Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M25/00—Catheters; Hollow probes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M35/00—Devices for applying media, e.g. remedies, on the human body
  • A61M35/003—Portable hand-held applicators having means for dispensing or spreading integral media
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

• Methicillin-resistant Staphylococcus aureus (MRSA) infection is caused by Staphylococcus aureus bacteria— often called "staph.” Decades ago, strains of staph emerged in hospitals that were resistant to the broad-spectrum antibiotics commonly used to treat them. These antibiotics include methicillin and other more common antibiotics such as oxacillin, penicillin and amoxicillin. Dubbed methicillin-resistant Staphylococcus aureus (MRSA), it was one of the first germs to be resistant to all but the most powerful drugs.
• MRSA methicillin-resistant Staphylococcus aureus
• Staph bacteria are generally harmless unless they enter the body through a cut or other wound. In older adults and people who are ill or have weakened immune systems, ordinary staph infections can cause serious illness. Staph infections, including MRSA. occur most frequently among persons in hospitals and healthcare facilities, such as nursing homes and dialysis centers, who have weakened immune systems.
• MRSA multi-viral staph
• CA-MRSA community-associated MRSA
• 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 antimicrobial resistant has been growing. In 1974, MRSA infections accounted for two percent of the total number of staph infections; in 1995 it was 22%; and in 2004 it was nearly 63%. Additionally, recent research has suggested that 30-50% of the population carries MRSA colonies on their bodies all the time, helping to facilitate the spread of infection.
• CDC Center for Disease Control and Prevention
• MRSA has traditionally been seen as a hospital-associated infection
• CA-MRSA infection in the community are usually manifested as skin infections, such as pimples and boils.
• These CA-MRSA infections can occur in otherwise healthy people, and commonly occur among athletes who share equipment or personal items including towels and razors.
• This epidemic among athletes is aided by the fact that MRSA grows very rapidly in warm, moist areas such as gyms and gym locker rooms.
• Common cuts and abrasions such as those frequently occurring in football and baseball now pose significant threats due to the possibility of an MRSA infection.
• Vancomycin is one of the few antibiotics still effective against hospital strains of MRSA infection, although the drug is no longer effective in every case.
• Several drugs continue to work against CA-MRSA, but CA-MRSA is a rapidly evolving bacterium, and it may be a matter of time before it, too, becomes resistant to most antibiotics.
• Chlorhexidine is a chemical antiseptic, and it combats both gram positive and gram negative microbes. It is bacteriostatic, hampering the growth of bacteria, and bacteriocidal, killing bacteria. It is often used as an active ingredient in mouthwash designed to kill dental plaque and other oral bacteria. Chlorhexidine also has non-dental applications. For example, it is used for general skin cleansing, as a surgical scrub, and as a pre-operative skin preparation.
• Chlorhexidine is typically used in the form of acetate, gluconate, or hydrochloride, either alone or in combination with other antiseptics such as cetrimide.
• the subject invention provides novel and highly effective methods, devices and compositions for efficient delivery of one or more medications or other active ingredients to a target site in a patient in order to reduce, prevent, and/or treat infection.
• agents that can be administered to a patient in accordance with the subject invention include, but are not limited to, anti-bacterial agents, anti-viral agents, fungicidal agents, chemotherapy agents, topical antiseptics, anesthetic agents, oxygenated fluids and/or agents, antibiotics, diagnostic agents, homeopathic agents, and over the counter medications/agents.
• the active agent is chlorhexidine gluconate, preferably at a concentration of less than 1.0%, more preferably less than 0.1% and most preferably at 0.05% or less.
• the subject invention provides a reservoir housing containing an irrigation solution with one or more active agents, wherein the reservoir housing has attached to it a discharge means having one or a plurality of ports through which a sufficient volume of the solution can pass at an appropriate pressure for effective delivery of the solution, including the active agent, to a target site.
• the subject invention provides novel, convenient, inexpensive, and effective drug delivery techniques that utilize, in one embodiment, a device having a reservoir housing and a discharge means for delivering an active agent to a target site.
• the subject invention also provides compositions and methods of use for the device and composition.
• the materials and methods of the subject invention make it possible to conveniently and easily apply fluid containing, for example, a medicinal agent to, for example, a wound.
• a wound is a surgical site.
• active agents refers to compounds or other entities that perform a therapeutic and/or diagnostic function. This function may be direct, such as promoting tissue repair or killing cancer cells, or may be indirect by eliciting a physiological response that ultimately results in the desired beneficial result.
• a sterile water (not saline) solution comprising 0.05% or less (or even less than 0.04% or even less than 0.03%) of chlorhexidine is applied to a wound in the skin of a human.
