US20120052025A1 - Borinic compositions - Google Patents

Borinic compositions Download PDF

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US20120052025A1
US20120052025A1 US13/319,809 US201013319809A US2012052025A1 US 20120052025 A1 US20120052025 A1 US 20120052025A1 US 201013319809 A US201013319809 A US 201013319809A US 2012052025 A1 US2012052025 A1 US 2012052025A1
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Prior art keywords
composition
compound
formula
substituted
topical
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Inventor
Venda Porter
Andre Morgan
Stanislav Jaracz
Jennifer Gronlund
Guofeng Xu
Donghui Wu
Michael Prencipe
Ravi Subramanyam
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Colgate Palmolive Co
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Colgate Palmolive Co
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Priority to US13/319,809 priority Critical patent/US20120052025A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/58—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing atoms other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur or phosphorus
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/02—Local antiseptics
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations

Definitions

  • the present invention relates to antimicrobial compositions containing a borinic acid derivative, e.g. a borinic ester.
  • the invention covers topical antimicrobial compositions, for example topical compositions for treating fungal or bacterial infections of the skin or nails, and oral compositions, for example dentifrice, for reducing bacteria in the mouth, e.g. for inhibiting and reducing plaque, gingivitis and dental caries.
  • borinic esters are effective as antibacterial agents, incorporating borinic esters into oral care compositions presents difficulties, as borinic esters have proven to be unstable when added to aqueous compositions.
  • borinic esters may hydrolyze and decompose, e.g., in oral care compositions.
  • borinic esters may be insoluble in aqueous compositions.
  • the solubility of 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane in water is only 100 ppm, and its solubility in various oils may be less than 0.5%.
  • the present invention is directed to the surprising discovery that certain borinic esters are stable, soluble, and retain antimicrobial activity when incorporated into an topical or oral care composition, e.g., a topical pharmaceutical composition or a dentifrice or mouthwash.
  • the borinic acid derivatives of the present invention are borinic esters, e.g. of formula A:
  • R 1 and R 2 are the same or different (e.g. the same), and are selected from arylalkyl, aryl, cycloalkyl, or heterocycle (e.g. substituted or unsubstituted aryl or heteroaryl, for example phenyl, chlorophenyl, methylphenyl, or methylchlorophenyl); and R 3 is heteroaryl, heteroarylalkyl, heteroarylcarbonyl, or heteroarylalkylcarbonyl (e.g., substituted or unsubstituted heteroaryl, for example quinolinyl or hydroxypyridinylcarbonyl), in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable carrier.
  • R 1 and R 2 are the same and are both aryl, e.g., phenyl, chlorophenyl, methylphenyl, or methylchlorophenyl.
  • Heteroaryl is for example an aryl group containing 1, 2 or 3 nitrogen atoms, for example pyridinyl, quinolinyl, hydroxypyridinyl, or hydroxyquinolinol.
  • Alkyl is for example C 1-4 alkyl. Substitutions are for example halogen, e.g., chloro or fluoro, hydroxy, or C 1-4 alkyl.
  • borinic esters useful in the present invention thus include, for example, (i) boron picolinates, e.g. diaryl boron picolinates, for example 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane or 3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane, as well as (ii) diaryl borinic esters, for example diphenylborane-8-hydroxyquinolinate (PBHQ).
  • boron picolinates e.g. diaryl boron picolinates
  • 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane or 3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane as well as diaryl borinic esters, for example diphenylborane-8-hydroxyquinolinate (PBHQ).
  • PBHQ
  • the borinic esters are compounds as described in WO 2006/102604, incorporated herein by reference, e.g., of Formula (I)
  • R* and R** are independently substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycle;
  • z is 0 or 1, with the proviso, that if z is 1, then A is CR 10 or N, and D is N or CR 12 , and with the further proviso that if z is 0 then D is O, S or NR 12a ;
  • E is hydrogen, hydroxy, alkoxy, (cycloalkyl)oxy, (cycloheteroalkyl)oxy, carboxy, or alkyloxycarbonyl;
  • m is 0 or 1;
  • R 12 is hydrogen, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyloxycarbonyl, amido, hydroxy, alkoxy, aryloxy, thio
  • R 9 and R 10 are independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, carbonyl, hydroxyimino, carboxy, alkyloxycarbonyl, alkylthio, alkylsulfonyl, arylthio, dialkylaminosulfonyl, alkylaminosulfonyl, aminosulfonyl, amino, alkoxy, nitro, sulfo, or hydroxy;
  • alkyl and alkaryl are sometimes used to refer to arylalkyl and alkylaryl respectively.
  • the alkyl or aryl portion of any moiety recited for R 9 , R 19 , or R 12 is optionally substituted, for example with hydroxy, halogen, or C 1-4 alkyl.
  • Alkyl is preferably C 1-4 alkyl. Cycloalkyl is preferably C 3-7 cycloalkyl. Aryl is preferably phenyl.
  • E is a member selected from hydrogen, hydroxy, or (cycloheteroalkyl)oxy such as 2-morpholinoethoxy.
  • Compounds of Formula 1 may exist in rotameric form, and the illustrated dative bond (arrow) may or may not be present, i.e., the present invention includes those compounds in which coordination between the boron atom and the nitrogen or hydroxy of the picolinate is present and those compounds where such coordination is missing.
  • the present invention also includes those compounds of Formula 1 in which a dative bond is formed between the boron and another atom of the molecule.
  • the compound of Formula 1 has a structure according to the following formula:
  • D is selected from N and CR 12 .
  • the compound of Formula 1 has a structure according to the following formula:
  • D is a member selected from O, S and NR 12a .
  • R* and R** are the same.
  • R* and R* * are substituted or unsubstituted aryl.
  • R* and R** are substituted or unsubstituted phenyl, wherein said substituted or unsubstituted phenyl has the structure:
  • each of R 4 -R 8 is a member independently selected from hydrogen, alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, alkylsulfonyl, diaminosulfonyl, alkylaminosulfonyl, aminosulfonyl, sulfo, cyano, halo, nitro, amino, 2°-amino, 3°-amino, aminosulfonyl, aminoalkyloxy, (alkylamino)alkyloxy, (dialkylamino)alkyloxy,
  • R 9 is H, z is 1, A is CH, D is CH, E is OH, and m is O.
  • R* and R** are both 3-chloro-4-methylphenyl.
  • R* and R** are both 2-methyl-4-chlorophenyl.
  • Particularly useful compounds include 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane and 3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane, in free or pharmaceutically acceptable salt form.
  • the borinic ester compounds may exist in rotameric form, wherein the form is largely pH dependent, and the boron may be linked by a coordinate covalent bond (dative bond) to the nitrogen in the heteroaryl.
  • the rotamer wherein the boron is nonpolar or associated with the hydroxy group on the picolinate moiety is predominantly or exclusively present at basic pH, while the more polar rotamer, wherein the boron is associated with the nitrogen on the picolinate or other heterocycle predominates at acidic pH.
  • the pH of the formulation be maintained above 7, e.g., by using a buffer to prevent a drop in pH which would result in formation of the more polar rotamer, and/or that the pH be maintained even at a higher level, e.g., 8-9.5, it having been surprisingly shown that the compounds are stable at higher pH, and not (as might be suspected) highly vulnerable to degradation by OH ⁇ ions.
  • This discovery allows preparation of stable aqueous formulations of the compounds.
  • this discovery is somewhat in contrast to the examples of WO 2006/102604 which describe topical emulsions, with the borinic ester in the oil phase, or else compositions having relatively low pH, e.g., 5.5.
