A process for producing solid dosage forms, in which (i) a plastic mixture of at least one pharmacologically acceptable polymeric binder with a K value of more than 75, at least one pharmaceutical active ingredient and, where appropriate, conventional pharmaceutical additives is prepared and (ii) the plastic mixture is shaped to the required dosage form, with step (i) being carried out under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as the difference in the K value, is less than 15 is described.

The invention relates to a process for producing solid dosage forms, in particular solid pharmaceutical dosage forms.
A continuous process for producing solid pharmaceutical forms has been known for some time and entails extruding an active ingredient-containing, solvent-free melt of a polymeric binder, and shaping this extrudate to the required drug form, for example in a calendar with molding rolls, see EP A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105 (melt extrusion). It is possible in this way to achieve specific shaping. Employed as polymeric binder are, in particular, polymers of N-vinylpyrrolidone or copolymers thereof, e.g. with vinyl acetate.
The known process has the disadvantage that polymeric binders with a K value of more than 75, in particular homo- or copolymers of vinylpyrrolidone, cannot be processed because they show crosslinking, discoloration or decomposition at the required temperatures and/or residence times in the extruder. Ancillary substances customary in pharmaceutical technology, such as polyvinylpyrrolidone with a K value of 90, have therefore not been usable to date for producing dosage forms by extrusion. The use of polymeric binders with high K values is of interest for producing solid solutions which permit slow release of active ingredient.
It is an object of the present invention to provide a process for producing solid dosage forms by shaping a plastic mixture which allows high molecular weight polymeric binders to be used.
We have found that this object is achieved by controlling the temperature and the shear energy input during the process.
The present invention therefore relates to a process for producing solid dosage forms, in which (i) a plastic mixture of at least one pharmacologically acceptable polymeric binder with a K value of more than 75, at least one pharmaceutical active ingredient and, where appropriate, conventional pharmaceutical additives is prepared and (ii) the plastic mixture is shaped to the required dosage form, with step (i) being carried out under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as the difference in the K value, is less than 15, preferably less than 10.
Dosage forms mean in this connection all forms suitable for use as drug products, plant treatment products, animal feed products and human food products and for delivering fragrances and perfume oils. These include, for example, tablets of any shape, pellets, granules, but also larger forms such as cubes, blocks (bricks) or cylindrical forms, which can be used, in particular, as animal or human food products.
The dosage forms obtainable according to the invention generally comprise:
a) from 0.1 to 90% by weight, in particular 0.1 to 60% by weight (based on the total weight of the dosage form) of an active ingredient,
b) from 10 to 99.9% by weight, in particular 40 to 99% by weight, of a polymeric binder and
c) where appropriate additives.
The polymeric binder has a K value of more than 75, in particular more than 80, preferably more than 85 and particularly preferably 90-200. The K values are determined by the method of H. Fikentscher, Cellulose-Chemie, volume 13, (1932) 58-64 and 71-74, in aqueous solution or in an organic solvent at 25xc2x0 C., at concentrations which are between 0.1% and 5% depending on the K value range. The K value of water-soluble polymers is generally determined in aqueous solution. If the polymer is not completely soluble in water, solvents such as THF, acetone, alcohols, e.g. ethanol, are employed.
Step (i) in the process according to the invention is carried out under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as difference in the K value, is less than 15, preferably less than 10. The skilled worker is able easily to establish suitable process parameters on the basis of simple tests. For this purpose, the K value of the polymeric binder in the resulting dosage form is determined and compared with the K value of the polymeric binder employed. The process parameters can be varied so that, while the mixing is adequate, the reduction in molecular weight of the polymeric binder is minimized.
Suitable binders are polymers, copolymers, cellulose derivatives and starch derivatives, for example:
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate or vinyl propionate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, polyacrylamides, polyethylene glycols, polyvinylformamide (where appropriate partially or completely hydrolyzed), cellulose esters, cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylethylcellulose, cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and mannans, in particular galactomannans. Of these, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxy alkylacrylates), poly(hydroxyalkyl methacrylates), polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses are particularly preferred.
Homo- or copolymers of vinylpyrrolidone, in particular those with at least 1% by weight, preferably at least 10% by weight, particularly preferably at least 25% by weight and, in particular, at least 50% by weight of vinylpyrrolidone units, are preferred. Suitable comonomers are vinyl esters of aliphatic C2-C24-carboxylic acids, such as vinyl acetate or vinyl propionate; C1-C24-alkyl(meth)acrylates, such as methyl methacrylate, ethyl acrylate, stearyl(meth)acrylate; vinyl ethers, such as methyl vinyl ether. Hydrophobic comonomers are generally preferred.
The polymeric binder must soften in the complete mixture of all the components in the range from 70 to 300xc2x0 C., preferably 80 to 250xc2x0 C., to form a plastic mixture. The glass transition temperature of the mixture must therefore be below 250xc2x0 C., preferably below 200xc2x0 C.
In preferred embodiments, the glass transition temperature is reduced by adding pharmacologically acceptable plasticizing ancillary substances. The amount of plasticizer is generally from 0.5 to 30, preferably 0.5 to 15, % of the total weight of the mixture.
Examples of such plasticizers are:
long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butandiols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, aromatic carboxylic esters (e.g. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacic esters, azelaic esters, citric and tartaric esters), fatty acid esters such as glycerol monoacetate, glycerol diacetate or glycerol triacetate or sodium diethyl sulfosuccinate, of which polyethylene glycols and polyethylene/propylene glycols are preferred.
The use of a plasticizer reduces the softening point of the polymeric binder. The formation of the plastic mixture and the shaping can take place at lower temperatures, which limits the reduction in molecular weight.
In preferred embodiments, the plastic mixture also contains pharmaceutically acceptable antioxidants. These can be used in an amount of from 0.001 to 10%, preferably 0.01 to 5%, of the total weight of the mixture. Examples of suitable antioxidants are gallic esters, ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, nordihydroguajaretic acid, 2,6-di-tert-butyl-4-methylphenol, alkali metal or alkaline earth metal sulfites or bisulfites and mixtures thereof.
The additional use of antioxidants makes it possible to limit further the reduction in molecular weight of the polymeric binder in the process according to the invention.
Examples of conventional pharmaceutical ancillary substances, the total amount of which can be up to 100% of the weight of the polymer, are extenders or bulking agents such as silicates or diatomaceous earth, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or salts thereof, e.g. the magnesium or calcium salt, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of from 0.02 to 50, preferably 0.20 to 20, % of the total weight of the mixture;
Lubricants such as aluminum, magnesium and calcium stearates, talc and silicones, in a concentration of from 0.1 to 5, preferably 0.1 to 3, % of the total weight of the mixture;
Flow regulators such as animal or vegetable fats, particularly in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50xc2x0 C. or above. Triglycerides of C12, C14, C16 and C18-fatty acids are preferred. Waxes such as carnauba wax can also be used, these fats and waxes can advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, in particular lecithin. The mono- and dyglycerides are preferably derived from the abovementioned fatty acid types. The total amount of fats, waxes, mono-, diglycerides and/or lecithins is 0.1 to 30, preferably 0.1 to 5, % of the total weight of the composition for the particular layer;
Dyes such as azo dyes, organic or inorganic pigments or dyes of natural origin, with inorganic pigments in a concentration of from 0.001 to 10, preferably 0.5 to 3, % of the total weight of the mixture being preferred;
Stabilizers such as light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
It is also possible to add wetting agents, preservatives, disintegrants, adsorbants, mold release and blowing agents (see, for example, H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).
Ancillary substances also mean for the purpose of the invention substances for producing a solid solution of the active ingredient. Examples of these ancillary substances are pentaerythritol and pentaerythritol tetraacetate, polymers such as polyethylene oxides and polypropylene oxides and block copolymers thereof (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40 stearate, and citric and succinic acids, bile acids, sterols and others as indicated, for example, by J. L. Ford, Pharm. Acta Helv. 61, 69-88 (1986).
Ancillary substances are also regarded as being additions of bases and acids to control the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind. 51, 98-101 (1989)).
The only precondition for suitability of ancillary substances is an adequate thermal stability.
Active ingredients mean for the purpose of the invention all substances with a physiological effect as long as they do not decompose under the processing conditions. They are, in particular, pharmaceutical active ingredients (for humans and animals), active ingredients for treating plants, insecticides, active ingredients for animal and human food products, fragrances and perfume oils. The amount of active ingredient per dose unit and the concentration may vary within wide limits depending on the activity and release rate. The only condition is that they suffice to achieve the desired effect. Thus, the concentration of active ingredient can be in the range from 0.1 to 95, preferably from 20 to 80, in particular from 30 to 70, % by weight. It is also possible to employ combinations of active ingredients. Active ingredients for the purpose of the invention are also vitamins and minerals. These vitamins include the vitamins of the A group, of the B group, meaning not only B1, B2, B6 and B12, and nicotinic acid and nicotinicamide, but also compounds with vitamin B properties such as, for example, adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid, and vitamin C, vitamins of the D group, E group, F group, H group, I and J groups, K group and P group. Active ingredients for the purpose of the invention also include therapeutic peptides. Plant treatment agents include, for example, vinclozolin, epoxiconazole and quinmerac.
The process according to the invention is suitable, for example, for processing the following active ingredients:
acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir, alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, amino acetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium-hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, chloramphenicol, chlorhexidine, chlor-pheniramine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulalic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, folinic acid, furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, imipramine, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, itraconazole, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, pentoxifylline, phenobarbital, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, selegiline, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolon-acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, zidovudine.
