Antiperspirant formulations containing an antiperspirant active and a continuous phase comprising a water-immiscible liquid carrier, such as, amongst other materials, cyclomethicones, that is structured using an amido-containing compound of the general formula

The present invention relates to antiperspirant compositions for application to human skin, especially the axilla.
A wide variety of cosmetic compositions for application to human skin make use of a thickened or structured liquid carrier to deliver colour or some other active material to the surface of the skin. A significant example of such cosmetic compositions are antiperspirant compositions which are widely used in order to enable their users to avoid or minimise wet patches on their skin, especially in axillary regions.
Antiperspirant formulations have been provided with a range of different product forms. One of these is a so-called xe2x80x9cstickxe2x80x9d which is usually a bar of an apparently firm solid material held within a dispensing container and which retains its structural integrity and shape whilst being applied. When a portion of the stick is drawn across the skin surface a film of the stick composition is transferred to the skin surface. Although the stick has the appearance of a solid article capable of retaining its own shape for a period of time, the material usually has a structured liquid phase so that a film of the composition is readily transferred from the stick to another surface upon contact.
Another possibility is that a stick is a softer solid composition accommodated in a dispensing container which in use extrudes the composition through one or more apertures.
Antiperspirant sticks can be divided into three categories. Suspension sticks contain a particulate antiperspirant active material suspended in a structured carrier liquid phase which generally is water-immiscible and may be anhydrous. Emulsion sticks normally have a hydrophilic phase containing the antiperspirant active in solution, this phase forming an emulsion with a second, more hydrophobic, liquid phase. The continuous phase of the emulsion is structured. Solution sticks typically have the antiperspirant active dissolved in a structured liquid phase which is polar and may be a mixture of water and a water-miscible organic solvent, or may be polar organic solvent without water. This classification into suspension, emulsion and solution types can be applied to both firm and soft solid compositions.
There is substantial literature on the structuring or thickening of antiperspirant compositions.
Conventionally, many sticks have been structured using naturally-occurring or synthetic waxy materials. In this way, it is possible to obtain either a soft solid or a firm solid. Examples of wax-structured sticks are described in an article in Cosmetics and Toiletries, 1990, Vol 105, P75-78 and in U.S. Pat. Nos. 5,169,626 and 4,725,432.
More specifically it has been common practice for sticks to be structured by incorporating fatty alcohol into the composition, often accompanied by a smaller amount of castor wax. Sticks which are structured with fatty alcohol tend to leave visible white deposits on application to human skin; moreover the deposits can also transfer onto clothing when it comes into contact with the skin and the wearer can, for example, find white marks at the armhole of the sleeveless garment. Fatty alcohols are often regarded as coming within the general category of waxy materials, but we have observed that they are a more significant source of white deposits than other waxy materials.
Some alternative structurants have been proposed. The term xe2x80x9cgellantxe2x80x9d is often employed instead of xe2x80x9cstructurantxe2x80x9d. Where the resulting product is liquid of increased viscosity rather than a solid or gel, the term xe2x80x9cthickenerxe2x80x9d can also be used. For example, the use of dibenzylidene sorbitol (DBS) or derivatives thereof as gellant has been proposed in a number of publications such as EP-A-512770, WO 92/19222, U.S. Pat. Nos. 4,954,333, 4,822,602 and 4,725,430. Formulations containing such gellants can suffer from a number of disadvantages, including instability in the presence of acidic antiperspirants, and comparatively high processing temperatures needed in the production of sticks.
U.S. Pat. No. 5,750,096 is one of several documents which teaches that gelation can be brought about using esters or amides of 12-hydroxystearic acid. The alcohol used to form such an ester or the amine used to form such an amide may contain an aliphatic, cycloaliphatic or aromatic group with up to 22 carbons therein. If the group is aliphatic it preferably contains at least three carbon atoms. A cycloaliphatic group preferably contains at least five carbon atoms and may be a fixed ring system such as adamantyl.
N-acyl amino acid amides and esters are also known to structure liquids. We have established that they do so by forming fibrous networks. They are described in U.S. Pat. No. 3,969,087. N-Lauroyl-L-glutamic acid di-n-butylamide is commercially available from Ajinomoto under their designation GP-1.
Further materials which have been disclosed as gelling agents are the amide derivatives of di and tribasic carboxylic acids set forth in WO 98/27954 notably alkyl N,Nxe2x80x2-dialkyl succinamides.
It is known from Hanabusa et al xe2x80x9cProminent Gelation and Chiral Aggregation of Alkylamides Derived from Trans 1,2 Diaminocyclohexanexe2x80x9d published in Angew. Chem. Int. Ed. Engl. 1996 35, page 1949 that alkylamides derived from trans-1,2-diaminocyclohexane are capable of causing the gelation of a number of organic liquids. The authors reported that the corresponding cis-compound did not bring about gelation of any of the liquids tested. Moreover, use of an optically active form of the trans-compound was necessary because the racemic form was found to give only an unstable gel.
Japanese published patent application JP-A-10-237034 (Polar Kasei Kogyo KK, inventors Hanabusa et al) discloses cosmetic compositions containing an organic oil gelled with such derivatives of 1,2-diaminocyclohexane.
WO 91/04009 (Gillette) discloses antiperspirant compositions containing dioctyl cyclohexane, but that material is a liquid present to prevent phase separation of the masking agent and does not function as a gellant.
We have now found that selected 1,2- and 1,3-substituted cyclohexane derivatives can be used as structurants for antiperspirant compositions. When used as a modest percentage of the composition, typically not more than 15% by weight and often less than 10% by weight, they are able to structure the composition, yet at the same time the composition gives a deposit with a low visible residue.
It is an object of the present invention to provide structured antiperspirant compositions, in which a liquid carrier material is thickened or structured using a structuring agent which is different from those mentioned above. A further object of the invention is to provide a structurant which can have superior properties to at least some of the structurants which have been used previously.
A yet further object of some embodiments of the invention is to provide compositions which exhibit low visible deposits.
Broadly, a first aspect of the present invention provides an antiperspirant composition comprising:
(i) a continuous phase which comprises water-immiscible liquid carrier,
(ii) a structurant therein which is at least one amido-containing compound of the general formula
wherein R and R1 each independently denote a branched or unbranched moiety containing 5 to 27 carbon atoms, m and n are each independently, zero or 1, Y is a cyclohexane ring bearing the amido-containing substituent groups
in 1,2 or 1,3 positions; and
(iii) an antiperspirant active material.
Each aliphatic group R or R1 may be an unsubstituted alkyl or an alkenyl group, or it may bear functional substituents which incorporate hetero atoms such as oxygen or nitrogen, or it may include hetero atoms in a linkage in the chain. If hetero atoms are present they may, desirably, be included in groups able to participate in hydrogen bonding.
R and R1 may, independently of each other, contain 11 to 17 carbon atoms. They may be mixed groups such as an aliphatic chain with an aromatic group or cycloalkyl group embedded in it.
If Y is a cyclohexane ring bearing the substituent groups in 1,3-positions, m and n are preferably 1. If Y bears the substituents groups in 1,2-positions m and n are preferably zero.
An amido-containing compound as above serves as a structuring agent or thickener for the water-immiscible liquid carrier and when used in a sufficient amount, which is likely to be less than 15% of the total composition, is able to structure this liquid into a gel with sufficient rigidity to sustain its own shape.
We have observed that the structuring compounds used in this invention form fibres or strands within the liquid phase.
Without being bound to any specific theory or explanation, we believe that upon gel formation a network of such fibres is formed which extends throughout the liquid phase. Upon heating the gel to the gel melting temperature, the strands of structurant dissolve and the liquid phase becomes more mobile.
In order to promote good sensory properties at the time of use it is preferred to include silicone oil in the water-immiscible carrier liquid. The amount of silicone oil may be at least 10% by weight of the composition and/or at least 40% by weight of the water-immiscible carrier liquid.
Ethanol gives a cooling effect on application to skin, because it is very volatile. It is preferred that the content of ethanol or any monohydric alcohol with a vapour pressure above 1.3kPa (10 mmHg) is not over 15% better not over 8% by weight of the composition.
Fatty alcohols which are solid at room temperature of 20xc2x0 C., such as stearyl alcohol, lead to deposits with an opaque white appearance and are preferably kept to low concentration or entirely excluded. As already mentioned, fatty alcohols are often regarded as coming within the general category of waxy materials. More generally the term xe2x80x9cwaxxe2x80x9d is conventionally applied to a variety of materials and mixtures (including some fatty alcohols) which have some diversity in chemical structure but similarity in physical properties. The term generally denotes materials which are solid at 30xc2x0 C., often also solid up to 40xc2x0 C., but which melt to a mobile liquid at a temperature below 95xc2x0 C. usually below 90xc2x0 C.
Possibly the composition does not include more than 3% of any material which is solid at 30xc2x0 C. but at 95xc2x0 C. is molten and soluble in the water-immiscible liquid of the continuous phase, yet which is unable to form a network of fibres in the continuous phase on cooling to 20xc2x0 C.
As will be explained in more detail below, the structured water-immiscible carrier liquid may be the continuous phase of a composition with a dispersed second phase, either an emulsion or a suspension of particulate solid. Such a solid may be a particulate antiperspirant active. A disperse phase may be a solution of antiperspirant active in water or other hydrophilic solvent.
Further advantages of preferred structurant materials of this invention are that they do not require high processing temperatures and that they are chemically stable, both during processing and in the resultant compositions. The avoidance of high processing temperatures can be especially valuable when the composition contains some water or other volatile constituent.
A composition of this invention will generally be marketed in a container by means of which it can be applied at time of use. This container may be of conventional type.
A second aspect of the invention therefore provides an antiperspirant product comprising a dispensing container having at least one aperture for delivery of the contents of the container, means for urging the contents of the container to the said aperture or apertures, and a composition of the first aspect of the invention in the container.
Means for urging the contents of the container to the said aperture or apertures, for flow through them, may be moving parts operable by the user.
However, if the composition is a soft solid, means for urging the contents of the container to the said aperture or apertures, may simply be flexible container walls so that the user can expel composition from the container by squeezing it.
The compositions of this invention can be produced by conventional processes for making cosmetic solids or soft-solids.
Thus, according to a third aspect of the present invention there is provided a process for the production of an antiperspirant composition comprising, not necessarily in any order, the steps of:
incorporating into a water-immiscible liquid carrier a structurant which is one or more structurant compounds as defined above, mixing the liquid carrier with a solid or a disperse liquid phase comprising antiperspirant active in particulate or dissolved form to be suspended therein, and which comprises an antiperspirant active,
