Low-concentration, highly viscous liquid detergents which maintain their degree of viscosity in storage in a range of climatic conditions, do not undergo any phase separation or agglomerate separation, and maintain their color under the influence of light. Liquid detergents with the desired properties contain 0.2 to 5 wt. % of a polyurethane or modified polyacrylate, 0.5 to 7 wt. % of a boron compound and 1 to 8 wt. % of a complexer.

The present invention relates to low-concentration, highly viscous liquid detergents which, as a result of using a thickening system, are storage- and viscosity-stable under very diverse climatic conditions, do not undergo phase separation, and have color stability even on exposure to light.
Highly viscous detergents and cleaners, and also cosmetics have been increasingly offered in recent years, those products having a xe2x80x9cgelxe2x80x9d-like consistency being widely accepted by the consumer. In the field of liquid detergents, highly viscous gel products have the advantage that fewer nonaqueous solvents can be used and the product can be applied in a targeted manner to stains without running. In this connection, conventional liquid detergents are customarily converted into highly viscous products by the use of thickening agents, such as agar agar, carrageen, tragacanth, gum arabic, alginates, pectins, polyoses, guar flour, carob seed grain, starch, dextrins, gelatin, casein, carboxymethylcellulose and also cellulose ethers, hydroxyethyl- and -propylcellulose and the like, seed grain ethers, polyacrylic and polymethacrylic compounds, vinyl polymers, polycarboxylic acids, polyethers, polyimines, polyamides, polysilicic acids, clay minerals, such as montmorillonites, zeolites and silicas. The use of these thickeners for increasing the viscosity in a very wide variety of liquids has belonged to the prior art for some time. The use of polymers in liquid detergents is also well-known.
The incorporation of said thickeners in cases of liquid detergents only leads to stable gels above certain surfactant contents. A gel will usually only form at surfactant contents above 35% by weight. Liquid detergents with surfactant contents below 35% by weight exhibit, after a few days, phase separation or agglomerate formation, which is evident from the formulation becoming opaque (xe2x80x9ccloud formationxe2x80x9d). Additionally, the viscosity of such products sometimes drops drastically during storage. Since highly viscous liquid detergents are usually offered in transparent bottles to highlight the esthetic features, it is also a requirement that the thickeners used are stable toward light since otherwise free-radical decomposition of the polymers arises, which manifests itself in the destruction of the product color and undesired xe2x80x9ccloud formationxe2x80x9d.
Liquid detergents with viscosities between 500 and 20,000 mPas, preferably from 2000 to 10,000 mPas, in which lamellar surfactant droplets are dispersed in an aqueous electrolyte phase, are described in European Patent Application EP-A 691 399 (Colgate). These compositions comprise 10 to 45% by weight of surfactant(s), at least one builder, and 0.01 to 5% by weight of a mercapto-terminally-capped polymer having an average molecular weight between 1500 and 50,000 gmolxe2x88x921.
The use of boron compounds in aqueous liquid detergents is described in EP-A 381 262 (Unilever). These liquid detergents comprise the boron compounds, and a polyol as enzyme-stabilizing system for a mixture of proteolytic and lipolytic enzymes, preferred stabilizing systems consisting of a sorbitol/borax mixture. Information about viscosity and stability of the liquid detergents is not given in this specification.
Liquid, aqueous detergent concentrates which retain or increase their viscosity upon dilution with water are described in EP-A 724 013 (Colgate). This effect is achieved by the use of two surfactants having varying stability toward electrolytes and the addition of a dissolved electrolyte, where the concentrate has a viscosity of less than 2500 mPas and, upon dilution with water, loses its micellar structure at the expense of the formation of a lamellar phase.
The International Patent Application WO 96/01305 (Unilever) describes an aqueous cleaner and liquid detergent which, upon dilution with at least twice the amount of water, forms a microemulsion which has particle sizes from 10 to 100 nm. The composition comprises 20 to 70% by weight of water, 15 to 40% by weight of a surfactant system which comprises at least one nonionic surfactant from the group of alkoxylated alcohols and not more than 20% by weight of anionic, cationic, amphoteric or zwitterionic surfactants, 5 to 30% by weight of solvents and 5 to 20% by weight of water-insoluble oil.
None of said specifications deals with the problem of providing low-concentration and highly viscous liquid detergents which guarantee a stable viscosity, do not lead to agglomerate formation (so-called xe2x80x9ccloud formationxe2x80x9d) or phase separation, and do not have a decrease in color stability on exposure to light. The solution to this problem was the object of the present invention.
It has now been found that liquid detergents with said profile of properties can be prepared if a thickening system comprising polyurethanes or modified polyacrylates, a boron compound and complexing agents is incorporated into the compositions.
The present invention therefore provides aqueous, highly viscous liquid detergents comprising surfactant(s) and other customary ingredients of detergents and cleaners, where the compositions comprise, as thickening system, in each case based on the total composition,
a) 0.2 to 5% by weight of a polyurethane or a modified polyacrylate,
b) 0.5 to 7% by weight of a boron compound, and
c) 1 to 8% by weight of a completing agent.
By using the thickening system according to the invention it is possible to prepare highly viscous liquid detergents which are free from said disadvantages. According to the invention, it is possible also to prepare concentrated highly viscous liquid detergents which have surfactant contents above 35% by weight. Since, however, said problems arise particularly in the case of low-concentration products, for the purposes of the present invention, preference is given to aqueous, highly viscous liquid detergents whose content of surfactant(s) is below 30% by weight.
The first component of the thickening system is a polyurethane or a modified polyacrylate which, based on the total composition, is used in amounts of from 0.2 to 5% by weight.
Polyurethanes (PUR) are prepared by polyaddition from di- and polyhydric alcohols and isocyanates and can be described by the general formula I
in which R1 is a low molecular weight or polymeric diol radical, R2 is an aliphatic or aromatic group, and n is a natural number. R1 is preferably a linear or branched C2-12-alk(en)yl group, but can also be a radical of a polyhydric alcohol, by means of which crosslinked polyurethanes are formed which differ from the formula I given above by virtue of the fact that further xe2x80x94Oxe2x80x94COxe2x80x94NH groups are bonded to the radical R1.
Industrially important PUR are prepared from polyesterdiols and/or polyetherdiols and, for example, from toluene 2,4-diisocyanate or 2,6-diisocyanate (TDI, R2=C6H3xe2x80x94CH3), methylene 4,4xe2x80x2-di(phenylisocyanate) (MDI, R2=C6H4xe2x80x94CH2xe2x80x94C6H4) or hexamethylene diisocyanate [HMDI, R2=(CH2)6]. Commercially available thickeners based on polyurethane are available, for example, under the names Acrysol(copyright) PM 12 V (mixture of 3-5% of modified starch and 14-16% of PUR resin in water, RohmandHaas), Borchigel(copyright) L75-N (nonionogenic PUR dispersion, 50% strength in water, Borchers), Coatex(copyright) BR-100-P (PUR dispersion, 50% strength in water/butyl glycol, Dimed), Nopco(copyright) DSX-1514 (PUR dispersion, 40% strength in water/butyl triglycol, Henkel-Nopco), thickener QR 1001 (20% strength PUR emulsion in water/diglycol ether, RohmandHaas) and Rilanit(copyright) VPW-3116 (PUR dispersion, 43% strength in water, Henkel).
Preferred liquid detergents comprise 0.2 to 4% by weight, preferably 0.3 to 3% by weight and in particular 0.5 to 1.5% by weight, of a polyurethane.
Modified polyacrylates which can be used for the purposes of the present invention are derived, for example, from acrylic acid or from methacrylic acid, and can be described by the general formula II
in which R3 is H or a branched or unbranched C1-4-alk(en)yl radical, X is Nxe2x80x94R5 or O, R4 is an optionally alkoxylated, branched or unbranched, optionally substituted C8-22-alk(en)yl radical, R5 is H or R4, and n is a natural number. In general, such modified polyacrylates are esters or amides of acrylic acid or of an xcex1-substituted acrylic acid. Of these polymers, preference is given to those in which R3 is H or a methyl group. In the case of the polyacrylamides (X=Nxe2x80x94R5), both mono-N-substituted (R5=H) and also di-N-substituted (R5=R4) amide structures are possible, it being possible to choose the two hydrocarbon radicals which are bonded to the N atom independently of one another from optionally alkoxylated, branched or unbranched C8-22-alk(en)yl radicals. Of the polyacrylic esters (X=O), preference is given to those in which the alcohol has been obtained from natural or synthetic fats or oils and has additionally been alkoxylated, preferably ethoxylated. Preferred degrees of alkoxylation are between 2 and 30, particular preference being given to degrees of alkoxylation between 10 and 15.
Since the polymers which can be used are technical-grade compounds, the designation of the radicals bonded to X is a statistical average value which can vary with regard to chain length or degree of alkoxylation in the individual case. The formula II merely gives formulae for idealized homopolymers. For the purposes of the present invention, however, it is also possible to use copolymers in which the proportion of monomer units which satisfy the formula II is at least 30% by weight. Thus, for example, it is also possible to use copolymers of modified polyacrylates and acrylic acid or salts thereof which still have acidic H atoms or basic xe2x80x94COOxe2x80x94 groups.
For the purposes of the present invention, preferred modified polyacrylates are polyacrylate-polymethacrylate copolymers which satisfy the formula IIa
in which R4 is a preferably unbranched, saturated or unsaturated C8-22-alk(en)yl radical, R6 and R7 independently of one another are H or CH3, the degree of polymerization n is a natural number, and the degree of alkoxylation a is a natural number between 2 and 30, preferably between 10 and 20. R4 is preferably a fatty alcohol radical which has been obtained from natural or synthetic sources, where the fatty alcohol has in turn preferably been ethoxylated (R6=H).
Products of the formula IIa are commercially available, for example under the name Acusol(copyright) 820 (RohmandHaas) in the form of 30% strength by weight dispersions in water. In said commercial product, R4 is a stearyl radical, R6 is a hydrogen atom, R7 is H or CH3 and the degree of ethoxylation a is 20.
Preferred liquid detergents comprise, based on the total composition, 0.2 to 4% by weight, preferably 0.3 to 3% by weight and in particular 0.5 to 1.5% by weight, of a modified polyacrylate of the formula II.
