I 1111111111111111 11111 1111111111 1111111111 111111111111111 IIIIII IIII IIII IIII
`US009028852B2
`
`c12) United States Patent
`Scholz
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,028,852 B2
`May 12, 2015
`
`(54) CATIONIC ANTISEPTIC COMPOSITIONS
`AND METHODS OF USE
`
`(75)
`
`Inventor: Matthew T. Scholz, Woodbury, MN
`(US)
`
`(73) Assignee: 3M Innovative Properties Company,
`St. Paul, MN (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1353 days.
`
`(21) Appl. No.: 10/936,135
`
`(22) Filed:
`
`Sep.7,2004
`
`(65)
`
`Prior Publication Data
`
`US 2006/0051385 Al
`
`Mar. 9, 2006
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 31114
`A61K 33/38
`A61K 8172
`A61K 8/00
`A61K 45106
`(52) U.S. Cl.
`CPC ................. A61K 31114 (2013.01); A61K 33/38
`(2013.01); A61K 45106 (2013.01)
`( 58) Field of Classification Search
`USPC ........ 424/405, 70.11, 70.21, 78.07, 404,618;
`514/642
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`Primary Examiner - Sue Liu
`Assistant Examiner - Andriae M Holt
`
`(57)
`
`ABSTRACT
`
`Antimicrobial compositions, especially those useful when
`applied topically, particularly to mucosa! tissues (i.e., mucous
`membranes), including a cationic antiseptic such as bigu(cid:173)
`anides and bisbiguanides such as chlorhexidine and its vari(cid:173)
`ous salts including but not limited to the digluconate, diac(cid:173)
`etate, dimethosulfate, and dilactate
`salts; polymeric
`quaternary ammonium compounds such as polyhexamethyl(cid:173)
`enebiguanide; silver and various silver complexes; small
`molecule quaternary ammonium compounds such as benza(cid:173)
`lkoium chloride and alkyl substituted derivatives; di-long
`chain alkyl (C8-C18) quaternary ammonium compounds;
`cetylpyridinium halides and their derivatives; benzethonium
`chloride and its alkyl substituted derivatives; and octenidine.
`The compositions can also include an enhancer component, a
`surfactant, a hydrophobic component, and/or a hydrophilic
`component. Such compositions provide effective topical anti(cid:173)
`microbial activity and are accordingly useful in the treatment
`and/or prevention of conditions that are caused, or aggravated
`by, microorganisms (including viruses).
`
`20 Claims, No Drawings
`
`BAXTER EXHIBIT 1012
`Page 1 of 42
`
`

`

`US 9,028,852 B2
`Page 2
`
`(56)
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`BAXTER EXHIBIT 1012
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`

`

`US 9,028,852 B2
`Page 3
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`* cited by examiner
`
`BAXTER EXHIBIT 1012
`Page 3 of 42
`
`

