapter 44, 1968, CA Lawrence and SS Block). In addition, it is often pointed out that surfactants contribute to irritation.

<p> Thus, it develops little tolerance and is well tolerated when used in mammalian tissues, especially in mammalian wet tissues such as the nasal passages, anterior nares, vagina, and wounds. There is still a need for effective antibacterial compositions.</p>

<p> The present invention provides an antibacterial composition, and a method for producing and using the composition. Such compositions are typically useful for topical application, especially to mucosal tissues (ie, mucosa), but can also treat a wide variety of surfaces. They can effectively reduce, prevent, and eliminate microorganisms, specifically bacteria, fungi, and viruses. It is preferred that the compositions of the invention have a broad antibacterial spectrum over a relatively wide range of these microorganisms.</p><p> The compositions of the present invention provide locally effective antibacterial activity, which is why they are caused by microorganisms (including viruses, bacteria, fungi, mycoplasmas, and protozoans) in the skin, wounds, and / or mucous membranes. It is useful for local treatment and / or prevention of exacerbated symptoms.</p><p> Importantly, in certain embodiments of the invention, it is extremely unlikely to cause clinical microbial resistance. Therefore, such compositions are used daily to treat local infections or to eradicate unwanted bacteria (eg, colonization of Staphylococcus aureus in the nose). It can be applied multiple times over several days. Moreover, the compositions of the present invention can be used in therapeutic methods in which the same patient is treated multiple times without worrying about causing resistance to the antibacterial agent. This is especially important for patients with chronic diseases who require anterior nares decolonization prior to hemodialysis and who disinfect chronic wounds such as leg ulcers due to diabetes. It becomes.</p><p> Moreover, the preferred compositions of the present invention generally have low levels of irritation on the skin, skin lesions, and mucous membranes (including the anterior nares, nasal cavity, and nasopharyngeal cavity). Moreover, certain preferred compositions of the present invention are practical as they ensure sufficient effectiveness over a relatively long period of time (ie, are difficult to remove by fluids).</p><p> The composition of the present invention contains a cationic disinfectant. Cationic disinfectants include biguanides and bisbiguanides, such as chlorides and various salts thereof, such as digluconate, diacetate, dimethosulfate, and dilactate salts (but not limited to), and mixtures thereof; High molecular weight quaternary ammonium compounds such as polyhexamethylene biguanide; silver and various silver complexes; low molecular weight quaternary ammonium compounds such as benzalkoium chloride and alkyl substituted derivatives, di-long chain alkyl (C6-C18) quaternary Examples include ammonium compounds, cetylpyridinium halides and derivatives thereof, benzethonium chloride and alkyl substituted derivatives thereof, and octenidin; and combinations thereof.</p><p> What is important here is that the compositions of the present invention are capable of destroying microorganisms on or in mammalian tissue. Therefore, its concentration used has been traditionally used to simply retain certain locally applied compositions, i.e., to prevent the growth of microorganisms in the local composition for purposes other than disinfection. In comparison, it is generally higher. For example, the concentration may be at least 0.1% by weight, preferably at least 0.2% by weight, more preferably at least 0.5% by weight. Generally, the disinfectant can be used at a concentration of at least 1% by weight, preferably at least 2% by weight, and often at least 3% by weight of the composition. All weight percent is based on the total weight of the composition that is "ready to use" or "as used".</p><p> Depending on the application, many of these compounds can be irritating when administered in simple aqueous or hydrophilic vehicle formulations at such concentrations. Many of the compositions of the present invention incorporate a substantial amount of a lipophilic or hydrophobic phase. The hydrophobic phase consists of one or more water-insoluble components. When administered in a hydrophobic phase, its irritation can be significantly reduced. By incorporating the hydrophobic phase, the likelihood that the compositions of the invention are irritating can be significantly reduced. Suitable lipophilic phase components have a solubility in water at 23 ° C of less than 0.5% by weight, often less than 0.1% by weight. In addition, the disinfectant is preferably present at a concentration close to or preferably above the dissolution limit of its hydrophobic phase.</p><p> Importantly, the composition has sufficient viscosity to prevent it from being inhaled into the lungs when used in the nose for applications such as nasal decolonization. That is what you are doing. Moreover, the relatively high viscosity of the compositions of the present invention minimizes possible migrations associated with other compositions, thereby reducing irritation and confusion. Despite the presence of the hydrophobic phase, many of the disinfectants, including the compositions, are extremely potent and exhibit rapid antibacterial activity.</p><p> In addition, antibacterial compositions containing hydrophilic components such as polyols (eg, glycerin and polyethylene glycol) that have little or no antibacterial activity on their own can improve the antibacterial activity of the composition to a large extent. .. Preferred examples of such a hydrophilic component include glycols, lower alcohol ethers, short chain esters, and combinations thereof, wherein the hydrophilic component is contained in water at 23 ° C. Dissolve in an amount of at least 20% by weight.</p><p> The compositions of the present invention preferably do not contain any antibiotics.</p><p> The composition further comprises a surfactant selected from the group consisting of sulfonates, sulfates, phosphonates, phosphates, amphoteric, poloxamers, cationic surfactants, or mixtures thereof. It is preferable to have. The composition further includes alpha-hydroxy acids, beta-hydroxy acids, chelating agents, (C1-C4) alkylcarboxylic acids, (C6-C12) arylcarboxylic acids, (C6-C12) aralkylcarboxylic acids, (C6). It is preferable that an enhancer component containing ~ C16) an alkylarylcarboxylic acid, a phenolic compound, (C1 ~ C10) an alkyl alcohol, an ether glycol, or a combination thereof is contained.</p><p> The present invention also provides various uses of the compositions of the present invention. In one embodiment, the invention provides a method of preventing and / or treating a disease caused or exacerbated by microorganisms on mammalian tissues such as skin and / or mucous membranes. The method involves contacting mammalian tissue with the antibacterial composition of the present invention.</p><p> In one embodiment, the invention provides a method for decolonizing microorganisms from at least a portion of a subject's nasal cavity, anterior nares, and / or nasopharynx. The method involves contacting the antibacterial composition of the invention with the nasal cavity, anterior nares, and / or nasopharynx in an amount effective to kill one or more microorganisms in or on the tissue. included.</p><p> In one embodiment, the invention provides a method for decolonizing microorganisms from at least a portion of the subject's pharynx / esophagus. The method involves contacting the esophageal cavity with the antibacterial composition of the invention in an amount effective to kill one or more microorganisms in or above the tissue of the pharynx.</p><p> In one embodiment, the invention provides a method for decolonizing microorganisms from at least a portion of the subject's pharynx / esophagus. In that method, a sufficient amount of the composition is effective to reduce or eliminate the colonization of bacteria in or above the tissue of the pharynx, in an amount effective to reduce or eliminate the antibacterial activity of the present invention. Includes contacting the composition with the oral cavity and / or nose.</p><p> In one embodiment, the invention provides a method for decorating microorganisms from at least a portion of the subject's oral cavity. The method involves contacting the oral cavity with the antibacterial composition of the invention in an amount effective to kill one or more microorganisms in or on the soft tissues of the oral cavity.</p><p> In one embodiment, the invention provides a method for treating a respiratory disease (eg, chronic sinusitis in a subject). The method includes the antibacterial compositions of the invention and at least a portion of the bronchi (particularly, in particular) in an amount effective to reduce or eliminate colonization of bacteria in or on soft tissues within the bronchi. It involves contacting the upper airway system, including the nasal cavity, anterior nares, and / or the nasopharynx.</p><p> In one embodiment, the invention provides a method for treating impetigo on the skin of a subject. The method involves contacting the affected area with the antibacterial composition of the invention in an amount effective to reduce or eliminate clinical signs of infection.</p><p> In other embodiments, the invention provides a method for killing or inactivating microorganisms. As used herein, the term "killing or inactivating" is used by killing or otherwise inactivating microorganisms (eg, viruses). , Means to nullify the microorganism. The present invention provides methods for killing bacteria, such as Staphylococcus, Streptococcus, Escherichia, Enterococcus (for example). Includes antibiotic-resistant strains such as bancomycin-resistant Enterococcu), and bacteria of the genus Pseudomonas, and combinations thereof, but more specifically, Staphylococcus. aureus (including antibiotic-resistant strains such as Staphylococcus aureus), Staphylococcus epidermidis, Escherichia coli (E. coli) ), Pseudomonas aeruginosa (Pseudomonas ae.), And Streptococcus pyogenes, which are often on the subject's skin or mucosal tissue or Exists in. The method is in an amount effective to kill one or more microorganisms (eg, bacteria and fungi) or inactivate one or more microorganisms (eg, viruses, especially herpesviruses). It includes contacting the antibacterial composition of the present invention with a microorganism thereof.</p><p> For example, in one embodiment, the invention provides a method of killing or inactivating microorganisms in a subject's nose or nasal cavity. The method involves contacting the affected area with the antibacterial composition of the invention in an amount effective to kill one or more microorganisms on or in the tissue in the nose or nasal cavity.</p><p> In addition, the compositions of the present invention can be used to impart residual antibacterial activity on surfaces by leaving residues, or with surfaces (eg, in the skin, anterior nares, mucosal tissue, wounds, or such tissue). Conditions such as contacting medical devices, especially skin, mucosal tissue, and / or wounds) can be provided to maintain efficacy and confer significant antibacterial activity. This means that compositions with relatively high concentrations (generally greater than 30% by weight, preferably greater than 40% by weight, most preferably greater than 50% by weight) of hydrophobic components and / or relatively high viscosities. , For example, achieved by providing a composition having a viscosity greater than 1,000 cps, preferably greater than 10,000 cps as measured by a viscosity test.</p><p> For example, in one embodiment, the invention provides a method of imparting residual antibacterial activity on a subject's skin, in the anterior nares, in mucosal tissue, and / or in a wound, the method of which is the skin. , Mucosal tissue, and / or wounds are contacted with the antibacterial composition of the invention in an amount effective to kill one or more microorganisms.</p><p> Manufacturing methods are also provided.</p><p>Definition The following terms are used herein as defined below.</p><p> "Effective amount The term "amount)" refers to reducing, preventing, or eliminating the species of one or more microorganisms at acceptable levels when administered in a certain amount, at a certain frequency, for a period of time. It means the amount of one or more disinfectant components that, as a whole, give antibacterial (eg, antiviral, antibacterial, or antifungal) activity when added to the composition, such as causing. Typically, this is a level low enough that it does not cause clinical symptoms, preferably an undetectable level. It should be understood here that in the compositions of the present invention, the concentrations or amounts of the components do not have to be killed to acceptable levels when considered individually, or are undesirable microorganisms. It does not have to be killed in the broad spectrum of, or it does not have to be killed so quickly, but when used together, such components (under the same conditions, the same component) It gives higher antibacterial activity (compared to when used alone). In addition, the list of concentrations of those components (unless otherwise noted) can be used as is ("ready to use" or "as". It should also be understood that it is a "used") composition. The compositions can also be in concentrated form. That is, certain embodiments of the composition may be in the form of concentrates that the user dilutes with a suitable vehicle.</p><p> The term "hydrophilic" or "water-soluble" refers to at least 7% by weight, preferably at least 10%, at a temperature of 23 ° C, relative to the total weight of the hydrophilic substance and water. Deionized water (or other predetermined aqueous solution) in an amount of% by weight, more preferably at least 20% by weight, even more preferably at least 25% by weight, even more preferably at least 30% by weight, most preferably at least 40% by weight. ) Refers to a substance that will be dispersed or dissolved in. A container having a pathway of 4 cm when the compound is thoroughly mixed with water at 60 ° C for at least 4 hours, allowed to cool and placed at 23-25 ° C for 24 hours, and then when the composition is completely mixed. If the solution is a uniform solution with no visible cloudiness, phase separation, or precipitate, the component is considered to be dissolved. Typically, the sample exhibits a transmittance of greater than 70% when placed in a 1 x 1 cm cell and measured at a wavelength of 655 nm using a suitable spectrophotometer. The water-dispersible hydrophilic substance is dispersed in water to form a uniform cloudy dispersion after vigorously shaking the mixture of 5% by weight of the hydrophilic component in water. Suitable hydrophilic components are those that are water soluble.</p><p> The terms "hydrophobic" or "water-in soluble" refer to substances that are not significantly soluble in deionized water at 23 ° C. "Not noticeably (dissolved) The term "significantly)" means that the solubility of the substance in water is less than 5% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, based on the total weight of the hydrophobic substance and water. More preferably, it means less than 0.1% by weight. Solubility is that the compound and water are thoroughly mixed at an appropriate concentration at 23 ° C (or warmed, if necessary to dissolve the compound) for at least 24 hours, and then it is mixed at 23 ~. It can be determined by observing the sample after allowing it to stand at 25 ° C for 24 hours. In a glass container with a 4 cm path, the sample may be liquid or solid, separated at the top or bottom, or dispersed throughout the sample, but second. The phase should be clearly shown. In the case of crystalline compounds, care must be taken to prevent the formation of supersaturated solutions. The composition should be agitated before observing. The presence of cloudiness, visible precipitates, and separated phases suggests that the dissolution limit has been exceeded. Typically, the sample exhibits less than 70% transmission when placed in a 1 x 1 cm cell and measured at a wavelength of 655 nm using a suitable spectrophotometer. To measure lower solubility than is observable to the naked eye, the solubility is determined using a compound labeled with a radioisotope, which is described in the following literature: Henrik Vorum. Et., "Conventional Solubility Spectrums in Solubility of Long-Chain Fatty Acids in Phosphate Buffer at pH 7.4" (Biochimica et. Biophysica Acta., 1126 (1992), p.135-142.</p><p> The term "Stable" means physically stable or chemically stable, both of which are described in more detail below. Preferred compositions are both chemically and physically stable.</p><p> The term "microorganism or microbe" refers to bacteria, yeasts, molds, fungi, protozoa, mycoplasmas, and even viruses, including lipid-envelope RNA and DNA viruses.</p><p> The term "antibiotic" refers to organic compounds produced by microorganisms that can destroy or inhibit microorganisms even at dilute concentrations and are used in the treatment of infectious diseases. The term also includes semi-synthetic compounds, which are chemical derivatives of compounds produced by microorganisms, and synthetic compounds that act on highly specific biochemical pathways required for cell survival.</p><p> The term "antiseptic" means a chemical agent other than those referred to herein as "enhancers" that kill pathogenic and non-pathogenic microorganisms. Suitable disinfectants are 1 ~ when tested in a Mueller Hinton broth at 35 ° C. and a concentration of 0.25 wt% in a rate of kill assay with a suitable neutralizer. 3x10⁷Sixty minutes after the initial inoculation of cfu / mL, both P. aeruginosa and S. aureus show a logarithmic reduction of at least 4, which is described in the following literature: : G. Nicoletti, V. Boghossian, F. Gurevitch, R. Borland and P. Mogenroth, "The Antimicrobial Activity" in vitro of chlorhexidine, a mixture of isothiazolinones (Kathon CG) and cetyl trimethyl ammonium bromide (CTAB) ", Journal of Hospital Infection (1993), Vol. 23, pp. 87-111. Disinfectants generally interfere with cell metabolism and / or cell envelopes more extensively. The disinfectant may have a low molecular weight or a high molecular weight. Low molecular weight disinfectants generally have a molecular weight less than about 350 g / mol. The high molecular weight disinfectant may have a higher molecular weight.</p><p> The term "enhancer" means an ingredient that enhances the effectiveness of the disinfectant ingredient, and when used individually, a composition without the disinfectant ingredient or a composition without the enhancer ingredient, they are Overall, it does not give the same level of antibacterial activity as the composition. For example, enhancer components in the absence of disinfectant components do not exhibit measurable antibacterial activity. The enhancing effect is related to the killing level, kill rate, and / or spectrum of the killing microorganism and is not found in all microorganisms. In fact, enhanced levels of death are most often observed with Gram-negative bacteria such as Escherichia coli. The enhancer, when combined with the other components of the composition, exhibits higher activity as a whole than the sum of the activities of the composition without the enhancer component and the composition without the disinfectant component. , It should be a synergist.</p><p> The terms "mucosal membrane" and "mucosal tissue" are used interchangeably, including the nose (anterior nasal cavity, nasopharyngeal cavity, etc.), oral cavity (eg, mouth), external ear, Refers to the surface of the middle ear, vaginal cavity and other similar tissues. Examples include mucous membranes such as the oral cavity, gums, nose, eyeballs, trachea, bronchi, gastrointestinal tract, rectum, urethra, ureter, vagina, cervix, and uterine mucosa.</p><p> As used herein, the term "preservative" is used in a composition to prevent biological contamination of the composition and / or deterioration of the composition. Refers to the disinfectant added to. They are generally present at levels below 0.50% by weight, often less than about 0.1% by weight.</p><p> The term "affliction" refers to a condition to the body caused by sickness, disease, injury, or bacterial colonization.</p><p> The term "treat or treatment" means improving a subject's condition, which is associated with the clinical manifestations of the disease, typically the condition.</p><p> The term "decolonization" refers to a decrease in the number of microorganisms (eg, bacteria and fungi) present in or on tissues, although they do not necessarily cause immediate clinical symptoms. .. Examples of decolonization include, but are not limited to, nasal and wound decolonization. Usually, there are fewer microorganisms present in "colonized tissue" than in "infected tissue". When the tissue is completely decolonized, the microorganism is "eradicated."</p><p> "Subject" and "patient" include humans, sheep, horses, cows, pigs, dogs, cats, rats, mice, or other mammals.</p><p> The term "wound" refers to an injury to a subject, including the destruction of a normal skin or mucosal tissue barrier that exposes the underlying tissue, for example. , Tears, surgery, burns, such as pressure ulcers, damage to lower tissues due to poor circulation, etc. It should be understood that wounds include both acute and chronic wounds.</p><p> The term "comprise" and its variants have no limiting implications when those terms appear in the specification and claims.</p><p> As used herein, "a", "an", "the", "at least one", and "one or more" are used interchangeably. The term "and / or" means one or all of the listed elements (eg, preventing and / or treating a disease means preventing, treating, or treating a further disease. It means doing both prevention).</p><p> Further herein, when a numerical range is cited by termination, it includes all numbers contained within that range (eg, 1-5, 1, 1.5, 2, 2.75, 3, 3.80). , 4, 5, etc.) are included.</p><p> The above summary of the present invention is not intended to describe each or all of the disclosed embodiments of the present invention. The following description illustrates the embodiment as an explanation in more detail. A list of examples is provided in several places throughout the application, but these examples can be used in various combinations. In each case, the cited list serves only as a representative group and should not be taken as an exclusive list.</p>

The present invention provides antibacterial (including, for example, antiviral, antibacterial, and antifungal) compositions. Their compositions include one or more disinfectants selected from the group consisting of: biguanides and bisbiguanides, for example, chlorhexidine and various salts thereof, such as digluconate, diacetate, dimethosul. Fate, and dilactate salts (but not limited to), and combinations thereof; high molecular weight quaternary ammonium compounds such as polyhexamethylene biguanides; silver and various silver complexes; low molecular weight quaternary ammonium compounds such as chloride. Benzalcoium and alkyl substituted derivatives; di-long chain alkyl (C6-C18) quaternary ammonium compounds; cetylpyridinium halide and derivatives thereof; benzethonium chloride and alkyl substituted derivatives thereof; and octenidin. Disinfectants are sufficient to allow microorganisms to be decolonized or eradicated from mammalian tissue when applied to mammalian tissue at sufficient time, frequency, and dosage. Concentration (at least 0.20% by weight, typically higher than 0.30% by weight, most preferably higher than 0.50% by weight). Certain compositions also include one or more surfactants, one or more hydrophilic compounds, and / or one or more hydrophobic compounds.

It is preferred that such compositions have good adhesion to body tissues (eg, skin, mucosal tissues, and wounds), thereby being highly effective locally. However, what is important here is that their compositions are not bioadhesive and do not bind into the tissue. Therefore, the present invention provides a wide variety of uses of those compositions. Particularly preferred methods include topical administration, especially to mucosal tissues (ie, mucosa containing tissues of the anterior nose and other upper respiratory tracts), as well as skin (eg, skin lesions) and wounds.

Compositions containing multiple disinfectants can be used in certain applications where a broad antibacterial activity spectrum is desired. In other applications where limited antibacterial activity is desired, it is preferable to use a composition containing a disinfectant having a limited spectrum. For example, in certain situations it may be desirable to kill or inactivate only one or several types of microorganisms rather than all existing microorganisms. For example, many quaternary ammonium compounds have a higher minimum inhibitory concentration for Gram-positive microorganisms compared to Gram-positive microorganisms, so if you want to kill mainly Gram-positive microorganisms, They can be adopted. It is useful in the treatment of nasal decolonization, impetigo, and other local infections caused primarily by Gram-positive microorganisms.