  • composition 1.0 a composition, e.g., a topical composition, e.g., an oral care or topical pharmaceutical composition, comprising an antibacterially effective amount of a borinic acid derivative, e.g., of Formula A, for example a compound of Formula (I), having a pH of at least 8, e.g. 8.5-11, for example about 9, or buffered to at least pH 7, and optionally further comprising one or more antioxidants, surfactants and solubilizing agents.
  • a composition e.g., a topical composition, e.g., an oral care or topical pharmaceutical composition
  • an antibacterially effective amount of a borinic acid derivative e.g., of Formula A
  • a compound of Formula (I) having a pH of at least 8, e.g. 8.5-11, for example about 9, or buffered to at least pH 7, and optionally further comprising one or more antioxidants, surfactants and solubilizing agents.
  • the present invention includes Composition 2.0, a dentifrice, comprising Composition 1.0 and a dentifrice vehicle, having a pH of at least 8, e.g. 8.5-11, for example about 9, or buffered to at least pH 7, and optionally further comprising one or more antioxidants, surfactants and/or solubilizing agents.
  • the present invention comprises Composition 3.0, a topical composition, for example a topical pharmaceutical or oral care formulation, e.g., according to any of Compositions 1.0 to 2.0, comprising borinic acid derivatives, e.g. of Formula A, for example a Compound of Formula I, and a solubilizing agent, e.g., selected from polymers of polyoxyethylene and polyoxyethylene/polyoxypropylene.
  • a topical composition for example a topical pharmaceutical or oral care formulation, e.g., according to any of Compositions 1.0 to 2.0, comprising borinic acid derivatives, e.g. of Formula A, for example a Compound of Formula I, and a solubilizing agent, e.g., selected from polymers of polyoxyethylene and polyoxyethylene/polyoxypropylene.
  • composition 4.0 a topical composition, for example a topical pharmaceutical or oral care formulation, comprising an antibacterially effective amount of a borinic acid derivative, e.g., of Formula A, for example a compound of Formula (I), for example any of Compositions 1.0 et seq.—3.0 et seq. more fully described below, in combination with a suitable buffer, for example a phosphate buffer.
  • a suitable buffer for example a phosphate buffer.
  • the present invention also includes Composition 5.0, a topical composition (for example a topical antimicrobial product or an antimicrobial soap), comprising Composition 1.0, 3.0 or 4.0 and a pharmaceutically (including cosmetically) acceptable vehicle, having a pH of at least 8, e.g. 8.5-11, for example about 9, or buffered to at least 7, and optionally further comprising one or more antioxidants, surfactants and/or solubilizing agents.
  • a topical composition for example a topical antimicrobial product or an antimicrobial soap
  • a pharmaceutically (including cosmetically) acceptable vehicle having a pH of at least 8, e.g. 8.5-11, for example about 9, or buffered to at least 7, and optionally further comprising one or more antioxidants, surfactants and/or solubilizing agents.
  • the present invention also includes Method 6.0, a method for preparing a topical composition comprising mixing Composition 1.0, 3.0 or 4.0 with a pharmaceutically acceptable vehicle and adjusting or maintaining the pH at a level of at least 7, preferably at least 8, e.g., 8.5-11.
  • the present invention also includes Method 7.0, a method to reduce, inhibit, or treat topical microbial infections, for example to treat, reduce or inhibit topical skin infections, e.g., acne, superficial skin infections, minor cuts, pathogen colonization, and inflammatory skin conditions, comprising applying a Composition of the Invention to the affected skin or nails of a subject in need thereof.
  • topical skin infections e.g., acne, superficial skin infections, minor cuts, pathogen colonization, and inflammatory skin conditions
  • the present invention also includes Method 8.0, a method for preparing a topical, e.g., oral care composition comprising mixing any of Compositions 1.0-4.0 with an orally or topically acceptable vehicle and adjusting or maintaining the pH at a level of at least 7, preferably at least 8, e.g., 8.5-11.
  • the present invention also includes Method 9.0, a method to reduce, inhibit, or treat oral microbial infections, for example to reduce or inhibit formation of dental caries, to treat, reduce or inhibit gingivitis, to reduce levels of oral bacteria, to inhibit microbial biofilm formation in the oral cavity, to reduce plaque accumulation, and/or clean the teeth and oral cavity, comprising applying a Composition of the Invention to the oral cavity of a subject in need thereof.
  • FIG. 1 depicts percent of COMPOUND 1 recovery after two weeks at 60° C. as a function of formula pH in the (a) G-series base and (b) the low water base, as further described in the examples.
  • FIG. 2 shows the percentage of COMPOUND 1 recovery in a 50/50 acetonitrile/water solution as a function of pH after 1 day at 70° C., as further described in the examples.
  • ranges are used as a shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.
  • all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
  • the oral compositions of the present invention may include a dentifrice, mouth rinse, dental floss, dental paint, dental film, lozenge, or confectionery.
  • Dentifrice compositions may include a toothpaste, gel, or powder.
  • Orally acceptable salts are pharmaceutically acceptable acid or base addition salts that are safe for use in an oral care product such as a dentifrice in the amounts and concentrations provided by normal use of the product.
  • Compounds of Formula (I) which may be useful in the present invention include: 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane (or bis(3-chloro-4-methylphenyl)borinic acid 3-hydroxypicolinate ester), e.g. of Formula (II):
  • Composition 1 e.g., a composition, e.g., an oral care composition or topical pharmaceutical formulation, comprising an antibacterially effective amount of a borinic acid derivative, e.g., of Formula A, for example a compound of Formula (I), having a pH of at least 7, preferably at least 8, e.g. 8.5-11, for example about 9, and optionally further comprising one or more antioxidants, surfactants and solubilizing agents, includes, for example, any of the following compositions:
  • compounds of Formula A may be oxidized by oxygen, peroxides, or by peroxides that can be formed in oral and topical compositions, e.g., from ethers such as polyethylene glycol reacting with oxygen.
  • oxygen and/or peroxides may react with the borinic ester at the carbon-boron bond, leading to cleavage and formation of boronic acid derivatives and phenol derivatives, which are ineffective antibacterial agents.
  • the addition of antioxidants reduces the peroxides and other oxidizing agents that may be present or form in the oral compositions.
  • Composition 1.0 thus includes for example, any of the following compositions:
  • the compounds of formula (I) are solubilzed in the compositions of the present invention with a solubilizing agent, which may include for example polyethylene glycol, glycerin, co-polymers of polyethylene glycol and polypropylene glycol (e.g., Pluraflo L4370), or Triblock Copolymer Surfactant F127.
  • a solubilizing agent which may include for example polyethylene glycol, glycerin, co-polymers of polyethylene glycol and polypropylene glycol (e.g., Pluraflo L4370), or Triblock Copolymer Surfactant F127.
  • solubilizing agent which may include for example polyethylene glycol, glycerin, co-polymers of polyethylene glycol and polypropylene glycol (e.g., Pluraflo L4370), or Triblock Copolymer Surfactant F127.
  • the amounts of solubilizing agent required will be dependent upon the amount of the compounds of Formula (I)
  • compositions of the invention also may optionally include one or more chelating agents which are able to complex calcium found in the cell walls of the bacteria, which, it is believed weakens the bacterial cell wall and augments bacterial lysis.
  • Chelating agents may further sequester ions that could complex with and destabilize the borinic acid derivatives.
  • Agents suitable for use as chelating agents are known to those of skill in the art, and include di- or tetra-acids and their salts, such as the soluble pyrophosphates, polycarboxylic acids, and polyaminocarboxylic acids.
