KR20210111640A - FINE PARTICULATE TiO2 COMPOSITIONS AND TOPICAL FORMULATIONS INCLUDING THE SAME - Google Patents

Abstract

Provided are a particulate titanium dioxide (TiO_2) composition suitable for use in topical formulations, and a method for manufacturing the same. In a particle titanium dioxide (TiO_2) composition, a titanium dioxide (TiO_2) activator is entrapped in the pores of the particle and/or is coupled and/or loosely coupled to the particle surface via ionic and/or non-covalent bonding. In addition, provided are a formulation comprising the particle titanium dioxide (TiO_2) composition, and a method for using the same.

Description

FINE PARTICULATE TiO2 COMPOSITIONS AND TOPICAL FORMULATIONS INCLUDING THE SAME

Reference to related applications

Pursuant to 35 USC § (1) (19) (e) of the U.S. Patent Act, U.S. Provisional Patent Application No. 61/798,758, filed March 15, 2013, and Provisional U.S. Patent Application No. 61/938,080, filed February 10, 2014 claim priority, the disclosures of which are incorporated herein by reference.

The skin includes a superficial layer known as the epidermis, and a deep layer of connective tissue known as the dermis. The epidermis is constantly undergoing changes as the outermost cells are exfoliated and replaced by cells originating from the inner dermal layer. The dermis is composed of various cell types, including fibroblasts.

As the dermis becomes thinner and the number of dermal fibroblasts decreases, skin thickness begins to decrease in humans after the age of 20. As the skin ages, or is exposed to ultraviolet light and other environments, changes in the inner dermis can lead to functional and morphological changes associated with skin damage. A decrease in the number and function of fibroblasts containing abundant collagen and proteoglycans is thought to play an important role in wrinkles and skin damage.

Accordingly, the present invention provides a stable titanium dioxide (TiO2) composition, and a method for preparing the same.

Particulate titanium dioxide (TiO2) compositions suitable for use in topical formulations, and methods of making the same are provided. In a titanium dioxide (TiO2) composition, titanium dioxide (TiO2) is entrapped in the pores of the particle and/or connected and/or loosely connected to the particle surface via ionic and/or non-covalent bonding. Formulations comprising the titanium dioxide (TiO2) composition of the present invention and methods of using the same are also provided.

The compositions and methods of the present invention can provide stable particulate titanium dioxide (TiO2) compositions.

Or a range excluding both is also included in the present invention.

In the present specification, certain ranges are indicated by numerical values preceded by the term "about." As used herein, the term “about” is used to provide full support for the exact number and the number that approximates or approximates the number that the term precedes. In determining whether a number approximates or approximates a specified number, an unspecified number that approximates or approximates is a number that, within the context in which the number is indicated, provides a substantial equivalent of the specified number. Particulate titanium dioxide (TiO2) compositions suitable for use in topical formulations, and methods of making the same are provided. In particle titanium dioxide (TiO2) compositions, titanium dioxide (TiO2) is either trapped in the pores of the particle or is coupled or loosely coupled to the particle surface through ionic and/or non-covalent bonding. Formulations comprising the particulate titanium dioxide (TiO2) composition of the present invention and methods of using the same are also provided.

Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described and may be variously modified. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting, since the scope of the present invention is limited only by the appended claims.

Where a range of values is provided, each intervening value to the decimal point of the lower unit is between the upper and lower limits of that range, unless the context dictates otherwise, and any other stated or intermediate value within the stated range. is understood to be encompassed within the present invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are included within the invention subject to any specifically excluded limit within the stated range. Where the stated range includes either or both of these limits, either of those included limits

The methods described herein may be performed in any order of events, and in any order of events, logically possible.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are described below.

All publications cited herein are incorporated herein by reference for the purpose of disclosing and describing methods and/or materials related to these publications.

In the specification and appended claims, the singular forms "a", "an" and "the" include plural referents unless the context dictates otherwise. Furthermore, the claims may be written to exclude any optional element. Accordingly, this publication is intended to serve as an antecedent basis for the use of limiting terms such as "solely", "only", etc., or the use of "negative" limitations in connection with reference to a claim element.

The publications cited herein are provided solely for the purpose of their disclosure prior to the filing date of this application. Nothing herein is an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the publication date provided may be different from the actual publication date, which may require independent verification.

