Patent Application
20090258041
The present invention relates to the use of encapsulated forms of certain antioxidants, especially for the protection and stabilization of active ingredients in a cosmetical or pharmaceutical formulation. The protection is most effectively achieved by coencapsulation together with the active agent. The invention further relates to corresponding cosmetical or pharmaceutical compositions, and to the use for the preparation of medicaments or formulations for the treatment of radical induced impairments such as inflammatory or allergic conditions, collagen damages, DNA-damage, or reperfusion-damage (use as anti aging).
The use of certain phenolic antioxidants or amino compounds for the stabilization of cosmetics or household formulations has been proposed in WO 00/25731 and WO 03/103622. IPCOM000130489D (see e.g. under https://priorart.ip.com/viewPub.isp) inter alia suggests using such antioxidants for the protection of oxygen-sensitive components of the formulation.
It has now been found that certain antioxidants are especially useful when contained in a cosmetical or pharmaceutical formulation in encapsulated form. These antioxidants, which are selected from carbon or ester/amide bridged hindered phenoles, lactones of hindered phenoles, sterically hindered oxylamines and sterically hindered hydroxylamines, inter alia are suitable to protect other active ingredients, such as oxidizable natural substances or active ingredients such as vitamins, plant extracts, fragrances etc., from premature degradation or hydrolization, e.g. induced by light, oxygen and/or heat, especially when these antioxidants are encapsulated together with the ingredient (coencapsulation). Formulations may be purely cosmetical ones, or formulations making use of the pharmacological advantages of the active ingredient as well as the antioxidant. The formulations usually comprise at least one lipid phase and at least one water phase, preferably in the form of a microemulsion, microdispersion or especially nanoemulsion or nanodispersion. The present antioxidants further exhibit marked radical scavenging and antiinflammatory action in cellular and enzymatic in vitro assays and in in vivo assays on human volunteers, while showing good skin and cell compatibility. Damage of radicals in the organism of animals and humans, which may be prevented by the present antioxidants, has been described in further detail in U.S. Pat. No. 4,698,360. The use of the antioxidant is most advantageous for the protection of a vitamin such as vitamin A, E or C or modified form thereof.
Hindered phenoles are a group of antioxidants comprising active aromatic compounds containing at least one hydroxy substituent on an aromatic ring and one or two further aliphatic or aromatic substituents, often an alkyl group such as methyl or isopropyl or tert.-butyl or tert.-amyl, in ortho-position relative to said hydroxy substituent. Carbon bridged hindered phenoles contain at least one carbon bridging group, ester bridged hindered phenoles contain at least one ester (—COO— or —OCO—) bridging group, amide bridged hindered phenoles contain at least one amide (—CONR— or —NRCO—, where R usually is a carbon residue or hydrogen) bridging group. The bridging group(s) either link(s) 2 or more phenolic moieties together to form one single compound, or link(s) one phenolic moiety with an anchor group (such as an alkyl chain or an aromatic ring). In lactones of hindered phenoles, the (phenolic) hydroxy substituent has been esterified to form an annealed ring. Sterically hindered oxylamines and sterically hindered hydroxylamines each are tertiary amines containing 2 residues which are branched in alpha-position; as 3rd residue, the oxylamine contains an oxygen atom (thus being a radical), the hydroxylamine contains a hydroxy group.