The second component of the thickening system in the compositions according to the invention is a boron compound, which is used in amounts of from 0.5 to 7% by weight. Examples of boron compounds which can be used for the purposes of the present invention are boric acid, boron oxide, alkali metal borates, such as ammonium, sodium and potassium ortho-, meta- and pyroborates, borax in its various stages of hydration, and polyborates, such as, for example, alkali metal pentaborates. It is also possible to use organic boron compounds, such as esters of boric acid. Preferred liquid detergents comprise 0.5 to 4% by weight, preferably 0.75 to 3% by weight and in particular 1 to 2% by weight, of boric acid or sodium tetraborate.
As the third component of the thickening system, the liquid detergents according to the invention comprise 1 to 8% by weight of a complexing agent. For the purposes of the present application, the term xe2x80x9ccomplexing agentsxe2x80x9d means low molecular weight hydroxycarboxylic acids, such as citric acid, tartaric acid, malic acid, or gluconic acid or salts thereof.
Particularly preferred liquid detergents comprise, as component c) of the thickening system, citric acid or sodium citrate, preference being given to liquid detergents which comprise 2.0 to 7.5% by weight, preferably 3.0 to 6.0% by weight and in particular 4.0 to 5.0% by weight, of sodium citrate.
In addition to the constituents of the thickening system, the liquid detergents according to the invention comprise surfactant(s), use being made of anionic, nonionic, cationic and/or amphoteric surfactants. From an applications viewpoint, preference is given to mixtures of anionic and nonionic surfactants, where the proportion of anionic surfactants should be greater than the proportion of nonionic surfactants. The total surfactant content of the moldings is, as described above, preferably below 30% by weight, based on the total liquid detergent.
The nonionic surfactants used are preferably alkoxylated, advantageously ethoxylated, in particular primary alcohols having, preferably, 8 to 18 carbon atoms and, on average, 1 to 12 mol of ethylene oxide (EO) per mole of alcohol in which the alcohol radical can be linear or preferably methyl-branched in the 2-position, or can contain linear and methyl-branched radicals in a mixture, as are usually present in oxo alcohol radicals. However, alcohol ethoxylates containing linear radicals of alcohols of native origin having 12 to 18 carbon atoms, e.g. from coconut, palm, tallow fatty or oleyl alcohol, and, on average, 2 to 8 EO per mole of alcohol are particularly preferred. Preferred ethoxylated alcohols include, for example, C12-14-alcohols having 3 EO, 4 EO or 7 EO, C9-11-alcohol having 7 EO, C13-15-alcohols having 3 EO, 5 EO, 7 EO or 8 EO, C12-18-alcohols having 3 EO, 5 EO or 7 EO and mixtures of these, for example mixtures of C12-14-alcohol having 3 EO and C12-18-alcohol having 7 EO. The degrees of ethoxylation given are statistical mean values which can be an integer or a fraction for a specific product. Preferred alcohol ethoxylates have a narrowed homologue distribution (narrow range ethoxylates, NRE). As well as these nonionic surfactants, it is also possible to use fatty alcohols having more than 12 EO. Examples thereof are tallow fatty alcohol having 14 EO, 25 EO, 30 EO or 40 EO. Nonionic surfactants which contain EO and PO groups together in the molecule can also be used according to the invention. In this connection, block copolymers having EO-PO block units or PO-EO block units can be used, but also EO-PO-EO copolymers and PO-EO-PO copolymers. It is of course also possible to use mixed alkoxylated nonionic surfactants in which EO and PO units are not distributed blockwise, but randomly. Such products can be obtained by the simultaneous action of ethylene oxide and propylene oxide on fatty alcohols.
Furthermore, the other nonionic surfactants which may be used are also alkyl glycosides of the general formula RO(G)x, in which R is a primary straight-chain or methyl-branched, in particular methyl-branched in the 2-position, aliphatic radical having 8 to 22, preferably 12 to 18, carbon atoms, and G is the symbol which represents a glycose unit having 5 or 6 carbon atoms, preferably glucose. The degree of oligomerization x, which indicates the distribution of monoglycosides and oligoglycosides, is any number between 1 and 10; x is preferably 1.2 to 1.4.
A further class of preferred nonionic surfactants, which are either used as the sole nonionic surfactant or in combination with other nonionic surfactants, are alkoxylated, preferably ethoxylated or ethoxylated and propoxylated fatty acid alkyl esters, preferably having 1 to 4 carbon atoms in the alkyl chain, in particular fatty acid methyl esters, as are described, for example, in Japanese Patent Application JP 58/217598, or which are preferably prepared by the process described in the International Patent Application WO-A-90/13533.
Nonionic surfactants of the amine oxide type, for example N-cocoalkyl-N,N-dimethylamine oxide and N-tallow-alkyl-N,N-dihydroxyethylamine oxide, and the fatty acid alkanolamides may also be suitable. The amount of these nonionic surfactants is preferably not more than that of the ethoxylated fatty alcohols, in particular not more than half thereof.
Other suitable surfactants are polyhydroxy fatty acid amides of the formula III,
in which RCO is an aliphatic acyl radical having 6 to 22 carbon atoms, R1 is hydrogen, an alkyl or hydroxyalkyl radical having 1 to 4 carbon atoms, and [Z] is a linear or branched polyhydroxyalkyl radical having 3 to 10 carbon atoms and 3 to 10 hydroxyl groups. The polyhydroxy fatty acid amides are known substances, which can usually be obtained by reductive amination of a reducing sugar with ammonia, an alkylamine or an alkanolamine, and subsequent acylation with a fatty acid, a fatty acid alkyl ester or a fatty acid chloride.
The group of polyhydroxy fatty acid amides also includes compounds of the formula IV,
in which R is a linear or branched alkyl or alkenyl radical having 7 to 12 carbon atoms, R1 is a linear, branched or cyclic alkyl radical or an aryl radical having 2 to 8 carbon atoms, and R2 is a linear, branched or cyclic alkyl radical or an aryl radical or an oxy-alkyl radical having 1 to 8 carbon atoms, where C1-4-alkyl or phenyl radicals are preferred and [Z] is a linear polyhydroxyalkyl radical whose alkyl chain is substituted by at least two hydroxyl groups, or alkoxylated, preferably ethoxylated or propoxylated, derivatives of-this radical.
[Z] is preferably obtained by reductive amination of a sugar, for example glucose, fructose, maltose, lactose, galactose, mannose or xylose. The N-alkoxy- or N-aryloxy-substituted compounds can then be converted into the desired polyhydroxy fatty acid amides, for example in accordance with the teaching of the International Application WO-A-95/07331 by reaction with fatty acid methyl esters in the presence of an alkoxide as catalyst.
The content of nonionic surfactants in preferred liquid detergents is 5 to 20% by weight, preferably 7 to 15% by weight and in particular 9 to 14% by weight, in each case based on the total composition.
The anionic surfactants used are, for example, those of the sulfonate and sulfate type. Suitable surfactants of the sulfonate type are, in this connection, preferably C9-13-alkylbenzenesulfonates, olefinsulfonates, i.e. mixtures of alkene and hydroxyalkanesulfonates, and disulfonates, as are obtained, for example, from C12-18-monoolefins having a terminal or internal double bond by sulfonation with gaseous sulfur trioxide and subsequent alkaline or acidic hydrolysis of the sulfonation products. Also suitable are alkanesulfonates which are obtained from C12-18-alkanes, for example by sulfochlorination or sulfoxidation with subsequent hydrolysis or neutralization. Likewise, the esters of xcex1-sulfo fatty acids (ester sulfonates), e.g. the xcex1-sulfonated methyl esters of hydrogenated coconut, palm kernel or tallow fatty acids are also suitable.
Further suitable anionic surfactants are sulfated fatty acid glycerol esters. Fatty acid glycerol esters mean the mono-, di- and triesters, and mixtures thereof, as are obtained during the preparation by esterification of a monoglycerol with 1 to 3 mol of fatty acid or during the transesterification of triglycerides with 0.3 to 2 mol of glycerol. Preferred sulfated fatty acid glycerol esters are the sulfation products of saturated fatty acids having 6 to 22 carbon atoms, for example of caproic acid, caprylic acid, capric acid, myristic acid, lauric acid, palmitic acid, stearic acid or behenic acid.
Preferred alk(en)yl sulfates are the alkali metal, and in particular the sodium, salts of sulfuric half-esters of C12-C18-fatty alcohols, for example of coconut fatty alcohol, tallow fatty alcohol, lauryl, myristyl, cetyl or stearyl alcohol or of C10-C20-oxo alcohols and those half-esters of secondary alcohols of these chain lengths. Further preferred are alk(en)yl sulfates of said chain length which contain a synthetic, petrochemical-base-prepared straight-chain alkyl radical which have an analogous degradation behavior to the adequate compounds based on fat-chemical raw materials. From the point of view of washing, the C12-C16-alkyl sulfates and C12-C15-alkyl sulfates and C14-C15-alkyl sulfates are preferred. 2,3-Alkyl sulfates, which are prepared, for example, according to U.S. Pat. Nos. 3,234,258 or 5,075,041 and can be obtained as commercial products from Shell Oil Company under the name DAN(copyright), are also suitable anionic surfactants.
The sulfuric monoesters of the straight-chain or branched C7-21-alcohols, ethoxylated with 1 to 6 mol of ethylene oxide, such as 2-methyl-branched C9-11-alcohols with, on average, 3.5 mol of ethylene oxide (EO) or C12-18-fatty alcohols with 1 to 4 EO are also suitable. Because of their high foaming behavior, they are used in cleaners only in relatively small amounts, for example in amounts of from 1 to 5% by weight.
Other suitable anionic surfactants are also the salts of alkylsulfosuccinic acid, which are also referred to as sulfosuccinates or as sulfosuccinic esters, and the monoesters and/or diesters of sulfosuccinic acid with alcohols, preferably fatty alcohols and in particular ethoxylated fatty alcohols. Preferred sulfosuccinates comprise C8-18-fatty alcohol radicals or mixtures thereof. Particularly preferred sulfosuccinates comprise a fatty alcohol radical derived from ethoxylated fatty alcohols, which are in themselves nonionic surfactants (see below for description). In this connection, sulfosuccinates whose fatty alcohol radicals are derived from ethoxylated fatty alcohols having a narrowed homologue distribution are, in turn, particularly preferred. Likewise, it is also possible to use alk(en)ylsuccinic acid having, preferably, 8 to 18 carbon atoms in the alk(en)yl chain or salts thereof.