Method for producing dry particulates and dry particulates prepared using the same

As summarized above, the present invention comprises combining nanoporous calcium particles (e.g., calcium phosphate particles) and one or more titanium dioxide (TiO2) in a manner sufficient to prepare a dry particle titanium dioxide (TiO2) composition. which includes a method for preparing a particulate titanium dioxide (TiO2) composition. As noted above, in dry particle titanium dioxide (TiO2) compositions, the active agent is associated with the particle, for example entrapped in the pores of the particle and/or ionic and/or non-covalently bonded to the particle's surface and/or loosely coupled to the particle. In the practice of the method of the present invention, nanoporous calcium particles and at least one titanium dioxide (TiO2) activator, in the presence of a suitable solvent system, cause the active agent to enter the interior space of the particle and/or ionically bind to the surface of the particle and/or non- It is bound by covalent bonds and/or conditions in which it is loosely linked to the particle. Before describing the steps of the method, the particles, active agents and solvent systems that will be used in specific embodiments of the method are reviewed in more detail.

Nanoporous Calcium Particles

The particles used in the method of the present invention are nanoporous phosphate particles. "Nanoporous" means that the particle has a porosity of 30% or greater, such as 40% or greater, or 50% or greater, wherein the porosity is defined by ASTM D 4284-88 "Standard Test Method for Determining Pore Volume Distribution of Catalysts by Mercury Intrusion Porosimetry, as measured using a mercury porosimetry porosimetry protocol, for example, from 30% to 85%, for example from 40% to 70%, or 45%. to 55%. Porosity is also described in terms of "void volume (ml/g)" and, in this case, can range from 0.1 ml/g to 2.0 ml/g. In some cases, the particles may have their internal surface area ASTM D3663-03 Standard Test Method for Surface Area of Catalysts and Catalyst In the BET gas adsorption surface area measurement determined using the protocol as described in Carriers, 10m ² / g to 150m ² / g , for example, from 20 m ² /g to 100 m ² /g, has a porosity in the range ^{from 30 m 2} /g to 80 m ^{2 /g.} The pore diameter may, in certain instances, vary in the range of 2 to 100 nm, for example 5 to 80 nm, or 10 to 60 nm. Further, the particles may have a tap density (tap) in the range of ^{0.2 g/cm 3} to 0.5 g/cm ³ , for example 0.25 g/cm ³ to 0.45 g/cm ³ , or 0.3 g/cm ³ to 0.4 g/cm ^{3 .} density) can be obtained. Tap density can be measured using standard ASTMWK13023 - New etermination of Tap Density of Metallic Powders by a Constant Volume Measuring Method.

In some instances, the particles are hard particles that are uniform in shape and spherical. By “hard” it is meant that the particles are hard and therefore not flexible. By “uniform” it is meant that the shape of the particles does not change substantially, and thus the particles have substantially the same round shape. The term “spherical” is used in the traditional sense to mean a round body whose surface is substantially equidistant from the center at all points. Calcium phosphate particles having a mid-point diameter of 20 μm or less, for example 10 μm or less, or 5 μm or less, are preferred, wherein in some cases, the mid-point diameter is 4 μm or less, for example, 3 μm or less, or 2 μm or less. In certain calcium phosphate particulate compositions, all particles have a median point diameter of 20 μm or less, such as 10 μm or less, or 5 μm or less, and in some cases, a median point diameter of 4 μm or less. or less, for example, 3 µm or less, or 2 µm or less. In certain calcium phosphate particulate compositions, the average diameter of the total particles is 20 μm or less, for example, 10 μm or less, is 5 μm or less, in some cases, the average diameter is 4 μm or less; For example, 3 µm or less, or 2 µm or less. With respect to this range, the particles optionally have a diameter of 0.1 μm or more, for example 0.5 μm or more, for example 1.0 μm or more.

The particles are, in some cases, chemically pure. "Chemically pure" means that the particles are made of substantially one type of compound, for example a calcium compound such as a calcium phosphate mineral. Porous particles are calcium-containing particles, such as calcium-containing particles, made of molecules comprising a calcium-containing cation and a suitable anion (eg, carbonate, phosphate). In some instances, the particles are calcium carbonate particles, including, but not limited to, the calcium carbonate particles disclosed in US Pat. Nos. 5,292,495 and 7,754,176. In some instances, calcium phosphate particles are made of calcium phosphate and are described by the molecular formula Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ .

In some examples, the particles are ceramic particles. Ceramic means that the particles are produced using a method comprising subjecting these particles to high temperature conditions, where these conditions are exemplified below. The elevated temperature may range from 200 to 1000°C, for example from 300 to 900°C, or from 300 to 800°C. In some embodiments, the particles are particles sintered at a temperature of 400° C. to 900° C., as described in European Patent EP1840661, as measured using the SHIMADZU MCT-W500 Micro-Compression Test Machine Particle Strength Determination Protocol, 20 to 200 MPa , for example, a compression rupture strength in the range of 50 to 150 MPa, or 75 to 90 MPa. In some instances, the particles are biodegradable, meaning that they degrade, eg, dissolve, in a certain way over time under physiological conditions. Because the particles of these embodiments are biodegradable under physiological conditions, these particles begin to dissolve at a detectable rate under pH conditions of at least 5.8 or less, such as 5.5 or less, or 5.3 or less. Thus, the particles begin to degrade at a detectable rate under pH conditions of 5 or such as below 5, such as below 4.9.

The uniform, rigid, spherical, nanoporous calcium phosphate particles used in the examples of the method may be prepared using any convenient protocol. In one protocol, the particles are prepared by spray drying a slurry comprising nanocalcium phosphate (e.g., hydroxyapatite) crystals, which can have a size range of 2 nm to 100 nm, to produce uniform, round, nanoporous calcium phosphate particles. do. The resulting particles are then sintered for a sufficient time to provide mechanically and chemically stable and rigid spheres. In this step, the sintering temperature is 200°C to 1000°C, such as 300°C to 900°C, or 300°C for 1 hour to 10 hours, such as 2 hours to 8 hours, or 3 hours to 6 hours. It may range from °C to 800 °C.

In some cases, nanoporous calcium particles can be pretreated. Pretreated particles can be prepared via a number of different protocols. In some instances, such particles can be neutralized with a pH adjusting agent, such as an acid. The pH can be adjusted to the optimum range and, if necessary, specific to the active agent. Examples of the pH adjusting agent include weak or strong acids such as hydrochloric acid, glycolic acid, phosphoric acid, lactic acid and citric acid. In some instances, the particles may be pretreated with a phosphate such as sodium phosphate, or pretreated with a calcium salt such as calcium chloride. In some instances, mixtures of buffer systems are used, such as sodium citrate and citric acid or calcium chloride and lactic acid. If necessary, any salts formed during this protocol can be removed, for example, by filtration or decanting.

The weight percentage of calcium particles in a given amount of dry particulate composition can vary. In some cases, the weight % is from 10 to 95% by weight, such as from 20 to 90% by weight, such as from 25 to 90% by weight, from 50 to 90% by weight, from 50 to 70% by weight, from 55 to 65% by weight.

Titanium Dioxide (TiO2) Activator

The weight percent of titanium dioxide (TiO2) active agent in a given amount of dry particulate composition can vary. In some cases, weight percent includes 0.1 to 50 weight percent, such as 1 to 30 weight percent, such as 2 to 25 weight percent, 15 to 25 weight percent.

antioxidant

In some instances, titanium dioxide (TiO2) is stabilized by a single antioxidant or a mixture of antioxidants. In this case, the dry particulate active agent can be prepared by selecting the desired antioxidant or antioxidant mixture and dissolving it in a suitable organic- or water-based solvent. For organic solvents, retinaldehyde is added to the solution to become over-dissolved. Once dissolved, the calcium particles are added to the solution, eg, as above, and the suspension is evaporated to dryness by roto-evaporation, spray drying or other suitable method. For aqueous solvents, antioxidants are dissolved in aqueous solutions. Calcium particles are then added to the solution, eg, as above, and the solution is evaporated to dryness by rotary evaporation, spray drying or other suitable method. Retinaldehyde, as above, is dissolved in an organic-based solvent and added to the antioxidant-calcium particles.

The resulting suspension is evaporated to dryness by rotary evaporation, spray drying or other suitable method.

