FIELD OF THE INVENTION
The present invention relates to compositions useful as skin disinfectants, surgical hand preparations, patient skin preparations and antimicrobial hand lotions. More specifically the invention relates to stable hydroalcoholic compositions which are thickened using mixed emulsifier systems.
BACKGROUND OF THE INVENTION
Control of nosocomial infection and exposure to infectious disease is of paramount concern to doctors, nurses, and clinicians who work in hospitals and surgery centers. One of the most effective methods for controlling infection is regimented hand disinfection before and possibly after each patient contact and particularly before and after each surgical procedure. Hand disinfection is generally accomplished using antimicrobial soaps with water. These soaps are usually formulated to include either povidone-iodine (usually 7.5% by weight) or chlorhexidine gluconate (CHG) (usually 2 or 4% by weight) as the active antimicrobial agent. In addition, these formulated soaps may contain surfactants and possibly low levels of humectants such as glycerin.
Hand disinfection is also accomplished using presurgical scrub replacements. These are used instead of the soap and water scrub. Presurgical scrub replacements ideally achieve bacterial kill equal to or better than a traditional soap and water scrub and in a shorter period of time. Additionally, they maintain or improve the skin's natural barrier to microbial and chemical contamination while providing acceptable tactile properties. Examples of presurgical scrub replacements include hydroalcoholic gels which generally include high levels of either ethanol or isopropanol as the disinfecting agent and also include a thickener and optionally include a humectant (e.g. glycerin). To date, thickeners used in hydroalcoholic gels have been based on anionic polymers such as polyacrylic acid (sold under the tradename Carbopol by B F Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio). U.S. Pat. No. 4,915,934 to Tomlinson discloses the use of CHG-containing antiseptic foams based on hydroalcoholic solvents, a fatty alcohol, and a surfactant. The surfactant is selected from the group of ethoxylated sorbitan alkylates, ethoxylated fatty alcohols, and ethoxylated nonyl phenols.
Formulating stable viscous hydroalcoholic emulsions is difficult for two reasons. First, addition of short chain alcohols (such as ethanol) to an aqueous system decreases the surface tension dramatically. For example, 40% by weight ethanol in water has a surface tension of approximately 31 dyne/cm compared to pure water which has a surface tension of about 72 dyne/cm at 20° C. A hydroalcoholic solution at, 60% by weight ethanol has a dramatically decreased surface tension as compared to water. Such a composition has a surface tension of approximately 27 dyne/cm at 20° C. Second, many surfactants typically used in cosmetic emulsions become completely or partially soluble in hydroalcoholic systems.
In bulletin 51-0001-259 regarding skin care, Specialty Chemicals of ICI America of Wilmington, Del. stated that although ethanol can provide several benefits to skin care emulsions, formulators often avoid ethanol as it is difficult to prepare stable emulsions in its presence. In fact, the bulletin continued that ethanol is often used to break emulsions.
U.S. Pat. No. 4,956,170 to Lee discloses a hydroalcoholic skin moisturizing/conditioning antimicrobial gel. The gel comprises 60-75% ethanol and 0.4-2% of a polymeric thickening agent. The formulations also comprise polyethoxylated non-ionic surfactants/emulsifiers to stabilize the added emollient oils in addition to a fatty alcohol.
U.S. Pat. No. 5,167,950 to Lins discloses an antimicrobial aerosol mousse having a high alcohol content. The mousse comprises alcohol, water, a polymeric gelling agent and a surfactant system comprising a C16-C22 alcohol, aerosol propellant and a non-ionic polyethoxylated surfactant.
SUMMARY OF THE INVENTION
This invention provides compositions useful as products for skin disinfection such as presurgical hand preps, patient preps, and lotions. The preferred formulations of this invention, in general, have a very nice feel after both single and multiple applications. Additionally, preferred formulations maintain or improve the skin condition after multiple applications and no slimy or abnormal feeling is noticed during post application hand washing. When used as a presurgical scrub replacement, this invention achieves bacterial, fungal, and viral kill equal to or better than a traditional soap and water scrub in a shorter period of time while maintaining or improving the skin's natural barrier to microbial and chemical contaminants. The invention overcomes the shortcomings of past compositions by providing a viscous composition which includes a high concentration of a lower alcohol but does not require a polymeric thickener to make the composition viscous. Further, the composition has a cosmetically elegant feel and may be dispensed as a lotion or as a foam.
This invention provides a composition comprising a lower alcohol and water in a weight ratio of about 35:65 to 100:0, between at least 0.5% and 8.0% by weight thickener system comprised of at least two emulsifiers, each emulsifier present in at least 0.05% by weight wherein the emulsifiers are selected such that the composition free of auxiliary thickeners has a viscosity of at least 4,000 centipoise at 23 degrees C. and wherein each emulsifier is comprised of at least one hydrophobic group and at least one hydrophilic group, wherein: (i) the hydrophobic group is comprised of an alkyl group of at least 16 carbon atoms; an alkenyl group of at least 16 carbon atoms; or an aralkyl or an aralkenyl group of at least 20 carbon atoms; and (ii) the hydrophilic group of at least one emulsifier is comprised of an amide group having the structure —NHC(O)R′″ or —C(O)NHR′″ where R′″ is hydrogen or an alkyl group of 1-10 carbon atoms optionally substituted in available positions by N, O, and S atoms; an ester group of short chain alcohols or acids (e.g., L=—C(O)OR′ or —OC(O)R′ where R′ is C1-C4 branched or straight chain alkyl optionally substituted in available positions by hydroxyl groups); a polyglucoside group having 1-10 glucose units; a polyglycerol ester group having 1-15 glycerol units, a secondary amine group; a tertiary amine group; a quaternary amine group; an anionic group such as a sulfate, sulfonate, phosphate, phosphonate, or carboxylate group; or a zwitterionic group having the formula:
wherein each R″ is independently hydrogen or an alkyl group (having 1-5 carbon atoms) or alkenyl group (having 2-4 carbon atoms), which alkyl or alkenyl groups are optionally substituted with nitrogen, oxygen, or sulfur atoms, including alkyl or alkenyl carboxyl groups; Q is hydrogen or hydroxyl; x is 1 to 4; and L′ is
—CO2 −; —OP(O)(O−)(O−M+), —(O)P(OR′″)(O)(O−) (where R′″ is hydrogen or an alkyl group of 1-10 carbon atoms optionally substituted in available positions by N, O, or S atoms), —SO2O−, or —OSO2O−, where M+ is a positively charged counterion present in a molar ratio necessary to achieve a net neutral charge on the emulsifier and is selected from the group of hydrogen, sodium, potassium, lithium, ammonium, calcium, magnesium, or N+R″4; as well as combinations of these groups; and (iii) the hydrophilic group of at least one emulsifier is comprised of an alcohol group; an ethylene oxide/propylene oxide copolymer group having 2-150 moles of ethylene oxide plus propylene oxide per mole of hydrophobe
(“R”) and bonded to the hydrophobe through an ether or ester linkage, and optionally terminated by C1-C36 alkyl or C6 to C3-6 alkaryl ester; an
ester or ether group of a polyhydric alcohol and their polyalkoxylated derivatives; an ester or ether of sorbitan or polyalkoxylated sorbitan group, as well as combinations of these groups. Thus, it will be understood by one of skill in the art that the emulsifiers can include combinations of all “L” hydrophilic groups described herein (e.g., ester groups and amide groups in one molecule).
This invention further provides a method of preparing a stable hydroalcoholic composition comprising the steps of preparing a thickener system comprised of at least two emulsifiers as described above; and combining a hydroalcoholic solvent with the thickener system at a temperature sufficient to melt said thickener system and in an amount that provides a composition having between at least about 0.5% and 8.0% by weight thickener system.
This invention also provides a method of preparing a stable hydroalcoholic composition comprising the steps of: (a) heating a thickener system to a temperature sufficient to melt said thickener system, wherein the thickener system is comprised of at least two emulsifiers as described above; (b) combining the thickener system and an aqueous phase, and (c) adding a lower chain alcohol to the aqueous/thickener system combination wherein the alcohol to water weight ratio in the composition is between about 35:65 to 100:0 and the thickener system is present in the composition between at least about 0.5% and 8.0% by weight. Methods of applying such compositions to skin are also provided.