By using the compositions of the present invention, it is possible to impart effective local antibacterial activity, thereby treating and / or preventing a wide variety of diseases. For example, they are microorganisms (eg, on the skin and / or mucous membranes, such as the nose (anterior nasal passage, nasopharyngeal cavity, nasal cavity, etc.), outer ear, middle ear, oral cavity, rectum, vagina, or other similar tissue. Can be used in the treatment and / or prevention of diseases caused or exacerbated by (gram-positive bacteria, gram-negative bacteria, fungi, protozoa, mycoplasma, yeast, viruses, and even lipid-encapsulated viruses). .. Particularly related bacteria that cause or exacerbate such diseases include Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, and Escherichia. Genus, bacteria, and even Herpesvirus, Aspergillus, Fusarium, and Candida. Particularly relevant microorganisms include:

The compositions of the present invention can be used to prevent and / or treat one or more infections or other diseases caused by microorganisms. Specifically, the compositions of the present invention can be used to prevent and / or treat one or more of the following: for skin lesions such as herpes, eczema, infants and even incontinence. Skin symptoms such as adult staphylococcus, inflammation around ostomy equipment, herpes zoster, and bacterial infections in open wounds (eg, cuts, scratches, burns, lacerations, chronic wounds); necrotizing mycosis; Infections; Acute or Chronic staphylococcal infections caused by bacterial, viral, or fungal contamination; Vaginal or rectal fungal and bacterial infections; Vaginal yeast infections; Bacterial rhinitis; Eyes Infection; herpes simplex; genital herpes; Staphylococcus in the anterior nose Colonization by aureus (eg, preoperative or hemodialysis); mucositis (ie, inflammation as opposed to mucosal infections typically induced by non-invasive fungi); chronic sinusitis (eg,) Caused by bacterial or viral infections); Non-invasive fungus-induced nasal sinusitis; Chronic colitis; Crohn's disease; Burns; Trichophyton rash; Ringworm on the feet (ie, ringworm); Ringworm on the crotch (ie, ringworm) ); Ringworm (ie, ringworm); Candidosis; Streptococcal pharyngitis, Streptococcal pharyngitis, and other type A ringworm infections; Alcohol (often referred to as adult tinea); And respiratory diseases (eg, asthma). Taken together, the compositions of the invention can be used to prevent and / or treat a wide variety of local diseases caused by microbial infections (eg, yeast infections, viral infections, bacterial infections).

The compositions of the present invention can be widely used on various surfaces. For example, they can be used on skin, mucosal tissue, chronic wounds, acute wounds, burns and the like. They are further administered from swabs, cloths, sponges, foams and non-wovens, and paper products (eg, paper towels and wipes), for example, using them to deliver most of the disinfectant composition to tissues. It is possible to do. The term "significant portion" was administered at a dose, frequency, and amount sufficient to administer a sufficient composition and reduce or eliminate microorganisms on or in the tissue. Sometimes it means being able to stay on top of the organization.

Therefore, the present invention also provides various ways of using the compositions of the present invention. Various embodiments of the invention include: methods of preventing diseases caused or exacerbated by microorganisms on the skin and / or mucous membranes; the subject's nasal cavity, anterior nasal passage, and /. Or how to decorate the microbes from at least part of the nasopharynx; how to eradicate the microbes from at least part of the subject's nasal cavity, anterior nasal passage, and / or nasopharynx; How to treat chronic sinusitis in a subject (by introduction into the middle ear through a tube and / or by diffusion or direct injection into the tympanic membrane) (at least part of the respiratory system, especially the nasal cavity, anterior) By treating the upper airway system, including the nasal passages and / or the nasopharynx); How to treat pyoderma on the subject's skin; Treating infections of the subject's skin, mucosal tissue, and / or wounds and / Or how to prevent; how to treat burns; how to kill or inactivate microorganisms (eg, kill or inactivate bacteria and / or fungi); leave residues or Residual antibacterial activity (eg, by imparting conditions such that the surface (eg, skin, mucosal tissue, wounds, and / or medical devices in contact with their surface) remain effective and imparts significant antibacterial activity. For example, a method of imparting antibacterial, antifungal, and / or antiviral efficacy. Not all of the disinfectants disclosed herein are useful for all of those conditions. Suitable applications for each disinfectant are described below.

It should be understood that the compositions of the present invention can be used in situations where there are no clinical signs of the disease. For example, the compositions of the present invention include the subject's nasal cavity (ie, the space behind the nasal vestibule), the anterior nasal cavity (ie, the nasal opening leading to the nasal cavity, also referred to as the external nasal cavity), and / or the nasopharynx (ie, the nasopharynx). It can be used in the method of decorating microorganisms from at least part of the pharynx or "throat", which is located above the pharynx where food enters. A suitable in vivo model for testing the effectiveness of compositions that decorate the anterior nares has been established in K. Kiser et al., Infect and Immunity, 67 (10), 5001-5006 (1999). Have been described. The compositions of the present invention can also be used to decorate microorganisms from wounds. In the Examples section, the microorganisms are further contacted with a static coating of the antibacterial composition, in The in vitro model is disclosed. This test method is suitable for comparing the potential effectiveness of the compositions of the invention in most topical disinfection applications, including nasal decolonization.

The decolonization method using the compositions of the present invention is used in immunocompromised patients (tumor patients, diabetics, HIV patients, transplant patients, etc.), especially fungi such as Aspergillus and Fusarium. Especially useful for.

More specifically, the compositions of the present invention can be used to eliminate methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in chronic wounds, which include inflammation, pus, and pus. With or without clinical signs of infection such as exudates. In addition, certain compositions of the invention can also kill lipid enveloped viruses, but they are extremely difficult to kill, such as herpes zoster (herpes), chronic sinusitis, otitis media, and others. Has the potential to cause local disease.

Those skilled in the art will readily know that the compositions of the present invention have imparted antibacterial activity using assays and bacterial screening methods well known to those of skill in the art. One easily performed assay is, for example, Enterococcus, Aspergillus, Escherichia, Staphylococcus, Streptococcus, Pseudomonas, Alternatively, a method of exposing selected known or readily available raw microbial strains, such as the genus Salmonella, to the test composition in a medium at an appropriate temperature at a predetermined bacterial load level. For suitable compositions of the invention, this is most conveniently carried out by the antibacterial activity test described in the Examples section. Simply, the antibacterial composition is smeared onto a sterile surface and the bacterial suspension is sprayed directly onto the surface of the composition. After sufficient contact time, a sample containing the exposed bacteria is collected, added to the neutralized broth, the sample is removed, diluted and plate-cultured on agar. The plate-cultured sample is incubated at an appropriate temperature and humidity for 48 hours, and the number of viable colonies grown on the plate is counted. As long as the colonies are counted, the reduction in the number of bacteria caused by the test composition can be easily determined. Bacterial reduction is generally log₁₀Reported as a decrease, this is the log of the initial inoculum count₁₀And log of inoculation count after exposure₁₀It can be obtained from the difference with. In a suitable composition of the present invention, the test bacteria average at least 2 logarithmic reductions in 10 minutes, preferably 2.5 minutes.

Many of the suitable compositions were tested for antibacterial activity against MRSA (Glam-positive, ATCC No. 16266) and E. coli (Glam-negative, ATCC No. 11229) as described in the Examples section. .. Suitable compositions of the present invention also exhibit extremely rapid antibacterial activity. As seen in the Examples section, in a suitable formulation, after 10 minutes of exposure, preferably after 2.5 minutes of exposure, at least a 4 logarithmic mean for at least one of these two microorganisms. Logarithmic reduction can be achieved. In a more preferred composition, after 10 minutes of exposure, preferably after 2.5 minutes of exposure, an average logarithm of at least 5 logarithms, even more preferably at least 6 logarithms, to at least one of these two microorganisms. It is possible to achieve a reduction.

With respect to residual antibacterial activity, the compositions of the invention are at least 1 hour, more preferably at least 3 hours, even more preferably at least after application to the affected site or after testing the composition on the subject's forearm. At 24 hours, it retains an average logarithmic reduction of preferably at least 1 logarithm, more preferably at least 1.5 logarithms, and even more preferably at least 2 logarithms. To test this, approximately 4 milligrams / square centimeter (mg / cm) on the forearm of a healthy subject²), The composition was applied to the subject's forearm as a uniform liquid phase coating and held on the skin in an area of approximately 5 x 5 cm, typically for a minimum of 10 minutes. The composition was gently rinsed with normal saline (0.9 wt% sodium chloride) at 23 ° C. The site rinsed with saline was flushed with about 10 known amounts of bacteria in the inoculum.⁶Individual bacteria / mL (typically Staphylococcus epidermidis or E. coli) were exposed for 30 minutes. Bacteria were harvested, treated with an effective neutralizer and incubated to quantify residual bacteria. A particularly suitable composition maintains at least one log reduction, preferably at least two log reductions of bacteria, after pouring 500 mL of saline over the site and gently washing, but in that washing. , The saline container was placed as close to the site as possible to prevent the saline from running off the site.

Importantly, in certain embodiments of the invention, it is extremely unlikely to cause microbial resistance. For example, a suitable composition of the present invention has an increase in the first-to-last ratio of MIC levels (ie, minimum inhibitory concentration) of less than 16, more preferably less than 8, and even more preferably less than 4. The assay for the development of such resistance involves first exposing the microorganism to a subMIC level (eg, 1/2 of the MIC) disinfectant and then passing the microorganism through a broth containing twice the concentration of the disinfectant after 24 hours. Should be implemented. This is repeated for 8 days, the microorganisms are removed daily and a new MIC is measured. Therefore, compositions that are less likely to form such resistance treat local infections or eradicate unwanted bacteria (eg, colonization of Staphylococcus aureus in the nose). It can be applied multiple times over a period of one to several days.

Suitable compositions of the present invention include effective amounts of cationic disinfectants that rapidly kill or inactivate microorganisms on the skin, skin lesions, and mucous membranes. In certain embodiments, with one or more doses, substantially all microorganisms within 5 days, preferably within 3 days, more preferably within 2 days, most preferably within 24 hours. Eradicate or inactivate.

Suitable compositions of the present invention generally have low levels of irritation to the skin, skin lesions, and mucous membranes, including the anterior nares, nasal cavity, nasopharyngeal cavity, and other parts of the upper respiratory tract. For example, certain suitable compositions of the invention are BACTROBAN ointments (for skin) or BACTROBAN NASAL (for anterior nares) available from Glaxo Smith Kline. ) Not as irritating as the formulation.

Suitable compositions of the present invention are practical as they maintain sufficient effectiveness over a relatively long period of time. For example, certain compositions of the invention maintain antibacterial activity at the site of application for at least 1 hour, preferably at least 4 hours, more preferably at least 8 hours. This is facilitated by swabbing the site after a predetermined time and testing the active antimicrobial agent by suitable analytical means such as gas chromatography (GC) or high performance liquid chromatography (HPLC). Can be asked for.

Suitable compositions of the present invention are physically stable. By definition herein, a "physically stable" composition is a substantial precipitation, crystallization, during storage at 23 ° C. for at least 3 months, preferably at least 6 months. It is like that there is no significant change from the initial state due to crystallization, phase separation, etc. A particularly suitable composition is a sample of a 10 ml (10 mL) composition placed in a 15 mL conical graduated plastic centrifuge tube (made by Corning) and approximately 2275 x g (eg, Osterode am Harzia). Osterode, West Germany) Heraeus Sepatech GmbH (Heraeus Sepatech GmbH), Labofuge B model 2650 at 3,000 rpm (rpm) for 10 minutes) or similar centrifugal force at 2275 xg If there is no visible phase separation at the bottom or top of the centrifuge tube when treated, it is completely physically stable. A phase separation of less than 0.5 mL is considered stable if there are no other signs of physical separation in the sample.

Suitable compositions of the present invention exhibit good chemical stability. This can be particularly problematic for compounds that can be hydrolyzed or decomposed by heat and / or light, such as chlorhexidine. In the most preferred composition, an average of at least 97% of the disinfectant component is retained after an initial 5 day equilibrium period at 23 ° C and then aging at 40 ° C in a closed container for 4 weeks. It should be understood that retention retention means the weight percent of the disinfectant component retained. This is the amount remaining in the sample aged in a non-degradable airtight container (ie, aged beyond the first 5 day equilibrium period) (preferably the same batch). It can be determined by comparing with the measured levels of the sample prepared in exactly the same manner and allowed to stand at 23 ° C for 5 days. The level of the disinfectant component is preferably determined by gas chromatography or high performance liquid chromatography.

In general, the composition of the present invention may be one of the following forms.

Hydrophobic ointment: The composition is blended with a hydrophobic base (eg, petrolatum, thickening or gelled water-insoluble oil, etc.) and optionally contains trace amounts of a water-soluble phase.

Oil-in-water emulsion: In this composition, the disinfectant is a discrete phase of hydrophobic components, a continuous aqueous phase containing water, and in some cases one or more polar hydrophilic carriers, as well as salts and surfactants. , Emulsifiers, or other ingredients, such as those emulsified in an emulsion. The emulsions may contain a water-soluble or water-swellable polymer, as well as one or more emulsifiers that contribute to the stabilization of the emulsion. These emulsions generally have fairly high conductivity, as described in US Patent Application No. 09 / 966,511.

Water-in-oil emulsion: This composition comprises a disinfectant containing a continuous phase of hydrophobic components and an aqueous phase containing water and possibly one or more polar hydrophilic carriers, as well as salts or other components. It may be a formulation that contains, such as that incorporated into an emulsion. The emulsions may contain oil-soluble or oil-swellable polymers, as well as one or more emulsifiers that contribute to emulsion stabilization.

-Thickened aqueous gel: These systems consist of an aqueous phase thickened to a viscosity greater than 500 cps, preferably greater than 5000 cps. The most preferred system has a viscosity greater than 10,000 cps, more preferably greater than 25,000 cps, most preferably greater than 50,000 cps. Viscosity is determined using the viscosity test method described herein. The systems include the disinfectants described herein and are thickened with suitable natural, modified natural, or synthetic polymers as described below. The thickened aqueous gel can also be further thickened with a suitable emulsifier that effectively thickens the composition, for example, a surfactant of an alkyl alcohol and a polyethoxylated alkyl chain. Examples include Polawax, Behenyl TMS, Crodaphos CES, Cosmowax, and Crothix from Croda Inc. ..

-Hydrophilic gels: These are systems in which the continuous phase consists of at least one water-soluble hydrophilic component other than water. The formulation may optionally further contain up to about 20% by weight water. For some compositions, higher concentrations may be suitable. Suitable hydrophilic components include one or more glycols (eg, glycerin, propylene glycol, butylene glycol, etc.), polyethylene glycol (PEG), ethylene oxide, propylene oxide, and / or random or block copolymers of butylene oxide. Examples include polyalkoxylated surfactants having one or more hydrophobic residues per molecule, silicone copolyols, and combinations thereof. Those skilled in the art will recognize that the level of ethoxylation must be sufficient to make the hydrophilic component water-soluble or water-dispersible at 23 ° C. In most embodiments, the water content is less than 10% by weight, more preferably less than about 5% by weight, of the composition.

In most embodiments, the viscosity of the composition is at least 20 cps, preferably higher than 100 cps, more preferably higher than 1000 cps, even more preferably greater than 10,000 cps, as measured by the viscosity tests described herein. High, most preferably higher than 25,000 cps. For the purpose of ensuring long-term antibacterial activity, a high viscosity is preferable in order to suppress migration and further impart substance (resistance to being removed by a fluid). The most suitable compositions have viscosities greater than 50,000 cps, most preferably greater than 100,000 cps at 23-25 ° C, as measured by viscosity tests. The most suitable compositions are compatible with these viscosity values, even after heating to temperatures as high as 32 ° C, 35 ° C or 37 ° C, and even when in contact with mammalian tissue, their composition. Make things stay practical.

Disinfectant ingredient The disinfectant component is a component of the composition that imparts at least a portion of the antibacterial activity. That is, the disinfectant component has at least some antibacterial activity against at least one microorganism. It is generally considered to be the main ingredient of the compositions of the present invention. Disinfectant components include effective amounts of one or more disinfectants selected from the group consisting of: biguanides and bisbiguanides such as chlorhexidine and various salts thereof such as digluconate, diacetate, dime. Tosulfate and dilactate salts (but not limited to these) and combinations thereof; high molecular weight quaternary ammonium compounds such as polyhexamethylene biguanides; silver and various silver complexes; low molecular weight quaternary ammonium compounds such as , Benzalcoium chloride and alkyl substituted derivatives; di-long chain alkyl (C6-C18) quaternary ammonium compounds; cetylpyridinium halides and their derivatives; benzetonium chloride and alkyl substituted derivatives thereof; octenidin and combinations thereof suitable for formulation. .. The categories of cationic disinfectants will be described in more detail below.

Biguanides and bisbiguanides: This class of disinfectants is expressed by the following equation: R-NH-C (NH)-NH-C (NH) -NH (CH)₂)_nNHC (NH)-NH-C (NH) -NH-R Here, n = 3 to 10, preferably 4 to 8, most preferably 6; R = C4 to C18 branched or linear alkyl (possibly substituted with halogen where possible), Alternatively, it may be C6 to C12 aryl or arcuaryl (possibly substituted with halogen where possible).

A suitable compound in this category is chlorhexidine. It may be present as a free base, but acetate, gluconate, lactate, metosulfate (CH).₃OSO₃^-), Or a halide or a combination thereof is preferably present as a disalt. Most preferred are diacetate, digluconate, dilactate, and dimethosulfate salts, because all of these salts have a dissolution limit of greater than 1 g / 100 mL. For example, the dissolution limit for digluconate salts is 20 g / 100 mL and that for diacetate is 1.9 g / 100 mL. The most preferred compound is chlorhexidine digluconate (CHG). Other anions are also useful. However, in this category, and even in other cationic disinfectants, it is particularly important to use counterions in aqueous fluids that ensure higher solubility than the minimum inhibitory concentration (MIC) of the microorganism being treated. Is. If the dissolution limit is lower than the MIC, the treatment may be ineffective.

This class of disinfectants is particularly suitable for formulations that are non-aqueous and protected from light. It is considered that this is because the decomposition of the compound is suppressed. When used in compositions containing less than about 20% by weight of water, this class of disinfectants is preferably formulated with hydrophilic carriers that solubilize the disinfectants. Examples of suitable solvents for chlorhexidine gluconate include: glycols (compounds with at least 2 hydroxyl groups per molecule) such as less than 2000, preferably less than 1000, most preferably about 800. Less than Dalton PEG; glycerin and polyglycerol, propylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, random or block copolymers of ethylene oxide / propylene oxide, trimethylpropane, pentaerythritol, sorbitol, panetothenol, glucurono Diols, gluconic acids, and even other polar solvents such as N-methylpyrrolidone, propylene carbonate, butyrolactone.

When formulating chlorhexidine and even other cationic disinfectant compounds, care should be taken to avoid inactivation by their incorporation into micelles formed by incorporating surfactants and / or emulsifiers. Must be paid. Suitable formulations are hydrophilic ointments; high molecular weight thickeners that may be free of surfactants or may contain surfactants such as poloxamers that do not reduce the activity of CHG. An aqueous solution thickened with an agent; and an ointment containing a hydrophobic component as a main component, preferably a hydrophilic component.

Bis (biguanides) such as chlorhexidine are extremely basic and can form multiple ionic bonds with anionic substances. For this reason, the biguanide-containing composition preferably does not contain anionic compounds that can cause precipitation of the disinfectant. For this reason, thickener systems, if present, are preferably based on nonionic and / or cationic polymers or emulsifiers. Anionic surfactants, which are useful as wetting agents, for example, should also be avoided. Certain zwitterionic, highly water-soluble, or non-precipitating anionic emulsifiers and surfactants are also useful. Halide salts should be avoided. For example, chlorhexidine digluconate (CHG) will rapidly precipitate in the presence of halide salts in concentrations above about 0.1 M. Therefore, if the system contains CHG or other disinfectant such as CHG and the salt needs to be constructed for stability or other purposes, a gluconate salt such as triethanolamine gluconate or sodium gluconate It is preferable to use. In addition, if an additional disinfectant is incorporated into the composition, it is preferably nonionic or cationic.

High molecular weight quaternary amine compound Antibacterial polymers containing quaternary amine groups may also be used as the disinfectant of the present invention. They are typically polymers with a quaternary amine group having at least one alkyl or aralkyl chain of at least 6 carbon atoms, preferably at least 8 carbon atoms. The polymers may be linear, branched, hyperbranch, dendrimer and the like. Suitable antibacterial high molecular weight quaternary amine polymers include those described in the following documents: US Pat. No. 6,440,405; US Pat. No. 5,408,022; and US Pat. No. 5,084,096. Book; International Publication No. 02102244 Brochure; and S. Block, Disinfection, Sterilization and Preservation, 4th Edition, 1991, Chapter 13, Lea &amp; Febiger.

A particularly preferred class of high molecular weight quaternary ammonium disinfectant compounds is polybiguanides. Compounds in this category are represented by the following formula: XR¹-NH-C (NH)-NH-C (NH) -NH-R²-NHC (NH)-NH-C (NH) -NH-R³-X Where R¹, R², And R³Is a polymethylene group having a bridging group, for example preferably 2-10 methylene groups, more preferably 4-8 methylene groups, most preferably 6 methylene groups. The methylene groups may optionally be substituted with halogen, hydroxyl, or phenyl groups wherever possible. X is a terminal group, typically an amine, amine salt, or dicyandiamide group. A suitable compound in this category is polyhexamethylene biguanide (PHMB), which is commercially available from Aveci in Wilmington, Delaware as Cosmocil CQ.