heating the liquid carrier or a mixture containing it to an elevated temperature at which the structurant is soluble in the water-immiscible liquid carrier, followed by:
introducing the mixture into a mould which preferably is a dispensing container, and then
cooling or permitting the mixture to cool to a temperature at which it is thickened or solidified.
A suspended solid may be an antiperspirant active and a disperse liquid phase may be a solution of such an active in a hydrophilic or polar solvent.
According to a fourth aspect of the present invention, there is provided a cosmetic method for preventing or reducing perspiration on human skin comprising topically applying to the skin a composition comprising an antiperspirant active, a water-immiscible liquid carrier and a structurant compound as defined above.
As mentioned above the invention requires a structurant compound within a water-immiscible liquid phase. Other materials may also be present depending on the nature of the composition. The various materials will now be discussed by turn and preferred features and possibilities will be indicated.
The structurant compounds of the present invention have a general formula:
as given above. Two more specific possibilities are:
In the above formulae R and R1 are preferably the same.
In the formulae above the two ring carbon atoms (shown numbered) bonded to the amido group-containing side chains are both chiral centres. The compounds thus have the possibility of more than one stereochemical conformation of the aliphatic ring and also optical enantiomers of each stereochemical form.
We have found that all stereochemical and optical isomers will function as structurants, although optically active forms may be superior.
The amido-containing structurant compound(s) used in this invention may be a mixture of compounds within the general formulae given, or may be a single compound, possibly as a mixture of its optically active forms.
These amido-containing structurant compounds can be prepared by reacting the respective amine compound with an acid chloride, or possibly with an anhydride or an ester.
The amount of the said structurant compound(s) in a composition of this invention is likely to be from 0.1 or 0.5 to 15% by weight of the whole composition and preferably from 0.5 up to 8% or 10%, probably from 1 to 8%. In other instances, the amount is from 10 to 15% of the formulation. If the composition is an emulsion with a separate disperse phase, the amount of structurant compound(s) is likely to be from 0.5 to 20% or even 25% by weight of the continuous phase, more likely from 1% to 15% of this phase.
Carrier Liquid
The water-immiscible carrier liquid comprises one or a mixture of materials which are relatively hydrophobic so as to be immiscible in water. Some hydrophilic liquid may be included in the carrier, provided the overall carrier liquid mixture is immiscible with water. It will generally be desired that this carrier is liquid (in the absence of structurant) at temperatures of 15xc2x0 C. and above. It may have some volatility but its vapour pressure will generally be less than 4 kPa (30 mmHg) at 25xc2x0 C. so that the material can be referred to as an oil or mixture of oils. More specifically, it is desirable that at least 80% by weight of the hydrophobic carrier liquid should consist of materials with a vapour pressure not over this value of 4 kPa at 25xc2x0 C.
It is preferred that the hydrophobic carrier material includes a volatile liquid silicone, i.e. liquid polyorganosiloxane. To class as xe2x80x9cvolatilexe2x80x9d such material should have a measurable vapour pressure at 20 or 25xc2x0 C. Typically the vapour pressure of a volatile silicone lies in a range from 1 or 10 Pa to 2 kPa at 25xc2x0 C.
It is desirable to include volatile silicone because it gives a xe2x80x9cdrierxe2x80x9d feel to the applied film after the composition is applied to skin.
Volatile polyorganosiloxanes can be linear or cyclic or mixtures thereof. Preferred cyclic siloxanes include polydimethylsiloxanes and particularly those containing from 3 to 9 silicon atoms and preferably not more than 7 silicon atoms and most preferably from 4 to 6 silicon atoms, otherwise often referred to as cyclomethicones. Preferred linear siloxanes include polydimethylsiloxanes containing from 3 to 9 silicon atoms. The volatile siloxanes normally by themselves exhibit viscosities of below 10xe2x88x925 m2/sec (10 centistokes), and particularly above 10xe2x88x927 m2/sec (0.1 centistokes), the linear siloxanes normally exhibiting a viscosity of below 5xc3x9710xe2x88x926 m2/sec (5 centistokes). The volatile silicones can also comprise branched linear or cyclic siloxanes such as the aforementioned linear or cyclic siloxanes substituted by one or more pendant xe2x80x94Oxe2x80x94Si(CH3)3 groups. Examples of commercially available silicone oils include oils having grade designations 344, 345, 244, 245 and 246 from Dow Corning Corporation; Silicone 7207 and Silicone 7158 from Union Carbide Corporation; and SF1202 from General Electric.
The hydrophobic carrier employed in compositions herein can alternatively or additionally comprise non-volatile silicone oils, which include polyalkyl siloxanes, polyalkylaryl siloxanes and polyethersiloxane copolymers. These can suitably be selected from dimethicone and dimethicone copolyols. Commercially available non-volatile silicone oils include Dow Corning 556 and Dow Corning 200 series.
The water-immiscible liquid carrier may contain from 0% to 100% by weight of one or more liquid silicones. Preferably, there is sufficient liquid silicone to provide at least 10%, better at least 15%, by weight of the whole composition. If silicone oil is used, volatile silicone preferably constitutes from 20 to 100% of the weight of the carrier liquid. In many instances, when a non-volatile silicone oil is present, its weight ratio to volatile silicone oil is chosen in the range of from 1:3 to 1:40.
Silicon-free hydrophobic liquids can be used instead of, or more preferably in addition to liquid silicones. Silicon-free hydrophobic organic liquids which can be incorporated include liquid aliphatic hydrocarbons such as mineral oils or hydrogenated polyisobutene, often selected to exhibit a low viscosity. Further examples of liquid hydrocarbons are polydecene and paraffins and isoparaffins of at least 10 carbon atoms.
Other hydrophobic carriers are liquid aliphatic or aromatic esters, but these can be used as only part of the liquid carrier, desirably not above 20%, and possibly less than 10% by weight of the water-immiscible liquid carrier.
Suitable aliphatic esters contain at least one long chain alkyl group, such as esters derived from C1 to C20 alkanols esterified with a C8 to C22 alkanoic acid or C6 to C10 alkanedioic acid. The alkanol and acid moieties or mixtures thereof are preferably selected such that they each have a melting point of below 20xc2x0 C. These esters include isopropyl myristate, lauryl myristate, isopropyl palmitate, diisopropyl sebacate and diisopropyl adipate.
Suitable liquid aromatic esters, preferably having a melting point of below 20xc2x0 C., include fatty alkyl benzoates. Examples of such esters include suitable C8 to C18 alkyl benzoates or mixtures thereof.
Further instances of suitable hydrophobic carriers comprise liquid aliphatic ethers derived from at least one fatty alcohol, such as myristyl ether derivatives e.g. PPG-3 myristyl ether or lower alkyl ethers of polygylcols such as PPG-14 butyl ether.
Aliphatic alcohols which are solid at 20xc2x0 C., such as stearyl alcohol are preferably absent or present in low concentration such as less than 5% by weight of the whole composition since these lead to visible white deposits when a composition is used.
However, aliphatic alcohols which are liquid at 20xc2x0 C. may be employed. These include branched chain alcohols of at least 10 carbon atoms such as isostearyl alcohol and octyl dodecanol.
Silicon-free liquids can constitute from 0-100% of the water-immiscible liquid carrier, but it is preferred that silicone oil is present and that the amount of silicon-free constituents preferably constitutes up to 50 or 60% and in many instances from 20 to 60% by weight of the carrier liquid.
Liquid Disperse Phase
If the composition is an emulsion in which the amido-containing compound acts as a structurant in the continuous phase, the emulsion will contain a more polar disperse phase. The disperse phase may be a solution of an active ingredient.
The hydrophilic disperse phase in an emulsion normally comprises water as solvent and can comprise one or more water soluble or water miscible liquids in addition to or replacement for water. The proportion of water in an emulsion according to the present invention is often selected in the range of up to 60%, and particularly from 10% up to 40% or 50% of the whole formulation.
One class of water soluble or water-miscible liquids comprises short chain monohydric alcohols, e.g. C1 to C4 and especially ethanol or isopropanol, which can impart a deodorising capability to the formulation. A further class of hydrophilic liquids comprises diols or polyols preferably having a melting point of below 40xc2x0 C., or which are water miscible. Examples of water-soluble or water-miscible liquids with at least one free hydroxy group include ethylene glycol, 1,2-propylene glycol, 1,3-butylene glycol, hexylene glycol, diethylene glycol, dipropylene glycol, 2-ethoxyethanol, diethylene glycol monomethylether, triethyleneglycol monomethylether and sorbitol. Especially preferred are propylene glycol and glycerol.
In an emulsion the disperse phase is likely to constitute from 5 to 80 or 85% of the weight of the composition preferably from 5 to 50 or 65% more preferably from 25 or 35% up to 50 or 65%, while the continuous phase with the structurant therein provides the balance from 15 or 35% up to 95% of the weight of the composition. Compositions with high proportion of disperse phase, i.e. from 65 to 85% disperse phase, may also be advantageous. They can give good hardness even though the concentration of structurant may be only a small percentage of the total composition.
An emulsion composition will generally include one or more emulsifying surfactants which may be anionic, cationic, zwitterionic and/or nonionic surfactants. The proportion of emulsifier in the composition is often selected in the range up to 10% by weight and in many instances from 0.1 or 0.25 up to 5% by weight of the composition. Most preferred is an amount from 0.1 or 0.25 up to 3% by weight. Nonionic emulsifiers are frequently classified by HLB value. It is desirable to use an emulsifier or a mixture of emulsifiers with an overall HLB value in a range from 2 to 10 preferably from 3 to 8.
It may be convenient to use a combination of two or more emulsifiers which have different HLB values above and below the desired value. By employing the two emulsifiers together in appropriate ratio, it is readily feasible to attain a weighted average HLB value that promotes the formation of an emulsion.
Many suitable emulsifiers of high HLB are nonionic ester or ether emulsifiers comprising a polyoxyalkylene moiety, especially a polyoxyethylene moiety, often containing from about 2 to 80, and especially 5 to 60 oxyethylene units, and/or contain a polyhydroxy compound such as glycerol or sorbitol or other alditol as hydrophilic moiety. The hydrophilic moiety can contain polyoxypropylene. The emulsifiers additionally contain a hydrophobic alkyl, alkenyl or aralkyl moiety, normally containing from about 8 to 50 carbons and particularly from 10 to 30 carbons. The hydrophobic moiety can be either linear or branched and is often saturated, though it can be unsaturated, and is optionally fluorinated. The hydrophobic moiety can comprise a mixture of chain lengths, for example those deriving from tallow, lard, palm oil, sunflower seed oil or soya bean oil. Such nonionic surfactants can also be derived from a polyhydroxy compound such as glycerol or sorbitol or other alditols. Examples of emulsifiers include ceteareth-10 to -25, ceteth-10-25, steareth-10-25 (i.e. C16 to C18 alcohols ethoxylated with 10 to 25 ethylene oxide residues) and PEG-15-25 stearate or distearate. Other suitable examples include C10-C20 fatty acid mono, di or tri-glycerides. Further examples include C18-C22 fatty alcohol ethers of polyethylene oxides (8 to 12 EO).
Examples of emulsifiers, which typically have a low HLB value, often a value from 2 to 6 are fatty acid mono or possibly diesters of polyhydric alcohols such as glycerol, sorbitol, erythritol or trimethylolpropane. The fatty acyl moiety is often from C14 to C22 and is saturated in many instances, including cetyl, stearyl, arachidyl and behenyl. Examples include monoglycerides of palmitic or stearic acid, sorbitol mono or diesters of myristic, palmitic or stearic acid, and trimethylolpropane monoesters of stearic acid.
