POWDER AND METHOD TO IMPROVE THE TOPICAL APPLICATION OF AN ACID BENEFIT AGENT

专利摘要:
COMPOSITIONS AND METHODS TO IMPROVE THE TOPICAL APPLICATION OF AN ACID BENEFIT AGENT. The present invention relates to a powder that includes core / capsule particles that have an average particle size of less than 1000 microns, each particle containing a liquid core that is substantially free of water and includes A) a polar liquid having a percentage of surface polarity of at least 24%, an active ingredient, and C) from about 0.1% to about 20%, by weight of at least one solubility-enhancing agent that is not an active ingredient; and a capsule comprising hydrophobic particles. The powder can be used to topically administer the active ingredient to a human or animal.
公开号:BR112016022159B1
申请号:R112016022159-1
申请日:2015-03-10
公开日:2020-11-17
发明作者:Ying Sun；Jeffrey M. Wu；Ali Fassih
申请人:Johnson & Johnson Consumer Inc.；
IPC主号:

专利说明:

[0001] The present invention relates to compositions and methods for improving the topical application of a beneficial agent. The compositions are powder-to-liquid particles that comprise a liquid core that is substantially free of water and comprise a polar liquid that has a surface polarity percentage of at least 24%, at least one acidic active agent and at least one solubility-enhancing agent surrounded by a shell comprising hydrophobic particles. The particles are stable in dry form, but they quickly turn into a liquid or cream-like form when subjected to shear. They can be advantageously formulated with other ingredients, particularly those unstable in the presence of water, in personal care compositions. BACKGROUND OF THE INVENTION
[0002] It is known that in the presence of a hydrophobic powder, such as a hydrophobic silicon dioxide powder (silica powder coated with silicone), the water can be dispersed in fine droplets and surrounded by the hydrophobic material, thus preventing the droplets come together again. Such material has been described as "dry water", "powdered water" or "powder-to-liquid" and can have a water content of more than 95%. It is formed by intense mixing of water with hydrophobic material. During this process, the water droplets are coated by the solid particles and prevented from flowing together again. The first experiments on the use of "dry water" as a cosmetic base date back to the 1960s. See US 3,393,155. These fine, flow-free powders liquefy when rubbed onto the skin.
[0003] More recently, US 6,290,941 describes powder-to-liquid cosmetic or pharmaceutical compositions comprising hydrophobically coated silica particles in which water and a water-soluble polymer are incorporated, the said composition of which does not substantially contain no oil. Such compositions are said to require less silica while retaining the water holding capacity and allow substantial elimination of added oil from the formula.
[0004] WO 2011/075418 discloses a powder composition comprising a) at least one powder in the form of core-capsule particles, the core comprising liquid water or a liquid aqueous phase and the capsule comprising hydrophobic particles - spouts or hydrophobized, and b) at least one vehicle comprising powder, and b1) at least one liquid partially soluble in water and / or b2) a water-reactive substrate each located in and / or on the vehicle.
[0005] Eshtiaghi et al., Powder Technology, Vol.223, 2012, pages 65 to 76 describes a variety of powder-to-liquid materials and proposes mechanisms for their formation. The capsule materials used include hydrophobic silica (coated with silicone), hydrophobic glass microspheres and polytetrafluoroethylene (PTFE OR TEFLON) powder. The core materials include water, glycerol, and poly (ethylene glycol) (PEG). The particle sizes reported for materials containing glycerin were 1200 and 3400 microns.
[0006] US 2012/0315312 teaches about core-capsule particles, the capsule of which includes hydrophobized and aggregated silicon dioxide particles and the core of which includes a liquid phase. The ratio of the silicon dioxide particles to the liquid phase is from 2:98 to 40:60, based on the total weight of the particles, and 60 to 100% by weight of glycerol is present in the liquid phase.
[0007] US patent application serial number 13 / 719,649, filed on December 19, 2012, teaches a powder comprising core / capsule particles that have an average particle size less than 1000 microns, with each particle comprising : 1) a liquid core that is substantially free of water and comprises a polar liquid that has a percentage of surface polarity of at least 24%, and 2) a capsule that comprises hydrophobic particles. The particles can include an active agent.
[0008] US patent No. 6,946,120 teaches a pharmaceutical composition for topical administration, including, as the pharmaceutically active component, at least 5% by weight of minoxidil; an acid in an amount to completely solubilize minoxidil; a solvent composition including at least two components among water, a lower alcohol and a cosolvent selected from one or more of the group consisting of aromatic and polyhydric alcohols; where the co-solvent includes propylene glycol, it is present in an amount of less than approximately 10% by weight.
[0009] Although water-based powder-to-liquid compositions are commonly described, they are not suitable for formulation with active agents that are unstable with or incompatible with water, for example, plant extracts prone to oxidation and / or hydrolysis. In addition, water-containing particles, in general, lack structural stability and are prone to collapse or leak during storage, and allow water to evaporate from the core.
[0010] There is also a need for compositions that improve the penetration of beneficial agents into the skin. US patent 6,419,913 teaches about micellar compositions that enhance skin penetration. Although effective, these compositions can be difficult to manufacture and the cost of products is relatively high.
[0011] Applicants have now discovered innovative topical compositions and a method for enhancing the topical application of beneficial agents. The compositions include powder-to-cream particles, which contain a waterless core and at least a basic solubility enhancer. Such particles are stable and usable in formulation with a variety of active agents, even those that are prone to oxidation and / or hydrolysis. Compositions containing such particles are also convenient for use, while providing a pleasant tactile sensation on the skin, similar to cream, and adherence to the skin (ability to remain on the skin). The compositions can be used in cosmetic products, skin care products, wound care products, dermatological products and other personal care products, as well as in other applications and industries. SUMMARY OF THE INVENTION
[0012] The invention provides a powder that includes nucleus / capsule particles that have an average particle size of less than 1000 microns, each particle containing a liquid core that is substantially free of water and includes A) a polar liquid having a percentage of surface polarity of at least 24%, B) an acidic active ingredient, and C) from about 0.1% to about 20% by weight of at least one solubility-enhancing agent that is not an ingredient active; and a capsule comprising hydrophobic particles.
[0013] The invention also provides a method for topically administering the active ingredient by rubbing the powder onto the skin of a human or animal. The powder turns into a liquid or gel-like or cream-like composition from which the active or beneficial agent is absorbed into the skin. DETAILED DESCRIPTION OF THE INVENTION
[0014] As used here, and unless otherwise specified, all percentages are by weight, based on the total weight of the referred composition.
[0015] The descriptions of all patents and published applications mentioned in this document are hereby incorporated in their entirety, for reference.
[0016] As used herein, "substantially free" of an ingredient means containing about 5% by weight or less of that ingredient. Preferably, substantially free of an ingredient means containing about 2% or less, or about 1% or less, or about 0.5% or less, or about 0.1% or less, or about 0, 05% or less, or about 0.01% or less, by weight of such an ingredient. In certain embodiments, substantially free of an ingredient means completely free of the ingredient, that is, containing none of that ingredient.
[0017] As used herein, an "active agent" or "benefit agent" is a compound (for example, a synthetic compound or a compound isolated from a natural source) that has a cosmetic or therapeutic effect on the tissue (for example, a material capable of exerting a biological effect on the human body) such as therapeutic drugs and cosmetic agents. Examples of active agents include small molecule materials, peptides, proteins, nucleic acids and nutrients such as minerals and extracts. The amount of active agent used will depend on the active agent and / or the intended use of the final product. The active agents can be liquid, solid or semi-solid. In addition, the active agents or beneficial agents can be incorporated into the liquid core and / or the capsule of the core particles / capsule.
[0018] As used in the present invention, "solubility enhancer" means an agent used to enhance or enhance the solubility of the active or beneficial agent in the composition.
[0019] As used herein, "pharmaceutically acceptable", "cosmetically acceptable" or "dermatologically acceptable" means suitable for use in contact with tissues, for example, skin, hair, mucosa, epithelium or the like ) without inadequate toxicity, incompatibility, instability, irritation, or allergic response.
[0020] As used here, "safe and effective amount" means an amount sufficient to provide a desired benefit at a desired level, but low enough to avoid serious side effects. The safe and effective amount of the ingredient or composition will vary with the area to be treated, the age of the end user, the duration and nature of the treatment, the specific ingredient or specific composition employed, the specific vehicle used, and similar factors.
[0021] As used here, the term "treating" or "treating" means the relief or elimination of symptoms, the cure, prevention, or inhibition of a disease or medical condition, or the improvement of growth / healing of tissue or cosmetic conditions, such as reducing the appearance of wrinkles / fine lines on the skin, dark circles, cellulite, skin marks / hyperpigmentation or uneven skin tone.
[0022] To provide a more concise description, some of the quantitative expressions presented here are not qualified with the term "about". It should be understood that when the term "about" is used, explicitly or not, any and all quantities presented here are intended to refer to the actual value provided, and are also intended to refer to the approximation of that provided value that would be reasonably inferred based on the technique, including approximations due to experimental and / or measurement conditions for that value provided.
[0023] To provide a more concise description, some of the quantitative expressions of the present invention are referred to as a range from approximately a quantity X to approximately a quantity Y. It is understood that where a range is referred to, the range is not limited to the upper limits and below mentioned, but rather includes the total range from about quantity X to about quantity Y, or any quantity or range within that. Core / capsule particles
[0024] The powder of the present invention comprises core / capsule particles. Each particle comprises a liquid core that is substantially free of water and comprises a polar liquid, at least one active agent or acidic benefit and from about 0.1% by weight to about 20% by weight of at least one intensifying agent basic solubility. The polar liquid has a minimal surface polarity. The liquid core is surrounded by a capsule of hydrophobic particles.
[0025] The particles, according to the present invention, have a liquid core surrounded by a capsule of hydrophobic particles. The core includes an emulsion or suspension that comprises a polar liquid as the continuous (external) phase. The dispersed (internal) phase comprises a hydrophobic material and / or solid particles.
[0026] The hydrophobic particles of the capsule are in the form of loose powder held together only by weak liquid-powder and powder-powder interactions by means of weak Van der Waals forces. When subjected to slight forces, such as hand rubbing, the core / capsule particles collapse and the powder becomes a liquid, a cream or a gel.
[0027] In general, the average particle size of the core / capsule particles is less than about 1000 micrometers, usually from about 1 micrometer to about 1000 micrometers, or about 2 micrometers to about 200 micrometers, or about 3 mi-meters to about 100 micrometers, or about 5 micrometers to about 50 micrometers. The average particle size of the core / capsule particles can be determined by any particle size measurement method for dry particles known in the art, such as light microscopy, electron microscopy, or sieve analysis. The core
[0028] The liquid core comprises a polar liquid that is not water and from about 0.1% to about 20% by weight of at least one basic solubility-enhancing agent, and at least one active or acid-beneficial agent, and has a minimum polar component of total surface tension.
[0029] As known in the art, the surface tension of a liquid (that is, the total surface tension) is divided into two components, one representing a polar component and one representing a non-polar (or dispersive) component. The polar component, "percentage (%) of surface polarity", is determined using the Fowkes method described in Fowkes, Journal of Achievements in Materials and Manufacturing Engineering, 24.1 (2007) 137 to 145.