“Ambient temperature” as used herein refers to the temperature range between about 21 and 25 degrees C.
“Auxiliary thickeners” as used herein refers to additives (other than the emulsifiers which comprise the thickener system described below) which increase the viscosity of the solvent phase even in the absence of the thickener system. Certain auxiliary thickeners may act synergistically with the thickener system to increase the viscosity of the resultant formula. Auxiliary thickeners include but are not limited to soluble and swellable polymers and associative colloidal thickeners such as silica, magnesium aluminum silicate, and the like.
“Emollient” as used herein refers broadly to materials which are capable of maintaining or improving the moisture level, compliance, or appearance of the skin when used repeatedly.
“Emulsifier” as used herein is synonymous with “surfactant” and refers to molecules comprising hydrophilic (polar) and hydrophobic (non-polar) regions on the same molecule.
“Emulsion” as used herein refers to a stable dispersion of one liquid in a second immiscible liquid.
“Lotion” means liquid or cream, free of any propellant.
“Melt temperature” (Tm) as used herein refers to the temperature at which compositions or emulsions of the present invention dramatically lose viscosity.
“Polymer” as used herein refers to a natural or synthetic molecule having repetitive units and a number average molecular weight of at least 20,000.
“Solvent”, “solvent system” or “hydroalcoholic solvent” as used herein refer to the alcohol and water combination in the present invention.
“Stable” as used herein refers to a composition that displays less than or equal to 10% by volume separation after centrifuging at 2275×g for 30 minutes at ambient temperature.
“Surfactant” as used herein is synonymous with “emulsifier,” the definition of which is given above. “Thickener system” as used herein refers to a combination of at least two emulsifiers each present in a concentration of at least 0.05% by weight capable of providing a viscosity of at least 4,000 centipoise at 23° C. to the compositions of the present invention without auxiliary thickeners.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides a composition comprised of a lower chain alcohol, water, and thickening system. Alcohols used in the present invention are first discussed followed by a discussion of thickening systems. Ingredients which are optionally added to the composition such as antimicrobial agents and emollients are then discussed followed by a discussion of how to prepare compositions of the present invention.
The alcohol used in the present invention is a lower hydrocarbon chain alcohol such as a C1-C4 alcohol. In preferred embodiments the alcohol is chosen from ethanol, 2-propanol, or n-propanol, and most preferably ethanol. Ethanol is a preferred alcohol since it provides broad spectrum and quick killing of microbes and has an odor acceptable to consumers such as doctors, nurses and clinicians. The invention anticipates that a single alcohol may be used or that a blend of two or more alcohols may comprise the alcohol content of the composition.
The alcohol to water ratio in the present invention is between about 35:65 and 100:0 by weight. Compositions having alcohol to water ratios within the range 40:60 and 95:5 range ensure an efficacious immediate bacterial kill. In a preferred embodiment the alcohol:water ratio is between about 50:50 and 85:15, more preferably between about 60:40 and about 75:25, and most preferably the alcohol:water ratio is between about 64:36 and 72:28 by weight. Higher alcohol to water ratios are used in a preferred embodiment for optimum antimicrobial activity and to ensure the composition is fast drying.
The thickener system useful in this invention affects the cosmetic attributes of the final composition. Preferably, hand preps and lotions of the invention have the following desirable cosmetic attributes. The composition should not result in excessive clumping of glove powder beneath powdered surgical gloves and should not affect the integrity of the glove material. The composition should maintain an acceptable viscosity at 25° C. and preferably up to 35° C. Finally, in most the preferred embodiments formulations are stable to heat and cool cycles (heating up to 50° C. or higher and cooling to ambient temperature) as well as freeze/thaw cycles (cooling to −30° C. and warming to ambient temperature). All of these cosmetic attributes are affected by the types and amounts of emulsifiers chosen which comprise the thickener system of the present invention and are discussed below.
The thickener system of the invention must be compatible with the hydroalcoholic solvent system described above in order to provide acceptable cosmetic properties and appropriate viscosity. Compositions of this invention have a viscosity of at least about 4,000 cps at 23° C., preferably at least about 10,000 cps, more preferably at least about 20,000, even more preferably at least about 50,000 cps, even more preferably at least about 100,000 cps, and most preferably about 80,000 to about 500,000 cps measured using a very low shear viscometer such as Brookfield LVDV-I+ viscometer and T spindles with a heliopath adapter. Since the emollient system and other optional ingredients may affect the viscosity (either positively or negatively), the measured viscosity is that of the final composition without any added auxiliary thickeners.
The viscosity of the present invention is imparted by a thickener system comprised of at least two emulsifiers, and preferably at least two emulsifiers from different classes. In a preferred embodiment at least one of the emulsifiers is a solid at room temperature comprising at least one long chain hydrocarbon of at least 16 carbon atoms, preferably at least 18 carbon atoms, and more preferably at least 22 carbon atoms. At lower alcohol:water ratios of greater than 6:40 the long chain hydrocarbon preferably has greater than 22 carbon atoms. The thickener system of the present invention can be described in terms of the number average chain length of greater than about 22 carbon atoms.
Emulsifiers of this invention are comprised of molecules having hydrophilic (polar) and hydrophobic (non-polar) regions on the same molecule and conform to the general structure:
Where “R” represents a hydrophobic group, “L” represents a hydrophilic group, and “a” and “b” are independently 1 to 4.
In this invention “R” comprises an alkyl group of at least 16 carbon atoms, preferably at least 18 carbon atoms and more preferably at least 20 carbon atoms and most preferably at least about 22 carbon atoms; alkenyl group of at least 16 carbon atoms, preferably at least 18 and most preferably at least 20 carbon atoms; or aralkyl or aralkenyl group of at least 20 carbon atoms, preferably at least 24 carbon atoms and most preferably at least 26 carbon atoms. In a preferred embodiment R is unbranched.
In the above formula, “L” represents a hydrophilic group. For example, L can include an amide group having the structure —NHC(O)R′″ or —C(O)NHR′″ where R″. is hydrogen or an alkyl group of 1-10 carbon atoms optionally substituted in available positions by N, O, and S atoms; an ester group of short chain alcohols or acids (e.g., L=—C(O)OR′ or —OC(O)R′ where R′ is C1-C4 branched or straight chain alkyl optionally substituted in available positions by hydroxyl groups); a polyglucoside group having 1-10 glucose units and more preferably 1-3 glucose units; a polyglycerol ester group having 1-15 glycerol units, preferably 2-12 glycerol units, and more preferably 3-10 glycerol units; a secondary amine group; a tertiary amine group; and a quaternary amine group.
“L” can also include an anionic group such as a sulfate, sulfonate, phosphate, phosphonate, or carboxylate group, or a zwitterionic group having the formula:
wherein each R″ is independently hydrogen or an alkyl group (having 1-5 carbon atoms) or alkenyl group (having 2-4 carbon atoms), which alkyl or alkenyl groups are optionally substituted with nitrogen, oxygen, or sulfur atoms, including alkyl or alkenyl carboxyl groups; Q is hydrogen or hydroxyl; x is 1 to 4; and L′ is
—CO2 −; —OP(O)(O−)(O−M+), —(O)P(OR′″)(O)(O−) (where R′″ is hydrogen or an alkyl group of 1-10 carbon atoms optionally substituted in available positions by N, O, or S atoms), —SO2O−, or —OSO2O−, where M+ is a positively charged counterion present in a molar ratio necessary to achieve a net neutral charge on the emulsifier and is selected from the group of hydrogen, sodium, potassium, lithium, ammonium, calcium, magnesium, or N+R″4.
“L” can also include an alcohol group; a polyhydric alcohol group such as, but not limited to, ethylene glycol, propylene glycol, butylene glycol, pentaerythrytol, glycerol, and sorbitol; an ethylene oxide and/or propylene oxide group, preferably having 2-150 moles of ethylene oxide plus propylene oxide per mole of hydrophobe (“R”), which is bonded to the hydrophobe through an ether or ester linkage, and optionally terminated by C1-C36 alkyl ester, C2-C36 alkenyl ester, or C6 to C36 alkaryl ester (i.e., aralkyl ester); an ester or ether group of a polyhydric alcohol and their polyalkoxylated derivatives; an ester or ether of sorbitan or polyalkoxylated (i.e., polyalkyleneoxide) sorbitan group, preferably having 2-150 moles of alkylene oxide per mole of hydrophobic group; as well as combinations of these groups, e.g., a polyethoxylated polyglucoside group. Thus, it will be understood by one of skill in the art that the emulsifiers can include combinations of all “L” hydrophilic groups described herein (e.g., ester groups and amide groups in one molecule).