A particularly desirable class of emulsifiers comprises dimethicone copolymers, namely polyoxyalkylene modified dimethylpolysiloxanes. The polyoxyalkylene group is often a polyoxyethylene (POE) or polyoxypropylene (POP) or a copolymer of POE and POP. The copolymers often terminate in C1 to C12 alkyl groups.
Suitable emulsifiers and co-emulsifiers are widely available under many trade names and designations including Abil(trademark), Arlacel(trademark), Brij(trademark), Cremophor(trademark), Dehydrol(trademark), Dehymuls(trademark), Emerest(trademark), Lameform(trademark)T, Pluronic(trademark), Prisorine(trademark), Quest PGPH(trademark), Span(trademark), Tween(trademark), SF1228, DC3225C and Q2-5200.
Antiperspirant Actives
The composition will also contain an antiperspirant active. Antiperspirant actives, are preferably incorporated in an amount of from 0.5-60%, particularly from 5 to 30% or 40% and especially from 5 or 10% to 30 or 35% of the weight of the composition.
Antiperspirant actives for use herein are often selected from astringent active salts, including in particular aluminium, zirconium and mixed aluminium/zirconium salts, including both inorganic salts, salts with organic anions and complexes. Preferred astringent salts include aluminium, zirconium and aluminium/zirconium halides and halohydrate salts, such as chlorohydrates.
Aluminium halohydrates are usually defined by the general formula Al2(OH)xQy.wH2O in which Q represents chlorine, bromine or iodine, x is variable from 2 to 5 and x+y=6 while wH2O represents a variable amount of hydration. Especially effective aluminium halohydrate salts, known as activated aluminium chlorohydrates, are described in EP-A-6739 (Unilever NV et al), the contents of which specification is incorporated herein by reference. Some activated salts do not retain their enhanced activity in the presence of water but are useful in substantially anhydrous formulations, i.e. formulations which do not contain a distinct aqueous phase.
Zirconium actives can usually be represented by the empirical general formula: ZrO(OH)2n-nzBz.wH2O in which z is a variable in the range of from 0.9 to 2.0 so that the value 2nxe2x88x92nz is zero or positive, n is the valency of B, and B is selected from the group consisting of chloride, other halide, sulphamate, sulphate and mixtures thereof. Possible hydration to a variable extent is represented by wH2O. Preferable is that B represents chloride and the variable z lies in the range from 1.5 to 1.87. In practice, such zirconium salts are usually not employed by themselves, but as a component of a combined aluminium and zirconium-based antiperspirant.
The above aluminium and zirconium salts may have co-ordinated and/or bound water in various quantities and/or may be present as polymeric species, mixtures or complexes. In particular, zirconium hydroxy salts often represent a range of salts having various amounts of the hydroxy group. Zirconium aluminium chlorohydrate may be particularly preferred.
Antiperspirant complexes based on the above-mentioned astringent aluminium and/or zirconium salts can be employed. The complex often employs a compound with a carboxylate group, and advantageously this is an amino acid. Examples of suitable amino acids include dl-tryptophan, dl-xcex2-phenylalanine, dl-valine, dl-methionine and xcex2-alanine, and preferably glycine which has the formula CH2(NH2)COOH.
It is highly desirable to employ complexes of a combination of aluminium halohydrates and zirconium chlorohydrates together with amino acids such as glycine, which are disclosed in U.S. Pat. No. 3,792,068 (Luedders et al). Certain of those Al/Zr complexes are commonly called ZAG in the literature. ZAG actives generally contain aluminium, zirconium and chloride with an Al/Zr ratio in a range from 2 to 10, especially 2 to 6, an Al/Cl ratio from 2.1 to 0.9 and a variable amount of glycine. Actives of this preferred type are available from Westwood, from Summit and from Reheis.
Other actives which may be utilised include astringent titanium salts, for example those described in GB 2299506A.
The proportion of solid antiperspirant salt in a composition normally includes the weight of any water of hydration and any complexing agent that may also be present in the solid active. However, when the active salt is in solution, its weight excludes any water present.
If the composition is in the form of an emulsion the antiperspirant active will be dissolved in the disperse phase. In this case, the antiperspirant active will often provide from 3 to 60% by weight of the disperse phase, particularly from 10% or 20% up to 55% or 60% of that phase. Alternatively, the composition may take the form of a suspension in which antiperspirant active in particulate form is suspended in the water-immiscible liquid carrier. Such a composition will probably not have any separate aqueous phase present and may conveniently be referred to as xe2x80x9csubstantially anhydrousxe2x80x9d although it should be understood that some water may be present bound to the antiperspirant active or as a small amount of solute within the water-immiscible liquid phase. In such compositions, the particle size of the antiperspirant salts often falls within the range of 0.1 to 200 xcexcm with a mean particle size often from 3 to 20 xcexcm. Both larger and smaller mean particle sizes can also be contemplated such as from 20 to 50 xcexcm or 0.1 to 3 xcexcm.
Optional Ingredients
Optional ingredients in compositions of this invention can include disinfectants, for example at a concentration of up to about 10% w/w. Suitable deodorant actives can comprise deodorant effective concentrations of antiperspirant metal salts, deoperfumes, and/or microbicides, including particularly bactericides, such as chlorinated aromatics, including biguanide derivatives, of which materials known as Igasan DP300(trademark) (triclosan), Tricloban(trademark), and Chlorhexidine warrant specific mention. A yet another class comprises biguanide salts such as are available under the trade mark Cosmosil(trademark).
Other optional ingredients include wash-off agents, often present in an amount of up to 10% w/w to assist in the removal of the formulation from skin or clothing. Such wash-off agents are typically nonionic surfactants such as esters or ethers containing a C8 to C22 alkyl moiety and a hydrophilic moiety which can comprise a polyoxyalkylene group (POE or POP) and/or a polyol.
A further optional constituent of the formulation comprises one or more secondary structurants which can be employed in addition to the amido-containing compound which is the primary structurant. The amount of such secondary structurants in the formulation is often zero, and usually not more than 15% of the formulation. It is normally not greater than the amount of the primary structurant.
The secondary structurants employable herein can be non-polymeric or polymeric. Solid linear fatty alcohol and/or a wax may be included but are not preferred. In anhydrous compositions notably antiperspirants which are suspension sticks, non-polymeric secondary structurants, sometimes referred to as gellants, can be selected from fatty acids or salts thereof, such as stearic acid or sodium stearate or 12-hydroxy stearic acid. Fatty acids are preferably not used in aqueous sticks, e.g. aqueous emulsion sticks because they can form insoluble precipitates with aluminium ions. Other suitable gellants can comprise dibenzylidene alditols, e.g. dibenzylidene sorbitol. Further suitable gellants can comprise lanosterol, selected N-acyl amino acid derivatives, including ester and amide derivatives, such as N-lauroyl glutamic acid dibutylamide, which gellants can be contemplated in conjunction with 12-hydroxy stearic acid or an ester or amide derivative thereof. Still further gellants include amide derivatives of di or tribasic carboxylic acids, such as alkyl N,Nxe2x80x2dialkylsuccinamides, e.g. dodecyl N,Nxe2x80x2-dibutylsuccinamide.
Polymeric structurants which can be employed can comprise organo polysiloxane elastomers such as reaction products of a vinyl terminated polysiloxane and a cross linking agent or alkyl or alkyl polyoxyalkylene-terminated poly (methyl substituted) or poly (phenyl substituted) siloxanes. A number of polyamides have also been disclosed as structurants for hydrophobic liquids. Polymers containing both siloxane and hydrogen bonding groups, which might be used as secondary structurants, have been disclosed in WO 97/36572 and WO 99/06473. If an aqueous disperse phase is present, polyacrylamides, polyacrylates or polyalkylene oxides may be used to structure or thicken this aqueous phase.
One category of polymer which may be employed as a second structurant for the continuous phase is a polysaccharide esterified with monocarboxylic acid containing at least 8 carbon atoms.
Preferred in this category is a dextrin fatty acid ester having the formula:
wherein each R group, individually, is a hydrogen or an acyl group of up to 22 carbon atoms, provided that at least one R group per glucose unit is an acyl group of 8 to 22 carbon atoms, and m has a value from about 20 to 30. The dextrin fatty acid ester can be a partial ester, i.e. at least one R group is hydrogen. Another possibility is that the dextrin can be completely esterified with C8 to C22 acyl groups, i.e. every R group is a C8-C22 acyl group. In preferred embodiments, the degree of substitution with an R group which is a C8-C22 alkyl group is at least 2 (i.e., at least two R groups are C8-C22 acyl groups). A further possibility would be that some R groups are acyl groups of less than 8 carbon atoms while some R groups (at least one per glucose residue, preferably at least two) is a C8 to C22 acyl group. The C8-C22 fatty acids that provide acyl groups can be saturated or unsaturated acids.
The compositions herein can incorporate one or more cosmetic adjuncts conventionally contemplatable for antiperspirant solids or soft solids. Such cosmetic adjuncts can include skin feel improvers, such as talc or finely divided polyethylene, for example in an amount of up to about 10%; skin benefit agents such as allantoin or lipids, for example in an amount of up to 5%; colours; skin cooling agents other than the already mentioned alcohols, such a menthol and menthol derivatives, often in an amount of up to 2%, all of these percentages being by weight of the composition. A commonly employed adjunct is a perfume, which is normally present at a concentration of from 0 to 4% and in many formulations from 0.25 to 2% by weight of the composition.
Mechanical Properties and Product Packages
The compositions of this invention are structured liquids and may be firm or soft in appearance. Even a soft solid has an ability to sustain its own shape, for instance if it is removed from a mould without being subjected to shear it will retain its shape for at least 30 seconds, usually longer.
A composition of this invention will usually be marketed as a product comprising a container with a quantity of the composition therein, where the container has at least one aperture for the delivery of composition, and means for urging the composition in the container towards the delivery aperture. Conventional containers take the form of a barrel of oval cross section with the delivery aperture(s) at one end of the barrel.
A composition of this invention may be sufficiently rigid that it is not apparently deformable by hand pressure and is suitable for use as a stick product in which a quantity of the composition in the form of a stick is accommodated within a container barrel having an open end at which an end portion of the stick of composition is exposed for use. The opposite end of the barrel is closed.
Generally the container will include a cap for its open end and a component part which is sometimes referred to as an elevator or piston fitting within the barrel and capable of relative axial movement along it. The stick of composition is accommodated in the barrel between the piston and the open end of the barrel. The piston is used to urge the stick of composition along the barrel. The piston and stick of composition may be moved axially along the barrel by manual pressure on the underside of the piston using a finger or rod inserted within the barrel. Another possibility is that a rod attached to the piston projects through a slot or slots in the barrel and is used to move the piston and stick. Preferably the container also includes a transport mechanism for moving the piston comprising a threaded rod which extends axially into the stick through a correspondingly threaded aperture in the piston, and means mounted on the barrel for rotating the rod. Conveniently the rod is rotated by means of a hand-wheel mounted on the barrel at its closed end, i.e. the opposite end to the delivery opening.
If a composition of this invention is softer, but still capable of sustaining its own shape it will be more suited for dispensing from a barrel with a closure instead of an open end, where the closure has one or more apertures through which composition from the barrel can be extruded. The number and design of such apertures is at the discretion of the designer of the package.