Preferred active ingredients are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
To produce the solid dosage forms, a plastic mixture of the components is prepared and then subjected to a shaping step. The mixing of the components and the formation of the plastic mixture can take place in various ways. The mixing can take place before, during and/or after the formation of the plastic state. For example, the components can be first mixed and then softened or be mixed and softened simultaneously. If a homogenization of the plastic mixture takes place in order to obtain a thorough dispersion of the active ingredient, this must be carried out under low-shear conditions.
However, it has proven to be preferred, especially on use of sensitive active ingredients, first to soften and premix the polymeric binder, where appropriate together with conventional pharmaceutical additives, and then to mix in (homogenize) the sensitive active ingredient(s) in plastic phase with very short residence times in intensive mixers. The active ingredient(s) can moreover be employed in solid form or as solution or dispersion.
The components are generally employed as such in the production process. However, they can also be used in liquid form, i.e. as solution, suspension or dispersion.
A suitable solvent for the liquid form of the components is primarily water or a water-miscible organic solvent or a mixture thereof with water. However, solvents which can be used are also water-immiscible organic solvents. Suitable water-miscible solvents are, in particular, C1-C4-alkanols such as ethanol, isop-opanol or n-propanol, polyols such as ethylene glycol, glycerol and polyethylene glycols. Suitable water-immiscible solvents are alkanes such as pentane or hexane, esters such as ethyl acetate or butyl acetate, chlorinated hydrocarbons such as methylene chloride, and aromatic hydrocarbons such as toluene and xylene. Another solvent which can be used is liquid CO2.
The solvent used in the particular case depends on the component to be taken up and its properties. For example, pharmaceutical active ingredients are frequently used in the form of a salt, which is generally soluble in water. Water-soluble active ingredients can therefore be employed as aqueous solution or, preferably, be taken up in the aqueous solution or dispersion of the binder. A corresponding statement applies to active ingredients which are soluble in one of the solvents mentioned if the liquid form of the components used is based on an organic solvent.
It is possible where appropriate to replace the softening by dissolving, suspending or dispersing in the abovementioned solvents, if desired and/or necessary with the addition of suitable ancillary substances such as emulsifiers. The solvent is then generally removed to form the plastic mixture in a suitable apparatus, e.g. a kneading and plasticating device. This will be comprised by the term mixing hereinafter.
The softening and mixing take place under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as difference in the K value, is less than 15. The device used for this purpose must be selected on this basis. Twin screw extruders conventionally used for melt extrusion are usually unsuitable. The linking of the melting and mixing step in the extruder requires, in order to bring about adequate mixing, a relatively long residence time in a zone with high shear. This may result in local overheating and an excessive reduction in the molecular weight of the binder. It must also be borne in mind that, to avoid damage to the polymeric binder, the temperature cannot be increased indefinitely. However, the polymeric binders with a K value of more than 80 which are employed according to the invention have a very high viscosity at comparatively low temperatures. Twin screw extruders may be prone to blockage under these conditions.
It has emerged that the process according to the invention can advantageously be carried out in a continuously operating kneader. Preferred kneaders have a shaft which is provided with a screw flight in a cylindrical housing, and the shaft executes an axial movement to and fro in addition to the rotational movement about its own axis. The screw flight preferably has a plurality of interruptions, and the housing has fixed kneading cogs which pass through the interruptions during the movement of the shaft to and fro. Continuously operating kneaders of this type are supplied by Buss under the name Ko-kneader.
The charging of the mixing and plasticizing device takes place continuously or batchwise, according to its design, in a conventional way. Powdered components can be introduced in a free feed, e.g. via a weigh feeder. Plastic compositions can be put in directly or via a gear pump, which is advantageous in particular when the viscosities and pressures are high. Liquid media can be metered in through a suitable pump unit.
The mixture obtained by mixing and/or softening the binder, the active ingredient and, where appropriate, the additive or additives is usually party to viscous (plastic). The glass transition temperature of the mixture is below the decomposition temperature of all the components present in the mixture. The binder should preferably be soluble or swellable in a physiological medium.
The process steps of mixing and softening can be carried out in the same apparatus or in two or more separately operating devices. The preparation of a premix can be carried out in one of the conventional mixing devices described above. Such a premix can then be fed directly, for example, into a continuous kneader and then be extruded, where appropriate with addition of further components.
It is also possible according to the invention to produce multilayer pharmaceutical forms by coextrusion, in which case a plurality of mixtures of the components described above are fed together in extrusion die so that the required layer structure of the multilayer pharmaceutical form results. It is preferred to use different binders for different layers, employing in one layer a binder with a K value of more than 75.
Multilayer drug forms preferably comprise two or three layers. They can be in open or closed form, in particular as open or closed multilayer tablets.
At least one of the layers contains at least one pharmaceutical active ingredient. It is also possible to include another active ingredient in another layer. This has the advantage that two mutually incompatible active ingredients can be processed or that the release characteristics of the active ingredient can be controlled.
The shaping takes place by coextrusion, with the mixtures from the individual extruders or other units being fed through a common coextrusion die. The shape of the coextrusion dies depends on the required pharmaceutical form. For example, dies with a flat orifice, called slot dies, and dies with an annular orifice are suitable. The design of the die depends on the polymeric binder used and the required pharmaceutical form.
The resulting mixture is preferably solvent-free, i.e. it contains neither water nor an organic solvent.
The plastic mixture is usually subjected to a definitive shaping. This may produce a large number of forms depending on the die and mode of shaping. For example, on use of an extruder, the extrudate can be shaped between a belt and a roll, between two belts or between two rolls, as described in EP-A-358 105, or by calendering in a calendar with two molding rolls, see, for example, EP-A-240 904. Further forms can be obtained by extrusion and hot or cold cut of the extrudate, for example small-particle and uniformly shaped pellets. Hot-cut pelletization usually results in lenticular dosage forms (tablets) with a diameter of from 1 to 10 mm, whereas cold-cut pelletization normally leads to cylindrical products with a length to diameter ratio of from 1 to 10 and a diameter of from 0.5 to 10 mm. It is thus possible to produce monolayer, but on use of coextrusion also open or closed multilayer dosage forms, for example oblong tablets, coated tablets, pastilles and pellets. The resulting pellets can then also be ground to powders and compressed to tablets in a conventional way. Micropastilles can be produced by the Rotoform-Sandvik process. These dosage forms can be rounded and/or provided with a coating by conventional methods in a downstream process step. Examples of materials suitable for film coatings are polyacrylates such as Eudragit types, cellulose esters such as hydroxypropylcellulose phthalates, and cellulose ethers such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose.
It is possible for solid solutions to be formed. The term xe2x80x9csolid solutionsxe2x80x9d is familiar to the skilled worker, for example from the literature cited at the outset. In solid solutions of active ingredients in polymers, the active ingredient is in the form of a molecular dispersion in the polymer.

Process for producing solid dosage forms


Disclosed are dry-feel emollient compositions comprising fatty alcohols, alkyl esters and jojoba wax esters obtained by a novel process of a base catalyzed alcoholysis reaction between jojoba oil and an alcohol, such as isopropyl alcohol. The composition is essentially solid at room temperature, can be provided in various shapes and sizes (especially as particulates such as spheres). These new compositions increase the range of applications for cosmetic compositions by providing an emollient that is more polar and hydrophilic than is found in naturally occurring jojoba oils (jojoba wax esters). These compositions have use in personal care, cosmetic, cosemceutical and pharmaceutical products. Typical materials these compositions may be blended include, but are not limited to, cosmetic oils and waxes, both natural and synthetic, hydrogenated or partially hydrogenated oils, silicone oils, mineral oils, long chain esters, vitamins, long chain fatty acids, alcohols, cosmeceuticals, pigments, botanical extracts, esters and ethers, dimers, trimers, oligomers, polymers, and the like. These compositions may be combined with active ingredients to be delivered by the compositions.

This invention relates to emollient compositions for use in cosmetic, personal care and pharmaceutical preparations. The invention particularly relates to such emollient compositions and processes for their preparation, and more particularly to jojoba ester compositions which function as a dry carrier and vehicle for the delivery of actives such as fragrances, vitains, medications, repellants, sun screens, cosmeceuticals (materials that combine a cosmetic and therapeutic effect) and the like.
In the field of cosmetic, personal care, and pharmaceutical products emollients are usually defined as an agent that softens or smooths the skin and which tend to reduce the roughness, cracking and irritation of the skin. This smoothing is believed to be effected by the penetration of the emollient into the surface layers of tissue, through the slight congestion induced by rubbing and massage upon application, and especially through interference with sensible and insensible water loss. The ancient Greek physician, Galen, is thought to have made one of the first emollients consisting of beeswax, spermaceti, almond oil, borax and rosewater.
Emollients tend to be bland, fatty, oleaginous substances which may be applied locally to the skin, mucous membranes, or abraded tissue. One of the benefits of emollients is their ability to exclude water-soluble irritants, air, and air-bome bacteria when a layer of emollient is present. At the present, there are numerous ingredients which function as emollients in a wide variety of products, and which ingredients may act in subtly different ways. For example, certain emollients sit on the surface of the skin and serve to impede water loss from the skin. Such ingredients are generally comprised of large molecules that form a hydrophobic barrier to help prevent water from leaving the surface of the skin. Examples of such emollients are lanolin, mineral oil, silicone derivatives and petroleum jelly.