Suitable antioxidants include compounds of the formulae
—CmH2m—NH; a radical of formula
or a radical of formula
or —S—; or G3 is propyl substituted by OH or C2-C22alkanoyloxy;
Compounds of the formula 1, where e is 1, usually contain the spacer groups Q and (CO)—V, which corresponds to the condition b=c=1. Also useful are the compounds of formulae
Encapsulation has been found to enhance the action of the antioxidant, especially where small particle sizes are achieved (e.g. size of the loaded particle in the nanoscale range of diameters lower than 300 nm or even lower than 100 or 50 nm, see further below). Present compounds can be used alone or as mixtures with each other and/or further components, e.g. those described further below. Present invention therefore includes a method for the protection of an active ingredient in a cosmetical or pharmaceutical formulation against premature degradation, e.g. by light, oxygen and/or heat, characterized in that at least one antioxidant is encapsulated, especially together with the ingredient. The active ingredient often is selected from oxidizable natural substances, vitamins, plant extracts, fragrances, especially the vitamins A, C, E. Though some stabilized forms of vitamins (hereinafter recalled as “modified forms”) have already been developed, e.g. vitamin esters or vitamin ester salts such as vitamin A palmitate, vitamin C magnesium phosphate (ascorbyl 2-phosphate magnesium salt), sodium ascorbyl 2-phosphate 6-palmitate, vitamin E acetate, there is still need for improvement of the stabilization of the free substances as well as of these modified forms, which is advantageously effected by the present invention.
Active ingredients to be stabilized according to the invention further include the group consisting of
H(CH2)n(CHR)COOH (1)
CH3(CH2)mCH═CH(CH2)nCOOH (2)
where R is hydrogen atom or OH group, m, n are integral numbers from 0 to 22 where m+n sum is maximally 22;
H(CH2)n(CHR)COOH (3)
CH3(CH2)mCH═CH(CH2)nCOOH (4)
where R is hydrogen atom or OH group, m, n are integral numbers from 0 to 20 where m+n sum is maximally 21;
The present compositions, e.g. those containing an antioxidant of formulae (1), (2) and/or (3), and optionally a further active ingredient such as a vitamin, are useful for the treatment of inflammatory and allergic conditions (e.g. as described by Skaper et al., Free Radical Biology and Medicine 22, 669-78 (1997)), as well as for the treatment of conditions involving disturbances of cell proliferation. They are preferably used for the local treatment of radical-induced adverse reactions such as inflammatory and allergic conditions collagen damage, reperfusion damage, DNA-damage; especially for the skin treatment.
In vitro assays show that the present compositions inhibit the formation of different mediators that are an important factor in inflammation.
The hindered nitroxyl, hydroxylamine and hydroxylamine salt compounds (3) are for example of formulae A to EE and A* to EE* as described in IPCOM000130489D.
C1-C22Alkyl is straight-chain or branched alkyl radicals, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl or eicosyl.
C1-C22Alkylthio is straight-chain or branched alkylthio radicals, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, amylthio, heptylthio, octylthio, isooctylthio, nonylthio, decylthio, undecylthio, dodecylthio, tetradecylthio, pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio or eicosylthio.
C2-C22Alkylthioalkyl is alkylthio as described above attached by its sulfur atom to alkyl, where the total residue contains 2-22 carbon atoms.
C2-C18Alkenyl is, for example, allyl, methallyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methyl-but-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, isododecenyl, n-dodec-2-enyl or n-octadec-4-enyl.
C5-C7Cycloalkyl is cyclopentyl, cycloheptyl or, preferably, cyclohexyl.
C7-C9-Phenylalkyl includes phenylpropyl (such as cumyl), phenylethyl and, preferably, benzyl.
M as alkali often is Li, Na, K, Cs.
Useful compounds of present formulae (1) and (2) include those listed in Table 1:
Most preferred antioxidants are compounds Nos. 30 (referred to as AO6 in the below examples) and 31 (referred to as AO7 in the below examples).
Useful hindered amine compounds (3) include those mentioned in IPCOM000130489D; preferred hindered nitroxyl, hydroxylamine and hydroxylamine salt compounds of formula (3) are selected from 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidine; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium chloride; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium acetate; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium bisulfate; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium citrate; bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate; tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate; tetra(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) ethylenediaminetetraacetate; tetra(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) ethylenediaminetetraacetate; tetra(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium) ethylenediaminetetraacetate; penta(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) diethylenetriaminepentaacetate; penta(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) diethylenetriaminepentaacetate; and penta(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium) diethylenetriaminepentaacetate. For example, the compounds of formula (3) are hydroxylamine salts selected from 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium citrate; bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate; tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium DTPA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA; pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA; 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium EDTA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA; 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium citrate; bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) citrate; tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) citrate; 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium DTPA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA; pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA; 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium EDTA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA; 1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium citrate; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) citrate; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) citrate; 1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium DTPA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) DTPA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) DTPA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) DTPA; pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) DTPA; 1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium EDTA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) EDTA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) EDTA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA; 1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium citrate; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) citrate; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) citrate; 1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium DTPA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA; tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA; pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA; 1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium EDTA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) EDTA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) EDTA and tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) EDTA.