  • the pyrophosphate salts used in the present compositions can be any of the alkali metal pyrophosphate salts.
  • salts include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium.
  • the salts are useful in both their hydrated and unhydrated forms.
  • An effective amount of pyrophosphate salt useful in the present composition is generally enough to provide at least about 1 wt. % pyrophosphate ions, about 1.5 wt. % to about 6 wt. %, about 3.5 wt. % to about 6 wt. % of such ions.
  • Useful chelating agents include tetrasodium pyrophosphate, tetrapotassium pyrophosphate, ethylene diamine tetraacetic acid, ethylene glycol tetraacetic acid, sodium pyrophosphate, sodium tripolyphosphate, potassium tripolyphosphate, sodium hexametaphosphate, and citric acid. Accordingly, in a further embodiment, the invention provides
  • Composition 2.0 of the present invention is an oral care product, comprising an effective amount of Composition 1.0 and an orally acceptable carrier.
  • Acceptable carriers suitable for use in an oral care product are known by those of skill in the art, and may take the form of a paste, gel or mouthwash which includes water and/or a humectant, or may take the form of a powder, or a dental floss or dental device.
  • the components of the acceptable carrier may include Composition 1.0.
  • Humectants are known by those of skill in the art, and include edible polyhydric alcohols such as glycerine, sorbitol, xylitol, alkylene glycol such as polyethylene glycol or propylene glycol as well as other polyols and mixtures of these humectants.
  • the oral compositions of the present invention may comprise from about 5% to about 80% by weight of the humectant, with water and other components making up the balance of the carrier.
  • Composition 2 in the form of a paste, gel or liquid comprising any of compositions 1-1.24 in combination or association with water and/or a humectant.
  • 2.2 Composition 2.1 wherein the amount of water is less than 10%.
  • 2.3 Composition 2.1 or 2.2 wherein the amount of humectant is greater than 50%.
  • 2.4 Any of Compositions 2-2.3 wherein the humectant is selected from polyhydric alcohols (e.g. glycerine, sorbitol, xylitol) and alkylene glycol (polyethylene glycol or propylene glycol as well as other polyols and mixtures.
  • humectant is selected from polyhydric alcohols (e.g. glycerine, sorbitol, xylitol) and alkylene glycol (polyethylene glycol or propylene glycol as well as other polyols and mixtures.
  • Any of Compositions 2-2.4 which is a dentifrice.
  • the invention provides a topical or oral care composition, Composition 3.0, e.g., according to Composition 1.0 through 2.8, comprising borinic acid derivatives, e.g. of Formula A, for example a compound of Formula I, and at least one solubilizing agent selected from polymers of polyoxyethylene and/or polyoxypropylene, e.g.
  • solubilizing agent comprises a co-polymer of polyethylene glycol and polypropylene glycol, e.g., Fluraflo L4370 (BASF).
  • solubilizing agent comprises a poloxamer, e.g. a tri-block co-polymer of formula H—(O—CH 2 —CH 2 ) x —(O—CH(CH 3 )CH 2 ) y —(O—CH 2 —CH 2 ) z —OH.
  • 3.3 Composition 3.2 wherein the average molecular weight of the polyoxypropylene block in the poloxamer is approximately 3-4 kD, the polyoxyethylene content is approximately 65-75%, and the total average molecular weight of the poloxamer is approximately 12-13 kD, for example wherein x and z are each 90-110, e.g. about 101, and y is 50-65, e.g., about 56, for example wherein the poloxamer is poloxamer 407 (e.g., Pluronic® F-127 from BASF).
  • 3.3 Composition 3.0 wherein the solubilizing agent comprises polyethylene glycol, e.g.
  • solubilizing agent comprises an agent selected from co-polymers of polyethylene glycol and polypropylene glycol, poloxamers, polyethylene glycols, and mixtures thereof. It has also been discovered that the stability of the borinic acid derivatives is significantly enhanced by use of buffering agents, even to a large extent at neutral pH.
  • composition 4 a topical or oral care formulation, e.g., according to any of the preceding Compositions 1.0 through 3.4, comprising an antibacterially effective amount of a borinic acid derivative, e.g., of Formula A, for example a compound of Formula (I), and a buffer, having a pH of about 7 to about 11, for example a pH of at e.g., at least 8, for example having a phosphate buffer providing a pH of at least 7.2.
  • a borinic acid derivative e.g., of Formula A
  • a buffer having a pH of about 7 to about 11, for example a pH of at e.g., at least 8, for example having a phosphate buffer providing a pH of at least 7.2.
  • the oral care compositions of the present invention may also contain one or more fluoride ion sources, e.g., fluoride salts which may be soluble. Fluoride salts wherein the fluoride is covalently bound to another atom and/or sequestered from calcium are preferred.
  • fluoride ion-yielding materials can be employed as sources of soluble fluoride in the present compositions.
  • Representative fluoride ion sources include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof.
  • the fluoride ion source includes stannous fluoride, sodium fluoride, sodium monofluorophosphate as well as mixtures thereof.
  • the oral care composition of the invention may also contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 25 ppm to about 25,000 ppm of fluoride ions, generally at least about 500 ppm, e.g., about 500 to about 2000 ppm, e.g., about 1000—about 1600 ppm, e.g., about 1450 ppm.
  • Fluoride ion sources may be added to the compositions of the invention at a level of about 0.01 wt. % to about 10 wt. % in one embodiment or about 0.03 wt. % to about 5 wt. %, and in another embodiment about 0.1 wt. % to about 1 wt. % by weight of the composition in another embodiment.
  • Weights of fluoride salts to provide the appropriate level of fluoride ion will obviously vary based on the weight of the counter ion in the salt.
  • the oral compositions of the present invention may also comprise an additional antibacterial agent, which are know by those of skill in the art, such as a halogenated diphenyl ether (triclosan), herbal extracts or essential oils, biguanide antiseptics, phenolic antiseptics, hexetidine, povidone iodine, delmopinol, salifluor, metal ions (e.g., zinc salts, for example, zinc citrate), sanguinarine, and propolis.
  • an additional antibacterial agent such as a halogenated diphenyl ether (triclosan), herbal extracts or essential oils, biguanide antiseptics, phenolic antiseptics, hexetidine, povidone iodine, delmopinol, salifluor, metal ions (e.g., zinc salts, for example, zinc citrate), sanguinarine, and propolis.
  • an additional antibacterial agent such as a halogenated diphenyl ether
  • the oral compositions of the present invention may also comprise a tooth desensitizing agent, which are known by those of skill in the art, and include a potassium salt, capsaicin, eugenol, a strontium salt, a zinc salt, a chloride salt, or combinations thereof.
  • a tooth desensitizing agent which are known by those of skill in the art, and include a potassium salt, capsaicin, eugenol, a strontium salt, a zinc salt, a chloride salt, or combinations thereof.
  • the oral compositions of the present invention may comprise abrasives and/or polishing agents, such as calcium and silica abrasives, which are known by those of skill in the art.
  • Preferred calcium abrasives may include a calcium phosphate abrasive, e.g., tricalcium phosphate (Ca 3 (PO 4 ) 2 ), hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), or dicalcium phosphate dihydrate (CaHPO 4 .2H 2 O).
  • Useful silica abrasives may include precipitated silicas having a mean particle size of up to about 20 microns, such as Zeodent 115®, marketed by J. M. Huber.
  • Other useful abrasives also include sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof.
  • the silica abrasive polishing materials useful herein, as well as the other abrasives generally have an average particle size of about 0.1 and about 30 microns, about 5 and about 15 microns.