Other suitable anionic surfactants are, in particular, soaps. Saturated and unsaturated fatty acid soaps, such as the salts of lauric acid, myristic acid, palmitic acid, stearic acid, (hydrogenated) erucic acid and behenic acid, and, in particular, soap mixtures derived from natural fatty acids, e.g. coconut, palm kernel, olive oil or tallow fatty acids, are suitable.
The anionic surfactants, including soaps, can be present in the form of their sodium, potassium or ammonium salts, and as soluble salts of organic bases, such as mono-, di- or triethanolamine. The anionic surfactants are preferably in the form of their sodium or potassium salts, in particular in the form of the sodium salts.
The content of anionic surfactants in preferred liquid detergents is 5 to 25% by weight, preferably 7 to 22% by weight and in particular 10 to 20% by weight, in each case based on the total composition.
The viscosity of the compositions according to the invention can be measured using customary standard methods (for example Brookfield viscometer LVT-II at 20 rpm and 20xc2x0 C., spindle 3) and is preferably in the range from 500 to 5000 mpas. Preferred compositions have viscosities of from 1000 to 4000 mPas, values between 1300 and 3000 mPas being particularly preferred.
In addition to the thickening system and to surfactant(s), the compositions according to the invention can comprise further ingredients which further improve the application and/or esthetic properties of the liquid detergent. For the purposes of the present invention, preferred compositions comprise, in addition to the thickening system and to surfactant(s), one or more substances from the group of builders, bleaches, bleach activators, enzymes, electrolytes, nonaqueous solvents, pH regulators, fragrances, perfume carriers, fluorescence agents, dyes, hydrotropic agents, foam inhibitors, silicone oils, antiredeposition agents, optical brighteners, graying inhibitors, shrink preventatives, anticrease agents, dye-transfer inhibitors, antimicrobial active ingredients, germicides, fungicides, antioxidants, corrosion inhibitors, antistats, easy-iron agents, repellent and impregnation agents, swelling and nonslip agents, and UV absorbers.
Builders which may be present in the liquid detergents according to the invention are, in particular, silicates, aluminum silicates (in particular zeolites), carbonates, salts of organic di- and polycarboxylic acids, and mixtures of these substances.
Suitable crystalline, layered sodium silicates have the general formula NaMSixO2x+1.H2O, where M is sodium or hydrogen, x is a number from 1.9 to 4, and y is a number from 0 to 20, and preferred values for x are 2, 3 or 4. Such crystalline phyllosilicates are described, for example, in European Patent Application EP-A-0 164 514. Preferred crystalline phyllosilicates of the given formula are those in which M is sodium and x assumes the values 2 or 3. In particular, both xcex2- and also xcex4-sodium disilicates Na2Si2O5.yH2O are preferred, where xcex2-sodium disilicate can, for example, be obtained by the process described in International Patent Application WO-A-91/08171.
It is also possible to use amorphous sodium silicates having a Na2O:SiO2 modulus of 1:2 to 1:3.3, preferably from 1:2 to 1:2.8 and in particular from 1:2 to 1:2.6, which have delayed dissolution and secondary detergent properties. The dissolution delay compared with traditional amorphous sodium silicates can have been induced in a variety of ways, for example by surface treatment, compounding, compacting/compression or by overdrying. For the purposes of this invention, the term xe2x80x9camorphousxe2x80x9d also includes xe2x80x9cX-ray amorphousxe2x80x9d. This means that in X-ray diffraction experiments the silicates do not give sharp X-ray reflections typical of crystalline substances, but instead exhibit, at best, one or more maxima of the scattered X-rays having a width of several degree units of the diffraction angle. However, particularly good builder properties can result if in electron diffraction experiments the silicate particles give poorly defined or even sharp diffraction maxima. This is to be interpreted to the effect that the products have microcrystalline regions with a size ranging from 10 to a few hundred nm, preference being given to values up to at most 50 nm and in particular up to at most 20 nm. So-called X-ray amorphous silicates of this kind, which likewise have delayed dissolution compared to conventional waterglasses, are described, for example, in German Patent Application DE-A-44 00 024. Particular preference is given to compressed/compacted amorphous silicates, compounded amorphous silicates and overdried X-ray amorphous silicates.
The finely crystalline, synthetic zeolite used, containing bound water, is preferably zeolite A and/or P. Zeolite P is particularly preferably zeolite MAP(copyright) (commercial product from Crosfield). Also suitable, however, are zeolite X, and mixtures of A, X and/or P. A co-crystallizate of zeolite X and zeolite A (about 80% by weight of zeolite X), which is sold by CONDEA Augusta S.p.A. under the trade name VEGOBOND AX(copyright) and can be described by the formula
nNa2O.(1-n)K2O.Al2O3.(2-2.5)SiO2.(3.5-5.5)H2O
is, for example, also commercially available and preferred for the purposes of the present invention. The zeolite can be used as a spray-dried powder or else as an undried, stabilized suspension still moist from its preparation. If the zeolite is employed as a suspension, this suspension may comprise small additions of nonionic surfactants as stabilizers, for example 1 to 3% by weight, based on zeolite, of ethoxylated C12-C18-fatty alcohols having 2 to 5 ethylene oxide groups, C12-C14-fatty alcohols having 4 to 5 ethylene oxide groups or ethoxylated isotridecanoles. Suitable zeolites have a mean particle size of less than 10 xcexcm (volume distribution; measurement method: Coulter Counter) and preferably contain 18 to 22% by weight, in particular 20 to 22% by weight, of bound water.
It is of course also possible to use the generally known phosphates as builder substances, provided such a use must not be avoided for ecological reasons. The sodium salts of the orthophosphates, the pyrophosphates and, in particular, of the tripolyphosphates are particularly suitable.
Among the compounds used as bleaches which donate H2O2 in water, sodium perborate tetrahydrate and sodium perborate monohydrate are of particular importance. Other bleaches which can be used are, for example, sodium percarbonate, peroxypyrophosphates, citrate perhydrates, and H2O2-donating peracidic salts or peracids, such as perbenzoate, peroxophthalates, diperazelaic acid, phthaloimino peracid or diperdodecanedioic acid.
In order to achieve an improved bleaching effect when washing at temperatures of 60xc2x0 C. and below, bleach activators can be incorporated into the detergent and cleaner moldings. Bleach activators which can be used are compounds which, under conditions of perhydrolysis, give aliphatic peroxocarboxylic acids having, preferably, 1 to 10 carbon atoms, in particular 2 to 4 carbon atoms, and/or optionally substituted perbenzoic acid. Suitable substances are those which carry O -and/or N-acyl groups of the stated carbon number and/or optionally substituted benzoyl groups. Preference is given to polyacylated alkylenediamines, in particular tetraacetylethylenediamine (TAED), acylated triazine derivatives, in particular 1,5-diacetyl-2,4-dioxohexahydro-1,3,5-triazine (DADHT), acylated glycolurils, in particular tetraacetylglycoluril (TAGU), N-acyl imides, in particular N-nonanoylsuccinimide (NOSI), acylated phenolsulfonates, in particular n-nonanoyl- or isononanoyloxybenzenesulfonate (n- and iso-NOBS respectively), carboxylic anhydrides, in particular phthalic anhydride, acylated polyhydric alcohols, in particular triacetin, ethylene glycol diacetate and 2,5-diacetoxy-2,5-dihydrofuran.
In addition to, or instead of, the conventional bleach activators, it is also possible to incorporate so-called bleaching catalysts into the moldings. These substances are bleach-reinforcing transition metal salts or transition metal complexes such as, for example, Mn, Fe, Co, Ru or Mo salen complexes or carbonyl complexes. Mn, Fe, Co, Ru, Mo, Ti, V and Cu complexes with nitrogen-containing tripod ligands, and Co, Fe, Cu and Ru ammine complexes can also be used as bleaching catalysts.
Suitable enzymes are, in particular, those from the classes of hydrolases, such as the proteases, esterases, lipases and lipolytic enzymes, amylases, cellulases and other glycosyl hydrolases and mixtures of said enzymes. During washing, all of these hydrolases contribute to the removal of marks, such as protein-, grease- or starch-containing marks, and grayness. Moreover, cellulases and other glycosyl hydrolases may, by removing pilling and microfibrils, contribute to color retention and to an increase in the softness of the textile. For bleaching or for inhibiting color transfer it is also possible to use oxireductases. Particularly suitable enzymatic active ingredients are those obtained from bacterial strains or fungi, such as Bacillus subtilis, Bacillus licheniformis, Streptomyceus griseus and Humicola insolens. Preference is given to using proteases of the subtilisin type and in particular proteases obtained from Bacillus lentus. Of particular interest in this connection are enzyme mixtures, for example mixtures of protease and amylase or protease and lipase or lipolytic enzymes or protease and cellulase or mixtures of cellulase and lipase or lipolytic enzymes or mixtures of protease, amylase and lipase or lipolytic enzymes or protease, lipase or lipolytic enzymes and cellulase, but in particular protease and/or lipase-containing mixtures, or mixtures containing lipolytic enzymes. Examples of lipolytic enzymes of this kind are the known cutinases. Peroxidases or oxidases have also proven to be suitable in some cases. Suitable amylases include, in particular, xcex1-amylases, isoamylases, pullulanases and pectinases. The cellulases used are preferably cellobiohydrolases, endoglucanases and xcex2-glucosidases, which are also called cellobiases, or mixtures thereof. Since different cellulase types differ in their CMCase and avicelase activities, it is possible to adjust the desired activities by targeted mixing of the cellulases.
The enzymes can be adsorbed on carrier substances or embedded into enveloping substances in order to protect them from premature decomposition. The proportion of enzymes, enzyme mixtures or enzyme granules can, for example, be from about 0.1 to 5% by weight, preferably 0.12 to about 2% by weight.
The electrolytes from the group of inorganic salts used can be a large number of very different salts. Preferred cations are the alkali metals and alkaline earth metals, preferred anions are the halides and sulfates. From a preparation point of view, the use of NaCl or MgCl2 in the compositions according to the invention is preferred. The proportion of electrolytes in the compositions according to the invention is usually 0.5 to 5% by weight.
