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    • 专利摘要:
    The present invention relates to methods and materials for reducing infections in individuals. The methods and materials use chlorhexidine, which has surprisingly been found to be non-toxic. The absence of toxicity facilitates the use of chlorhexidine in settings that previously were not believed to be possible.
    公开号:BR112016013199A2
    申请号:R112016013199-1
    申请日:2014-12-12
    公开日:2020-06-30
    发明作者:Carolyn L. TWOMEY；Gareth CLARKE；Samuel J. ZAIDSPINER
    申请人:Innovation Technologies, Inc.；
    IPC主号:
    专利说明:

    [0001] [0001] This Order claims the priority benefit of United States Provisional Order Serial No. 61 / 915.281, deposited on December 12, 2013, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION
    [0002] [0002] The management and treatment of a wound, a surgical site, a surgical incision or otherwise tissue prone to infection in the body has three primary objectives: (1) infection prevention, (2) preservation and / or restoration function and (3) preservation and / or restoration of aesthetic appearance. The most important of these goals is the prevention of infection. Success in preventing infection directly affects the healing process and the degree to which function and aesthetic appearance can be preserved and / or restored.
    [0003] [0003] The number and virulence of bacteria present in a site are critical determinants for the site to become infected. Experimental evidence suggests that a critical level of bacteria is approximately 10º organisms per gram of tissue. Below this level, a site or tissue typically heals; at levels above 10º bacteria per gram of tissue, infections often develop. It is likely that dirty wounds or wounds that have not been treated within six hours will be contaminated with bacteria at levels that are greater than the critical level. Reducing the number of bacteria in and around the wound is essential to prevent infection and accelerate wound healing.
    [0004] [0004] Methicillin-resistant Staphylococcus aureus infection (Methicillin-Resistant Staphylococcus Aureus - MRSA) is caused by Staphylococcus aureus bacteria - often called "staph."
    [0005] [0005] Tight bacteria, in general, are harmless unless they enter the body through a cut or other wound. In older adults and people who are sick or have weakened immune systems, stress infections. common conditions can cause serious illness. Strain infections, including MRSA, occur more frequently among people in hospitals and health facilities, such as nursing homes and dialysis centers, who have weakened immune systems; however, in the 1990s, a type of MRSA began to appear in a wider community. Today, this form of stress, known as community-associated MRSA, or CA-MRSA, is responsible for many serious infections of the skin and soft tissues and a severe form of pneumonia. If not treated properly, MRSA infection can be fatal.
    [0006] [0006] MRSA infections in the community usually manifest themselves as infections of the skin, such as pimples and boils. These CA-MRSA infections can occur in healthy people and commonly occur among athletes who share equipment or personal items, including towels and razors. In fact, from 2000 to the present, there have been several outbreaks of CA-MRSA affecting high school and professional sports teams. This epidemic among athletes is helped by the fact that MRSA grows very quickly in hot and humid areas, such as gyms and dressing rooms in exercise rooms. Common cuts and abrasions, such as
    [0007] [0007] MRSA infections are spreading rapidly in the United States and worldwide. According to the Center for Disease Control and Prevention (CDC), the proportion of infections that are resistant to antimicrobials has been increasing. In 1974, MRSA infections were responsible for two percent of the total number of infections caused by stress; in 1995, it was 22%; and, in 2004, it was almost 63%. In addition, recent research suggests that 30-50% of the population carry MRSA colonies on their bodies at all times, helping to facilitate the spread of infection.
    [0008] [0008] Vancomycin is one of the few antibiotics still effective against hospital strains of MRSA infection, although the drug is no longer effective in all cases. Several drugs continue to work against CA-MRSA, but CA-MRSA is a bacterium that evolves quickly and can be a matter of time before it also becomes resistant to most antibiotics.
    [0009] [0009] Chlorhexidine is a chemical antiseptic and combats both Gram-negative and Gram-positive microbes. It is bacteriostatic, preventing the growth of bacteria, and bactericidal, killing bacteria. It is often used as an active ingredient in mouthwashes designed to kill dental plaque and other oral bacteria. Chlorhexidine also has non-dental applications. For example, it is used for cleaning the skin in general, as a surgical scrub and as a preoperative preparation for the skin. Chlorhexidine is typically used in the form of acetate, gluconate or hydrochloride, either alone or in combination with other antiseptics, such as trimethers.
    [0010] [0010] The use of chlorhexidine in wound irrigation applications has been previously described. See, for example, United States Published Order No. 2011-0288507A and United States Published Order No. 2011-0097372A, both of which are incorporated herein by reference in their entirety. BRIEF SUMMARY OF THE INVENTION
    [0011] [0011] The present invention provides materials and methods for preventing or treating an infection by administering a disinfectant composition comprising chlorhexidine, directly or indirectly, to the site of the infection or potential infection. In preferred modes, the disinfectant composition is sterile.
    [0012] [0012] Advantageously, it has been found that solutions containing chlorhexidine can be administered to an individual according to the present invention without causing hemolysis or other deleterious effects on the blood, blood cells or vascular system. In addition, when administered according to the procedures of the present invention, the chlorhexidine-containing solutions of the present invention do not result in deleterious chlorhexidine absorption, systemic toxicity or fibrosis. In addition, the compositions of the present invention can be applied to the tissue of the nervous system, including the tissue of the central nervous system (Central Nervous System - CNS), without causing deleterious effects.