`

`US 9,028,852 B2
`
`1
`CATIONIC ANTISEPTIC COMPOSITIONS
`AND METHODS OF USE
`
`BACKGROUND
`
`The use of antimicrobial agents plays an important part in
`current medical therapy. This is particularly true in the fields
`of dermatology as well as skin and wound antisepsis, where
`the most effective course of treatment for skin or mucous
`membranes, which are afflicted with bacterial, fungal, or viral
`infections or lesions, frequently includes the use of a topical
`antimicrobial agent, such as antibiotics. For decades medi(cid:173)
`cine has relied primarily upon antibiotics to fight systemic as
`well as topical infections.
`Antibiotics are organic molecules produced by microor(cid:173)
`ganisms that have the capacity in dilute solutions ( e.g., solu(cid:173)
`tions less than 10 µg/ml and often less than 1 µg/ml) to destroy
`or inhibit the growth of bacteria and other microorganisms.
`They are generally effective at very low levels and are often
`safe with very few, if any, side effects. Antibiotics are com(cid:173)
`monly of a narrow spectrum of antimicrobial activity. Fur(cid:173)
`thermore, they often act on very specific sites in cell mem(cid:173)
`branes or on very specific metabolic pathways. This can tend
`to make it relatively easy for bacteria to develop resistance to
`the antibiotic(s) (i.e., the genetically acquired ability to tol(cid:173)
`erate much higher concentrations of antibiotic) either through
`natural selection, transmission of plasmids encoding resis(cid:173)
`tance, mutation, or by other means. Not only does resistance
`eliminate the ability of a medication to treat an affliction, but
`it can also put the patient at further risk, especially if the
`antibiotic is one that is routinely used systemically.
`In the past few decades it as been quite well established that
`colonization of the anteriornares with Staphylococcus aureus
`(SA) can lead to multiple problems. Medicine has relied
`primarily upon antibiotics for nasal decolonization. For
`example, bacitracin, neomycin sulfate, polymyxin B sulfate,
`gentamicin, framycetin-gramicidin, lysostaphin, methicillin,
`rifampin, tobramycin, nystatin, mupirocin, and combinations
`thereof, have been used with varying success for nasal 40
`decolonization.
`For example, nasal colonization with SA in presurgical
`patients has resulted in higher infection rates and higher rates
`of other nosocomial infections such as catheter infections.
`Nasal colonization with SA in hemodialysis patients has 45
`resulted in a much higher incidence of blood stream infec(cid:173)
`tions. Furthermore, it has been well established that the ante(cid:173)
`rior nares is the ecological niche for SA colonization and thus
`spread of methicillin resistant staphylococcus aureus
`(MRSA) in a hospital or other health care facilities in the 50
`event of an outbreak can be mitigated by decolonizing the
`anterior nares of patients and healthcare workers.
`Mupirocin, marketed as the calcium salt in Bactroban
`Nasal by GlaxoSmithKline, is the only antibiotic approved
`by the Food and Drug Administration for nasal decoloniza- 55
`tion use in the United States. For example, there are multiple
`reports of resistance to mupirocin when used as a nasal
`decolonizing agent. Resistance rates have been reported as
`high as 25% and even as high as 50% (see, for example, E.
`Perez-Roth et al., Diag. Micro. Infect. Dis., 43:123-128 60
`(2002) and H. Watanabe et al., J. Clin. Micro., 39(10): 3775-
`3777 (2001 )). Even though presurgical decolonization of the
`anterior nares using mupirocin has been shown to decrease
`the risk of surgical site infection by as much as 2 to 10 times
`(T. Perl et al., Ann. Pharmacother., 32:S7-S16 (1998)), the 65
`high resistance rates to this antibiotic make it unsuitable for
`routine use.
`
`2
`Antiseptics, on the other hand, are synthetic molecules that
`destroy or inhibit microorganisms and virus by inhibiting