The hydrophobic and hydrophilic groups on non-ionic emulsifiers are generally selected to have a hydrophile/lipophile balance (HLB) of 2 to 20 and more preferably 4 to 16. Furthermore, the weight average HLB of the thickener system is preferably 4 to 16 and more preferably 8 to 12. (For example, a thickener system comprised of 40% by weight of an emulsifier with an HLB of 10 and 60% by weight of an emulsifier with an HLB of 15 has a weight average HLB of 13.)
The emulsifiers which comprise thickener systems may be chosen from a single class of surfactants (e.g., a mixture of chain length alkyl polyglucosides) but is preferably a mixture of emulsifier classes. Many commercially available emulsifiers are actually comprised of a mixture of chain lengths. For example, some behenyl alcohol as commercially supplied is actually a mixture of alcohols consisting of primarily C22 and C20 fractions but contain detectable levels of C24, C18 and C16 fractions. For this reason, the chain lengths specified herein refer to the number average chain length. Furthermore, in multiple emulsifier thickener systems of the present invention, each emulsifier must be present in a concentration of at least about 0.05% and more preferably at least about 0.1% by weight to be considered a component of a thickener system. Thickener systems of the present invention are capable of achieving high viscosities at relatively low total emulsifier concentrations. The total concentration of emulsifiers present as a thickener system is generally less than about 8% by weight, preferably less than about 5% by weight, more preferably less than about 4% by weight, and most preferably less than about 3% by weight of the total composition of the present invention. Typically, the thickener system is present in the composition in an amount of at least about 0.5% by weight, based on the total weight of the composition. In the most preferred compositions of this invention, the thickener system comprises between about 0.75% by weight to about 5% by weight, more preferably between about 1.0% by weight to about 3.5% by weight and most preferably between about 1.5% by weight to about 3% by weight of the composition. As used herein an emulsifier is considered part of the thickener system if its presence in the formula results in an increase in the viscosity of the composition. If a certain emulsifier does not result in increasing the viscosity of the composition, it is considered an emollient or stabilizer as defined below.
Preferred compositions of the present invention which are substantially free of polymeric thickening agents have a “melt temperature” (Tm). If compositions are heated above this melt temperature, they dramatically lose viscosity. The compositions of the present invention preferably have melt temperatures greater than 25° C. in order to maintain a high viscosity at room temperature. More preferably the melt temperature is greater than 35° C. in order to maintain viscosity once applied to the skin. The most preferred formulations have a melt temperature greater than 40° C. in order to allow shipping and handling without refrigeration. Thickener systems affect the melt temperature of a given composition. In order to obtain a preferred melt temperature a preferred thickener system includes at least one emulsifier which is solid at ambient temperature. Preferably, all emulsifiers of a thickener system are solid at ambient temperature to increase the melt temperature of the resultant composition.
The structure of emulsifiers in a thickener system affects the melt temperature of the resultant composition. In a preferred embodiment at least one emulsifier in a thickener system is capable of promoting a crystalline structure. Crystallinity is promoted by long straight chain alkyl groups, therefore, at least one emulsifier preferably comprises a saturated straight chain hydrocarbon of at least 16, preferably at least 18 and most preferably at least 20 carbon atoms. Certain hydrophilic head groups have been found to particularly promote association and crystallization. Suitable crystalline emulsifiers include alkyl alcohols, alkyl polyglucosides, polyglycerol alkyl esters, C1-C4 esters of alkyl alcohols, C1-C4 esters of alkyl carboxylates, optionally substituted alkyl amides, alkyl betaines and alkyl phosphates or phospholipids, alkyl quaternary amines, alkyl amine oxides polyethoxylated alkyl alcohols and alkyl esters of polyethylene glycol.
In addition to affecting the melt temperature of a composition, the emulsifier chain length also helps to determine the maximum level of ethanol which can be used in the composition and the concentration of emulsifiers required in the thickener system. At higher levels of alcohol, longer chain emulsifiers are required to produce viscous stable emulsions. It is believed that higher levels of alcohol tend to swell or solubilize the emulsifiers to a greater degree than lower levels of alcohol. Therefore, as the concentration of ethanol increases the chain length of the hydrocarbon chains in a thickening system must also increase in order to maintain a melt temperature over 35° C. That is, the amount of lower alcohol in the hydroalcoholic system can affect the choice of surfactant (i.e., emulsifier), and vice versa. For example, if the composition includes a lower alcohol to water ratio in excess of about 50:50, the thickener system should include at least one surfactant having a number average chain length of at least 16 carbon atoms. If the composition includes a lower alcohol to water ratio in excess of about 60:40, the thickener system should include at least one surfactant having a number average chain length of at least 18 carbon atoms. If the composition includes a lower alcohol to water ratio in excess of about 64:36, the thickener system should include at least one surfactant having a number average chain length of at least 20 carbon atoms.
For example, systems based on a C16/C18 alkyl polyglucoside (Montanov 68 available from Seppic, Inc. of Fairfield, N.J.) in combination with a C18 polyethoxylate (Brij 76 available from ICI of Wilmington, Del.) in 68:32 ethanol:water have a melt temperature of approximately 35° C. Similar systems having C22 hydrocarbon chains have melt temperatures of 45° C. or higher. In addition, as the chain length of the hydrophobic component in the thickener system increases, the amount of emulsifier required to achieve a certain viscosity decreases. For example, the Montanov 68 (C16/C18 alkyl polyglucoside)/Brij 76 (polyethoxylated C18 alcohol) thickener system requires approximately 5% total emulsifier to achieve a suitable viscosity. A similar system based on C22 hydrophobes achieves a suitable viscosity at only 2% total emulsifier.
The nature and size of hydrophilic head groups of emulsifiers are important and help to determine which thickening systems produce viscous stable systems. Certain combinations of emulsifiers will produce viscous stable emulsions. Without being bound by theory, it is believed that the size, charge, and degree of hydrogen bonding are important parameters to determine how emulsifiers interact.
Many preferred thickener systems are capable of producing viscoelastic compositions which are very stable. By varying the ratio of emulsifiers, the degree of elasticity can be adjusted from almost a purely viscous composition to a highly elastic and even stringy composition. If emollients are added, increasing the elasticity of the system imparts added stability to prevent separation of immiscible emollients. Excessive elasticity, however, is not preferred since an elastic composition usually does not provide a cosmetically appealing product. Addition of certain emulsifiers with at least two hydrophobic components has been shown to limit the viscoelasticity while ensuring viscous stable compositions. A favored class of multiple hydrophobic component emulsifiers are quaternary ammonium salts conforming substantially to the following structure:
where: R′ and R″ are long chain alkyl or alkenyl hydrocarbon chains of at least 16 carbon atoms;
R′″ is a short chain alkyl group of 1 to 4 carbon atoms, preferably methyl or ethyl;
R″″ is equivalent to either R′ or R′″ and is preferably equivalent to R′″; and
X is a halogen, R′″SO3—, R′″SO4—, or R′″CO2—
Some preferred structures include distearyldimethylammonium chloride, dibehenyldimethylammonium chloride, and dibehenyldimethylammonium methosulfate, while dibehenyldimethylammonium methosulfate is a more preferred structure. Other suitable multiple hydrophobic emulsifiers include dialkylglycerol esters, trialkylglycerol esters, polyglycerol alkyl esters, ethylene glycol dialkylesters, polyethylene glycol dialkylesters, dialkylamides of diamines such as ethylene diamine, polyalkylesters of pentaerythritol and dialkyl (optionally ethoxylated) phosphates, and alkyl esters of polyethyoxylated alkyl alcohols.
The following emulsifier classes are offered as nonlimiting examples of suitable emulsifiers for use in the present invention. Examples of some preferred emulsifiers are provided for each emulsifier class. For the present invention an emulsifier must be present with at least one coemulsifier to provide a thickener system to produce stable viscous compositions.