  • the silica abrasives can be from precipitated silica or silica gels, such as the silica xerogels, which may be are marketed under the trade name Syloid® by the W. R. Grace & Co., Davison Chemical Division.
  • the precipitated silica materials include those marketed by the J. M. Huber Corp. under the trade name Zeodent®, including the silica carrying the designation Zeodent 115 and 119.
  • abrasive materials useful in the practice of the oral care compositions in accordance with the invention include silica gels and precipitated amorphous silica having an oil absorption value of about less than 100 cc/100 g silica and in the range of about 45 cc/100 g to about 70 cc/100 g silica. Oil absorption values are measured using the ASTA Rub-Out Method D281.
  • the silicas are colloidal particles having an average particle size of about 3 microns to about 12 microns, and about 5 to about 10 microns.
  • the abrasive materials comprise very small particles, e.g., having a d50 less than about 5 microns.
  • small particle silica SPS
  • Sorbosil AC43® Sorbosil AC43® (Ineos).
  • SPS small particle silica
  • Sorbosil AC43® Sorbosil AC43®
  • Such small particles are particularly useful in formulations targeted at reducing hypersensitivity.
  • the small particle component may be present in combination with a second larger particle abrasive.
  • the formulation comprises about 3—about 8% SPS and about 25—about 45% of a conventional abrasive.
  • compositions containing silica and the compounds of Formula (I) change color, from white to yellow, which is undesirable. Such a color change is observable even if the composition contains antioxidants (previously discussed).
  • the present invention is also based on the surprising discovery that the addition of a chelating agent to the oral composition can inhibit such color change, indeed, reverse such color change. Chelating agents useful to prevent such color change have been previously discussed.
  • Low oil absorption silica abrasives particularly useful in the practice of the invention are marketed under the trade designation Sylodent XWA® by Davison Chemical Division of W.R. Grace & Co., Baltimore, Md. 21203.
  • Sylodent 650 XWA® a silica hydrogel composed of particles of colloidal silica having a water content of about 29% by weight averaging about 7 to about 10 microns in diameter, and an oil absorption of less than about 70 cc/100 g of silica is an example of a low oil absorption silica abrasive useful in the practice of the present invention.
  • the abrasive is present in the oral care composition of the present invention at a concentration of about 10 to about 60% by weight, in other embodiment about 20 to about 45% by weight, and in another embodiment about 30 to about 50% by weight.
  • the oral care compositions of the invention also may include an agent to increase the amount of foam that is produced when the oral cavity is brushed, and such agents are known by those of skill in the art.
  • agents that increase the amount of foam include, but are not limited to polyoxyethylene and certain polymers including, but not limited to, alginate polymers.
  • the polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care carrier component of the present invention.
  • Polyoxyethylene is also commonly known as polyethylene glycol (“PEG”) or polyethylene oxide.
  • PEG polyethylene glycol
  • the polyoxyethylenes suitable for this invention will have a molecular weight of about 200,000 to about 7,000,000. In one embodiment the molecular weight will be about 600,000 to about 2,000,000 and in another embodiment about 800,000 to about 1,000,000.
  • the polyoxyethylene may be present in an amount of about 1% to about 90%, in one embodiment about 5% to about 50% and in another embodiment about 10% to about 20% by weight of the oral care carrier component of the oral care compositions of the present invention.
  • the dosage of foaming agent in the oral care composition i.e., a single dose
  • compositions of the present invention may also a surfactant or a mixture of compatible surfactants, which are known by those of skill in the art.
  • Suitable surfactants are those which are reasonably stable throughout a wide pH range, for example, anionic, cationic, nonionic or zwitterionic surfactants, including mixtures thereof.
  • Anionic surfactants useful herein include the water-soluble salts of alkyl sulfates having about 10 to about 18 carbon atoms in the alkyl radical and the water-soluble salts of sulfonated monoglycerides of fatty acids having about 10 to about 18 carbon atoms, e.g., sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates. Mixtures of anionic surfactants may also be utilized.
  • Cationic surfactants useful herein may include derivatives of aliphatic quaternary ammonium compounds having one long alkyl chain containing about 8 to about 18 carbon atoms, e.g., lauryl trimethylammonium chloride, cetyl pyridinium chloride, cetyl trimethylammonium bromide, di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconut alkyltrimethylammonium nitrite, and cetyl pyridinium fluoride.
  • lauryl trimethylammonium chloride cetyl pyridinium chloride
  • cetyl trimethylammonium bromide di-isobutylphenoxyethyldimethylbenzylammonium chloride
  • coconut alkyltrimethylammonium nitrite and cetyl pyridinium fluoride.
  • Nonionic surfactants that can be used in the compositions of the invention can be defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature.
  • nonionic surfactants useful in the present invention include the Pluronics, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.
  • Poloxamers are a particular type of nonionic surfactant that can be used in the invention.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
  • Poloxamers are also known by the trade name Pluronics. Because the lengths of the polymer blocks can be customized, many different poloxamers exist that have slightly different properties.
  • Zwitterionic synthetic surfactants useful in the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate or phosphonate.
  • Illustrative examples of the surfactants suited for inclusion into the composition include, but are not limited to, sodium alkyl sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine and polysorbate 20, and combinations thereof.
  • the surfactant or mixtures of compatible surfactants can be present in the compositions of the present invention in about 0.1% to about 5.0%, in another embodiment about 0.3% to about 3.0% and in another embodiment about 0.5% to about 2.0% by weight of the total composition.
  • the oral care compositions of the invention may also include one or more flavoring agents, which are known by those of skill in the art.
  • Flavoring agents which are used in the practice of the present invention include, but are not limited to, essential oils as well as various flavoring aldehydes, esters, alcohols, and similar materials.
  • the essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, rosemary, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange.
  • Also useful are such chemicals as menthol, carvone, and anethole, and other extracts, such as green tea extract.
  • the flavoring agent is incorporated in the oral composition at a concentration of about 0.1 to about 5% by weight and about 0.5 to about 1.5% by weight.
  • the dosage of flavoring agent in the individual oral care composition dosage (i.e., a single dose) is about 0.001 to about 0.05% by weight and in another embodiment about 0.005 to about 0.015% by weight.
  • the oral care compositions of the invention also optionally include one or more polymers, which are known by those of skill in the art, such as polyethylene glycols, polyvinylethyl ether maleic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum).
  • polysaccharides e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum.
  • Acidic polymers for example polyacrylate gels, may be provided in the form of their free acids or partially or fully neutralized water soluble alkali metal (e.g., potassium and sodium) or ammonium salts.
  • Certain embodiments include about 1:4 to about 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, for example, methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000.
  • methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000.
  • M.W. methyl vinyl ether
  • These copolymers are available for example as Gantrez AN 139(M.W. 500,000), AN 119 (M.W. 250,000) and S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals Corporation.
  • Such copolymers may improve the antibacterial activity of the compounds of Formula (I) (IR8387).
  • operative polymers include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
  • a further class of polymeric agents includes a composition containing homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalykane sulfonic acids such as 2-acrylamide 2 methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid, incorporated herein by reference.
  • polyamino acids particularly those containing proportions of anionic surface-active amino acids such as aspartic acid, glutamic acid and phosphoserine, as disclosed in U.S. Pat. No. 4,866,161 Sikes et al., incorporated herein by reference.
  • thickening material In preparing oral care compositions, it is sometimes necessary to add some thickening material to provide a desirable consistency or to stabilize or enhance the performance of the formulation.
  • Such thickening materials are known by those of skill in the art, and may include carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose.