Nonaqueous solvents which can be used in the compositions according to the invention originate, for example, from the group of mono- or polyhydric alcohols, alkanolamines or glycol ethers, provided they are miscible with water in the given concentration range. The solvents are preferably chosen from ethanol, n- or i-propanol, butanols, glycol, propane- or butanediol, glycerol, diglycol, propyl or butyl diglycol, hexylene glycol, ethylene glycol methyl ether, ethylene glycol ethyl ether, ethylene glycol propyl ether, ethylene glycol mono-n-butyl ether, diethylene glycol methyl ether, diethylene glycol ethyl ether, propylene glycol methyl, ethyl or propyl ether, dipropylene glycol monomethyl or -ethyl ether, diisopropylene glycol monomethyl or -ethyl ether, methoxy-, ethoxy- or butoxytriglycol, 1-butoxyethoxy-2-propanol, 3-methyl-3-methoxybutanol, propylene glycol t-butyl ether and mixtures of these solvents. Nonaqueous solvents can be used in the liquid detergents according to the invention in amounts between 0.5 and 10% by weight, but preferably below 5% by weight and in particular below 3% by weight.
In order to bring the pH of the compositions according to the invention into the desired range, it is possible to use pH regulators. Use can be made here of any known acids or alkalis, provided their use is not precluded for application or ecological reasons or for reasons of consumer protection. The amount of these regulators does not usually exceed 5% by weight of the total formulation.
In order to improve the esthetic impression of the compositions according to the invention, they can be colored with suitable dyes. Preferred dyes, the choice of which does not present any problems at all to the person skilled in the art, have high storage stability and high insensitivity toward the other ingredients of the compositions and toward light, and do not have marked substantivity toward textile fibers in order not to dye these.
Suitable foam inhibitors which can be used in the compositions according to the invention are, for example, soaps, paraffins or silicone oils which can optionally be deposited on carrier materials. Suitable antiredeposition agents, which are also referred to as soil repellents, are, for example, nonionic cellulose ethers, such as methylcellulose and methyl-hydroxypropylcellulose having a proportion of methoxy groups of from 15 to 30% by weight and of hydroxypropyl groups of from 1 to 15% by weight, in each case based on the nonionic cellulose ethers, and the polymers, known from the prior art, of phthalic acid and/or terephthalic acid or derivatives thereof, in particular polymers of ethylene terephthalates and/or polyethylene glycol terephthalates or anionically and/or nonionically modified derivatives thereof. Of these, particular preference is given to the sulfonated derivatives of phthalic acid and terephthalic acid polymers.
Optical brighteners can be added to the compositions according to the invention in order to eliminate graying and yellowing of the treated textiles. These substances attach to the fibers and effect a brightening and simulated bleaching action by converting invisible ultraviolet radiation into visible longer-wavelength light, the ultraviolet light absorbed from sunlight being irradiated as a pale bluish fluorescence and, together with the yellow shade of the grayed or yellowed laundry, producing pure white. Suitable compounds originate, for example, from the classes of substance of 4,4xe2x80x2-diamino-2,2xe2x80x2-stilbene-disulfonic acids (flavonic acids), 4,4xe2x80x2-distyrylbiphenylene, methylumbelliferones, coumarins, dihydroquinolinones, 1,3-diarylpyrazolines, naphthalimides, benzoxazole, benzisoxazole and benzimidazole systems, and pyrene derivatives substituted by heterocycles. The optical brighteners are usually used in amounts between 0.05 and 0.3% by weight, based on the finished composition.
Graying inhibitors have the task of holding the soil detached from the fiber in suspended form in the liquor, thus preventing soil reattachment. Suitable for this purpose are water-soluble colloids, mostly of an organic nature, for example glue, gelatin, salts of ether sulfonic acids of starch or of cellulose or salts of acidic sulfuric esters of cellulose or of starch. Water-soluble polyamides which contain acidic groups are suitable for this purpose. In addition, it is possible to use soluble starch preparations, and starch products other than those mentioned above, e.g. degraded starch, aldehyde starches, etc. It is also possible to use polyvinylpyrrolidone. Preference is, however, given to using cellulose ethers, such as carboxymethylcellulose (Na salt), methylcellulose, hydroxyalkylcellulose and mixed ethers, such as methylhydroxyethylcellulose, methylhydroxypropyl-cellulose, methylcarboxymethylcellulose and mixtures thereof in amounts of from 0.1 to 5% by weight, based on the compositions.
Since textile sheet materials, in particular those made of rayon, viscose, cotton and mixtures thereof, can tend to crease because the individual fibers are sensitive to bending, kinking, pressing, and squashing transversely to the direction of the fibers, the compositions according to the invention can comprise synthetic anticrease agents. These include, for example, synthetic products based on fatty acids, fatty acid esters, fatty acid amides, fatty acid alkylol esters, fatty acid alkylolamides or fatty alcohols, which are mostly reacted with ethylene oxide, or products based on lecithin or modified phosphoric esters.
To control microorganisms, the compositions according to the invention can comprise antimicrobial active ingredients. A distinction is drawn here, depending on the antimicrobial spectrum and effectivity mechanism, between bacteriostats and bactericides, fungistats and fungicides etc. Important substances from these groups are, for example, benzalkonium chlorides, alkylaryl sulfonates, halogenated phenols and phenol mercuriacetate, it also being possible to dispense with these compounds completely in the case of the compositions according to the invention.
In order to prevent undesired changes to the compositions and/or the treated textiles caused by the effect of oxygen and other oxidative processes, the compositions can comprise antioxidants. This class of compound includes, for example, substituted phenols, hydroquinones, pyrocatechols and aromatic amines, and organic sulfides, polysulfides, dithiocarbamates, phosphites and phosphonates.
Increased wear comfort can result from the additional use of antistats which are additionally added to the compositions according to the invention. Antistats increase the surface conductivity and thus permit an improved flow of charges formed. External antistats are usually substances having at least one hydrophilic molecular ligand and produce a more or less hygroscopic film on the surfaces. These mostly surface-active antistats can be subdivided into nitrogen-containing antistats (amines, amides, quaternary ammonium compounds), phosphorus-containing antistats (phosphoric esters) and sulfur-containing antistats (alkylsulfonates, alkyl sulfates) External antistats are described, for example, in the Patent Applications FR 1,156,513, GB 873 214 and GB 839 407. The lauryl-(or stearyl-) dimethylbenzylammonium chlorides disclosed therein are suitable as antistats for textiles or as additives for detergents, a softening effect additionally being achieved.
To improve the water absorption capacity, the rewettability of the treated textiles, and to facilitate ironing of the treated textiles, silicone derivatives, for example, can be used in the compositions according to the invention. These additionally improve the rinse-out behavior of the compositions according to the invention by their foam-inhibiting properties. Preferred silicone derivatives are , for example, polydialkyl- or alkylarylsiloxanes in which the alkyl groups have one to five carbon atoms and are completely or partially fluorinated. Preferred silicones are polydimethylsiloxanes which can optionally be derivatized and then are aminofunctional or quaternized, or have Sixe2x80x94OH, Sixe2x80x94H and/or Sixe2x80x94Cl bonds. The viscosities of the preferred silicones are, at 25xc2x0 C., in the range between 100 and 100,000 mPas, it being possible to use the silicones in amounts between 0.2 and 5% by weight, based on the total composition.
Finally, the compositions according to the invention can also comprise UV absorbers, which attach to the treated textiles and improve the light resistance of the fibers. Compounds which have these desired properties are, for example, the compounds and derivatives of benzophenone having substituents in the 2- and/or 4-position which are effective by nonradiative deactivation. Furthermore, substituted benzotriazoles, acrylates phenyl-substituted in the 3-position (cinnamic acid derivatives), optionally with cyano groups in the 2-position, salicylates, organic Ni complexes, and natural substances such as umbelliferone and endogenous urocanic acid, are also suitable.
In order to avoid the decomposition of certain detergent ingredients catalyzed by heavy metals, it is possible to use substances which form complexes with the heavy metal. Suitable heavy metal complexing agents are, for example, the alkali metal salts of ethylene-diaminetetraacetic acid (EDTA) or of nitrilotriacetic acid (NTA), and alkali metal salts of anionic polyelectrolytes, such as polymaleates and polysulfonates.
A preferred class of complexing agents are the phosphonates, which are present in preferred liquid detergents in amounts of from 0.01 to 1.5% by weight, preferably from 0.02 to 1% by weight and in particular from 0.03 to 0.5% by weight. These preferred compounds include, in particular, organophosphonates, such as, for example, 1-hydroxyethane-1,1-diphosphonic acid (HEDP), aminotri(methylenephosphonic acid) (ATMP), diethylenetriaminepenta(methylenephosphonic acid) (DTPMP or DETPMP), and 2-phosphonobutane-1,2,4-tricarboxylic -acid (PBS-AM), which are used in most cases in the form of their ammonium or alkali metal salts.
Particularly preferred liquid detergents comprise, as component c) of the thickening system, 1-hydroxyethane-1,1-diphosphonic acid in the form of its ammonium or alkali metal salts.
The compositions according to the invention are prepared by simply mixing the constituents in stirred-tank reactors, water, nonaqueous solvents and surfactant(s) advantageously being introduced first, and the other constituents being added in portions thereto. Separate heating during the preparation is not required, but if it is desired, the temperature of the mixture should not exceed 80xc2x0 C.

Low-concentration highly viscous liquid detergents

Henkel Kommanditgesellschaft Auf Aktien (KGaA)


The present invention relates to a delivery system for topical application to the skin comprising a freeze-dried, partially cross-linked polymeric gel membrane which can be reversibly returned to a dissolvable gel form upon the application of a wetting agent. The membrane can be used to deliver biologically active agents to the skin.

The present invention relates to a delivery system for application to the skin. In particular, the invention relates to a membrane-based system useful in delivering biologically active materials to the skin.