A chief use of emollients is to provide vehicles for lipid-soluble drugs (as in balms, ointments and alcohol-based liniments). Although it has often been suggested that such emollient vehicles facilitate the transport of such drugs through the skin, it has been found that when the oil:water partition coefficient is greater than 1.0, the penetration of lipid-soluble drugs tends to be impeded. Emollient substances are commonly employed in cleansing and antiphlogistic creams and lotions. Compound ointment bases, creams, and other medical applications are also general areas of use for emollients. Amongst the more common emollient materials are castor oil, corn oil, cottonseed oil, rose water ointment, apricot kernel oil, avocado oil, grape seed oil, hazelnut oil, olive oil, sesame oil, theobroma oil, almond oil, myristyl alcohol, and recently other natural oils such as jojoba oil.
Other ingredients that have been used as emollients include a number of fatty acids derived from either plants or animal sources. Fatty acids generally comprise aliphatic hydrocarbon or other organic chains with carboxylic substituents on them, typically having between 8 and 24 carbon atoms in the chain backbone. Fatty acids are often used in creams, lotions, shaving creams, lipsticks and as pressing agents in pressed powders and blushes. Fatty acids which are used in cosmetics formulations generally include at least stearic acid, oleic acid, myristic acid and palmitic acid. Other typical fatty acids include linoleic acid, behenic acid, and other common fatty acids of the general formula CnH2n+1COOH.
Fatty alcohols are also used as emollients. They are said to be less sticky and less heavy than many other fatty materials, such as the fatty acids, and are frequently used to improve the viscosity and stability of lotions and creams. They also have utility in reactive hair dying and perming products. Examples of fatty alcohols which find use in the field of cosmetics and personal care products are cetyl alcohol, lauryl alcohol, stearyl alcohol and oleyl alcohol.
Additional examples of emollients are fatty esters. One of the best qualities of fatty esters is that they do not feel as oily to the touch as some other types of emollient fatty ingredients. Examples include isopropyl palmitate, isopropyl myristate and glyceryl stearate.
An important emollient is jojoba oil which is derived from the seed of the species Simmondsia chinensis. Jojoba is a seed oil with excellent skin feel. The oil is composed almost exclusively of wax esters, with little or no triglycerides present. A major portion of the production of jojoba oil is used by the cosmetic industry as an emollient in a variety of products.
The art of perfumery is an ancient skill with origins generally traced to the first Dynasty of Egypt, which was ruled by Menes sometime between 3500 and 500 BC. Sesame, almond and olive oils were used as solvents to extract the aromatics from vegetable materials and also as vehicles for delivery of the aromatics to the skin. Early Greek writers recorded the use of oils to xe2x80x9cfixxe2x80x9d or to retard evaporation of fragrance compounds. The early Romans showed little interest in perfumes and in fact perfumed unguents were forbidden in Rome by edict in about 188 BC. By the time Nero was Emperor in A.D. 54, the Romans had migrated into southern Italy and acquired a more intimate knowledge of the aesthetic side of life from the Greeks who occupied the area. Greeks and Romans used sesame, olive, or bean oils to extract and deliver the fragrance compounds and according to Pliny, resin and gum were added to xe2x80x9cfixxe2x80x9d the odor lest xe2x80x9cit is apt to die away and disappear with the greatest rapidity if these substances are not employed.xe2x80x9d The first alcoholic perfume base appeared in 1370 and was known as xe2x80x9cHungary Water,xe2x80x9d a name attributed to Queen Elizabeth of Hungary who first commissioned its preparation. The use of alcoholic bases to deliver fragrance compounds to the skin became the method of choice around the world. Some Middle Eastern regions still adhere to the more traditional use of sesame or olive oils as fragrance carriers.
Modem purveyors of perfumes and perfumed cosmetics have social and legal mandates to reduce the amount of Volatile Organic Compounds (VOC""s) released into the atmosphere by their products. Modern technology has also identified alcohol as an agent which dries the skin and therefore there has been a desire for xe2x80x9calcohol freexe2x80x9d cosmetic and personal care products. Additional carriers and vehicles for perfumes that are acceptable to the industry and consumers are also needed.
One of the problems with typical emollients is that the emollient itself provides a wet or oily feel to the applied areas. This can lead to an uncomfortable feeling or appearance to the user, which is very important in the cosmetic and pharmacological industry. An additive for cosmetic, personal care and topical treatment (medicament) products has been marketed under the name of xe2x80x9cConfettixe2x80x9d(trademark) (with different alphanumeric identifiers as to specific ingredients, e.g., Confetti(trademark) AL with allantoin, and Confetti(trademark) EA, MT, PA, RG and SG identifying the color of the material). This material is advertised as decorative microcapsules which contribute beneficial moisturizing and delivery of alcohol soluble ingredients to the skin. Confetti(trademark) is advertised as having a good balance of structural integrity and rub-in characteristics, rubbing into the skin completely without any extra pressure. The Material Safety Data Sheets (MSDS) on Confetti(trademark) products identifies them as containing a natural oil (e.g., coconut oil, tocopheryl acetate, retinyl palmitate), propylene glycol, synthetic beeswax, petrolatum, allantoin, PVM/MA Decadiene crosspolymer and benzophenone, as well as pigments and/or dyes.
Jojoba ester compositions have been found to function well as a dry carrier or vehicle for the application of active materials to the skin or hair of customers. These esters have been found to be useful in pure or blended forms as carriers or vehicles in the personal care, cosmetic, and/or pharmaceutical fields of use. The esters to be used may be provided with a range of properties (from the composition of the ester itself or from additives and blended materials) and can provide improved feel when used with other conventional carriers, vehicles, bases, actives and additives. Upon application and xe2x80x98rubbing inxe2x80x99 of the compositions, the jojoba ester based compositions leave the skin feeling soft (which is typical of high quality emollients), yet provide a mildly persistent coating which carries the actives without leaving a wet or oily feel to the skin of the user.
The present invention describes a very effective dry-feel emollient composition additive for use in personal care, cosmetic and pharmaceutical products and a novel method of producing that composition. The composition is essentially solid at room temperature, can be provided in various shapes and sizes (especially as spheres), and can be produced from combinations of fatty alcohols, isopropyl esters and wax esters obtained from the oil contained in the seed of the jojoba plant (Simmondsia chinensis), jojoba oil.
These new emollient compositions preserve the excellent skin feel attributed to jojoba oil, which has long been used as an emollient. These new compositions also increase the range of applications for cosmetic compositions through an emollient that is more polar and hydrophilic than is found in jojoba oils, (which may also be referred to in the art as jojoba wax esters). The composition forms stable emulsions much more readily than does jojoba oil. The composition may also further provide excellent emolliency to normally dry cosmetic systems involving high levels of pigments, with the emollient acting as a pigment wetting agent and as an aid to a smooth and even application of the dry system. It also functions as an excipient in pressed powder.
The compositions comprising fatty alcohols, isopropyl esters and jojoba wax esters (jojoba oil) may be obtained by the base catalyzed alcoholysis reaction between jojoba oil and an alkyl alcohol. In the alcoholysis reaction, examples of the base catalyst materials include, but are not limited to metal alkoxides and especially alkali metal alkoxides, inorganic hydroxides, especially alkali metal hydroxides, and the like such as NaOCH3 sodium methoxide, NaOCH2CH3 sodium ethoxide (potassium, calcium and lithium counterparts), KOH and NaOH (e.g., anhydrous alkali metal hydroxides in alcohol solution, with the alcohol of the solution being the alcohol used in the reaction).
The fundamental reactions used in the practice of the present invention may be generally considered in the following manner. Starting materials could include:
I. The Alcohol,
R4xe2x80x94OH (with isopropyl alcohol (IPA, HOxe2x80x94CHxe2x80x94(CH3)2) being primarily emphasized),
II. Jojoba Wax Esters
R1xe2x80x94COOxe2x80x94CH2xe2x80x94R1, and
III. Fully hydrogenated Jojoba Wax Esters
R2xe2x80x94COOxe2x80x94CH2xe2x80x94R2
wherein R4 is an alkyl group or other aliphatic group, preferably of 1 to 12 carbon atoms, more preferably an iso-alkyl group, and most preferably an isopropyl group,
R1 comprises CH3xe2x80x94(CH2)7xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(CH2)xxe2x80x94, and
R2 comprises CH3xe2x80x94(CH2)yxe2x80x94
wherein x is 6, 8, 10 and/or 12, and y is 16, 18, 20 and/or 22.
R4 comprises CnH2n+1xe2x80x94, wherein n=1 to 12.
Typical product components from the preferred synthetic reactions used in the practice of the present invention with jojoba oil may include:
Partially saturated wax esters:
IV. R1xe2x80x94COOxe2x80x94CH2xe2x80x94R2 and/or
V. R2xe2x80x94COOxe2x80x94CH2xe2x80x94R1,
(Where isopropyl alcohol was used) Iso-propyl esters
VI. R1xe2x80x94COOxe2x80x94CHxe2x80x94(CH3)2 [generically R1xe2x80x94COOxe2x80x94R4] and/or
VII. R2xe2x80x94COOxe2x80x94CH xe2x80x94(CH3)2 [generically R2xe2x80x94COOxe2x80x94R4] and Fatty alcohols comprising
VIII. R1 CH2xe2x80x94OH and/or
IX. R2CH2xe2x80x94OH.
The basic reactions which may be used in the preparation of the emollient compositions of the invention derived from jojoba oil may include at least the following procedures.