    [0013] [0013] Based on these findings, it is now possible to use solutions containing chlorhexidine in new and advantageous forms, as described here, to effectively treat and / or prevent infections in a wide variety of tissues and locations in an individual.
    [0014] [0014] Advantageously, the antimicrobial compositions of the present invention are useful against drug resistant microbes, including MRSA. In addition, microbes do not readily acquire resistance to the treatments of the present invention.
    [0015] [0015] In a preferred embodiment, the active agent is chlorhexidine gluconate, preferably in a concentration of about 1.0% or less, more preferably about 0.1% or less and, even more preferably, about 0.05% or less and, for some uses, 0.02% or less. Chlorhexidine dissolved in pure water or a solution containing salt, for example, saline, can be used according to the present invention.
    [0016] [0016] In certain modalities, the administration of the solution containing chlorhexidine is followed by a rinse, for example, with saline solution. In other modalities, such a rinse is not applied. In certain modalities, such as in the case of surgery and / or irrigation of a body cavity, the administration of chlorhexidine can be followed by suction. Suction can be applied, for example, 1 to minutes after chlorhexidine is administered.
    [0017] [0017] The aqueous solution, or other material, containing chlorhexidine may have other components including, for example, pH modifiers, buffers, local anesthetic agents, agents that promote wound healing (such as agents that help to degrade bio-film), agents that stop bleeding and / or promote the formation of clots and other therapeutic and non-therapeutic components. In one embodiment, the composition "essentially consists" of an aqueous CHG solution, which means that the solution does not contain any other active agents that materially alter the solution's ability to control microbial growth.
    [0018] [0018] The disinfectant composition of the present invention can be used in a variety of applications aimed at preventing and / or treating infections. The treatment can be applied, for example, to a surgical site, a surgical incision on the skin, blood, urogenital tract, an implant, a joint, the respiratory tract, an intraperitoneal site, an eye site, the colon, the sinuses, an intra-articular site, a site in the mediastinum, a site in scar tissue,
    [0019] [0019] The present invention also provides kits and containers comprising the disinfectant composition and equipment or devices for administering the disinfectant composition to the individual. In preferred embodiments of the composition, the kits and containers are sterile. DETAILED DESCRIPTION OF THE INVENTION
    [0020] [0020] The present invention provides materials and methods for preventing and / or reducing the development of an infection or treating an existing infection at a location in an individual. The individual can be, for example, a human being or another animal.
    [0021] [0021] Chlorhexidine-containing solutions can be administered to an individual, in accordance with the present invention, without causing hemolysis or other deleterious effects on the blood, blood cells or vascular system. In addition, when administered according to the procedures of the present invention, the solutions containing chlorhexidine of the present invention do not result in deleterious absorption of chlorhexidine, systemic toxicity or fibrosis. In addition, the compositions of the present invention can be applied to the tissue of the nervous system, including the tissue of the central nervous system (Central Nervous System - CNS), without causing deleterious effects.
    [0022] [0022] Based on these results, it is now possible to use solutions containing chlorhexidine in new and advantageous forms, as described here, to effectively treat and / or prevent infections in a wide variety of tissues and locations in or on a individual.
    [0023] [0023] Advantageously, the antimicrobial compositions of the present invention are useful against drug-resistant microbes, including MRSA. In addition, microbes do not acquire resistance to the treatments of the present invention.
    [0024] [0024] In one embodiment, the method of the present invention comprises the steps of: (a) providing a sterile disinfectant composition comprising an active agent comprising chlorhexidine in a concentration of about 1% or less, and (b ) administration of the sterile disinfectant composition, directly or indirectly, to the location in the individual.
    [0025] [0025] The location to which chlorhexidine is applied can be any location that is at risk of developing an infection or has an existing infection. Examples of sites that are suitable for practicing the method of the present invention include surgical sites, surgical incisions on the skin, blood, urogenital tract, implants, the respiratory tract, intraperitoneal sites, eye infections, the colon, the sinuses , an intra-articular site, a site in the mediastinum, an intracranial, cerebrospinal, or other nerve system tissue.
    [0026] [0026] Advantageously, the disinfectant composition of the invention is effective in combating infection, even when biological materials (including blood, tissue and / or dirt and debris) are present.
    [0027] [0027] The sterile disinfectant composition of the present invention contains an active agent which preferably comprises chlorhexidine in a concentration of less than about 1%, less than about 0.1%, less than about 0, 05%, less than about 0.025% or less than about 0.02%. Chlorhexidine can be, for example, chlorhexidine gluconate (ChlorHexidine Gluconate - CHG), chlorhexidine acetate, chlorhexidine hydrochloride or a combination thereof. Chlorhexidine can also be modified, for example, with a phosphate group to improve effectiveness, further reducing the likelihood of the development of resistant microbes. The disinfectant composition may still contain one or more active agents
    [0028] [0028] In specific embodiments, the compositions of the present invention can be used to prevent or reduce the formation of biofilm, for example, in the context of surgical implants, stents, catheters and other long-term medical devices. Solutions containing chlorhexidine can be used to reduce biofilm formation in other settings including, for example, biofilm associated with sinus infections and conjunctivitis.
    [0029] [0029] In certain modalities, chlorhexidine can be incorporated into a long-term medical device itself and / or a coating that can be applied to such a device. If desired, chlorhexidine can be released over time through the use, for example, of a hydrogel or other suitable polymer. In specific modalities, chlorhexidine can preferably be released in the presence of an infection. This can be achieved, for example, by incorporating chlorhexidine in a material that releases chlorhexidine when a pH change associated with the presence of bacteria occurs.