Class 1. Alkyl or Alkenyl Polyglucosides:
where R is a straight chain alkyl or alkenyl group of at least 16 carbon atoms, preferably at least 18 carbon atoms, and most preferably at least 20 carbon atoms; or an aralkyl or aralkenyl group of at least 22 carbon atoms, preferably at least 24 carbon atoms and most preferably at least 26 carbon atoms; and n=0-10 (when n=0, the valence of the oxygen atom is completed by H), preferably 1-5 and more preferably 1-3.
Nonlimiting examples of preferred alkyl or alkenyl polyglucoside emulsifiers include cetearyl glucoside sold as “MONTANOV” 68 by Seppic, Inc. of Fairfield, N.J.; behenyl glucoside, produced experimentally as “ESSAI 624” MP, an alkyl polyglucoside prepared with 92% C-22 alcohol and corn-derived glucoside by Seppic, Inc.; and oleyl glucoside.
Class 2. Short Chain Esters of long chain Alcohols or Acids:
RC(O)OR′ or ROC(O)R′
where R is as defined immediately above for Emulsifier Class 1; and
R′ is C1-C4 branched or straight chain alkyl group, optionally substituted in available positions by hydroxyl groups.
Some preferred short chain esters of long chain alcohols or acids include but are not limited to methyl behenate sold as “KEMESTER 9022” by Witco, Humko Chemical Division of Memphis, Tenn.; methyl stearate sold as “KEMESTER 4516” by Witco; methyl oleate sold as “KEMESTER 205” by Witco; arachidyl proprionate available as “WAXENOL 801” from Alzo of Sayreville, N.J.; behenyl lactate, stearyl acetate; and glycerol monoerucate available from Croda, Inc. of Parsippany, N.J.
Class 3. Alkyl and Alkenyl Alcohols:
where R6 is a straight or branched chain alkyl or alkenyl hydrocarbon chain of at least 16 carbon atoms, preferably at least 18, more preferably at least 20 carbon atoms, and most preferably at least 22 carbon atoms, optionally substituted in available positions by N, O, or S atoms; or an aralkyl or aralkenyl group of at least 22 carbon atoms, preferably at least 24 carbon atoms and most preferably at least 26 carbon atoms optionally substituted in available positions by N, O, and S atoms.
Nonlimiting examples of preferred alkyl and alkenyl alcohol emulsifiers useful in a thickener system of the invention include stearyl alcohol available as “LANETTE 18” from Henkel's Emery Division of Cincinnati, Ohio; behenyl alcohol available as “LANETTE 22” from Henkel; oleyl alcohol available as “NOVOL” from Croda; C-24 alcohol available as “UNILIN 350” from Petrolite of Tulsa, Okla.; C3-1 alcohol available as “UNILIN 425” from Petrolite; and arachidyl alcohol available as “AR-20” from M. Michel and Co. of New York, N.Y.
where each R1 is independently hydrogen or a straight chain alkyl group of at least 16 carbon atoms, preferably at least 18 and more preferably at least 20 carbon atoms; or an aralkyl or aralkenyl group of at least 22 carbon atoms, preferably at least 24 carbon atoms, and most preferably at least 26 carbon atoms; and n=0 to 15, preferably 1 to 12, and most preferably 2 to 10.
Some examples of preferred polyglycerol ester emulsifiers useful in a thickener system of the present invention include but are not limited to decaglycerol monostearate available as “POLYALDO 10-1-S” from Lonza Inc. of Fairlawn, N.J.; tetraglycerol monostearate available as “TETRAGLYN 1-S” from Barnet Products Corporation of Englewood Cliffs, N.J.; and decaglyceroltetrabehenate.
Class 5. Quaternary Amine
where R is as defined above in Emulsifier Class 1; R2 is the same as R3 or a long chain alkyl or alkenyl hydrocarbon chain of at least 16 carbon atoms, preferably at least 18 and more preferably at least 20 carbon atoms optionally substituted in available positions by N, O, and S; or an aralkyl or aralkenyl group of at least 22 carbon atoms, preferably at least 24 carbon atoms, and most preferably at least 26 carbon atoms;
R3 is a short chain alkyl group of 1 to 4 carbon atoms, preferably methyl or ethyl;
R4 is equivalent to either R2 or R3 and is preferably equivalent to R3; and
X is a halogen, R5SO3—, R5SO4 −, R5CO2 −, (R5)2PO4 −, or (R5)PO4═; where R5 is defined in Class 6 below.
Nonlimiting examples of quaternary amine emulsifiers include dibehenyldimethylammonium methosulfate available as “INCORQUAT DBM-90” from Croda; behenyltrimethylammonium chloride available as “NIKKOL CA-2580” from Barnet; and tallowtrimethylammonium chloride available as “ARQUAD T-27W” from Akzo Chemicals, Inc. of Chicago, Ill.
Class 6. Tertiary Amine and its Protonated Salts
where R, R2, and R3 are as defined above in Class 5 and R2 and R3 may also be selected from polyethoxylated or polyproxylated alkyl or alkenyl alcohol chains having 1-50 moles of ethylene oxide or propylene oxide groups per mole of emulsifier and Y is a halogen, R5SO3—, R5SO4—, R5CO2—, (R5)PO4 −, or (R5)PO4═, where R5 is an alkyl or alkenyl group of 1-22 carbon atoms optionally substituted in available positions by N, O, and S.
Some examples of emulsifiers from the class of tertiary amines and their protonated salts useful in a thickener system of the invention include but are not limited to behenamidopropyldimethylamine available as “INCROMINE BB” from Croda; behenamidopropyldimethylamine gluconate; tallowdimethylamine hydrochloride; dihydrogenated tallow methyl amine; stearyl diethanolamine hydrochloride; polyethoxylated stearyl diethanolamine hydrochloride.
where R2 and R3 are as defined above for Class 6 and R6 is as defined above for Class 3.
Nonlimiting examples of emulsifiers from the class of amine oxides suitable in a thickener system of the invention include behenamine oxide (behenyldimethylamine oxide) available as “INCROMINE B-30P” from Croda; stearamine oxide available as “INCROMINE Oxide S” from Croda; behenamidopropyldimethyl amine oxide; and bis(2-hydroxyethyl)tallow amine oxide available as “AROMOX T/12” from Akzo.
Class 8. Polyethoxylated and/or Polypropoxylated Alcohols and Esters and Derivatives Thereof
where R6 is as defined above for Emulsifier Class 3; m=0-200, preferably 2-50, most preferably 4-20;
p=0 or 1;
R8=H or —C(O)—R12, where R12 is an alkyl or alkenyl group of 1-36 carbon atoms optionally substituted by N, O or S, or an aralkyl group of 6 to 36 carbon atoms; and
Some examples of preferred emulsifiers from the class of polyethoxylated alcohols and esters include but are not limited to steareth-2 available as “BRIJ 72” from ICI Americas Inc. of Wilmington, Del.; steareth-10 available as “BRIJ 76” from ICI; beheneth-5 available as “NIKKOL BB-5” from Barnet Products Inc.; beheneth-10 available as “NIKKOL BB-10” from Barnet; C31 alkyl-10EO available as “UNITHOX 450” from Petrolite Corp. of Tulsa, Okla.; C3-1 alkyl-40 EO available as “UNITHOX 480” from Petrolite, and the lauric ester of “UNITHOX 480” available from Petrolite as X-5171.
Class 9. Zwitterionics:
wherein R is as defined above for Emulsifier Class 1; each R7 is independently hydrogen or an alkyl group (having 1-5 carbon atoms) or alkenyl group (having 2-4 carbon atoms), which alkyl or alkenyl groups are optionally substituted with nitrogen, oxygen, or sulfur atoms, including alkyl or alkenyl carboxyl groups; Q is hydrogen or hydroxyl; x is 1 to 4; and L′ is —CO2 −, —OP(O)(O—)(O−M+), —(O)P(OR′″)(O)(O−M+) (where R′″ is hydrogen or an alkyl-group of 1-10 carbon atoms optionally substituted in available positions by N, O, or S atoms) —SO2O—, or —OSO2O−, where M+ is a positively charged counterion present in a molar ratio necessary to achieve a net neutral charge on the emulsifier and is selected from the group of hydrogen, sodium, potassium, lithium, ammonium, calcium, magnesium, or N+R′4 where each R′ is independently an alkyl group of 1 to 4 carbon atoms optionally substituted with N, O, or S atoms.