• the wound is then rinsed within five minutes (preferably within 1-3 minutes) with a sterile saline or water liquid that does not contain chlorhexidine.
• the solution is applied to a surgical site.
• chlorhexidine gluconate used according to the subject invention has the following chemical structure:
• a wound In a preferred embodiment, about 15-25 mg of chlorhexidine gluconate is applied to a wound.
• the wound is an abrasion or laceration and the solution is applied prior to repair/closure.
• the pH of the solution is neutral or slightly acidic.
• the pH is 5.0 to 7.5. More preferably the pH is 5.5. to 7.0.
• the chlorhexidine is applied without a sudsing agent.
• the composition does not have any ingredients that would promote microbial growth.
• the composition does not comprise a consistency builder as that term is used in U.S . Published Application 2007/0184114, which is incorporated herein in its entirety.
• a CHG-containing solution is applied to an open surgical wound.
• the solution may be applied under pressure or not under pressure.
• the solution is not applied by jet lavage.
• the fluid is not applied under pressure.
• the patient is a human.
• the patient may also be, for example, a dog, horse, cat, pig or cattle.
• the site is washed with saline within 1, 5, or 10 minutes.
• the CHG-containing solution is preferably in a sterile container.
• the container may be sterilized by, for example, irradiation.
• CHG may be provided in a small ampule such that the contents of the ampule can be added to, for example, a standard sized bottle of water, or to an IV bag or line, to create a CHG solution having a concentration of CHG as described herein.
• the solution of the subject invention can also be provided in an IV bag.
• the subject invention provides antimicrobial lotions, creams, sponges, and suppositories. These embodiments preferably contain CHG as the active ingredient. These embodiments provide CHG, at the concentrations set forth herein, directly to a location wherein antimicrobial activity is needed.
• the aqueous solution containing CHG may have other components including, for example, pH modifiers, buffers, local anesthetic agents, agents that promote wound healing (such as agents that help degrade biofilm) and other therapeutic and non-therapeutic compounds.
• the composition "consists essentially" of an aqueous solution of CHG, which means that the solution contains no other active agent that materially changes the ability of the solution to control bacteria growth.
• the wound is rinsed with saline after application of a CHG- containing solution.
• Rinsing with saline not only rinses the CHG off but also the saline chemically neutralizes the CHG thereby preventing or reducing edema.
• the rinse is preferably applied about 30 seconds to about 5 minutes after the administration of the CHG.
• the rinse may be from about 100 ml to 1000 ml of saline and is typically applied for about 5 seconds to about 1 minute.
• the application of the irrigation solution of the subject invention results in a reduction in the number of bacteria at the wound when compared to either an untreated wound or a wound irrigated with saline or water that does not contain chlorhexidine.
• the use of CHG according to the subject invention can result in effective control of an infection without causing tissue damage.
• the irrigation solution of the subject invention is effective in combating infection, even when organic materials (including blood, tissue, and/or dirt and debris) are present. Of course, such materials are present in all skin wounds.
• the formulations of the subject invention can also "depathogenize" certain bacteria including, for example, E. coli and Klebsiella aerogenes, making these bacteria less able to cause infection.
• compositions and methods of the subject invention can be used to effectively treat wounds even when biofilm is present.
• the drug delivery methods of the subject invention can be used in conjunction with the delivery of an active agent by many of the routes set forth in Table 1. Of particular interest are: cutaneous, intra-abdominal, intracranial, intralesional, intrathoracic (during surgery), irrigation, nasal, in the ear canal, as an oral bowel prep, for gastric lavage, as an eye wash, periodontal, rectal, soft tissue, subcutaneous, and vaginal routes.
• the compositions of the subject invention can also be used to control acne and other skin infections, including infections of the feet and scalp.
• the chlorhexidine composition of the subject invention is used to heat an abscess. Preferably the solution is applied deep into the abscess using, for example, a device with an elongated discharge port to facilitate effective administration.
• the drug delivery devices and methods of the subject invention are utilized by trained medical technicians; however, because of the simplicity and convenience of the devices of the subject invention, they can be used to greatly enhance the effectiveness of drug delivery regardless of the training level of the operator performing the irrigation.
• the target sites to which an active ingredient can be administered according to the subject invention include, but are not limited to, wounds and surgical sites.
• the surgical sites may include, for example, joint replacements, abdominal surgery, brain surgery, and oral/periodontal surgery sites.
• the ability to deliver the active agent to a specific site, at an appropriate dosage, is unique and highly advantageous.
• the solution that carries the active agent can be, for example, water, saline, or a balanced salt solution.