`metabolic pathways or altering the cell envelope or both.
`They tend to have broader spectrum of antimicrobial activity
`5 and often act by nonspecific means such as disruption of cell
`membranes, oxidation of cellular components, denaturation
`of proteins, etc. This nonspecific activity makes it difficult for
`microorganisms to develop clinical resistance to antiseptics.
`For example, there are very few reports of clinical resistance
`10 to antiseptics such as iodine, lower alcohols (ethanol, pro(cid:173)
`panol, etc.), chlorhexidine, quaternary amine surfactants,
`chlorinated phenols, and the like. Some of these compounds,
`however, need to be used at concentrations that often result in
`irritation or tissue damage, especially if applied repeatedly.
`15 Furthermore, unlike antibiotics, many antiseptics are not
`active 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 organic matter such as that in nasal or
`20 vaginal secretions, and perhaps even on skin.
`Many antiseptic compounds are viewed as irritants. For
`example, compositions containing iodine and/or chlorhexi(cid:173)
`dine have been reported to cause skin and mucosa! tissue
`irritation. This is particularly true for sensitive mucosa! tis-
`25 sues, such as the anterior nares, nasal and esophageal cavities,
`which can have a high level of microbial colonization in
`certain otherwise healthy individuals, as well as individuals
`with infectious diseases such as chronic sinusitis. Addition(cid:173)
`ally, due to the irritating nature many of these compounds
`30 may be unsuitable for application to irritated or infected der(cid:173)
`mal tissue to treat skin conditions, such as lesions from impe(cid:173)
`tigo and shingles.
`Also, for certain applications, especially in the nose and
`mouth, it is particularly desirable for the compositions to have
`35 little or no color, little or no odor, and an acceptable taste.
`Many antiseptics have undesirable characteristics, such as
`iodine and iodophors, which have an orange to brown color
`and a definite odor at concentrations typically employed for
`antisepsis.
`Chlorhexidine gluconate (in combination with neomycin
`sulfate) has been suggested for use in nasal decolonization
`with limited success. For example, Naseptin is an antibiotic
`emulsified cream comprising neomycin sulphate (3250 units/
`g) and chlorhexidine gluconate (0.1 wt-%) that in combina(cid:173)
`tion destroys bacteria. The product also contains arachis oil,
`cetostearyl alcohol/ethylene oxide concentrate, cetostearyl
`alcohol in a water base. The product must be used 4 times/day
`over 10 days to eradicate nasal carriage of staphylococci. In
`addition, U.S. Pat. No. 6,214,866 discloses the use of chlo(cid:173)
`rhexidine in combination with the antibiotic mupirocin.
`Povidone-iodine has also been suggested for use in nasal
`decolonization (R. L. Hill and M. W. Casewell, Journal of
`Hospital Infection, 2000, Vol. 45, 198-205). Betadine Cream
`(5 wt-% povidone iodine) has been found to kill methicillin
`resistant staphylococcus aureus in vitro in an enrichment
`culture technique. Addition of nasal secretions decreased the
`activity of the povidone-iodine by 80-90% by reaction of the
`free iodine with the organic load. Other drawbacks of 5%
`povidone-iodine for use in patients included: 1) a very dark
`brown color, 2) a low pH which can cause irritation, 3) a
`strong iodine odor.
`The formulation of components can affect the performance
`and potential irritation of antimicrobial agents. For example,
`many conventional antimicrobial compositions are too low in
`viscosity and/or too hydrophilic in nature to maintain suffi(cid:173)
`cient substantivity and persistence to provide sufficient anti-
`microbial activity on moist tissue, such as the anterior nares or
`
`BAXTER EXHIBIT 1012
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`
`