The above named counter-ions are ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA) or diethylenetriaminepentamethylenephosphonic acid (DTPMPA).
G1 and G2 preferably are, independently of each other, C1-C1-8alkyl and, in particular, C1-C5alkyl, especially tert.-butyl. In preferred compounds of the formula (1) or (2), G1 is located in meta-position relative to G2.
G3 is most preferred as hydrogen; C1-C22alkyl; SO3M; propyl substituted by OH and/or by C2-C22alkanoyloxy; a direct bond; —CH2—;
propyl substituted by OH or C2-C22alkanoyloxy;
Preferred G4 and G5 independently are H or C1-C4alkyl, especially methyl.
Of specific technical interest are those compounds of the formula (1) containing a thio group, i.e. those wherein G1 and/or G3 are selected from alkylthio, alkylthioalkyl, —S—.
It is preferred to use compounds of formula (1) and/or (2), especially wherein
or propyl substituted by OH or C2-C22alkanoyloxy;
or propylene substituted by OH or C12-C22alkanoyloxy;
where M is alkali and q is 0 or 1;
or propyl substituted by OH or C2-C22alkanoyloxy; where M is alkali and q is 0 or 1;
Most preferred compound of the formula (3) is of the formula
or is an acid addition salt thereof, especially as defined above.
Particularly interesting compounds (1) include those of formula
wherein
G1 and G2 are each independently of the other C1-C5alkyl, or G1 and G2 especially are 2,6-ditert.butyl;
a is 1 or 2, especially 1; and
G3, Q, V, T, b, c, d and e have the meanings cited for formula (1), or especially
b is 1 and Q is ethylene;
d is 1 and T is CH2 or phenylene; and
e is 1 and G3 is H. C1-C1-8alkyl such as methyl or C1-7alkyl, or is SO3Na; or
e is 4 and G3 is a carbon atom;
or each of b, c and d is 0, e is 2 and G3 is methylene or ethylidene.
Most preferred compounds are those of formula (1), especially wherein G1 and G2 are the tert-butyl radical; and a is 1.
It is also preferred to use compounds of formula
wherein
G1 and G2 are each independently of the other C1-C5alkyl;
G3 is a direct bond; —O—; —S—; —CH2—; or
a is 1 or 2;
m is 1 to 5; and
T has the meaning cited in formula (1).
Interesting compounds of formula (1) are those, wherein
Q is ethylene; or
G3 is a direct bond.
Likewise preferred are compounds of formula
wherein
G1 and G2 are each independently of the other C1-C5alkyl;
G3 is the radical of formula (1g); (1h); (1i); or (1k);
m and n are each independently of the other 1 to 3;
a is 1 or 2; and
b and d are each independently of the other 0 or 1.
Other antioxidants which are preferably used conform to formula
wherein
A is a radical of formula
Other preferred antioxidants are those of formula
wherein
B is a radical of formula
A number of present antioxidant compounds, e.g. those of formulae (1), (2) and (3), previously have been known as antioxidants for plastics and certain other organic materials.
Within the present invention, they can be used as individual compounds or as mixtures of several individual compounds. Some of the present antioxidants, essentially those of formula (1) wherein e is 2, 3 or especially 4 and those of formula (2), combine high antioxidant activity and tissue/skin compatibility with rather low solubility in water. Encapsulation of these compounds, especially in nanoscaled particles such as described further below, brings about the further advantage that a higher loading and activity of these compounds in the final formulation may be achieved than by mere addition (without encapsulation).