The problem of effective delivery of active ingredients to the desired target site is one which continues to be problematic for both the cosmetic and pharmaceutical industries. Topical delivery of active agents is particularly difficult because, unlike parenteral or oral delivery, while the skin is certainly readily accessible, the exposure of the site at which the product is delivered can work against the goal of fully efficient receipt of the active by the target area. Typical vehicles for topical applications have normally been lotions, creams and gels, relatively viscous fluids that are rubbed into the skin, providing immediate contact with the target region. These vehicles are frequently very successfully used for active delivery, both of cosmetic and pharmaceutical delivery. They are, however, without more, not capable of delivering the active therein over long periods of time, which is sometimes required for the greatest efficacy of the active. In addition, from a strictly practical point of view, they are not frequently very portable, so that the user is frequently required to carry a bulky jar or bottle if the product is to be used outside the home.
Dermal patches represent an alternative to the liquid forms of application. These devices can come in a variety of forms, all having the capability of adhering to the skin, and thereby permitting prolonged contact between the active-containing composition and the target area, They also have the advantage of being relatively compact and portable, and permitting very precise delivery of product to the area to be treated. These patches come in a variety of forms, some containing fluid reservoirs for the active component, others containing dry ingredients that are released upon contact with moisture in the skin. Many require some form of adhesive to retain them in connection with the skin for an adequate period. A different type of patch is applied dry, with water applied to wet the patch to form a sticky film that is retained on the skin. Such films normally need to be washed or peeled off the skin, and can be very visible; for this reason they can be aesthetically unpleasant.
There thus continues to be a need for a topical delivery system which will be more convenient to use and more elegant than previous delivery forms and devices, while at the same time retaining the efficiency of providing the desired actives to the target location. The present invention now provides such a system.
The invention provides a delivery system for topical application to the skin comprising a freeze-dried, partially cross-inked polymeric gel membrane which can be reversibly returned to a dissolvable gel form upon the application of a wetting agent. In a preferred embodiment, the membrane also incorporates biologically active agents for delivery to the skin. Unlike previous xe2x80x9cpatchesxe2x80x9d or similar spot treatments, that need to washed or peeled off, the membrane of the present invention, when wet, assumes its previous gel form, which can be readily rubbed into the skin, thereby delivering the active agents and leaving substantially no residue to be removed from the application area. An additional benefit is that the membrane also stabilizes the actives contained therein, thereby allowing for prolonged storage and shelf-life of otherwise potentially unstable active materials.
The membranes of the invention are based on a partially cross-linked gel network of polymeric material having sufficient structure to permit the suspension of one or more actives and to survive a freeze-drying process, but the structure of which is also reversible, so as to subsequently allow the return of the membrane to the gel condition when water or other wetting agent is applied. The reversibility of the structure allows the user to then rub the gel film into the skin, thereby avoiding the necessity of rinsing or peeling off a dried film, as is required with other types of skin patches.
A number of different types of polymers can be used as the base of the membrane. The polymers employed must of course be sufficiently water soluble to respond to the aqueous wetting agent that will eventually be applied. Preferred polymers are those which produce a fibrous type of gel network when cross-linked, the strength of the fibers being adequate to withstand the freeze-drying process, but as noted, adequately water-soluble to permit rewetting. Particularly preferred are gels based on alginic acid, for example, i.e., sodium or calcium alginate gels. However, other types of cross-linkable gel-forming polymers can also be used; examples of alternate bases for the gel include collagen, particularly partially hydrolyzed collagen, or cross-linkable starches.
The membrane is formed by standard methods of crosslinking of the chosen gel-forming polymer. For example, if the chosen gel is an alginate, this is normally achieved by the addition of a solution containing metal ions to a slurry of the alginate and water. Examples of useful sources of such metal ions include, but are not limited to, strongly electrolytic cosmetically or pharmaceutically acceptable acid salts of mono-, or more preferably, di- or trivalent metals, such as K+, Ca+2, Al+2, Fe+2, Fe+3, Cu+2, or Mn+2. The relative proportions of the components in the slurry are not very critical; however, for the wet gel, the polymer will normally constitute from about 0.5 to about 10% by weight; and the metal salts normally will be added in an amount of about 0.5 to about 3%. The amount of the polymer relative to the remaining dry ingredients to be included in the membrane will normally be from about 30 to about 70% by weight, preferably from about 45 to about 55% by weight of the dried composition. Gels based on other polymers are similarly prepared in accordance with known techniques. For example, if collagen is the chosen base for the gel, the cross-linking agent is normally an aldehyde, and with starch, a large number of crosslinking agents, such as phosphorus oxychloride, or epichlorohydrin, are also useful. In all cases, to this point, the procedure of gel formation is a routine preparation of the chosen type of gel.
However, for the purposes of the present membrane, it is desirable to interfere somewhat with the cross-linking, but only partially, so as to form an adequately supportive network, but to also permit reversal of the structure of the matrix back to its original gel state on contact with water. To achieve this, a cross-linking disrupter is added to the slurry of metal ions and polymer. In general terms, the disrupter is a hygroscopic material, and preferably of a fairly high molecular weight. The size of the molecule aids in the interference with cross-linking, while the hygroscopic property aids in the ultimate rewetting of the membrane at the appropriate time. Examples of materials of this type include breakdown products and derivatives of chitin and mucopolysaccharides, for example, chitosan, hyaluronic acid, glucuronic acid, and oligosaccharides(natural or synthetic) comprising glucosamine, galactosamine, and/or mannosamine monomeric units; hygroscopic, water soluble amino acids or peptides composed thereof, for example, glycine or lysine, or glycerin and glycerin derivatives. A particularly preferred cross-linking disrupter is hyaluronic acid . The disrupter is used in an amount sufficient to constitute from about 0.01 to about 10%, preferably about 1 to about 8%, by weight of the dried membrane.
Although the gel formed by the crosslinked polymer forms an adequate film to retain the product on the skin at the time of wetting, it may also be desirable to add small amounts of additional film-forming agents to the membrane mixture. Such film-forming agents should also be water soluble, and should be used in such amounts so as to not interfere with the dissolvability of the membrane on the skin. Examples of useful film-forming agents for this purpose include, but are not limited to, collagen derivatives, cellulose derivatives, e.g., carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, homo- and copolymers of vinyl pyrrolidone, e.g., PVP, or PVP/PVA copolymers; homo-or copolymers of vinyl alcohol, such as polyvinyl alcohol, homo- or copolymers of acrylic and/or methacrylic acids, and salts and esters thereof, or gums, e.g., xanthan gum, guar gum, alginates, or carrageenan. If used, the additional film-former will be used in an amount of about 0.001% to about 25% by weight of the dry membrane, preferably about 0.1 to about 20%. It may also be desired, but not essential, to use small amounts of fibrous material, such as rayon, to supplement the structure of the membrane while freeze drying. If used at all, the amount is preferably less than about 10%, more preferably less than 5%.
The membrane is made by first preparing a slurry of the chosen polymer in water, and then adding the disrupter, as well as any additional materials, such as film forming agents and actives. The aqueous solution containing the requisite crosslinking agent is then added to the slurry, thereby setting up, by virtue of the presence of the disrupter, a partially crosslinked matrix. The solid matrix is then freeze-dried, under known and standard conditions, to remove any water thereby forming a dry film or block. The dried film or block is then sliced or otherwise divided or cut to prepare application pieces of the desired size and shapes, with a thickness generally of about 0.1 mm to about 1.5 mm, preferably, from about 0.2 mm to about 1 mm, and more preferably about 0.2 mm to about 0.6 mm. The final thickness will be a matter of choice dependent upon the intended use. The shapes of the application pieces can also be varied in accordance with their intended end use, and can be as large or as small as required for the purpose.
In order to function on the skin, the membrane must be rewetted with a wetting solution or activator. The wetting solution may be as simple as ordinary water, depending on the relative water solubility of the polymer used in preparation of the matrix and the nature of the additional components in the membrane. However, it is preferred that the wetting solution be slightly acidic, i.e., having a pH of between about 2 to about 6, preferably about 4 to about 6, in order to facilitate dissolution of the matrix. Thus, any aqueous solution containing a cosmetically or pharmaceutically acceptable acid will be appropriate for use in rewetting. However, in one embodiment of the invention, it particularly preferred that the wetting solution contain at least one alpha or beta hydroxy acid as the acid component. As is well documented, these acids themselves have a beneficial effect on the skin, as well as being able to enhance the rewetting of the membrane. Examples of useful acids for this purpose include, but are not limited to, lactic acid, glycolic acid, citric acid, alpha-hydroxyoctanoic acid, alpha-hydroxydecanoic acid, alpha-hydroxylauric acid, tartaric acid, glucouronic acid, galactouronic acid, acrylic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, malic acid, mandelic acid, phosphoric acid, pyruvic acid, tartronic acid, lactobionic acid and salicylic acid. The acid is preferably used in a concentration of about 0.01 to about 20% by weight of the wetting solution. In an alternate embodiment, for example, in a case in which the membrane contains an acidic active, it may be desirable to incorporate a bicarbonate into the solution, so that the reaction between the bicarbonate and the acid creates an additional force for dissolution of the membrane. In such a case, the wetting solution will ordinarily contain little or no acid, so as to avoid a premature reaction of acid and bicarbonate. The bicarbonate will ordinarily be sodium or potassium bicarbonate, present in an amount of about 0.1 to about 10% by weight of the solution. In a reversal of this process, the bicarbonate can alternately be incorporated into the membrane, and then will react with an acidic wetting solution. Again, in such a case, care must be taken so as to avoid a premature reaction with acid; therefore, if the membrane contains an acidic active, the bicarbonate can be sprinkled upon the dried membrane, and then activated by exposure to the wetting solution, which can be either ordinary or acidic water.
Either the membrane or the wetting solution can also contain additional optional cosmetic ingredients that contribute to the aesthetics of the system. For example, either component of the system may contain cosmetic oils, particularly silicone oils or esters, to enhance the emolliency of the gel in use on the skin. In fact, the wetting solution itself may be a water and oil emulsion or biliquid foam, rather than a simple aqueous solution. Either portion of the system may also comprise optical diff-users (soft focus powders), and/or silicone polymers, which will aid in softening the appearance of the membrane on the skin. Perfluoroethers can also be employed to assist in preventing feathering in areas prone to this occurrence, such as the upper lip. It is also possible to incorporate active components into the wetting agent. Other possible components will be readily apparent to those skilled in the art, given the understanding that the additional components cannot interfere with the integrity of the membrane upon drying, or with the ability of the wetting agent to dissolve the gel membrane.