`

`US 9,028,852 B2
`
`3
`open, exuding, or infected lesions. It has been reported that
`the presence of solvents can diminish the antimicrobial activ(cid:173)
`ity of many antiseptics. Furthermore, it has been reported that
`many surfactants can reduce the efficacy of antiseptics by
`sequestering the antiseptic in micelles. (H. B. Kostenbauer,
`Chapter 44 in Disinfection, Sterilization, and Preservation,
`First addition, 1968, C. A. Lawrence and S.S. Block). Addi(cid:173)
`tionally, surfactants are often implicated in contributing to
`irritation.
`Thus, there is still a need for effective antimicrobial com(cid:173)
`positions that develop little resistance and are well-tolerated
`when used on mammalian tissue and especially on moist
`mammalian tissue such as in the nasal passages, anterior
`nares, vagina, and wounds.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides antimicrobial composi(cid:173)
`tions and methods of using and making the compositions.
`Such compositions are typically useful when applied topi(cid:173)
`cally, particularly to mucosa! tissues (i.e., mucous mem(cid:173)
`branes), although a wide variety of surfaces can be treated.
`They can provide effective reduction, prevention, or elimina(cid:173)
`tion of microbes, particularly bacteria, fungi, and viruses.
`Preferably, the microbes are of a relatively wide variety such
`that the compositions of the present invention have a broad
`spectrum of activity.
`Compositions of the present invention provide effective
`topical antimicrobial activity and are accordingly useful in 30
`the local treatment and/or prevention of conditions that are
`caused, or aggravated by, microorganisms (including viruses,
`bacteria, fungi, mycoplasma, and protozoa) on skin, wounds,
`and/or mucous membranes.
`Significantly, certain embodiments of the present invention
`have a very low potential for generating clinical microbial
`resistance. Thus, such compositions can be applied multiple
`times over one or more days to treat topical infections or to
`eradicate unwanted bacteria (such as nasal colonization of
`Staphylococcus aureus). Furthermore, compositions of the
`present invention can be used for multiple treatment regimens
`on the same patient without the fear of generating antimicro(cid:173)
`bial resistance. This can be particularly important for chroni(cid:173)
`cally ill patients who are in need of decolonization of the
`anterior nares before hemodialysis, for example, or for anti(cid:173)
`septic treatment of chronic wounds such as diabetic foot
`ulcers.
`Also, preferred compositions of the present invention have
`a generally low irritation level for skin, skin lesions, and
`mucosa! membranes (including the anterior nares, nasal cavi- 50
`ties, and nasopharangyl cavity). Also, certain preferred com(cid:173)
`positions of the present invention are substantive (i.e. resist
`removal by fluids) for relatively long periods of time to ensure
`adequate efficacy.
`Compositions of the present invention include a cationic 55
`antiseptic. The cationic antiseptics include biguanides and
`bisbiguanides such as chlorhexidine and its various salts
`including but not limited to the digluconate, diacetate,
`dimethosulfate, and dilactate salts as well as mixtures thereof;
`polymeric quaternary ammonium compounds such as poly- 60
`hexamethylenebiguanide; silver and various silver com(cid:173)
`plexes; small molecule quaternary ammonium compounds
`such as benzalkoium chloride and alkyl substituted deriva(cid:173)
`tives, di-long chain alkyl (C8-C18) quaternary ammonium
`compounds, cetylpyridinium halides and their derivatives, 65
`benzethonium chloride and its alkyl substituted derivatives,
`and octenidine; and combinations thereof.
`
`15
`
`4
`Importantly, the compositions of the present invention are
`capable of destroying microorganisms on or in mammalian
`tissue. Therefore, the concentrations employed are generally
`greater than those that have been used to simply preserve
`5 certain topically applied compositions, i.e., prevent the
`growth of microorganism in topical compositions for pur(cid:173)
`poses other than antisepsis. For example, the concentration
`may be at least 0 .1 wt%, preferably at least 0 .2 wt% and more
`preferably at least 0.5 wt%. Commonly, the antiseptics may
`10 be employed at concentration of at least 1 wt-%, preferably at
`least 2 wt-% and often at least 3% by weight of the compo(cid:173)
`sition. All weight percents are based on the total weight of a
`"ready to use" or "as used" composition.
`Depending on the application, many of these compounds at
`these concentrations can be irritating if delivered in simple
`aqueous or hydrophilic vehicle formulations. Many of the
`compositions of the present invention incorporate a substan(cid:173)
`tial amount of a lipophilic or hydrophobic phase. The hydro-
`20 phobic phase is comprised of one or more water insoluble
`components. If delivered in a hydrophobic phase, the irrita(cid:173)
`tion can be significantly reduced. The incorporation of the
`hydrophobic phase may significantly reduce the irritation
`potential of the present compositions. Preferred lipophilic
`25 phase components have a solubility in water ofless than 0.5%
`by weight and often less 0.1 % by weight at 23 ° C. In addition,
`the antiseptic is preferably present at a concentration
`approaching or preferably exceeding the solubility limit of
`the hydrophobic phase.
`Importantly, the compositions also have sufficient viscos-
`ity to prevent inhalation into the lungs if used in the nose for
`applications such as nasal decolonization. The relatively high
`viscosity of the compositions of the present invention also
`minimizes migration that can be associated with other com-
`35 positions thus reducing irritation and mess. Despite the pres(cid:173)
`ence of the hydrophobic phase many of the antiseptic con(cid:173)
`taining compositions exhibit very effective and rapid
`antimicrobial activity.
`In addition, antimicrobial compositions that include
`40 hydrophilic components such as polyols (e.g., glycerin and
`polyethylene glycols) that themselves have little or no anti(cid:173)
`microbial activity can considerably enhance the antimicro(cid:173)
`bial activity of the compositions. Preferably, the hydrophilic
`component includes a glycol, a lower alcohol ether, a short
`45 chain ester, and combinations thereof, wherein the hydro(cid:173)
`philic component is soluble in water in an amount of at least
`20 wt-% at 23° C.
`The compositions of the present invention are preferably
`free of antibiotics.
`Preferably, the compositions also include a surfactant
`selected from the group of sulfonate, a sulfate, a phosphonate,
`a phosphate, amphoteric, a poloxamer, a cationic surfactant,
`or mixtures thereof. Preferably, the compositions also include
`an enhancer component comprising an alpha-hydroxy acid, a
`beta-hydroxy acid, a chelating agent, a (Cl-C4)alkyl car(cid:173)
`boxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)
`aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid, a
`phenolic compound, a (Cl-Cl0)alkyl alcohol, an ether gly(cid:173)
`col, or combinations thereof.
`The present invention also provides various methods of use
`of compositions of the present invention. In one embodiment,
`the present invention provides a method of preventing and/or
`treating an affliction caused, or aggravated by, a microorgan(cid:173)
`ism on mammalian tissue, such as skin and/or a mucous
`membrane. The method includes contacting the mammalian
`tissue with an antimicrobial composition of the present inven-
`tion.
`
`BAXTER EXHIBIT 1012
`Page 5 of 42
`
`