A preferred subject of the invention therefore is a cosmetical or pharmaceutical composition containing an antioxidant of the formula (1) wherein e is 2, 3 or especially 4, or of the formula (2), encapsulated in a lipid particle. Representative examples for these “lipophilic” antioxidants are compounds Nos. 7-15, 17, 19, 23-27, 29, 31 and 33 listed above; most preferred among them are compounds Nos. 9, 29 and especially 31 (denoted in the below examples as AO4, AO4, AO5, AO7).
One of the forms of such a composition is a liquid microemulsion or microdispersion containing the antioxidant loaded particles as the dispersed phase in an aqueous continuous phase. The composition may, however, be in a solid or semisolid form as well, as explained further below. Preferred methods of encapsulation and preparation of such a composition, as well as properties thereof, are also described further below.
Present antioxidants, e.g. those of formulae (1), (2), (3), can also be incorporated together with further components, especially coencapsulated oxidizable and/or lipophilic components such as those described in IPCOM000130489D. Also of importance is the concomitant use of a more “hydrophilic” antioxidant of formula (1), where e is 1 (such as the compound AO6), or of formula (3) and/or a further active ingredient, in free form, e.g. in the continuous phase of a corresponding microemulsion or microdispersion.
The antioxidant component, the optional further active ingredient component, and an optional further component apart from the carrier, each is usually contained within the concentration range from 0.0001% to 10% of the total weight of the preparation/composition %, and most preferably from 0.0005 to 5% by weight of the total composition. If an active ingredient is present, the weight ratio of the antioxidant:active ingredient in the preparation/composition usually ranges from 1:10 to 10:1, preferably is larger than 1:1 such as from the range 1:1 to 10:1.
Of special technical interest is a preparation containing a vitamin such as vitamin C in free or modified form in an amount of at least 0.05% by weight, such as 0.05-1.0% by weight, and 0.05 to 2.0% by weight, preferably the same amount or more, of an antioxidant, with the encapsulated antioxidant being present in an amount of at least 0.05% by weight of the total preparation.
Further kinds of antioxidants useful for encapsulation according to the present invention include components that interrupt the photochemical reaction chain triggered when UV radiation penetrates the skin or hair. Typical examples of such antioxidants are amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g. urocanic acid) and derivatives thereof, peptides, such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g. anserine), carotinoids, carotenes, lycopene and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g. dihydrolipoic acid), aurothioglycose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl and glyceryl esters thereof) and also salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and also sulfoximine compounds (e.g. buthionine sulfoximines, homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, hepta-thionine sulfoximine), also (metal) chelating agents (e.g. hydroxy fatty acids, palmitic acid phytic acid, lactoferrin, chitosan and derivatives such as phosphonomethylated chitosan) and preferably those disclosed in U.S. Pat. No. 5,487,884; WO91/16035; WO91/16034; hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g. linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (e.g. vitamin E acetate), vitamin A and derivatives (e.g. vitamin A palmitate) and also coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and salts thereof, for example the disodium salts), zinc and derivatives thereof (e.g. ZnO, ZnSO4), selenium and derivatives thereof (e.g. selenium methionine), stilbene and derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide) and the derivatives suitable according to the invention (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of those mentioned active ingredients. Further HALS (“Hindered Amine Light Stabilizers”) compounds may also be mentioned.
Further synthetic and natural antioxidants are listed e.g. in WO 00/25731 (see e.g. structures 1-3 (page 2), structure 4 (page 6), structures 5-6 (page 7) and compounds 7-33 (page 8-14)).