Nonlimiting examples of emulsifiers from the class of zwitterions useful in the emulsifier system of the invention include stearamidopropylPG-dimmonium chloride phosphate available as “PHOSPHOLIPID SV” from Mona Industries of Paterson, N.J.; and behenyl betaine available as “INCRONAM B-40” from Croda.
Class 10. Alkyl and Alkenyl Amides:
where R6, R7, and R12 are as defined above in Classes 3, 9, and 8 respectively.
Examples of some preferred emulsifiers from the class of alkyl and alkenyl amides useful in a thickener system of the invention include but are not limited to behenamide available as “KEMAMIDE B” from Witco; stearamide available as “UNIWAX 1750” from Petrolite; Behenamidopropyldimethyl amine available as “INCROMINE BB” from Croda; stearyldiethanolamide available as “LIPAMIDE S” from Lipo Chemicals Inc. of Paterson, N.J.; and Erucamide available as “ARMID E” from Akzo.
Class 11. Esters and Ethers of Polyhydric Alcohols
wherein t=0-4; each R9 is independently chosen from H, —CH2OR10, —OH, or a hydrocarbon chain of 1 to 4 carbon atoms, preferably containing 1 carbon atom; s=0 or 1; wherein R10 =H or R12 wherein R19 is as defined above for Emulsifier Class 8.
Examples of esters and ethers include glycerol monobehenate, pentaerythritol distearate and glycerol tribehenate.
Esters and ethers of polyethoxylated polyhydric alcohols are also useful. For example, these include but are not limited to polyethoxylated glycerol monostearate, polyethoxylated penta erythritol behenate, polyethoxylated propylene glycol monostearate.
Class 12. Anionics
Where R14 is an alkyl, alkenyl, or aralky group of at least 16 carbon atoms, preferably at least 18 carbon atoms and most preferably at least 20 carbon atoms optionally comprising oxygen, nitrogen, or sulfur atoms within or substituted upon the alkyl or alkenyl chain; or a polyethoxylated and/or polypropoxylated alkyl, alkenyl or aralkyl group, which alkyl, alkenyl, or aralkyl group comprises at least 16 carbon atoms, preferably at least 18 carbon atoms and most preferably at least 20 carbon atoms optionally comprising oxygen, nitrogen, or sulfur atoms within or substituted upon the alkyl, alkenyl, or aralkyl chain. When R14 comprises a polyethoxylated or polypropoxylated substituent or a copolymeric substituent of ethylene oxide and propylene oxide, these subunits are present in amounts of 1 to 100 moles, preferably 1 to 20 moles per mole of hydrophobe; L is sulfate (—OSO2O−), sulfonate (—SO2O−), phosphate ((—O)2P(O)O− or —OP(O)(O−)2), or carboxylate (—CO2 −); M is hydrogen (H+), sodium (Na+), potassium (K+), lithium (Li+), ammonium (NH4 +), calcium (Ca+2), magnesium (Mg+2), or R″A+, wherein R″ is hydrogen or an alkyl or cycloalkyl group of about 1 to 10 carbon atoms, and A+ is selected from the group consisting of N+(R)3 (e.g., R″A+ can be N+(CH3R)4, HN+(CH2CH2OH)3, H2N(CH2CH2OH)2) or a heterocyclic —N+B wherein B comprises 3 to 7 atoms selected from the group consisting of carbon, nitrogen, sulfur and oxygen atoms which complete the nitrogen-containing heterocyclic ring and satisfy the valence on the nitrogen atom; and wherein R is the same as R″ and may also be substituted in available positions with oxygen, nitrogen or sulfur atoms;
a and c are independently 1 or 2;
b and d are independently 1, 2 or 3; and
e is equal to (c times d)/b.
Nonlimiting examples of preferred emulsifiers from the anionic class of emulsifiers suitable for use in a thickener system of the invention include behenic acid available as Croacid B from Croda, Inc.; stearyl phosphate available as Sippostat 0018 from Specialty Industrial Products, Inc. of Spartanburg, S.C.; and sodium stearate available from Witco.
Class 13. Sorbitan Fatty Acid Esters
where R6 is as defined above in Emulsifier Class 3, R13 is H or —C(O)R6 and each v is independently 0-30.
Fatty acid esters of sorbitan and its polyethoxylated derivatives, polyoxyethylene derivatives of mono and poly-fatty esters are also examples of additional emulsifiers useful in the present invention.
Certain combinations of the above-listed emulsifiers are useful in some preferred embodiments to form viscous stable thickener systems of the present invention. These preferred systems are listed below.
|Nonlimiting Examples of Suitable Thickener Systems: |
|System # ||Emulsifier 1/(Class)* ||Emulsifier 2/(Class)* ||Emulsifier 3/(Class)* ||Emulsifier 4(Class)* |
|1 ||alkyl polyglucoside ||(1) ||polyethoxylated alkyl alcohol ||(8) ||quaternary amine ||(5) || || |
|2 ||alkyl polyglucoside ||(1) ||polyethoxylated alkyl alcohol ||(8) ||amine Oxide ||(7) |
|3 ||alkyl polyglucoside ||(1) ||tertiary amine ||(6) |
|4 ||alkyl polyglucoside ||(1) ||quaternary amine ||(5) |
|5 ||polyglycerol ester ||(4) ||polyethoxylated alkyl alcohol ||(8) ||alkyl alcohol ||(3) |
|6 ||polyglycerol ester ||(4) ||polyethoxylated alkyl alcohol ||(8) ||alkyl alcohol ||(3) ||alkyl ester ||(2) |
|7 ||polyglycerol ester ||(4) ||polyethoxylated alkyl alcohol ||(8) ||quaternary amine ||(5) |
|8 ||polyglycerol ester ||(4) ||alkyl ester ||(2) ||quaternary amine ||(5) |
|9 ||polyglycerol ester ||(4) ||amine oxide ||(7) ||quaternary amine ||(5) |
|10 ||alkyl/alkenyl alcohol ||(3) ||alkyl ester ||(2) ||quaternary amine ||(5) |
|11 ||alkyl/alkenyl alcohol ||(3) ||alkyl ester ||(2) ||amine oxide ||(7) |
|12 ||alkyl ester ||(2) ||polyethoxylated alkyl alcohol ||(8) ||quaternary amine ||(5) |
|13 ||alkyl betaine ||(7) ||polyethoxylated alkyl alcohol ||(8) |
|14 ||alkyl phospholipid ||(9) ||polyethoxylated alkyl alcohol ||(8) |
|15 ||alkyl ester ||(2) ||alkyl alcohol ||(3) || || ||dialkoxydimethicone |
|16 ||hydroxyfunctional ester ||(2) ||polyethoxylated alcohol ||(8) |
|17 ||hydroxyfunctional ester ||(2) ||alkyl alcohol ||(3) ||quaternary amine ||(5) |
|18 ||hydroxyfunctional ester ||(2) ||quaternary amine ||(5) |
|19 ||polyglycerol ester ||(4) ||polyethoxylated alkyl alcohol ||(8) |
|20 ||alkyl carboxylate || (12) ||polyethoxylated alkyl alcohol ||(8) |
It is a simple matter to test certain combinations of emulsifiers to determine if they provide a suitable thickener system. Screening methodology is set forth in the Examples. The examples illustrate the importance of the head group size with respect to the ratio of the mixed emulsifiers required to produce a stable emulsion. For example, systems based on a C16/C18 alkyl polyglucoside combined with C18 polyethoxylates of varying level of ethoxylation (Brij) produce stable emulsions at widely varying ratios.