    [0030] [0030] Other embodiments of the present invention include nasal sprays or other forms of nasal irrigation solutions to facilitate nasal irrigation to treat infections, including those caused by antibiotic resistant microbes, such as MRSA. In one embodiment, the invention provides a method for treating a nasal infection by administering, to an individual who has been diagnosed with a nasal infection, a solution that contains an anti-infective amount of chlorhexidine. In one embodiment, chlorhexidine is CHG. In another specific embodiment, the infection is an MRSA infection.
    [0031] [0031] In another embodiment, the compositions of the present invention can be used to prevent or reduce eye infections.
    [0032] [0032] Other uses include the administration of chlorhexidine in the context of breast implants or collagen implants to reduce the likelihood of infection and the need for subsequent surgery.
    [0033] [0033] The chlorhexidine solutions of the present invention can also be used, according to the invention, to disinfect acupuncture needles, earrings and other penetrating objects that can be inserted into the body afterwards.
    [0034] [0034] In addition, an urogenital tract irrigation system can be used to administer the sterile disinfectant composition to the individual's urogenital tract.
    [0035] [0035] The disinfectant composition of the invention can also be administered to the individual's respiratory system.
    [0036] [0036] In addition, a cerebrospinal irrigation system can be used to deliver the sterile disinfectant composition to a location in an individual's nervous system.
    [0037] [0037] The use of CHG in wound irrigation applications has been previously described. See, for example, United States Published Order No. 2011-0288507A and United States Published Order No. 2011-0097372A, both of which are incorporated herein by reference in their entirety. These Patent Applications describe various uses of solutions that contain CHG. In certain embodiments, the materials and compositions of the present invention specifically exclude those uses that have been described in United States Published Orders No. 2011-0288507A and 2011-0097372A.
    [0038] [0038] The terms "about", "approximately", "approximate" and "around" are used in the present patent application to describe some quantitative aspects of the invention, for example, the concentration of the active agent. It should be understood that absolute precision is not necessary in relation to these aspects for the invention to work. When these terms are used to describe a quantitative aspect of the invention, the relevant aspect can be varied up to + 10%. Thus, the terms "about", "approximately", "approximate" and "around" allow variation of the various quantitative aspects described in the invention by + 1%, + 2%, + 3%, + 4%, + 5%, + 6%, + 7%, + 8%, + 9% or even + 10%. For example, a sterile disinfectant composition comprising about 1% active agent can contain from 0.9% to 1.1% active agent.
    [0039] [0039] Advantageously, the disinfectant composition of the invention is effective in combating infection, even when biological materials (including blood, tissue and / or dirt and debris) are present. FORMULATIONS
    [0040] [0040] In an embodiment of the present invention, a low chlorhexidine concentration solution can be used to prevent or treat infections effectively. Advantageously, it has been found that solutions containing chlorhexidine can be administered to an individual, according to the present invention, without causing hemolysis or other deleterious effects on the blood, blood cells or vascular system. In addition, when administered according to the procedures of the present invention, the chlorhexidine-containing solutions of the present invention do not result in deleterious chlorhexidine absorption, systemic toxicity or fibrosis. In addition, the compositions of the present invention can be applied to the tissue of the nervous system, including the tissue of the central nervous system (Central Nervous System - CNS), without causing deleterious effects.
    [0041] [0041] Based on these findings, it is now possible to use solutions containing chlorhexidine in new and advantageous forms, as described here, to effectively treat and / or prevent infections in a wide variety of tissues and locations in an individual.
    [0042] [0042] In specific embodiments, the concentration of chlorhexidine is less than about 2%, less than about 1%, or less than about 0.1%. In another embodiment, the concentration of chlorhexidine is less than about 0.05%. In still other modalities, the concentration of chlorhexidine is between 0.02% and 0.05%. Specifically exemplified here is the use of CHG.
    [0043] [0043] In a specific embodiment, the CHG used in accordance with the present invention has the following chemical structure: HN 6 NH
    [0044] [0044] The pH of the disinfectant composition is preferably neutral or slightly acidic. Preferably, the pH is 5.0 to 7.5. Most preferably, the pH is 5.5 to 7.0.
    [0045] [0045] In a preferred embodiment, administration of the disinfectant composition of the present invention to the site of infection results in a reduction in the number of bacteria or other microbes at the site when compared to an untreated site or a site to which solution has been administered saline or water that does not contain chlorhexidine. Advantageously, the administration of the disinfectant composition according to the present invention can result in the effective control of an infection without causing tissue damage.
    [0046] [0046] Examples of additional active agents that can be administered to an individual according to the present invention include, but are not limited to, antibacterial agents, antiviral agents, fungicidal agents, chemotherapeutic agents, topical antiseptics, anesthetic agents, fluids and / or oxygenated agents, antibiotics, diagnostic agents, homeopathic agents, agents that stop bleeding and over-the-counter drugs / agents. In one embodiment, the additional agent may be an antimicrobial peptide (Anti-Microbial Peptide - AMP). AMPs are well known in the art.
    [0047] [0047] In certain embodiments, the additional agent is a diagnostic agent. The diagnostic agent can be, for example, an antibody, protein or polynucleotide that binds to a target biomolecule. Such a link can then be visualized using technologies known to those skilled in the art.