The preparation for topical application may additionally contain at least one further component with anti-inflammatory effect as active ingredient, preferably from 0.01% to 10% more preferably about 0.5% to about 5%, of the composition, such as:
R1(CH2)m-(CHOH)—(CH2)nR2 (5)
where R1 and R2 are hydrogen atoms or OH group, m, n are integral numbers from 0 to 17 where m+n sum is maximally 21;
phytosterols and their polyethoxylate derivatives of the general formulas (6) and (7) below, where R is isoalkyl or isoalkenyl group with 8-10 carbon atoms, where n is integral number from 0 to 50, especially campesterol, β-sitosterol, stigmasterol, cholesterol, Δ-5-avenasterol, Δ-7-avenasterol, brassicasterol, spinasterol and fukosterol
The cosmetical or pharmaceutical compositions include liquid, semisolid or solid preparations.
Examples of liquid compositions are injectable solutions, infusion solutions, drops, sprays, aerosols, emulsions, lotions, suspensions, drinking solutions, drinking gargles and in-halants.
Examples of semisolid compositions are ointments, creams (O/W emul-sions), rich creams (W/O emulsions), gels, lotions, foams, pastes, suspensions, ovula, plasters, including applications for transdermal systems such as masks, compresses, pads.
Examples of solid compositions are tablets, coated tablets, capsules, gra-nules, effervescent granules, effervescent tablets, lozenges, sucking and chewing tablets, suppositories, implants, lyophilisates, adsorbates or powders.
The present compositions may also be used as food additives or dietary food or supplements, functional food, enriched foods, or for the preparation thereof.
Preferred are liquid or semisolid preparations.
Galenic compositions comprising the present compounds will be understood as meaning in particular emulsions, ointments, gels, sprays and powders; for example creams, gels, lotions, alcoholic and aqueous/alcoholic solutions, emulsions, wax/fat compositions, stick preparations such as lip sticks or deodorants, powders or ointments.
The final formulations listed may exist in a wide variety of presentation forms, for example:
Several particulate formulations, especially skin care delivery systems, are:
A] Nanoemulsions and nanoparticles are mainly based on lecithin or fractionated phospholipids, especially
A nanoemulsion or nanodispersion creates a large surface-to-volume ratio for emulsion particles that contact skin. Thus, more active ingredients contact the skin at the surface-to-surface interaction between the emulsion and the skin. The components of the invention may, for example, be incorporated into the bi-layers, into the aqueous core or distributed in both.
B] Microcapsules with particle size>1 μm based on matrix or encapsulation layer (spherical system based on a core material containing the active; the core is, then, surrounded by one or several coating layers or shells).
Polymers used to form those microcapsules include natural gums, cellulosic ingredients, polysaccharides, synthetic polyacrylates or polyacrylamides, polyvinyl alcohol (PVA), lipids, inorganics (silicates/clays), high molecular weight proteins such as gelatin, albumin etc.; examples include Nylon micro-porous spheres (Orgasol range from Elf Atochem), Mineral fillers such as sericite surface-treated by bifunctional coating (reaction between reactive fatty acid derivatives and the aqueous solution of sericite); Glycospheres (core based on modified starch and outer lipid membrane based on fatty acids and polar lipids); carbon nanotubes; Silica shells, made of silicates, for non aqueous and solid end-products such as sticks, dry powders etc.
C] Matrix particulate systems which entrap the active ingredient within the uniform core matrix; examples:
According to a preferred method, the present compounds are applied in nanodispersed or encapsulated form of type [A] mentioned above, such as described in US-2005-0191330 (see especially sections [0007-0079], [0120-0133] and examples) and US-2003-0190347 (see especially sections [0005-0087] and examples).
The invention therefore includes a method for the encapsulation of an antioxidant, especially for the protection of an active ingredient, as initially described, wherein the encapsulation is achieved by mixing
(a) a membrane-forming molecule,
(b) a coemulsifier and
(c) a lipophilic component comprising an antioxidant,
until a homogeneous liquid is obtained.
The liquid thus obtained is then added to a water phase.
Component (a) is advantageously selected from the phospholipid classes or corresponding components described in US-2005-0191330 or US-2003-0190347.