Compounds of this category are typically used at a level of at least 0.05% by weight, preferably at least 0.1% by weight, most preferably at least 0.25% by weight, and most preferably at least 0.5% by weight. Compounds of this category are preferably used at levels of less than about 8%, more preferably less than about 6%, and most preferably less than about 4% by weight of the composition. Poly (biguanide) disinfectants such as PHMB are extremely basic and can form multiple ionic bonds with anionic substances. For this reason, the biguanide-containing composition preferably does not contain anionic compounds that can lead to precipitation and / or inactivation of the disinfectant. For this reason, thickener systems, if present, are preferably based on nonionic and / or cationic polymers or emulsifiers. Anionic surfactants, which are useful as wetting agents, for example, should also be avoided. Certain zwitterionic, highly water-soluble, or non-precipitating anionic emulsifiers and surfactants are also useful. Halide salts should also be avoided.

Silver and silver complex: Silver is also known to be an effective disinfectant and has been used in creams to treat wounds and other local infections. Silver is also useful in nasal decoration. The active form of silver is the Ag + of the ion, which is delivered from a variety of known silver salts and complexes, including: silver sulphate; inorganic silver salts, eg. Silver nitrate, silver chloride, silver sulphate, silver thiosulfate; alkyl, aryl, and silver aralkyl carboxylates (favorable carboxylic acid anions have less than about 8 carbon atoms, such as acetates, lactates, salicylates, and gluconic acids. Salt); silver oxide, colloidal silver, nanocrystallin silver, silver-coated microspheres, silver complexes with various polymers, as described in US Pat. No. 6,579,906 and US Pat. No. 6,224,898. Silver delivered from dendrimers; and silver antibacterial complexes such as sphadiazine silver. Silver may optionally be complexed with primary, secondary, tertiary, and quaternary amines, as well as their high molecular weight morphology and silver protein complexes.

If skin discoloration is undesirable, for example, as disclosed in U.S. Pat. No. 6,468,521; U.S. Pat. No. 5,326,567; U.S. Pat. No. 5,429,819; and U.S. Pat. No. 5,326,567. It is also possible to use certain types of silver complexes, such as those found in the above. Surprisingly, those silver compounds and ions can be delivered from the hydrophobic vehicle compositions of the present invention. Particularly suitable compositions have hydrophilic components incorporated into the composition. The silver disinfectant may also be delivered from a composition comprising hydrophobic formation as a vehicle.

The silver-containing composition must be protected from light and sedimenting additives. For example, some anionic surfactants can inactivate silver. Therefore, suitable wetting agents, penetrating enhancers, and / or emulsifiers are nonionic, cationic or zwitterionic. The anion of the cationic surfactant must also be selected so as to prevent the inactivation of silver. Suitable surfactants are nonionic and amine-functional surfactants, including primary, secondary, tertiary and quaternary amine group-containing surfactants.

The concentration of silver ions in the disinfectant composition is preferably at least 0.20% by weight, more preferably at least 0.5% by weight, and most preferably at least 0.75% by weight, based on the total weight of the composition. The silver concentration is preferably less than 10% by weight, more preferably less than 8% by weight, and most preferably less than 6% by weight, based on the total weight of the composition. Silver salts and complexes should be adjusted relative to the molecular weight so that the silver ion concentration is in the stated range, which is well understood by those skilled in the art.

When used in the compositions of the present invention, silver compounds are capable of generating silver ions upon contact with microorganisms. Examples of them are silver salts and silver oxide. Suitable compounds are silver nitrate, silver thiosulfate, silver chloride, silver phosphate, silver sulphate, and halide salts of silver.

Low molecular weight quaternary ammonium compound: Compounds in this category typically include one or more quaternary ammonium groups, where the quaternary ammonium group is attached to at least one C6-C18 linear. Alternatively, it is a branched alkyl or aralkyl chain. Suitable compounds include those disclosed in the following literature: S. Block, Disinfection, Sterilization and Preservation, 4th Edition, 1991, Chapter 13, Lea &amp; Febiger). Particularly suitable compounds in this category have one or two C8-C18 alkyl or aralkyl chains and can be represented by the following formula: R¹R²NR³R⁴⁺X^-Where R¹And R²Is a C1-C18 linear or branched alkyl, alkylaryl, or aralkyl chain that may be substituted with N, O, or S where possible, provided that at least one R.¹Or R²Are C8-C18 linear or branched alkyl, alkylaryl, aralkyl chains that may be substituted with N, O, or S where possible. R³And R⁴Is a C1-C6 alkyl, phenyl, benzyl, or C8-C12 alkylaryl group. R³And R⁴May form a ring, such as a pyridine ring, with nitrogen of a quaternary ammonium group. X is an anion, preferably a halide, most preferably a Cl- or Br-. Other anions include metosulfate, etosulfate, phosphate and the like. Suitable compounds in this category include monoalkyltrimethylammonium salts, monoalkyldimethylbenzylammonium salts, dialkyldimethylammonium salts, benzethonium chloride, octenidin and the like.

Examples of suitable quaternary ammonium disinfectants include alkyl chain lengths of C8 to C18, more preferably C12 to C16, and most preferably benzalkonium halide containing a mixture of various chain lengths. For example, a typical benzalkonium chloride sample consists of a 40% C12 alkyl chain, a 50% C14 alkyl chain, and a 10% C16 alkyl chain. They are commercially available from many sources, including Lonza (Barquat MB-50); alkyl group-substituted benzalkonium halides on the phenyl ring. A commercially available example is Barquat 4250, available from Lonza; dimethyldialkylammonium halides, the alkyl groups of which have a chain length of C8 to C18. A mixture of chain lengths, such as a mixture of dioctyl, dilauryl, and dioctadecyl, is particularly useful. Examples of such compounds are Bardac 2050, 205M and 2250, available from Lonza; cetylpyridinium halides such as cetylpyridinium chloride, Cepacol from Merrel labs. Available as Chloride); benzethonium halides and alkyl-substituted benzethonium halides, such as Hyamine 1622 and Hyamine 10X; octenidin available from Rohm and Haas.

The disinfectant is typically added to the composition at a concentration of at least 0.50% by weight, more preferably at least 0.75% by weight, most preferably at least 1.0% by weight, based on the total weight of the composition. Its concentration is preferably less than 6% by weight, more preferably less than 4% by weight, and most preferably less than 3% by weight, based on the total weight of the composition. The pH of aqueous compositions (or the aqueous phase of those compositions) containing these disinfectants is typically in the range of 3-9, most preferably 3.5-7.

The compositions of the present invention contain one or more disinfectants at levels suitable for obtaining the desired results. Such compositions are preferably at least 0.2 weight percent (% by weight) based on the total weight of the composition, which is the sum of the disinfectants and is ready to use or "as used". ), More preferably at least 0.25% by weight, even more preferably at least 0.35% by weight, even more preferably at least 0.5% by weight, even more preferably at least 1, at least 2, and even at least 3% by weight. In a preferred embodiment, the disinfectant is added to a total of 20% by weight or less, more preferably 15% by weight or less, even more preferably 10% by weight or less, based on the total weight of the ready-to-use composition. More preferably, it is present in an amount of 6% by weight or less. For certain compositions, higher concentrations may be used if they are intended to be diluted before use.

The disinfectant of the present invention may be used alone or in combination to effectively kill the microorganisms on the tissue. While certain combinations of disinfectants are particularly useful, other combinations can result in unstable formulations and inactivation of antibacterial activity. For example, it is inappropriate to combine cationic disinfectants such as biguanides and bisbiguanides, high molecular weight quaternary ammonium compounds, quaternary ammonium compounds, and silver with alkylcarboxylic acids. On the other hand, the combination of different disinfectants may have an enhanced or synergistic effect.

The disinfectant of the present invention may be used alone or in combination with other disinfectants to effectively kill the microorganisms on the tissue. Additional disinfectants for use with those described herein include: peroxides, C6-C14 alkyl carboxylic acids and alkyl ester carboxylic acids, antibacterial natural oils. , As well as combinations thereof that are suitable for formulation (the title of the invention "Antiseptic Compositions and Methods of Use" (US Patent Application No. 10 / 936,133, filing date September 7, 2004). ); Diphenyl ether, phenol, halogenated phenol, bisphenol, resorcinol and derivatives thereof, anilide, and combinations thereof (the title of the invention "Phenolic Antiseptic Compositions and Methods of Use" (US). (Patent application No. 10 / 936,171, filing date September 7, 2004)).

While certain combinations of disinfectants are particularly useful, other combinations can result in unstable formulations and inactivation of antibacterial activity. For example, it is inappropriate to combine cationic disinfectants such as biguanides and bisbiguanides, high molecular weight quaternary ammonium compounds, quaternary ammonium compounds, and silver with alkylcarboxylic acids. On the other hand, the combination of different disinfectants may have a synergistic or enhancing effect.

In certain embodiments, the disinfectants of the invention may optionally be combined with an effective amount of an antibacterial lipid disinfectant, including: C7 ~ C14) Saturated fatty acid esters, polyhydric alcohols (C8 ~ C22) unsaturated fatty acid esters, polyhydric alcohols (C7 ~ C14) saturated aliphatic ethers, polyhydric alcohols (C8 ~ C22) unsaturated aliphatic ethers , Their alkoxylated derivatives, or combinations thereof (where, those alkoxylated derivatives contain less than 5 mol of alkoxides per mol of polyhydric alcohol, provided that in polyhydric alcohols other than sucrose, to their esters. Contains monoesters, the ethers of which contain monoethers, and in the case of sucrose, the esters contain monoesters, diesters, or combinations thereof, the ethers of monoethers, diethers, or combinations thereof. including). Useful disinfectants in this category are the applicant's co-pending application "Antimicrobial Compositions and Methods of". Use (US Patent Application No. 10 / 659,571, filing date September 9, 2003) further. As used herein, the term "fatty" refers to alkyl and alkylene hydrocarbon chains of odd or even carbon atoms from C6 to C18.

Alternatively, the antibacterial lipid is a (C8-C12) aliphatic alcohol ester of (C2-C8) hydroxycarboxylic acid ((C8-C12) aliphatic alcohol ester (C2-C8) hydroxycarboxylic acid ester. (Sometimes called), (C2-C8) hydroxycarboxylic acid (C8-C22) mono-or poly-unsaturated fatty alcohol esters ((C8-C22) mono-or poly-unsaturated fatty alcohols (C2) ~ C8) It may be called a hydroxycarboxylic acid ester), or an alkoxylated derivative thereof. These alkoxylated derivatives have less than 5 moles of alkoxide per mole of polyhydric alcohol or hydroxylic acid. Hydroxycarboxylic acid residues include aliphatic and / or aromatic groups. For example, it may be an aliphatic alcohol ester of salicylic acid. Useful disinfectants of this category are further described in the applicant's co-pending application "Antimicrobial Compositions and Methods" (US Provisional Patent Application No. 60 / 660,594, filing date March 10, 2005). There is.

As used herein, "fatty alcohol" is an alkyl or alkylene monofunctional alcohol having an even or odd carbon atom, and "fatty acid" is an even or odd carbon. It is an alkyl or alkylene monofunctional carboxylic acid having an atom.

In order to obtain rapid antibacterial activity, the formulation should incorporate one or more disinfectants with a composition close to or preferably above the dissolution limit in the hydrophobic phase. Although not bound by theory, the inventors of the present application think that disinfectants that are easily distributed in hydrophobic components are almost always present in the aqueous phase or in the aqueous phase. It is not easily available to kill the microorganisms involved in it. In most compositions, the disinfectant is preferably incorporated at a rate of at least 60%, preferably 75%, more preferably 100%, most preferably 120% of the dissolution limit of the hydrophobic component at 23 ° C. This can be easily determined by the following method: make a disinfectant-free formulation, allow phase separation (eg, using centrifugation or other suitable separation method), and add the disinfectant in small amounts. The dissolution limit is determined by adding until precipitation occurs while increasing the amount. Alternatively, if the formulation is known, the components forming the lipophilic phase are used and they are mixed in appropriate proportions to determine the dissolution limit. As one of ordinary skill in the art is familiar with, supersaturated solutions must be prevented for accurate measurements.

Enhancer ingredient An enhancer may be added to the composition of the present invention to enhance the antibacterial activity. Enhancing activity is particularly useful against Gram-negative bacteria, such as E. coli and Pseudomonas. It is preferred that the selected enhancer act on the bacterial cell envelope. Without being bound by theory, enhancers are working to make it easier for disinfectants to enter the cytoplasm and / or to destroy the cell envelope. I am thinking at this stage. Enhancer components include: alpha-hydroxy acids, beta-hydroxy acids, other carboxylic acids, (C1 ~ C4) alkyl carboxylic acids, (C6 ~ C12) aryl carboxylic acids, (C6 ~ C12) aralkylcarboxylic acids, (C6 to C16) alkarylcarboxylic acids, chelating agents, phenolic compounds (eg, certain antioxidants and parabens), (C1 to C10) monohydroxy alcohols, or glycol ethers (ie, ethers). Glycol). If desired, various enhancers can be used in combination.

Alpha-hydroxy acids, beta-hydroxy acids, and other carboxylic acid enhancers are preferably present in the form of their protonated, free acids. However, not all of these acid enhancers must be present in the form of a free acid, and the suitable concentrations described below correspond to the amounts present in the form of a free acid. Further, the chelating agent enhancer containing a carboxylic acid group preferably exists having at least one, more preferably at least two carboxylic acid groups in the form of those acids. The concentrations shown below assume this situation. The chelating agent enhancer may further contain a phosphate or phosphonic acid group. Alternative enhancers must be considered if precipitation is caused by interaction with other composition components. While nonionic enhancers are useful in all categories of disinfectants of the invention, anionic enhancers such as carboxylic acids and chelating agents can be incompatible with cationic disinfectants. .. If precipitation occurs, an alternative enhancer should be used.

In some embodiments, another enhancer may be useful, such as siderophore and iron-binding proteins (US Patent Application No. 10 / 936,949, Filing Date 2004: 9). 8 May, title of invention "Antimicrobial Compositions and Methods"); and sugar and / or alcohol (US Provisional Patent Application No. 60 / 660,830, filing date March 10, 2005, title of invention "Methods". Of Reducing Microbial Conatmination ).

The desired results can be obtained by using one or more enhancers in the compositions of the present invention at appropriate levels. In a preferred embodiment, they are in excess of 0.01% by weight, preferably in excess of 0.1% by weight, more preferably in excess of 0.2% by weight, based on the total weight of the ready-to-use composition. It is more preferably present in an amount greater than 0.25% by weight, most preferably in an amount greater than about 0.4% by weight. In a preferred embodiment, they are present in a total amount of 20% by weight or less in total, based on the total weight of the ready-to-use composition. Such concentrations are typically applied to alpha-hydroxy acids, beta-hydroxy acids, other carboxylic acids, chelating agents, phenolic compounds, ether glycols, and (C5-C10) monohydroxy alcohols, etc. To. Generally speaking, higher concentrations are required for (C1 to C4) monohydroxy alcohols, which will be described in more detail below.

Alpha-hydroxy acids, beta-hydroxy acids, and other carboxylic acid enhancers, as well as chelating agents containing carboxylic acid groups, are preferably present at concentrations of 100 mmol or less per 100 grams of compounded composition. In most embodiments, a chelating agent containing alpha-hydroxy acids, beta-hydroxy acids, and other carboxylic acid enhancers, as well as carboxylic acid groups, is preferably no more than 75 millimolars per 100 grams of the composition formulated. It is more preferably present at a concentration of 50 mmol or less per 100 gram, most preferably 25 mmol or less per 100 gram.

The total concentration of the disinfectant component versus the total concentration of the enhancer component, on a weight basis, preferably ranges from (10: 1) to (1: 300), more preferably (5: 1) to (1:10). The range is up to.

Further considerations when using enhancers are solubility and physical stability in the composition. Many of the enhancers described herein are insoluble in suitable hydrophobic components such as mineral oil and petrolatum. Adding a small amount (typically less than 30% by weight, preferably less than 20% by weight, more preferably less than 12% by weight) of hydrophilic components only improves the solubility and physical stability of the composition. However, it was also found that the antibacterial activity was also improved. Separately, enhancers may be present beyond the dissolution limit if the composition is physically stable. This can be achieved by using a composition that is sufficiently viscous so that layering of the disinfectant (eg, sedimentation or creaming) does not occur significantly.

Alpha-hydroxy acid Alpha-hydroxy acids are typically compounds represented by the following formulas: R⁵(CR⁶OH)_nCOOH Here: R⁵And R⁶Are independently H, (C1 to C8) alkyl groups (linear, branched, or cyclic), (C6 to C12) aryl groups, (C6 to C12) aralkyl groups, or (C6 to C12) arcs. Aryl groups (where the alkyl groups of aralkyl or alkylaryl are linear, branched, or cyclic), where R⁵And R⁶May optionally be substituted with one or more carboxylic acid groups; and n = 1 to 3, preferably n = 1 to 2.

Examples of alpha-hydroxy acids include, but are not limited to: lactic acid, malic acid, citric acid, 2-hydroxybutanoic acid, mandelic acid, gluconic acid, glycolic acid (ie,). , Alpha-hydroxyethane acid), tartrate acid, ascorbic acid, alpha-hydroxyoctanoic acid, and alpha hydroxycapric acid, and their derivatives (eg, hydroxyl, phenyl group, hydroxyphenyl group, alkyl group, halogen, and even them. Compounds substituted with the combination of). Suitable alpha-hydroxy acids include lactic acid, malic acid, mandelic acid and the like. These acids may be in D, L, or DL form and may be present as free acids, lactones, or partial salts thereof. All of these forms are included in the term "acid". The acid is preferably present in the form of a free acid. In certain preferred embodiments, the alpha-hydroxy acids useful in the compositions of the invention are selected from the group consisting of lactic acid, mandelic acid, and malic acid, and mixtures thereof. Other suitable alpha-hydroxy acids are described in US Pat. No. 5,665,776 (Yu).

The desired results can be obtained by using one or more alpha-hydroxy acids in the compositions of the present invention at appropriate levels. In a preferred embodiment, they total at least 0.25% by weight, more preferably at least 0.5% by weight, even more preferably at least 1% by weight, based on the total weight of the ready-to-use composition. Make it exist. In a preferred embodiment, they total 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, based on the total weight of the ready-to-use composition. Make it exist. The higher the concentration, the stronger the irritation.

The ratio of the alpha-hydroxy acid enhancer to the overall disinfectant component is preferably at most 10: 1, more preferably at most 5: 1, and even more preferably at most 1: 1. The ratio of the alpha-hydroxy acid enhancer to the overall disinfectant component is preferably at least 1:20, more preferably at least 1:12, and even more preferably at least 1: 5. The preferred ratio of alpha-hydroxy acid enhancer to overall disinfectant component ranges from (1:12) to (1: 1).

Beta-hydroxy acid Beta-hydroxy acids are typically compounds represented by the following formulas: R⁷(CR⁸OH)_n(CHR⁹)_mCOOH or<chemistry num="1"><img file="JP5154933B2_D0001.tif" /></chemistry>Where R⁷, R⁸, And R⁹Are independently H, (C1 to C8) alkyl groups (saturated linear, branched, or cyclic groups), (C6 to C12) aryl groups, (C6 to C12) aralkyl groups, or (C6 to). C12) Alkaryl group (where the alkyl group of aralkyl or alkaryl is linear, branched, or cyclic), where R⁷And R⁸May optionally be substituted with one or more carboxylic acid groups; m = 0 or 1; n = 1 to 3 (preferably n = 1 to 2); and R²¹Is H, (C1 ~ C4) alkyl or halogen.

Examples of beta-hydroxy acids include, but are not limited to, beta-hydroxybutanoic acid, 3-hydroxybutanoic acid, tropic acid, and tretocanoic acid. In certain preferred embodiments, the beta-hydroxy acids useful in the compositions of the invention are selected from the group consisting of salicylic acid, beta-hydroxybutanoic acid, and mixtures thereof. Other suitable beta-hydroxy acids are described in US Pat. No. 5,665,776 (Yu).

The desired results can be obtained by using one or more beta-hydroxy acids at appropriate levels in the compositions of the present invention. In a preferred embodiment, they total at least 0.1% by weight, more preferably at least 0.25% by weight, even more preferably at least 0.5% by weight, based on the total weight of the ready-to-use composition. Make it exist. In a preferred embodiment, they total 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, based on the total weight of the ready-to-use composition. Make it exist. The higher the concentration, the stronger the irritation.

The ratio of beta-hydroxy acid enhancer to total disinfectant component is preferably at most 10: 1, more preferably at most 5: 1, and even more preferably at most 1: 1. The ratio of beta-hydroxy acid enhancer to total disinfectant component is preferably at least 1:20, more preferably at least 1:15, and even more preferably at least 1:10. The preferred ratio of beta-hydroxy acid enhancer to total disinfectant component ranges from (1:15) to (1: 1).

In systems with low or substantially water-free water concentrations, esterification can be the main pathway for enhancers to disappear, for example by reacting with disinfectants or hydroxyl functional hydrophilic components. There is sex. Therefore, certain alpha-hydroxy acids (AHA) and beta-hydroxy acids (BHA) are particularly preferred because they are less likely to esterify by reaction with the hydroxyl groups of AHA or BHA. Because it can be considered. For example, salicylic acid may be particularly preferred in certain formulations because phenolic hydroxyl groups are much more acidic than aliphatic hydroxyl groups and are therefore much less reactive. is there. Other compounds particularly suitable for anhydrous or low water content formulations include lactic acid, mandelic acid, malic acid, citric acid, tartaric acid, glycolic acid and the like. Benzoic acid and substituted benzoic acid containing no hydroxyl group are also preferable because they are not hydroxyl acids but have a low tendency to form ester groups.