[0030] Specifically, the total surface tension of a sample is measured five times using the Wilhelmy plate method (described by Derelinch et al. "Measurement of Interfacial Tension in Fluid-Fluid Systems" in Encyclopedia of Surface and Colloid Science, pages 3152 to 3166, Ed. by Arthur T. Hubbard, Marcel Dekker, Inc., 2002), using a Kruss Tensiometer K100 instrument. The plate used is a standard platinum plate with a diameter of 19.9 mm x 0.2 mm.
[0031] The contact angle of each sample is also measured five times with a cleaning piece of poly (tetrafluoroethylene) PTFE using a KrussDSA10 Drop Shape Analysis System. The measurement of the PTFE contact angle is performed as a means of separating the total surface tension of each sample into polar and dispersive components. According to Fowkes' theory of surface energy, the dispersive component of a liquid can be determined by knowing its total surface tension and its contact angle against PTFE (which is a completely non-polar surface). The procedure is as follows: p_σL2 (cos θpTFE +1) 2σL 72 when 0PTFE = the measured contact angle between PTFE and the sample liquid. The dispersive surface tension (OLD) component can be determined for any liquid for which the total surface tension (OL) is known simply by measuring the contact angle between the liquid and the PTFE (OPTFE) and using the above equation. The net polar surface tension component for the liquid is then determined by the difference (OLP = OL - OLD). The percentage of surface polarity is (% = OLP * 100% / OL). See also F.M. Fowkes, Journal of Physical Chemistry, 67 (1963) 2538-2541.
[0032] The liquid has a percentage of surface polarity of at least 24%, or at least 25%, or at least 26%, or at least 30%.
[0033] The liquid core is substantially free of water. The liquid core can be completely free of water, that is, anhydrous.
[0034] The liquid core contains a safe and effective amount of an acidic active agent. The acidic active agent is present in the composition from about 0.001 percent to about 20 percent or from about 0.01 percent to about 10 percent, or from about 1 percent to about 5 percent in weight of the composition.
[0035] Compounds suitable for use in the present invention are weak acid active agents or drugs containing at least one functional group of carboxylic acid or phenol, which can be ionized to carry a negative charge. Although any weak acid compound can be used in the present invention, the preferred classes of compounds that belong to this group include NSAIDs, conversion enzyme inhibitors, antimicrobial agents, prostaglandins, and active agents for topical treatment of skin & hair, such as caffeine, lactic acid and any compounds from plant extracts with at least one carboxylic acid functional group in the molecular structure.
[0036] Non-steroidal anti-inflammatory compounds (NSAID'S) are typically weak organic acids containing carboxyl moieties. Representative NSAIDs for use in the invention include salicylic acid, salicylates and their derivatives, such as acetylsalicylic acid, propionic acid compounds, such as ibuprofen, diclofenac, naproxen, ketoprofen, indole derivatives, such as indomethacin, compounds of namate, such as meclophenamic acid and pyrrolalkanoic acid compounds such as tolmetin.
[0037] Another class of compounds belonging to those containing a derivable carboxyl group and for use in the present invention is that of 6-fluoroquinolones, which have antimicrobial activity. The preferred drugs are those that have a carboxyl function in position 3 of the quinolone ring system and that have antibacterial activity.
[0038] A preferred use for fluoroquinola compounds is in the treatment of Mycobacterium infection, especially, intracellular complexes of M. tuberculosis, M. kansasil, M. xenopi, M. fortuitum, and M. avium. Quinolone-based antibacterial agents are believed to penetrate bacterial cells and inhibit DNA gyrase, an essential bacterial enzyme that maintains super-helical twists in DNA (Klopman, et al., 1993). An antibacterial agent for the treatment of Mycobacterium infection, particularly M. avium-M. intracellular, is ciprofloxacin.
[0039] Cephalosporins are also included in this class of antimicrobials. The cephalosporins for use in the present invention are derived from 7-aminocephalosporanic acid having various substituents at positions 3 and 7, and containing a carboxyl group at position 2 of the ring. Cephalosporins typically have weights in the range of 400 to 450 and include cephalothin, cephalexin, cephazoline, cephaphrine, cephapirin, cephamandol and cephaxitin. Depending on the drug generation, cephalosporins are known to be highly active against Gram-positive and Gram-negative organisms. Many cephalosporins are active against E. coli, Klebsiella, and some strains of Proteus and Enterobacter. Cephalosporins are typically administered intravenously since relatively few of the compounds are sufficiently well absorbed after oral ingestion to provide adequate systemic levels for treatment. Cephalosporin drugs are especially suitable for liposomal administration for the treatment of infection, since liposomal application can reduce the associated toxicity effects including anaphylaxis, urticaria and fever.
[0040] Another class of compounds suitable for use in the present invention are prostaglandins. The basic structure common to all prostaglandins is "prostanoic acid", which consists of a cyclopentane ring with two aliphatic side chains, one of which ends in a carboxyl group. There are 9 groups of prostaglandins, designated by the letters A to I. The primary clinical applications of prostaglandin agents refer to their effects on smooth muscle. Due to their ability to contract uterine smooth muscle, prostaglandins are useful for gynecological applications, such as inducing abortion or labor. Prostaglandins can also be used to treat peripheral vascular disease or to block gastric acid secretion.
[0041] Another class of compounds suitable for use in the present invention are conversion enzyme inhibitors. Conversion enzyme inhibitors are drugs that block the conversion of angiotensin I to angiotensin II and also inhibit the breakdown of bradykinin, making these compounds useful as antihypertensive agents. Two of such carboxyl-containing compounds suitable for use in the present invention are those derived from L-proline, enalapril and captopril.
[0042] The liquid contains from about 0.1% by weight center to about 30%, for example, from about 0.1% to about 20% or from about 0.1% to about 10 %, or from about 1% to about 10%, or from about 1% to about 5%, by weight, of at least one basic solubility enhancing agent that is not an active ingredient or beneficial agent . This otherwise allows insoluble or difficult to solubilize acid active agents or beneficial agents to be solubilized in the core.
[0043] Suitable solubility enhancing agents for active agents or acidic beneficial agents include bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, carbonate calcium, magnesium carbonate, ethylamine, diethylamine, triethylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, triisopropanolamine and mixtures thereof.
[0044] The liquid core is substantially free of preservatives. The liquid core can be completely free of preservatives.
[0045] The liquid core can be single-phase (one-phase). Alternatively, the liquid core can comprise multiple phases, for example, the liquid core can be an emulsion or suspension, while at least one acidic active agent is completely dissolved in the polar liquid as the continuous phase of the liquid core. Alternatively, for a liquid core composed of an emulsion, at least one acidic active agent is completely dissolved in the liquids that make up the liquid core, that is, the acidic active agent in its dissolved form distributed between the internal liquid phase (for example , oily phase), the outer polar liquid phase (eg, glycerol, polyglucolole, or other polyol phase) is the continuous phase of the liquid core.
[0046] In one embodiment, the liquid core is a single phase substantially, or completely uniform, that is, it is a homogeneous transparent liquid containing no visually detectable inhomogeneity, such as droplets or particles in suspension, when seen with the naked eye at a distance of approximately 30 cm (12 inches). The liquid core as a single phase can contain other organic liquids in addition to the polar liquid, as long as such organic solvents are soluble or substantially soluble, miscible or substantially miscible in the polar liquid to maintain the homogeneity and clarity of the liquid core. When other organic liquids that are partially soluble in, or partially miscible with, the polar liquid are used, their amounts must be below their saturation concentrations to ensure that the liquid core remains a clear solution.
[0047] The polar liquid may comprise one or more polyols. Such polyols include, but are not limited to, glycerol (glycerin) polyglycerols, glycols, polyglycols, and mixtures thereof.
[0048] Examples of polyglycerols include, but are not limited to, diglycerol (diglycerin), triglycerol (polyglycerin-3 or polyglycerol-3), tetra-glycerol (polyglycerin-4 or polyglycerol-4), other polyglycerols (polycerol-n, where n> 4), and mixtures thereof.
[0049] Examples of glycols include, but are not limited to, propylene glycol, ethylene glycol, butylene glycol, and their isomers, (eg, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2, 3-butanediol), hexylene glycol and its isomers, propanediol, dipropylene glycol, ethoxydiglycol, methylpropanediol, isopentyldiol, and mixtures thereof.
[0050] Examples of polyglycols include, but are not limited to, poly (ethylene glycol) of various molecular weights, namely molecular weights in the range of 300 g / mol to 10,000,000 g / mol, (for example, PEG-200, PEG-400, PEG-1000, PEG-2000 PEG-4000, PEG-6000), poly (propylenic glycol) (PPG) of various molecular weights, and mixtures thereof.
[0051] The polar liquid may comprise a combination of a polyol with one or more other organic liquids. Such organic liquids include, but are not limited to, alcohols, isosorbides, esters, ethers, lactones, and any organic compounds acceptable for therapeutic, cosmetic or personal use products and capable of maintaining the polarity percentage of the polar liquid at 24% or above.
[0052] Examples of alcohols include, but are not limited to, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, amyl alcohol, benzyl alcohol, octyldecanol, hexildecanol, butyloctanol and mixtures thereof.
[0053] Examples of isosorbides include, but are not limited to, dimethyl isosorbide, diethyl isosorbide, ethyl methyl isosorbide and mixtures thereof. Preferably, the isosorbide is an alkyl ester of isosorbide, such as dimethyl isosorbide.
[0054] Examples of esters include, but are not limited to, benzyl benzoate, triacetin, glycerol trioctanoate, diethyl phthalate and mixtures thereof.
[0055] Examples of ethers include, but are not limited to, tipprilic ether, dipropylene glycol monomethyl ether and mixtures of the same.
[0056] Examples of lactones include, but are not limited to, glucoconolactone.
[0057] In one embodiment of the invention, the polar liquid is a mixture of a glycerol or polyglycerol with one or more glycols or polyglycols.
[0058] In an alternative embodiment of the invention, the polar liquid is a mixture of a glycerol or polyglycerol with one or more alcohols.
[0059] In yet another embodiment of the invention, the polar liquid is a mixture of a glycerol or polyglycerol with one or more isosorbides.
[0060] Preferably, the polar liquid comprises a glycerol, polyglycerol or a mixture thereof. The amount of glycerol, polyglycerol, or a mixture thereof can be about 50% to about 100%, or more than about 70%, or more than about 80%, or 85% or more, by weight of the liquid polar of the liquid core. The remainder of the liquid core can be one or more organic liquids, such as non-glycerol polyols, alcohols, or isosorbides.
[0061] In one embodiment, the liquid core may additionally comprise at least one hydrophilic polymer, for example, natural or synthetic hydrophilic polymers. Such a hydrophilic polymer can be soluble or partially soluble in the liquid core. Suitable hydrophilic polymers include, but are not limited to, vinylpyrrolidone homopolymers and copolymers (for example, PVP, or PVP / PVA copolymer), vinyl alcohol homopolymers or copolymers (for example, poly (vinyl alcohol) or PVA), polyacrylamide , homopolymers or copolymers of acrylic and / or methacrylic acids, and salts and esters thereof (for example, CARBOPO / CARBOMER 934, 940, 941, 980, 1342, and 1382, and ULTREZ 10 and 21), cellulosic polymers (for example , hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxyethylcellulose), polyurethanes, starch and its derivatives, and natural and synthetic gums (for example gum arabic or xanthan gum). Preferred hydrophilic polymers are acrylate polymers and copolymers, particularly polyacrylate neutralized by anhydrous neutralizers. Polyvinyl ether or copolymer of methyl and vinyl ether / maleic anhydride (eg Gantrez®AN-119, 139, 149 etc.).
[0062] The incorporation of such polymers in the liquid core intensifies the interactions between the liquid core and the hydrophobic particles of the capsule, thus facilitating the formation of the core-capsule particle and improving the physical stability of the core / capsule particles, which avoids the premature collapse of the particle and the leakage of liquid during storage.
[0063] If used, the amount of hydrophilic polymer is generally up to about 10%, or equal to or less than about 5%, or equal to or less than about 3%, or equal to or less than about 2%, in net core weight.
[0064] In general, the liquid core can contain any additional ingredients (for example, active agents, or formulation excipients) soluble or dispersible in the polar liquid or its components, provided the additional ingredients do not impair the surface polarity percentage of the core liquid. Pharmaceutically or cosmetically acceptable active agents or excipients, such as plant or mineral extracts, low molecular weight natural or synthetic compounds or polymers, acids or bases (particularly weak acids or bases) for adjusting acidity, buffers, chemicals, antioxidants, thickening or gelling agents can be used.