Component (b) is preferably selected from polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty alcohols, polyethoxylated fatty acids, polyethoxylated vitamin E derivatives, polyethoxylated lanoline or lanoline derivatives, polyethoxylated fatty acid glycerides and partial glycerides, polyethoxylated alkylphenols, sulfuric acid semiesters of a polyethoxylated fatty alcohol or salt thereof, polyethoxylated fatty amines or amides, polyethoxylated carbon hydrates; the antioxidant of component (c) is preferably selected from compounds AO3-AO8 described further below, and especially are preferred as AO6 or AO7.
Lipophilic component (c) may also comprise the active ingredient, if this is to be coencapsulated together with the antioxidant for best protection. The lipophilic component often further comprises a cosmetically acceptable lipid; this may be selected, for example, from mono-, di- or especially triglycerides, especially of fatty esters, and/or other components such as (INCI-names): Propylene glycol, C12-15 alkyl benzoate, Diisopropyl adipate, Dioctyl adipate, Di-2-ethylhexyl succinate, Propylene glycol dicaprylate, Octyl octanoate Dioctyl terephthalate, Trioctyl citrate, Trioctanoin+, Octyl dodecanol, Caprylyl pyrrolidone, Triethyl citrate, 2-Butyl-1-octanol, Propylene carbonate, Dibutyl carbonate, Neopentyl glycol dioctanoate. Preferred for the antioxidant of formula 31 (i.e. AO7), for example, is a triglyceride (e.g. a C4-C18fatty acid triglyceride like those of the Miglyol®-series; CONDEA), or Diisopropyl adipate, Dioctyl adipate, Di-2-ethylhexyl succinate, Caprylyl pyrrolidone, Dibutyl carbonate.
The weight ratio of the antioxidant:cosmetically acceptable lipid in the prephase usually ranges from 1:10 to 10:1, preferably from 1:5 to 5:1.
The homogenous liquid thus obtained (i.e. the “prephase”) usually is clear (unless clouded by the active ingredient). It may contain one or more further components (d) such as an alcohol. In a preferred method, the homogeneous liquid obtained after mixing components (a), (b), (c) and optionally (d) is essentially anhydrous.
In a preferred method,
(a) 5 to 20% by weight of a phospholipid,
(b) 15 to 40% by weight of a coemulsifier,
(c) 30 to 70% by weight of a lipophilic component consisting of an antioxidant of formulae (1) to (3) as described above, and optionally a cosmetically acceptable lipid and/or an active ingredient selected from oxidizable natural substances, vitamins, plant extracts, fragrances; and optionally
(d) 0 to 30%, especially 3 to 30%, by weight of an alcohol, such as a C1-C5alkanol or C1-C5alkanediol, especially ethanol,
are mixed, with the sum of percentages of the components (a), (b), (c) and optionally (d) adding to 100%.
As described in US-2005-0191330 and US-2003-0190347 mentioned above, a microemulsion or microdispersion prepared in this way usually is obtained, for practical reasons, first as a concentrate, which is then employed for the preparation of the final ready-for-use preparation. The preparation step from the prephase to the concentrate usually brings about a dilution of the prephase of 1:5 to about 1:20. The concentrate may be further diluted (i.e. combined with further components) to obtain the final product; this is often done in the same ratio of 1:5 to about 1:20. Thus, the final product contains the ingredients of the prephase usually in a dilution from about 1:25 to about 1:400 or, more often, in a dilution of about 1:50 to about 1:200, free components added as part of a diluting phase not included. Formulations as described in the present invention encompass prephase, concentrate as well as the final formulation ready for end use.
The nanodispersions obtained in the above process contain particles usually having an average diameter of less than 80 nm (e.g. 10-80 nm), typically of less than 50 nm, and preferably about 30 nm or less. The distribution typically is monodisperse and corresponds to a Gaussian distribution.