Without intending to be bound by theory, the physical structure of the composition of the invention is believed to be that of an emulsion. A classic definition of an emulsion is a stable dispersion of one liquid in a second immiscible liquid. However, as stated earlier, the present composition is preferably formed using at least one emulsifier which is a wax at room temperature. Although compositions of the present invention are not well characterized, they are believed to be a viscous stable mixture of a solid, semisolid, or liquid phase in a second liquid phase. It is believed that if certain hydrophobic emollients are added to the present invention, hydrophobic emulsifiers and immiscible emollients form an “oil” or hydrophobic phase which is dispersed in the hydroalcoholic liquid phase to form an “oil” in “water” emulsion. The hydroalcoholic phase is referred to herein as the “water” phase. Since many preferred emulsions are somewhat viscoelastic, these emulsions are believed to be liquid crystalline emulsions which have been cooled below the crystallization temperatures of the chosen emulsifiers to form a semi-crystalline gel-like network. Certain formulations may be simply swollen crystalline precipitates forming a strongly interacting network in the hydroalcoholic phase (so called coagel phase). The compositions of the present invention may also exist as combinations of these structures. Liquid crystalline and coagel phases in aqueous systems are described in “Application of Emulsion Stability Theories to Mobile and Semisolid O/W Emulsions,” Cosmetics and Toiletries, Vol. 101, pp 73-92 (1986), and “Influence of Long Chain Alcohols (or Acids) and Surfactants on the Stability and Consistencies of Cosmetic Lotions and Creams,” Cosmetics and Toiletries, Vol. 92, pp. 21-28 (1977) both of which are hereby incorporated by reference. The exact type of molecular association that occurs depends on many factors including the nature, size, and physical and chemical states of the polar and hydrocarbon portions of the emulsifiers which comprise the thickener system at a specified temperature.
Emulsifiers other than those required in the composition to provide a thickener system may also be added as emollients or stabilizers. These emulsifiers are referred to herein as auxiliary emulsifiers. For example, certain emollients are also comprised of hydrophobic and hydrophilic regions and are useful in the present invention since they are believed to become incorporated into the liquid crystalline network. These emollients tend to enhance the stability of the composition as is discussed more fully below. Furthermore, certain dimethicone copolyol surfactants can actually improve the stability of formulations incorporating emollients. This is also discussed in more detail below.
In addition to alcohol, water and thickener system, the compositions of the present invention may optionally include ingredients such as salts, emollients, stabilizers, antimicrobials, fragrances, therapeutic agents, propellants and additional emulsifiers. Each of these optional ingredients along with the effect each has upon the properties of the final composition is discussed below.
The melt temperature of the compositions of the present invention may be increased by adding salts. As the concentration of salt is increased, the ratio of emulsifiers will often need to change in order to maintain a stable composition. It is important to choose salts which do not create an unstable system and are compatible with any antimicrobials present in the system. For example, chlorhexidine digluconate (CHG) will precipitate rapidly in the presence of halide salts above a concentration of about 0.1M. Therefore, if a system includes CHG, preferably gluconate salts such as triethanolamine gluconate or sodium gluconate, are used.
A stable composition is one which does not separate more than 10% by volume after centrifuging at 2275×g for 30 minutes as measured at the longitudinal midpoint of the sample tube. It is also recognized that stability may be time dependent due to crystallization of emulsifiers and/or emollients present in the system, coalescence of emollients, emulsifiers and the like and, therefore, preferred compositions do not exhibit separation of more than 10% after standing for 6 months at ambient conditions. Two types of stabilizers are useful in the present invention. These include (1) those stabilizers that complex with emulsifier hydrophilic head groups, and (2) those that associate with the emulsifier hydrophobic tails. Certain stabilizers may perform both functions. For example, emulsifiers comprising 1,2 diol-containing head groups such as alkylpolyglucosides, monoalkylglycerides, and polyglycerol alkyl esters, may be “stabilized” by adding borate ion. Without intending to be bound by theory, it is believed that borate ions complex with adjacent head groups which may increase the association of hydrophobic tails by holding them in close proximity. Natural or synthetic polymers comprised of pendent long chain alkyl groups (greater than 12 and preferably greater than 16 carbon atoms) such as stearyl modified cellulose derivatives, stearyl modified proteins such as wheat protein, stearyl modified collagen and the like are capable of stabilizing compositions of the present invention. Such added components may also increase the melt temperature of compositions of the present invention. It is believed that the pendent alkyl groups in these polymers associate by Van der Waals interactions with the hydrophobes of a thickening system, thereby enhancing the stability of the crystalline structure. Polymeric thickeners which do not have associative pendent alkyl chains may also increase the melt temperature presumably by increasing the viscosity of the continuous phase. A nonlimiting example of such thickeners are quaternary celluloses such as Celquat™ 230M as available from National Starch of Bridgewater, N.J. In a preferred embodiment stearyldimonium hydroxypropyl cellulose commercially available as Crodacel QS from Croda Inc., Parsippany, N.J. is added as a stabilizer.
Emollients are typically added to hand lotions or hand preps because they act to increase the moisture content of the stratum corneum. Emollients are generally separated into two broad classes based on their function. The first class of emollients function by forming an occlusive barrier to prevent water evaporation from the stratum corneum. The second class of emollients penetrate into the stratum corneum and physically bind water to prevent evaporation. The first class of emollients is subdivided into compounds which are waxes at room temperature and compounds which are liquid oils. The second class of emollients includes those which are water soluble and are often referred to as humectants.
For the purposes of this invention the thickener system is considered separate and distinct from any emollients which may be added even though it is recognized that the emulsifiers may function as occlusive emollients and aid in maintaining or improving the skin condition. Emollients are included in a preferred embodiment of the invention and preferably comprise between about 3 and 30%, more preferably between about 4 and 20% and most preferably between about 5 and 12% by weight of the formulation.
The ratio of wax to liquid emollients (oils and humectants) in a preferred embodiment of the invention is between about 5:1 to 1:5 and preferably between about 1:3 to 3:1. Also, the ratio of wax emollients and wax emulsifiers to liquid emollients and liquid emulsifiers in a preferred embodiment of this invention is from about 1:5 to about 5:1, and more preferably, from about 1:3 to about 3:1. Emollients may be selected from any of the classes known in the art. A general list of useful emollients appears in U.S. Pat. No. 4,478,853 and EPO patent application 0 522 624 A1 and in the CTFA Cosmetic Ingredient Handbook published by The Cosmetic, Toiletry, and Fragrance Association, Wash. D.C. (1992) under the listings “Skin Conditioning agents,” “emollients,” “humectants,” “miscellaneous” and “occlusive,” each of these references is hereby incorporated by reference.
In preferred embodiments, emollients are chosen from the following nonlimiting list of general emollients, occlusive emollients and humectants. Examples of general emollients include short chain alkyl or aryl esters (C1-C6) of long chain straight or branched chain alkyl or alkenyl alcohols or acids (C8-C36) and their polyethoxylated derivatives; short chain alkyl or aryl esters (C1-C6) of C4-C12 diacids or diols optionally substituted in available positions by —OH; alkyl or aryl C1-C9 esters of glycerol, pentaerythritol, ethylene glycol, propylene glycol, as well as polyethoxylated derivatives of these and polyethylene glycol; C12-C22 alkyl esters or ethers of polypropylene glycol; C12-C22 alkyl esters or ethers of polypropylene glycol/polyethylene glycol copolymer; and polyether polysiloxane copolymers. In addition to many of the emulsifiers of preferred thickener systems, additional examples of occlusive emollients include cyclic dimethicones, polydialkylsiloxanes, polyaryl/alkylsiloxanes, long chain (C8-C36) alkyl and alkenyl esters of long straight or branched chain alkyl or alkenyl alcohols or acids; long chain (C8-C36) alkyl and alkenyl amides of long straight or branched chain (C8-C36) alkyl or alkenyl amines or acids; hydrocarbons including straight and branched chain alkanes and alkenes such as squalene, squalane, and mineral oil; polysiloxane polyalkylene copolymers, dialkoxy dimethyl polysiloxanes, short chain alkyl or aryl esters (C1-C6) of C12-C22 diacids or diols optionally substituted in available positions by OH; and C12-C22 alkyl and alkenyl alcohols. Nonlimiting examples of preferred humectant type emollients include glycerol, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, sorbitol, pantothenol, gluconic acid salts and the like.