Other carboxylic acids Carboxylic acids other than alpha- and beta-carboxylic acids are also suitable for use in enhancer components. Such are typically alkyl, aryl, aralkyl, or alkylaryl carboxylics having 16 or less carbon atoms, preferably 12 or less carbon atoms, and even more preferably about 8 or less carbon atoms. Suitable categories of them, such as acids, can be expressed by the following equation: R¹⁰(CR¹¹₂)_nCOOH Where R¹⁰And R¹¹Are independently H, (C1 to C4) alkyl groups (which may be linear, branched, or cyclic groups), (C6 to C12) aryl groups, both aryl and alkyl groups. (C6 to C16) groups, which may be linear, branched, or cyclic groups, where R¹⁰And R¹¹May optionally be substituted with one or more carboxylic acid groups; and n = 0 to 3, preferably n = 0 to 2. The carboxylic acid is preferably (C1 to C4) alkylcarboxylic acid, (C6 to C12) aralkylcarboxylic acid, or (C6 to C16) alkarylcarboxylic acid.

Examples of acids include, but are not limited to, acetic acid, propionic acid, benzoic acid, benzylic acid, nonyl benzoic acid and the like. Benzoic acid is particularly preferred.

The desired results can be obtained by using one or more carboxylic acids (other than alpha- and beta-hydroxy acids) at appropriate levels in the compositions of the present invention. In a preferred embodiment, they are added together to at least 0.1% by weight, more preferably at least 0.25% by weight, even more preferably at least 0.5% by weight, most preferably at least Exist in an amount of 1% by weight. In a preferred embodiment, they are present in an amount of 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, based on a ready-to-use composition.

The ratio of the total concentration of carboxylic acids (other than alpha- or beta-hydroxy acids) to the total concentration of disinfectant components is by weight, preferably in the range (10: 1) to (1: 100), and more. It is preferably in the range of (2: 1) to (1:10).

Chelating agent A chelating agent (ie, a chelator) is typically an organic compound capable of having multiple coordination sites with metal ions in solution. Typically, their chelating agents are polyanionic compounds that best coordinate with polyvalent metal ions. Chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and salts thereof (eg, EDTA (Na)):₂, EDTA (Na)₄, EDTA (Ca), EDTA (K)₂), Sodium pyrophosphate, sodium hexametaphosphate, adipic acid, succinic acid, polyphosphoric acid, sodium pyrophosphate, sodium hexametaphosphate, acidified sodium hexametaphosphate, nitrilotris (methylenephosphonic acid), diethylenetriamine pentaacetic acid, 1-hydroxyethylene, 1,1-diphosphoric acid, and diethylenetriaminepenta- (methylenephosphoric acid). Certain carboxylic acids, especially alpha-hydroxy and beta-hydroxy acids, such as malic acid and tartaric acid, also function as chelating agents. In addition, compounds that are highly specific for ferrous or ferric ions, such as siderophores, and iron-binding proteins such as lactoferrin and transferrin, can be mentioned as chelating agents.

In certain preferred embodiments, chelating agents useful in the compositions of the present invention include those selected from the group consisting of ethylenediaminetetraacetic acid and salts thereof, succinic acid, and mixtures thereof. It is preferred to use either the free acid or mono- or di-salt form of EDTA.

The desired results can be obtained by using one or more chelating agents in the compositions of the present invention at appropriate levels. In a preferred embodiment, they total at least 0.01% by weight, more preferably at least 0.05% by weight, even more preferably at least 0.1% by weight, even more preferably, based on the weight of the ready-to-use composition. Is present in an amount of at least 0.25 wt%. Alternatively, in a preferred embodiment, the chelating agent, even if it contains multiple phases, totals at least 300 uM (micromol), based on the total weight / volume of the composition. It is preferably present in an amount of at least 500uM, more preferably at least 1000uM, and most preferably at least 2000uM. In a preferred embodiment, they are present in an amount of 10% by weight or less, more preferably 5% by weight or less, even more preferably 1% by weight or less, based on the weight of the ready-to-use composition. Let me.

The ratio of the total concentration of chelating agents (other than alpha- or beta-hydroxy acids) to the total concentration of disinfectant components is by weight, preferably in the range of (10: 1) to (1: 100). More preferably, it is in the range of (1: 1) to (1:10).

Phenolic derivative compounds Phenolic compound enhancers are typically compounds with the following general structure (including at least one group attached to the ring via oxygen):<chemistry num="2"><img file="JP5154933B2_D0002.tif" /></chemistry>Here, m is 0 to 3 (particularly 1 to 3), n is 1 to 3 (particularly 1 to 2), and each R is.¹²Independently, up to 12 carbon atoms (especially 8) optionally substituted with O (eg, as a carbonyl group) in or on the chain or OH on the chain. (Carbon atom) up to alkyl or alkenyl, each R¹³Are independently H, or optionally up to 8 carbon atoms (especially as carbonyl groups) substituted with O (eg, as a carbonyl group) or substituted with OH on the chain. , Up to 6 carbon atoms) alkyl or alkenyl, but R¹³If is H, n is preferably 1 or 2.

Examples of phenolic derivative enhancers include, but are not limited to: butylated hydroxyanisole, eg, 3 (2) -tert-butyl-4-methoxyphenol (BHA), 2 , 6-di-tert-butyl-4-methylphenol (BHT), 3,5-di-tert-butyl-4-hydroxybenzylphenol, 2,6-di-tert-4-hexylphenol, 2,6- Di-tert-4-octylphenol, 2,6-di-tert-4-decylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-4-butylphenol, 2, 5-Di-tert-butylphenol, 3,5-di-tert-butylphenol, 4,6-di-tert-butyl-resorcinol, methylparaben (4-hydroxybenzoic acid methyl ester), ethylparaben, propylparaben, butylparaben, 2-Phenoxyethanol, and even combinations thereof. A preferred group of phenolic derivative compounds is the phenolic species having the above-mentioned general structure, R.¹³= H and R¹²Is an alkyl or alkenyl of up to 8 carbon atoms and n is 1, 2, or 3, especially at least one R¹²Is butyl, especially tert-butyl, and especially the non-toxic of them. Some suitable phenolic derivative enhancers include BHA, BHT, methylparaben, ethylparaben, propylparaben, and butylparaben, and combinations thereof.

Desirable results can be obtained by using one or more phenolic derivative compounds in the compositions of the present invention at appropriate levels. The concentration of phenolic compounds in pharmaceutical grades can vary widely, but if the above esters are present in the above range, even trace amounts of 0.001% by weight based on the total weight of the composition are effective. .. In a preferred embodiment, they are present in an amount of at least 0.01% by weight, more preferably at least 0.10% by weight, even more preferably at least 0.25% by weight, based on the weight of the ready-to-use composition. Let me. In a preferred embodiment, they are present in an amount of 8% by weight or less, more preferably 4% by weight or less, even more preferably 2% by weight or less, based on a composition that can be used as is.

The ratio of the total concentration of phenolic compounds to the total concentration of disinfectant components is preferably in the range (10: 1) to (1: 300), more preferably (1: 1) to (1: 1) on a weight basis. The range is up to 1:10).

The above concentrations of the phenolic derivative enhancer are those commonly used unless the purpose is to later dilute the concentrated formulation. On the other hand, the minimum concentration of phenolic compounds and disinfectants for obtaining antibacterial effect varies depending on the specific application.

Monohydroxy alcohol A further category of enhancers includes monohydroxy alcohols having 1 to 10 carbon atoms. This includes lower (ie, C1 to C4) monohydroxy alcohols (eg, methanol, ethanol, isopropanol, and butanol), as well as longer chain (ie, C5 to C10) monohydroxy alcohols (eg, isobutanol,). t-butanol, octanol, and decanol) are included. In certain preferred embodiments, the alcohol useful in the compositions of the invention is selected from the group consisting of methanol, ethanol, isopropyl alcohol, and mixtures thereof.

The desired results can be obtained by using one or more alcohols in the compositions of the present invention at appropriate levels. In one embodiment, short chain (ie, C1 to C4) alcohols are added to a total of at least 5% by weight, even more preferably at least 10% by weight, based on the total weight of the ready-to-use composition. Even more preferably, it is present in an amount of at least 15% by weight, even more preferably at least 20% by weight. In a preferred embodiment, the (C1 to C4) alcohols total 50% by weight or less, more preferably 40% by weight or less, even more preferably 30% by weight, based on the total weight of the ready-to-use composition. Exist in an amount less than or equal to%.

In certain applications, lower alcohols may be undesirable due to their strong odor, which can be tingling and irritating. This is especially likely to occur at high concentrations. For applications where irritation or burning sensation is a problem, the concentration of (C1 to C4) alcohol is preferably less than 20%, more preferably less than about 15%.

In a preferred embodiment, long chain (ie, C5 to C10) alcohols total at least 0.1% by weight, more preferably at least 0.25% by weight, even more preferably, relative to a concentrate composition that is ready to use. It is present in an amount of at least 0.5% by weight, most preferably at least 1.0% by weight. In a preferred embodiment, the (C5 to C10) alcohols total 10% by weight or less, more preferably 5% by weight or less, even more preferably 2% by weight, based on the total weight of the ready-to-use composition. Exist in an amount less than or equal to%.

Ether glycol A further category of enhancers includes ether glycols. Examples of ether glycols include: R'-O- (CH₂CHR O)_n(CH₂CHR O) H Where R'= H, (C1 ~ C8) alkyl, (C6 ~ C12) aryl or (C6 ~ C12) aralkyl or (C6 ~ C12) alkaryl; and each R is independent, = H, Methyl, or ethyl; and n = 0-5, preferably 1-3. Examples include: 2 phenoxyethanol, dipropylene glycol, triethylene glycol, trade name dowanol (2) Products available as DOWANOL DB (di (ethylene glycol) butyl ether), Dowanol (DOWANOL) DPM (di (propylene glycol) monomethyl ether), and Dowanol (DOWANOL) TPnB (tri (propylene glycol) monobutyl ether), as well as Is a number of products available from Dow Chemical in Midland, MI, Michigan.

The desired results can be obtained by using one or more ether glycols at appropriate levels in the compositions of the present invention. In a preferred embodiment, they are present in a total amount of at least 0.01% by weight based on the total weight of the ready-to-use composition. In a preferred embodiment, they are present in a total amount of 20% by weight or less in total, based on the total weight of the ready-to-use composition.

Surfactant The compositions of the present invention contain one or more surfactants to help emulsify the composition and allow the composition to wet the surface and / or contact with microorganisms. You may. As used herein, the term "surfactant" is amphipathic, capable of reducing the surface tension of water and / or the interfacial tension between water and immiscible liquids. It means a substance (a molecule having both a polar region and a non-polar region that are covalently bonded). What the term means includes soaps, detergents, emulsifiers, surfactants and the like. Surfactants may be cationic, anionic, nonionic, or amphoteric. This includes a wide variety of commonly used surfactants. If desired, surfactants can be used in combination.

Certain ethoxylated surfactants may reduce or eliminate the antibacterial activity of the disinfectant component. The exact mechanism is unknown, but not all ethoxylated surfactants have such a negative effect. For example, poloxamer (polyethylene oxide / polypropylene oxide) surfactants have been found to be suitable for formulation with some disinfectant components, but with ethoxylated sorbitan fatty acid esters, for example, by ICI (ICI). The ones sold under the trade name TWEEN are not only unsuitable for formulation, but are even useful for neutralizing disinfectants in microbiological assays.

In addition, certain anionic surfactants may not be suitable for formulation with the cationic surfactants of the present invention. It should be noted here that these are broad generalizations and the activity depends on the formulation. Those skilled in the art can easily determine the mixability of the surfactant by producing the formulation and testing the antibacterial activity as described in the Examples section.

It should be noted that certain disinfectants are amphipathic and have surface activity. For example, the low molecular weight quaternary ammonium compound disinfectants described herein may have surface activity. In those compositions containing both amphipathic disinfectants and surfactants, the surfactant is a separate component from the amphipathic disinfectant.

Suitable surfactants are those having at least 4, more preferably at least 8 HLBs (ie, hydrophilic-lipophilic balance). Even more preferred surfactants have at least 12 HLBs. The most preferred surfactant has at least 15 HLBs.

Examples of various types of surfactants are described below. In certain preferred embodiments, the surfactants useful in the compositions of the invention are sulfonates, sulphates, phosphonates, phosphates, poloxamers (polyethylene oxide / polypropylene oxide block copolymers), cationic. It is selected from the group consisting of surfactants and mixtures thereof. Cationic, amphoteric, and nonionic surfactants, especially ethylene oxide / propylene oxide surfactants such as poloxamers, are particularly suitable for use with cationic disinfectants.

The desired results can be obtained by using one or more surfactants at appropriate levels in the compositions of the present invention. In a preferred embodiment, they total at least 0.01% by weight, preferably 0.1% by weight, more preferably at least 0.5% by weight, even more preferably at least, based on the total weight of the ready-to-use composition. Exist in an amount of 1.0% by weight. For example, in preferred embodiments where irritation is an issue, they total up to 10% by weight, more preferably 5% by weight or less, and even more, based on the total weight of the ready-to-use composition. It is preferably present in an amount of 2% by weight or less. The ratio of the total concentration of surfactant to the total concentration of disinfectant is preferably in the range of (5: 1) to (1: 100), more preferably (3: 1) to (1) on a weight basis. The range is up to 10), most preferably the range from (2: 1) to (1: 3).

Cationic surfactant Examples of cationic surfactants include, but are not limited to: optionally polyoxyalkyleneized primary, secondary, or tertiary aliphatic amine salts; quaternary. Ammonium salts such as tetraalkylammonium, alkylamide alkyltrialkylammonium, trialkylbenzylammonium, trialkylhydroxyalkylammonium, or suitable anionic counterions such as halides (preferably chloride or bromide), or alkylsulfates, for example. Alkylpyridinium with metosulfate or etosulfate and even other anionic counterions; imidazoline derivatives; amine oxides with cationic properties (eg, at acidic pH), and mixtures thereof.

In certain preferred embodiments, the cationic surfactants useful in the compositions of the invention are selected from the group consisting of tetraalkylammonium, trialkylbenzylammonium, and alkylpyridinium halides, and mixtures thereof.

Further particularly preferred are amine oxide surfactants of the formula below, including alkyl and alkylamide alkyldialkylamine oxides: (R¹⁴)₃-N O Where R¹⁴Are (C1 to C30) alkyl groups (preferably (C1 to C14) alkyl groups) or (C6 to C18) aralkyl or alkylaryl groups, where these groups are optionally in the chain or Above, it may be substituted with N-, O-, or S-containing groups such as amides, esters, hydroxyls, and the like. Each R¹⁴May be the same or different, but at least one R¹⁴The group contains at least 8 carbons. In some cases, multiple Rs¹⁴The groups may combine with nitrogen to form a heterocyclic ring to form a surfactant such as an amine oxide such as alkyl morpholine, alkyl piperazine. 2 R¹⁴Group is methyl, 1 R¹⁴The group is preferably a (C12-C16) alkyl or alkylamidopropyl group. Examples of amine oxide surfactants are those commercially available under the trade names AMMONYX LO, LMDO, and CO, which are lauryldimethylamine oxides, laurylamide propyldimethylamine oxides, and cetylamine oxides (AMMONYX LO, LMDO, and CO). All include Stepan Company in Northfield, IL, Illinois.

Anionic surfactant Examples of anionic surfactants include, but are not limited to: sarcosinate, glutamate, alkyl sulphate, sodium or potassium alkyres sulphate, ammonium alkires sulphate, ammonium laures-n-ammonium sulphate, Laures-n-sulfate, ISEthionate, alkyl and aralkyl glyceryl ether sulfonate, alkyl and aralkyl sulfosuccinate, alkyl glyceryl ether sulfonate, alkyl phosphate, aralkyl phosphate, alkyl phosphonate, and Aralkyl phosphophosphate. These anionic surfactants may have metal or organic ammonium counterions. In certain preferred embodiments, the anionic surfactants useful in the compositions of the invention are selected from the group consisting of:

1. Sulfates and sulfates Suitable anionic surfactants include: sulfonates and sulphates, such as alkyl sulphates, alkyl ether sulphates, alkyl sulfonates, alkyl ether sulphonates, alkylbenzene sulphates , Alkylbenzene ether sulfate, alkyl sulfoacetate, secondary alkane sulfonate, secondary alkyl sulfate, etc. Many of them can be expressed by: R¹⁴-(OCH₂CH₂)_n(OCH (CH)₃) CH₂)_p-(Ph)_a-(OCH₂CH₂)_m-(O)_b-SO₃^-M⁺and R¹⁴-CH [SO₃-M⁺] -R¹⁵Where a and b are 0 or 1; n, p, and m are 0 to 100 (preferably 0 to 20, more preferably 0 to 10); R.¹⁴Is defined earlier, but R¹⁴Or R¹⁵At least one of them is at least C8; R¹⁵Is a (C1-C12) alkyl group (saturated linear, branched, or cyclic group), but optionally substituted with an N, O, or S atom, or a hydroxyl, carboxyl, amide, or amine group. May be; Ph is phenyl; and M is a cationic counterion such as H, Na, K, Li, ammonium, or a proton such as triethanolamine or quaternary ammonium group. It is a tertiary amine.

In the above formula, the ethylene oxide groups (ie, the "n" and "m" groups) and the propylene oxide groups (ie, the "p" groups) may be in reverse order or even random. , Sequentially, or an array of blocks may be taken. In this category, R¹⁴But the alkylamide group, for example R¹⁶-C (O) N (CH₃) CH₂CH₂-And even ester groups such as -OC (O) -CH₂-Preferably contains, but here R¹⁶Is a (C8 to C22) alkyl group (branched, linear, or cyclic). Examples thereof include, but are not limited to: alkyl ether sulfonates such as lauryl ether sulphates, such as Stepan Company of Northfield, IL. ), POLYSTEP B12 (n = 3-4, M = sodium) and B22 (n = 12, M = ammonium), and methyl taurine sodium (Tokyo, Japan) Nikko Available from Nikko Chemicals Co. under the trade name NIKKOL CMT30); Secondary Alcan Sulfate For example, Hostapur SAS (which is (C14 ~ C17) Sodium Secondary Alcan Sulfonate (Alpha) -Olefin Sulfate)) (Clariant, Charlotte, NC, North Carolina) Available from Corp.); Methyl-2-sulfoalkyl Esters For example, sodium methyl-2-sulfo (C12-16) and disodium 2-sulfo (C12-C16) fatty acids (from Stepan Company). , Under the trade name ALPHASTEP PC-48); Alkyl sulfoacetate and alkyl sulfosuccinate (sodium lauryl sulfosuccinate (trade name LANTHANOL LAL) and disodium laures sulfosuccinate (Stepan Mild) All available as STEPAN MILD SL3) from Stepan Company); Alkyl sulphate eg ammonium lauryl sulphate (commercially available from Stepan Company under the trade name STEPANOL AM); Dialkyl sulfosuccinate eg Dioctyl sodium sulfosuccinate (available as Aerosol OT from Cytec Industries).

2. Phosphate and phosphonate Suitable anionic surfactants also include phosphates such as alkyl phosphates, alkyl ether phosphates, aralkyl phosphates, and aralkyl ether phosphates. Many are expressed by: [R¹⁴-(Ph)_a-O (CH₂CH₂O)_n(CH₂CH (CH)₃) O)_p]_q-P (O) [O^-M⁺]_rHere, Ph, R¹⁴, A, n, p, and M are defined earlier; r is 0 ~ 2; and q is 1-3; where r = 2 when q = 1. When q = 2, r = 1 and when q = 3, r = 0. In the above formula, the ethylene oxide group (ie, the "n" group) and the propylene oxide group (ie, the "p" group) may be in reverse order, and may be random, sequential, or even. It may be an array of blocks. For example, mono-, di- and tri- (alkyl tetraglycol ether) -o-phosphate (commonly called trilaureth-4-phosphate, trade name from Clariant Corp.) (Commercially available as HOSTAPHAT) 340KL), PPG-5 Setes 10 Hosphate (available from Clarian, NJ, New Jersey, under the trade name CRODAPHOS SG), and There is a mixture of them.

Amphoteric surfactant Examples of the amphoteric type surfactant include a surfactant containing a tertiary amine group which may be protonated, and a zwitterionic surfactant containing a quaternary amine. The following can be mentioned as particularly useful ones.

1. Ammonium carboxylate amphoteric compound This category of surfactant can be expressed by the following equation: R¹⁷-(C (O) -NH)_a-R¹⁸-N⁺(R¹⁹)₂-R²⁰-COO^-Where a is 0 or 1; R¹⁷Are (C7 to C21) alkyl groups (saturated linear, branched, or cyclic groups), (C6 to C22) aryl groups, or (C6 to C22) aralkyl or alkylaryl groups (saturated linear, Branched or cyclic alkyl group), but here R¹⁷May optionally be substituted with one or more N, O, or S atoms, or one or more hydroxyl, carboxyl, amide, or amine groups; R¹⁹Is an H or (C1 to C8) alkyl group (saturated linear, branched, or cyclic group), where R¹⁹Is optionally with one or more N, O, or S atoms, or one or more hydroxyl, carboxyl, amine groups, (C6 to C9) aryl groups, or (C6 to C9) aralkyl or alkylaryl groups. May be replaced; and R¹⁸And R²⁰Are independent of each other (C1 to C10) alkylene groups, but they may be the same or different, and in some cases one or more N, O, or S atoms, or one. Alternatively, it may be substituted with a plurality of hydroxyl or amine groups.