As noted above, the wetting of the membrane can be achieved with ordinary water, so that the membrane can stand alone as the delivery system. However, in a preferred embodiment of the invention, a specially adapted wetting solution, as described above, and the membrane application pieces are packaged and purchased together in kit form. The use of the delivery system is very simple. A membrane application piece is removed from its container, which may be, for example, a compact, envelope, foil packet or the like. Application to the skin can be achieved in either of two ways, each of which requires a light wetting of the membrane to achieve adhesion to the skin. The skin can either be wet lightly with ordinary water or wetting solution and the membrane applied to the prewetted area; alternately, the user can wet the membrane slightly, enough to give adhesion but not to dissolve it, on her finger or in the palm of her hand, and then place the damp patch on the skin surface to be treated. Once the membrane is in place, the user applies additional water or wetting solution to the membrane, sufficient to return it back to its original dissolvable gel form. The gel can then be rubbed completely into the skin, or left in place for a time, then rubbed in.
The membrane prepared as described above has a number of uses. Without any additional components, the membrane can be applied to the skin and rewetted, and the dissolved membrane on the skin can serve to temporarily stretch, smooth, tighten and remoisturize skin, particularly skin with fine lines and wrinkles. However, the greatest advantage of the membrane is in the delivery of active materials to the skin. Thus, it is particularly preferred that the membrane incorporate one or more active ingredients, either cosmetic or pharmaceutical, either water-soluble or oil-soluble, having a specific beneficial effect on the skin. The membrane serves as an excellent delivery system for a variety of actives, especially for those actives which have particular benefit in spot applications to affected areas. One particular example is the use of the membrane for the application of anti-acne actives. For this purpose, anti-acne compounds, such as salicylic acid or benzoyl peroxide, are incorporated into the gel in the amounts known to be effective for acne treatment, the membrane thus prepared can then be cut to provide, for example, small discs that can be applied directly to a blemish. An additional example is for the application of agents for the treatment of the symptoms of chrono-or photoaging, which thus can be applied selectively to those regions of the skin in need of treatment, for example, at the corner of the eyes or along the upper lip. Actives usefull for this purpose include but are not limited to alpha and beta hydroxyacids, retinoids, soluble collagen, or collagen-stimulating compounds such as Vitamin C or derivatives thereof, Vitamin E and derivatives thereof N-acetyl cysteine, elastin, whey protein, colostrum, N-acetyl D-glucosamine, luteolin, or antioxidants such as green tea and active fractions thereof(EGCG/ECG). Whitening agents, such as kojic acid, licorice extracts, ascorbyl phosphates, ascorbyl glucosides, ascorbic acid or arbutin, can be incorporated to permit localized treatment of age spots, freckles, and skin discolorations associated with hormonal changes. Skin conditioning agents, e.g., compounds that moisturize the skin, or enhance the skin""s natural lipid barrier, such as ceramides, cholesterol sulfate, fatty acids, white birch extract, and sclareolide, can also be applied to areas in need by this method. Enzymes having utility in or on the skin, for example, proteases, lipases, cerebrosidases, or melanases, can be incorporated into the membrane. The membranes can also be used to deliver hormones, such as estrogen, progesterone, or DHEA. In the case of inclusion of one or more actives in the membrane, the active(s) will be incorporated in an amount sufficient to deliver the known effective dosage for that particular active.
The foregoing examples are provided as specific illustrations only; those skilled in the art will immediately recognize the scope of utility of the present delivery system. It can be used to deliver virtually any cosmetic or pharmaceutical ingredient, active or otherwise, that has an effect when delivered topically. Further examples of therapeutic actives include but are not limited to analgesics, anesthetics, antibacterials, antiyeast agents, antifungal agents, antiviral agents, antidermatitis agents, antipruritic agents, antiemetics, anti-motion sickness agents, antiirritant agents, anti-inflammatory agents, antihyperkeratolytic agents, anti-dry skin agents, antiperspirants, antipsoriatic agents, antiseborrheic agents, antiaging agents, antiasthmatic agents and bronchodilators, sunscreen agents, antihistamine agents, wound-healing agents, vitamins, corticosteroids, or tanning agents.
The membrane delivery system, as described above, has a number of advantages over traditional vehicles used for delivery of actives to the skin, as well as over other types of patches. The application pieces are convenient to use and easier to carry and store than bottles and jars of lotions and creams. Like other patch-type products, the membrane of the invention can remain on the skin for prolonged periods, and therefore does permit sustained delivery of active ingredients to the skin; however, unlike other skin patches and films, the rewetted membrane does not have to be peeled or washed off after use, but simply dissolves and is rubbed into the skin, and in fact can provide immediate benefits by the rubbing in of the gel right after application and wetting, thereby avoiding the potentially unattractive appearance of a patch in a highly visible location such as the face. These advantages alone make the membrane a superior product. An additional advantage can be found, however, in the fact that the membrane also serves as a stabilizer for the active ingredients. Because the application pieces are maintained in a dry state until use, active ingredients that are normally adversely affected by the presence of water, or other environmental factors, e.g., retinoids, green tea polyphenols, enzymes, or Vitamin C, substantially retain their activity even after prolonged periods of storage. Normally compounds such as these have to be specially formulated or delivered in special packaging in order to retain their activity before the product reaches the consumer. It is quite unexpected that such labile actives can be rendered stable in so simple and relatively inexpensive a manner. In some cases, however, it may be desirable to provide particularly labile actives in encapsulated form to further stabilize their activity.


This invention relates to polypeptide antigens of T.ovis suitable for use in vaccines to protect ruminants against infection by cestode parasites. The antigens are preferably obtained by expression of DNA coding therefor in a recombinant host cell. Aspects of the invention include DNA encoding the antigens, vectors containing the DNA and hosts which express the antigens.. The invention also provides antibody and DNA probes for use in identifying protective antigens of cestode parasites other than T.ovis.

The Taenia ovis tapeworm exists in adult form in the small intestine of its primary host, the dog. The cystic stage is carried in the musculature of its secondary or intermediate hosts, notably sheep and goats. Current control measures include prevention of feeding of infected carcases to dogs and treatment of dogs with cestocidal drugs, notably praziquantel (Droncit, Bayer) to prevent transmission of the parasite to ruminants. These control measures are costly to implement and are not effective in eradicating T.ovis.
Accordingly, as an adjunct to current control measures and to effect eradication of the disease, it would be preferable to immunise the secondary hosts to protect them from infection and also to preserve carcase quality for the meat industry.
It is an object of the present invention to provide a protective antigen for use in vaccines for the protection of ruminants against T.ovis infection or at least to provide the public with a useful choice.
Previous investigations conducted into vaccination against T.ovis infection with oncosphere antigens are reviewed by Rickard, M. D and Williams, J. F. Hydatidosis/Cystercercosis: Immune mechanisms and Immunisation against infection, Adv Parasitology 21, 230-296 (1982). However, in the work reviewed no attempt was made to identify which antigenic component of the oncospheres was responsible for the immune response. As will be appreciated. T.ovis contains a large number of antigenic components, most of which are not immunologically effective against infection.
Earlier attempts have been made to identify a host protective antigen for T.ovis (Howell, M. J & Hargreaves, J J Mol Biochem Parasitol 28, 21-30 (1988)). A cDNA library was prepared using mRNA extracted from adult T.ovis tape worms. Recombinants expressing antigenic determinants as -galactosidase fusion proteins were selected using antibodies in serum from sheep infected with T.ovis. Some fusion proteins were shown to correspond with native antigens (92.5 to 180kD) present in adult and oncosphere states of T.ovis, but trials of the host-protective nature of purified fusion proteins were not reported.


A method is shown for splitting a static pool of Internet Protocol (IP) addresses in a Remote Access Server (RAS) of a network server device into a dynamically assignable pool and a fixed assignment pool. The IP addresses of the dynamically assignable pool are available to any remote client connecting to the network server. The IP fixed assignment pool contains IP addresses that have a predetermined assignment to specific remote clients. When a remote client connects to the network server, it requests assignment of an IP address from the RAS. If the remote client does not specify an IP address in its IP address request, then an IP address from the dynamically assignable pool is assigned to the remote client for the duration of its connection to the network server. If the remote client does specify an IP address in its IP address request, then the fixed assignment pool is searched for the requested IP address and the address is assigned to the remote client. The IP addresses of the fixed assignment pool are never assigned to a remote client that does not request a specific IP address.

The present invention relates to communications in computer networks. More specifically, it relates to the assignment of fixed Internet Protocol (IP) addresses by a Remote Access Server (RAS) of a network server device.
The Internet, a world-wide-network of interconnected computers, provides multi-media content including audio, video, and graphics, that users can access through an Internet Service Provider (ISP).
In order to access the Internet, a user, or client, must be connected to a server that provides access to the Internet. The client can be connected to a local area network (LAN) having a network server with access to the Internet. Alternatively, the client is often located at a site that is remote from the server, in which case the user typically has a modem, such as a telephone or cable modem, connected to the user""s customer premise equipment (CPE), such as a personal computer (PC). The modem is connected to a communications medium, such as the PSTN or cable system, through which the modem communicates with a modem termination system that is part of a dial-up server.
An example of a dial-up connection configuration 1 is shown in FIG. 1. In the dial-up configuration 1, a CPE 2 is connected to modem 4 that is connected to public switched telephone network (PSTN) 6. Modem 4 communicates with a network server 10 through PSTN 6. The network server 10 is, in turn, connected to internet 8 and can send and receive IP network packets.
In order to perform data communications, CPE 2 sends data packets to modem 4, which sends the data packets upstream via the communications medium of the PSTN 6 to the modem termination system on network server 10. The network server 10 then sends the data packets to appropriate hosts on the internet data network 8. The network server 10 sends response data packets from these hosts back to the modem 4 attached to the user""s CPE 2.
When a modem device initially connects to a network server, it must register with a remote access service (RAS) in the modem termination system in order to receive data over the communications connection and from a data network (e.g., the Internet or an Intranet). The modem forwards configuration information it receives in a configuration file during initialization to the modem termination system in the network server as part of a registration request message to the RAS. The modem also helps initialize and register any attached customer premise equipment with the modem termination system.