Although a thickener system is responsible for the stability and overall consistency of compositions of the present invention, emollients may also affect the viscosity, stability, and melt temperature of a composition. It is anticipated that a single emollient may be added to the present invention or two or more emollients may be added to the composition. A wide range of emollients may be added to the formulations of the present invention. Preferably wax and oil type emollients along with water soluble emollients are used. In a preferred embodiment, emollient systems are comprised of humectants in addition to occlusive wax and oil emollients in concentrations which achieve a moisturizing but not greasy composition which maintains and improves the condition of the skin upon repeated use. Ideally, emollients are non-comedogenic and are chosen to ensure no skin irritation or sensitization reaction occurs. This is particularly critical since the composition of the present invention will likely be worn in an occluded condition under surgical gloves. Furthermore, emollients should be chosen which do not affect the integrity of the glove material. For example, since hydrocarbon emollients such as mineral oil and petrolatum can detrimentally affect the tear strength of surgical gloves, these emollients may need to be avoided for compositions employed as presurgical disinfectants.
Without being bound or limited by theory, it is believed that if emollients are added to the present compositions, they may be present in four distinct regions. The emollients could occur (1) as a soluble species in the solvent phase, (2) dispersed as emulsified droplets within the mixed emulsifier micelle or crystalline gel network, (3) incorporated into the mixed emulsifier micelle or crystalline gel network, or (4) as a separate and distinct emulsion. As earlier stated, emollients can affect the melt temperature of a composition. Those emollients that are soluble or dispersible in the solvent phase tend to have little or no affect on the melt temperature and are therefore preferred. These emollients include the humectant and general emollients. The most preferred general emollients are those which are essentially insoluble in water but soluble in the hydroalcoholic solvent. These emollients are also preferred since they remain soluble and uniformly dispersed even above the melt temperature so that upon cooling to room temperature a uniform composition results. In addition, they are also believed to have little effect on surgical gloves. Such general emollients typically do not have alkyl or alkenyl chains greater than about 14, preferably not greater than 12 and most preferably not greater than about 9 carbon atoms.
Those emollients which are insoluble in the hydroalcoholic solvent may associate with the emulsifiers of the thickener system and/or become incorporated into the micelle or crystalline gel network. Preferred emollients within this class are those emollients that are very hydrophobic since they tend to maintain a high melt temperature. For example, hexadecane was found to increase the viscoelasticity of certain thickener systems. Those emollients which are capable of associating with and disrupting the emulsifiers of the thickener system tend to decrease the melt temperature and may influence the stability of the composition. Certain branch alkyl esters of greater than about 12 carbon atoms per hydrophobe have been found to be particularly effective at decreasing the melt temperature. For example, trioctyldodecyl citrate has been found to significantly decrease the melt temperature of some systems.
Emollients which become incorporated into the thickener system tend to decrease the melt temperature. For example, laureth-4 (Brij 30) appears to incorporate into the thickener system since it does not phase out when heated above the melt temperature at concentrations below about 1% by weight. Laureth-4 also tends to decrease the melt temperature of the composition.
Certain emollients which are insoluble in the hydroalcoholic solvent can be emulsified in what is believed to be a separate and distinct emulsion. These emollients have little affect on the melt temperature of a composition. For example, certain cyclic silicones, polysiloxanes, and dialkoxypolysiloxanes can be emulsified in hydroalcoholic solvents using polyether/polysiloxane copolymers surfactants. Cyclic silicones such as DC344 (available from Dow Corning of Midland, Mich.) in the presence of certain polyether/polysiloxane copolymers such as Abil B88183 available from Goldschmidt Chemical Corp. of Hopewell, Va., can form a thermally stable emulsion such that the compositions remain uniform both above and below the melt temperature. In fact, the combination of a long chain dialkoxypolysiloxane and polyether/polysiloxane copolymer has been found to actually promote the stability of certain thickener systems. The dialkoxypolysiloxane is believed to interact with the thickener system as well as the polyether/polysiloxane copolymer. These compounds have the following structures:
where R is a straight chain alkyl group of 14-50, preferably 16-24 carbon atoms, and
Polyether/Polysiloxane Copolymers (Dimethicone Copolyols):
x+y=5-400, preferably 15-200, and
R8 is a polyether substituted alkyl group with the structure:
R9 is an alkyl group of 1 to 6 carbon atoms;
R10 is hydrogen or an alky group of 1-22 carbon atoms;
R11 is an alkyl group of 1 to 22 carbon atoms or phenyl;
p=2-300, preferably 8-100; and
Note that branched chain polysiloxanes modified as shown in the two structures above are also possible.
The following are nonlimiting examples of emulsifier/emollient components which improve thickening/stability of compositions of the present invention.
a. Certain wax emulsifiers/emollients have been found to be particularly useful and include solid waxy esters such as: Myristyl Myristate, Cetyl Palmitate, Myristyl Stearate, Stearyl Behenate, Behenyl Isostearate, Isostearyl Behenate, Behenyl Behenate, Lauryl Behenate, Behenyl Erucate. These have the following formula:
R1 is at least 14 carbon atoms; and
R2 is an alkyl or alkenyl of at least 4 carbon atoms.
b. Long chain hydrocarbon di-esters, tri-esters, of polyhydric alcohols with melting point greater than 23° C. include solid esters such as glycerol tribehenate and sorbitan tristearate.
c. Pure lanolins and lanolin derivatives (e.g. hydrogenated lanolin) provide excellent emolliency but can also improve the stability of the emulsion when used in combination with oil emollients.
d. Petrolatums provide excellent emolliency and can also improve the stability of the emulsion when used in combination with oil emollients. Petrolatums are mixtures of oily and waxy long chain hydrocarbons.
e. Microcrystalline waxes and branched hydrocarbon waxes with a melting point greater than 50° C. and a molecular weight greater than 400. An example of this includes but is not limited to Vybar 103 which is a branched hydrocarbon with a number average molecular weight of 2800 and is available from Petrolite Corp. of Tulsa, Okla. and “ULTRAFLEX” which is a microcrystalline wax also available from Petrolite Corp.
f. Oxidized waxes and modified hydrocarbon waxes may find application in the present invention. These are prepared from waxes modified by oxidation, salts of oxidized waxes, maleic anhydride adducts of polyolefins and urethane derivatives of oxidized synthetic or petroleum waxes. Applicable waxes could include Petrolite's Cardis or Petronauba microcrystalline and polyethylene-based oxidized products, Polymekon (salts) and Ceramer (anhydride adducts).
g. Fully saturated homopolymers of polyethylene or copolymers of various alkene monomers may be used to form polymers with a molecular weight at or below 3,000 with a melting point below 130° C. and low melt viscosities.
Applicable waxes could include “POLYWAX” available from Petrolite Corp.
The formulations may also comprise a fragrance. If fragrances are included the fragrances must be chosen carefully since some fragrances are known to cause skin irritation and/or sensitization reactions.
In addition to the lower alcohols present in the composition of the present invention, other antimicrobials may be added to enhance the antimicrobial action of the compositions of the present invention. This may be particularly desirable in critical uses such as presurgical hand scrubs or presurgical patient skin scrub replacements. Suitable additional antimicrobials include iodine and its complexed forms such as povidone/iodine, chlorhexidine salts such as chlorhexidine digluconate (CHG), parachlorometaxylenol (PCMX), hexachlorophene, phenols, surfactants comprising a long chain hydrophobe (C12-C22) and a quaternary group, triclosan, Lauricidin, quaternary silanes, hydrogen peroxide, silver, silver salts such as silver chloride, silver oxide and silver sulfadiazine and the like. In order to reduce chances for irritation and yet maintain efficacy, the antimicrobial level should be adjusted to the minimum level which maintains a low bacteriological count for 6 and most preferably for 12 hours after application.
The most preferred additional antimicrobial is chlorhexidine since it is capable of ensuring long term antimicrobial efficacy. If chlorhexidine is added to the present invention it is preferably present as a soluble salt. The diacetate and digluconate salts are preferred. The most preferred antimicrobial is chlorhexidine digluconate (CHG). CHG is preferably present at a concentration of 0.05-5.0%, more preferably from 0.1-3% and most preferably from 0.25-2% by weight. Chlorhexidine is a bis(diguamide) and therefore is very basic and is capable of forming multiple ionic bonds with anionic materials. For this reason, chlorhexidine-containing thickener system are preferably based on non-ionic and/or cationic emulsifiers. Certain zwitterionic, very insoluble, or non-precipitating anionic emulsifiers may also be useful.