More preferably in the above equation, R¹⁷Is an (C1 ~ C18) alkyl group, R¹⁹Is preferably a (C1 to C2) alkyl group substituted with a methyl or benzyl group, most preferably a methyl group. R¹⁹If is H, it should be understood that the surfactant may be present as a cationic counterion, such as Na, K, Li, or a tertiary amine with a quaternary amine group, where the pH is high.

Examples of such amphoteric surfactants include, but are not limited to: certain betaines, such as cocobetaine and cocamidopropyl betaine (University Park, Illinois). , IL) from McIntyre Group Ltd. under the trade names McCam CB-35 and McCam L); monoacetate, eg sodium lauroamphoacetate; diacetate, eg lauroanho Disodium acetate; amino- and alkylamino-propionates, such as lauraminopropionic acid (from McIntyre Group Ltd., trade names McCam 1L, McCam 2L, and McCam, respectively. (MACKAM) Commercially available as 151L).

2. Ammonium sulfonate amphoteric compound This class of amphoteric surfactants is often referred to as "sultane" or "sulfobetaine" and can be expressed by the following equation: R¹⁷-(C (O) -NH)_a-R¹⁸-N⁺(R¹⁹)₂-R²⁰-SO₃^-Here R¹⁷~ R²⁰And "a" are those defined above. Examples include cocamidopropyl hydroxysultane (commercially available from McIntyre Group Ltd. as McIntyre 50-SB). Sulfonic acid compounds may be preferred over carboxylic acid amphoteric compounds because the sulfonate groups remain ionized at lower pH values.

Nonionic surfactant ), As well as polymerizable (reactive) surfactants (eg, SAM 211 (alkylene polyalkoxysulfate), Pittsburgh, PA). -Available as a MAZON surfactant under the trade name from Industries, Inc. (PPG Industries Inc.). In certain preferred embodiments, the nonionic surfactants useful in the compositions of the invention are poloxamers such as PLURONIC from BASF, sorbitan fatty acid esters, and theirs. Selected from the group consisting of mixtures.

Hydrophilic component The compositions of the present invention solubilize and / or physically stabilize the disinfectant and / or enhancer components in the composition and / or increase the rate of antibacterial activity and / or antibacterial activity. It may contain a hydrophilic or water-soluble component for the purpose of Incorporating a sufficient amount of hydrophilic component into the hydrophobic ointment results in a composition having significantly better antibacterial activity, both at the rate of killing and to the extent of killing. Although not bound by theory, the incorporation of hydrophilic components allows more disinfectant to be utilized on the surface during use or to diffuse more quickly on the surface of the ointment. It is thought that this is the case. Certain compositions are solutions, emulsions (one liquid / gel / paste dispersed in another liquid / gel / paste), or dispersions (solids in liquid / paste / gel). It may be. Generally, in order to obtain improved antibacterial activity, the ratio of total hydrophilic component to total hydrophobic component (water-insoluble component) is at least 5:95 (weight / weight), preferably at least 10:90 (weight / weight). Weight / weight), more preferably at least 15:85 (weight / weight), most preferably at least 20:80 (weight / weight). Some types, even those with high levels of total hydrophilic to total hydrophobic (water-insoluble) ratios such as 30:70, 40:60, 50:50 (weight / weight) or higher. It may be suitable in the composition.

Hydrophilic substances typically have a solubility in water at 23 ° C of at least 7% by weight, preferably at least 10% by weight, more preferably at least 20% by weight, even more preferably at least 25% by weight, even more. The compound is preferably at least 40% by weight. Most preferably, the hydrophilic component is infinitely mixed with water at 23 ° C.

Examples of hydrophilic components include, but are not limited to: water, polyhydric alcohols, lower alkyl ethers (ie, carbon atoms to meet the dissolution limits described above). N-methylpyrrolidone, alkyl esters (ie, those with a sufficiently small number of carbon atoms to meet the dissolution limits described above), and lower monohydroxy alcohols as described in the enhancer section. Furthermore, their combination. Therefore, lower monohydroxy alcohols can serve as both hydrophilic compounds and enhancers. It is preferable that the hydrophilic component contains a polyhydric alcohol, a lower alkyl ether, and a short chain ester. It is more preferable that the hydrophilic component contains a polyhydric alcohol.

Suitable polyhydric alcohols (ie, organic compounds having two or more hydroxyl groups) have a molecular weight of less than 500, preferably less than 400, more preferably less than 200. Examples of polyhydric alcohols include, but are not limited to: glycerol, propylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, polyethylene glycol, diethylene glycol, pentaerythritol, trimethylol. Propane, trimethylolethane, trimethylolbutane, sorbitol, mannitol, xylitol, pantotenol, polyhydric alcohol ethylene glycol adduct, polyhydric alcohol propylene oxide adduct, 1,3-butanediol, dipropylene glycol, diglycerin, poly Glycerin, erythritol, sorbitan, sugars (eg, sucrose, glucose, fructose, mannose, xylose, saccharose, trehalose), sugar alcohols, etc. Certain suitable polyhydric alcohols include glycols (ie, those containing two hydroxyl groups), including glycerin and propylene glycol. Other suitable polyhydric alcohols of some kind include xylitol, mannitol, sorbitol, sucrose and polyglycerin.

Ethers include, for example, dimethyl isosorbide, polyethylene glycol and methoxypolyethylene glycol, block and random copolymers of ethylene oxide and propylene oxide, and substances such as Laures-4. Examples of the alkyl ester include an ester of triacetin, methyl acetate, a glycol polyethoxylated, and a combination thereof.

In certain preferred embodiments, the hydrophilic components useful in the compositions of the present invention include those selected from the group consisting of glycols, in particular glycerin and propylene glycol, and mixtures thereof.

If the composition contains a component that may esterify with the hydroxyl functional hydrophilic component, select conditions that minimize esterification. For example, select conditions such as not heating these components together for a long time, or, if possible, keeping the pH close to neutral.

The desired results can be obtained by using one or more hydrophilic substances in the compositions of the present invention at appropriate levels. In certain preferred embodiments, which also include a hydrophobic component as the main component (ie, the most used component, also referred to as the "vehicle"), the hydrophilic component is based on the weight of the ready-to-use composition. In total, they are present in an amount of at least 0.1%, preferably at least 1% by weight, more preferably at least 4% by weight, and even more preferably at least 8% by weight. Higher levels of hydrophilic components may be used in certain embodiments, for example where the rate of killing is desired to be increased. In such cases, the hydrophilic components are present in a total amount of at least 10% by weight, more preferably at least 20% by weight, and most preferably at least 25% by weight. In a preferred embodiment, the hydrophilic components are present in an amount of 70% by weight or less, more preferably 60% by weight or less, still more preferably 50% by weight or less, based on the composition which can be used as it is. Let me. When the hydrophilic component is present in the maximum amount, it is called a "vehicle". When the disinfectant is to be released more slowly, the hydrophilic component should be present in an amount of about 30% by weight or less.

In certain applications, it is desirable to blend those disinfectants into a composition containing a hydrophilic component vehicle that has been thickened with a thickener, but such thickeners include. Soluble, swellable, or insoluble (eg, insoluble) organic high molecular weight thickeners, or inorganic thickeners, such as silica, fumed silica, precipitated silica, silica airgel and carbon black; other particle fillers, for example. Calcium carbonate, magnesium carbonate, kaolin, talc, titanium dioxide, aluminum silicate, diatomaceous earth, ferric oxide and zinc oxide, clay, etc .; Ceramic microsphere or glass microbubbles; Ceramic microsphere For example, trade name from 3M (3M) These include those available as "ZEOS PHERES" or "Z-LIGHT". The above-mentioned fillers may be used alone or in combination.

When water is used in certain embodiments, the water is, relative to a ready-to-use composition, less than 20% by weight, preferably less than 10% by weight, more preferably less than 5% by weight, and even more. It is preferably present in an amount of less than 2% by weight. This makes the composition chemically stable and can reduce irritation. In certain other embodiments, it is possible to use larger amounts of water and even be the main component, as long as the composition is highly viscous. Such highly viscous compositions preferably have at least 500 centipoise (cps), more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps. It has a viscosity of even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even about 500,000 cps, 1,000,000 cps, or more). The viscosity can be measured as described in the "Viscosity Test" below. The most suitable compositions are compatible with these viscosity values, even after heating to temperatures as high as 32 ° C or even 35 ° C, or 37 ° C, and they are in contact with mammalian tissue. Allows the composition of the above to remain practical.

Hydrophobic component Certain suitable compositions of the present invention also include one or more hydrophobic substances. Hydrophobic substances are typically liquid, gelatinous, semi-solid or solid at 23 ° C and have a solubility in water of less than 5% by weight, preferably less than 1% by weight, more preferably 0.5%. It is an organic compound of less than% by weight, even more preferably less than 0.1% by weight. Such substances include compounds that are typically considered emollients in the cosmetics industry.

Examples of common skin softeners include, but are not limited to: long-chain (ie, C8-C36) straight or branched alkyl or alkenyl alcohols or acids. Short chain (ie, C1-C6) alkyl or (C6-C12) aryl esters, and polyethoxylated derivatives of their alcohols; optionally substituted with -OH, (C4-C12) diic acid. Or short chains of (C4 ~ C12) diols (ie, C1 ~ C6) alkyl or (C6 ~ C12) aryl esters; (C2 ~) of glycerol, pentaerythritol, ethylene glycol, propylene glycol and even their polyethoxylated derivatives. C18) Alcohol or (C6 ~ C12) aryl ester; (C12 ~ C22) alkyl ester of polypropylene glycol or (C12 ~ C22) ether; (C12 ~ C22) alkyl ester or (C12 ~ C22) of polypropylene glycol / polyethylene glycol copolymer Ester; and polyether polysiloxane copolymer. Further examples of hydrophobic components include: cyclic dimethicones containing volatile cyclic silicones such as D3 and D4, polydialkylsiloxanes, polyaryl / alkylsiloxanes, silicone copolyxanes, long chains (ie, C8 ~ C18) Linear or branched alkyl or alkenyl Long chain of alcohol or acid (ie C8 to C36) alkyl and alkenyl ester, long linear or branched chain (ie, C8 to C36) long chain of alkyl or alkenylamine or acid (Ie, C8-C36) alkyl and alkenylamides; linear and branched alkanes and alkenes, such as isoparaffins (eg, isooctane, isododecane, isooctadecane, etc.), squalanes, and hydrocarbons, polysiloxane polyalkylene copolymers including mineral oils. , Dialkoxydimethylpolysiloxane;

In certain preferred embodiments, the hydrophobic components useful in the compositions of the invention include those selected from the group consisting of: US Pharmacy Vaseline, and long chains (ie, C8-C36). ) Linear or branched alkyl or alkenyl alcohols or short chains of acids (ie C1-C6) alkyl or (C6-C12) aryl esters and polyethoxylated derivatives of those alcohols; optionally by -OH Substituted short chain of (C4 to C12) diacid or (C4 to C12) diol (ie, C1 to C6) alkyl or (C6 to C12) aryl ester (eg, diisopropyl adipate, diisopropyl sebacate); glycerol, (C1-C9) alkyl or (C6-C12) aryl esters of pentaerythritol, ethylene glycol, propylene glycol (eg, tricaprylic acid / glyceryl caprate); and mixtures thereof. In certain particularly preferred embodiments, the hydrophobic component is petrolatum.

The desired results can be obtained by using one or more hydrophobic substances in the compositions of the present invention at appropriate levels. In a preferred embodiment (the composition contains little or no water), the hydrophobic component is at least 30% by weight, preferably at least 50% by weight, more preferably at least, based on a ready-to-use composition. It is present in an amount of 60% by weight, even more preferably at least 70% by weight. In a preferred embodiment, the hydrophobic component is present in an amount of 99% by weight or less, more preferably 95% by weight or less, still more preferably 92% by weight or less, based on the composition which can be used as it is. Let me. When the hydrophobic component is present in the maximum amount, it is called a "vehicle". If the hydrophobic and hydrophilic components are present at the same concentration, the continuous phase is considered a "vehicle". If the hydrophobic and hydrophilic components are present at the same concentration, the continuous phase is considered a "vehicle".

Additives of optional ingredients The compositions of the present invention may further use ancillary ingredients commonly found in pharmaceutical compositions in a manner established in the pharmaceutical industry and at a level established in the pharmaceutical industry. Thus, for example, the composition may contain a suitable, pharmaceutically active substance for concomitant therapy (eg, ancillary anti-inflammatory drugs, anthelmintics, antipruritic agents, astringents, local anesthetics, steroids, etc. Non-steroidal anti-inflammatory drugs, or other anti-inflammatory drugs) may be further included, or substances useful for physically incorporating the present invention into various dosage forms, such as excipients, pigments, fragrances. , Fragrances, lubricants, thickeners, stabilizers, skin penetration enhancers, preservatives, or antioxidants.

As will be appreciated by those skilled in the art, the levels or ranges selected for the essential or optional ingredients described herein will either formulate compositions for direct use or. Concentrates for dilution before use are compounded or even depend on the particular ingredients selected, the end use of the composition, and other factors well known to those of skill in the art.

In applications where emulsions are desirable, emulsifiers are preferred. As used herein, the term "emulsifier" means a low molecular weight or high molecular weight amphipathic compound that helps stabilize an emulsion. The emulsifiers used herein include not only the many surfactants disclosed, but also many other amphipathic molecules. When centrifuging and / or freezing and thawing are examined, the emulsion is clearly more stable with the emulsifier than without the emulsifier.

It is also recognized and taken into account that additional disinfectants, fungicides, or antibiotics may be included. Such things include, for example, metals such as silver, copper, zinc; iodine and iodophore: "azole" antifungal agents such as chlortrimazole, miconazole, econazole, ketoconazole, and salts thereof. Is included. Antibiotics such as neomycin sulfate, bacitracin, mupirocin, tetracycline, polymyxin, etc. may be included. However, suitable compositions do not contain antibiotics as resistance may develop.

Formulation and method of formulation Many of the compositions of the present invention exhibit an extensive antibacterial activity spectrum and are therefore generally not final sterilized, but may be sterilized by various industry standard methods if desired. For example, it is also preferred to use an electron beam to sterilize the composition in the final packaging form. It is also possible to sterilize the sample by gamma irradiation or heating. Other forms of sterilization are also acceptable. It is also preferable to add a preservative to the formulation to suppress the growth of certain microorganisms. Suitable preservatives include industry standard compounds such as: parabens (methyl, ethyl, propyl, isopropyl, isobutyl, etc.), 2bromo-2nitro-1,3diol; 5bromo-5- Nitro-1,3 dioxane, chlorbutanol, diazolidinylurea; iodopropylnylbutyl carbamate, phenoxyethanol, cresol halides, methylchloroisothiazolinone, and even combinations of their compounds.

In order to deliver an antibacterial agent to a desired site over an extended period of time, even in the presence of sweating, drainage (eg, mucous secretion), or mild washing, the compositions of the invention can be used. It preferably adheres well to mammalian tissues (eg, skin, mucosal tissue, and wounds). The composition is typically non-aqueous, but for high viscosity compositions it is possible to add large amounts of water. The maximum amount of component (ie, vehicle) in the formulation of the present invention may be various commonly used vehicles commonly used in the topical treatment of human or animal skin. Formulations are typically selected from one of five types: (1) Hydrophobic vehicles (ie, can contain one or more hydrophobic compounds, as the maximum amount. Formulations with (existing, hydrophobic components), which may be anhydrous, almost anhydrous, or even contain an aqueous phase; (2) water-insoluble continuous " An oil-in-oil emulsion-based formulation in which the "oil" phase consists of one or more hydrophobic components; (3) contains a hydrophilic vehicle (ie, one or more hydrophilic compounds). In a formulation with a hydrophilic component), which is possible and is present in the maximum amount, it may be anhydrous, almost anhydrous, or may further contain an aqueous phase; (4) High-viscosity water-based formulation, which may be a solution or an oil-in-water emulsion; and (5) Hydrophobic, including disinfectants, optionally enhancers, and optionally surfactants. An undiluted composition that is substantially free of sex or hydrophilic vehicle components. In this last case, the composition may optionally be dissolved in a volatile carrier solvent for delivery to the desired treatment site, or a dry powder, liquid, or semi-solid composition. As a thing, it may be delivered to the site. The various types of compositions will be further described below.

(1) Anhydrous or almost anhydrous formulations using hydrophobic vehicles: In certain preferred embodiments of the invention, the composition comprises a disinfectant component in a hydrophobic vehicle, optionally in combination with a surfactant, an enhancer component, and a small amount of a hydrophilic component. In many cases, these enhancers do not dissolve in their hydrophobic components at room temperature, but may dissolve at warm temperatures. The hydrophilic component is generally present in an amount sufficient to stabilize (and possibly solubilize) the enhancer in the composition. For example, when formulated with organic acid enhancers or certain solid surfactants or certain disinfectants in Vaseline, many disinfectants, enhancers, and surfactants are used at temperatures above 85 ° C. It dissolves in vaseline, but when cooled, their disinfectants, enhancers and / or surfactants precipitate from the solution as crystals or precipitates, making it difficult to produce a uniform formulation. A stable formulation can be obtained by adding at least 0.1% by weight, preferably at least 1.0% by weight, more preferably at least 5% by weight, most preferably at least 10% by weight of a hydrophilic compound (eg, glycol). Those formulations form an emulsion in which the enhancer and / or surfactant is dissolved, emulsified, or dispersed in a hydrophilic component, which is emulsified in a hydrophobic component. it is conceivable that. These compositions are stable even when cooled or centrifuged.

The hydrophilic component also helps stabilize many of the surfactants used in suitable formulations. For example, sodium dioctyl sulfosuccinate (DOSS) dissolves in glycerin at elevated temperatures and helps keep DOSS physically stable in the composition. Furthermore, it is considered that the antibacterial activity is improved by incorporating a hydrophilic component into the formulation. The mechanism of this is unknown, but it may increase the rate of release of enhancer and / or disinfectant components.

The water content of these formulations minimizes the chemical decomposition of existing disinfectants, and also suppresses the problem of microbial contamination in the composition during storage and the tissue to which it is applied. In order to suppress irritation to, it is preferably less than 20% by weight, more preferably less than 10% by weight, even more preferably less than 5% by weight, and most preferably less than 2% by weight.

These formulations can be produced relatively easily. In the following description, the production is described assuming that all the components are present. However, it should be understood that certain compositions may not contain one or more of those components. In one method, the composition is first heated to 85 ° C for its hydrophobic component, added with a surfactant, hydrophilic component, and optional enhancer component, and cooled to 65 ° C. It is produced by a step and a step of adding a disinfectant component (which may be above its melting point). Alternatively, the enhancer component (if used) is dissolved in the hydrophilic component (possibly with a surfactant) and added to the hydrophobic component, but before the disinfectant component is added. May be later. If either the disinfectant component or the hydrophobic component is solid at room temperature, this is done at the lowest temperature required to ensure dissolution and uniformity of the composition. To avoid transesterification reactions, it should be avoided to expose ester-containing disinfectants or excipients to enhancers or components containing either acids or hydroxyl groups for extended periods of time at elevated temperatures. There are exceptions to this, for example, where lower purity fatty acid esters are combined with glycol hydrophilic components and heated to produce higher purity monoesters.

Therefore, the present invention provides a method for production. One method includes the following steps: the step of stirring and combining the hydrophobic vehicle with the hydrophilic component to form a mixture; optionally before or after combining the hydrophobic vehicle with the hydrophilic component. The step of heating the mixture to a temperature sufficient to form an injectable liquid (in many hydrophobic vehicles, this is above its melting point); the step of adding the disinfectant component to the mixture; and The step of cooling the mixture before or after adding the disinfectant component.

One preferred method includes the following steps: dissolving at least a portion of the enhancer component in the hydrophilic component; combining the hydrophobic vehicle with the hydrophilic component in which the enhancer component is dissolved by mixing. The process of forming a mixture; optionally, before or after combining the hydrophobic vehicle with the hydrophilic and enhancer components, at a temperature sufficient to heat it to form an injectable liquid (in many hydrophobic vehicles). This is a temperature above its melting point); the step of adding the disinfectant component to the mixture; and the step of cooling the mixture before or after adding the disinfectant component.

The hydrophilic component may or may not be present in the formulation containing the hydrophobic vehicle. Therefore, another suitable method for production involves the following steps: In some cases, before or after combining the hydrophobic vehicle with the enhancer component of any component, it is heated to form an injectable liquid. Sufficient temperature (for many hydrophobic vehicles, this is above its melting point); the step of adding the disinfectant component to the mixture with stirring; and before or before adding the disinfectant component. Later, the step of cooling the mixture.

Surprisingly, these compositions were found to be significantly less irritating than formulations using hydrophilic vehicles. In a human blind trial, with 0.5 g (g) of a hydrophobic component (eg, petrolatum) -based ointment containing an AHA enhancer, surfactant, and 10% by weight hydrophilic component (eg, glycerin). In addition, participants were asked to instill a hydrophilic component (eg, PEG400) -based ointment with the same enhancer and surfactant. 100% of the participants preferred an ointment with a hydrophobic vehicle.