Reaction A I and IIn (catalyst)xe2x86x92VI, VIII and IIr. This product is referred to herein as xe2x80x9cFloraesters-IPJxe2x80x9d and is a liquid.
Reaction B I and IIIn (catalyst)xe2x86x92VII, IX and IIIr. This product is referred to herein as xe2x80x9cFloraesters-HIPYxe2x80x9d and is a solid.
Reaction C I, and IIn and IIIn (catalyst)xe2x86x92IV, V, VI, VII, VIII, IX, IIr and IIIr. This product is referred to herein as xe2x80x9cthe broad melting range emollientxe2x80x9d and the properties of the emollient depend upon the relative amounts of IIn and IIIn.
The subscripts n and r respectively represent n=the naturally occurring distribution of wax esters and r=the randomized distribution of wax esters resulting from rearrangements which occur during the reactions. It is to be noted that mixing of the reaction products from A and B will give emollients with a wide range of melting points, but will not be identical to the reaction product of C because of the absence of IV and V.
A process for producing an emollient may comprise the steps of:
a) providing a composition comprising jojoba oil,
b) adding an alcohol, e.g., having from 1 to 12 carbon atoms, to said composition,
c) effecting alcoholysis on said jojoba oil mixed with said alcohol to produce an emollient, and
d) effecting interesterification of remaining wax esters.
In preparing the emollient composition, refined jojoba oil (or hydrogenated jojoba oil or a mixture of the oil and hydrogenated oil) is introduced into an appropriate vessel (capable of excluding air) equipped with stirring and means of heating and cooling. The jojoba oil is first dried under vacuum at a temperature of 90 C. to remove most or all moisture. The anhydrous isopropyl alcohol (or other alcohol) is then added with the amount of isopropyl used being from about 20% to about 50% by weight of jojoba oil. The reactor is sealed and heat is applied to bring the temperature of the reaction mixture to about 70-75xc2x0 C. It is important that air be excluded and that the reactor be vented through a condenser to recover any unreacted alcohol. When the temperature has reached 70-75xc2x0 C., a first addition of catalyst (e.g., a catalyst for alcoholysis and interesterification such as sodium methoxide) is made. The amount added ranges from about 0.05 or from 0.1% to about 0.6% by weight of the jojoba oil with about 0.3% being preferred. After about 2 hours, a sample is taken and analyzed for the presence of the wax esters. If the wax ester content is greater than about 25% by weight, and it is desired to have a lower level of wax esters present in the reaction mixture, a second addition of catalyst is made, about 0.1% by weight of the original amount of jojoba oil. The reaction is then continued for an additional one hour. The reaction mixture is then sampled and analyzed again. If the residual wax ester content is less than about 25-35%, the reaction may be considered to be complete. Heating is discontinued but no cooling is applied. If the reaction is considered incomplete, a third catalyst addition may be made and the reaction continued as previously described. Any remaining catalyst can be neutralized and deactivated by the addition of citric acid. After about 15 minutes of agitation the neutralized catalyst (sodium citrate) is removed by filtration. Once the catalyst has been removed, any remaining isopropyl alcohol can be distilled from the product and the recovered isopropyl alcohol should be kept absolutely dry in order to be able to be used again.
As used in this description of the present invention, Floraesters 70 is III, Floraesters 15 is IIr, Floraesters 20, 30 and 60 are combinations of IIr, IV, V, and IIIr, Floraesters IPJ is a mixture of IIr, VI, and VIII, and Floraesters HIPJ is a combination of IIIr, VII and IX.
Jojoba oil and its derivatives comprise a family of wax esters which have melting points which range from 10 to 71xc2x0 C. At room temperature (xcx9c20xc2x0 C.), this family of esters varies from pourable liquids, to soft creams, to pasty waxes, to a brittle hard wax. Jojoba esters may be used individually or can be blended with the different melting point esters within the family to form products with selected melting points and specific physical properties or feel. These esters, whether exclusively jojoba esters or when combined with other carrier and vehicle components (including other emollients or binders) can form excellent carrier and vehicle or delivery compositions for use in the cosmetic, personal care and/or pharmaceutical field, including the cosmeceutical field where cosmetic compositions also provide pharmaceutical or other therapeutic benefits. Typical materials with which the jojoba esters may be blended in accordance with the practice of the present invention include, but are not limited to, cosmetic oils and waxes, both natural and synthetic, including hydrogenated or partially hydrogenated oils, silicone oils, mineral oils, long chain esters, vitamins (especially vitamin E), long chain fatty acids, alcohols, cosmeceuticals, pigments, botanical extracts, esters and ethers, dimers, trimers, oligomers, and polymers, and the like. These blended compositions may of course be combined with the active ingredients intended to be delivered by the compositions used in the present invention. The proportions of the jojoba esters should be chosen to provide the dry-feel to the composition which is highly desired. This will usually require at least 10%, often at least 20%, preferably at least 30%, more preferably at least 40 or 50%, by weight, and most preferably at least 60, at least 70, at least 80, and at least 90% (up to 100% by weight) by weight of carrier material (excluding solvent and actives) in the composition.
The dry-feel compositions of the present invention may be applied to the skin as particulate materials, usually in a cosmetic, personal care, cosmeceutical or pharmaceutical composition. The processes of making the particles generally provides them as spherical or oblong particles, but they may be shaped by pressing, molding, spray drying, atomization or other stresses to provide shaped particles, including platelets. The jojoba esters have particular properties which renders them especially suitable for use in fragrance dispensing compositions and topical applications, and those properties include their spreadability, emolliency, non-volatility, lack of color and lack of odor. The lack of odor is mildly important in pharmaceutical applications, but is viewed as particularly essential in the provision of fragrances. Perfume and cosmetic providers have extremely rigid standards on non-essential odor contribution in their products.
By skillful blending, a mixture of jojoba esters with fragrance oils can be prepared that melt at slightly below skin temperature. When formed into spherical particles and rubbed into the skin, these spherical particles disappear into the skin. Indeed they soften, melt and are adsorbed onto the surface of the skin where they deposit a layer of the jojoba esters containing fragrance. Jojoba esters are non-volatile and form an imperceptible film on the skin that slows down the release of the fragrance. These jojoba esters, being low in odor and superior skin emollients, provide an excellent carrier and delivery system for fine fragrances.
Spheres formed from the present invention which contain fragrance or perfume can be incorporated into a larger variety of cosmetic and personal care products for the purpose of providing emolliency to the skin. At the same time, these fragrances bearing spheres serve to deliver fragrance oils to the skin. Traditional methods of fragrance delivery utilize fragrance oils incorporated in alcohol, typically ethyl alcohol. These traditional carriers of fragrance oils are, by definition Volatile Organic Compounds (VOC""s) which evaporate into the air after being applied to the skin. The present invention provides a method to deliver fragrance oils to the skin and minimize VOC emissions.
Jojoba (Simmondsia chinensis) is a New World crop recently domesticated and now cultivated around the world in regions with a climate similar to the Sonora Desert of Arizona and northern Mexico where jojoba originated. Jojoba oil is extracted from the seed of the female jojoba bush. The oil is found in the seed at levels normally exceeding 50% by weight but usually less than 55%. This xe2x80x9coilxe2x80x9d is not a triglyceride such as sesame or almond oils, but is instead a long chain ester, typically 42 carbons in length and composed of monounsaturated fatty acids combined with monounsaturated fatty alcohols. The viscosity and appearance of jojoba oil are not unlike triglyceride oils although the tactile properties of jojoba oil render it an excellent xe2x80x9cnon oilyxe2x80x9d skin emollient. Jojoba has an unusual affinity for the skin. Unlike sesame oil or almond oil, jojoba oil is unusually resistant to oxidative degradation and rancidity. Jesuit missionaries in the southwestern USA and northern Mexico recorded the use of jojoba oil by the indigenous people of the area as a treatment for wounds and as a hair preparation.
Jojoba esters are prepared by processes described herein, which processes result in a randomized molecular combination of saturated with unsaturated jojoba fatty acids and fatty alcohols. These esters are a complex mixture of different jojoba fatty acids and fatty alcohols combined randomly and composed of differing chain lengths. The fatty acids and fatty alcohols may be either fully saturated, monounsaturated or with both the fatty alcohol and the fatty acid containing one point of unsaturation, as described above. The melting point, consistency, and physical appearance of these jojoba esters can be manipulated to produce a family of wax esters ranging from pourable liquids to hard, crystalline waxes.
Jojoba esters are excellent carriers of fragrance oil. As fragrance oil carriers they are not prone to the development of rancidity or other unpleasant odors, resulting in delivery of the fragrance compound to consumers in a form as near that created by the perfumer as possible. The physical form of the jojoba ester and fragrance oil system can be adjusted to accommodate any type of consumer product application desired. As an example, fragrance oils can be incorporated in liquid, pourable jojoba esters that at ambient temperatures can be used by a consumer in a manner similar to the traditional use of alcohol and fragrance oil blends. Jojoba esters containing fragrance oil can be formed into spheres and these spheres subsequently incorporated into cosmetic bases with a wide range of physical and chemical properties. In this spherical form (as a discontinuous phase or dispersed phase), the jojoba esters serve to minimize the level of contact of the fragrance oil with the cosmetic base (as a continuous phase). This is a desirable effect when the fragrance oil contains components that are not compatible with the cosmetic base, or vice versa. The particles are usually present as a dispersion of the particles in a flowable continuous phase carrying medium which is not a solvent for said particles. By flowable, it is meant that the carrying medium may be a liquid, higher viscosity fluid (such as a gel) or other material which can be spread by manual pressure in applications to the skin. The aspect of non-dissolvability of the particles within the carrying medium is desirable so that the particles do not dissolve into the carrying medium and destroy the dispersed nature of the combination. The combination may use a solvent carrier for the esters, if it is acceptable in the particular use to have the particles dissolved and the ester carried as a solute.