An example for a cosmetical or pharmaceutical composition is a nanodispersion, which is obtained by
mixing of
(a) 5 to 20% by weight of a phospholipid,
(b) 15 to 40% by weight of a coemulsifier,
(c) 30 to 70% by weight of a lipophilic component consisting of a triglyceride, an antioxidant of formulae (1) to (3), especially of formula (AO3), (AO4), (AO5), (AO6), (AO7), (AO8) as described below, and an active ingredient selected from oxidizable natural substances, vitamins, plant extracts, fragrances; and
(d) 3 to 30% by weight of an alcohol,
with the sum of percentages of the components (a), (b), (c) and (d) adding to 100%, followed by addition of the liquid thus obtained to a water phase. The composition thus obtained usually is then supplemented by further components, e.g. those important for the specific end use.
The composition may contain further components, e.g. as listed in WO00/25731, WO03/103622, IPCOM000130489D, or as mentioned in the below formulations.
Examples for end formulations containing the composition of the invention also include
Of special importance as preparations for the skin are daily care and/or anti-aging preparations, including light-protective preparations, such as sun milks, lotions, creams, oils, sunblocks or topicals, pretanning preparations or after-sun preparations, also skin-tanning preparations, for example self-tanning creams, skin whitener preparations, skin lightener preparations or combinations of such systems. Of particular interest are anti-aging preparations in combination with UV-protecting systems such as dayly care creams, dayly care lotions, dayly care milk and dayly care preparations in the form of a spray.
The compositions/preparations according to the invention may, where appropriate, also contain one or one more additional compounds as described below, especially in preparations for skin treatment; examples include
Fatty alcohols, Esters of fatty acids, Other adjuvants,
Natural or synthetic triglycerides including glyceryl esters and derivatives,
Pearlescent waxes, Hydrocarbon oils,
Silicones or siloxanes (organosubstituted polysiloxanes) such as dimethicone and related substances,
Fluorinated or perfluorinated oils, Emulsifiers, Adjuvants and additives, Super-fatting agents, Anti-wrinkle actives, Skin lightening agents, Surfactants,
Consistency regulators/thickeners and rheology modifiers, Polymers,
Biogenic active ingredients, Deodorising active ingredients, Anti-dandruff agents,
Hydrotropic agents, Preservatives and Bacteria-inhibiting agents, Perfume oils, Colourants, and/or Other adjuvants, such as the components listed in IPCOM000130489D under these headlines.
Present components usually are used in cosmetical or pharmacological compositions with conventional carriers; further useful components include penetration enhancers, for example urea, dextrane, propylene glycol, oleic acid and the like.
The cosmetical or pharmaceutical composition will usually contain each of the present components antioxidant and further ingredient in amounts of 0.001 to 10% by weight, preferably of 0.01 to 5%, especially 0.01 to 2% by weight, of the final ready-to-use formulation. For the treatment of the conditions listed hereinabove, the pharmaceutical composition of this invention may contain, in addition to the present compounds, further pharmaceutical or cosmetic agents, e.g. having antiphlogistic activity, typically including antiinflammatory agents, vitamins, and/or, where appropriate, antipsoriatic agents, further skin actives, cell proliferation regulators, antiallergic, UV protecting, moisturizing, antiageing, gastroprotective, antiasthmatic agents, DNA-protectants.
The composition of this invention may contain antioxidants and/or light stabilisers apart from present formulae (1)-(3), especially UV absorbers. Suitable components of these classes include those described in EP-A-955355, WO00/25730, WO00/25731, WO03/103622, EP-A-1366763.
Examples are components listed below:
As water- and oil-containing emulsions (e.g. W/O, O/W, O/W/O and W/O/W emulsions or microemulsions) the preparations contain, for example, from 0.1 to 30% by weight, preferably from 0.1 to 15% by weight and especially from 0.5 to 10% by weight, based on the total weight of the composition, of one or more UV absorbers, from 1 to 60% by weight, especially from 5 to 50% by weight and preferably from 10 to 35% by weight, based on the total weight of the composition, of at least one oil component, from 0 to 30% by weight, especially from 1 to 30% by weight and preferably from 4 to 20% by weight, based on the total weight of the composition, of at least one emulsifier, from 10 to 90% by weight, especially from 30 to 90% by weight, based on the total weight of the composition, of water, and from 0 to 88.9% by weight, especially from 1 to 50% by weight, of further cosmetically acceptable adjuvants.