• the solution is preferably sterile. In the case of CHG, the solution is preferably water.
• the device can be sterilized by known sterilization techniques, including boiling, autoclaving, gas sterilization, irradiation, and the like, either separately or together with the reservoir housing.
• the use of chlorhexidine is particularly advantageous because it is broad spectrum, binds to the skin (to provide residual activity), works rapidly and, when used according to the subject invention, is non-toxic.
• Chlorhexidine is a chemical antiseptic that can be used to combat both gram positive and gram negative microbes. It is both bacteriostatic and bactericidal. Various species of bacteria are involved in the pathogenesis of wound infection and/or secondary cellulitis. At times these infections can result in disfigurement, loss of extremities, prolonged convalescences, and/or death.
• the therapeutic effect of the irrigation solution of the subject invention is to combat microbes typically involved in the pathology of these infections by its antiseptic properties and those associated with the irrigation process itself. Controlling the microbial load in wounds is a vital factor in minimizing infection and thus decreasing and/or preventing disease.
• Chlorhexidine is active against aerobic and anaerobic gram-positive and gram-negative bacteria.
• the drug also has some activity against Chlamydia trachomatis, certain fungi, and certain viruses.
• Chlorhexidine is highly active against a variety of gram-positive aerobic bacteria, including Streptococcus /nutans, S. pyogenes (group A ⁇ -hemolytic streptococci), S. salivarius, and S. sanguis. Chlorhexidine is active against Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis, and S. simulans. The drug is active against both oxacillin-resistant (ORSA) and oxacillin-susceptible staphylococci (also known as methicillin-resistant [MRSA] or methicillin-susceptible staphylococci). Chlorhexidine is active against Enterococcus, including E. faecalis and E. faecium, and is active against both vancomycin-susceptible and vancomycin-resistant strains.
• RSA oxacillin-resistant
• MRSA methicillin-resistant
• Chlorhexidine is active against some anaerobic bacteria.
• the drug is active against some strains of Bacteroides, Propionibacterium, Clostridium difficile, and Sclenomonas, but is less active against Veillonella. Fungi
• Chlorhexidine has some 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 some activity against dermatophytes, including Epidermophyton floccosum, Microsporum gypseum, M. canis, and Trichophyton mentagrophytes.
• Chlorhexidine appears to have antiviral activity against viruses that have a lipid component in their outer coat or have an outer envelope such as cytomegalovirus (CMV), human immunodeficiency virus (HIV), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), influenza virus, parainfluenza virus, and variola virus (smallpox virus).
• CMV cytomegalovirus
• HAV human immunodeficiency virus
• HSV-1 herpes simplex virus types 1
• HSV-2 herpes simplex virus types 1
• influenza virus parainfluenza virus
• variola virus smallpox virus
• a low concentration solution of chlorhexidine can be used to effectively reduce infections at, for example, a wound, surgical site, or other tissue opening.
• the chlorhexidine solution is less than 4%.
• the chlorhexidine is less than 2%, or less than 1% or even less than 0.1%.
• the chlorhexidine solution is 0.05%.
• the chlorhexidine solution is between 0.02% and 0.05%. Specifically exemplified herein is the use of chlorhexidine gluconate.
• the device of the subject invention is used to deliver an active agent, such as an antimicrobial agent, to a target site, such as a wound.
• an active agent such as an antimicrobial agent
• the site can then be flushed with, for example, saline to remove at least any excess of the active agent.
• this flushing occurs within five minutes of the administration of the chlorhexidine solution. More preferably, this flushing occurs within one to three minutes of the administration of the chlorhexidine solution. In this way, any potential toxicity associated with the active agent can be reduced or eliminated.
• rinsing with an irrigation fluid removes excess chlorhexidine that has not bound to, for example, proteins of the skin.
• a diagnostic agent can be administered using the device and method of the subject invention.
• the diagnostic agent may be, for example, an antibody, protein, or polynucleotide that binds to a target biomolecule. Any such binding may then be visualized utilizing technologies known to those skilled in the art. These technologies include, for example, the use of flourophores or other labels that can be visualized either by the naked eye or through appropriate detection instruments.
• the diagnostic applications of the subject invention include the detection of bacteria, viruses, parasites and other pathogens. Cancer cells can also be visualized using the diagnostic methods of the subject invention.
• the device and method can be used to deliver growth factors and/or protease inhibitors to a target site.
• growth factors and/or protease inhibitors which can, for example, expedite the healing of wounds, are well known to those skilled in the art.
• the method of the subject invention can be used to deliver oxygenated water and/or "enhanced water" to a target site.