    [0048] [0048] For the purposes of the present invention, a pure aqueous solution of the active agent comprises the active agent and / or a second agent in an aqueous solution that is essentially devoid of solutes that give osmolarity to the solution, for example, a salt or a sugar . For the purposes of the present invention, an isotonic solution refers to a solution that has the same osmotic pressure as blood. Typically, isotonic solutions contain about 0.85% NaCl in water. Consequently, an isotonic solution containing the active agent according to the present invention refers to a solution of the active agent and / or a second agent in NaCl at about 0.85% in water. Activity Spectrum
    [0049] [0049] Chlorhexidine is active against gram-positive and gram-negative aerobic and anaerobic bacteria. Chlorhexidine also has activity against Chlamydia trachomatis, certain fungi and certain viruses.
    [0050] [0050] Chlorhexidine is highly active against a variety of aerobic Gram-positive bacteria, including mutants of Streptococcus, S. pyogenes (group A of B-hemolytic streptococci), S. saliva- rius and S. sanguis. Chlorhexidine is active against Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis and S. simulans. Chlorhexidine is active both against oxacillin resistant staphylococci (Oxacillin-Resistant Staphylococcus Aureus - ORSA) and oxacillin sensitive (also known as methicillin resistant staphylococci [MRSA] or sensitive to methicillin). Chlorhexidine is active against Enterococcus, including E. faecalis and E. faecium, and is active against both strains susceptible to vancomycin and resistant to vancomycin.
    [0051] [0051] Chlorhexidine is also active against some anaerobic bacteria. Chlorhexidine is active against some strains of Bacteroides, Propionibacterium, Clostridium difficie and Selenomonas, but is less active against Veillonella.
    [0052] [0052] Chlorhexidine has activity against Candida albicans, C. dubliniensis, C. glabrata (formerly Torulopsis glabrata), C. guillermondii, C. kefyr (formerly C. pseudotropicalis), C. krusei, C. lusitaniae and C. tropicalis (formerly C. parapsilosis). Chlorhexidine also has activity against dermatophytes, including Epidermophyton flocco-sum, Microsporum gypseum, M. canis and Trichophyton mentagrophytes.
    [0053] [0053] Chlorhexidine also has antiviral activity against viruses that have a lipid component in their outer coating or have an outer envelope, such as cytomegalovirus (CytoMegaloVirus - CMV), human immunodeficiency virus (Human Immunodeficiency Virus), herpes simplex virus from types 1 (HSV-1) and 2 (HSV 2), influenza virus, parainfluenza virus and smallpox virus ("small-pox" virus).
    [0054] [0054] In addition to killing bacteria, the sterile disinfectant composition of the present invention can also "depatogenize" certain bacteria including, for example, Escherichia coli and Klebsiella aerogenes, making these bacteria less potent to cause infection.
    [0055] [0055] In a preferred embodiment, administration of the disinfectant composition of the present invention to the site of infection results in a reduction in the number of bacteria or other microbes at the site when compared to an untreated site or a site to which solution has been administered saline or water that does not contain chlorhexidine. Advantageously and unexpectedly, administration of the disinfectant composition according to the present invention can result in effective control of an infection without causing tissue damage. Administration Modes
    [0056] [0056] The methods of the present invention can be used in conjunction with the delivery of a solution containing chlorhexidine via many routes. Of particular interest are: cutaneous, intra-abdominal, intracranial, intralesional, intrathoracic (during surgery), nasal, to the ear canal, as an oral intestinal preparation, gastric lavage, as an eye drop, periodontal, rectal, soft tissue , subcutaneous and vaginal.
    [0057] [0057] The chlorhexidine solutions of the present invention can be administered using any of a wide variety of devices, systems and delivery methods currently available. These include delivery via a catheter to treat a range of pathologies, or potential pathologies including, but not limited to, urinary tract infections, bloodstream infections, intracranial infections and joint infections. In certain conditions, the chlorhexidine solution can be administered via a syringe to treat and / or prevent spinal cord infections including, but not limited to, for example, meningitis.
    [0058] [0058] The chlorhexidine solutions of the present invention can also be formulated as a spray or a nebulizer to treat suitable sites, such as chronic wounds and burns, or for nasal administration.
    [0059] [0059] In another embodiment, the present invention provides soap for the entire body or parts of the body to disinfect an individual who has been, or is suspected to have been, exposed to a pathological agent such as, for example, in the context of a biological weapon.
    [0060] [0060] The chlorhexidine solution of the present invention can also be formulated for inhalation, for example, by people who are suffering from pneumonia or other respiratory tract infections. In a specific modality, the chlorhexidine solution is formulated for inhalation by patients with cystic fibrosis (Cystic Fibrosis - CF) who have developed a lung infection or who are at risk of developing such an infection. In a specific modality, the individual was diagnosed with (CF).
    [0061] [0061] In another embodiment, chlorhexidine can be incorporated into a material that can be used to disinfect the skin and other body surfaces including, for example, the ear canal. The material can be, for example, a scarf, fabric or a cotton swab. Preferably, the handkerchief, fabric, cotton swab or other material containing chlorhexidine can be formulated for use even on sensitive skin, such as the skin of babies or the elderly. Such handkerchiefs, fabrics, swabs and other materials can then be used in lieu of soaps or showers for individuals who cannot use a shower or take a bath easily. In specific embodiments, the material in which chlorhexidine has been incorporated does not include alcohol or includes less than 1% or less than 5% alcohol.