The compositions of the present invention may also be formulated into an aerosol foam or mousse by addition of an appropriate propellant. The propellant must be chosen to ensure proper delivery from the container to prevent clogging of the valve. The propellant can be chosen from chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), perfluorinated alkanes, and lower alkanes (C1-C5) as well as nitrous oxide dimethyl ether and other solvent-soluble propellants. Preferred propellants are lower alkanes such as propane, butane, and isobutane since these result in a dramatic loss in viscosity making the formulation easy to dispense. A 70/30 mixture of propane/isobutane is a particularly preferred embodiment. In order to produce an aerosol composition the antimicrobial lotion is first formulated and charged into an appropriate pressure rated container. If convenient, the formulation may be heated above the melt temperature in order to facilitate filling. The propellant is then added under pressure at approximately 2-30% preferably 3-20% by volume. The propellant may form a separate layer or may remain emulsified in the composition.
Alternate Applications for Hydro-Alcoholic Liquid Crystalline Solutions:
The compositions of this invention may be compounded with UV absorbers and oils to deliver fast-drying sunscreens. Antimicrobials such as benzoyl peroxide may also be added to the formulations and the formulations may be useful as an acne medication. The systems of this invention may also be formulated with barrier compounds to form barrier creams and lotions. Materials which may be added to provide barrier protection for use as skin barriers to protect against diaper rash include but are not limited to 0.1 to 60% aldioxa, allantoin, aluminum acetate, aluminum hydroxide, bismuth subnitrate, boric acid, calamine, cellulose (microporous), cholecalciferol, cocoa butter, cod liver oil (in combination), colloidal oatmeal, cysteine hydrochloride, dexpanthenol, dimethicone, glycerin kaolin, lanolin (in combination), live yeast cell derivative, mineral oil, peruvian balsam, peruvian balsam oil, petrolatum, protein hydrolysate (1-leucine, 1-isoleucine, 1-methionine, 1-phenylalanine, and 1-tyrosine), racemethionine, shark liver oil, sodium bicarbonate, sulfur, talc, tannic acid, topical starch, vitamin A, white petrolatum, zinc acetate, zinc carbonate and zinc oxide. Formulations are also contemplated containing antifungal agents for treating fungal infections of the skin such as athlete's foot and the like.
A related patent application entitled, “Stable Hydroalcoholic Compositions,” U.S. patent application Ser. No. 08/493,695, filed on Jun. 22, 1995 by inventors Asmus, Scholz and Charpentier is hereby incorporated by reference.
Since many of the compositions of the present invention contain antimicrobials, it is important that they be dispensed in an efficacious and precise amount. The compositions of the present invention can be dispensed in a discreet, substantially uniform amount using the dispensers disclosed in Applicants' Assignee's Copending U.S. patent application Ser. No. 08/668,198, filed Jun. 21, 1996, entitled “Dispenser for Antimicrobial Liquids,” issued as U.S. Pat. No. 5,897,031, and Ser. No. 08/668,270, filed Jun. 21, 1996, entitled “Drip Resistant Nozzle for a Dispenser,” issued as U.S. Pat. No. 5,799,841.
Methods of Preparation
The compositions of the present invention may be prepared by a variety of techniques. For example, the process can often be as simple as adding the thickener system to the hydroalcoholic solvent at a temperature above the melting point of the emulsifiers, mixing briefly and cooling. Nevertheless, to ensure a composition of maximum stability the components are preferably subjected to high shear (e.g. homogenized) for a limited time period while above the melting point of the thickener system followed by low shear mixing while cooling. The system should be mixed under high shear long enough to ensure a very small “droplet” size, however, excessive high shear mixing may result in decreased viscosity and stability.
The cooling rate may be important depending on the particular thickener system. Certain thickener systems can be homogenized and then allowed to cool slowly, however, rapid cooling appears beneficial for most systems.
The order of adding the components may also affect the stability and viscosity of the system. In general it works well to melt the mixed emulsifiers with aqueous-insoluble emollients together in one vessel. The hydroalcoholic solvent and any aqueous miscible emollients are mixed in a second vessel. Both components are heated above the melting temperature of the thickener system. The hot liquid components are mixed together rapidly followed by approximately 1 to 5 minutes of homogenization for typical batches under 500 grams. While still low in viscosity the system is stirred using moderate agitation and cooled. It is also possible to add the molten thickener system along with any solvent insoluble emollients to hot water (i.e., water at a temperature above the melting temperature) followed by high shear mixing and subsequent dilution with alcohol. The processing variables including amount and intensity of high shear mixing, rate of cooling, and order of addition are easily determined by one skilled in the art.
In the following Examples (except where indicated) viscosity was measured at 23° C. at ambient pressure using a Brookfield LVDV-I+
viscometer equipped with a model D Brookfield heliopath and T spindles B-F. The spindle and speed was chosen for each particular sample such that the viscometer was operating in the middle of its range. All samples were allowed to equilibrate at 23° C. for 24 hours prior to measurement. Preferably the viscosity is taken at the lowest speed possible while staying within 20-80% of the viscometer range and more preferably between 30-70% of the range. In all cases the sample size and container geometry was chosen to ensure that there were no wall effects. By “wall effects” it is meant the viscosity value is not affected by the container and is essentially equivalent to the viscosity taken in an infinitely large container. For this reason lower viscosity samples required a larger sample size to accommodate the larger spindles. The following table outlines preferred spindles for various sample viscosities.
|Sample Viscosity ||T Spindle to Use |
| 1,000-100,000 ||B |
| 10,000-200,000 ||C |
| 50,000-500,000 ||D |
| 100,000-1,250,000 ||E |
| 500,000-3,000,000 ||F |
The viscosity of each sample was taken as the highest relatively stable reading achieved on the first path the spindle traversed using the heliopath adapter.
The stability of samples was measured 24 hours after conditioning at ambient conditions by placing 12 ml of a formulation that formed a lotion/cream in a 15 ml graduated centrifuge tube. The tube was then centrifuged in a Labofuge B (Heraeus Sepatech GmbH, Model 2650, rotor 2150 and buckets #2101) at 3000 rpm (2275×g when measured at the longitudinal midpoint of the sample tube) for 30 minutes at 23° C. Stability is recorded as a volume percent separation in the Examples below.
Melt Temperature (Tm)
The melt temperature was measured by placing approximately 15 grams sample in a 25 cc sealed glass vial and placing the vial in a water bath. The temperature of the bath was increased periodically in discrete increments and the contents checked after approximately 1 hour at a given temperature. The melt temperature was taken as the temperature at which the mixture became very low in viscosity.
Minimum Inhibitory Concentration (MIC)
An overnight culture of E. coli ATCC 8739 (lab strain 223) and/or S. Aureus ATCC 14154 (lab strain 502) grown on trypticase soy agar plates was resuspended in Mueller-Hinton Broth to a cell density of 0.6-1.2×106 colony forming units per milliliter. Chlorhexidine samples were prepared by adjusting CHG to 512 μg/ml in Mueller-Hinton Broth and serially diluting in two-fold steps in Mueller-Hinton Broth. The CHG-containing Mueller-Hinton Broth was placed in 96-well sterile microliter plates and each well was inoculated with the bacteria. The plates were then incubated for 24-48 hrs at 37° C. Bacterial growth was determined visually by comparing the plates. The MIC was determined as the lowest concentration of CHG that resulted in complete kill of the test organism.
Cosmetic Properties/Tactile Testing
For use in presurgical disinfection the compositions of this invention are preferably formulated with emollients to achieve a moisturized but relatively dry feel. Lotions with excessive emollients tend to be perceived as greasy and can result in excessive clumping of the powder under surgical gloves. The formulations of this invention do not provide a tacky or sticky feel even in high humidity environments throughout the application process. The invention formulations preferably yield a smooth, soft, non-tacky, and moisturized feeling. Testing of the cosmetic or tactile properties of the compositions was conducted with preferably greater than ten evaluators who applied a premeasured amount of product, approximately 2 ml. Since hand washing can affect the feel of the compositions, evaluators washed thoroughly with Ivory Skin Cleansing Liquid Gel hand soap available from Procter and Gamble, Cincinnati, Ohio before applying the sample. After drying, the composition was rubbed uniformly over the surfaces of both hands until the composition was dry. The feel of the composition on the skin during subsequent washing with soap and water was also important. Approximately 30-60 min. after application of the composition the feel during subsequent washing was evaluated. Preferred formulations did not result in an abnormal feeling such as slimy, slippery, or sticky characteristics.