The component parts of such containers are often made from thermoplastic materials, for example polypropylene or polyethylene. Descriptions of suitable containers, some of which include further features, are found in U.S. Pat. Nos. 4,865,231, 5,000,356 and 5,573,341.
Measurement of Properties
i) Penetrometer
The hardness and rigidity of a composition which is a firm solid can be determined by penetrometry. If the composition is a softer solid, this will be observed as a substantial lack of any resistance to the penetrometer probe.
A suitable procedure is to utilises a lab plant PNT penetrometer equipped with a Seta wax needle (weight 2.5 grams) which has a cone angle at the point of the needle specified to be 9xc2x0 10xe2x80x2xc2x115xe2x80x2. A sample of the composition with a flat upper surface is used. The needle is lowered onto the surface of the composition and then a penetration hardness measurement is conducted by allowing the needle with its holder to drop under a total weight, (i.e. the combined weight of needle and holder) of 50 grams for a period of five seconds after which the depth of penetration is noted. Desirably the test is carried out at a number of points on each sample and the results are averaged. Utilising a test of this nature, an appropriate hardness for use in an open-ended dispensing container is a penetration of less than 30 mm in this test, for example in a range from 2 to 30 mm. Preferably the penetration is in a range from 5 mm to 20 mm.
In a specific protocol for this test measurements on a stick were performed in the stick barrel. The stick was wound up to project from the open end of the barrel, and then cut off to leave a flat, uniform surface. The needle was carefully lowered to the stick surface, and then a penetration hardness measurement was conducted. This process was carried out at six different points on the stick surface. The hardness reading quoted is the average value of the 6 measurements.
ii) Texture Analyser
This test apparatus can move a blunt probe into or out from a sample at a controlled speed and at the same time measure the applied force. The parameter which is determined as hardness is a function of the peak force and the projected area of indentation.
A specific test protocol used a Stable Micro systems TA.XT2i Texture Analyser. A metal sphere, of diameter 9.5 mm, was attached to the underside of the Texture Analyser""s 5 kg load cell such that it could be used for indenting a sample placed beneath it on the base plate of the instrument. After positioning the sample, the sphere position was adjusted until it was just above the sample surface. Texture Expert Exceed software was used to generate the subsequent motion profile used in the test method. This profile initially indented the sphere into the sample at an indentation speed of 0.05 mm/s until a designated force was reached, which was chosen such that the distance of penetration into the sample was less than the radius of the sphere. At this load the direction of motion of the sphere was immediately reversed to withdraw the sphere from the sample at the same speed of 0.05 mm/s. During the course of the test, the data acquired were time(s), distance (mm) and force (N) and the data acquisition rate was 25 Hz.
Suitable samples for measurement were either contained in stick barrels, which had a screw mechanism (if firm solids), or in 15 ml glass jars (if soft solids). For the barrel samples, the stick was wound up until it protruded above the edges of the barrel and then a knife was used to skim the top of the barrel in such a way as to leave a flat uniform surface. The stick was then pushed back into the barrel as far as possible to minimise any mechanical interference resulting from the compliance of the screw mechanism in the pack. Two indents were generally made either side of the screw. Soft-solid samples in the 15 ml jars needed no surface preparation but only had enough surface area for a single indentation test to be performed.
The data associated with each test were manipulated using standard spreadsheet software and used to calculate the hardness, H, using the following equation:       H              [              N        /                  mm          2                    ]        =                    F                  m                                xe2x80x83                              a                                xe2x80x83                              x                                  [        N        ]                            A        p                          [                  mm          2                ]
where Fmax is the peak load and Ap is the projected area of the indentation remaining on unloading. This area can be calculated geometrically from the plastic indentation depth. This is slightly less than the total penetration depth measured under load because of elastic deformation of the sample. The plastic indentation depth is calculated from a graph of the unloading-force-versus-total-penetration-depth. The initial slope of this unloading data depends on the initial elastic recovery of the sample. The plastic indentation depth is estimated from an intercept between the zero force axis and a straight line drawn at a tangent to the initial part of the unloading slope.
Similar hardness measurements were also done using a desktop Instron Universal Testing Machine (Model 5566) fitted with a 10 N load cell, and the data analysis performed in the same way.
iii) Deposition by Firm Sticks
Another test of the properties of a composition is the amount of the composition which is delivered onto a surface when the composition is drawn across that surface (representing the application of a stick product to human skin). To carry out this test of deposition when the composition is a firm stick, able to sustain its own shape, a sample of the composition with standardised shape and size is fitted to apparatus which draws the sample across a test surface under standardised conditions. The amount transferred to the surface is determined as an increase in the weight of the substrate to which it is applied. If desired the colour, opacity or clarity of the deposit may subsequently be determined. A specific procedure for such tests of deposition and whiteness applicable to a firm solid stick used apparatus to apply a deposit from a stick onto a substrate under standardised conditions and then measures the mean level of white deposits using image analysis.
The substrates used were:
a: 12xc3x9728 cm strip of grey abrasive paper (3M(trademark) P800 WetorDry(trademark) Carborundum paper)
b: 12xc3x9728 cm strip of black Worsted wool fabric.
The substrates were weighed before use. The sticks were previously unused and with domed top surface unaltered.
The apparatus comprised a flat base to which a flat substrate was attached by a clip at each end. A pillar having a mounting to receive a standard size stick barrel was mounted on an arm that was moveable horizontally across the substrate by means of a pneumatic piston.
Each stick was kept at ambient laboratory temperature overnight before the measurement was made. The stick was advanced to project a measured amount from the barrel. The barrel was then placed in the apparatus and a spring was positioned to biassed the stick against the substrate with a standardised force. The apparatus was operated to pass the stick laterally across the substrate eight times. The substrate was carefully removed from the rig and reweighed. The whiteness of the deposit could subsequently be measured as described at (v) below.
(iv) Deposit of Soft Solid
A procedure for a soft solid composition was as follows. The test substrate was a rectangular strip of black worsted fabric 9 cm by 15 cm. This was placed in an apparatus consisting of a metallic base onto which was hinged a metallic frame defining a rectangular aperture of 5 cm by 9 cm. The test substrate was laid on the base. The hinged frame was placed over the fabric and secured to the base by means of two screws thereby clamping the test substrate in place but exposing an area of 5 cmxc3x979 cm through the aperture.
A sample of soft solid composition in a dispensing container was kept at ambient laboratory temperature (about 20xc2x0 C.) before it was required for measurement. A portion of the composition was then extruded from the container through the dispensing apertures at one end. A weighted amount (0.51 g) of the extruded composition was spread uniformly across the 5 cmxc3x979 cm area of test substrate enclosed by the frame. Spreading was carried out using a plastic spreading tool. After spreading the sample of composition, the substrate was removed from the apparatus and weighed to check that the mass of applied sample was 0.5xc2x10.01 gms.
(v) Whiteness of Deposit
The deposits from the at test (iii) above, or made as in (iv) above, were assessed for their whiteness after an interval of 24 hours approximately.
This was done using a Sony XC77 monochrome video camera with a Cosmicar 16 mm focal length lens positioned vertically above a black table illuminated from a high angle using fluorescent tubes to remove shadowing. The apparatus was initially calibrated using a reference white card, after the fluorescent tubes had been turned on for long enough to give a steady light output. A cloth or Carborundum paper with a deposit thereon from the previous test was placed on the table and the camera was used to capture an image. An area of the image of the deposit was selected and analysed using a Kontron IBAS image analyser. This notionally divided the image into a large array of pixels and measured the grey level of each pixel on a scale of 0 (black) to 255 (white). The average of the grey intensity was calculated. This was a measure of the whiteness of the deposit, with higher numbers indicating a whiter deposit. It was assumed that low numbers show a clear deposit allowing the substrate colour to be seen.
Preparation
Compositions of this invention can be produced by conventional processes for making cosmetic solids or soft-solids. Such processes involve forming a heated mixture of the composition at a temperature which is sufficiently elevated that all the structurant dissolves, pouring that mixture into a mould, which may take the form of a dispensing container, and then cooling the mixture whereupon the structurant solidifies into a network of fibres extending through the water-immiscible liquid phase.
A convenient process sequence for a composition which is a suspension comprises first forming a solution of the structurant in the water-immiscible liquid. This is normally carried out by agitating the mixture at a temperature sufficiently high that all the structurant dissolves (the dissolution temperature) such as a temperature in a range from 50 to 120xc2x0 C. Thereafter the particulate constituent, for example particulate antiperspirant active, is blended with the hot mixture. This must be done slowly, or the particulate solid must be preheated, in order to avoid premature gelation. The resulting blend is then introduced into a dispensing container such as a stick barrel. This is usually carried out at a temperature 5 to 30xc2x0 C. above the setting temperature of the composition. The container and contents are then cooled to ambient temperature. Cooling may be brought about by nothing more than allowing the container and contents to cool. Cooling may be assisted by blowing ambient or even refrigerated air over the containers and their contents.
In a suitable procedure for making emulsion formulations, a solution of the structurant in the water-immiscible liquid phase is prepared at an elevated temperature just as for suspension sticks. If any emulsifier is being used, this is conveniently mixed into this liquid phase. Separately an aqueous or hydrophilic disperse phase is prepared by introduction of antiperspirant active into the liquid part of that phase (if this is necessary: antiperspirant actives can sometime be supplied in aqueous solution which can be utilised as is). If possible, this solution of antiperspirant active which will become the disperse phase is preferably heated to a temperature similar to that of the continuous phase with structurant therein, but without exceeding the boiling point of the solution, and then mixed with the continuous phase. Alternatively, the solution is introduced at a rate which maintains the temperature of the mixture. If it is necessary to work at a temperature above the boiling temperature of the disperse phase, or at a temperature where evaporation from this phase is significant, a pressurised apparatus could be used to allow a higher temperature to be reached. With the structurant materials of this invention this is usually unnecessary. After the two phases are mixed, the resulting mixture is filled into dispensing containers, typically at a temperature 5 to 30xc2x0 C. above the setting temperature of the composition, and allowed to cool as described above for suspension sticks.