Individual jojoba esters or blends of the esters can be warmed to just above their melting point, a fragrance oil incorporated, and then the molten blend poured into a jar or other dispersing package where it will solidify upon cooling. The consistency of the blended product in the container can be adjusted to facilitate its application to the skin by use of the fingers or by a method of application using the packaging material.
Fragrance oils are normally compounded to exhibit a range of natural volatility. Jojoba esters function as xe2x80x9cfixativesxe2x80x9d which help control the premature release of volatile components of fragrance oils. This xe2x80x9cfixativexe2x80x9d function of jojoba esters can be manipulated for optimum compatibility with different fragrance oils by skillful blending of jojoba esters of different melting points, without the jojoba oil reacting with the fragrance oil. Jojoba esters in the present invention are utilized as oxidatively stable carriers of fragrance oils and are capable of being modified or blended in different ratios to arrive at the optimum xe2x80x9cskin feelxe2x80x9d and xe2x80x9cfixativexe2x80x9d function that might be desired.
The emolliency of jojoba is well known to those skilled in the art of cosmetic formulation. When applied to the skin, jojoba esters function as emollients to preserve and retain the natural moisture levels in the skin. Unlike volatile alcohols, jojoba esters are non-drying and in fact soften and moisturize the skin. The use of these jojoba esters as carriers for delivery of fragrance oils results in lower VOC emissions, a fixative effect for the fragrance oils, and also results in enhancing the moisture level of skin to which the jojoba esters are applied. When botanical extracts are incorporated with the jojoba esters, the esters also serve to disperse the botanicals evenly over the skin.
Typical Properties of Jojoba Esters:
This blend of Jojoba Esters and fragrance oil melts at approximately skin temperature and if desired, can be formed into small spheres for direct application to the skin or for incorporation in other cosmetic base formulas.
This blend of Jojoba Esters and fragrance oil is liquid at ambient temperature and can be applied to the skin in the manner of traditional perfumes.
This blend of two Jojoba Esters plus fragrance oil melts at just above skin temperature and is suitable for direct application to the skin or can first be formed into spheres for subsequent incorporation in other cosmetic bases.
This blend of three Jojoba Esters with fragrance oil has the consistency of a free flowing semi-solid paste. Application of stronger levels of fragrance which are long lasting on the skin are possible utilizing this carrier system.
This blend of three Jojoba Esters with fragrance oils is a non-flowing semi-solid which is appropriate for direct application to the skin. A pigment has been added to increase the visual impact of the invention.
This blend of two Jojoba Esters with fragrance oil includes a pigment selected for stability in high pH (greater than 8.0) aqueous cosmetic bases. This blend is suitable for formation into spheres and subsequent incorporation in cosmetic bases such as shower gels, facial creams, eye creams, body lotions, etc. The pigment has been selected for its compatibility with aqueous cosmetic bases.
Other compatible cosmetic ingredients may be added to any of the above formulas to achieve different melting points, flow characteristics, water resistance, etc. Examples of other cosmetic ingredients which may be suitable for addition to the above formulas are beeswax, castor wax, carnauba wax, vegetable oils, partially hydrogenated vegetable oils, surfactants such as Tween 60(trademark) or Tween 80(trademark), silicone preparations, fatty alcohols, fatty acids and fatty acid esters, alpha and beta hydroxy acids, vitamins (such as vitamin E, vitamin E acetate, vitamin A palmitate, beta caratene, vitamin C, etc.), herbal extracts, alpha-bisabolol, conjugated linolenic acid (CLA) antioxidants such as tocopherols or mixed natural tocopherols, other antioxidants such as BHA or BHT. Pigments may also be added to any of the above to create unique visual effects. For example:
When formed into spheres and incorporated into low pH cosmetic bases such as cosmetic pancake, this blend of Jojoba Esters, carnauba wax, fragrance oil and pigment exhibits a resistance to softening and deterioration. Inclusion of the carnauba wax results in an even more dry feeling on the skin. This formula would be more appropriate as a fragrance delivery for individuals with oily skin.
Skin Moisture Determinations
The NOVA meter is an instrument designed to measure skin moisture. During a period of one week the instrument was used to determine a baseline moisture reading for an area of skin on the forearm approximately 4 inches above the wrist. Readings taken during the one-week period established the baseline at a reading of 101 units (as measured, for example, by a NOVA DPM 9003 instrumen, which measures impedance or the capacitive reactance of the skin, cf. The NOVA(trademark) Technology Corporation Newsletter, Summer 1997) for the panelists. A higher reading indicates a more moist skin, a lower reading indicates a drier skin. The area of skin to be tested was divided laterally and marked with a pen to delineate the two skin testing areas. A 30% solution of fragrance oil (Shaw Mudge M-7108) in ethanol was prepared for application to one of the skin test areas. Formula 3 in the preceding examples was prepared for application to the other skin test area. NOVA meter readings were taken in each test area 10 minutes after application of the test materials, 30 minutes after application, one hour and three hours after application. Readings were taken in triplicate and the average taken and recorded as the result below:
Where the solvent effects of the ethanol in the alcoholic fragrance treated skin caused a decrease in the moisture content of the treated area, the jojoba ester treated skin exhibited an increase in skin moisture.

Dry emollient composition composing mono-unsaturated jojoba esters


Methods of treating ground water and methods for reducing contaminants (e.g., chlorinated compounds in contaminated ground water) to harmless compounds in the presence of an elemental metal treatment composition. Said methods comprise injecting a treatment solution comprising a colloidal suspension of elemental metal particles (e.g., iron, a tin, a zinc, a palladium and mixtures thereof) having a nanoscale particle size and a carbohydrate in an organic liquid (e.g., dodecane, butyl acetate and polypropylene glycol ethyl ether acetate and mixtures thereof) into the ground, proximate to the contaminated ground water.

Since the mid-1990's, there have been a series of dramatic developments for the in-situ treatment of chlorinated solvents. The approach of the present invention is based on the sequential reduction of chlorinated hydrocarbons to innocuous end products such as methane, ethane or ethene. In principal the process has been recognized in scientific circles but it is just beginning to be investigated for environmental application. The process exploits the use of zero valence state elemental metals to reductively dehalogenate halogenated hydrocarbons. In addition, elemental metals may be used to reduce soluble metals such as chromate to insoluble species (Cr (III)) or metalloids such as arsenic or selenium.
The most common metal being utilized for this purpose is iron. But other metals including tin, zinc, and palladium have also been shown to be effective. The process may be best described as anaerobic corrosion of the metal by the chlorinated hydrocarbon. During this process, the hydrocarbon is adsorbed directly to the metal surface where the dehalogenation reactions occur. Increasing surface area (by reducing the size of iron particles) increases the effectiveness of the process.
The variations of the process are complex. Recent research on iron systems indicates three mechanisms at work in the reductive process.                Metallic iron may act as a reductant by supplying electrons directly from the metal surface to the adsorbed halogenated compound.        Metallic iron may act as a catalyst for the reaction of hydrogen with the halogenated hydrocarbon. The hydrogen is produced on the surface of the iron metal as the result of corrosion with water.        Also ferrous iron solubilized from the iron metal due the above reactions may act as a reductant for the dehalogenation of halogenated hydrocarbons.
The rate of the reaction of the metallic iron with halogenated hydrocarbons has been demonstrated to be partially dependent upon the surface area of the metallic iron. As the size of the metallic iron is reduced, surface area goes up as well as chemical reactivity. Initial applications of this technology used iron filings. More recent applications have used iron colloids in the micron size range. The applications of the metallic iron reduction of the present invention incorporate nanoscale colloids. These are colloids that range in size from 1 to 999 nanometers. A colloid of this size may have several advantages in application for in-situ groundwater treatment or for use in above ground treatment reactors. These advantages include:                High surface area with greater reaction kinetics as a result. The increase in kinetics allows for a lower mass loading of iron in the treatment zone or reactor because the residence time required for complete dehalogenation is decreased.        The small size and greater reactivity of the colloid allows for the application of the technology through direct in-situ injection into the subsurface.        The smaller size allows for advective colloidal transport.        The greater reactivity, due to the small size, allows for much lower overall iron mass requirements.
To further enhance the physical and chemical character of the colloid, a metallic catalyst may be used to create a bimetallic colloid. The catalyst further increases the rates of reactions, which further lowers the amount of iron colloid that must be used to create an effective reductive dehalogenation treatment zone in the subsurface or a surface reactor. Metals that may be used as a catalyst with the iron include palladium, platinum, nickel, zinc, and tin.
Production of Nano-Scale Iron Colloids
Introduction
A key limitation on the development of the technology of the present invention is the lack of availability of nanoscale metallic colloids. Research, driven primarily by the materials science needs (hi-tech electronic chips or component industry products) has, over the last decade, contributed to general technologies designed to produce nanoscale colloids. Although, generally the research has been in the area of colloids that are composed of ceramic or other non-metallic inorganic materials and not metal colloids. A significant part of the development effort for the technology of the present invention was the adaptation of the non-metallic nanoscale colloid production methods to the production of metallic nanoscale colloids of the present invention.