• the enhanced water can be that which is described in, for example, published U.S. Patent Application 20050191364 and the references cited therein (all of which are incorporated herein by reference in their entireties).
• the use of the subject method for the effective delivery of such oxygenated or enhanced water can be used to promote tissue healing and reduce infections.
• the device and method of the subject invention can be used to efficiently deliver anti-microbial peptides (AMPs) to a target site.
• AMPs are well known in the art.
• Antimicrobial peptides are predominantly small polypeptides that inhibit the growth of microbes. As effectors of innate immunity, antimicrobial peptides directly kill a broad spectrum of bacteria, fungi, and viruses. In addition, these peptides modify the local inflammatory response and activate mechanisms of cellular and adaptive immunity.
• Cathelicidins and defensins comprise the major families of AMPs in the skin, although other cutaneous peptides, such as proteinase inhibitors, chemokines, and neuropeptides, also demonstrate antimicrobial activity. See, for example, Braff, M. et al, (2005) "Cutaneous Defense Mechanisms by Antimicrobial Peptides," J Invest Dermatol, 125:9-13.
• the device of the subject invention can be, for example, the device as shown in U.S. Published Application No. US-2008-0159963-A1 , which is incorporated herein, in its entirety, by reference.
• the reservoir may be, for example, from 100 ml to 1000 ml.
• the subject invention provides a reservoir housing containing a solution with one or more active agents, wherein the reservoir housing has attached to it a discharge means having one or a plurality of ports through which a sufficient volume of the solution can pass at an appropriate pressure for effective delivery of the solution, including the active agent, to a target site.
• the reservoir housing and contents can be stored in a sterile environment, e.g. , sterile packaging which is opened immediately prior to use.
• the reservoir housing can be directed towards the wound and squeezed or compressed to expel or discharge the solution in the desired direction, and at the desired pressure to effect irrigation of a wound to remove contaminants or debris and to deliver the active agent(s).
• the discharge means can be packaged separately from the reservoir housing.
• the discharge means is packaged in a sterile environment.
• the drug delivery device is provided in a sterile tray.
• the laceration tray can have, for example, in addition to the drug delivery device of the subject invention, other items conveniently provided for treating wounds.
• Contemplated items that can be included in a tray include, but are not limited to, needle holders (i.e. , 5" floor-grade smooth); scissors (i. e. , 4.5" floor-grade straight Iris scissors); hemostats (i.e. , 5" floor-grade curved mosquito hemostat); forceps (/ " . e. , floor-grade tissue forceps with 1 x2 teeth); cups ( .
• syringes i.e. , l Occ Luer Lock syringe
• needles i.e. , 25 gauge x 5/8" needle; 27 gauge x 1 .5" needle; 18 gauge x 1.5" needle
• dressings i. e. , gauze dressings
• drapes i. e. , polylined fenestrated drapes
• towels i. e. , absorbent towels).
• tissue injury For examination of the wound, it is assumed that a medical professional would have performed a detailed evaluation of the extent of tissue injury, including but not limited to: anatomical area considerations, depth of the wound, type of injury, e.g. , crash injury, puncture wound, bites, missiles, cuts with sharp objects, or the like. Included in this examination would be a determination of the type(s) of contamination, time elapsed between the occurrence of the injury to presentation, gross contamination of a wound, and other medical factors associated with an increased incidence of infection (for example, diabetics, AIDS patients, and chemotherapeutics patients).
• wound and surrounding tissue at the option of the health care professional, could be anesthetized using topical, local, or general anesthetics before the wound-cleansing method begins.
• an anesthetic may be delivered using the device and method of the subject invention.
• Irrigation of skin wounds such as cuts, scrapes, punctures, abrasions, etc. are particularly well-suited for irrigation according to the subject invention, as is irrigation of surgical sites.
• Table 1 provides a listing of various routes of administration that can be used according to the subject invention.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Anesthesiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Hematology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Oncology (AREA)
• Dermatology (AREA)
• Communicable Diseases (AREA)
• Pulmonology (AREA)
• Surgery (AREA)
• Biophysics (AREA)
• Medical Informatics (AREA)
• Epidemiology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Medicinal Preparation (AREA)

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• 2010
  • 2010-10-24 WO PCT/US2010/053884 patent/WO2011056486A2/en active Application Filing
  • 2010-10-24 CA CA2778081A patent/CA2778081A1/en not_active Abandoned
  • 2010-10-24 CN CN201080048369XA patent/CN102711709A/zh active Pending
  • 2010-10-24 EP EP10828816.8A patent/EP2493442A4/en not_active Ceased
  • 2010-10-24 JP JP2012536912A patent/JP2013508457A/ja active Pending

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