    [0062] [0062] Examples of tissues for body cleaning include United States Patent No. 5,725,311; 5,906,278; 5,956,794;
    [0063] [0063] In an embodiment of the present invention, the sterile disinfectant composition can be administered to an internal surgical site (or other site of potential infection or infection) by depositing a porous material containing the active agent that releases the active agent to the over a period of time on site. The presence of the active agent in and around the site can prevent and / or treat an infection. The porous material that contains the active agent can be administered to a surgical site when the surgery is performed. In certain modes of the invention, the porous material is a disc, a sphere or a shape designed to fit the location.
    [0064] [0064] The porous material containing the active agent can release the active agent over a period of about 1 hour to about 6 months, about 2 months to about 5 months, about 3 months to about 4 months, about | week to about 4 weeks, about 2 weeks to about 3 weeks or any other permutation of these time periods.
    [0065] [0065] Non-limiting examples of materials that can be used to produce porous implants include feldspar silicate matrix, hydroxyapatite, porous titanium or sponge. Other examples of materials suitable for producing extended-release implants are well known to those skilled in the art and such materials are within the scope of the present invention. For example, hydrogels or other such coatings that incorporate chlorhexidine in them can also be used.
    [0066] [0066] In preferred embodiments of the invention, the disinfecting composition is administered to a site of scar tissue. For the purposes of the present invention, a scar tissue site is an area of tissue that has suffered an injury or illness and is recovering after treatment for the injury or illness. A scar tissue site can be on the surface of the skin or internally.
    [0067] [0067] In certain embodiments of the present invention, the disinfectant composition is administered to a scar tissue site through a plaster, compress or dressing containing chlorhexidine; a thick, viscous solution containing chlorhexidine; or a suture that contains chlorhexidine.
    [0068] [0068] Advantageously, chlorhexidine binds to scar tissues, for example, to subcutaneous layers of the skin, to confer an antimicrobial and / or healing effect. Consequently, the sterile disinfectant composition of the present invention provides an active agent that can bind to a scar tissue to improve scar tissue recovery, prevent infection and / or treat an existing infection.
    [0069] [0069] In further embodiments of the invention, the sterile disinfectant composition can be administered to a site such as a tablet taken orally, microcapsule delivery spheres, non-particles, targeted nanoparticles (e.g., mediated targeted nanoparticles per receiver), a time-controlled release system, a frozen block of the sterile disinfectant composition, a simple aqueous solution of the active agent, an isotonic solution of the active agent or an implantable delivery system for with time. In certain embodiments, the disinfectant composition is left in place after administration.
    [0070] [0070] In another embodiment of the invention, after administration of the disinfectant composition of the present invention to a site or tissue, the site or tissue is rinsed, for example, with a sterile solution devoid of the active agent. Examples of solutions devoid of the active agent include, but are not limited to, pure water,
    [0071] [0071] Under ideal circumstances, the methods of the present invention are used by trained medical technicians; however, in view of the simplicity and convenience of the present invention, it can be used to considerably increase the effectiveness of administering the disinfectant composition regardless of the level of training of the user who performs the irrigation.
    [0072] [0072] The individual may be a mammal. Non-limiting examples of mammals that can be treated according to the methods of the present invention include humans, non-human primates, dogs, cats, cattle, horses and pigs.
    [0073] [0073] The following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. EXAMPLE 1 - SURGICAL APPLICATIONS
    [0074] [0074] In an embodiment of the present invention, the sterile disinfectant composition is administered to a surgical site to prevent or treat an infection at the surgical site. Surgical sites may include, for example, prosthetic placement sites, abdominal surgery, brain surgery and oral / periodontal surgery.
    [0075] [0075] An infection developed at the surgical site is referred to here as "infection at the surgical site" or "SSI". A surgical site is at risk of developing an SSI, for example, by improperly manipulated surgical instruments or airborne infectious agents to the operating room. SSI can be treated by administering antibiotics to patients; however, a second surgery is often required to treat SSI. Additional surgery to treat SSI is undesirable for several reasons, for example, repeated surgical trauma to the patient, risk of repeated infection, inadequate healing of the surgical site and additional costs.
    [0076] [0076] The present invention provides an easy and inexpensive alternative to the second surgery for the treatment of an SSI. The method of the present invention, as it applies to the treatment of SSI, comprises administering to the surgical site a sterile disinfectant composition comprising an active agent comprising chlorhexidine in a concentration of about 1% or less, about 0.05 % or less or about 0.02% or less.
    [0077] [0077] The sterile disinfectant composition can be administered to the surgical site as a pure aqueous solution, an isotonic solution or another solution containing salt of the active agent. In one embodiment, after a period of time sufficient for the active agent to kill and / or inhibit the growth of an infectious agent at the surgical site, it can be rinsed with a sterile solution devoid of the active agent. Alternatively, or in addition, suction can be applied to the site. The amount of time sufficient for the active agent to kill and / or inhibit the growth of the infectious agent can be about 1 minute to about 10 minutes, about 2 minutes to about 8 minutes, about 3 minutes to about 7 minutes, about 4 minutes to about 6 minutes or about 5 minutes.