The method for the production of metal colloids in the nanoscale range may be divided into two primary approaches:                "Bottom Up" in which colloids of the appropriate size are produced by being assembled from individual atoms.        "Top Down" in which colloids of the appropriate size are produced by attrition of larger existing particles of the metal.
The "Bottom Up" approach has a greater number of potentially applicable methods, including:                Chemical reduction using sodium borohydride; various soluble metal salts (such as ferrous or ferric chloride for iron) in suspensions of water or various hydrocarbon solvents. This process may or may not be enhanced with sonofication during reaction processes.        Other chemical precipitation reactions in aqueous or hydrocarbon solutions capable of producing metals from soluble salts that may or may not include sonofication during reaction processes.        Various methods of metal volatilization and subsequent deposition, typically under vacuum. These include:                    Gas Evaporation            Active Hydrogen-Molten Metal Reactions            Sputtering            Vacuum Evaporation to Running Oil Surface            Evaporation Using Direct Electrical Current Heating            Hybrid Plasmas
The "Top Down" approach uses two primary variations of milling or mechanical comminuation, this includes:                Using mechanical agitation of a mixture of the desired colloidal metal, a grinding media, and an organic or aqueous suspension fluid. Examples include ball mills and rod mills.        Systems similar to the above where the mechanical agitation is provided by high-speed gas jets.Upon searching for a supply of nanoscale colloids the inventors of the present invention found that the only method of production capable of producing nanoscale colloids in large kilogram amounts was the sodium borohydride reduction method. However, this was expensive (up to $5,000 per kilogram) and not practical for full-scale application of the technology.
After an evaluation of other production methods the following determinations were made:                Metal volatilization was also expensive, the reactors available for the production of colloids were limited to kilogram capacities, and the colloids produced are at the lower end of the nanoscale range (typically less than 10 nanometers). With time and further development these technologies may also be applied to the production of nanoscale iron colloids for environmental use.        "Top Down" mechanical attrition had the potential of:                    Generating colloids of the proper size            Colloid production at a reasonable cost ($100 a kilogram or less)            Production capacity in the 100 to 1000 kilogram range.
However, at the time of the evaluation there was no existing capacity (of any size) for the production of iron colloids using mechanical attrition. All work in the field was being performed on ceramics or other non-metallic inorganic materials. The inventors of the present invention sought a provider of nanoscale ceramic production and generated the specifications and requirements for the production of nanoscale iron colloids.
Production of Nanoscale Colloids by Mechanical Attrition
Nanoscale colloids have been produced in amounts up to 10 kilograms, with scale-up production volumes readily and cost effectively available. The process developed to date includes the following components:
Feed material consisting of approximately <325 mesh sized iron particles.
Organic suspension solvent fluids that:                Have high flash points to prevent explosions; and        Are not reactive to the surface of the iron colloid                    Examples may include dodecane, butyl acetate, and polypropylene glycol ethyl ether acetate                        Dispersants to act as surface acting agents to prevent the agglomeration of the colloids during the milling process were used.                    Examples include SOLSPERSE® 20,000, SOLSPERSE® 24,000, SOLSERSE® 32,600, SOLSEPERSE® 32,500, DISPERBYK® 108, DISPERBYK® 164, and DISPERBYK® 167.                        The materials are placed in a high energy ball milling system that is capable of using grinding media as small as 0.2 mm        Rate of agitation and time of milling are further parameters that are used to control generation of a nanoscale iron colloid of the desired properties. Lower energy milling is used initially to insure proper mixing of the solvent, dispersion, and iron components.Production Method Effects on Colloid Morphology
Each of the production methods described above produces colloids that have distinct morphology and internal crystal structure. In addition, it is important to recognize that in the nanoscale range quantum size effects begin to become apparent. For example a colloid of 10-nanometer diameter has about 30% of its atoms in grain boundaries (which are highly reactive and subject to quantum effects). These features may have an effect on the physical/chemical behavior of the colloid in use. These effects fall into two broad categories that reflect on production by "Bottom Up" or "Top Down" methods.                A colloid produced by chemical precipitation or reduction, or through the various vapor deposition methods may be nano-structured. This means that the colloid may have nanoscale crystal domains with sharp boundaries between crystals. The grain boundaries are typically only 1 atom thick and there is low dislocation density in the crystal structures.        The reactivity of a colloid of this type may be controlled primarily through the selection of an appropriate overall colloid size and resulting surface area. Smaller size means greater surface area and reactivity; larger size means lower surface area and reactivity.        A colloid produced by mechanical attrition may be nano-crystalline. The crystal domains in the colloid are, relative to the overall colloid size, small. The individual crystal domains are separated by wide amorphous transition regions that exhibit a very high dislocation density. These transition regions may be as large as the crystal domains, but are still termed grain boundaries.                    The amorphous transition regions may be highly reactive. The size and intensity of dislocation density of the amorphous boundary regions rather than the absolute size of the colloid may dominate the reactivity of the colloid. A relatively large colloid produced by this method may have the same or greater reactivity than a much smaller colloid produced by "Bottom Up" methods.
Control of the reactivity of the colloid is a critical feature. The iron undergoes anaerobic corrosion when reacted directly with halogenated solvents or when reacted with water to produce hydrogen. As the reactivity of the colloid increases the hydrogen production rate increases as well. By controlling the rate of hydrogen production using the methods described above, one may design reactive metal colloids with reactivity that will generate hydrogen at the rate required for the desired dehalogenation processes rather than at excessively higher rates (with just water) at which the iron colloid would be consumed (by the water) without reacting with the halogenated solvents undergoing treatment. Control of this type is particularly important for in-situ applications.
Important factors in the control of the colloid morphology using chemical precipitation include:
Concentration of reagents
Variations in the composition of the metal salt used as a feed material
Composition of the suspending solvents
Composition of the reducing agent
Temperature at which the reactions take place
The use and energy of mechanical agitation including sonification.
Important factors in the control of the colloid morphology using vapor deposition methods include:
Temperature of vaporization reactor
Temperature in the deposition/collector zone
Composition of metal (effects of alloying in addition to elemental composition)
Composition of coating fluids in the collector
Rate of deposition
Important factors in the control of the colloid morphology using mechanical attrition include:
Composition of metal (alloy effects as well elemental composition)
Type and concentration of suspending solvent
Type and concentration of dispersion agent
Size and shape of metal feed stock particles (and concentration in suspension)
Size and shape of grinding media (and amount in suspension)
Energy/rate of ball milling
Time of milling
If gas agitation is used:                Gas composition        Gas pressure, flow rate and configuration of injection system.
Post-production processes may also impact colloid morphology and crystal structure, these post-production processes include:
Annealing                To various temperatures ranging from room temperature to the melting point of the colloid        At various heating rates and total annealing times        In the presence of various gases
Treatment with other aqueous or organic solutions
Drying processes including:                The use of heat        The use of evaporation        Vacuum drying
The composition of the blanketing gas used during the drying process.
Through the manipulation of the colloid size, morphology, and crystal structure using the above process it is possible to design colloids for variations in specific contaminant types, concentrations, groundwater or reactor flow velocities, subsurface permeability, and provide some control over the transport properties of the colloids during injection.

Method of making and using nanoscale metal


A topical composition is disclosed for reducing a urushiol-induced allergic response and the dermatitis associated therewith. The composition is a preparation having an acorn derivative and a nontoxic dermatologically acceptable aqueous dispersion material. The acorn derivative is acorn ash, acorn mash, roasted acorn, or acorn extract and comprises about 0.1 to 50 percent by weight of the treating preparation. After the initial preparation, preservatives are then added. Optionally, additional ingredients such as surfactants and emulsifying agents, antihistamines, topical anesthetics, colloidal oatmeal, topical antipruritics, astringents, and emollients may be added to the aqueous acorn dispersion. With processing varied according the examples provided, the ingredients are combined so as to create sprays, creams, gels, ointments, and lotions.

1. Field of the Invention
This invention relates to a treatment for allergic contact dermatitis. More particularly, the invention relates to a dermatitis treatment with a topical composition having an active ingredient of an acorn derivative, namely, a powdered acorn or an acorn extract from acorn ash, acorn mash, or roasted acorn.
2. Background Information
Poison ivy, poison oak, or poison sumac dermatitis is often referred to as rhus dermatitis and is a common, seasonal, allergic contact dermatitis. In the United States, poison ivy (Toxicodendron radicans) and poison oak (Toxicodendron diversilobum or quercifolium) are the main causes of rhus dermatitis. Poison ivy, which is particularly abundant in eastern United States and southeastern Canada, is found as either a shrub or a vine.
Before contact dermatitis develops, sensitization is experienced whereby, upon exposure to the toxic agent, toxicodendrol, the individual acquires hypersensitivity thereto. Therefore, not everyone who is exposed to the plants has an allergic reaction. However, it is estimated that at least 70% of the U.S. population could react after casual exposure to the plants.
Toxicodendrol, the previously mentioned toxic agent, is a phenolic oleoresin that is present in all the poisonous species. Toxicodendrol contains the complex active principle urushiol, which, in turn, is distributed widely in the roots, stems, leaves, and fruit of the plant, but not in the flower, pollen, or plant epidermis. Therefore, contact with the intact epidermis of the plant is harmless and contact dermatitis occurs only upon contact with a bruised or injured plant or with a carrier of the juices therefrom, e.g. from the coat of a dog. As little as 1 xcexcg of crude urushiol causes dermatitis in sensitive individuals.