Abstract: in which R and R1 each independently denote a branched or unbranched moiety containing 5 to 27 carbon atoms, m and n are each independently, zero or 1, Y is a cyclohexane ring bearing the amido-containing substituent groups

Abstract: in 1,2 or 1,3 positions.

Unilever Home and Personal Care USA division of Conopco, Inc.


The present invention, in one aspect, is a cooling system for a marine engine and includes cylinder cooling jackets, cylinder head cooling jackets, and thermostatic and pressure controls which facilitate safely operating the engine with low water flow rates. In one specific embodiment, the cooling system is employed in a marine engine including a V-type cylinder block with two cylinder banks and a valley between the banks. Each cylinder bank includes a plurality of cylinder bores (e.g., each cylinder bank includes three cylinder bores in a six cylinder engine), and respective exhaust ducts extend from and are in flow communication with each cylinder bore. Respective coolant flow paths extend from the valley to a section of each cylinder bore water jacket adjacent each cylinder exhaust duct. Specifically, water is provided from the valley to adjacent each exhaust duct in the cylinder banks. Each cylinder bore water jacket includes an outlet at an upper portion of each said cylinder bank. A water flow path extends from each cylinder bore water jacket outlet to a respective cylinder head water jacket. Variable thermostats are in flow communication with each cylinder bore water jacket, and each thermostat is in flow communication with a dump. Each flow path through the respective thermostats is in parallel with a respective cylinder head. The thermostats allow cooling of the cylinders to be thermostatically controlled. Specifically, the amount of water supplied to the cylinder head cooling jackets depends on the temperature condition at the thermostats. The cylinder head water jackets are in flow communication with a parallel connected blow off valve and thermostat. The blow off valve and thermostat are in flow communication with the water dump. When the blow off valve opens, maximum cooling is provided in that water flows unrestricted from the valley, to the cylinder cooling jackets, to the cylinder head cooling jackets, through the blow off valve to the dump.

This invention relates generally to marine engines and, more specifically, to cooling engine components during engine operation.
Marine engines typically include a cooling system for cooling at least portions of the engine exhaust system and the engine cylinders. For example, and in a known V-type marine engine, cooling water is supplied into a space between the cylinder banks, sometimes referred to herein as the engine valley. Water flows from the valley and to each cylinder bank. Specifically, a flow path is provided from the valley to each cylinder bank. The flow path to each cylinder bank does not, however, typically result in water flowing over the exhaust port of each cylinder, and water is not supplied directly to each cylinder from the valley. As a result, the hottest part of each cylinder (i.e., the exhaust port) is not directly cooled with the water, and the distribution of water to each cylinder bank and to each cylinder is not even. Therefore, an imbalance can result in the operation of each cylinder, and such imbalance can adversely impact engine operation.
In addition, and with at least some known marine engines, each cylinder bank includes a blow off valve and a thermostat connected in series in the flow path between the cylinder water jackets and the cylinder head water jackets. At lower speeds, there may not be sufficient pressure to open the blow off valve even though the thermostat may be fully open due to the engine temperature. Such an operating condition can lead to over heating the cylinder heads since only a small volume of water is supplied to the cylinder head.
Further, and since a blow off valve and a thermostat are provided for each cylinder bank, one cylinder bank may operate hot while the other bank is operating within a normal range. For example, if the thermostat of one cylinder bank fails in a closed condition, then very little water will be supplied to the cylinder head for that cylinder bank, and the cylinder head will be hot. The cylinder head for the other cylinder bank may, however, be within the normal temperature range.
The present invention, in one aspect, is a cooling system for a marine engine and includes cylinder cooling jackets, cylinder head cooling jackets, and thermostatic and pressure controls which facilitate safely operating the engine with low water flow rates. In one specific embodiment, the cooling system has multiple failure modes so that even if one of the controls fails, the cooling system still provides sufficient cooling to facilitate avoiding severe damage to engine.
In an exemplary embodiment, the cooling system is employed in a marine engine including a V-type cylinder block with two cylinder banks and a valley between the banks. Each cylinder bank includes a plurality of cylinder bores (e.g., each cylinder bank includes three cylinder bores in a six cylinder engine), and respective exhaust ducts extend from and are in flow communication with each cylinder bore. The exhaust ducts are in flow communication with an engine exhaust housing.
Respective flow paths extend from the valley to a section of each cylinder bore water jacket adjacent each cylinder bore. Specifically, water is provided from the valley to the cylinder bore water jackets near each cylinder exhaust duct extending from each cylinder bore. For example, in a six cylinder engine, respective flow paths extend from the engine valley to each cylinder, i.e., six flow paths. By supplying cooling water from the valley to adjacent each cylinder exhaust duct, a hottest part of the engine is cooled by cooling water from the valley. Providing water from the valley to adjacent each cylinder exhaust duct facilitates uniform cooling of each cylinder and balanced operation of the engine.
Each cylinder bore water jacket includes an outlet at an upper portion of each said cylinder bank. A water flow path extends from each cylinder bore water jacket outlet to a respective cylinder head water jacket. A temperature sensor is thermally coupled to each cylinder head cooling jacket, and provides a signal representative of cylinder head temperature to an electronic control unit (ECU). In the event that the temperature at either cylinder head exceeds a pre-set temperature, ECU limits operation of engine, e.g., to below a pre-set rpm.
Also, variable thermostats are in flow communication with each cylinder bore water jacket, and each thermostat is in flow communication with a water dump passageway, or dump. Each flow path through the respective thermostats is in parallel with a respective cylinder head. Any suitable thermostatic valve which opens above a pre-determined temperature can be employed. The thermostats provide that cooling of the cylinders is thermostatically controlled.
The cylinder head water jackets are in flow communication with a parallel connected blow off valve and thermostat. The blow off valve and thermostat are in flow communication with the water dump. When the blow off valve opens, maximum cooling is provided in that water flows unrestricted from the valley, through the cylinder cooling jackets and the cylinder head cooling jackets, and through the blow off valve to the dump.
The cooling system has multiple failure modes which, in the event of failure of the one of the controls, facilitate avoiding severe damage to engine. For example, in the event one of the thermostats connected between the cylinder and dump fail, the thermostat connected in parallel with the blow-off valve still provides thermostatic control of flow through system. In addition, if all the thermostats fail, the blow-off valve still provides pressure control of flow through system. If the blow-off valve fails, then the thermostats still provide control of flow through system. Further, if the blow off valve fails open, coolant still flows through the engine although the engine may operate cold. While operating the engine cold may not provide optimum efficiency, operating the engine cold facilitates avoiding severe damage to the engine.