[0065] In particular, active agents or beneficial agents are present in the liquid core. The liquid core may comprise one or more emulsifying surfactants (emulsifiers) commonly used in pharmaceutical or cosmetic products.
[0066] In one embodiment, the liquid core comprises an emulsion (for example, simple emulsion, multiemulsion, or nanoemulsion), in which there is at least one internal phase (for example, oil phase), and at least one liquid phase external polar (for example, glycerol, polyglycerol, or other polyol phase) as the continuous phase of the liquid core. The internal phase includes at least one lipophilic substance, which is a liquid at room temperature, and is essentially immiscible with the external polar liquid phases. Some non-limiting examples of oils include oils of vegetable origin (for example, vegetable oils and plant oil extracts - seeds, vegetables or fruits), mineral oils, silicone fluids / oils and their derivatives, and any acceptable lipophilic solvents for products topical cosmetics or pharmaceuticals.
[0067] The oils used for the internal oil phase of the liquid core can be volatile or non-volatile in nature. Hydrophobic solvents suitable for use in the volatile hydrophobic solvent component are selected from the group consisting of branched-chain hydrocarbons, silicones, fatty acid esters, branched-chain liquid fatty alcohols, and triglycerides (for example, capric / caprylic triglyceride) ), isopropyl myristate, isopropyl palmitate, and mixtures thereof. Preferably hydrophobic branched chain hydrocarbons useful as the solvent component of the present invention contain from about 7 to about 14, more preferably, from about 10 to about 13 and most preferably, from about 11 to about 12 carbon atoms. Saturated hydrocarbons are preferred, although it is not intended to exclude unsaturated hydrocarbons. Examples of such preferred branched chain hydrocarbons include isoparaffins of the above chain sizes. Isoparaffins are commercially available from Exxon Chemical Co; examples include Isopar E (isoparaffins C.sub.8- C.sub.9), Isopar ™ H and K (C.sub.11-C.sub. 12 isoparaffins), and Isopar ™ L (C.sub. 11-C.sub.13 isoparaffins) or mixtures thereof. Other suitable branched chain hydrocarbons are isododecane and isoundecane. Isododecane is preferred and is available commercially from Presperse, Inc. (South Plainfield, N.J., USA) as Permethyl ™ M 99A.
Preferred silicones useful as the volatile hydrophobic solvent component include volatile siloxanes such as phenylpentamethyl disiloxane, phenyl ethyl pentamethyl disiloxane, hexamethyl disyloxane, methoxy propyl heptamethyl cyclotetrasiloxane, chloropropyl pentamethyl disiloxane, cyclamethylamine, hydroxypropyl and mixtures thereof. Among the most preferred silicones are cyclomethicone, examples of which include hexamethyl disiloxane, octamethyl cyclotetrasiloxane, decamethyl cyclopentassiloxane, cyclohexylsiloxane, which are commonly called cyclomethicone D4 D5 and D6, respectively.
[0069] The internal phase of the oil (s) in the liquid core of the emulsion is physically stabilized by surfactants in the liquid core of the emulsion. In one embodiment, the liquid core comprises at least one polymeric surfactant having a molecular weight in the range of about 1,000 Daltons to 50,000 Daltons, including, but not limited to, homopolymers such as poly (ethylene oxide), poly (vinylpyrrolidone) and polyl (vinyl alcohol), block and graft copolymer polymeric surfactants as diblock or triblock polymeric surfactants known as PLURONICS manufactured by BASF (Germany) or SYNPERONIC PE manufactured by ICI (United Kingdom) consisting of two poly blocks -A of poly (ethylene oxide) (PEO) and a block of poly (propylene oxide) (PPO), and polystyrene-block-poly (vinyl alcohol) diblocks, triblocks of poly (methyl methacrylate) - poly-block (ethylene oxide) -poly (methyl methacrylate) block, polystyrene-poly block diblocks (ethylene oxide) and poly (ethylene oxide) triblocks - polystyrene-poly block (ethylene oxide), as well as an antipathic graft copolymer consisting of a main chain in. imérica B (polystyrene or poly (methyl methacrylate) and several A chains ("teeth") like poly (ethylene oxide) called "comb" stabilizers can be used.
[0070] In one embodiment, the liquid core comprises at least one hydrophobically modified polysaccharide. Useful polysaccharides include sugars (for example, inulin), sugar analogs (for example, dextrans), starches (for example, potato or tapioca starches), water-soluble celluloses (for example, hydroxypropyl cellulose), inulin hydrophobically modified (polyfructose) as disclosed in US 6,534,647 (including commercially available INUTEC SP1) (ORAFTI, Tienen, Belgium), hydrophobically modified dextran as disclosed by O. Carrier et al. ("Inverse emulsions stabilized by a hydrophobically modified polysaccharide", Carbohydrate Polymers, 84 (2011) 599-604), hydrofically modified potato or tapioca starches as disclosed in US 8,258,250, US 7,417,020, US20110082105A1, and US 20110082290A1, (including NATURASURFTM PS-111, AKZO NOBEL CHEICALS INTERNATIONAL, BV commercially available) and hydrophobically modified water-soluble hydroxypropylcellulose as disclosed by C. Claro et al. ("Surface tension and rheology of aqueous dispersed systems containing a new hydrophobically modified polymer and surfactants", International Journal of Pharmaceutics, 347 (2008) 45- 53). Other examples of hydrophobically modified polysaccharides include, but are not limited to, PEMULEN TR-1, PEMULEN TR- 2, ETD 2020, CARBOPOL 1382 (Acrylates / C10-30 alkyl acrylate cross polymer, available from Noveon / Lubrizol, Cleveland , OH, USA), NATROSOL CS Plus 330, 430, POLYSURF 67 (cetyl hydroxyethyl cellulose, Hercules, Wilmington, DE, USA), ACULYN 22 (stearet-20 acrylate / methacrylate copolymer, Rohm & Haas, Philadelphia, PA, USA), ACULYN 25 (acrylate copolymer / lauret-25 methacrylate, Rohm & Haas), ACULYN 28 (acrylate copolymer / 25-methacrylate, Rohm & Haas), ACULYN 46 (PRG-150 copolymer / stearyl alcohol / SMDI, Rohm & Haas), STABYLEN 30 (vinyl acrylates / isodecanoate, 3V-Sigma, Georgetown, SC), STRUCTURE 2001 (acrylate copolymer / estearet-20 itaconate, National Starch), STRUCTURE 3001 (copolymer of acrylates / ketet-20 itaconate, National Starch), STRUCTURE PLUS (acrylates / aminoacrylates / C itaconate copolymer) 10-30 alkyl PEG 20, National Starch), QUATRISOFT LM-200 (polyquaternium-24, Amerchol, Greensburg, LA, USA), CAPSULE, HI-CAP 100, N-CREAMER 46, CAPSUL TA, Ed N-LOK-1930 (all available from Ingredion Incorporated, formally National Starch or Corn Products International, Inc.), Westchester, IL, USA.
[0071] The amount of hydrophobically modified polysaccharide can be in the range of about 0.01% to about 20%, or from about 0.1% to about 10%, or from about 0.5% to about from 5%, or from about 0.1% to about 1%, by weight of the liquid core.
[0072] Other useful surfactants are described by Tadros ("Polymeric Surfactants in Disperse Systems", Advances in Colloid and Interface Science, 147-148,2009, pages 281 to 299), and R.Y. Lochhead and S. Jones ("Polymers in Cosmetics: Recent Advances", Article 2004/07, Happi.com).
[0073] In one embodiment, the composition comprises at least one surfactant typically used to prepare oil in water (O / W) emulsions as disclosed in US 6,174,533.
[0074] The liquid core can comprise from about 0.05% to about 5% or from about 0.05% to about 1%, by weight of such surfactant. Without intending to stick to the theory, it is believed that the surfactant helps in the dispersion of the hydrophobic component in the polar liquid. The surfactant, at a minimum, needs to be hydrophilic enough to disperse in the hydrophilic component. Preferred surfactants are those that have an HLB of at least about 8. The exact surfactant to be chosen will depend on the pH of the composition and the other components present.
[0075] The surfactant can be any of the anionic surfactants, non-ionic surfactants, amphoteric surfactants, zwithionic surfactants, cationic surfactants and mixtures clearly as are well known in the art.
[0076] Examples of non-ionic surfactants that are useful to the present invention are those that can be broadly defined as condensation products such as long-chain alcohols, for example, C8-30 alcohols, with polymers of sugar or starch, that is, glycosides . These compounds can be represented by the formula (S) n-O-R where S is a portion of sugar such as glucose, fructose, mannose and galactose; n is an integer from about 1 to about 1000; and D is a C8-30 alkyl group. Examples of long-chain alcohols from which the alkyl group can be derived include decyl alcohol, cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol and the like. Examples of such surfactants include those in which S is a glucose moiety, R is a C8-C20 alkyl group, and n is an integer from about 1 to about 9. Commercially available examples of these surfactants include decylpoliglycoside (available as APG 325 CS from Henkel) and lauryl polyglycoside (available as APG 600 CS and 625 CS from Henkel).
[0077] Other useful non-ionic surfactants include condensation products of alkylene oxides with fatty acids (i.e., alkylene oxide esters of fatty acids). These materials have the general formula RCO (X) nOH where R is a C10-30 alkyl group, X is —OCH2CH2-- (ie, derived from ethylene oxide or ethylene glycol) or --OCH2CHCH3-- (ie , derived from propylene oxide or propylene glycol), and n is an integer from about 6 to about 200. Other non-ionic surfactants are condensation products of alkylene oxides with 2 moles of fatty acids (ie, diameters fatty acid alkylene oxide). These materials have the general formula RCO (X) nOOCR where R is a C10-30 alkyl group, X is --OCH2CH2-- (i.e., derived from ethylene oxide or ethylene glycol) or --OCH2CHCH3-- (this ie, derived from propylene oxide or propylene glycol), and n is an integer from about 6 to about 100.
[0078] Other non-ionic surfactants are the condensation products of alkylene oxides with fatty alcohols (ie, alkylene oxide ethers of fatty alcohols). These materials have the following general formula R (X) nOR 'where R is a C10-30 alkyl group, X is --OCH2CH2-- (ie, derived from ethylene oxide or ethylene glycol) or -OCH2CHCH3 - (ie, derived from propylene oxide or propylene glycol), n is an integer from about 6 to about 100, and R 'is H or a C10-30 alkyl group. Still other non-ionic surfactants are the condensation products of alkylene oxides with fatty acids and fatty alcohols (ie, in which the poly (alkylene oxide) portion is esterified on one end with a fatty acid and etherified (ie, connected via an ether bond) at the other end with a fatty alcohol). These materials have the general formula RCO (X) nOR 'where R and R' are C10-30 alkyl groups, X is -OCH2CH2 (ie, derived from ethylene oxide or ethylene glycol) or --OCH2CHCH3 (derived from oxide propylene or propylene glycol), and n is an integer from about 6 to about 100. Some non-limiting examples of these non-ionic surfactants derived from alkylene oxide include cetet-6, cetet-10, cetet-12, cetearet-6, cetearet-10, cetearet-12, stearet-6, estearet-10, estearet-12, PEG-6 stearate, PEG-10 stearate, PEG-100 stearate, PEG-12 stearate, PEG-20 glyceryl stearate , PEG-80 glyceryl sebate, PEG-10 glyceryl stearate, PEG-30 glyceryl cocoate, PEG-80 glyceryl cocoate, PEG-200 glyceryl sebate, PEG-8 dilaurate, PEG-10 distearate, and mixtures of the same.
[0079] Other non-ionic surfactants suitable for use in the present invention include sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, alkoxylated derivatives of fatty acid esters C1-C30 fatty alcohols C1-C30, alkoxylated ethers of C1-C30 fatty alcohols, C1-C30 fatty acid polyglyceryl esters, C1-C30 polyol esters, C1-C30 polyol ethers, alkyl phosphates, ether phosphates polyoxyalkylene fat, fatty acid amides, acyl lactylates, and mixtures thereof. Some non-limiting examples of these silicone-free emulsifiers include: poly (ethylene glycol) sorbitan monolaurate 20 (Polysobarto 20 or TWEEN 20), polyethylene glycol soy sterol 5, Estearet-20, Cetearet-20, PPG methyl glucose ether distearate -2, Cetet-10, Polysobarto 80 (TWEEN 80), Polysobarto 40 (TWEEN 40), cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, Polysobarto 60 (TWEEN 60), glyceryl stearate, polyoxyethylene sorbitan trioleate 20 (Polysobarto 85), sorbitan monolaurate, polyoxyethylene sodium stearate lauryl ether 4, polyglyceryl-4 isostearate, hexyl laurate, PPG-2 distearate glucose methyl ether, PEG-100 stearate, and mixtures of themselves.
[0080] Other emulsifiers usable here are blends of fatty acid ester based on a mixture of sorbitol or sorbitan fatty acid ester and sucrose fatty acid ester, the fatty acid in each case being preferably C8-C24, more preferably, C10-C20. The preferred fatty acid ester emulsifier is a blend of sorbitan fatty acid ester or C16-C20 sorbitol with sucrose fatty acid ester C10-C16, especially sorbitan stearate and sucrose cocoate. This material is available commercially from ICI, under the name ARLATONE 2121.
[0081] Surfactants useful in the present invention may alternatively or additionally include any of a wide variety of monomeric units of cationic, anionic, zwitterionic and amphoteric surfactants as are known in the art. The cationic surfactants usable here include cationic ammonium salts such as quaternary ammonium salts, and amino-amides. Some non-limiting examples of anionic surfactants include the alkyl isethionates (for example, C12 - C30), alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, methyl taurates alkyl (for example, C12 - C30), and soaps (for example, alkali metal salts, for example, sodium or potassium salts) of fatty acids.