    [0078] [0078] In one embodiment, a chlorhexidine solution is administered in conjunction with robotic or other minimally invasive surgeries (Minimally Invasive Surgery - MIS) in order to reduce the risk of infection. In this context, the tubing that delivers the chlorhexidine solution can be included with other tubes (for example, tubes with optical components, tubes for distribution or removal of other fluids or fabrics and tubes for handling devices) that distribute or remove material from the surgical site or which would otherwise assist in the process.
    [0079] [0079] Thus, in one embodiment, the present invention provides an MIS system that has, as a component, a tube through which a solution containing chlorhexidine is discharged at a distal end of the tube. The proximal end of the tube can be configured to receive the chlorhexidine containing solution from a reservoir which can be, for example, a bag, vial or other suitable container. Preferably, the system is sterilized. The system may have additional tubes and other elements useful for carrying out an MIS procedure.
    [0080] [0080] The MIS system can be adapted for surgeries including, for example, coronary, vascular, prostatic, laparoscopic, spinal and neurological. EXAMPLE 2 - INTRAVASCULAR ADMINISTRATION
    [0081] [0081] In another embodiment of the invention, the disinfectant composition can be administered to the blood of an individual through intravascular injection.
    [0082] [0082] Preferably, the injection is intravenous. The disinfectant composition can be a pure aqueous solution, an isotonic solution or another solution containing chlorhexidine-containing salt.
    [0083] [0083] In certain embodiments of the invention, an isotonic solution containing chlorhexidine is prepared immediately before administration to the individual. For example, the isotonic solution containing the active agent can be prepared in less than 1 minute, less than 2 minutes, about 1 minute to about 30 minutes, about 5 minutes.
    [0084] [0084] In certain embodiments, an isotonic solution containing chlorhexidine is prepared by mixing a saline solution and chlorhexidine in an appropriate amount of water. In certain embodiments, a volume of a pure aqueous solution of chlorhexidine that contains twice the concentration of chlorhexidine compared to the desired concentration of chlorhexidine in the final working solution is mixed with an equal volume of a solution that has 2X the isotonicity of isotonic solution to prepare the appropriate isotonic chlorhexidine solution for administration to an individual's blood. EXAMPLE 3 - APPLICATIONS IN THE UROGENITAL TRACT
    [0085] [0085] In another embodiment of the invention, the sterile disinfectant composition can be administered to an individual's urogenital tract through an urogenital tract irrigation system.
    [0086] [0086] An urogenital tract irrigation system refers to a device useful for washing one or more organs of the urogenital tract. Non-limiting examples of urogenital tract irrigation systems include bladder irrigation systems and urethral irrigation systems.
    [0087] [0087] The sterile disinfectant solution used in the urogenital tract irrigation system can be, for example, a pure aqueous solution of the active agent or an isotonic solution of the active agent. EXAMPLE 4 - INTRA-ARTICULAR APPLICATIONS AND LONG STAY DEVICES
    [0088] [0088] In yet another embodiment of the present invention, the sterile disinfectant composition is administered to an intra-articular site through an intra-articular injection. The intra-articular sites that can be injected according to the methods of the present invention include, but are not limited to, elbow, shoulder, wrist, hip joints, knees, ankles and intervertebral sites.
    [0089] [0089] In yet another embodiment of the present invention, the disinfectant composition can be administered to the site of an implant or other long-term device by incorporating the sterile disinfectant composition into or on the implant or other devices.
    [0090] [0090] For the purposes of the present invention, an implant refers to a medical device intended to remain in the body for a long period of time. The long period of time can be, for example, more than 5 minutes, more than 1 hour, more than 12 hours, more than a day, more than a week, more than a month and / or more than a year.
    [0091] [0091] The implant can be designed, for example, to replace a missing biological structure, sustain a damaged biological structure or improve the biological function of an existing structure. Implants are man-made devices, in contrast to a transplant, which is a transplanted biomedical tissue.
    [0092] [0092] The implant surface that contacts the individual's tissue can be made of a biomedical material, such as titanium, silicone, hydrogel (or other polymer) or apatite. In some cases, the implants contain electronic parts, for example, artificial pacemakers and cochlear implants.
    [0093] [0093] The active agent can be incorporated into the implant, which then releases the active agent over a period of time. The materials and time durations discussed above in relation to porous materials used to treat infections are also applicable to this embodiment of the present invention. EXAMPLE 5 - RESPIRATORY SYSTEM APPLICATIONS
    [0094] [0094] The chlorhexidine solution of the present invention can also be formulated for inhalation, for example, by people who are suffering from pneumonia or other respiratory tract infections. In a specific modality, the chlorhexidine solution is formulated for inhalation by patients with cystic fibrosis (Cystic Fibrosis - FC) who have developed a lung infection or are at risk of developing such an infection. In a specific modality, the individual was diagnosed with (CF).
    [0095] [0095] The disinfectant composition can be administered to the respiratory tract of an individual through inhalation, for example, vapors, particles and / or aerosols containing the active agent. Non-limiting examples of devices suitable for the production of steam, particles and / or aerosols for inhaling the active agent include inhalers and blowers. Additional examples of devices that can be used to produce inhalable vapors, particles and / or aerosols are well known to those skilled in the art and such modalities are within the scope of the present invention. EXAMPLE 6 - APPLICATIONS IN BODY CAVITIES
    [0096] [0096] In an embodiment of the invention, the disinfectant composition is administered to a body cavity, such as an intraperitoneal site, through injection, infusion or irrigation of the sterile disinfectant composition.