Cosmetic or pharmaceutical preparations in general can be prepared by physically mixing the active component(s) with the adjuvant using customary methods, for example by simply stirring together the individual components.
Examples for compounds especially useful in the present invention include those listed below:
AO3: Reaction product of glycerine, coconut oil and a compound of the formula
AO5 is a mixture of the compounds of the formulae:
AO7: pentaerythritol-tetrakis(3-[3′,5′-di-tert.butyl-4′-hydroxyphenyl]-propionate)
The following Examples will serve to illustrate the invention without implying any restriction to what is described therein. Unless otherwise indicated, percentages are by weight (% w/w; % b.w.). The abbreviation “qs” denotes a percentage adjustable to fulfill product specifications; e.g. fragrance: 0.1-0.2%; colorant 0.05-0.2%.
A clear homogenous prephase is obtained by mixing
(a) 5 to 20% by weight of a phospholipid (e.g. lecithin),
(b) 15 to 40% by weight of a coemulsifier (e.g. a polyethoxylated sorbitan fatty acid ester, polyethoxylated fatty alcohol, polyethoxylated fatty acid, polyethoxylated vitamin E derivative, polyethoxylated lanoline or lanoline derivative, polyethoxylated fatty acid glyceride or partial glyceride, polyethoxylated alkylphenol, sulfuric acid semiester of a polyethoxylated fatty alcohol or salt thereof, polyethoxylated fatty amine or amide, polyethoxylated carbon hydrate),
(c) 30 to 70% by weight of a lipophilic component consisting of a triglyceride, a compound of the invention such as AO3-AO8, and optionally a further active agent, where the weight ratio of active agent(s):triglyceride usually ranges from 1:5 to 5:1, and
(d) 3 to 30% by weight of an alcohol such as ethanol,
with the sum of percentages of the components (a), (b), (c) and (d) adding to 100%,
and
adding the liquid obtained to a water phase. The water phase (e.g. 90 kg) is placed, with stirring (e.g. magnetic agitator), at 50° C. in a vessel. The liquid prephase (e.g. 10 kg) is added to the water phase with stirring (e.g. with a magnetic agitator). The formulation thus obtained may be further diluted or admixed.
Good results are also achieved when compound AO7 is replaced by AO3, AO4 or AO5.
The preparation is pleasantly cooling and has good antiphlogistic action.
Good results are also achieved when compound AO3 is replaced by AO7, AO6 or AO8.
Day Cream with UV Protection (O/W)
A) Coencapsulation Together with the Antioxidant:
C) Coencapsulation Together with the Antioxidant Plus Free Antioxidant:
Concentrated dispersions of high stability are thus obtained.
Good results are also achieved when compound AO7 is replaced by AO3, AO4 or AO5.
Aqueous solution of Vitamin C (concentration=40.5 mM), buffered at pH=6 (Phosphate buffer, previously evacuated and then flushed with Nitrogen to remove as much Oxygen as possible).
Absorption measurement with Perkin Elmer Lambda 16; cuvette length d=0.1 cm Irradiation chamber Atlas CPS+; temperature of measurement=35° C.
Spectral absorption of Vitamin C (Ascorbic Acid) at its maximum wavelength (Imax=265 nm); maximum extinction at time after exposure to air with storage in the dark. Experiments were done at 20° C.
Vitamin C is efficiently protected by the encapsulated antioxidant.
A nanodispersion prephase is prepared by mixing the following components:
The nanodispersion (concentrate) is generated by combining 5% to 50% b.w., and most preferably from 10% to 30% b.w., of the prephase to deionized water (ad 100%) with stirring.
The final formulation is then obtained using from 0.1% to 90%, usually from 0.1% to 20%, of the concentrate (based on the total weight of the cosmetic or pharmaceutic application).
Each formulation listed below is obtained by mixing the parts indicated in a table.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2005/055475 | Oct 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/063421 | 6/21/2006 | WO | 00 | 4/14/2008 |