The viscosity of those formulations intended for use on the skin or in the anterior nares is preferably relatively high so that excessive dripping does not occur at the treatment site. Formulations intended for use on the skin, anterior nares, or where dripping is a problem, are substantially gelatinous at room temperature and do not flow easily at temperatures below 35 ° C. Most preferably, it has a sufficient yield point. Viscosity is measured using the viscosity test methods described herein. Certain gelatinous vehicles may have a characteristic temperature at which they "melt" or dramatically reduce their viscosity. It is preferable that this temperature is higher than the body temperature so that the composition at the treatment site does not cause excessive dripping. Therefore, the melting point of this composition is preferably higher than 32 ° C, more preferably higher than 35 ° C, and even more preferably higher than about 37 ° C. Its melting point shall be the lowest temperature at which the viscosity begins to drop dramatically or is below 100,000 cps.

Alternatively, the formulation can be considered to gel or thicken when warmed to body temperature. For example, poloxamer-based aqueous compositions based on Pluronic F127 (eg, containing more than about 17% by weight) and even other similar structures have relatively low viscosities at 4 ° C. However, when warmed to body temperature, it becomes extremely viscous. For these applications, its viscosity should be measured at 35 ° C.

Similarly, the viscosity and / or melting temperature incorporates crystalline or semi-crystalline emulsifiers and / or hydrophobic carriers such as refractory petrolatum, or adds insoluble fillers / thixotropes, or high molecular weight. It can be increased by either adding a thickener (eg, polyethylene wax in petrolatum vehicle). The high molecular weight thickener may be linear, branched, or slightly crosslinked. The relatively softness of the formulation and the ease with which it can be spread, especially so that it can be easily applied over wounds, rashes, or infected areas, or into the anterior nostril. It is important for comfort. A particularly suitable vehicle for use on the skin, in the anterior nares, or in other areas where high viscosity is desired is US Pharmacopeia white petrolatum, which has a melting point higher than 40 ° C.

(2) Water-in-oil emulsion: The disinfectant component of the present invention can be incorporated into a water-in-oil emulsion in combination with an enhancer and a surfactant. Particularly suitable compositions include at least 35% by weight, preferably at least 40% by weight, more preferably at least 45% by weight, and most preferably at least 50% by weight of the oil phase. As used herein, "oil" "Phase)" consists of all components that are insoluble in water or soluble in oils preferably present at 23 ° C. One method for preparing such emulsions is described in US Patent Application No. 09 / 966,571, which is pending at the same time by Applicants. Generally speaking, the hydrophobic component (oil) is mixed in a first container, optionally with an emulsifier containing a high molecular weight emulsifier, to a temperature sufficient to obtain a homogeneous composition and then a stable emulsion. Heat. Typically, the temperature is raised to at least 60 ° C, preferably at least 80 ° C, more preferably 100 ° C or higher. In a separate second container, mix the hydrophilic components, including one or more of the following: water, hydrophilic components, enhancers, surfactants, and final Acid / base for adjusting the pH of the composition. The contents of the second container are preferably at a temperature sufficient to obtain a stable final emulsion composition without causing significant deterioration of any of the components, typically above 40 ° C. Is heated to a temperature higher than 50 ° C, more preferably to a temperature higher than 60 ° C. While still hot, the contents of the second vessel are added to the first vessel using a high shear mixer. The composition may be cooled (T &lt;40 ° C) with continuous mixing, or allowed to cool as long as the contents are homogeneously mixed. If the disinfectant is sensitive to heat, add it while mixing while cooling. If it is less sensitive to heat, it may be added to either container. The viscosity of those compositions varies the level of emulsifiers; the ratio of water to the oil phase; chooses the oil phase (eg, more viscous or less viscous oils (hydrophobic components)). (Select); may be adjusted by adding a high molecular weight or fine particle thickener, and the like.

(3) Hydrophilic vehicle: The disinfectant component of the present invention can be blended in a hydrophilic component such as the one based on the above-mentioned hydrophilic compound, optionally in combination with an enhancer and a surfactant. Particularly suitable are polyethylene glycols (PEGs), glycols, and combinations thereof, including blends of PEGs of different molecular weights, optionally containing one or more glycols. When the hydrophilic component is used as a vehicle (ie, the component used in the maximum amount, which may contain one or more hydrophilic compounds), a hydrophobic vehicle is preferably used. It should be selected to maintain the same viscosity and melting temperature properties as described above for anhydrous or almost anhydrous formulations with.

Similarly, either crystalline or semi-crystalline hydrophilic compounds, such as incorporating sufficiently high molecular weight PEG, adding insoluble fillers / thixotropes, or adding high molecular weight thickeners. It is also possible to increase the viscosity by carrying out. The high molecular weight thickener may be linear, branched, or slightly crosslinked. The formulation is relatively soft and can be easily spread so that it can be easily applied, especially in the anterior nares or over wounds, rashes, or infected areas. , Important for comfort. For this reason, particularly suitable vehicles are based on a blend of liquid or semi-solid PEG (PEG400-1000) and more crystalline PEG (PEG1000-2000). Particularly suitable are blends of PEG400 and PEG1450 in a 4: 1 ratio.

In certain preferred embodiments of the invention, the composition is in the form of an ointment or cream. That is, the composition is in a relatively viscous form and is suitable for application to the nasal passages.

(4) Water-based formulation: The aqueous composition of the present invention is present in the maximum amount of water and is therefore a "vehicle". In such systems, it is particularly important to give the composition a relatively high viscosity so that the antibacterial composition does not rapidly disperse and disappear from the therapeutic area. The formulations also adhere well to the tissue, which delivers the disinfectant to the site of interest over an extended period of time, even with sweating, dripping (eg, mucosal secretions), or mild irrigation. It becomes possible to do. Such high viscosities can be provided by thickener systems. The thickener systems of the present invention are suitable for formulation with the disinfectant compositions described above, and thus have appropriate antibacterial activity, chemical and physical stability, acceptable cosmetic properties, and suitable retention in the affected area. Viscosity can be given.

A thickener system suitable for use in the composition of the present invention can produce an extremely stable viscoelastic composition. By varying the type and amount of thickener, the degree of elasticity can be varied from an almost pure viscous composition to a highly elastic and even gelled composition. When a emollient is added, increasing the elastic and / or yield stress of the system provides additional stability and prevents the immiscible emollient from separating. However, too high elasticity is not preferred, as overly elastic compositions usually do not give cosmetically attractive products.

What is important here is that the thickener system used in the present invention can give a high viscosity even if the overall concentration is relatively low. The total concentration of the thickener system is preferably less than 8% by weight, more preferably less than 5% by weight, and most preferably less than 3% by weight, based on the total weight of the composition that can be used as is. The total concentration of the thickener system is preferably as low as about 0.5% by weight based on the total weight of the composition. However, in certain embodiments, the total concentration of the thickener system is greater than 1% by weight based on the total weight of the ready-to-use composition.

Thickeners include organic polymers or inorganic thixotropic agents such as silica gel, clay (eg, betonite, laponite, hectorite, montmorillonite, etc.), and organically modified inorganic particulate matter. As used herein, an organic polymer is considered part of a thickener system if its presence in the composition increases the viscosity of the composition. Certain polymers that do not have such properties can also be present in the composition, but they do not significantly affect the viscosity of the composition. For the purposes of the present invention, they are not considered to be part of the thickener system. For example, certain nonionic polymers, such as low molecular weight polyethylene glycols (eg, those with a molecular weight of less than 20,000), do not significantly increase the viscosity of the composition. They are considered, for example, part of a hydrophilic component rather than part of a thickener system.

Thickener systems can be prepared from one or more nonionic, cationic, anionic, zwitterionic, or associative polymers, but they are incorporated into the disinfectant and enhancer components of the composition. Must be aptitude. For example, certain acidic enhancers, such as those containing carboxylic acid groups, are most effective when in their protonated form. For that purpose, the composition needs to have an acidic pH. For this reason, many anionic thickeners based on neutralized carboxylic acid groups are not suitable. For example, polyacrylate-based Carbopol-type thickeners typically do not thicken well at pH less than 5, and do not reliably thicken at pH 4.5. Therefore, at lower pH values (ie, in the presence of acidic enhancers), if the aqueous composition is thickened with an anionic polymer, the polymer is sulfonic acid, sulphate, phosphonic acid. , Or is preferably based on a phosphite base. These polymers are capable of thickening at lower pH due to the low pKa of their acid groups. Suitable polymers in this category include: ARISTOFLEX HMB (ammonium acryloyl dimethyl taurate / Behenes-25 methacrylate crosspolymer) and ARISTOFLEX from Clariant Corporation: ASV (ammonium acryloyl dimethyl taurate / NVP copolymer). Other suitable sulfonic acid polymers are those described in US Pat. No. 5,318,955.

Compositions containing acidic enhancer components are preferably thickened using a cationic or nonionic thickener because they perform well at low pH. In addition, many of the nonionic and cationic polymers can withstand higher levels of salts and other additives and still maintain high viscosities.

Suitable groups of nonionic high molecular weight thickeners include: modified cellulose, guar, xanthan rubber, and other natural polymers such as polysaccharides and proteins, nonionic ethylenically unsaturated monomers. From the group consisting of associative polymers based on which at least one comonomer has at least 16 carbon atoms, and acrylate, acrylamide, vinyl lactam, vinyl acetate and hydrolyzed derivatives thereof, methyl vinyl ether, styrene, and acrylonitrile. A polymer based on the selected ethylenically unsaturated monomer.

Suitable groups of cationic high molecular weight thickeners include: cationically modified celluloses, quaternized natural amino functional polymers, and acrylates, acrylamides, vinyllactams, vinyl acetates, methyl vinyl ethers, styrenes, And a polymer based on an ethylenically unsaturated monomer selected from the group consisting of acrylonitrile.

The cationic polymer for use in the compositions of the present invention is permanently charged. charged) Using quaternary polymers (polymers containing quaternary amines such as Polyquaternium 4, 10, 24, 32, and 37, which are described below), as well as with the appropriate protonic acid. You can choose from any of the protonated primary, secondary, and tertiary amine functional polymers. Suitable protonated cationic polymers are based on tertiary amines. The protonated cationic polymer is preferably protonated with an appropriate acid that does not cause excessive skin irritation. Such include: for example: alkylcarboxylic acids (eg, acetic acid, alpha-hydroxy acids, eg, lactic acid, gluconic acid, benzoic acid, mandelic acid) optionally substituted with oxygen (eg, acetic acid, alpha-hydroxy acid). (C1 to C10) alkyl sulfonic acids (eg, methyl sulfonic acid and ethyl sulfonic acid), (C1 to C10) alkyl hydrogen sulfate (eg, methyl hydrogen sulfate) and mineral acids (eg, hydrochloric acid, bromide) Hydrogenic acid, sulfate, phosphoric acid, etc.).

The charge on the protonated cationic polymer depends on the pH. For this reason, the pH should be adjusted appropriately, preferably in the range of 2 to 9.5, more preferably 2 to 8, most preferably 2.5 to 7.5, in order for the polymer to be fully protonated. Is. A suitable composition containing an acidic enhancer should have a low pH, typically 2-5, preferably 2-4. Note that it is not necessary to protonate all the amines on a particular polymer. The level of protonation will depend to some extent on pH. For some polymers, it may be convenient to protonate only a small percentage of the amine groups present in order to keep the skin irritation low for optimal thickening. On the other hand, in the case of other polymers, it may be convenient to protonate virtually all of the amine groups. This can be easily determined by those skilled in the art.

These quaternary, tertiary, secondary, and primary amine functional polymers can be selected from natural polymers, modified natural polymers, and even synthetic polymers. These polymers may be soluble in aqueous solvents or swellable. Furthermore, these polymers have hydrophobic side chains and may be associative polymers.

Polymers can be classified as soluble, swellable, or associative in aqueous compositions. Some polymers may be classified into one or more of those categories. For example, certain associative polymers may be soluble in water systems. In aqueous systems, depending on whether they are considered soluble, swellable, or associative, polymers suitable for use in the compositions of the present invention may be film-forming, even if they are film-forming. It does not have to be. The film-forming polymer can retain the active antibacterial agent component in the affected area for a long time. This can be desirable in certain applications. For example, some film-forming polymers can create compositions that, after being applied and dried, cannot be easily removed by washing with water.

As used herein, a soluble polymer is in a dilute solution (ie, 0.01-0.1% by weight in a desired aqueous solvent system defined to contain water and various other hydrophilic compounds). After heating for sufficient time to solubilize all potentially soluble ingredients, for example, Malvern Masteri, available from Malvern Co. in Boston, MA, Massachusetts. Remarkably observable particles with a particle size of more than 1 micron when measured using the light scattering method using the Malvern Masterisizer E Laser Particle Size Analyzer. Does not include.

As used herein, a swellable polymer is a component that may dissolve by heating in a dilute solution (ie, 0.01-0.1% by weight in a desired aqueous solvent system) for a sufficient period of time. After all solubilization, for example, when measured using a light scattering measurement method using the Malvern Masterisizer E Laser Particle Size Analyzer. It contains a significant (ie, detectable) number of observable particles with a particle size greater than 1 micron.

As used herein, an associative polymer is one that has at least 3 hydrophobic chains per molecule of polymer with more than 12 carbon atoms, preferably more than 16 carbon atoms. Such polymers will be described later.

Soluble polymer: Cationic natural polymer derivative There is a description in the literature that cation-modified cellulosic polymers are soluble in water. Such polymers have been found to be useful in the present invention. The most preferred modified cellulose products are CELQUAT (manufactured by National Starch and Chemicals Corp. of Bridgewater, NJ) and UCARE (New Jersey). Sold as Amerchol Corporation in Edison, NJ. CELQUAT is a copolymer of polyethoxylated cellulose and dimethyldiallylammonium chloride and is a Cosmetic, Toiletry and Fragrance Association. In the Assocation (CTFA) name, it is Polyquaternium-4.

Alkylated quaternary ammonium salts of hydroxyethyl cellulose and trimethylammonium chloride substituted epoxides can also be used. The polymer, under the CTFA name Polyquaternium 24, is marketed as QUATRISOFT LM-200 by Amerchol Corp. in Edison, NJ. There is.

A particularly suitable type of cationic polysaccharide polymer that can be used is a cationic guar rubber derivative, such as guar hydroxypropyltrimonium chloride (commercially available under the trade name "JAGUAR" from Rhone-Poulenc). ..

Soluble polymer: Cationic synthetic polymer Synthetic cationic linear polymers useful in the present invention preferably have extremely high cationic charge densities and are generally more than 10% by weight, preferably more than 25% by weight, more preferably more than 50% by weight. Contains monomer. As a result, a good feel as a cosmetic product can be obtained, and the water solubility can be actually improved. Generally speaking, the polymers useful in the present invention are generally less than 5% by weight polymer sufficient to provide a thickening effect, but lotions / creams / ointments are slimy or threaded. It has a molecular weight that is not high enough to give the feel of pulling. The composition of the polymer has a dramatic effect on the molecular weight at which sufficient thickening occurs, but the polymer preferably has a molecular weight of at least 250,000 daltons, more preferably at least 500,000 daltons. The polymer preferably has a molecular weight of 3,000,000 daltons or less, more preferably 1,000,000 daltons or less. Homopolymers are preferably prepared from methacryloyloxyalkyltrialkylamium salts, acryloyloxyalkyltrialkylammonium salts, and / or quaternary dialkylaminoalkylacrylic amidine salts. The polymer is preferably a copolymer from at least two monomers selected from the group consisting of: trialkylaminoalkyl acrylate and trialkylaminoalkyl methacrylate, dialkyldialylammonium salt, acrylamidealkyltrialkyl. Salts, methacrylicamide alkyltrialkyl salts, and alkylimidazolinium salts, N-vinylpyrrolidinone, N-vinylcaprolactam, methylvinyl ethers, acrylates, methacrylates, styrene, acrylonitrile, and combinations thereof. Typically, in the case of salts, the counterion is preferably F.^-, Cl^-, Br^-, And CH₃(CH₂)_nSO₄^-(Here, n = 0 to 4).

Various quaternary copolymers with varying degrees of quaternization can be synthesized on the basis of homopolymers or copolymers of aminoacrylates having methyl, ethyl, or propyl side chains. These monomers can also be copolymerized with other nonionic monomers, including homopolymers of 2-methacryloxyethyl trimethylammonium chloride and 2-methacryloxyethyl methyl diethylammonium bromide. A copolymer of a quaternary acrylate monomer, including a quaternary acrylic homopolymer; and a water-soluble monomer, such as Petrolite Product No. Q-0043, which is a linear quaternary acrylate and acrylamide. It is a copolymer (high molecular weight of 40 to 5 million MW) for which a patent right exists.

Another useful soluble cationic polymer is poly (N, N-dimethylaminopropyl-N-acrylic amidine) (quarterized with diethyl sulfate) attached to a block of polyacrylonitrile. This block copolymer is available under the trade name Hypan QT-100 from Lipo Chemicals Inc. of Paterson, NJ. As such, it has an extremely high effect of thickening the aqueous system and has a good cosmetic feel. However, this polymer, as it is available, has an unpleasant amine odor. The odor can be masked with a suitable fragrance, but removed prior to formulation (eg, using a solvent cleaning process) so that the formulation can be delivered without fragrance. Is preferable. Suitable compositions are free of fragrances and colorants.

Suitable cationic polymers are, for example, copolymers of 1-vinyl-2-pyrrolidin and 1-vinyl-3-methyl-imidazolium salt (eg, chloride salt) in the industry, cosmetic toiletries and -The one called Polyquaternium-16 by the Cosmetic, Toiletry and Fragrance Assocation (CTFA) can be mentioned. This substance is from BASF Wyandotte Corporation. Commercially available from Corp. (Parsippany, NJ, USA) under the trade name LUVIQUAT (eg, LUVIQUAT FC370); 1-vinyl-2-pyrrolidine and dimethyl methacrylate. Aminoethyl copolymer, called Polyquaternium-11 in the industry (CTFA). This material is commercially available from ICI Corp. in Wayne, NJ, under the trade name GAFQUAT; a cationic diallyl quaternary ammonium-containing polymer, for example. , Dimethyldialylammonium chloride homopolymer, and a copolymer of acrylamide and dimethyldiallylammonium chloride, referred to in the industry (CTFA) as Polyquaternium 6 and Polyquaternium 7, respectively. ing.

Soluble polymer: Nonionic In the literature, it is reported that various cellulose ethers are soluble in water. Substances in this category that have been found to be nonionic and useful include: Methyl hydroxypropyl cellulose (Aqualon to BENECEL in Wilmington, DE): Available as MP943); Hydroxypropyl Cellulose (Aqualon Available as KLUCEL (LF, GF, MF, HF)); Hydroxybutyl Methyl Cellulose (3.5 wt% Hydroxybutyl and 30 wt% methoxyl) (New York) Scientific Polymer in Ontario, Delaware From Products); and hydroxyethyl cellulose (available from Aqualon under the trade name NATROSOL). Xanthan gum, guar, carob gum, and other polysaccharides may also be suitable. These polymers may be produced from plant sources or from cell cultures of microorganisms. Polyvinyl alcohol (PVA) may also be suitable. For example, PVA made from polyvinyl acetate with a hydrolysis rate of about 87% has high water solubility at room temperature. Those with higher hydrolysis rates will gradually become more crystalline and may need to be heated to make a solution. Protein thickeners such as gelatin and pectin can also be useful.

Other soluble polymers: For example, as described in U.S. Pat. No. 6,123,933, marketed by Clariant Corp. under the trade names DIAFORMER Z-711, Z-712, Z-731, and Z-751. Amine oxide polymers are also useful. In addition, zwitterionic polymers such as the methacryloyl ethyl betaine / acrylate copolymer commercially available from Clariant Corp. under the trade name DIAFORMER Z-400 can also be used. Zwitterionic polymers as described in US Pat. No. 6,590,051 may also be useful.

Naturally-derived carboxylic acid functional polymers such as hyaluronic acid and derivatives of natural polymers such as carboxymethyl cellulose, alginic acid and other alginate polymers, fucogel (Fucogel, a polysaccharide consisting of three mono-saccharides, fucose, galactose, and galacturonic acid). Carboxylic acid functional polymers such as, hyaluronic acid, etc. may also be useful. For example, synthetic polymers based on carboxylic acids, phosphonic acids, or sulfonic acid functional monomers may also be useful, including, but not limited to: acrylic acids, methacryl. Acids, maleic anhydride, itaconic anhydride, sodium AMPS (sodium salt of 2-acrylamide-2-methylpropanesulfonic acid), sulfopropyl acrylate or methacrylate, sulfomethylated acrylamide, allyl sulfonate, sodium vinyl sulfonate, combinations thereof, Alternatively, polymers derived from these or other water-soluble forms of polymerizable carboxylic acids or sulfonic acids.

Swellable polymer Many slightly crosslinked, swellable polymers act as thickeners in aqueous solvent systems. In general, these swelling polymers are preferred because they are less prone to "slimy" when the hands are sweated or exposed to water after treatment. Excessive cross-linking will result in a polymer that does not swell enough to increase the viscosity of the composition. When a chemical cross-linking agent is used, the concentration of the cross-linking agent is extremely low, for example, less than about 1000 ppm, preferably less than 500 ppm, based on the weight of the dry polymer, in order to allow sufficient swelling.