    [0097] [0097] The disinfectant composition injected into the intraperitoneal site can be, for example, a pure aqueous solution of chlorhexidine, an isotonic solution, a gel containing chlorhexidine, an emulsion or a suspension. EXAMPLE 7 - EYE APPLICATIONS
    [0098] [0098] In certain embodiments of the present invention, the sterile disinfectant composition is administered to an ocular site as an ophthalmic composition containing chlorhexidine. The ophthalmic composition can be, for example, a solution, suspension or an ointment containing the active agent.
    [0099] [0099] In a specific embodiment, a chlorhexidine solution is applied to the eye in conjunction with an eye surgical procedure. The ocular surgical procedure can be, for example, cataract surgery, retinal surgery, lens replacement surgery or surgery to correct traumatic injuries including, but not limited to, corneal abrasion. The chlorhexidine solution can be applied before, during or after surgery. The chlorhexidine solution of the present invention can also be used to treat conjunctivitis.
    [0100] [0100] The concentration of chlorhexidine can be less than 1%, preferably less than 0.16%, less than 0.05%, less than 0.02% or even less than 0.01 %. The administration of the chlorhexidine solution can be followed by a rinse, for example, with saline, but it need not be followed by a rinse.
    [0101] [0101] In one embodiment, the present invention provides a container with a sterile solution of chlorhexidine with a dropper contained in or associated with it. The container may itself be sterile for use in a surgical environment. EXAMPLE 8 - USE FOR CHRONIC WOUNDS AND BURNS
    [0102] [0102] In additional embodiments, the chlorhexidine compositions of the present invention can be used for the treatment of acute and / or chronic wounds and burns. In this context, chlorhexidine can be incorporated into dressings or formulated in pastes or nebulisations that do not cause discomfort when applied to the chronic wound or burn site. EXAMPLE 9 - SUBCUTANEOUS APPLICATIONS
    [0103] [0103] In another embodiment, compositions containing chlorhexidine can be injected to treat subcutaneous infections, such as those that can occur at the site of a breast implant. Advantageously, such infections can be treated in accordance with the present invention without the need for a more invasive procedure.
    [0104] [0104] According to the present invention, advantageously, it has been discovered that chlorhexidine binds to subcutaneous tissue. Repeated application increases chlorhexidine bound to the tissue, thus creating a cumulative effect that facilitates the establishment of a protective barrier layer against infection. In specific modalities, chlorhexidine is applied repeatedly, or continuously, to obtain better protection against infection by establishing an antimicrobial layer. EXAMPLE 10 - PIERCINGS AND ACUPUNCTURE
    [0105] [0105] The compositions according to the present invention can also be incorporated into, or applied to, earrings and other body piercing articles and acupuncture needles to reduce the incidence of infection associated with body piercings and / or acupuncture. EXAMPLE 11 - ORAL ADMINISTRATION
    [0106] [0106] In another embodiment, the chlorhexidine-containing compositions of the present invention can be formulated for oral delivery for the treatment of sore throats as well as diseases of the digestive tract. In this context, the compositions of the present invention can be used to treat influenza or other viruses, as well as food poisoning and bacteria associated with inflammation and ulcers of the digestive tract. EXAMPLE 12 - TREATMENT OF NASAL INFECTIONS
    [0107] [0107] According to other embodiments of the present invention, the sterile disinfectant composition is administered to the nasal sinuses through an irrigation system, a nasal swab, a nasal wash, a nasal shower or a Neti pot. A natural irrigation system is designed to rinse the sinuses and wash the blocked nasal passages using a solution, for example, a saline solution,
    [0108] [0108] In certain embodiments of the present invention, the sterile disinfectant composition is administered to a cerebrospinal site through cerebrospinal injection or cerebrospinal irrigation. EXAMPLE 14 - SUTURES
    [0109] [0109] In addition, sutures containing chlorhexidine can be used to suture a surgical incision or a wound in an individual. The sutures can then release chlorhexidine at the site of administration over a period of time. Chlorhexidine can also be added, according to the present invention, to surgical adhesives and liquid compresses. EXAMPLE 15 - KITS AND CONTAINERS
    [0110] [0110] An additional embodiment of the present invention provides kits comprising the sterile disinfectant composition and equipment or devices for administering the sterile disinfectant composition to the individual site.
    [0111] [0111] Equipment and devices for administering the sterile disinfectant composition to the site to the individual include, but are not limited to, a vial to deliver the pure aqueous solution of the active agent or the isotonic solution of the active agent to the site, a transdermal patch, a porous material, a sponge, sutures, an urogenital tract irrigation system, an implant, a vapor inhalation device, a nasal irrigation system, a nasal wash, a nasal shower, a Neti pot, an injection system or a cerebrospinal irrigation system. This can also be achieved through
    [0112] [0112] For the purposes of the present invention, an injection system may comprise a syringe and needle and / or a catheter. The size of the needle and syringe depends on the location to which the sterile disinfectant composition is administered. Those skilled in the art can determine the appropriate syringe and needle size in a particular situation.