The natural course of contact dermatitis is divided into two phases; a sensitization phase, during which a specific hypersensitivity to the allergen is acquired, supra, and an elicitation phase, during which subsequent contact with the allergen elicits a visible dermatologic response. The reaction timexe2x80x94the interval between contact with the allergen and the appearance of the responsexe2x80x94varies with the degree of sensitivity and the amount of allergen contacted. Reaction time is usually between 12 hours and up to 2 to 3 days. This interval is a result of delayed hypersensitivity reactions involving cell-mediated immunity.
In the elicitation phase, following exposure to the antigen, there develops an initial reaction, namely, an erythema or rash. This is followed by the development of raised lesions (erythematous macules and papules). Finally, fluid accumulation causes the formation of vesicles and bullae in the epidermis.
In preparing for this application several references became known to the inventors hereof. Both chemical and medical databases revealed sparse information on the principal active ingredient hereof, namely, acorn derivatives; however, the U.S. Department of Agriculture (USDA) and the International Food Ingredient Council Foundation (IFIC) have ascertained basic nutritional information for the acorn. According to the analysis provided, the acorn, like other nuts, is composed or water, protein, lipid, carbohydrate, minerals, and vitamins. For a more detailed account as to content of this ingredient, see infra.
Further and also in preparing for this application several patents became known to the inventors hereof in which oak bark ash is described as a therapeutic agent in treating poison ivy symptoms. R. Thomas Stanley in U.S. Pat. No. 5,080,900 describes the use of oak bark ash and later technical developments are described by David N. Hon and R. Thomas Stanley in U.S. Pat. No. 6,149,947. Although reported as having therapeutic advantages, Karl in U.S. Pat. No. 6,113,929 indicates that the tannic acid in the oak bark ash formulations acts as an astringent and does not remove all the oleoresin, toxicodendrol, from the skin, However, when used after an alkaline cleanser, removes some of the resin, the oak bark preparation removes the remaining resin portion and closes the skin pores to prevent residual resin working its way into the pores. There is thus some question as to the efficacy of astringent preparations, particularly oak bark ash, and the methodology with which the same should be used.
By way of further background as to the active ingredient, the acorn derivative, the heating of acorns generate, as would be expected, Maillard reaction products. Initial reactions of Maillard reaction involves condensation, enolization, and Amadori rearrangement of proteins, sugars, and free amino groups. Intermediate reactions involve sugar dehydration, sugar fragmentation, formations of dicarbonyl compounds, reductones, and pigments. During the final stages of Maillard reactions, red-brown and dark brown color is generated. The reactions involved in the final stages of Maillard reaction involve aldol condensation, polymerization, and Strecker degradation. Roasted aromas develop as well as colloidal and insoluble melanoidins also form. The acorn derivatives herein, including those from roasted acorns, are differentiated from oak bark and tannic-acid-containing products by the constituents mentioned and by a pH above 4.5. are above what would be expected for a high tannic acid material. It is believed that trace amounts of tannins occur in acorn derivatives and are believed to stem from the shells and hats of the acorn.
West U.S. Pat. No. 5,443,847 identified a detoxification agent for urushiol using divalent metals such as manganese. West ""847 indicates that organic molecules containing hydroxyl (xe2x80x94OH) and carboxyl (xe2x80x94COOH) groups are reactive to polyvalent metals and that urushiol has two hydroxyl groups that can form stable chelates by replacing the hydrogens with divalent metals that are present in the agent. West claims the use and method of manganese salts (0.01 to 10.0 percent Mn) in an aqueous solution between pH 5 and 7.
The discussion of the above documents is not intended as an admission that any such document constitutes prior art against the claims of the present application. Applicant does not waive any right to take any action that would be appropriate to antedate or otherwise remove any listed document as a competent reference against the claims of the present application.
In general terms, the invention disclosed hereby includes an aqueous solution of an acorn derivative suitable for application to the site of contact dermatitis. The acorn derivatives as discussed hereinbelow are extracts, suspensions, and dispersions prepared from acorn ash, acorn mash, and roasted acorns. Acorns utilized in the present invention are from Red Oak (Quercus rupra), Black Oak (Quercus shumardi i Buckl.) Scarlet Oak (Quercus coccinea Muenchb.), Willow Oak (Quercus phellos L.) and other species of the Erythrobalanus group.
In the description which follows the term treating preparations is defined as solutions, suspensions, or emulsions in the form of topical ointments, creams, lotions and sprays. In the formulations of the present invention varying amounts of acorn derivatives have been found to be efficacious in treating the allergic response induced by the urushiol resin and the dermatitis arising therefrom. Thus, treating preparations having from 0.1 to 50 percent by weight of acorn derivative are set forth. The treating preparations, namely solutions, suspensions, and emulsions hereof have, in addition to the acorn derivative, a nontoxic dermatologically acceptable aqueous dispersion material.
Various topical compositions forming sprays, creams and ointments require in addition to the acorn derivative and water such inactive components as surfactants, antioxidants, emulsifiers, stabilizers, dispersants, and preservatives. In another aspect of the invention additional active components of the topical composition are disclosed such as anesthetics, antipruritics and antihistamines.
As discussed in some detail in the Background Information, it is believed that the allergic response to urushiol has an initial sensitization phase followed by a delayed hypersensitivity reaction in the dermal layers of the skin. While the exact reaction mechanism is not fully understood, researchers believe that the urushiol resins enter the superficial layers of the human dermis where it attaches to tissue proteins to produce a hapten in about 10 minutes or less. The protein molecules are attached on the surface of specialized white blood cells known as Langerhans cells in the epidermis and to macrophages in the dermis skin layers. The Langerhans cells communicate the antigen information to inducer lymphocyte cells, which proliferate into circulating T-memory and T-effector lymphocytes. The immune lymphocytes are now sensitized to additional urushiol entry into the skin layers.
With subsequent urushiol exposure, the subject has a delayed hypersensitivity reaction, which allows T-cells to invade the skin area containing the newly deposited urushiol. It is further hypothesized that the acorn extract provides a physical and mechanical barrier which protects exposed skin or mucous membrane surfaces from harmful stimuli and annoying irritants. Exposed skin or mucous membranes surfaces are isolated from harmful stimuli and annoying irritants because the physical and chemical properties of acorn derivatives include a protective demulcent effect. It is also hypothesized that the proteins, carbohydrates, lipids, divalent metals in the acorn derivatives, and the Maillard reaction components in the acorn extract preferentially bind and thereby inactivate urushiol resin.
Additionally, the acorn extract also binds and inactivates the urushiol components during the elicitation phase of the antigenic response. The aqueous acorn extract hereof also controls the osmotic pressure of water with respect to the skin and permits adequate water to enter into the stratum corneum. The acorn extract leaves a thin occlusive film or coating on the skin which retains the absorbed moisture. As a result of this coating, a dual action occurs, namely: (1) the acorn extract proteins, carbohydrate, divalent metals and Maillard reaction products bind the urushiol stimuli components and reduce further antigenic response; and, (2) the lipid, protein, carbohydrate, and Maillard reaction components protect against urushiol irritation by moisturizing the skin. Acorn extract thereby acts as an antipuritic and has a generally soothing demulcent effect.
Several examples of various ointments, creams, aqueous solutions, sprays and the like for the treatment of contact dermatitis are presented hereinbelow. All of the preparations contain a most efficacious active ingredient, namely, a vegetable product derived from the acorn. The acorns utilized can be from Red Oak (Quercus rupra), Black Oak (Quercus shumardi i Buckl.) Scarlet Oak (Quercus coccinea Muenchb.), Willow Oak (Quercus phellos L.) and other species of the Erythrobalanus group. For purposes of this application an acorn derivative is defined as any of the following forms; an acorn powder produced by roasting the acorn nuts, shells and caps and further processing the product thereof by, for example, triturating, grinding, milling, and/or screening; an acorn ash or the solid residue remaining after burning the combustible portion; an acorn mash, namely, a solution of crushed acorn nuts; and, an acorn extract, namely, a suspension or dispersion using powder, ash, and/or mash and suitable aqueous and non-aqueous diluents.
Acorn is composed of water, proteins, lipids, carbohydrates, minerals, and vitamins. When the acorn is roasted, the roasting process generates Maillard or sugar-amine reactions and produces sugar fragmentation and other reaction products. In this regard the acorn extract is distinguished from oak bark and tannic acid mentioned, supra, based on composition and Maillard reaction products. While some tannins may be derived from the acorn shells and hats, the coloration of the roasted product suggests the formation of some melanoids as a result of the roasting process.
In one method, prior to preparing an extract, the raw or roasted acorns are converted into ash by burning off the organic materials. The ash inorganic material is cooled and screened to provide a powder.
Acorn extract, suspensions, and dispersions for use in the present invention are prepared from raw acorn mash, roasted acorns or acorn ash. Acorn mash is prepared by breaking up the shells and hats of raw acorns in order to expose the inner nut portion of the acorn. Roasted acorns are prepared by heating raw acorns between about 90xc2x0 C. and about 350xc2x0 C. for between about 5 minutes to 10 hours. The preferred roasting conditions are 200xc2x0 C. for one hour. The roasted acorns are cooled then prepared for extraction by breaking up the shells and hats in order to expose the inner portion of the acorn.
Various extracts, suspensions, and dispersions can be prepared by those familiar with the art. The extracts can be prepared from water, super critical CO2, or various polarity solvents. The solvents include alcohols, ethers, hexanes, methylene chloride, and others. The preferred extract, suspension, and dispersion are prepared using water.