Classes of crosslinked polymers suitable for use in the compositions of the present invention include: acrylamide and trialkylaminoalkyl acrylates and methacrylates, dialkyldialylammonium salts, acrylamidealkyltrialkylammonium salts, At least one other quaternary monomer selected from the group consisting of monomers containing methacrylamide alkyltrialkylammonium salts and imidazolinium salts. Its counterion is preferably F^-, Cl^-, Br^-, And CH₃(CH₂)_nSO₄^-(Here, n = 0 to 4). Other comonomer may be added, such as: N-vinylpyrrolidone, N-vinylcaprolactam, methyl vinyl ether, acrylate, methacrylate, styrene, etc. A particularly suitable polymer is poly (2-methacryloxyethyl trimethylammonium chloride) polydimethylaminoethyl methacrylate, which in the CTFA name is Polyquaternium 37. Other suitable polymers include acrylamide and methacryloyloxyethyltrimethylammonium chloride, which is consistent with Polyquaternium 32 in the CTFA name. They are marketed as SALCARE SC95, SC96, and SC92 by Allied Colloids Inc. in Suffolk, VA, Virginia.

Other swellable polymers (ie, slightly crosslinked polymers) can be prepared by irradiating with ionizing radiation to crosslink. For example, polymers of N-vinyllactam, such as N-vinylpyrrolidone, may increase in molecular weight and actually crosslink when exposed to gamma irradiation. Cross-linking in this way allows for more efficient thickening (less polymer is required to achieve a certain level of viscosity) and provides an improved cosmetic feel. Other polymers that crosslink when exposed to gamma radiation include: LUVIQUAT HM552 (copolymer of vinyl imidazolium methchlorolide with vinylpyrrolidone, polyquaternium named CTFA): -16), and polymers such as GAFQUAT HS-100 (vinylpyrrolidone / methacrylamide propyltrimethylammonium chloride copolymer, CTFA-named Polyquaternium-28).

Chemical cross-linking with polyunsaturated monomers such as diallyl maleate can also be useful. Other suitable cross-linking agents are compounds with multiple ethylenically unsaturated compounds, the ethylenic groups of which are vinyl groups (including substituted vinyl groups such as isopropenyl groups), allyl groups, and / or metaallyls. It is a group, and those groups are bonded to a nitrogen atom or an oxygen atom. As used herein, vinyl, allyl, and metaallyl groups also include substituted derivatives. Examples of the compound include divinyl, diallyl or dimethallyl ester, ether, amide, urea and the like. Specific examples are disclosed in US Pat. No. 5,225,473 (Duan) and US Pat. No. 4,931,282 (Asmus et al.).

A series of cross-linked polyvinylpyrrolidone (PVP) materials were prepared by covalent cross-linking with diallyl maleate or by radiation cross-linking of linear PVP powder. Crosslinked PVPs prepared by these methods can produce colloidal particles, which are highly swellable in aqueous solution, thus resulting in a viscous solution. These polymers are also nonionic and have excellent mixability with cationic excipients.

Anionic swelling high molecular weight thickeners can also be useful. As mentioned earlier, suitable anionic polymers for use with antibacterial compositions containing (and consequently formulated at low pH) carboxylic acid functional enhancers are sulfonic acids, sulfonates, phosphones. It is a polymer having an acid or a phosphate base.

Associative polymer Similarly, associative polymers can be used to thicken the compositions of the invention. Such polymers thicken as a result of hydrophobic or hydrophobic side chain van de Waals associations. Such associative polymers are capable of forming viscous or gelled aqueous solutions, even though they themselves have a relatively low molecular weight. Alcohol-soluble polymers can be modified by adding long-chain hydrophobic groups. A suitable class of such associative polymers is based on nonionic ethylenically unsaturated monomers, where at least one comonomer has at least 12 carbons, preferably at least 16 carbon atoms. Has an atom.

One example is cetyl hydroxyethyl cellulose, which is available from Aqualon as NATROSOL PLUS and utilizes an association mechanism to increase the viscosity it produces. The grafted side chain of the cetyl alkyl group can associate with a neighboring alkyl hydrophobic compound. The association between these polymers can dramatically improve the thickening efficiency of the polymer. Long chain alkryl, alkenyl, and aralkyl groups may also be suitable. For example, another suitable associative polymer is Arsitoflex HMB, which is a crosspolymer of ammonium acryloyldimethyltaurate / Behenes-25 methacrylate and is Clariant Corp. ) Is available.

(5) Undiluted composition: The disinfectant composition of the present invention may further be administered to the treatment site in undiluted form or in a volatile solvent such that it evaporates rapidly, leaving the undiluted composition thereafter. .. Such compositions may be solid, semi-solid or liquid. If the composition is in solid form, the disinfectant and / or enhancer and / or surfactant may be microencapsulated to produce a powder that is easy to deliver or administer. It can also be made easier. Alternatively, the composition can be micronized into a fine powder without the addition of other ingredients, or optionally contains fillers and other ingredients that facilitate the production of the powder. You may. Suitable powders include, but are not limited to: calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

When using a hydrophobic disinfectant, a method for micronizing the hydrophobic agent can be used, where the polymer is used as described in US Pat. No. 6,746,635. Dissolve the hydrophobic agent in an effective amount of the first solvent, which is completely free. The hydrophobic drug and its solvent form a mixture with a continuous phase. A second solvent and then an aqueous solution are introduced into the mixture. By introducing the aqueous solution, precipitation of the hydrophobic drug occurs, and a micronized hydrophobic drug composition having an average particle size of 1 micron or less can be obtained. The particle size used for delivery to the nose or other tissue may be significantly larger for delivery directly to the appropriate site. For example, larger particles may be required to administer the disinfectant powder to the nose, nasal cavity, and / or pharynx without going through the lungs.

Optionally, the bioadhesive polymer can be added to the undiluted composition and even other physical forms. Many suitable bioadhesive polymers are discussed in WO 93/21906. Particularly important, representative bioadhesive polymers are described in HS Sawhney, CP Pathak and JA Hubell, Macromolecules, 1993, 26, 581-587, such as: , Bioerodible hydrogels include: polyhyaluronic acid, casein, gelatin, glutin, polyacid anhydride, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (Butyl methacrylate), Poly (isobutyl methacrylate), Poly (hexyl methacrylate), Poly (isodecyl methacrylate), Poly (lauryl methacrylate), Poly (phenyl methacrylate), Poly (methyl acrylate), Poly ( Isopropyl acrylate), poly (isobutyl acrylate), and poly (octadecyl acrylate). Suitable polymers are polyacrylic acid (eg, carbomer) and poly (fumaric acid-co-sebacic acid). Other bioadhesive and biodisintegrating polymers are described in US Pat. No. 6,746,635. Particularly suitable are slightly crosslinked polyacrylic acids, such as those sold by BF Goodrich under the CARBOPOL brand.

The antibacterial composition may further comprise a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to: calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. ..

The undiluted disinfectant composition according to the present invention can also be conveniently administered in the form of an aerosol spray from a pressure vessel or nebulizer, in which case suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane. Use methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit of administration can be determined by providing a valve that allows a measured amount to be administered. For example, gelatin capsules and cartridges for use in inhalers or injectors may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Those skilled in the art can easily determine various parameters and conditions for producing an aerosol agent without extra experimentation. In some embodiments, inhaled dosing is preferred for direct delivery to the lungs. Several types of metered dose inhalers are commonly used for administration by inhalation. These types of tools include metered dose inhalers (MDIs), respiratory actuated MDIs, dry powder inhalers (DPIs), spacers / holding chambers in combination with MDIs, and nebulizers. Methods of preparing aerosol delivery systems are well known to those of skill in the art. Generally speaking, such systems should use ingredients that do not significantly impair the biological properties of the drug (eg, Scialra and Cutie Aerosols). , Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 1694-1712).

These compounds can also be formulated as rectal or vaginal compositions, such as those containing commonly used suppository bases such as cocoa butter or other glycerides, such as suppositories or retention enemas. Is.

viscosity Suitable compositions of the present invention have a viscosity of at least 500 centipoise (cps) for easy topical application. The compositions of the present invention are more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably. It has a viscosity of at least 100,000 cps, even more preferably at least 250,000 cps (and even higher, about 500,000 cps, 1,000,000 cps, or higher). The viscosity can be measured as described in "Viscosity Test" below. Formulations with high viscosities are preferred, even after application to mammalian tissues at 32-37 ° C. The viscosity to be measured is the final composition, as certain optional components, such as enhancers, hydrophilic compounds, hydrophobic compounds, etc., can affect the viscosity (plus or minus). Is the viscosity of.

However, it is also possible to use lower viscosity compositions for certain applications, such as the treatment of middle ear infections and chronic sinusitis. For example, diseases of the middle ear (eg, otitis media or infections of the middle ear) can be more easily administered through the outer ear, through the nose, or in the Eustaky tube using the compositions of the invention with viscosities below 1000 cps. May be treated by Viscosity is measured by the viscosity test method described herein. Suitable compositions meet the viscosity limits described above, even when warmed to 32 ° C. The most suitable compositions meet the viscosity limits described above, even when warmed to 35 ° C.

Delivery method and equipment The antibacterial compositions of the present invention can be provided to medical professionals as a single composite formulation or as multiple components. For example, the composition may contain a disinfectant component in one component and an enhancer in one component (eg, in two separate containers or in two compartments in the same container. Can be provided as a two-component type (put in). The other components of the composition can be incorporated into either of the two component types. Alternatively, other constituents can be added to the third component.

For the therapy of topical antimicrobial therapy in carrying out the present invention, safe and effective amounts of the compositions described herein may be applied to infected or endangered skin, wounds, or. It involves direct application to the mucous membranes, especially the nasal passages and passages, which are particularly susceptible to microbial contamination. The dose and frequency of application depends on many factors, including the condition to be treated, the concentration of enhancers of disinfectants and optional ingredients, and the microorganisms to be killed. Typically, for most administrations, the composition is at least 10 mg / cm.²(Tissue), preferably 20 mg / cm²(Tissue), more preferably at least 30 mg / cm²(Tissue), most preferably at least 50 mg / cm²Administer at a (tissue) dose. Administration can be on a daily basis or more, only once a day, or multiple times (eg, 2-4 times). Typically, the composition is administered 1-2 times daily over 1-7 days. For example, to decorate the anterior nares, it should be administered at a dose of 0.25 grams (g) per nasal cavity 1-3 times daily for 1-5 days. For the treatment of impetigo, it is necessary to administer about 0.5 g / 15 cm2 (33 mg / cm2) 1 to 3 times a day for 3 to 10 days.

The composition of the present invention can be administered using various methods. Typically, the composition is administered to the skin and / or mucosal tissue in such a way that it can penetrate into the skin and / or mucosal tissue, which is delivered through the tissue into the bloodstream. Is in contrast. This results in a locally high concentration of the composition at the site requiring treatment. This delivery can be performed in the area to be treated by spraying, dipping, wiping, dripping, injecting, toweling, inhaling and the like.

In the methods of the invention, the disinfectant composition can be obtained as a formulation suitable for delivery to mammalian tissues (eg, skin and / or mucosal surfaces). Suitable formulations include, but are not limited to: creams, gels, foams, ointments, lotions, balms, waxes, ointments, solutions, Suspensions, dispersions, water-in-oil or oil-in-water emulsions, microemulsions, pastes, powders, oils, oral tablets, large rounds, and sprays.

The compositions can also be sprayed from a pressurized vessel. Pressure can be applied, for example, by external means such as squeezing the container, by using a mechanical pump, or by using a propellant. Suitable propellants include: chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), hydrofluoroethers (HFEs), perfluorocarboned alkanes, and (C1-C5). Alkanes, as well as nitrous oxides and dimethyl ethers.

When administered as a foam, for example, F2 Finger Pump Foamer from Air Spray International in Pompano Beach, FL. The composition can be dispensed from an aeration dispenser. Alternatively, foams can be generated using suitable propellants as described above.

In the case of very viscous formulations, the composition may be administered by making it into a substantially solid dosage form and placing the composition in or on the tissue to be treated. For example, a small suppository-type delivery may be placed in the anterior nares to eradicate the genus Staphylococcus.

Various other administration modes well known to those skilled in the art can be used depending on the desired position for contacting the antibacterial composition of the present invention. For example, diseases of the middle ear (eg, otitis media or infections of the middle ear) can be treated by administering the compositions of the invention into the Eustaky tube through the nose, or through the eardrum of the middle ear. It is also possible to inject directly into it. The formulation may be crossed the eardrum using an injection tube, or it may be done by diffusion. A transdermal absorption enhancer may be used to promote diffusion across the eardrum.

For application to skin or mucosal tissue, the composition may be applied directly to the tissue, for example from an extrusion vessel such as a flexible tube, blow / fill / seal container, pouch, capsule, etc. .. In this embodiment, the composition may be delivered directly onto the tissue using the main container itself, or may be used to deliver the composition to another applicator. For example, the composition can be dispensed directly from the tube and spread by various means for delivery to the nose or other local tissue, which may be done by repeatedly pinching the outside of the nose. Alternatively, the tip of the tube may be used or wiped with another tool such as a spatula, cotton, rayon or other natural or synthetic fiber swab.

Other application tools may be used, including applicators with foam tips, applicators with brushes and the like. What is important here is that the applicator must be able to deliver the required amount of composition to the tissue. Therefore, in most cases, applicator tools such as webs and swabs exceed 50% by weight of dry webs, preferably more than 100% by weight of dry webs (only the weight of the web on the swab is included). , Coat on the applicator web.

Crushable vessels can be manufactured in a variety of single layer, laminated or coextruded structures. Constituent materials include: Polyolefins such as low-density, medium-density or high-density polyethylene (including low-density and linear low-density polyethylene), polypropylene, and even ethylene and / or propylene and others. Copolymers with polar or non-polar comonomer; polyamides such as nylon, polyesters such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate; polyurethane, polyacrylate, etc. For some constituents, it may be preferable to include a barrier material to prevent evaporation of one or more components of the formulation. Suitable barrier materials include: polyesters (eg polyethylene terephthalate, polyethylene naphthalate and polyvinylidene terephthalate, etc.), fluorinated layers such as polytetrafluoroethylene (PTFE, eg Teflon®) ( TEFLON®)), polyamide (eg, nylon), chlorotrifluoroethylene (ACLAR), polyvinylidene chloride, and copolymers of perfluoropolymers and partially fluoropolymers, eg, tetrafluoroethylene / hexa. Fluoropropylene / vinylidene chloride copolymer (THV Fluorothermoplastic from Dyneon Company), polyvinyl chloride, polyvinylidene chloride (PVDC, eg SARAN HB), ethylene vinyl Alcohol (EVOH), polyolefins (eg, polyethylene, high density polyethylene, polypropylene, and combinations thereof). Oriented or biaxially oriented polymers are particularly suitable.

Particularly suitable barrier constituents include: metal foil barriers such as aluminum foil laminates, HDPE, PET, PETG, polyester and PEN laminates of polyolefins (particularly PET / HDPE or HDPE / PET / HDPE). , PET and EVOH laminates, biaxially oriented nylon, PVDC, nylon / EVOH / nylon (OXYSHIELD OUB-R), chlorotrifluoroethylene and its laminates, silicon oxide (SiO)_x, Here a ceramic layer containing a thermoplastic coated with x = 0.5-2, preferably 1-2), and a ceramic-coated PET (Oak Ridge, NJ) CCL Container / Tube Division. (CERAMIS) available from (CCL Container / Tube Division).

The antibacterial composition can be applied to the mucosal surface using delivery tools such as neck caps, diaphragms, and solid matrices such as tampons, cotton sponges, swabs, foam sponges, and suppositories. Thus, the compositions of the invention are incorporated into, for example, cloths, sponges, paper products (eg, paper towels, small towels, and wipes), tampons, undercast padding, and dental floss (eg, dental floss). , Delivered from them).

In some embodiments, the applicator may be used to place the tool and / or antibacterial composition in a suitable location, eg, on a mucosal surface such as the vagina, nasal cavity, rectum. Examples of such applicators include, for example, paperboard or plastic tube applicators commonly used for inserting tampons and suppositories.

The compositions of the present invention can be delivered from a variety of substrates for delivery to tissues. Compositions can be delivered from them, for example, by using wipes or pads and giving the tissue at least a portion of the composition when they come into contact with the tissue. When applied to the nasal cavity, a non-woven swab, such as a "Q-tip" brand swab, can provide the composition to a foam tip applicator or the like. The substrate can be used to deliver the composition substantially immediately or to be in contact with the tissue. For example, the tubular form of the substrate can be fed to the anterior nares using a suitable applicator and left in the anterior nares. The annular design of the device allows the patient to deliver the active ingredient while breathing freely through the nose.

Further, the composition of the present invention can be applied on a medical device that comes into contact with skin, mucous membranes, wounds and the like. Examples of such devices include catheters such as urethral catheters and vascular access catheters.

The following examples further illustrate the objectives and advantages of the invention, but the specific substances cited in those examples and their amounts, as well as other conditions and details, are unreasonable to limit the invention. Do not receive it.

Test protocol Death of microorganisms on tissues Many of the compositions of the present invention are intended to kill microorganisms on mammalian tissues such as skin and mucosal tissues. The degree of death can be determined by the following method. Identify those who are naturally coronized by the target microorganism from the subject. This is preferred over the method of artificially coronized tissue with aboriginal bacteria. For example, by swabbing the anterior nares and culturing the swabs, Staphylococcus in the anterior nares Can identify subjects whose aureus) (SA) is coronized. This is usually repeated at least once more to ensure that the subject is a "chronic carrier", i.e., that the person carries the microorganism at all times or almost all the time. In addition, swabs can be taken for several days prior to the start of treatment to increase the probability that the subject is a true carrier. The subject is then treated with the prescribed composition at the indicated dose and at a certain frequency. Swab the anterior nares one more time to see if the bacteria have been reduced or eradicated (decolonized). It is preferred that the formulation eradicates SA within less than 72 hours, more preferably less than 48 hours, most preferably within 24 hours. The same procedure is used for the skin, but a control site different from the treatment site may be selected on the day of treatment. In this case, the logarithmic reduction can be obtained. The procedure on the skin is described in Federal Register 21 CFR Parts 333 and 369: Tentative Final Monograph for Healthcare Antiseptic Drug Products; Proposed Rule, 1994 (scrub cup method. When performing this method on the skin, the disinfectant composition is generally applied to a suitable dressing, such as Tegaderm (3M Company). The antibacterial activity is checked by keeping it in contact with the skin for at least 6 hours under (manufactured by). Suitable formulations are at least 1 pair over 6 hours on dry skin areas (eg, abdomen). It shows a decrease, preferably at least 1.5 logarithmic decrease.

Antibacterial activity test This method simulates the actual conditions of use for many topical disinfectants. Often, a topical disinfectant is applied to the area, optionally with some rubbing, to maintain contact there and kill the various microorganisms present therein, in a substantially static state. In this assay, the composition is spread over a film to form a homogeneous coating 10 mils (250 μm) thick, a suspension of bacteria is inoculated directly onto the surface of the composition for a predetermined period of time. After that, the inoculated disc is placed in a neutralized broth, at least a part thereof is diluted, and the plate is cultured to count the number of viable bacteria. It should be noted here that wetting is taken into consideration in this in-vitro method, just as in the case of in-vivo conditions. In certain compositions, the bacterial suspension will wet and spread the composition very well. For other compositions, the bacterial suspension may remain as individual droplets. This is believed to simulate in-vivo performance in wetting tissues and bacterial biofilms. A suitable composition of the present invention is an ointment, which is very well applied. For lower viscosity compositions, a suitable blending thickener should be added to reach a viscosity of at least 20,000 cps, preferably at least 50,000 cps.

Initial experiments were performed on all disinfectants used in this assay to determine if their neutralizing broth was effective in neutralizing the disinfectants without damaging the microorganisms. .. Generally, to confirm neutralization, 100 μL of inoculum (target microbial concentration, 10-100 CFU / mL) was warmed (36 ° C) and 20 mL of neutralizer broth (for DE neutralizer). In addition, a vortexed, ointmented sample disc was placed in the broth (zero time, t0) and the tube was vigorously mixed. This was done using vortex for the 20 mL sample and using hand shaking for the 100 mL sample. Overlapping, 1 mL aliquots were injected and plated at three time points: 1) immediately after (less than 1 minute), 2) 30 minutes after inoculation, and 3) 60 minutes after inoculation (all at room temperature). Plating was performed using Triptych Soy Agar (TSA). The plates were incubated at 36 ° C for up to 48 hours. Plates were counted to calculate CFU / mL. The data was converted to log10 CFU / mL. Both test samples and numbers Control) was tested. The number control consists of 100 μL of inoculum added to 20 mL of PBW (phosphate buffered water) to bring the microbial concentration to 10-100 CFU / mL. PBW was prepared as follows: 34 grams of potassium dihydrogen phosphate was dissolved in 500 mL of deionized water to prepare a standard solution. The pH of this was adjusted to 7.2 with 10N sodium hydroxide and then correctly diluted to 1 liter with deionized water. The standard solution was sterilized by filtration, divided into sterile bottles, and stored in a refrigerator. PBW was prepared by adding 1.25 mL standard solution to 1 liter of deionized water and steam sterilizing at 121 ° C for 25 minutes. After sterilization, the solution was mixed by shaking to ensure homogeneity. Toxicity control was also performed by adding 100 μL of the inoculum to 20 mL of neutralizing broth to a microbial concentration of 10-100 CFU / mL.

Neutralizer effectiveness: A neutralizer is considered effective if the test sample has a log10 CFU / mL of 0.3 logarithm or less than the corresponding number control.