[0082] Amphoteric and zwitterionic surfactants are also useful for the present invention. Examples of amphoteric and zwitterionic surfactants that can be used in the compositions of the present invention are those that can be widely described as derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight or branched chain and one of the aliphatic substituents contains from about 8 to about 22 carbon atoms (preferably C8-C18) and one contains an anionic water solubilizing group, for example, carboxy, sulfonate, sulfate, phosphate or phosphonate. Examples are alkyl imino acetates, and derivatives of iminodialcanoates and aminoalkanoates, imidazoline and ammonium. Other suitable amphoteric and zwitterionic surfactants are those selected from the group consisting of betaines, sulphates, hydroxysultaines, alkylsarcosinates (eg, C12 - C30), and alkanoyl sarcosinates.
[0083] The liquid core compositions of the present invention can include an emulsifier or surfactant containing silicone. A wide variety of silicone emulsifiers are useful in the present invention. These silicone emulsifiers are typically organopolysiloxanes organically modified, also known to those skilled in the art as silicone-based surfactants. Useful silicone emulsifiers include dimethicone copolyols. These materials are polydimethyl siloxanes that have been modified to include polyether side chains, such as poly (ethylene oxide) chains, poly (propylene oxide) chains, mixtures of these chains, and polyether chains containing portions derived from ethylene oxide and propylene oxide. Other examples include alkyl-modified dimethicone copolyols, i.e. compounds that contain C2-C30 pendant side chains. Other useful dimethicone copolyols include materials that have several cationic, anionic, amphoteric, and zwitterionic moieties.
[0084] Dimethicone copolyol emulsifiers can also be used. Some non-limiting examples of dimethicone copolyols and other silicone-based surfactants useful as emulsifiers in the present invention include polyether polydimethylsiloxane copolymers with pendant poly (ethylene oxide) side chains, polyether polydimethylsiloxane copolymers with poly (poly) side chains pendant propylene oxide), polyether polydimethylsiloxane copolymers with pendant mixed poly (ethylene oxide) and poly (propylene oxide) side chains, polyether polydimethylsiloxane copolymers with pendant mixed poly (ethylene oxide) (propylene) side chains polyether polydimethylsiloxane copolymers with hanging organobetaine side chains, polyether polydimethylsiloxane copolymers with hanging carboxylate side chains, polyether polydimethylsiloxane copolymers with hanging quaternary ammonium ammonium side chains; and also other modifications of the above copolymers containing pendant linear, branched, or cyclic C2-C30 alkyl moieties. Examples of commercially available dimethicone copolyols usable in the present invention and sold by Dow Corning Corporation are DOW CORNING fluid 190, 193, Q2-5220, 2501 Wax, 2-5324, and 3225C (the latter material being sold as a mixture with cyclomethicone ). Cetyl dimethicone copolyol is commercially available as a mixture with polyglyceryl-4 (e) hexyl laurate isostearate and is sold under the trade name ABIL® WE-09 (available from Goldschmidt). Cetyl dimethicone copolyol is commercially available, too, in the form of a mixture with hexyl laurate (e) polyglyceryl-3 (e) cetyl dimethicone oleate and sold under the trade name ABIL® WS-08 (also available from Goldschmidt). Other non-limiting examples of dimethicone copolyols also include lauryl dimethicone copolyol, dimethicone copolyol acetate, dimethicone copolyol adipate, dimethicone copolyolamine, dimethicone copolyol butyl, dimethicone butyl ether copolyol, dimethicone hydrolysteate copolyol, copolyol isohydrolysearolate and dimethylolate. dimethicone, dimethicone copolyol laurate, dimethicone methyl ether copolyol, dimethicone phosphate copolyol, and dimethicone stearate copolyol. The capsule
[0085] The capsule comprises hydrophobic particles. As used herein, "hydrophobic" includes both hydrophobic particles themselves and hydrophobic particles obtained by reacting the surface of the hydrophilic particles with a hydrophobic surface modifying agent.
[0086] Useful hydrophobized particles include, but are not limited to, silicon or silane coated powders, or fluoropolymer coated powders, such as talc, kaolin, mica, sericite, dolomite, phlogopite, synthetic mica, lepidolite, biotite, lithium mica , vermiculite, magnesium carbonate, calcium carbonate, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, metal salts of tungsten acid, magnesium, silica, zeolite, barium sulfate, sulfate calcined calcium, calcium phosphate, fluorapatite, hydroxyapatite, titanium oxide, colloidal titanium oxide, zinc oxide, alumina and smoked alumina. Other hydrophobic particles include, but are not limited to, particles of hydrophobic compounds or polymers, such as long-chain fatty acids and their esters, alcohols, and metal salts (e.g., stearic acid, stearyl alcohol, and magnesium stearate), hydrophobic waxes (for example, paraffin wax and beeswax), and fluoropolymers (for example, poly (vinyl fluoride, polyl (vinylidene fluoride), polytetrafluoroethylene, polychlorotrifluoroethylene, perfluoroalkoxy polymer, fluorinated ethylene propylene, polyethylene ethylene - trafluoroethylene, polyethylene chlorochlorofluoroethylene, perfluorinated elastomer, fluorocarbon, chlorotrifluoroethylenovinylidene fluoride and perfluoro-polyether.
[0087] Among these, the hydrophobized silica particles that form a three-dimensional network, an aggregate structure, are a preferred capsule material. The silica can be a precipitated silica or a smoked silica, the latter being preferred. Smoked silica is obtained in a flame oxidation or flame hydrolysis process. Its purity is greater than 99% by weight, normally greater than 99.8% by weight. Smoked silica generally forms a three-dimensional network of aggregated primary particles and is porous. The primary smoked silica particles have hydroxyl groups on their surface and are non-porous.
[0088] Other hydrophobic smoked metal oxides can also be used, such as aluminum oxide and hydrophobic smoked titanium oxide, such as Aeroxide. TÍO2 T805, and Aeroxide Alu C805 (both from EVONIK, Piscataway, NJ, USA).
[0089] The precipitated and smoked silica particles, as well as other hydrophilic particles can be hydrophobized in a subsequent step. The procedures for this step are known to the person skilled in the art.
[0090] WO2011 / 076518 discloses these and other hydrophobic or hydrophobized silica particles suitable for use as the capsule material of the present invention.
[0091] Hydrophobic surface modifying agents include silanes, including organosilanes, holo-organosilanes and cyclic polysiloxanes, which can be used individually or as a mixture. Examples of hydrophobic surface modifying agents include, octyltrimethoxysilane, octyltriethoxysilane, hexamethyldisilazane, hexadecyltrimethoxysilane, hexadecyltriethoxysilane, dimethylpo-lysiloxane, nonafluoro-hexyltrimethoxylane, tridecyl fluoroane, tridecafluoro-tridecafluoro-tridecluoroane With particular preference, it is possible to use hexamethyldisilazane, octyltriethoxysilane and dimethylpolysiloxanes.
[0092] Hydrophobic particles can be hydrophobized silica particles that have a BET surface area of 30 m2 / g to 500 m2 / g, or 100 m2 / g to 350 m2 / g. Due to the reaction with the surface modifying agent, these particles may contain 0.1 to 15% by weight, generally 0.5 to 5% by weight of carbon.
[0093] Examples of useful hydrophobic particles include AEROSIL® R104 (octamethylcyclotetrassiloxane; 150 m2 / g; 55); AEROSIL® R106 (octamethylcyclotetrassiloxanes; 250 m2 / g; 50), AEROSIL® R202 (polydimethylsiloxane; 100 m2 / g; 75), AEROSIL® R805 (® octylsilane; 150 m2 / g; 60), AEROSIL® R812 (hexamethyldisil; m2 / g; 60), AEROSIL® R812S (hexamethyldisilazane; 220 m2 / g; 65), and AEROSIL® R8200 (hexamethyldisilazane; 150 m2 / g; 65). The indications in parentheses refer to the surface modifying agent, the approximate BET surface area and the approximate methanol wettability.
[0094] It may also be beneficial to use smoked silica particles hydrophobized in compacted form or as granules.
[0095] Other suitable hydrophobic particles include fine, inorganic, organic particles, or fine polymeric powders coated with silicon, silane or fluorine compounds, which can be used alone or as a mixture with hydrophobic silica or hydrophobic smoked silica powder.
[0096] The amount of hydrophobic particles in the powder is about 2% to about 30%, or about 2.5% to about 20%, or about 3% to about 10% or about 3% to about 8% by weight based on the total weight of the powder.
[0097] In one embodiment, the capsule consists of hydrophobized smoked silica particles that are obtained by reacting a hydrophilic smoked silica having a BET surface area of 30 to 500 m2 / g.
[0098] In another embodiment, the hydrophobized smoked silica particles are obtained by reacting a hydrophilic smoked silica having a BET surface area of 270 to 330 m2 / g with hexamethylsilazane to produce hydrophobized smoked silica particles having a BET surface area from 200 to 290 m2 / g and a carbon content of 2 to 4% by weight and methanol wettability of at least 50.
[0099] In one embodiment, the active agents and / or additional ingredients are present in the capsule. Second powder
[0100] The powder comprising the core / capsule particles can be mixed with a second powder. The mixing process is usually done during the product manufacturing process. However, the mixing process can also be carried out after production by a user before use. In that case, the second powder and the powder comprising the core / capsule particles can be packaged in a double chamber container or separate containers.
[0101] In one embodiment, the second powder comprises one or more solid active agents, liquid active agents impregnated in absorbent powder materials, excipients of pharmaceutical formulation / solid cosmetic, or excipients of pharmaceutical formulation / liquid cosmetic impregnated in absorbent powder materials.
[0102] Solid active agents that can be used in the second powder include unstable actives such as certain vitamins (eg, ascorbic acid), and natural extracts containing antioxidants suitable for use in the compositions of the present invention include, but are not limited to , plant extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavanoids, mono-, di- and tri-terpenes, sterols and their derivatives. Examples of such plant extracts include grape seed, green tea, pine cork and extracts of propolis and vegetable extracts and the like.
[0103] Absorbent powder materials include pharmaceutically or cosmetically acceptable porous powders such as silica and fumed silica, starch powders, and clays, synthetic and natural fibers, as well as materials described as useful for the hydrophobic particles of the capsule. Method for making core / capsule particles
[0104] A single phase liquid core can be produced by simply mixing or combining the liquid ingredients until uniformity is achieved. High shear is not necessary for this step, as mixing miscible liquids does not require high energy. The mixing of liquid for this step can be done with equipment such as mixers, laboratory scale mixers, or homogenizers. The sample can be heated in cases where an active agent contained therein requires higher temperatures to dissolve in the liquid mixture. The resulting homogeneous liquid can be converted into a powder by mixing with hydrophobic particles from the capsule under high shear, such as a mixer or a rotor-stator mixer or other high speed rotational in-line mixers. It is preferable to carry out the dusting step with all contents at room temperature or below.
[0105] In the case of a liquid core comprising an emulsion, the ingredients of the liquid core, including immiscible liquids and / or active agents, and the emulsifiers are mixed together under high shear until an emulsion is formed. The mixing for this stage can be done with equipment such as mixers or homogenizers. The sample can be heated in cases where the active agent requires a higher temperature to dissolve in the liquid. The resulting emulsion can be converted into a powder by mixing with hydrophobic particles under high shear, as with a rotor-stator mixer or mixer or other in-line rotational high speed mixers. It is preferable to carry out the dusting step with all contents at room temperature or below.
[0106] Methods of using high speed rotational mixers for powder-liquid mixing to prepare core / capsule compositions are known in the art. The mixing energy must be high enough to break the liquid into fine droplets to be covered or encapsulated by the hydrophobic powder capsule. L. Ford et al. ("Influence of mixing characteristics for water encapsulation by self-assembling hydrophobic silica nanoparticles," Powder Technology 189, 2009, pages 263 to 269) describe the method of preparation, which is hereby incorporated by reference in its entirety.
[0107] The powder comprising the core / capsule particles has great application versatility, and can be used in many medical and consumer products for human and animal use, such as ingestible compositions (such as tablets and capsules), topical compositions (such as creams) , lotions, gels, shampoos, cleansing creams, powders, dressings, bandages, and masks for application to skin or mucous membranes), garments (such as underwear, underwear, bras, shirts, pants, pantyhose, socks, caps, face masks, gloves, and mittens), bedding (such as towels, pillow protectors or pillowcases and sheets) sanitary products for home and clinical use, microcides for plants, and devices (such as toothbrushes, dental floss, periodontal implants or inserts, orthodontic appliances, wraps / supports for joints, oral dressings, ocular inserts or implants, such as contact lenses, nasal implants or inserts, and cleaning products eza of contact lenses, wound dressings, diapers, sanitary napkins, wet wipes, rectal and vaginal tampons and suppositories, and in linings or surfaces embedded in medical devices and other surfaces where antimicrobial effects or other benefits are desired).