Marine engine cooling systems and methods


This invention relates to waste water treatment, more specifically this invention relates to transportable decontamination system for water which is pumped from manholes and equipment vaults. The separation of water and contaminants is accomplished by a five module system. The first module removes 98% of the solids from the waste stream by use of staggered baffles. Module two reclamates the free oil present in the liquid flow with an coalescing water oil separator. The third module removes solids still left in the stream which are greater than 20 microns by use of a size discriminating filter. The fourth and fifth modules are bonding tanks used to encapsulate hydrocarbons and heavy metals respectively. The sequence in which the contaminated flow enters each of the modules is essential to the effectiveness and efficiency of the filtration process.

Treating waste water from a manhole or equipment vault is considerably more complex than treating an industrial waste water stream. In an industrial waste water stream, the contaminants in the water are usually constant and, once ascertained, a specific treatment process aimed at those contaminants can be implemented.
In contrast, contaminants in waste water from a manhole or equipment vault are varied in type and concentrations requiring treatment aimed at a multiplicity of contaminants. Furthermore, while industrial streams can implement permanent treatment facilities, treatment equipment for manholes and equipment vaults must be portable as the system will need to be transported to the various contamination sites.
Contaminants frequently present in waste water from a manhole or equipment vault are petroleum products, heavy metals, and a mixture of solids: dirt, leaves, cooking fats, etc. Due to the varying densities of these contaminants, as well as different cohesive and adhesive properties, the liquid in the manholes and equipment vaults will tend to separate into three (3) primary layers if left standing for a sufficiently long period of time.
The petroleum products are found in all three layers as they are present in various forms or states: free, dissolved, and emulsified. The presence of various petroleum states within a single waste water site creates severe problems for clarification as most petroleum removal devices and processes are not designed to remove more than a single petroleum state, which typically is the free oil state. Furthermore, these older designs are ineffective at removing emulsified and dissolved oils which are frequently present within the waste water of manholes and equipment vaults.
The heavy metals, also present in all three layers, are a similarly inconsistent group of contaminants. Varying type and concentrations of the metals renders any remediation method that is metal specific virtually useless.
Solids, typically present in the bottom layer, further complicate the decontamination process as these organic and inorganic materials must be removed before treatment of petroleum products and heavy metals can proceed.


Various ink formulations utilizing particular magenta dyes have excellent printing characteristics with high chroma and good lightfastness on plain paper and minimal humid bleed and hue shift on special media. The magenta humid bleed shift has been greatly reduced, especially on photo glossy materials. A single dye may be used in comparison to blended dyes which have been used in the past.

The invention relates generally to inks for ink-jet printing, and, in particular, to a specific magenta inkjet ink formulations having high plain paper chroma, sufficient lightfastness and having little or no humid bleed/hue shift and associated dye sets.
Ink-jet printing is a system in which ink droplets are formed by ink ejection methods of various types, such as system utilizing electrostatic attraction, systems wherein mechanical vibration or displacement is imparted to the ink by a piezoelectric device, and systems in which ink is heated to cause it to bubble and pressure produced when it bubbles, causing the ink to adhere to a printing mediums such as paper.
Ink compositions used in such ink-jet printing systems are typically prepared by dissolving or dispersing water-soluble dyes or pigments of various types in water or mixed solvents of water and water-soluble organic solvents are known and put into use. Such ink compositions have various performances generally suited for their particular use. For example, inks should not suffer from humid bleed (i.e., they should not result in a mutual color mixture of different colors at the respective boundary areas under humid conditions) or hue shift, but should still retain high plain paper chroma.
Various high quality ink-jet inks are commercially available and attempts have been made to balance these two ideals. Unfortunately, however, in order to balance the desired high chroma on plain paper and lightfastness on special media with magenta inks, magenta inks have been formulated to contain a combination of dyes. Such mixtures are relatively more difficult to produce, and the inherent characteristics of the particular dyes need to be addressed in formulating the remainder of the composition, thus occasionally unduly complicating the formulation.
As disclosed in International Application Number PCT/GB98/01853 to Zeneca Ltd (publication date Jan. 14, 1999, and designating the United States of America), the entire contents of which are incorporated by this reference, a monoazo dye useful for the production of inks has the formula:
wherein
A is N, Cxe2x80x94Cl, Cxe2x80x94CN or Cxe2x80x94NO2;
L1 is xe2x80x94OR2;
Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
R1 is H, alkyl, or a substituted alkyl;
each W is independently selected from the group consisting ofxe2x80x94CO2Q or SO3Q;
each X is independently selected from the group consisting of an amino group, a substituted amino group, a group that is substituted by an optionally substituted amino group, halo, hydroxy, nitro, cyano, optionally substituted alkoxy, optionally substituted aryl, optionally substituted aralkyl, xe2x80x94SRa, xe2x80x94CORa, xe2x80x94COORa, xe2x80x94SO3Ra, or xe2x80x94SORa;
Ra is C1-4alklyl, optionally substituted by carboxy, sulpho, hydroxy, nitro, halo, or cyano;
each Q is independently selected from ammonium, substituted ammonium, sodium, lithium, potassium, tetramethylammonium ion, and similar moieties;
m has a value of from zero (0) to three (3);
n has a value of from one (1) to three (3); and
(m+n) has a value of from one (1) to five (5).
Surprisingly it has been found that by carefully selecting and choosing from the numerous moieties in formula I, and incorporating the selection into an ink formulation, a magenta ink-jet ink results which can be utilized as a single dye, which ink balances both high chroma on plain paper and lightfastness and humid bleed/hue shift on special media.
A magenta ink of the present invention comprises one or more magenta dyes, wherein one of the dyes has the formula of the herein described Formula II, wherein Formula II is the moieties of Formula (I) moieties wherein A is selected to be nitrogen, L1 is OR2, Z is xe2x80x94NH, R1 is H, W is xe2x80x94SO3Q, m is one, X is xe2x80x94CH3, n is two, and the composition is denoted herein as xe2x80x9cFormula (II)xe2x80x9d:
These magenta ink formulations have excellent printing characteristics with high chroma on plain paper and minimal humid bleed and lightfastness on special media. The magenta humid bleed shift has been greatly reduced, especially on photo glossy materials. A single dye may optionally be used in comparison to blended dyes which have been used in the past.
The present invention also provides an ink-jet printing process carried out by jetting an ink composition to a printing medium in the form of droplets to make a record, wherein the ink composition comprises a water-based magenta ink composition.
The invention described herein is directed to a magenta ink particularly suitable for use in printing inkjet images using commercially available inkjet printers such as DESKJET(trademark) printers manufactured by Hewlett-Packard Company of Palo Alto, Calif.
As previously described, methods for making compositions such as (but not specifically including) the magenta dye used herein are described in International Application Number PCT/GB98/01853, wherein appropriate constituents are substituted for those described in the International Application as would be known by one of ordinary skill in the art of making azo dyes. For instance, a condensation reaction, performed in the presence of a base, is designed and performed between appropriately selected compounds (see, e.g., pages 5-7 of the previously incorporated International Application). After condensation, isolation may be accomplished by precipitating the product as a salt or a free acid by acidifying the reaction mixture. The resulting product may be converted to the ammonium or substituted ammonium salt by the addition of ammonia, ammonium hydroxide, primary, secondary, tertiary or quaternary amine.
The resulting dye preferably has a target absorbance of from about 0.06 to about 0.40 (peak absorbance value measured at 1:10,000 dilution (100 ppm) wt/wt for the individual dye in each ink), at a nominal lambda (max.) of from about 542 to about 548 nm. More preferably, the resulting dye has a target absorbance of from about 0.15 to about 0.17 (peak absorbance value measured at 1:10,000 dilution (100 ppm) wt/wt for the individual dye in each ink), at a nominal lambda (max.) of from about 542 to about 548 nm. Most preferably, the resulting dye has a target absorbance of 0.16 (peak absorbance value measured at 1:10,000 dilution (100 ppm) wt/wt for the individual dye in each ink), a nominal lambda (max.) of 545 nm, and a nominal dye load of 4.5 weight per cent.
The dye of Formula II is present in a salt form wherein the counterion can be a cation such as ammonium, substituted ammonium (e.g., tetramethylammonium or xe2x80x9cTMAxe2x80x9d), sodium, lithium, etc.
Salt forms of the dye, such as potassium, lithium, ammonium, and alkanolammonium, for example, may be readily prepared in known manner, by proceeding from the corresponding salts of the intermediates, or by conversion of the sodium salts of the dyes.
The aqueous medium used in the water-based magenta ink composition of the present invention is water, or a mixed solvent of water and a water-soluble organic solvent. Particularly preferably, it may be a mixed solvent of water and one or more water-soluble organic solvents. As the water, it is preferable to use not commonly available water containing various ions, but deionized water.
The water-soluble organic solvent(s) used as its mixture with water may include, for example, lower alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol and tert-butyl alcohol; amides such as dimethylformamide and dimethylacetamide; ketones or ketoalcohols such as acetone and diacetone alcohol; polyalkylene glycols such as polyethylene glycol and polypropylene glycol; alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol, thiodiglycol and hexylene glycol; 1,5-pentanediol; glycerol; 2-pyrrolidone; N-methyl-2-pyrrolidone; and 1,3-dimethyl-2-imidazolidinone.
Surfactants suitably employed in the practice of the invention include anionic and nonionic surfactants. Examples of anionic surfactants include: Sulfonate surfactants such as Sulfosuccinates (Aerosol OT, A196; AY and GP, available from CYTEC) and Sulfonates (Aerosol DPOS-45, OS available from CYTEC; Witconate C-50H available from WITCO; Dowfax 8390 available from DOW); and Fluoro surfactants (Fluorad FC99C available from 3M). Examples of nonionic surfactants include: Fluoro surfactants (Fluorad FC170C available from 3M); Alkoxylate surfactants (Tergitol series 15S-5, 15S-7, and 15S-9 available from Union Carbide); and Organosilicone surfactants (Silwet L-77 and L-76-9 available from WITCO).
Buffers optionally employed in the practice of the invention to modulate pH can be organic-based biological buffers or inorganic buffers, preferably, organic-based. Examples of preferably-employed buffers include tris(hydroxymethyl)aminomethane (TRIS), available from companies such as Aldrich Chemical (Milwaukee, Wis.), 4-morpholineethanesulfonic acid (MES), 4-morpholinepropanesulfonic acid (MOPS), and beta-hydroxy-4-morpholinepropanesulfonic acid (MOPSO). Further, the buffers employed should provide a pH ranging from about 3 to about 9 in the practice of the invention, preferably about 4 to about 6 and most preferably from about 4 to about 5.
Any of the biocides commonly employed in inkjet inks may optionally be employed in the practice of the invention, such as Nuosept 95, available from Huls America (Piscataway, N.J.); Proxel GXL, available from Zeneca (Wilmington, Del.); and glutaraldehyde, available from Union Carbide Company (Bound Brook, N.J.) under the trade designation Ucarcide 250.
Inks according to the invention may optionally also include a metal chelator. Such chelators are used to bind transition metal cations that may be present in the ink. Examples of preferred metal chelators include: ethylenediaminetetraacetic acid (xe2x80x9cEDTAxe2x80x9d), diethylenediaminepentaacetic acid (xe2x80x9cDPTAxe2x80x9d), trans-1,2-diaminocyclohexanetetraacetic acid (xe2x80x9cCDTAxe2x80x9d), ethylenedinitrilotetraacetic acid (xe2x80x9cEGTAxe2x80x9d), or other chelators.
Inks according to the invention may also include lightfastness additives in appropriate amounts known to those of skill in the art.
Inks according to the invention will typically have a pH of from about 3.0 to about 5.0, preferably from about 3.5 to about 4.5.
The ink composition of the invention is suitable employed with any ink jet printer for any drop on demand ink jet technology. However, it is also useful in piezoelectric ink jet technology.
All concentrations given herein are parts by weight, unless usage indicates to the contrary. The purity of the components is preferably that employed in normal commercial practice for inkjet inks.
The invention is further explained by the use of the following illustrative example:


A system and method for a protocol to identify patterns among caregivers and predict the root cause of burnout, whereby the system leverages proprietary data and data collected form third party sources to assess the risk of caregivers and then adjusts accordingly based on previous data of the caregivers as well as other similar caregivers.

There is no such thing as an "average" caregiver. Specific families, cultures, and expectations concerning duties they are supposed to perform—even the amount of pressure they feel to take on the caregiving role in the first place—are all variables that affect the experience of a caregiver. And because every caregiver experience is a unique situation, knowing how one caregiver experiences the role tells us very little about how other caregivers, even if they are performing similar duties, experience their own role.
When trying to identify challenges and prevent caregiver burnout, most people tend to focus on the following duties of caregivers—how many hours are spent cooking, cleaning, providing personal care, and more. However, through our 35+ years of research, we have discovered that burnout is not a result of the hours put into doing laundry or picking up medication from the pharmacy. Instead, it's a result of identity discrepancy.
The first time a woman bathes her mother-in-law. The first time a wife has to take away her husband's car keys. The first time a person ceases to see themselves as a daughter or wife—but instead as a caregiver. This is called Identity Discrepancy—a conflict between how a caregiver sees themselves in relation to their loved one and the caregiving tasks they are now required to provide. Taking on new responsibilities as a caregiver makes caregivers see themselves as more of a nurse or a home aide, rather than a loved family member. And this conflict between their identities is what can cause distress. The level of distress depends on how much a caregiver's current identity within their relationship clashes with what the caregiver duties they are now responsible for.
Caregiving is a series of transitions that result from changes in the caregiving context. Over time, the needs of a family member will increase in quantity and intensity, and so naturally, the duties of a caregiver will increase as well. In the beginning, caregiving might look like picking up groceries for mom on the way home from work. Over time, it could evolve into the caregiver moving in with mom to give them 24/7 care. The visits become less about "catching up and spending time" and more about "cleaning, cooking, and taking care." Through these changes, caregivers will experience different stages of caregiving.
The process of identity change in caregiving often includes some of the below phases:
A son may start taking his mother shopping for groceries when it becomes difficult for her to go on her own. A wife may take on financial tasks when her husband's dementia progresses even though, at one point, it was part of his responsibilities in the household.
In many cases, these activities involve helping a loved one with personal grooming. For some caregivers—adult children, for example—and for recipients, this type of care can cause varying levels of discomfort. This phase may require duties that the caregiver is not comfortable with, and can cause the caregiver to leave their caregiving role. This can cause other changes like a move to a nursing home for a family member.
Caregivers see themselves more as caregivers than a loved one who occasionally drops by. And although the option of moving the care receiver into a nursing home is considered at every stage, it is now reconsidered more frequently.
A care recipient may be moved to a different setting and the caregiver turns over the primary responsibility for care to formal care providers but informal caregiving doesn't end here; the new arrangement allows the caregivers to recover a part of their original identity. Typically, the responsibilities of the caregiver now include legal, financial, and future care planning of the recipient in the new living environment. Not every caregiver goes through every phase, and transitions aren't always necessarily in one direction. The only uniform part of the process is that caregivers experience distress when their identity doesn't match up with the activities they are doing—and this prompts a movement between phases. Their distress is relieved by the transition, as their identities once again begin to match up with their caregiving activities.
Thus exists the need that is grounded on focusing on identity discrepancy as the primary driver of the emotional drain on a caregiver. By addressing these transitions in a caregiver's journey and tailoring interventions specific to their needs, we have found great success in reducing caregiver burnout. Currently, 84% of caregivers report lower levels of stress and depression in as few as six months after a TCARE intervention, and nursing home placement is delayed by 21 months.

System and method for psychosocial technology protocol focused on the reduction for caregiver burnout and nursing home placement


The present invention is directed to a method of blocking the cytotoxic activity of Fcxcex3RIII receptor-positive immune cells in a patient with amyotrophic lateral sclerosis using protein V specific for IgG1 and/or IgG3. In one aspect of the invention, protein V blocks the binding of IgG1 and/or IgG3 to the Fcxcex3RIII receptor, which inactivates the receptor, and destroys cellular forms containing the receptor.