  • Natural gums such as karaya, gum arabic, and gum tragacanth can also be incorporated.
  • Colloidal magnesium aluminum silicate or finely divided silica can be used as component of the thickening composition to further improve the composition's texture.
  • thickening agents in an amount of about 0.5% to about 5.0% by weight of the total composition are used.
  • the oral care compositions of the invention may also optionally include one or more enzymes known by those of skill in the art.
  • Useful enzymes include proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases or compatible mixtures thereof.
  • the enzyme is a protease, dextranase, endoglycosidase and mutanase.
  • the enzyme is papain, endoglycosidase or a mixture of dextranase and mutanase.
  • An enzyme of a mixture of several compatible enzymes in the current invention constitutes about 0.002% to about 2% in one embodiment or about 0.05% to about 1.5% in another embodiment or in yet another embodiment about 0.1% to about 0.5%.
  • the embodiments of this invention can contain a variety of optional dentifrice ingredients some of which are described below.
  • Optional ingredients include, for example, but are not limited to, adhesives, sudsing agents, flavoring agents, sweetening agents, additional antiplaque agents, abrasives, and coloring agents, which are known by those of skill in the art.
  • compositions of the present invention can be made using methods which are common in the oral product area.
  • the present invention in one method aspect involves applying to the oral cavity a safe and effective amount of the oral care compositions described herein, e.g. with brushing, to (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit pre-carious lesions of the enamel, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), (iii) reduce or inhibit demineralization and promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial biofilm formation in the oral cavity, (x) raise and/or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xii) reduce dry mouth, (xiii) clean the teeth and oral cavity (xi
  • the oral compositions may also comprise one or more suitable solvents.
  • suitable solvents The ability of any solid substance (solute) to dissolve in any liquid substance (solvent) is dependent upon the physical properties of the solute and the solvent. When solutes and solvents have similar physical properties the solubility of the solute in the solvent will be the greatest. This gives rise to the traditional understanding that “like dissolves like.”
  • Solvents can be characterized in one extreme as non-polar, lipophilic oils, while in the other extreme as polar hydrophilic solvents. Oily solvents dissolve other non-polar substances by Van der WaI interactions while water and other hydrophilic solvents dissolve polar substances by ionic, dipole, or hydrogen bonding interactions. All solvents can be listed along a continuum from the least polar, i.e.
  • hydrocarbons such as decane to the most polar solvent being water.
  • a solute will have its greatest solubility in solvents having equivalent polarity.
  • less polar solvents will provide improved solubility with the solvent having polarity nearly equivalent to the solute providing maximum solubility.
  • Most drugs have intermediate polarity, and thus experience maximum solubility in solvents such as propylene glycol or ethanol, which are significantly less polar than water. If the drug has greater solubility in propylene glycol (for example 8% (w/w)) than in water (for example 0.1% (w/w)) 5 then addition of water to propylene glycol should decrease the maximum amount of drug solubility for the solvent mixture compared with pure propylene glycol. Addition of a poor solvent to an excellent solvent will decrease the maximum solubility for the blend compared with the maximum solubility in the excellent solvent.
  • the concentration of active ingredient in the formulation may be limited by the solubility of the active ingredient in the chosen solvent and/or carrier.
  • Non-lipophilic drugs typically display very low solubility in pharmaceutically acceptable solvents and/or carriers.
  • the solubility of some borinic acid complexes in water is less than 0.00025% wt/wt.
  • the solubility of the same borinic acid complexes can be less than about 2% wt/wt in either propylene glycol or isopropyl myristate.
  • diethylene glycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of Formula I.
  • the borinic acid complexes useful in the present formulation are believed to have a solubility of from about 10% wt/wt to about 25% wt/wt in DGME.
  • a DGME water cosolvent system is used to dissolve the compounds of Formula I.
  • the solvent capacity of DGME drops when water is added; however, the DGME/water cosolvent system can be designed to maintain the desired concentration of from about 0.1% to about 5% wt/wt active ingredient.
  • the active ingredient is present from about 0.5% to about 3% wt/wt, and more preferably at about 1% wt/wt. This increased solubility reduces the likelihood of reduced bioavailability caused by precipitation.
  • Liquid forms may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, thickeners, and the like.
  • Solid forms such as creams or pastes or the like may include, for example, any of the following ingredients, water, oil, alcohol or grease as a substrate with surfactant, polymers such as polyethylene glycol, thickeners, solids and the like.
  • Liquid or solid formulations may include enhanced delivery technologies such as liposomes, microsomes, microsponges and the like. Additionally, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • the invention comprises topical pharmaceutical compositions comprising an effective amount of a compound of formula A.
  • effective amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect.
  • Topicically effective,” “cosmetically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.
  • Topicically effective refers to a material that, when applied to the skin, produces a desired pharmacological result either locally at the place of application or systemically as a result of transdermal passage of an active ingredient in the material.
  • Cosmetically effective refers to a material that, when applied to the skin, produces a desired cosmetic result locally at the place of application of an active ingredient in the material.
  • “Pharmaceutically acceptable salts” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and are not toxic at the levels of exposure provided by normal use of the products of the invention.
  • Such salts may include, by way of example only, hydrochloric, phosphoric, hydrobromic, sulfuric, sulfuric, formic, toluenesulfonic, methanesulfonic, hydroxy-ethanesulfonic, nitric, benzoic, citric, tartaric, maleic, fumaric hydroiodic, lactic, succinic, alkanoic such as acetic, HOOC—(CH 2 ) p —CH 3 where p is 0-4, and the like.
  • pharmaceutically compatible salts can be formed with many acids, including but not limited to non-toxic pharmaceutical base addition salts including salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of nontoxic pharmaceutically acceptable addition salts.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of a active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
  • Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Part 8 of Remington's Pharmaceutical Sciences, 17.sup.th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.
  • “Pharmaceutically acceptable topical carrier” and equivalent terms refer to pharmaceutically acceptable carriers, as described herein above, suitable for topical application;
  • An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin is an example of a pharmaceutically-acceptable topical carrier.
  • This term is specifically intended to encompass carrier materials approved for use in topical cosmetics as well.
  • pharmaceutically acceptable additive refers to preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients known or used in the field of drug formulation and that do not unduly interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
  • Additives for topical formulations are well-known in the art, and may be added to the topical composition, as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not cause deterioration in the stability of the composition.
  • enhancement refers to an increase in the permeability of the skin to a drug, so as to increase the rate at which the drug permeates through the skin.
  • the enhanced permeation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through animal or human skin using a diffusion cell apparatus.
  • a diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162.
  • permeation enhancer or “penetration enhancer” intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin to a drug.
  • excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
  • topical administration refers to the application of a pharmaceutical agent to the external surface of the skin, such that the agent is locally active and/or crosses the external surface of the skin and enters the underlying tissues. Topical administration includes application of the composition to intact skin, to broken, raw or open wound of skin.
  • Topical administration of a pharmaceutical agent can result in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can result in systemic distribution of the agent.
  • transdermal delivery refers to the diffusion of an agent across the barrier of the skin resulting from topical administration or other application of a composition.
  • stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin.
  • the epidermis and dermis are permeable to many solutes and absorption of drugs therefore occurs more readily through skin that is abraded or otherwise stripped of the stratum corneum to expose the epidermis.
  • Transdermal delivery includes injection or other delivery through any portion of the skin or mucous membrane and absorption or permeation through the remaining portion. Absorption through intact skin can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers. As used herein, transdermal delivery is intended to include delivery by permeation through or past the integument, i.e. skin, hair, or nails.