[0108] The powder comprising the core / capsule particles can be incorporated into fibers, nonwovens, hydrocolloids, adhesives, films, polymers and other substrates. In one embodiment, the powder is in contact with a fabric interface. Methods for applying the powder to the substrates include electrostatic spray coating, mechanical sieving, coextrusion, or adhesive spray.
[0109] The powder comprising the core / capsule particles can contain a wide range of active agents used for various applications as described in the sections below.
[0110] The powder comprising the core / capsule particles can be administered topically, locally (buccally, nasally, rectally or vaginally), or systemically (eg, perorally) to an individual (eg, a human being) ) that needs treatment for a condition or disease, or otherwise to provide a therapeutic effect. Such therapeutic effects include, but are not limited to, antimicrobial effects (for example, antibacterial, antifungal, antiviral and antiparasitic effects); anti-inflammatory effects including effects on superficial and deep tissues (for example, reduction or elimination of soft tissue edema or redness); elimination or reduction of pain, itching or other sensory discomfort; improved regeneration or healing of hard tissues (for example, improves the rate of nail growth or regrowth of hair lost due to alopecia) or increased soft tissue volume (for example, increased collagen or elastin in the skin or lips) ; increased adipocyte metabolism or improved body appearance (for example, effects on body contour or shape, and reduction of cellulite); and increased blood or lymphocyte circulation.
[0111] The powder comprising core / capsule particles can be combined with one or more other active agents not contained in a second powder. Topical compositions for skin
[0112] In one embodiment, the invention provides a topical composition containing the powder comprising nucleus / capsule particles that is suitable for administration to a mammalian skin, such as human skin. In one embodiment, such a topical composition contains a safe and effective amount of (i) the powder comprising core / capsule particles, and (i) a cosmetically or pharmaceutically acceptable carrier.
[0113] Topical compositions can be made in a wide variety of products that include, but are not limited to, non-rinsing products (such as lotions, creams, gels, sticks, sprays and ointments), skin cleansing products (such as liquids wash, solid bars and wet wipes), hair products (like shampoos, conditioners, sprays and mousses), shaving creams, film-forming products (like masks), cosmetics (as a base, eyeliner and eye shadows) , deodorant and antiperspirant compositions, and the like. These types of products can contain any of a variety of cosmetically or pharmaceutically acceptable carriers that include, but are not limited to, solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels and solid carrier forms. Other product forms can be formulated by those skilled in the art.
[0114] In one embodiment, the topical composition is used to treat skin conditions. Examples of such skin conditions include, but are not limited to, acne (for example, open and closed comedones), rosacea acne, nodule-cystic lesions and other microbial infections of the skin; visible signs of skin aging (for example, wrinkles, sagging, yellowing and age spots); loose or loose skin, folliculitis and pseudofolliculitis of the beard; excess sebum (for example, to reduce sebum or to control or inhibit the oily / glossy appearance of the skin; pigmentation (for example, to reduce hyperpigmentation, such as freckles, melasma, ousenil actinic lentigo, age spots, post-inflammatory hypermelanosis, Becker's nevus, facial melanosis or accentuating the pigmentation of fair skin); excessive hair growth (for example, hair on the legs), or insufficient hair growth (for example, on the scalp); dermatitis (for example, atopic dermatitis, contact, seborrheic), eczema, dark circles under the eyes, stretch marks, cellulite, excessive sweating (eg hyperhidrosis) and / or psoriasis. Topical anti-acne / anti-rosacea compositions
[0115] In one embodiment, the topical composition also contains an anti-acne and / or anti-rosacea active agent. Examples of anti-acne and anti-rosacea agents include, but are not limited to, retinoids, such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, oleic acid and retinol; salicylic acid; resorcinol; sulfacetamide; urea; antibiotics, such as tetracycline, clindamycin, metronidazole and erythromycin; anti-inflammatory agents, such as corticosteroids (for example, hydrocortisone), ibuprofen, naxoprene and heptrophene; and imidazois, such as ketoconazole and elubiol; and salts and prodrugs thereof. Other examples of anti-acne active agents include essential oils, alpha-bisabolol, dipotassium glycyrrhizinate, camphor, β-glucan, allantoin, marijuana, flavonoids such as soy isoflavones, dwarf palm, chelating agents such as EDTA, lipase inhibitors, such as dish ions and copper, hydrolyzed vegetable proteins, inorganic chloride ions, iodide, fluoride and their non-ionic derivatives of chlorine, iodine, fluoride, synthetic phospholipids and natural phospholipids, such as ARLASILK ™ CDM, SV, EFA, PLN, and GLA (commercially available from Uniqema, ICI Group of Companies, Wilton, United Kingdom). Topical anti-aging compositions
[0116] In one embodiment, the topical composition also contains an anti-aging agent. Examples of anti-aging agents include, but are not limited to, retinoids; dimethylaminoethanol (DMAE), copper-containing peptides, vitamins such as vitamin E, vitamin A (retinol and its derivatives, eg retinyl palmitate), vitamin C (ascorbic acid and its derivatives, eg ascorbic acid 2-glycoside / AA2G), and vitamin B (for example, niacinamide, niacin) and vitamin salts or derivatives such as ascorbic acid diglycoside and vitamin E acetate or palmitate; alpha-hydroxide acids and their precursors, such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxy-isobutyric acid, alpha-hydroxy-isocaproic acid, atrolatic acid , alpha-hydroxy-isovaleric acid, ethyl pyruvate, galacturonic acid, glycoheptonic acid, glycoheptone 1,4-lactone, glyconic acid, glycone-lactone, glycuronic acid, glycuronolactone, isopropyl pyruvate, methyl pyruvate, musclic, pyruvic acid, saccharic acid, 1,4-lactone saccharic acid, tartaric acid and tartaric acid; beta-hydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid and beta-phenylpyruvic acid; tetrahydroxypropylethylenediamine, N, N, N ', N-tetrakis (2-hydroxypropyl) ethylenediamine (THPED); and botanical extracts such as green tea, soy, milk, thistle, seaweed, aloe, angelica, bitter orange, coffee, Coptis herb, grapefruit, "hoellen", honeysuckle, tears of our lady, weed-of-the-seven-bleeds, blackberry, peony, pueraria, "nice" and saffron and salts and prodrugs thereof. Topical stripping compositions
[0117] In one embodiment, the topical composition contains a depigmentation agent. Examples of suitable depigmentation agents include, but are not limited to, soy extract; soy isoflavones; retinoids like retinol; cojic acid; cojic dipalmitate; hydroquinone; arbutin; tranexamic acid; vitamins such as niacinamide, niacin and vitamin C (ascorbic acid and AA2G; azelaic acid; linolenic acid and linoleic acid; placenta; licorice; and extracts such as chamomile, grape seeds and green tea; and salts and prodrugs thereof. Topical antipsoriatic compositions
[0118] In one embodiment, the topical composition contains an active antipsoriatic agent. Examples of active antipsoriatic agents (for example, for the treatment of seborrheic dermatitis or eczema) include, but are not limited to, corticosteroids (for example, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorascona diacetate, propionate propionate halobetasol, triamcinonide, dexamethasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, aclomethasone dipropionate, methacrylone hydrochloride, methacrylate, hydrochloride) cyclosporine, calcipotriene, anthralin, bituminous shale and derivatives thereof, elubiol, ketoconazole, coal tar, salicylic acid, zinc pyrithione, selenium sulfide, hydrocortisone, sulfur, menthol and pramoxin hydrochloride, and salts and prodrugs thereof. Other topical ingredients
[0119] In one embodiment, the topical composition contains a plant extract as an active agent. Examples of plant extracts include, but are not limited to, feverfew, soy, soy glycine, oats, wheat, aloe vera, cranberry, witch hazel, alnus, arnica, artemisia capillaris, deasiasarum root, birch, marigold, chamomile, cinder, comfrey, fennel, galla rhois, hawthorn, houttuynia, hypericum, jujube, kiwi, licorice, magnolia, olive, peppermint, philodendron, sage, sasa albo-marginata, natural isoflavonoids, soy isoflavones and natural essential oils.
[0120] In one embodiment, the topical composition contains one or more buffering agents, such as citrate buffer, phosphate buffer, lactate buffer, malate buffer, glycolate buffer, gluconate buffer, or gelling agent, thickener or polymer.
[0121] In one embodiment, the composition or product contains an effective fragrance to reduce stress, calm and / or affect sleep such as lavender and chamomile.
[0122] The powder comprising core / capsule particles can be incorporated into compositions for the treatment of periodontal disease with assets such as, but not limited to, minocycline. Compositions for treating wounds, injuries and scars
[0123] In one embodiment, the powder comprising core / capsule particles is incorporated into wound dressings or bandages to accelerate healing or prevent scarring. Wounds or injuries that can be treated include, but are not limited to, acute wounds as well as chronic wounds, including diabetic ulcers, varicose ulcers, and pressure ulcers.
[0124] In one embodiment, the wound dressing or bandage contains an active agent commonly used as a topical treatment for wounds and scars, such as antibiotics, antimicrobials, wound healing enhancing agents, antifungal drugs, antipsoriatic drugs and anti-inflammatory agents .
[0125] Examples of antifungal drugs include, but are not limited to, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole, butocona-zol, tioconazole, acid, zolconol, zolconol, zazole, zolconol undecylenic, haloprogin, butenafine, to I naphtha, nystatin, cyclopyropolamine, terbinafine, amorolfine, naphthifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts and prodrugs. In one embodiment, the antifungal drug is an azole, an allylamine or a mixture thereof.
[0126] Examples of antibiotics (or antiseptics) include, but are not limited to, mupirocin, neomycin sulfate and bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlorethracycline hydrochloride, oxytetracycline-10 hydrochloride and tetracycline hydrochloride) , clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzonium chloride, phenol, quaternary ammonium compounds, tea tree oil, and their pharmaceutically acceptable salts and prodrugs.
[0127] Examples of antimicrobials include, but are not limited to, chlorhexidine salts, such as iodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine isothionate, and chlorhexidine hydrochloride. Other cationic antimicrobials can also be used, such as benzalkonium chloride, benzethonium chloride, trilocarban, polyhexamethylene biguanide, cetylpyridinium chloride, methyl chloride and benzethonium. Other antimicrobials include, but are not limited to, halogenated phenolic compounds, such as 2,4,4 ', - trichloro-2-hydroxy-dipheniether (Triclosan); xylenol parachloromethane (PCMX); and short-chain alcohols, such as ethanol, propanol and the like. In one embodiment, the alcohol is in a low concentration (for example, less than about 10% by weight of the vehicle, such as less than 5% by weight of the vehicle) so that it does not cause undue drying of the barrier membrane.
[0128] Examples of antiviral agents for viral infections such as herpes and hepatitis, include, but are not limited to, imiquimod and its derivatives, podofilox, podophyllin, interferon alfa, acyclovir, famciclovir, valciclovir, reticles and cidofovir and salts and prodrugs thereof. .
[0129] Examples of anti-inflammatory agents include, but are not limited to, suitable steroidal anti-inflammatory agents, such as corticosteroids, such as hydrocortisone, hydroxyltriamcinolone alfamethyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, clobetasol valerate, deson deoxymethasone, deoxycorticosterone acetate, dexamethasone, dichlorisone, difloresin diacetate, diflucortolone valerate, fluadrenolone, fluclaroone canvas acetonide, fludrocortisone, flumetasone pivalate, fluosinol-acetonide, flucinolone, fluoroinolone, is fluprednidene (fluprednilidene), flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, acetonide triamcino-canvas, cortisone, cortodoxone, flucetonide, fludrocortisone, amidone, fluoronehydride, ammonidone, fluorohydride, ammonia chlorprednisone, chlorprednisone acetate, clocortelone , clescinolone, dichlorisone, difluprednate, flucloronide, fluinisolide, fluorometallone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, dipretone, betamethasone, prednisone, trietnamone, prednisone, prednisone, prednisone its salts and prodrugs. In one embodiment, the steroidal anti-inflammatory for use in the present invention is hydrocortisone. A second class of anti-inflammatory agents that is useful in the compositions of the present invention includes non-steroidal anti-inflammatory agents.
[0130] Examples of wound healing enhancing agents include recombinant human platelet-derived growth factor (PDGF) and other growth factors, ketanserin, iloprost, prostaglandin E1 and hyaluronic acid, scar reducing agents such as mannose-6 -phosphate, analgesic agents, anesthetics, hair growth or hair enhancing agents such as minoxadil, hair growth retardants or hair such as eflornithine hydrochloride, antihypertensives, drugs to treat coronary artery disease, anticancer agents, endocrine medication and metabolic, neurological medications, medication for cessation of chemical dependencies, motion sickness (motion sickness), protein and peptide drugs. Topical treatment of microbial infections of the body