    [0113] [0113] Non-limiting examples of kits and containers according to the present invention include a pure aqueous solution of the active agent, an isotonic solution of the active agent, a pure aqueous solution of the active agent in a concentration of 2X the active agent compares - mixed with the final working solution and a solution without active agent having 2X the isotonicity of the active agent in a solid form and sterile water or a sterile isotonic solution, a transdermal patch containing the active agent, a porous material that contains contains the active agent, a sponge that contains the active agent, a thick viscous solution that contains the active agent, a spray mist that contains the active agent, sutures that contain the active agent, a system for irrigating the tract urogenital and a sterile disinfectant composition, an implant containing the active agent, a vapor inhalation device and a sterile disinfectant composition, an aerosol inhalation device and a desi composition sterile nefetant, an ophthalmic emulsion containing the active agent, an ophthalmic solution containing the active agent, an ophthalmic suspension containing the active agent, an ophthalmic ointment containing the active agent, a nasal irrigation system and a desin composition - sterile fetus, a nasal wash and a sterile disinfectant composition, a nasal shower and a sterile disinfectant composition, a Neti pot and a sterile disinfectant composition, an injection and a
    [0114] [0114] Kits and containers (including custom packaging) can be used to practice the methods of the present invention. For example, a user can use a kit that comprises a pure aqueous solution of the active agent or the isotonic solution of the active agent by administering the solution of the active agent to the site in the individual. Similarly, a user can mix equal amounts of the pure aqueous solution of the active agent in a concentration of 2X and the solution devoid of active agent which has an isotonicity of 2X to prepare an isotonic working solution of the active agent. A user can also dissolve the active agent in solid form in sterile water or sterile isotonic solution to prepare an isotonic working solution for the active agent.
    [0115] [0115] It should be understood that the examples and modalities described here are for illustrative purposes only and that various modifications or alterations, in the light of the same, will be suggested for those skilled in the art and should be included within the spirit and scope of this Order and the scope of the appended claims.
    权利要求:
    Claims (23)
    [1]
    1. Use of chlorhexidine in a concentration of 1% or less, characterized by the fact that it is for the preparation of an aqueous composition or solution to reduce infection in a location in an individual, where the location is selected from: a) blood, b) an urogenital tract, c) a respiratory tract, d) an intraperitoneal site, e) an ocular site, f) the colon, g) the sinuses, h) an intra-articular site, i) a mediastinal site, and j) a cerebrospinal site.
    [2]
    2. Use according to claim 1, characterized by the fact that the concentration of chlorhexidine is about 0.05% or less.
    [3]
    3. Use according to claim 1, characterized by the fact that chlorhexidine is chlorhexidine gluconate.
    [4]
    4. Use according to claim 1, characterized by the fact that the composition further comprises a second agent, which is selected from antibacterial agents, anti-viral agents, fungicidal agents, chemotherapeutic agents, anesthetic agents, agents that reduce bleeding and diagnostic agents.
    [5]
    5. Use, according to claim 1, characterized by the fact that it also includes application of suction to the site.
    [6]
    6. Use, according to claim 1, characterized by the fact that the composition is formulated so that chlorhexidine is administered to the site by means of a sustained release material containing chlorhexidine.
    [7]
    7. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the blood by means of intravenous injection.
    [8]
    8. Use according to claim 7, characterized by the fact that an isotonic solution containing chlorhexidine is prepared less than 5 minutes before the solution is administered by intravenous injection.
    [9]
    9. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the respiratory tract through inhalation of steam and / or an aerosol.
    [10]
    10. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the eye location as an emulsion, solution, suspension or ointment.
    [11]
    11. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the nasal sinuses through an irrigation system, a nasal wash, a nasal shower or a Neti pot.
    [12]
    12. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the intra-articular site through an intra-articular injection.
    [13]
    13. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered to the cerebrospinal site by means of a cerebrospinal injection or a cerebrospinal irrigation system.
    [14]
    14. Use, according to claim 1, characterized by the fact that the composition is formulated to be administered as a tablet taken orally, microcapsule beads, nanoparticles, a controlled release system over time, a frozen block, a pure aqueous solution, an isotonic solution or an implantable release delivery system over time.
    [15]
    15. Use, according to claim 1, characterized by the fact that the infection involves a biofilm.
    [16]
    16. Use, according to claim 1, characterized by the fact that the infection is caused by methicillin resistant Staphylococcus aureus (MRSA).
    [17]
    17. Use of chlorhexidine at a concentration of 1% or less, characterized by the fact that it is for the preparation of an aqueous composition or solution to treat a biofilm infection at a location in an individual.
    [18]
    18. Long-term medical device characterized by the fact that it has chlorhexidine incorporated in it.
    [19]
    19. Device, according to claim 18, characterized by the fact that it is selected from compresses, dressings, sutures, implants and catheters.
    [20]
    20. Device according to claim 18, characterized by the fact that chlorhexidine is incorporated through a coating on the surface of the device.
    [21]
    21. System for minimally invasive surgery, said system characterized by the fact that it comprises a tube adapted for distribution of a solution comprising chlorhexidine, in which said tube is adapted to receive chlorhexidine from a reservoir containing a solution chlorhexidine and is further adapted to deliver chlorhexidine to the site in an individual where the surgery is being performed.
    [22]
    22. Kit characterized by the fact that it comprises a medical device as defined in claim 18.
    [23]
    23. Invention, in any form of its embodiments or in any applicable category of claim, for example, product or process or use encompassed by the material initially described, revealed or illustrated in the patent application.
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    法律状态:
    2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-07-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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    US201361915281P| true| 2013-12-12|2013-12-12|
    US61/915,281|2013-12-12|
    PCT/US2014/070059|WO2015089421A1|2013-12-12|2014-12-12|Materials and methods for controlling infections|
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