The modem termination system in the network server typically manages connections to multiple remote clients, such as CPE 2. Most of the modems are attached to host customer premise equipment, such as computers or internet telephony devices. In order to send and receive data packets to and from the Internet 8, the modem 4, CPE 2 and other network devices require an Internet Protocol (xe2x80x9cIPxe2x80x9d) network address that is dynamically assigned by the RAS in the network server. The IP is an addressing protocol well known in the art, that is designed to route traffic within a network or between networks, i.e., the Internet 8.
Many RAS systems use a Dynamic Host Configuration Protocol (xe2x80x9cDHCPxe2x80x9d) as a standard messaging protocol to dynamically allocate network addresses such as Internet Protocol (xe2x80x9cIPxe2x80x9d) addresses. DHCP is a protocol for passing configuration information to network devices on a network and is well known in the art. DHCP is designed to negotiate with a computer newly connected to the network to automatically assign the computer an IP address. The IP address is typically randomly assigned from a pool of IP addresses reserved for the subnetwork to which the newly connected computer is attached or, if the newly connected computer requests a particular IP address, DHCP tries to assign the requested IP address to the computer. See the Internet Engineering Task Force (IETF) RFC 2131 for the DHCP. Information for IETF RFCs can be found on the World Wide Web at URLs xe2x80x9cds.internic.netxe2x80x9d or www. ietf . org.
However, some network server devices, such as servers running the Windows NT operating system, by Microsoft Corporation of Redmond, Washington, can be configured to use a static IP address pool that is assigned by an RAS that does not have DHCP activated. In this case, the CPE 2 negotiates for an IP address using Internet Protocol Control Protocol (xe2x80x9cIPCPxe2x80x9d). The IPCP is defined in detail in RFC-1332, incorporated herein by reference. During IPCP negotiation, the CPE 2 negotiates an IP address with the RAS in network server 10. Within such a static IP address pool, it is often desirable that a particular IP address be assigned to a particular modem each time the modem initializes. For instance, if the modem serves an internet telephony device, such as a telephone or facsimile machine, having a particular IP address for the device can be advantageous. Also, it may be helpful to have the same IP address assigned to a remote printer device each time it connects to a network.
However, there is presently no mechanism for reserving a predetermined IP address in a fixed IP address pool for a particular user. Conventional network address servers will dynamically assign any IP address within the fixed pool, including a particular IP address needed by a particular user, to any user""s modem in the course of a dynamic assignment algorithm. The particular user, when it attempts to initialize and obtain its predetermined IP address, may find that its predetermined IP address is in use by another user.
Therefore, the need remains for a method for reserving predetermined IP addresses within a fixed IP pool for the users to which they""ve been assigned.
In accordance with a preferred embodiment of the present invention, some of the problems associated with predetermined IP Addresses in network servers are overcome.
One aspect of the invention includes a method for reserving a predetermined Internet Protocol (IP) address in a remote access server (RAS) of a network server. The method involves providing a finite series of IP addresses having a first address and a last address in sequence and specifying a first fixed address that is intermediate to the first and last addresses, where a portion of the series of IP addresses from the first fixed address to the last address comprises a fixed IP address pool and a remaining portion of the series of IP addresses comprises a dynamic IP address pool, and where the fixed IP address pool includes the predetermined IP address. The method also calls for permitting a remote client that connects to the network server to request an IP address value in an IP address request to the RAS and receiving an IP address request from a remote client. The method then calls for searching only the dynamic IP address pool for an available IP address if the IP address value in the IP address request from the remote client is a predetermined value and, if an available IP address is found, assigning it to the remote client. Finally, the method sets forth searching only the fixed IP address pool for the IP address value in the IP address request from the remote client when the IP address value in the IP address request is not the predetermined value and, if the IP address value in the IP address request is found and is available, assigning the predetermined IP address to the remote client.
The foregoing and other features and advantages of a preferred embodiment of the present invention will be more readily apparent from the following detailed description, which proceeds with references to the accompanying drawings.

Method for preserving preassigned IP addresses in a remote access server


A highly accurate resistor for audio/video signal circuits is disclosed, and includes a substantially cylindrical substrate composed of dielectric material, such as ceramics, and a film layer of resistive material, such as tantalum with high purity. The film layer is arranged exclusively on the outer peripheral surface of the substrate such that the dielectric material is exposed on both end surfaces of the substrate. Undesirable eddy currents are prevented or suppressed from being induced on the end surfaces of the substrate as audio/video signal current is supplied to and conducted through the resistor, realizing a significant improvement in the high fidelity or definition of the reproduced sound/picture image.

1. Field of the Invention
The present invention relates to a resistor for high-fidelity audio/video signal circuits; more particularly, it pertains to a novel resistor whereby the characteristic of audio/video signal current conducted therethrough can be effectively prevented from undesirable degradation.
2. Description of the Related Art
With a recent significant improvement in the reproduced sound/picture image quality of audio/video equipments, various proposals have hitherto been made with respect to novel material and/or arrangement of highly accurate electronic components for such equipments. Among others, known proposals include application of high-quality wire material for signal conductors, such as large- or mono- crystal oxygen-free copper, and also application of accurate resistors or the like circuit elements with excellent linearity, both to high grade audio/video circuit.
As a basic circuit element, so-called metal film resistors are widely used and include a substrate made of dielectric material, usually a ceramic material with a solid or hollow cylindrical configuration, and a resistive metal film layer formed on the outer surface of the substrate. This type of resistor is generally believed to provide excellent linearity and to be thus very accurate.
However, even by adopting the above-mentioned measures in an attempt to improve reproduced sound/picture image quality, it can be clearly recognized by a number of enthusiastic users that there still remains a delicate difference between the reproduced sound and original sound, in case of audio equipments, which can be clearly discriminated by the human ear, and that the reproduced picture image quality of video equipments needs to be further refined to achieve the desired high definition. Consequently, there have been strong demands for still positive measures, including those related to resistors or the like circuit elements, which make it possible to further improve the high fidelity and definition of the reproduced sound/picture image.


This invention provides a process for purifying a cyclosporin, e.g. cyclosporin A, or a macrolide, to a high degree of purity on a large scale. In another aspect this invention provides a bulk quantity of cyclosporin A with an impurity level of less than about 0.7%, e.g. about 0.5%, and compositions thereof.

The present invention relates to a purification process, and in particular to a process for purifying a product from impurities having relatively close distribution coefficients one with another.
Extraction processes are well-known for separating hydrocarbons in the petrochemical industry. It is known that distribution coefficients of the hydrocarbons between given phase systems in such applications differ substantially one from another.
Reviews of extraction methods are published, for example, in Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 10, p. 125-180, pub. John Wiley and Sons 1993, and in The Handbook of Solvent Extraction, ed. Lo, Baird and Hanson, pub. Krieger 1991. The contents of these publications are incorporated herein by reference.
Presently large-scale purification of products of biotechnological processes is generally carried out by extraction or adsorption chromatography. Such products include peptides, macrolides and proteins which are generally produced as mixtures of products having closely-related structural and/or physical properties. Fractional extraction processes known in the petrochemical industry have hitherto not been applied in the biotechnology industry on a large scale for purification of active agents, e.g. peptides, having closely-related physical properties one with another. The present applicants consider a major problem to be that the respective distribution coefficients of biotechnological products and impurities between given phases are close one with another.
Accordingly, in one aspect, the present invention provides a process for purifying a product from a feedstock containing one or more impurities having closely-related physical properties to the product, which process comprises
feeding the feedstock into an extraction column under conditions adapted for separating more- or less-polar impurities from the feedstock, wherein a lighter phase flows counter to a heavier phase, thereby forming an output in one phase containing the product containing less more- or less-polar impurities so that the output contains the product in a substantially purified form.
The feedstock for the above process may be provided by output from a chromatographic purification or other pre-purification step, e.g. decantation. This process may be conducted such that the output serves as input for a subsequent chromatographic purification, e.g. in a series arrangement.
In another aspect, this invention provides a process for purifying a product from a feedstock containing one or more impurities having closely-related physical properties to the product, which process comprises
a) feeding the feedstock into a first extraction column under conditions adapted for separating more- or less-polar impurities from the feedstock, wherein a lighter phase flows counter to a heavier phase, thereby forming a first output in one phase containing the product containing less more- or less-polar impurities, and
b) feeding the first output into a second extraction column under conditions adapted for separating less- or more-polar impurities respectively from the first output, wherein the lighter phase flows counter to the heavier phase, thereby forming in one phase a second output, so that the second output contains the product in a substantially purified form.
The feedstock may be prepared by known methods, for example by fermentation. When the product is produced in a fermentation broth, the broth may be filtered and mixed with a solvent from which the product may be precipitated in an impure state, e.g. containing about 15% to about 30% by weight impurities. Typically the fermentation broth may undergo several cleaning and work-up steps prior to use as feedstock in the process of this invention. Initial filtration(s) and precipitation(s) serve to remove, for example, natural dyes and easily separable impurities from the product, and may serve to enhance phase separation in the extraction steps.
As used herein, the term xe2x80x9cphasexe2x80x9d is understood to mean a system having at least one component. The phase may comprise a single solvent or a mixture of, for example 2, 3 or more solvents.
As used herein, the term xe2x80x9cclosely-related physical propertiesxe2x80x9d is understood to mean that the product is difficult to separate from the one or more impurities. The closely-related physical properties may include, for example, the respective distribution coefficients of the product and one or more impurities between two phases. For a cyclopeptide, e.g. a cyclosporin, and in particular cyclosporin A, ratios of distribution coefficients, i.e. distribution coefficient of cyclosporin A/distribution coefficient of impurity, may be between about 3 and about 0.4, e.g. between about 1.5 and about 0.8. These ratios are known as selectivities.
As used herein, the term xe2x80x9clarge scalexe2x80x9d as applied to purification plant, is understood to mean a plant having an output of about one or more tonnes of purified product per annum, e.g. 10 tonnes per annum, or more e.g. around 20 to around 40 tonnes.
As used herein, the term xe2x80x9cimpurityxe2x80x9d is understood to mean an undesirable component.