[0131] In one embodiment, the powder comprising core / capsule particles is used, with or without other active antifungal agents, to treat or prevent fungal infections (eg, dermatophytes, such as trichophyte mentagrophytes), including, but not limited to, not limited to, sporotrichosis onychomycosis, tinea of the nails, tinea of the feet (athlete's foot), tinea cruris (itching in the groin), tinea corporis (ringworm), tinea bees, tinea versicolor, and diseases related to infection by candida fungus (eg Candida albicans) such as diaper erythema, oral candidiasis, cutaneous and vaginal candidiasis, genital erythema, diseases related to Malassezia furfur infection, such as Pityriasis versicolor, Pityriasis folliculitis, seborrheic dermatitis, and dandruff.
[0132] In one embodiment, the powder comprising core / capsule particles is used, with or without other active antibacterial agents, to treat or prevent bacterial infections, which include, but are not limited to, acne, cellulite, erysipelas, impetigo, folliculitis and boils and carbuncles, as well as acute wounds and chronic wounds (varicose ulcers, diabetic ulcers and pressure ulcers).
[0133] In another embodiment, the powder comprising core / capsule particles is used, with or without other active antiviral agents, to treat and prevent viral infections of the skin and mucosa, which include, but are not limited to, molluscum contagiosum, warts, herpes simplex virus infections, such as cold sores, thrush and genital herpes.
[0134] In another embodiment, the powder comprising core / capsule particles is used, with or without other anti-parasitic active agents, to treat and prevent parasitic infections, which include, but are not limited to, hookworm infection, lice , scabies, eruptions caused by sea water and swimmer itching.
[0135] In one embodiment, the powder comprising core / capsule particles is administered to treat ear infections (such as those caused by streptococcus oneumoniae), rhinitis and / or sinusitis (such as those caused by Haemophilus influenzae, Moraxella catarrhalis, Sta-phylococcus aureus and Streptococcus pneumoniae), and streptoococcal pharyngitis (such as those caused by Streptococcus pyogenes).
[0136] In one embodiment, the powder comprising the core / capsule particles is administered orally by an animal (for example, as an animal feed) or a human being (for example, as a dietary supplement) to prevent the onset of carried diseases by food (for example, derived from foodborne pathogens such as Campylobacter jejuni, Listeria monocytogenes and Salmonella enterica). Topical nail treatment
[0137] The powder comprising the core / capsule particles can also be used to stimulate nail growth, enhance nail strength and reduce nail infection or discoloration. The powder comprising the core / capsule particles can be incorporated into compositions for the treatment of onychomycosis with actives such as, but not limited to, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voricoriazole, clioquinol, bifoconazole, terco - nazole, butoconazole, thioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogine, butenafine, tolnaftate, nystatin, cyclopyroxolamine, terbinafine, amorolfine, naphthymine, elubiol, gri- pharmaceutically acceptable. The powder comprising the core / capsule particles can be incorporated into the compositions to improve the appearance and touch of nails with ingredients such as, but not limited to, biotin, calcium panto- tenate, tocopheryl acetate, panthenol, phyanthriol, cholecaliferol , calcium chloride, Aloe Barbadensis (leaf juice), silk protein, soy protein, hydrogen peroxide, carbamide peroxide, green tea extract, acetylcysteine and cysteine. Topical treatment for hair, hair follicles and scalp
[0138] The powder comprising the core / capsule particles can be combined with certain active agents for hair growth or to enhance or thicken hair on the scalp, eyebrow or eyelashes, or beard and can be used to treat capillary conditions topically. Compositions containing the drug (s) and / or active agents to stimulate hair growth and / or prevent hair loss, including, but not limited to, minoxidil, finasteride, or lumigan can be used.
[0139] The powder comprising the core / capsule particles has a unique advantage over conventional hair treatment compositions due to its excellent fluidity. For example, the powder can easily reach the scalp through thin hair in the case of alopecia treatment. The powder is easily broken by gently rubbing it with one hand or comb, releasing the active agent (for example, minoxidil, finasteride, bimatoprost) to the scalp skin close to the roots of the hair follicles (that is, the hair bulb, which is the target site for topical treatment of hair growth) without loss of active on the hair strands, disturbing the hairstyle, or causing an undesirable appearance of the hair in the form of liquid gel, aerosol, foam, or spray products can do that. Topical compositions for pain and itching
[0140] The powder comprising the core / capsule particles may contain certain active analgesic agents and as such can be prepared for topical treatment of pain, such as back pain or part of the back, shoulders, joints, muscle pain, menstrual cramps, or pain from cold sores or thrush. Active pain-relieving agents include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, salicylic acid, ketoprofen and diclofenac, and their pharmaceutically acceptable salts. Other topical analgesic active agents for treating pain and itching include, but are not limited to, methyl salicylate, menthol, trolamine salicylate, capsaicin, lidocaine, benzocaine, pramoxin hydrochloride, and hydrocortisone. Inquisitive compositions
[0141] Ingestible compositions suitable for ingestion by a mammal, such as a human being, can be produced using the powder of the invention.
[0142] In one embodiment, an ingestible composition contains a safe and effective amount of (i) at least one active agent or drug, and (ii) the powder comprising the core / capsule particles within which or with which active agent or drug is located. The active agent can be any category of drug for any treatment, including as an oral medication, or it can be a nutritional supplement. In one embodiment, the ingestible composition contains, per unit dosage (for example, powder, capsule, full teaspoon, or the like) an amount of the active agent needed to deliver an effective dose for the necessary treatment.
[0143] In one embodiment, the ingestible composition comprises a hard gelatin capsule filled with the powder of the invention, one or more active agents being loaded into the liquid core, the capsule, and / or out of the powder but within of the hard gelatin capsule. In one embodiment, the composition is in unit dosage form as packaged unit capsules, powders, or granules.
[0144] In another embodiment, an ingestible composition comprises two or more powders of the invention each containing an active agent loaded within the liquid core or capsule of each powder. This composition is particularly suitable for active agents that are chemically incompatible.
[0145] Ingestible compositions comprising active agents contained in the powders of the invention are advantageous in that: (a) a part or all of the active agent can be dissolved in the liquid core of the core / capsule particles, thus allowing rapid absorption gastrointestinal compared to solid dosage forms such as tablets, dry powders, or hard gelatin capsules filled with conventional dry particles; and (b) chemically incompatible active agents can be dissolved in separate powders to avoid unwanted chemical interactions / reactions but still provide the convenience and safety of a unique product (as in a hard gelatin capsule) for the patient.
[0146] Exemplary treatments using ingestible compositions containing a powder of the invention and active agents, include the following. Treatment of gastrointestinal dysfunction
[0147] In one embodiment, the ingestible compositions according to the invention are used for the treatment of gastrointestinal disorders, such as ulcers, diarrhea and gastrointestinal pain.
[0148] The active agents to treat diarrhea include, but are not limited to: bismuths (such as bismuth subsalicylate), loperamide, simethicone, nitazoxanide, ciprofloxacin and rifaximin, salts and prodrugs (such as esters).
[0149] Active agents to treat gastric ulcers include, but are not limited to: Lansoprazole, Naproxen, Esomeprazole, Famotidine, Nizatidine, Ranitidine, and Omeprazole, and salts and prodrugs thereof.
[0150] Active agents for the treatment of intra-abdominal infections include, but are not limited to: Moxifloxacin, Ciprofloxacin, Ceftazidime, Gentamicin, Ertapenem; Cefepime, Cefoxitin, Cyphenatine, Imipenemo; Ceftriaxone, Clavulanate, and Ticarcillin, and salts and prodrugs thereof. Treatment of pain or cough unreasonable compositions
[0151] In one embodiment, the ingestible compositions according to the invention are used to treat pain (such as sore throat). Oral dosage forms can be in the form of, but are not limited to, hard gelatin capsules, lozenges, or spray powder. Active agents known to treat sore throat include, but are not limited to: Acetaminophen, Dextromethorphan, Pseudoephedrine, Chlorpheniramine, Pseudoephedrine, Guaifenesin, Doxylamine, Zinc, and Ibuprofen, and their salts and prodrugs. Inquisitive compositions of medicinal food and oral supplement
[0152] In one embodiment, the ingestible compositions according to the invention, such as hard gelatin capsules or powdered dosage form, can be used for oral supplement products. Active agents for the purposes of the present invention include vitamins and minerals, which include, but are not limited to: Dibasic calcium phosphate, magnesium oxide, potassium chloride, microcrystalline cellulose, ascorbic acid (Vit. C), ferrous fumarate , calcium carbonate, dl-alpha-tocopheryl acetate (Vit. E), acacia, ascorbyl palmitate, beta-carotene, biotin, BHT, calcium pantothenate, calcium stearate, chromic chloride, citric acid, crospovidone, cupric oxide, cyanocoballamine (Vit. B 12), Ergocalciferol (Vit. D), folic acid, gelatin, hypromolesterol, lutein, lycopene, magnesium borate, magnesium stearate, manganese sulfate, niacinamide, nickel sulphate, phytonadione (Vit . K), potassium iodide, pyridoxine hydrochloride (Vit. B), riboflavin (Vit. B 2), silicon dioxide, sodium aluminum silicate, sodium ascorbate, sodium benzoate, sodium borate, sodium citrate , sodium metavanate, sodium molybdate, sodium selenate, sorbic acid, stannous chloride, sucrose, thiamine mononitrate (Vit. B 1), titanium dioxide, tribasic calcium phosphate, vitamin A acetate (Vit. A), and zinc oxide, and salts and prodrugs thereof.
[0153] For ingestible compositions comprising the powder of the invention, the hydrophobic smoked silica, AEROSIL 972 Pharma, available from EVONIK DEGUSSA CORPORATION, is particularly suitable for use as the hydrophobic particles of the capsule. Examples
[0154] The examples are presented below to further illustrate the nature of the invention and the way to carry it out. However, the invention should not be considered to be limited to the details shown. Example 1 - Preparation of 5% minoxidil powder
[0155] A 200 g total weight powder was produced following the procedures and the composition below (in% by weight): 1. Citric acid 5%, glycerin 82%, and minoxidil powder 5% were added to a glass container and mixed until the solution became clear at room temperature.2. The above liquid mixture was added to the high speed mixer (for example, Oztis mixer model BCBG08). 8% smoked silica (for example, AEROSIL R812S, Evonik Degussa) was added at room temperature and the mixture was mixed at its highest setting for about 10 to 20 seconds, resulting in an off-white powder. Example 2 - In vitro skin permeation of 5% minoxidil compositions through human cadaver skin.
[0156] A skin penetration study evaluated the penetration of minoxidil into different layers of the skin for powder samples of the inventive cream prepared as revealed in Example 1 versus a commercially available 5% minoxidil solution sample (Rogaine hair regrowth treatment Extra Resistance for men, 5% minoxidil solution).
[0157] A well-known Franz diffusion cell method (taught in US20020006418 A1 which was incorporated into the present invention for reference) was used. Franz cells had a diameter of 0.5 cm2 and a volume of the recipient liquid of 5 ml. A magnetic stirrer was added to the donor compartment. The liquid receiver was filled with phosphate-buffered saline (FTS). The air bubbles formed in the donor compartment were removed. The system was thermostated at 37 ° C above a magnetic stirrer to ensure homogeneity of the liquid receiver during the experiment. A sample of cadaver skin from a commercial tissue bank (Ohio Valley Tissue and Skin Center, Cincinnati, OH, USA dermatomated approximately 0.4 mm) was cut to fit the glass diffusion cell and the skin mounted on the cell of Franz. A 20 microliter test sample was applied to the skin surface. The samples were collected from the receiving compartment at programmed time intervals of 0, 1.3 and 6 hours.
[0158] At the end of the study, the skin surface was washed with a cotton pad of liquid receptor (PBS). After washing, skin extraction was performed on the entire skin or on separate layers of skin from the epidermis and dermis. The samples collected from the recipient compartment and skin extraction were analyzed for minoxidil levels with a Walters high performance liquid chromatography (HPLC) system according to the procedure described below. The results are shown in Table 1. The final averages of minoxidil levels in the different skin layers are recorded in micrograms (pg) for 3 different replicates. The study of minoxidil mass balance was also performed and the% recovery of minoxidil was better than 95% for both the control formulation and the formulation of the invention.