The invention relates to the use of substances having a well-directed, i.e. selective, effect on a certain receptor family (Fcxcex3R) or on those immune system cells with defined surface characteristics which express said receptor and whose presencexe2x80x94in examinations performed by the applicantxe2x80x94has been found to be specific, or its number specifically increased, in the case of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (in the following referred to as ALS, its abbreviation) is a neurodegenerative disease of the human motoneuron system which usually takes a lethal course within 3 to 5 years, whose causes have not been determined etiologically and for which there is no, or no significant, therapy as yet. The progressive decay of nerve cells of the first and second motor neurons are the cause of an increasing paralysis of the voluntary muscles, eventually leading to a total walking inability and the increasing paralysis of the respiratory musculature. It has largely been proven that cellular and humoral (antibody-mediated) immunological processes play an important role, if yet unexplained in the individual case, in the pathogenesis of ALS. Worldwide, the prevalence of this disease is 4 in 100,000 and its incidence is 1 in 100,000 inhabitants.
Numerous examination results seem to imply that immunological mechanisms are at play in the pathogenesis of amyotrophic lateral sclerosis. The following findings substantiate this assumption: Cytotoxic serum activity of ALS patients in neuronal cell cultures; serum immunoglobulin G (IgG) toxicity against spinal and cortical neurons as well as voltage-dependent calcium channel proteins; cytotoxicity of the cerebrospinal fluid of ALS patients against glutamate receptors; changes of the serum concentration of IgG isotypes; immune response of peripheral blood lymphocytes of ALS patients to isolated cell membranes; detection of invasive immune system cells in the motoneuron system of ALS patients Here, these cells seem to be involved in the motoneuron damaging mechanisms (the quotations of the individual above data can be found in: Westarp, M. E. et al., Neurosci. Lett. 173, 124-126, 1994).
Although this data seems to imply a probable involvement of the cellular immune system in ALS, it has been impossible so far to detect definite quantitative or qualitative changes in the cellular immune system in the case of ALS. In particular, no ALS specific cell types have so far been found in the blood of ALS patients which would be identifiable by their molecular cell surface characteristics and clearly differ from immune cells of healthy experimentees or present in other neurological diseases. Nevertheless, countless therapies involving medication with a relatively broad effectivity as well as an undirected action were attempted in order to suppress or at least modulate immune functions. However, any such therapy attempt has remained without ascertained therapeutical success (cf. e.g. Brown, R. H. et al.: Arch. Neurol. 43, 383-384, 1986; and e.g. Dalakas, M. C. et al.: Arch. Neurol. 51, 861-864, 1994). A disadvantage of such approach is that these forms of therapy (blind or unaware of specific cell parameters with ALS) are not well-directed, i.e. they do not block or suppress exclusively those cell types which are specifically present, or present in significantly increased numbers, in ALS patients.
Tests performed by the applicant have shown that the blood of ALS patients contains mononucleic cells of the immune system which are not found with any other neurological disease or in healthy persons (ALS specific immune cells, cf. Table 1). Contrary to the immune cell types so far observed to be present in increased numbers in ALS patients which are known as prior art (Schubert, W.; Neurosci. Lett. 198, 29-32, 1995), the cell types discovered according to the invention and listed in Table 1 are totally ALS specific. These cell types express receptors for immunoglobulins (Fcxcex3 receptors), preferably for immunoglobulin G (IgG) of under-class 1 (IgG1) and 3 (IgG3) (in the following referred to as Fcxcex3RIII). The increased number, or the ALS specific occurrence, of said immune cells is an explanation of the hitherto unexplained reduction of IgG1 and IgG3 in the serum of patients diagnosed with ALS which was reported e.g. by Westarp et al. (Westarp, M. E. et al., Neurosci. Lett. 173, 124-126, 1994): Fcxcex3RIII receptors selectively bind to these immunoglobulins, i.e. a multiplication of cells expressing said receptors (as discovered in applicant""s own studies) will result in increased binding to IgG1 and IgG3 and thus an IgG1-IgG3 clearance in this disease. In applicant""s own studies, it has been found for the first time that these Fcxcex3 receptor-positive cells exhibit a series of molecular activation characteristics on the cellular surface and, when cultured, will cause damage to, or even the destruction of, nerve cells. These cells are therefore directly involved in the pathomechanism of ALS and, as a cellular form, for the first time constitute a concrete target structure for a well-directed, i.e. specific, therapy with immunoactive substances.
The present invention is therefore based on the discovery of Fcxcex3 receptor positive, in particular Fcxcex3RIII positive, activated cellular forms in the blood stream which are ALS unspecific, or significantly increased in number in the case of ALS, and relates to a use of substances for the selective suppression, destruction or selective functional blocking of said cellular forms, or blocking or functional inactivation of Fcxcex3 receptors, by infusion or injection of defined substances as specified in claim 1.
Fcxcex3 receptors have been known for quite some time in immunology. There are three different, yet related classes of human Fcxcex3 receptors: Fcxcex3RI, Fcxcex3RII and Fcxcex3RIII. The amino acid sequences of the members of this receptor family as well as the genes coding for said receptors are known: Fcxcex3RI (Allen, J. M., Seed B.: Science 243, 378-380, 1989), Fcxcex3RII (Ravetch, J. V., Kinet, J.-P.: Annu. Rev. Immunol. 9, 457-492, 1991), Fcxcex3RIII (Ravetch, J. V., Perussia, B: J. Exp. Med. 170, 481-497, 1989). Most subtypes of these three receptor classes are anchored in the cell membrane of certain immune cells. However, all three classes also contain soluble receptor proteins, i.e. proteins not anchored in the cell membrane, which are naturally-released by immune cells. The mechanisms are different, however. Soluble Fcxcex3RI receptors are generated by a stop codon in the extracellular domain. Soluble Fcxcex3RII receptors are generated by alternative RNA splicing, and soluble Fcxcex3RIII receptors are generated by proteolytic splitting of the receptor anchored in the cell membrane (cf. summarizing survey in: Jan, G. J. et al.: Immunology Today, 14, 215-221, 1993).
Said Fcxcex3 receptors are particularly relevant for a number of important immunologic functions. All these functions are based on the fact that Fcxcex3 receptors specifically bind to G immunoglobulins. The binding of such immunoglobulins to Fcxcex3 receptors stimulates or triggers a variety of different cellular activities: Phagocytosis, endocytosis, antibody-dependent cell-mediated cytotoxicity, the release of soluble, inflammation-promoting factors (mediators) as well as the increase of antigen presenting mechanisms. G immunoglobulins bind to Fcxcex3 receptors via their Fc parts. If G immunoglobulins for example bind to Fcxcex3 receptors anchored on the surface of certain immune cells in this manner, said immune cells will then be capable of binding very specifically to antigen-bearing target cells and destroying them. These mechanisms probably play an important pathogenetic part in numerous so called auto immune diseases. In some cases it has been possible to show that blocking or functionally inactivating said mechanisms largely prevents the disease specific destruction of target cells. One example hereof is a rare form of an auto immune disease in humans, the so called acute immuno-thrombocytopenic purpura, in which an Fcxcex3 receptor-mediated cytotoxic activity of the immune system against blood platelets results in an acute diminution of said platelets (thrombocytes) in the blood of affected patients. In this case, it has been possible to show that the infusion of soluble Fcxcex3 receptor fragments results in a clear recovery from the symptoms and the cellular signs of the disease (Debr xc3xa9 et al.: Lancet, 342, 945-948, 1993).
In the case of ALS, however, an immunological pathomechanism based on the activity of Fcxcex3 receptors has not been known so far. Also, a form of therapy directed at specifically inactivating or blocking such mechanism has not been developed or conducted.
Now, however, the existence of accordingly specific cellular forms and such mechanisms has been confirmed by the results of examinations conducted by the applicant.
In detail, it has been found
that the blood of ALS patients contains mononucleic cells bearing Fcxcex3 receptors on their cellular surfaces, additionally or simultaneously bearing a different number of various other receptor proteins which exhibit an unusual form of cellular surface activation. The surface receptors variably co-expressed together with Fcxcex3 receptors, above all Fcxcex3RIII receptors, are individually designated in Table 1. The abbreviations (CD) used therein are in keeping with the international nomenclature (cf. Barcley, A. N. et al.; The leucocyte antigen facts book. Academic press. London. 1993). This special combination of Fcxcex3 receptors (e.g. CD16) with other receptor proteins indicated in Table 1 is ALS specific since it could not be detected in healthy persons or with other neurological control diseases or other immunological, non-neurological diseases;
that these cells, after being isolated from the blood of ALS patients, could be cultivated in cell culture media (the standard protocols on which this was based are described in Lindl, T., Bauer, J.: Zell- und Gewebekultur, published by G. Fischer Verlag, Stuttgart, 1987),
that said cells, after enrichment and in co-cultivation with nerve cells and serum of ALS patients, develop a cytotoxic activity resulting in the destruction of the nerve cells,
that it is possible to block said cytotoxic activity by the addition of various soluble factors:
a) by monoclonal antibodies against Fcxcex3 receptors at a concentration of between 20 and 100 xcexcmol,
b) by soluble Fcxcex3 receptors at a concentration of between 10 and 60 xcexcmol,
c) by anti-sense messenger ribonucleic acid species (mRNA) which are complementary to Fcxcex3 receptor-specific mRNA sequences (e.g. 20 xcexcmol of a no. 23 anti-sense oligonucleotide, derived from EMBL/gene bank Fcxcex3RIII sequence X16863),
d) by protein V isolated from Gardnerella vaginalis (EP: 0595997) at concentrations of between 150 to 170 xcexcmol in the simultaneous presence of serum from ALS patients.
Consequently, the solution according to the invention is the blocking of the Fcxcex3 receptor-mediated cytotoxic activity of the ALS-specific Fcxcex3 receptor-positive immune cells, or the blocking or the inactivation of Fcxcex3 receptors, or the destruction thereof, by the administration of the abovementioned substances, so as to prevent the direct or indirect pathological effects of these cells or the Fcxcex3 receptors on the motoneuron system.
Said substances will therefore be applied in the respective therapeutic dosage and after a toleration test in bolus (see the examples). Approximate values are the following concentrations, for example: for Fcxcex3R specific antibodies (10 to 1,000 mg/weight kg, once or twice a day i.v.) , for Fcxcex3receptor specific anti-sense RNA (10 to 20 mg/kg), for soluble Fcxcex3 receptors (10 to 1,000 mg/kg), for protein V (10 to 1,000 mg/kg).
However, an exact therapeutic dose can only be decided on with respect to the individual case concerned It depends, amongst other things, on the response of the Fcxcex3 receptor-positive cells to the administration of the substances as indicated in claim 1 and on the individual toleration which may be determined by single bolus administrations (see example 1) Such response may e.g. be established by the determination of the number of such cellular forms in the blood or by in-vitro cytotoxicity assays. If necessary, the dosage and the distribution of the daily dosis may have to be modified according to the individual case concerned.
The solution according to the invention has the following advantages:
1. In contrast to all other forms of immunosuppressive or immunomodulating therapy performed so far which were substantially unspecific and affected the entire immune system, the form of therapy disclosed herein constitutes a well-directed form of therapy, i.e. directed at ALS specific forms of immune cells.
2 Based on the knowledge, according to the invention, of the ALS specific surface characteristics, i.e. the combinatorial receptor patterns of these cells (see Table 1), it is possible to ascertain before each therapy whether these cells are present at all, or, after their isolation and in-vitro testing, to determine whether they exhibit any cytotoxic, in particular neurotoxic, activity.
3 Based on the knowledge, according to the invention, of the cell surface characteristics of these cells, the therapeutical success can not only be determined clinically, but also on a cellular level, with the therapy according to claim 1 in full progress, by the examination of blood samples for a therapy-related decrease in the number, or even a total elimination, of the Fcxcex3 receptor-positive cellular forms from the blood stream.
4. Based on the findings of above step 3, the dosage of the administered substances may be adapted accordingly, i.e. increased or decreased, depending on whether or not there is a response of the Fcxcex3 receptor-positive cellular forms.
5. Since the knowledge, according to the invention, of the cell surface characteristics of the ALS specific cellular forms for the first time constitutes a disease-specific cell parameter for ALS, it is possible to correlate the clinical course of the disease precisely with this parameter so that, even after a discontinuation of the therapy in accordance with the inventive muse of Fcxcex3 receptor-specific substances, a potential re-increase of the Fcxcex3 receptor-positive cells will allow exact determination of the time for a further therapy cycle.

Method of blocking cytotoxic activity in patients with amyotrophic lateral sclerosis using protein V