The process of this invention may be applied to a wide variety of products, e.g. peptides, such as cyclosporins, for example Cyclosporin A and derivatives thereof, Cyclosporin D and derivatives thereof, or Cyclosporin G and derivatives thereof. An example of a Cyclosporin D derivative is, for example ([3xe2x80x2-desoxy-3xe2x80x2-oxo-MeBmt]1-[Val]2-Ciclosporin) as disclosed in EP 296122; or macrolides, for example rapamycins and derivatives thereof, and ascomycins and derivatives thereof, produced for example by fermentation. Examples of macrolides which may be purified using the process of this invention include rapamycin; 40-O-(2-hydroxy)ethyl rapamycin as described in PCT/EP93/02604; ascomycin; 33-epi-chloro-33-desoxyascomycin as described in EP 427680 in Example 66a; ascomycin derivatives disclosed e.g. in EP 569337 and in EP 626385, for example 5,6-dehydro-ascomycin as disclosed in EP 626385; or an ascomycin derivative known as FK506.
A method for producing Cyclosporin A is disclosed, for example, in Example 1 of British patent specification 1,491,509. Methods of preparing FK506 are described in EP 184162.
A variety of columns are known and available commercially. In one embodiment of this invention, a single column is used which is a countercurrent column adapted for mechanical agitation and/or stirring of the feedstock/phase system. In another embodiment of this invention, two or more columns are used, at least one of which is a countercurrent column adapted for mechanical agitation and/or stirring of the feedstock/phase system.
Preferably the column(s) includes mechanical agitation, e.g. rotary agitation or reciprocating plate. An extraction column adapted for mechanical agitation is available commercially from the Kuehni company, Switzerland.
In another aspect, this invention provides a countercurrent liquid-liquid extraction column adapted for rotary agitation having a sufficient number of trays or compartments to effect, in use, separation of a pharmaceutical from impurities.
In a further aspect, this invention provides the use of a countercurrent liquid-liquid extraction column adapted for rotary agitation for separating a pharmaceutical from impurities.
The column(s) may be adapted for temperature adjustment of the phases. A jacket may be provided, for example, to maintain a desired temperature within the column. When purifying, for example a cyclosporin, temperatures may be maintained within each column at between about 0 and about 100xc2x0 C., preferably between about 20 and about 80xc2x0 C., and more preferably between about 30 and about 60xc2x0 C.
It may be advantageous to conduct the process using a first column in series arrangement with a second and a third column, wherein the second column is in parallel arrangement with the third column. The Applicants contemplate such a configuration when, for example, the plant is to be situated in a building having a covering of limited height.
The phases chosen for the extraction step(s) of the process may depend on the distribution coefficient between phases, and solubility of the product in each phase under consideration. Fast and efficient separation of the phases is desirable, and separation may be substantially complete, for example within about one minute, preferably 30 seconds, more preferably within about 20 seconds.
A two-phase system is used in the process of this invention, wherein the phases are immiscible or substantially immiscible one with another. At least one phase may be an aqueous phase. The two-phase system separates to form a lighter, e.g. non-aqueous organic, phase comprising at least one solvent component, and a heavier, e.g. aqueous, phase comprising at least one solvent component and water. The product to be purified may be more readily soluble in one phase component which, therefore, serves as extracting component.
Preferably one phase is an aqueous phase and one phase is a non-aqueous phase. The aqueous phase may contain at least about 20%, e.g. more than about 40% by weight water, and may contain up to 100% by weight water. The aqueous phase may be the heavier phase.
The phase systems used in the processes of this invention may comprise, as organic phase, at least one hydrocarbon, e.g. a C5 to C12 alkane, e.g. n-heptane, cyclohexane or methylcyclohexane. As aqueous phase, the present applicants contemplate, in addition to water, ketones, e.g. acetone; esters, e.g. amyl acetate, n-butyl acetate or isopropyl acetate; or alcohols, e.g. methanol, ethanol, propanol, isopropanol, n-butanol, s-butanol, t-butanol or a pentanol. Acetone is a preferred extracting solvent for cyclosporin A.
It will be appreciated that at least one component is common to both phases. The common component may comprise any of the above-mentioned solvents, e.g. water; hydrocarbons; alcohols; ketones; or esters.
The present applicants have found an n-heptane/acetone/water system to be effective for purifying acomycin and derivatives thereof, rapamycin and derivatives thereof and cyclosporin A. In one embodiment, the following phase system is used to purify cyclosporin A: the lighter phase comprises a mixture in weight-% of about 75% n-heptane and about 25% acetone; the heavier phase comprises a mixture of about 50% acetone and about 50% water. The water content of the lighter, substantially non-aqueous phase is typically less than 10% by weight, preferably less than about 2% by weight based on the total weight of the non-aqueous phase.
In another embodiment, the following phase system is used to purify 40-O-(2-hydroxy)ethyl rapamycin: the lighter phase may comprise a mixture in weight-% of about 75%, e.g. 74%, n-heptane, about 25%, e.g. 25.5% acetone and a small quantity of water, e.g. 0.5% water. The heavier phase may comprise a mixture of a small amount e.g. 0.4% n-heptane, about 50%, e.g. 52.8%, acetone and about 50%, e.g. 46.8%, water.
The present applicants have found an n-heptane/isopropanol/water system to be effective for purifying 33-epi-chloro-33-desoxyascomycin. In one embodiment, the following phase system is used to purify 33-epi-chloro-33-desoxyascomycin: the lighter phase comprises a mixture in weight-% of about 90% n-heptane, e.g. 89%, and about 10% isopropanol, e.g. 11%; the heavier hase comprises a mixture of about 32% isopropanol, e.g. 31%, and about 68% water, e.g. 69%.
The distribution coefficient is defined herein as the ratio of the concentration (in g/unit volume) of product in the lighter phase to the concentration (in g/unit volume) of product in the heavier aqueous phase at 40xc2x0 C. The following distribution coefficients are obtained for cyclosporins between 75% n-heptane /25% acetone as lighter organic phase, and 50% acetone 50% water as heavier aqueous phase:
From the above, it will be apparent that the respective distribution coefficients for cyclosporins are relatively close one with another. When purifying Cyclosporin A, for example, the impurities to be separated from Cyclosporin A typically include other cyclosporins.
One advantage of this process is that Cyclosporin A may be prepared substantially free from impurities such as other Cyclosporins, e.g. Cyclosporin B, Cyclosporin C, or dihydro-Cyclosporin A. Thus the respective amounts of cyclosporin derivative impurities, e.g. Cyclosporin B, Cyclosporin C and Cyclosporin G in Cyclosporin A purified using the process of this invention, are typically at or below analytically detectable limits using HPLC. Thus the impurities in cyclosporin A are found to amount to less than about 0.7% by area using HPLC, e.g. about 0.5% or less, e.g. about 0.3%.
In another aspect, therefore, this invention provides a bulk quantity, i.e. 1 kg or more, e.g. 10 kg or more, e.g. 20, 30, 40, 50 kg or more cyclosporin A with an impurity level of less than about 0.7%, e.g. 0.5% or less, by area using HPLC. This invention further provides a bulk quantity of cyclosporin A having a purity level of 99.5% or greater, e.g. 99.7% or greater. The impurities found in purified cyclosporin A of this invention consist of other cyclosporins.
In another aspect this invention provides a composition comprising cyclosporin A as active agent in a bulk purified form, wherein the amount of impurities present is below 0.7%, e.g. 0.5 % by area using HPLC.
The composition may be orally administrable and may be an emulsion, microemulsion, a microemulsion preconcentrate or a solid dispersion. The composition may comprise components disclosed for example in published UK patent application GB 2 222 770, the contents of which are incorporated herein by reference.
Distribution coefficients for 40-O-(2-hydroxy)ethyl rapamycin are found to lie between 0.7 and 1.4 when using n-heptane/acetone/water phases. Ratios of distribution coefficients, i.e. selectivities, for rapamycin to 40-O-(2-hydroxy)ethyl rapamycin typically range from about 1.4 to about 2.3, e.g. around 1.5.
The distribution coefficient for 33-epi-chloro-33-desoxyascomycin is found to be around 7.6 using the above n-heptane/isopropanol/water phase system. The selectivity of ascomycin derivative side product to 33-epi-chloro-33-desoxyascomycin is found to be approximately 1.44.
The pH of the aqueous phase, when present, is typically between about 2 and about 9, for example pH 7.
The extraction process conditions, including the number of theoretical stages, may be selected using routine experimentation and, for example, computer simulation. A program suitable for such a purpose is available commercially under the trade name ASPEN PLUS.
Exact conditions for working this invention typically depend on a number of factors, including the dimensions of the column(s), fluid dynamics, stirrer speed, efficiency and number of trays or compartments.
Compartments having an efficiency of about 10 to 30%, e.g. 12 to 25%, may be suitable for the column(s) of this invention. Column efficiency, as used herein, is understood to mean the number of actual stages divided by the number of theoretical stages.
It will be appreciated by those skilled in this art that an extraction column, in use, may exhibit a flooding point. The respective flow rates of the phases may therefore be chosen to maintain the system in the or each column at below the flooding point, for example around 10 or 20% below the flooding point. In this way, high turbulence and fast mass transfer between phases may be obtained.
The present applicants have found that for a given column, the flooding point may be reached when a particular stirrer speed is reached and/or exceeded, hereinafter referred to as the critical speed. Stirrer speeds applied in a column in the process of this invention may be between about 15 and about 200 rpm. On a large scale, typical stirrer speeds may be between about 5 and about 60 rpm. The applicants have obtained good results using a stirrer speed about 10 to 20% below the critical speed.
In one embodiment of this invention, the same solvent system(s) may be used in each column, and the respective flow rates may be varied so that the desired product may be extracted into either phase. The respective flow rates may be determined using routine experimentation and computer simulation using, for example, the above-mentioned computer program.
The processes of this invention may result in a highly pure product, in particular when combined, for example, with distillation, precipitation and/or crystallisation steps. After a crystallisation step, solvent(s) may be distilled off, collected and recycled. The product may be obtained in known solid form.
The process of this invention may be applied to the purification of, for example, cyclosporins to achieve purity greater than 98.5%, e.g. 99.3% or greater by area using HPLC, and improved overall yield compared to chromatographic purification.
The order of extraction used in the two-step process of this invention may be reversed: the less polar impurities may be removed from the impure product in the first column, and the more polar impurities removed in the second column. If the product to be purified is to be separated from a single impurity, or only from less polar components, or only from more polar components, the process may be adapted to include a single extraction step, for example, only above step a) or only step b).