[0159] Since the target tissue for topical application of minoxidil is that of the hair follicles (hair roots) that are deep in the dermis, only the minoxidil that penetrated in and through the dermis layer was able to reach the hair follicles and therefore, they are of practical significance. It is surprising that the powder-to-liquid composition of the present invention has a significantly improved depth of application of minoxidil on human skin (i.e., by about 100% into the dermis, where the hair bulb is located) compared to the commercial minoxidil solution of the same drug concentration, as shown by the results in Table 1. This is an unexpected finding since the commercial minoxidil solution contains a significant amount of two well-known skin permeation enhancers, ethanol (30% ) and propylene glycol (50%), while the powder-to-liquid composition of the present invention contains none of these skin permeation enhancers, but only glycerin. Glycerin is not generally considered to enhance skin permeation. HPLC procedure for quantification of minoxidil
[0160] An HPLC system (Walters Alliance® HPLC system) was used to measure minoxidil with UV absorption response at 286 nm. A 5 pM C18 (2) 250 x 4.6-mm Luna HPLC column (Phenomenex) was used to separate the minoxidil analyte from other impurities in the extract samples in the surface washing, strip removal, extraction processes the epidermis and dermis, and the receiving solution. The mobile phase was an 80% isocratic mixture (70: 29: 1 water / methanol / acetic acid - pH 3.3): 20% methanol. Example 3. Study of hair or mouse hair growth Procedure
[0161] An in vivo hair or hair growth study was conducted on a mouse model similar to that described in US6419913 B1. Five female mice (C3H mice, Charles River Breeding Laboratories, Kingston, NY, USA) were included for each test article. The mice were shaved with a short hair clipper to be hairless on the back (2 x 5 cm2 area) at the beginning of the study. The test articles were applied to the shaved areas of the mice daily at 0.2 ml per dose. Both the anagen phase of the hair and the hair cover were visually observed and recorded daily during each hair condition or the mouse hair (telogen phase: rest phase in the hair growth cycle - the shaved skin shows no roots / dark hair bulbs; anagen phase: anagen follicles, that is, follicles in the growth state in the hair growth cycle - the shaved skin shows dark roots / hair bulbs).
[0162] As shown in Table 2, the composition according to the present invention resulted in hair follicles going from the resting state to the growth state about four days before the commercially available composition.
[0163] As shown in Table 3, the composition according to the present invention started hair growth earlier and more hair grew than with the commercially available composition. Table 2 - Record of the anagen phase
Hair coverage scoring systemRating Description0 No hair at all1 Some patches of hair growth or hair, less than% of the back area2 Hair growth covering about% of the back area3 Hair growth covering about% of the back area4 Hair growth covering more than% of area5 Hair growth completely covering the treatment areaTable 3 - Hair / hair coverage score table for mice hair / shaved hair with (n = 5 per cell at the beginning of the study)