The mash or roasted acorns are extracted in water for a period of time. The water temperature can range from about 10xc2x0 C to 100xc2x0 C., with stirring for a period of time ranging from 10 minutes to 24 hours in order to prepare an intermediate. The time temperature relationship is also concentration dependent. The preferred extract, suspension, or dispersion is prepared from about 10% material at 100xc2x0 C. for 1-hour. The intermediate is screened to remove the large particles and thereby reduces the concentration of the acorn extract to about 5%. These extracts may also be filtered. The aqueous extracts in accordance with the invention are complex mixtures of organic and inorganic materials.
The mash or roasted acorns are extracted in intermediate polarity solvents such as alcohol for a period of time. The preferred alcohol is ethanol at room temperature or with slight heating. The alcohol may also be distilled and condensed over the acorn material to provide continuous extraction with pure solvent similar to that used in a soxlet extractor in order to prepare an intermediate. The time temperature relationship is concentration dependent and varies from one concentration to another. The preferred extract from about 10% material at for 1-hour.
The intermediate is screened to remove the large particles and thereby reduces the concentration of the acorn extract to about 5%. These extracts may also be filtered. The alcoholic extracts in accordance with the invention are complex mixtures of organic and inorganic materials. The alcohol may be evaporated off to produce a concentrated extract or used as is to formulate.
The mash or roasted acorns are extracted in non-polar solvents such as hexane, methylene chloride, and ethers for a period of time. The preferred nonpolar solvent is hexane at room temperature or with slight heating. The hexane may also be distilled and condensed over the acorn material to provide continuous extraction with pure solvent similar to that used in a soxlet extractor in order to prepare an intermediate. The time temperature relationship is also concentration dependent. The preferred extract from about 10% material at for 1-hour. The intermediate is screened to remove the large particles and thereby reduces the concentration of the acorn extract to about 5%. These extracts may also be filtered. The nonpolar solvent extracts in accordance with the invention are complex mixtures of organic and inorganic materials. The nonpolar solvent is evaporated off to produce a concentrated extract. Acorn Ash can be used to formulate directly. Additional nonpolar acorn extracts may be prepared by using super critical CO2 extractions techniques. In particular, compositions containing about 0.1% or more, preferably 0.5 to 75% and more preferably 0.5 to 10% or acorn extract according to the invention can be used to treat poison ivy.
The compositions prepared as described in general hereinbelow are prepared from acorn derivatives, including acorn mash, acorn roast and acorn ash. These ingredients which are initially in particulate form are, prior to manufacturing, screened to select particle size using USA Standard Testing Sieves Nos. 70 to 30, preferably No. 50. Prior to final screening, a particle size reduction step is employed utilizing herringbone-perforated or round-hole-perforated reducing screens. For aqueous dispersions, the screened and reduced particle-size acorn material is then mixed with purified water with a commercially available mixer, such as a Lightnin"" Mixer.
After mixing, preservatives are then added to the mixture. If desired additional ingredients such as surfactants and emulsifying agents, antihistamines, topical anesthetics, colloidal oatmeal, topical antipruritics, astringents, and emollients may be added to the aqueous acorn dispersion. The ingredients may be added in such a ratio and processing varied as to create a spray, cream, gel, ointment, or lotion.
The most frequently used preservative for the formulations herein are benzoic acid and derivatives thereof, namely, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, and mixtures thereof. Typical use of benzoic-acid-derived preservative is a mixture of methylparaben comprising up to 0.3 percent by weight of the treating composition and propylparaben comprising up to 0.1 percent by weight of the treating composition.
Other useful preservatives include alcohol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, glycerin, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylene glycol, sodium propionate, sorbic acid and thimerosal.
Among the inactive ingredients are surfactants and emulsifying agents. These ingredients take on importance as the use thereof improves absorption, coverage, appearance, and feel of the product. Some suitable emulsifying agents are acacia, anionic emulsifying wax, carbomer, carboxymethyl cellulose, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, glyceryl monostearate, hydrous lanolin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lanolin, lanolin alcohols, lecithin, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, sodium lauryl sulfate, sorbitan esters, stearic acid, triethanolamine, and xanthan gum. Frequently mixtures of complimentary surfactants are used in a given formulation.
In the examples applying the present invention anionic, cationic and nonionic surfactants are selected. The anionic surfactants are lauryl sulfates, including sodium lauryl sulfate, triethanolamine lauryl sulfate, and ammonium lauryl sulfate; laureth sulfates,including sodium laureth sulfate, triethanolamine laureth sulfate, and ammonium laureth sulfate; sarcosines, including lauryl sarcosine, and sodium lauryl sarcosinate; sulfosuccinates, including disodium oleamine sulfosuccinate, and sodium dioctyl sulfosuccinate; and docusate sodium. The cationic surfactants are benzalkonium chloride, benzethonium chloride, and cetrimide. The nonionic surfactants are glyceryl monooleate, polyvinyl alcohol, sorbitan esters, povidone, crospovidone, polyoxyethylene fatty alcohols, polyoxyethylene sorbitol esters, and alkanolamides. Additionally, in the examples applying the present invention, amphoteric detergents such as betaines, sultaines, and imidazolinium derivatives are used, and particularly ingredients such as cocamidopropyl betaine and sodium lauraminopropionate.
In the ointment and cream preparations hereinbelow, emollients form a vehicle to carry the active ingredients to the site of the urushiol response and the associated dermatitis. The emollient group from which these carriers are selected include allantoin, cetostearyl alcohol, cetyl esters wax, cocoa butter, cholesterol, dimethicone, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, kaolin, lecithin, light mineral oil, mineral oil, mineral oil and lanolin alcohols, petrolatum, and petrolatum and lanolin alcohols.
One of the functions of the formulations is to remove the urushiol resin from the skin. This requires astringent activity, and while the acorn derivative provides a satisfactory level of astringency the addition of aluminum acetate, zinc oxide, zinc acetate, sodium bicarbonate, calamine, witch hazel, zinc carbonate, and aluminum hydroxide has been employed to enhance this physical property.
It has been found that the antipruritic activity of the acorn derivative hereof is compatible with other well-known antipruritic agents and when combined therewith provide unexpected synergy. Such agents include phenol, camphor, menthol, hydro-cortisone, hydrocortisone acetate, camphorated metacresol, phenolated sodium, and mixtures thereof. As is shown in the examples which follow the effect is gained by the addition of menthol comprising up to 0.2 percent by weight of the formulation or the addition hydrocortisone acetate comprising up to 1.0 percent by weight of the formulation.
The antihistamines added to the topical compositions are typically from the structural classes of ethylenediamines, aminoalkylethers, and alkylamines. Among the ethylenediamine group are such antihistamines as antazoline phosphate, clemizole hydrochloride, chlorcyclizine hydrochloride, chlorothen, methapheniline hydrochloride, dorastine hydrochloride, methdilazine hydrochloride, promethazine hydrochloride, pyrathiazine hydrochloride, pyrilamine maleate, quinetolate, thenaldine, thenyldiamine hydrochloride, thonzylamine hydrochloride, tripelennamine, and zolamine hydrochloride. Among the aminoalkylether group are such antihistamines as chlorphenoxamine hydrochloride, carbinoxamine maleate, clemastine, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, doxylamine succinate, and pyroxamine maleate. Among the alkamine group are such antihistamines as azatadine maleate, bromdiphenhydramine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, phenindamine tartrate, pheniramine maleate, brompheniramine maleate, dexbrompheniramine maleate, chlorpheniramine maleate, dex-chlorpheniramine maleate, closiramine, cycliramine maleate, mianserin hydrochloride, pyrrobutamine phosphate, terfenadine, and triprolidine hydrochloride. Besides the above, some compositions in structural groups, which groups are not primarily antihistamines such as phenothiazines, piperidines, and piperazines, have antihistaminic characteristics. These groups include promethazine, astemizole, fexofenadine, loratadine, desloratadine, terfenadine, cetirizine, and meclizin, which are antihistaminic.
Another active ingredient used in the formulations hereof is the employment of a topical anesthetic in conjunction with the antipruritic and demulcent effect of the acorn derivative. Here in by the addition of this class of compounds, the user experiences the reversible abolition of sensory perception, especially the sensations of pain and extreme irritation. While some of these topical anesthetic compounds are structurally related to the antihistamines in the preceding paragraph, the compounds take on a disinct role in preparations described. The first group are esters of benzoic acid and diethylaminoethyl alcohols, namely, benzocaine, chloroprocaine, procaine, and tetracaine. Other synthetic anesthetic compounds, which are not esters of benzoic acid and are pharmacologically grouped together, are bupivacaine, dibucaine, lidocaine, mepivacaine, and prilocaine. Besides these two groups, the compounds of etidocaine and pramoxine are also applicable. In one of the topical spray formulations described below the anesthetic, pramoxine hydrochloride, comprises up to 1.0 percent by weight thereof.
Colloidal oatmeal, when used in the formulations hereinbelow, because of the hydrophilic nature thereof, acts at the site of application to control the osmotic pressure of water with respect to the skin and permits adequate water to enter into the stratum corneum. Oatmeal leaves an occlusive film on the skin that serves to hold in moisture, which protects the skin against irritation and acts as an antipruritic. The USP grade of colloidal oatmeal described in this invention was obtained from Beacon CMP Corporation, 611 Springfield Road, Kenilworth, N.J. 07033.

Allergic contact dermatitis treatment and composition therefor