`

`US 9,028,852 B2
`
`6
`tion of the present invention in an amount effective to kill one
`or more microorganisms on or in the tissue in the nose or nasal
`cavity.
`The compositions of the present invention can also be used
`for providing residual antimicrobial efficacy on a surface that
`results from leaving a residue or imparting a condition to the
`surface ( e.g., skin, in the anterior nares, mucosa! tissue,
`wound, or medical device that comes in contact with such
`tissues, but particularly skin, mucosa! tissue, and/or wound)
`10 that remains effective and provides significant antimicrobial
`activity. This is accomplished by providing compositions
`with relatively high concentrations of a hydrophobic compo(cid:173)
`nent (generally greater than 30% by weight, preferably
`greater than 40% by weight and most preferably greater than
`15 50% by weight) and/or a composition with a relatively high
`viscosity, e.g., in excess of 1,000 cps and preferably in excess
`of 10,000 cps when measured by the Viscosity Test.
`For example, in one embodiment, the present invention
`provides a method of providing residual antimicrobial effi-
`20 cacy on the skin, in the anterior nares, mucosa! tissue, and/or
`in a wound of a subject, the method includes contacting the
`skin, mucosa! tissue, and/or wound with an antimicrobial
`composition of the present invention in an amount effective to
`kill one or more microorganisms.
`Methods of manufacture are also provided.
`
`5
`
`5
`In one embodiment, the present invention provides a
`method of decolonizing at least a portion of the nasal cavities,
`anterior nares, and/or nasopharynx of a subject of microor(cid:173)
`ganisms. The method includes contacting the nasal cavities,
`anterior nares, and/or nasopharynx with an antimicrobial
`composition of the present invention in an amount effective to
`kill one or more microorganisms in or on tissue.
`In one embodiment, the present invention provides a
`method of decolonizing at least a portion of the throat/
`esophagus of a subject of microorganisms. The method
`includes contacting the esophageal cavity with an antimicro(cid:173)
`bial composition of the present invention in an amount effec(cid:173)
`tive to kill one or more microorganisms in or on the tissue in
`the throat.
`In one embodiment, the present invention provides a
`method of decolonizing at least a portion of the throat/
`esophagus of a subject of microorganisms. The method
`includes contacting the oral cavity and/or nasal with an anti(cid:173)
`microbial composition of the present invention in an amount
`effective to allow a sufficient quantity of the composition to
`pass down the throat to reduce or eliminate bacterial coloni(cid:173)
`zation in or on the tissue in the throat.
`In one embodiment, the present invention provides a
`method of decolonizing at least a portion of the oral cavity of 25
`a subject of microorganisms. The method includes contacting
`the oral cavity with an antimicrobial composition of the
`present invention in an amount effective to kill one or more
`microorganisms in or on the soft tissue in the oral cavity.
`In one embodiment, the present invention provides a
`methodoftreating respiratory afflictions ( e.g., chronic sinusi(cid:173)
`tis in a subject. The method includes contacting at least a
`portion of the respiratory system (particularly the upper res(cid:173)
`piratory system including the nasal cavities, anterior nares,
`and/or nasopharynx) with an antimicrobial composition of 35
`the present invention in an amount effective to reduce or
`eliminate bacterial colonization in or on the soft tissue in the
`respiratory system.
`In one embodiment, the present invention provides a
`method of treating impetigo on the skin of a subject. The 40
`method includes contacting the affected area with an antimi(cid:173)
`crobial composition of the present invention in an amount
`effective to reduce or eliminate clinical signs of infection.
`In other embodiments, the present invention provides
`methods for killing or inactivating microorganisms. Herein, 45
`to "kill or inactivate" means to render the microorganism
`ineffective by killing them ( e.g., bacteria and fungi) or other(cid:173)
`wise rendering them inactive (e.g., viruses). The present
`invention provides methods for killing bacteria such as Sta(cid:173)
`phylococcus spp., Streptococcus spp., Escherichia spp., 50
`Enterococcus spp. (including antibiotic resistant strains such
`as vancomycin resistant Enterococcu), and Pseudamonas
`spp. bacteria, and combinations thereof, and more particu(cid:173)
`larly Staphylococcus aureus (including antibiotic resistant
`strains such as methicillin resistant Staphylococcus aureus), 55
`Staphylococcus epidermidis, Escherichia coli (E. coli),
`Pseudomonas aeruginosa (Pseudomonas ae.), and Strepto(cid:173)
`coccus pyogenes, which often are on or in the skin or mucosa!
`tissue of a subject. The method includes contacting the micro(cid:173)
`organism with an antimicrobial composition of the present 60
`invention in an amount effective to kill one or more microor-
`ganisms ( e.g., bacteria and fungi) or inactivate one or more
`microorganisms (e.g., viruses, particularly herpes virus).
`For example, in one embodiment, the present invention
`provides a method of killing or inactivating microorganisms
`in the nose or nasal cavity of a subject. The method includes
`contacting the affected area with an antimicrobi