  • Active agents useful in the presently claimed topical formulations are compounds that are active against acne vulgaris and/or secondarily infected skin conditions. Examples of active agents useful in the presently claimed topical formulations are disclosed in U.S. patent application Ser. No. 10/867,465 filed on Jun. 16, 2004, which application is incorporated herein in its entirety. Preferably the active agents are the borinic acid complexes of Formula A described herein above.
  • the present invention includes topical pharmaceutical compositions.
  • These topical pharmaceutical compositions can be manufactured in a manner that is itself known, e.g., by means of a conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the desired product chosen.
  • compositions of the present invention comprises fluid or semi-solid vehicles that may include but are not limited to polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and a solvent or mixed solvent system.
  • the solvent or mixed solvent system is important to the formation because it is primarily responsible for dissolving the drug.
  • the best solvent or mixed solvent systems are also capable of maintaining clinically relevant levels of the drug in solution despite the addition of a poor solvent to the formulation.
  • the topical compositions useful in the subject invention can be made into a wide variety of product types.
  • disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate Techniques for formulation and administration can be found in “Remington's Pharmaceutical Sciences.” Mack Publishing Co, Easton, Pa. The formulation can be selected to maximize delivery to a desired target site in the body.
  • Lotions which are preparations that are to be applied to the skin surface without friction, are typically liquid or semi-liquid preparations in which finely divided solid, waxy, or liquid are dispersed. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.
  • Creams containing the active agent for delivery according to the present invention are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase is generally comprised of petrolatum or a fatty alcohol, such as cetyl- or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation as explained in Remington: The Science and Practice of Pharmacy, supra, is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • Gel formulations can also be used in connection with the present invention. As will be appreciated by those working in the field of topical drug formulation, gels are semisolid. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also may be a solvent or solvent blend.
  • Ointments which are semisolid preparations, are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well, e.g., emolliency or the like.
  • an ointment base should be inert, stable, nonirritating and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • W/O water-in-oil
  • O/W oil-in-water
  • Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy, supra, for further information.
  • Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin for delivery.
  • Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the drug or active agent can be dissolved.
  • the carrier evaporates, leaving concentrated active agent at the site of administration.
  • the topical pharmaceutical compositions may also comprise suitable solid or gel phase carriers.
  • suitable solid or gel phase carriers include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the topical pharmaceutical compositions may also comprise a suitable emulsifier which refers to an agent that enhances or facilitates mixing and suspending oil-in-water or water-in-oil.
  • a suitable emulsifier which refers to an agent that enhances or facilitates mixing and suspending oil-in-water or water-in-oil.
  • the emulsifying agent used herein may consist of a single emulsifying agent or may be a nonionic, anionic, cationic or amphoteric surfactant or blend of two or more such surfactants; preferred for use herein are nonionic or anionic emulsifiers.
  • Such surface-active agents are described in “McCutcheon's Detergent and Emulsifiers,” North American Edition, 1980 Annual published by the McCutcheon Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J. 07452, USA.
  • high molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate.
  • Other examples are ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60), diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate (CRODESTA F-160), polyoxyethylene lauryl ether (BRIJ 30), polyoxyethylene (2) stearyl ether (BRIJ 72), polyoxyethylene (21) stearyl ether (BRIJ 721), polyoxyethylene monostearate (Myrj 45), polyoxyethylene sorbitan monostearate (TWEEN 60), polyoxyethylene sorbitan monooleate (TWEEN 80), polyoxyethylene sorbitan monolaurate (TWEEN 20) and
  • Cholesterol and cholesterol derivatives may also be employed in externally used emulsions and promote w/o emulsions.
  • Especially suitable nonionic emulsifying agents are those with hydrophile-lipophile balances (HLB) of about 3 to 6 for w/o system and 8 to 18 for o/w system as determined by the method described by Paul L. Lindner in “Emulsions and Emulsion”, edited by Kenneth Lissant, published by Dekker, New York, N.Y., 1974, pages 188-190. More preferred for use herein are one or more nonionic surfactants that produce a system having HLB of about 8 to about 18.
  • HLB hydrophile-lipophile balances
  • nonionic emulsifiers include but are not limited to “BRIJ 72”, the trade name for a polyoxyethylene (2) stearyl ether having an HLB of 4.9; “BRIJ 721”, the trade name for a polyoxyethylene (21) stearyl ether having an HLB of 15.5, “Brij 30”, the trade name for polyoxyethylene lauryl ether having an HLB of 9.7; “Polawax”, the trade name for emulsifying wax having an HLB of 8.0; “Span 60”, the trade name for sorbitan monostearate having an HLB of 4.7; “Crodesta F-160”, the trade name for sucrose stearate” having an HLB of 14.5.
  • each emulsifying agent is present in amount from about 0.5 to about 2.5 wt %, preferably 0.5 to 2.0%, more preferably 1.0% or 1.8%.
  • the emulsifying agent comprises a mixture of steareth 21 (at about 1.8%) and steareth 2 (at about 1.0%).
  • the topical pharmaceutical compositions may also comprise suitable emollients.
  • Emollients are materials used for the prevention or relief of dryness, as well as for the protection of the skin.
  • Useful emollients include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol, and the like.
  • suitable emollients are known and can be used herein. See e.g., Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), and U.S. Pat. No. 4,919,934, to Deckner et al., issued Apr. 24, 1990, both of which are incorporated herein by reference in their entirety.
  • each emollient is present in an amount from about 0.1 to 15%, preferably 0.1 to about 3.0, more preferably 0.5, 1.0, or 2.5 wt %.
  • the emollient is a mixture of cetyl alcohol, isopropyl myristate and stearyl alcohol in a 1/5/2 ratio.
  • the emollient may also be a mixture of cetyl alcohol and stearyl alcohol in a 1/2 ratio.
  • the topical pharmaceutical compositions may also comprise suitable antioxidants, substances known to inhibit oxidation.
  • Antioxidants suitable for use in accordance with the present invention include, but are not limited to, butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone and tocopherols such as vitamin E, and the like, including pharmaceutically acceptable salts and esters of these compounds.
  • the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, pharmaceutically acceptable salts or esters thereof, or mixtures thereof.
  • the antioxidant is butylated hydroxytoluene. These materials are available from Ruger Chemical Co, (Irvington, N.J.).
  • the topical formulations of the present invention contain at least one antioxidant, the total amount of antioxidant present is from about 0.001 to 0.5 wt %, preferably 0.05 to about 0.5 wt %, more preferably 0.1%.
  • the topical pharmaceutical compositions may also comprise suitable preservatives.
  • Preservatives are compounds added to a pharmaceutical formulation to act as an antimicrobial agent.
  • preservatives known in the art as being effective and acceptable in parenteral formulations are benzalkonium chloride, benzethonium, chlorohexidine, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof. See, e.g., Wall Later, K.-H., Develop. Biol.
  • the preservative is selected from methylparaben, propylparaben and mixtures thereof. These materials are available from Inolex Chemical Co (Philadelphia, Pa.) or Spectrum Chemicals.
  • the topical formulations of the present invention contain at least one preservative, the total amount of preservative present is from about 0.01 to about 0.5 wt %, preferably from about 0.1 to 0.5%, more preferably from about 0.03 to about 0.15.
  • the preservative is a mixture of methylparaben and proplybarben in a 5/1 ratio. When alcohol is used as a preservative, the amount is usually 15 to 20%.
  • the topical pharmaceutical compositions may also comprise suitable chelating agents to form complexes with metal cations that do not cross a lipid bilayer.