* Two test mice were sacrificed after the week 5 evaluation for tissue histology Example 4 - Ibuprofen powder
[0164] Preparation of 200 grams of Formula A and Formula B containing the respective ibuprofen were prepared with the compositions shown in Table 4 below, using the process described in Example 1. Although these powder-to-liquid powder compositions have been made initially, the powders of these compositions started to adhere to each other and formed aggregates after one day, indicating that these powder-to-liquid compositions were not stable as free flowing powder due to the presence of many non-polar components (DMI and / or TE Neutral, in addition to the drug ibuprofen) in the liquid nucleus. Table 4. (in parts)

[0165] Preparation of 215 grams of Formula C and Formula D containing the respective ibuprofen were prepared with the compositions shown in Table 5 below, using the process described in Example 1. In contrast to Formulas A & B, the powder structures of Formulas C and D from powder-to-liquid remained stable with an excellent free flow property. Table 5. (in parts)

[0166] Although the invention has been described above with reference to specific modalities, it will be evident that many changes, modifications and variations can be made without departing from the concept of the invention disclosed herein. Consequently, the objective is to cover all these changes, modifications and variations in the spirit and the broad scope of the attached claims.

权利要求:
Claims (14)
[0001]
1. Powder comprising core / capsule particles with an average particle size less than 1000 microns, characterized by the fact that each particle comprises: a water-free liquid core and comprising: A) a polar liquid having a percentage of surface polarity 24%, B) an acidic active agent consisting of 0.001% to 20% ibuprofen by weight of the powder, eC) 0.1% to 20% by weight of a solubility-enhancing agent that is not an active ingredient ; and a capsule comprising hydrophobic particles.
[0002]
2. Powder according to claim 1, characterized in that the hydrophobic particles comprise hydrophobic smoked silica.
[0003]
3. Powder, according to claim 2, characterized by the fact that the polar liquid comprises a polyol selected from the group consisting of glycerols, polyglycerols, glycols, polyglycols and combinations thereof.
[0004]
4. Powder, according to claim 3, characterized by the fact that the polyol is selected from the group consisting of glycerol, diglycerol, triglycerol, tetraglycerol, polyglycerols having more than 4 glycerol groups, and mixtures thereof.
[0005]
5. Powder according to claim 3, characterized in that the polar liquid comprises at least about 50 weight percent of a glycerol, polyglycerol, or a mixture thereof.
[0006]
6. Powder according to claim 1, characterized by the fact that the acidic active agent comprises from 0.01% to 10% by weight of the powder.
[0007]
7. Powder according to claim 6, characterized in that the acidic active agent comprises from 0.1% to 5% by weight of the powder.
[0008]
8. Powder according to claim 1, characterized by the fact that the solubility enhancer is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate , sodium carbonate, calcium carbonate, magnesium carbonate, ethylamine, diethylamine, triethylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, triisopropanolamine and mixtures thereof.
[0009]
9. Powder according to claim 1, characterized by the fact that the basic solubility enhancer is in an amount of 1% to 5% by weight of the powder.
[0010]
10. Method for improving the topical application of a beneficial agent characterized in that it comprises administering topically to a human or animal a powder composition as defined in claim 1.
[0011]
11. Method according to claim 10, characterized by the fact that the active agent comprises from 0.01% to 10% by weight of the powder.
[0012]
12. Method according to claim 11, characterized by the fact that the active agent comprises from 0.1% to 5% by weight of the powder.
[0013]
13. Method according to claim 10, characterized in that the solubility enhancer is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate , sodium carbonate, calcium carbonate, magnesium carbone, ethylamine, diethylamine, triethylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, ethylene diamine, triisopropanolamine and mixtures thereof.
[0014]
14. Method according to claim 13, characterized by the fact that the acid solubility enhancer is in an amount of 1% to 5% by weight of the powder.

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同族专利:

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RU2016142398A|2018-05-03|

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法律状态:
2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-07-14| B09A| Decision: intention to grant|

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2020-11-17| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/03/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US14/230,535|US9468606B2|2014-03-31|2014-03-31|Compostions and methods for enhancing the topical application of an acidic benefit agent|

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US14/230,535|2014-03-31|

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PCT/US2015/019588|WO2015153073A1|2014-03-31|2015-03-10|Compositions and methods for enhancing the topical application of an acidic benefit agent|

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