Neutralizer toxicity: A sampled solution is considered non-toxic if the toxicity control (TC) is less than 0.3 logarithm less than the corresponding number control.

Test microorganisms for antibacterial activity test Test microorganisms for this assay were methicillin-resistant Staphylococcus aureus, MRSA (ATCC33953), Staphylococcus epidermidis (ATCC35984), and E. coli (ATCC11229). )Met. The first suspension was prepared by suspending bacterial colonies from plates grown overnight in phosphate buffered water (PBW). Using a 0.5 McFarland turbidity standard, a cell density of approximately 1.0 × 108 CFU / mL was obtained.

Test substance for antibacterial activity test Samples for this assay were spread on a clean, 70% isopropanol-sterilized 100 μm thick polyester terephthalate (PET) film biaxially oriented at room temperature using a laboratory knife coater, 10 The thickness of the mill (250 μm) was uniform. The coated samples were placed on sterile Petri dishes and sealed with Parafilm to prevent evaporation and maintain cleanliness. Spread samples containing various volatile solvents such as water were used within 24 hours after spreading. Test samples were cut from the same PET coating film using a 23 mm die disinfected with 70% isopropyl alcohol (IPA), which will be discussed in the next section. The sample discs were stored in sterile Petri dishes until tested.

Preparation of inoculum for antibacterial activity test Inoculate 10,000 times (10) with Phosphate Buffered Water (PBW)^-4) Continuously dilute to 1 ~ 5 × 10⁴The concentration was CFU / mL. Suspensions of the inoculum were counted at the beginning and end of the test period. The final count was in the range of 0.1 log / mL of the first count. 10 on each disc^6.5~10^7.5Inoculated among individual bacteria.

Neutralization broth: DE broth was Dey Engle broth, purchased as a solid, and dissolved according to the instructions of Difco Laboratoris in Detroit Michigan, Michigan. The DE broth was used in all of the disinfectants of the invention below: chlorhexidine gluconate (CHG), polyhexamethylene biguanide (PHMB), benzethonium chloride, benzalkonium chloride, Healthshield silver zeolite, silver nitrate. , Phospholipid CDM.

Measurement of antibacterial activity: After the first confirmatory neutralization, the samples were tested for antibacterial activity using an in vitro model that attempted to simulate conditions of use. Using sterile techniques and steam sterilized materials (excluding ointments), 23 mm discs were cut out from each formulation using a 23 mm 70% IPA sterilized die. The following three bacteria were tested: Staphylococcus aureus MRSA (ATCC33953), Staphylococcus epidermidis (ATCC35984), and E. coli (ATCC11229). Each inoculation was prepared by suspending bacterial colonies from plates grown overnight in phosphate buffered water (PBW). Using the McFarland turbidity standard, the cell density is approximately 1.0 x 10⁸CFU / mL was obtained. A 50 μL inoculum was quickly spotted (with 8-12 small droplets) on the surface of the test ointment. After dropping the last droplet, the bacterium was kept in contact with the ointment for a predetermined period of time (eg, 2.5 and 10 minutes). At the end of that exposure time (the time the bacteria were in contact with the composition), the inoculated disc was placed in a warm (36 ° C) neutralizer broth (DE, 20 mL) and mixed vigorously (VWR Vortex). Vortexed for 2 minutes with Jenny 2 (VWR Vortex Genie 2). Two 1/100 times diluted solutions were prepared in neutralized broth, and bacteria were counted using a pour plate. The plates were incubated at 36 ° C for up to 48 hours. Colony forming units (CFU) were counted.

Multiplying the CFU in each plate by the dilution factor gives CFU / mL, which was converted to log10 CFU / sample. The log10 reduction was calculated by averaging the log10 CFU / sample in the double-repeat test. The logarithmic reduction was calculated by subtracting the log10 bacterial recovery of the test substance from the control log10 bacterial recovery (100 μL inoculum in 20 mL warm D / E neutralized broth).

Most of the compositions of the invention were analyzed for their ability to kill MRSA and E. coli in 2.5 and 10 minutes. The selected compositions were analyzed for their ability to kill Staph Epi in 10 minutes. In contrast, with Bactroban Nasal ointment, virtually no killing of this strain of MRSA was observed in this assay at 2.5 minutes. (Logarithmic reductions were 0.030 and -0.040.) In fact, Bactroban Nasal showed virtually no death after 2 hours of contact. It is a great advantage that the compositions of the present invention are capable of rapidly killing microorganisms. With a suitable composition, at least a 1.5 logarithmic reduction is achieved in 10 minutes, more preferably at least 2 logarithmic reductions in 10 minutes, and most preferably at least 3 logarithmic reductions in 10 minutes. With a particularly preferred composition of the invention, at least a 1.5 logarithmic reduction is achieved in 2.5 minutes, more preferably at least 2 logarithmic reductions in 2.5 minutes, and most preferably at least 3 logarithmic reductions in 2.5 minutes.

Viscosity test In the selected embodiment, at an ambient pressure of approximately 22 ° C, a Model D Brookfield heliopath and a Brookfield LVDV-I with an LV spindle attached.⁺The viscosity was measured using a viscometer. A spindle and speed were selected for each specific sample and the viscometer was operated in the middle of its measurement range. Prior to measurement, all samples were equilibrated at approximately 22 ° C for 24 hours. Viscosity was measured at the lowest possible rate, preferably within 20-80% of the viscometer range, more preferably within 30-70% of that range. In all cases, sample size and container size were selected to prevent wall effects. The term "wall effect" means that the viscosity value is unaffected by the vessel, which is substantially equivalent to the viscosity measured in a substantially infinitely large vessel. For this reason, samples with lower viscosities require a larger sample size to accommodate larger spindles. For the viscosity of each sample, a heliopath adapter was used to adopt the maximum of the relatively stable readings obtained on the first pass across the spindle.

<tables num="1"><img file="JP5154933B2_D0003.tif" /></tables><tables num="2"><img file="JP5154933B2_D0004.tif" /></tables><tables num="3"><img file="JP5154933B2_D0005.tif" /></tables>

The emulsified polymer GG was prepared by the following method. A mixture of isooctyl acrylate (IOA, 21.6 parts) and MPEG (5.4 parts) [IOA / MPEG (80/20), each weight ratio] is mixed with VAZO 67 radical initiator (0.081 parts) in ethyl acetate (0.081 parts). It was dissolved in 33 parts). The solution was placed in a flint glass bottle, covered with a metal cap lined with Teflon® and kept at 65 ° C for 50 hours. At 50 hours, the conversion of the monomers (measured by percentage solids from the loss when dried at 105 ° C) was virtually complete. Solvent exchange was performed by adding isopropyl palmitate (IPP) to the ethyl acetate solution and distilling off low boiling point ethyl acetate on a ROTOVAP evaporator to give a 25 weight percent solution of the polymer in IPP. It was.

Polymer QQ was prepared by the following method. A mixture of SMA (10.8 parts), IOA (10.8 parts), and M90G (5.4 parts) [each by weight 80/20], ethyl acetate (33 parts) containing VAZO 67 radical initiator (0.081 parts) Part) was dissolved. The solution was placed in a flint glass bottle, covered with a metal cap lined with Teflon® and kept at 65 ° C for 50 hours. At 50 hours, the conversion of the monomers (measured by percentage solids from the loss when dried at 105 ° C) was virtually complete. Solvent exchange was performed by adding isopropyl palmitate (IPP) to the ethyl acetate solution and distilling off low boiling point ethyl acetate on a ROTOVAP evaporator to give a 25 weight percent solution of the polymer in IPP. It was.

Preparation of Examples: Example compositions were prepared according to the following procedure. These example samples were tested by antibacterial activity test for 2.5 and 10 minutes for both MRSA and E. coli, or 10 minutes for Staph Epi. Was done.

Control example C1 ~ C2 For each example, 250 grams each of antibacterial control compositions were prepared using the ingredients shown in Table 2a. In the first glass container, Carbowax 1450 PEG was heated in a furnace to dissolve it. In a second glass container, glycerin, Carbowax 400 and Aerosol OT-75DOSS were also heated to 70 ° C. The contents of the second container were added to the first container, shaken by hand, mixed and reheated to 70 ° C. The composition was removed from the furnace and allowed to cool while mixing on a roller to at least about 40 ° C.

Examples 1-9 Using the ingredients shown in Tables 2a-2b, 125 grams of antibacterial composition was prepared. In Examples 1 to 6, the disinfectant components silver zeolite, phospholipid CDM, Irgasan DP300, benzethonium chloride, or benzalkonium chloride were added to the first glass container in Pluronic P-. Combined with 65 and glycerin, heated in a furnace to 70 ° C. Heat and melt the Carbowax 1450 in a separate container, then add it to the first container with the rest of the ingredients, shake by hand to mix, then reheat in the oven. It was set to 70 ° C. The composition was removed from the furnace, mixed on a roller, allowed to cool to about 40 ° C, then transferred into a jar and sealed. Examples 7-8 containing PHMB and Example 9 containing CHG were prepared in the same manner as above, but without the need for initial heating, these disinfectants combine all other ingredients. Added after.

Examples 1-9 include hydrophilic vehicles containing a mixture of PEG compound and glycerin. Examples 1 and 2 contain a quaternary ammonium compound as an antibacterial agent for phospholipid CDM. Antibacterial activity against both MRSA and E. coli was higher than 3 log in 2.5 minutes in Example 1. In Example 2, EDTA is further incorporated as an enhancer. Despite the anionic nature of this enhancer, it improved the antibacterial activity of its quaternary ammonium compound. In Example 2, MRSA was given 3.9 logarithm death and E. coli was given 7.1 logarithm (complete death) in 2.5 minutes. Examples 3 and 6 contain the antibacterial quaternary ammonium compounds benzethonium chloride and benzalkonium chloride, respectively. The compositions showed higher than 2 log mortality rates for MRSA and E. coli after 2.5 minutes of exposure. In Example 5, a quaternary ammonium compound (benzalkonium chloride) and a phenolic disinfectant (triclosan) were both used in combination at low concentrations, but after 2.5 minutes of exposure, 3.9 pairs for MRSA. The mortality rate of E. coli was 5.2 pairs. In Example 4, a silver / zeolite complex was used. This composition did not reach a two-logarithmic mortality rate for either MRSA or E. coli after 2.5 minutes of exposure, because silver was fast enough. Because it was not released. In contrast, in Example 10 with silver nitrate (below), after 2.5 minutes of exposure, the mortality rate was 6.3 logarithm for MRSA and 4.8 logarithm for E. coli. Death rate was obtained. In Examples 7 and 8, PHMB was used at 0.2 and 5%, respectively. These compositions were completely dead (6.8 logarithmic) against MRSA and at least 4. E. coli after 10 minutes of exposure. An 8 logarithmic mortality rate was obtained. Example 9 contained a total of 1.9% CHG (18.9% solution x 10.4% by weight = 1.9%), but this composition had 3.1 logarithmic MRSA and 6.1 logarithmic after 2.5 minutes of exposure. It was the E. coli mortality rate.

Example 10 250 grams of antibacterial composition was prepared using the ingredients shown in Table 2b. Carbowax 1450 was preheated in a furnace to melt (about 65 ° C) and placed in a glass container. All other ingredients except silver nitrate were combined with the Carbowax 1450 and hand shaken to mix. The composition was allowed to cool to about 50 ° C, and then silver nitrate was added. The solution was allowed to cool further to about 40 ° C and then transferred to a light-blocked storage jar.

Examples 11-14 Each 120 grams of antibacterial composition was prepared using the ingredients shown in Table 2c. Vaseline was added to the first glass container and heated in a furnace to about 70 ° C. All other ingredients were added to the second glass vessel, which was also heated in the furnace to about 70 ° C. The component mixture in the second vessel was then added to the first vessel and further mixed at high speed for 1 minute using a high shear rotor / stator Silverson homogenizer. Slow agitation was continued using a Gast overhead air mixer with radial agitation blades until just before the composition solidified at about 40 ° C. The composition was removed from the mixer, poured into a jar and sealed.

Examples 11-14 were blended in a hydrophobic vehicle. Example 11 incorporates CHG as a disinfectant and glycerin as a hydrophilic component, 4.4 logarithm and 7.1 for MRSA and E. coli, respectively, after 2.5 minutes of exposure. A logarithmic mortality rate was obtained. Examples 12 and 13 contained phospholipid CDM as a disinfectant and glycerin as a hydrophilic component. Example 12 further included the surfactant Pluronic P-65. The antibacterial activity of Example 12 was 4.2 log and 2.9 log mortality rates against MRSA and E. coli, respectively. The antibacterial activity of Example 13 was 5.7 log and 6.3 log, respectively, against MRSA and E. coli, respectively.

Examples 15-16 Examples 15 to 16 also shown in Table 2c were prepared in the same manner as in Examples 11 to 14 described above, except that benzalkonium chloride was added to petrolatum before heating. In Examples 11 to 16, petrolatum is used as a hydrophobic vehicle.

Example 15, incorporating glycerin as a hydrophilic component, was completely killed against both MRSA and E. coli after 2.5 minutes of exposure. In Example 16 without the incorporation of hydrophilic components, no logarithmic mortality was reached for either MRSA or E. coli after 2.5 minutes of exposure.

Control Examples C3, C4 and Examples 17-18 Control Examples C3 to C4 and Examples 17 to 18 without the disinfectant and CHG antibacterial composition were prepared in an amount of 250 grams using the ingredients shown in Table 2d for each example. Vaseline was used as a hydrophobic vehicle, added to the first glass container and heated in a furnace to about 70 ° C. All other ingredients were added to the second glass vessel, which was also heated in the furnace to about 70 ° C. The component mixture in the second vessel was then added to the first vessel and further mixed at high speed for 1 minute using a high shear rotor / stator Silverson homogenizer. Slow agitation was continued using a Gast overhead air mixer with radial agitation blades until just before the composition solidified at about 40 ° C. The composition was removed from the mixer, poured into a jar and sealed.

In Examples 17 and 18, CHG was used as a disinfectant component. Note that CHG was incorporated as an aqueous solution. Examples C3 and C4 were vehicle controls. After 2.5 minutes of exposure, Example 17 had a 2.5 log mortality rate and a 4.8 log mortality rate for MRSA and E. coli, respectively.

Examples 19-21 The ingredients shown in Table 2d were used to prepare 120 grams of each antibacterial composition. Vaseline was added to the first glass container and heated in a furnace to about 70 ° C. All other components except CHG were added to the second glass vessel and heated in a furnace to about 50 ° C. The contents of the second container were added to the first container and the container was shaken by hand to mix. CHG was then added and the mixture was shaken by hand to mix.

Note that the disinfectant component CHG was incorporated as an aqueous solution. Several enhancers were evaluated, including lactate / propylparaben and Dowanol ether. A 10-minute exposure resulted in a mortality rate of at least 2.5 logarithms for both MRSA and E. coli in all three examples.

Control Example C5, Examples 22-26 Using the ingredients shown in Table 2e, control example C5 without disinfectant and examples of antibacterial compositions were prepared in an amount of 120 grams each. Water, glycerin and Lurol ASY were added to a glass vessel and heated in a furnace to about 70 ° C. In Examples 22, 25-26, the pH was adjusted to about 4.5 with sodium hydroxide. All the remaining ingredients were added to the second glass container, shaken by hand and heated in a furnace to about 110 ° C. The contents of the first vessel were then added to the second vessel and a high shear rotor / stator Silverson homogenizer was used at high speed to mix for about 1-2 minutes. Each composition was placed in a steam bath and mixed at low speed using a Gast overhead air mixer with radial stir blades. In Examples 22-26, CHG was then added, followed by again using a Silverson homogenizer for high speed shear mixing for about 1-2 minutes. Mixing was continued using a Gast overhead air mixer until the temperature of the composition fell below 40 ° C.

These examples are water-in-oil emulsions. In Examples 24-26 incorporating an anionic phosphate surfactant (Lurol ASY), at least 3 logarithmic mortality rates were obtained for one of the test microorganisms. In Examples 25 and 26, lactic acid was further incorporated, and a mortality rate of more than 6 logarithms was obtained for Staphylococcus epidermidis.

Examples 27 ~ 32 250 grams of antibacterial composition was prepared using the ingredients shown in Table 2f. A mixture of Polawax, mineral oil, Incroquat Behenyl TMS and Centroflex F was added to the first container and heated in a furnace to 70 ° C. Water was heated to 70 ° C in another container. The water was added to the first container, and finally CHG or Cosmocil CQ was further added. Each composition was mixed at high speed for 1 minute using a high shear rotor / stator Silverson homogenizer.

These examples are oil-in-water emulsions containing CHG or PHMB as a disinfectant. In Example 27, which did not contain lecithin, 6.7 and 7 log mortality rates were obtained for MRSA and E. coli in 2.5 minutes. Example 28 (2% total CHG) contained lecithin. Lecithin partially inactivates CHG and is significantly less effective against both MRSA and E. coli. Example 30 (only 0.1% of all CHGs) was able to kill E. coli at 2.5 logarithms on a 10-minute exposure, despite low CHG levels. Example 31 was similar to Example 30, but contained lecithin. Apparently CHG was neutralized by lecithin, due to its virtually no antibacterial activity and the observed growth of bacteria in the sample upon standing. I understand. The sample was not intentionally inoculated. Example 32 contained high levels of CHG (0.5% total CHG), but due to the presence of lecithin, a mortality rate lower than 0.5 log was obtained for the test microorganism.

Control Example 6C, Example 33 Control Example 6C and Antibacterial Composition Example 33 were prepared in an amount of 250 grams using the ingredients shown in Table 2g. Benzethonium chloride (Example 33 only) was combined with Ceraphyl 494 in a container and heated in a furnace to about 80 ° C. Pluronic P-65 and AC540 were added to the vessel, shaken briefly by hand and then further heated in the oven to about 110 ° C. The composition was removed from the furnace, shaken by hand and allowed to cool without agitation.

In Example 33, Ceraphyl 494 was used as the hydrophobic vehicle, but MRSA was completely killed in 2.5 and 10 minutes, and E. coli was treated after 10 minutes. It showed a 4.4 logarithmic mortality rate.

Preparation of antibacterial composition: Tables 2a-2g show the respective components in the compositions of each Example in weight / weight% concentration, and further show their antibacterial activity results. "NT" in the test result means "not tested".

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<tables num="5"><img file="JP5154933B2_D0007.tif" /></tables>

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Placebo Subject Acceptability: First Panel Evaluation A panel of 10 healthy volunteers over the age of 18 evaluated the ingredient composition without active disinfectant to examine its tolerability and develop evaluation test methods for future evaluation.

The evaluated compositions are shown in Table 3.

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Procedure of test The dose was 0.5 mL of composition W or X and was applied using a pre-filled 1 mL plastic injectable tube. Volunteers applied the first dose after seeing a demonstration of the technique. Volunteers applied second and third doses during the first day.

On the first day, half of the volunteers (5) were given composition W, and the other half of the volunteers were given composition X, before and after the first day of administration, and 24 hours after the second day. Later, a nasal examination was performed. On the 8th day, the volunteers who received the composition W on the 1st day received the composition X, and those who received the composition X on the 1st day received the composition W. They underwent nasal examination before and after administration on day 8 and 24 hours after day 9.

Volunteers were surveyed on the 1st and 9th days.

result: All 10 volunteers successfully completed both trial periods. A descriptive analysis was performed on the categorical variables in this trial.

Composition W was well received by 10 out of 10 volunteers. Five of the ten volunteers were unable to complete three applications for Composition X. The main reasons they cited were irritation, burning sensation and runny nose. Composition X caused rhinorrhea more than composition W. Volunteers using Composition X felt that the ointment was available for less time than in Composition W. I felt that Composition W stayed in the vestibule of the nose for a longer time (average 218 minutes) than Composition X (average 145 minutes).

Placebo Subject Acceptability: Second Panel Evaluation A second panel evaluation was performed to determine the tolerability of a substantially anhydrous ointment based on a hydrophobic vehicle containing lactic acid or mandelic acid. The criteria for this panel were the same as for the first panel. The evaluated compositions are shown in Table 4.

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The test procedure was the same as that used for the first panel, except that the composition was applied using a cotton swab instead of a tube.

result: Both ointments were acceptable with few side effects. The preference for the two ointments was quite divided into two. Four of the ten volunteers said the mandelic acid composition was slightly better, three of the ten volunteers said the lactic acid composition was slightly better, and ten volunteers. Three of them said that there was no difference in their composition.

A 0.5 mL composition was applied to each volunteer, but always about 0.1 g remained in the swab. Therefore, the dose was about 0.2 mL per nasal cavity. It has been pointed out that the amount of time the ointment stays in the volunteer's nose varies from volunteer to volunteer, but the ointment stays there for up to 24 hours. Two volunteers reported that they felt that the ointment was accumulating with each application.

The feel and odor of the ointment in the nose were the most annoying properties of any ointment, but all of these properties were acceptable.

Viscosity test results The viscosities of the selected Example compositions are shown in Table 5. These were tested at approximately 22 ° C (72 ° F) according to the viscosity test method.

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All disclosures of patents, patent documents, and publications cited herein are incorporated herein by reference in their entirety, as if they were individually incorporated. Various modifications and modifications of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. It is not intended that the invention is unreasonably limited by the explanatory embodiments and examples referred to herein, and those embodiments and embodiments are presented for illustration purposes only. However, it should be understood that the scope of the invention is limited only by the claims mentioned earlier herein.