  • suitable chelating agents include ethylene diamine tetraacetic acid (EDTA), ethylene glycol-bis(beta-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) and 8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N 5 N,N′,N′-tetraacetic acid, tetrapotassium salt (QUIN-2).
  • the chelating agents are EDTA and citric acid. These materials are available from Spectrum Chemicals.
  • the total amount of chelating agent present is from about 0.005% to 2.0% by weight, preferably from about 0.05% to about 0.5 wt %, more preferably about 0.1% by weight.
  • the topical pharmaceutical compositions may also comprise suitable basifying agents and buffers to adjust and maintain the pH of the formulation to a range of at least pH 8.
  • suitable basifying agents and buffers to adjust and maintain the pH of the formulation to a range of at least pH 8.
  • the topical formulations of the present invention contain at least one basifying or buffering agent, the total amount of agent present is from about 0.1 wt % to about 10 wt %, preferably 0.1 wt % to about 5.0 wt %, and more preferably about 1.0 wt %.
  • the agent is generally added in whatever amount is required to bring the formulation to the desired pH.
  • the topical pharmaceutical compositions may also comprise suitable viscosity increasing agents. These components are diffusible compounds capable of increasing the viscosity of a polymer-containing solution through the interaction of the agent with the polymer.
  • CARBOPOL ULTREZ 10 may be used as a viscosity-increasing agent. These materials are available from Noveon Chemicals, Cleveland, Ohio.
  • the topical formulations of the present invention contain at least one viscosity increasing agent, the total amount of viscosity increasing agent present is from about 0.25% to about 5.0% by weight, preferably from about 0.25% to about 1.0 wt %, and more preferably from about 0.4% to about 0.6% by weight.
  • the topical pharmaceutical compositions may also comprise one or more suitable solvents.
  • suitable solvents The ability of any solid substance (solute) to dissolve in any liquid substance (solvent) is dependent upon the physical properties of the solute and the solvent. When solutes and solvents have similar physical properties the solubility of the solute in the solvent will be the greatest. This gives rise to the traditional understanding that “like dissolves like.”
  • Solvents can be characterized in one extreme as non-polar, lipophilic oils, while in the other extreme as polar hydrophilic solvents. Oily solvents dissolve other non-polar substances by Van der WaI interactions while water and other hydrophilic solvents dissolve polar substances by ionic, dipole, or hydrogen bonding interactions. All solvents can be listed along a continuum from the least polar, i.e.
  • hydrocarbons such as decane to the most polar solvent being water.
  • a solute will have its greatest solubility in solvents having equivalent polarity.
  • less polar solvents will provide improved solubility with the solvent having polarity nearly equivalent to the solute providing maximum solubility.
  • Most drugs have intermediate polarity, and thus experience maximum solubility in solvents such as propylene glycol or ethanol, which are significantly less polar than water. If the drug has greater solubility in propylene glycol (for example 8% (w/w)) than in water (for example 0.1% (w/w)) 5 then addition of water to propylene glycol should decrease the maximum amount of drug solubility for the solvent mixture compared with pure propylene glycol. Addition of a poor solvent to an excellent solvent will decrease the maximum solubility for the blend compared with the maximum solubility in the excellent solvent.
  • the concentration of active ingredient in the formulation may be limited by the solubility of the active ingredient in the chosen solvent and/or carrier.
  • Non-lipophilic drugs typically display very low solubility in pharmaceutically acceptable solvents and/or carriers.
  • the solubility of some borinic acid complexes in water is less than 0.00025% wt/wt.
  • the solubility of the same borinic acid complexes can be less than about 2% wt/wt in either propylene glycol or isopropyl myristate.
  • diethylene glycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of Formula I.
  • the borinic acid complexes useful in the present formulation are believed to have a solubility of from about 10% wt/wt to about 25% wt/wt in DGME.
  • a DGME water cosolvent system is used to dissolve the compounds of Formula I.
  • the solvent capacity of DGME drops when water is added; however, the DGME/water cosolvent system can be designed to maintain the desired concentration of from about 0.1% to about 5% wt/wt active ingredient.
  • the active ingredient is present from about 0.5% to about 3% wt/wt, and more preferably at about 1% wt/wt, in the as-applied topical formulations. Because DGME is less volatile than water, as the topical formulation evaporates upon application, the active agent becomes more soluble in the cream formulation. This increased solubility reduces the likelihood of reduced bioavailability caused by the drug precipitating on the surface of the skin.
  • Liquid forms such as lotions suitable for topical administration or suitable for cosmetic application, may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, thickeners, penetration enhancers, and the like.
  • Solid forms such as creams or pastes or the like may include, for example, any of the following ingredients, water, oil, alcohol or grease as a substrate with surfactant, polymers such as polyethylene glycol, thickeners, solids and the like.
  • Liquid or solid formulations may include enhanced delivery technologies such as liposomes, microsomes, microsponges and the like. Additionally, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Topical treatment regimens according to the practice of this invention comprise applying the composition directly to the skin at the application site, from one to several times daily.
  • Formulations of the present invention can be used to treat, ameliorate or prevent conditions or symptoms associated with bacterial infections, acne, inflammation and the like.
  • Anti-inflammatory agents include, but are not limited to, bisaboloL mentholatum, dapsone, aloe, hydrocortisone, and the like.
  • Vitamins include, but are not limited to, Vitamin B, Vitamin E, Vitamin A, Vitamin D, and the like and vitamin derivatives such as tazarotene, calcipotriene, tretinoin, adapalene and the like.
  • Anti-aging agents include, but are not limited to, niacinamide, retinol and retinoid derivatives, AHA, Ascorbic acid, lipoic acid, coenzyme Q1O, beta hydroxy acids, salicylic acid, copper binding peptides, dimethylaminoethyl (DAEA), and the like.
  • Sunscreens and or sunburn relief agents include, but are not limited to, PABA, jojoba, aloe, padimate-O, methoxycinnamates, proxamine HCl, lidocaine and the like.
  • Sunless tanning agents include, but are not limited to, dihydroxyacetone (DHA).
  • Anti-microbial agents include, but are not limited to, clotrimazole, miconazole nitrate, terbinafine HCL, triclosan, and the like.
  • Psoriasis-treating agents and/or acne-treating agents include, but are not limited to, salicylic acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide, pyrithione (zinc and/or sodium), tazarotene, calcipotriene, tretinoin, adapalene and the like.
  • Agents that are effective to control or modify keratinization including without limitation: tretinoin, tazarotene, and adapalene.
  • compositions comprising an active agent of Formula I, and optionally at least one of these additional agents, are to be administered topically. In a primary application, this leads to the boronic acid and any other active agent working upon and treating the skin. Alternatively, any one of the topically applied active agents may also be delivered systemically by transdermal routes.
  • an additional cosmetically or pharmaceutically effective agent such as an anti-inflammatory agent, vitamin, anti-aging agent, sunscreen, anti-microbial agent, and/or acne-treating agent, for example, is usually a minor component (from about 0.001% to about 20% by weight or preferably from about 0.01% to about 10% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Incorporating Compound 1 into low-water dentifrice enhances the stability of the active ingredient in comparison to dentifrice formulas with higher water content.
  • These low water formula options exhibit antibacterial and anti-inflammatory efficacy in-vitro equivalent to a positive control, Colgate Total® with triclosan as antibacterial agent.
  • the difference in water levels among these formulations is significant.
  • the G series has a water activity level (expressed as vapor pressure of water in sample over vapor pressure of free water at the same temperature) of 0.75, compared to 0.25 for the 6% water formulation, and 0.09 for the formulation with no added water.
  • the stability of Compound 1 over time in the different formulations is shown in the following table:
  • the 0% and 6% added water formulations are tested in an assay measuring inhibition of growth of A. viscosus and shown to retain their antibacterial efficacy.
  • the 0% added water formulation is also tested in an anti-inflammatory assay measuring induction of PGE2 and shown to be as effective as the positive control, Total® toothpaste with triclosan, with a value of ⁇ 200 pg/ml PGE2 vs >1200 pg/ml for placebo control, and about 400 pg/ml for the G formulation.
  • the stability of a dentifrice formulation containing the active ingredient, 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane (COMPOUND 1), in a silica base is evaluated at different water levels. It is found that the stability of COMPOUND 1 in dentifrice is dependent on the pH of the formula. Specifically, a significant increase in stability is observed when the pH of the dentifrice is increased from 7 to 9, without negative impact on the antibacterial or anti-inflammatory efficacy of the formulation.
  • the first formula base is referred to as the G-series and the second referred to as the low water formula, corresponding to the G-series and 6% added water formulations of the preceding example.
  • the major difference between the two formulas is the level of added water.
  • the G-series has about 32% added water while the low water formula has 6% added water.
  • the level of COMPOUND 1 is 0.75%.
  • the pH is varied by adjusting the ratio of sodium hydroxide to glycerin in the formulations of the previous example to obtain dentifrices at pH 7, 8.5 and 9.
  • FIG. 1 shows the percentage of COMPOUND 1 recovery after two weeks at 60° C. as a function of formula pH in the (a) G-series base and (b) the low water base.
  • FIG. 2 shows the percentage of COMPOUND 1 recovery in a 50/50 acetonitrile/water solution as a function of pH after 1 day at 70° C.
  • the anti-inflammatory effect of COMPOUND 1 does not appear to have been impacted by an increase in dentifrice pH. Both the G-series and low water formulas at pH 7 and 9 performed well in the suppression of the anti-inflammatory marker PGE2.
  • the antibacterial effect of COMPOUND 1, as measured by growth inhibition of A. viscosus is comparable to that of the pH 7 paste as well as commercial high quality toothpaste.
  • the minimum inhibitory concentration for COMPOUND 1 against common oral bacteria is found to be as follows. Ethanol is used as vehicle.
  • the poor solubility of Compound A presents some formulation challenges. Its solubility in water is less than 100 ppm, and its solubility in flavor oils (often used to solubilize actives) is less than 0.5%.
  • co-polymers of polyethylene glycol and polypropylene glycol are able to solubilize Compound 1.
  • Fluraflo L4370 (BASF) is able to solubilize 1% Compound 1 (% w/w). It is necessary to stir the solution over low heat to fully solubilize the active. The resulting solution is cloudy, reflecting the nature of the Fluraflo L4370 itself.
  • Tri-block Co-polymer Surfactant F127 is able to further enhance solubilization of Compound 1.
  • Compound 1 is not completely soluble over time, as evidenced by precipitation and crystallization over time.
  • experimental liquid dentifrice formulas Table 4
  • Tri-block Co-polymer Surfactant F127 is able to further solubilize Compound 1 and is suitable for use in formulations.
  • a solution of 2% Compound 1 in PEG 300 is diluted 1:1 with 2% SLS in water to produce a solution composed of 1% Compound 1, 1% SLS, 50% PEG 300 in water which is then tested in a biofilm disruption assay.
  • the percent reduction achieved versus the negative control is 76%, indicating that Compound 1 retains its antibacterial activity when solubilized in PEG 300.
  • compositions of Compound 1 in conjunction with other excipients are further evaluated by diluting a solution of Compound 1 in PEG 300 into other solvents such as propylene glycol and glycerin at varying ratios.
  • a solution containing 1% Compound 1 in 19% PEG 300 and 80% propylene glycol is clear.
  • This solution is then diluted 1:1 with 1% SLS in water to produce a solution composed of 0.5% Compound 1, 0.5% SLS, 9.5% PEG 300 and 40% propylene glycol in water which is then tested in the biofilm disruption assay.
  • the percent reduction achieved versus the negative control is 80%.
  • Two pH 7.2 formulations of Compound 1 are prepared, one with phosphate buffer, one without, and the decomposition of Compound 1 is measured over 14 days. While measurable decomposition is seen in both formulations, the slope of the rate of decomposition Compound 1 in the buffered formulation is decreased by 3.3 fold compared to that of the unbuffered formulation.
  • compositions are prepared as follows:
  • Table 8 shows three silica-based toothpaste formulations comprising Compound 1, component amounts given as % w/w, water adjusted to compensate for difference in glycerin level:
  • G H I Compound 1 0.75 0.75 0.75 Sodium fluoride 0.243 0.243 0.243 99.0-101.0% 30.84 20.84 40.84 vegetable glycerin Demineralized water qs qs qs Gantrez S-97 15 15 15 Dental type Silica - 10 10 10 Zeodent 105 - high cleaning silica Dental type silica 8.5 8.5 8.5 abrasive (Zeodent 115) Polyethylene glycol 6.72 6.72 6.72 300 Dental type silica - 2.5 2.5 2.5 2.5 Zeodent 165-synth.
  • a silica-based dentifrice quickly changes color from white to yellow upon addition of 0.25-1% of Compound 1 in the final step of the formulation. This color change is observed with or without presence of an antioxidant, such as butylated hydroxytoluene (BHT), vitamin E or vitamin C.
  • BHT butylated hydroxytoluene
  • the addition of a small amount of a metal chelating agent returns the dentifrice to its original white color.
  • Chelating agents effective for this purpose include 0.5% Tetrasodium pyrophosphate (TSPP), as well as tetrapotassium pyrophosphate, ethylene diamine tetraacetic acid, ethylene glycol tetraacetic acid, sodium pyrophosphate, sodium tripolyphosphate, potassium tripolyphosphate, sodium hexamephosphate, and citric acid.
  • TSPP Tetrasodium pyrophosphate
  • tetrapotassium pyrophosphate ethylene diamine tetraacetic acid
  • ethylene glycol tetraacetic acid ethylene glycol tetraacetic acid
  • sodium pyrophosphate sodium tripolyphosphate
  • potassium tripolyphosphate sodium hexamephosphate
  • citric acid citric acid
  • Borinic esters can be oxidized by molecular oxygen or peroxides that can be formed from ethers such as PEG by the action of oxygen in the air. These highly oxidative species can attack the carbon-boron bond leading to cleavage and formation of corresponding boronic acid derivatives and phenol derivatives. The oxidation products are then inactive. Addition of oxygen scavengers and/or antioxidants such as vitamins C (ascorbic acid), vitamin E ( ⁇ -tocopherol) or 2,6-di-tert-butyl-4-methyl-phenol (butylated hydroxytoluene or BHT) eliminates the oxygen and reduces the peroxides already present in the formulation. The amount of antioxidant does not need to exceed the amount of borinic ester used in a given formulation.
  • composition of formula I is significantly reduced the formulation containing sodium ascorbylphosphate, and is even less in the formulation containing ⁇ -tocopherol. This demonstrates that the use of an antioxidant enhances the stability of Compound 1 in formulation.

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CO6460708A2 (es) 2012-06-15
AU2010256609A1 (en) 2011-11-17
AU2010256610A1 (en) 2011-11-17
CN102781519B (zh) 2018-02-23
RU2011154329A (ru) 2013-07-20
TW201110996A (en) 2011-04-01
MX2011011858A (es) 2011-12-06
EP2437854A2 (fr) 2012-04-11

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