The antioxidant may be a mixture of one or more selected from the following list: Acacia victoria fruit extract, visceral maple leaf extract, acetamidocaproic acid, acetyl benzoyloxy prasterone, acetyl cysteine, 2-acetylhydroquinone, agrimony. (Agrimonia Eupatoria) root extract, Alchemilla vulgaris leaf extract, walnut stem/leaf water, aminoethanesulfonic acid, aminopropyl andrographolide, ascorbyl phosphate, aminopropyl tocopheryl phosphate, anserine, apigenin, Arabidopsis extract , arbutin, alpha arbutin, burdock fruit extract, rhizome extract, ascorbic acid, ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl glucoside, ascorbyl linoleate, ascorbyl methylsilanol pectinate , ascorbyl palmitate, ascorbyl stearate, ascorbyl tetraisopalmitate, ascorbyl tocopheryl malate, asiaticoside, avena sativa (oat), kernel extract, astaxanthin, bacillus/ Rice bran extract/soybean extract fermented filtrate, benzoguanamine, beta vulgaris (sugar beet) root extract, BHA, BHT, bis-dimethoxycurcumin, Budelya axillaris leaf extract, butyl xylenol, 4-butylresokinol, Caffeic Acid, Calcium Ascorbate, Longhwasoo Seed Oil, Green Tea Tree Catechins, Green Tea Tree Leaf Extract, Green Tea Tree Leaf Oil, Caparis Mooney Fruit Extract, Carnosic Acid, Carotenoids, Kayaponia Tuyuya Root Extract, Bacterifolia Flower/ Leaf/stem extract, chitosan ascorbate, chitosan glycol, chitosan salicylate, chlorogenic acid, mountain ginseng flower extract, horseradish extract, citron seed extract, cobalt DNA, copper adenosine triphosphate, yellow lily extract, croton, curcumin, guar from India (Guar) root-knot extract, honeybush leaf extract, cysteine, cysteine HCl, Davidsonia fruit extract, decyl mercaptomethylimidazole, dimethoxycurcumin, diacetylcurcumin, diamylhydroquinone, di-T-butylhydroquinone, dicetyl Thiodipropionate, digalloyl trioleate, dilauryl Thiodipropionate, dimethoxy di-p-cresol, dioleyl tocopherylmethylsilanol, diosmin, disodium ascorbyl sulfate, disodium rutinyl disulfate, disodium salicyl phosphate, disodium ubiquinone, Distearyl Thiodipropionate, Dodecyl Gallate, Dunariella Powder, Ellagic Acid, Epigallocatechin Gallate, Yin Yanggak Leaf/Stem Extract, Ergothionine, Bifoliar Protoplast, Erythorbic Acid, Ethyl Ferrulate, Ethyl Hexyl Ferrulate, Ethyl Hexyl Gallate, Euterpe Oleracea (Acai Berry) Extract, Ferulic Acid, Phoeniculum Bulgare (Fennel) Seed Extract, Fragilaria Pinnata Extract, Fulfuryl Palmitate , genistein glucoside, ginkgo leaf terpenoid, glucosyl rutin, glutathione, glycine soya (soybean) oil, licorice root extract, licorice root water, Maitake mycelium ferment filtrate extract, hematococcus extract, Hematococcus Oil, Hematococcus Powder, Hesperetin, Hesperetin Laurate, Hesperidin Methyl Chalcone, Honokiol, Hydrolyzed Aspergillus/Ginseng Extract Ferment, Hydrolyzed Gardenia Extract, Hydrolyzed proanthocyanidin, hydrolyzed soybean extract, hydroquinone, P-hydroxyanisole, hydroxydecyl ubiquinone, hydroxylamine HCl, hydroxylamine sulfate, hypericin, inositol hexaniacinate hexaascor Bate, isooctyl thioglycolate, isoquercetin, kaempferol, kojic acid, kozyl glucoside, kozyl methylenedioxycinnamate, lentil root nodule extract, chrysanthemum root extract, flaxseed oil ascorbate ester, bee yellow root nodule extract, lutein , Lycopene, Bidecassoside, Magnesium Ascorbate, Magnesium Ascorbate/PCA, Magnesium Ascorbyl Phosphate, Magnolol, Acerola Fruit Extract, Manganese Adenosine Triphosphate, Manganese Dioxide, Mango, Mangosteen, Alfalfa root nodule Extract, Melaleuca (Tea Tree) Leaf Oil, Melatonin, Methoxy PEG-7 Ascorbic Acid, Methoxy PEG-7 Rutinyl Succinate, Methyl Di-t-butyl hydroxyhydrocinnamate, methylsilanol ascorbic acid, fermented red yeast rice/rice, niacinamide hydroxybenzoate, nordihydroguayretic acid, octanicotinoyl epigallocatechin gallate , Olive Fruit Extract, Palmitoyl Green Tea Extract, Palmitoyl Grape Seed Extract, Phenylthioglycolic Acid, Phloroglucinol, Pikea Robusta Extract, Red Pepper Seed, Pea Root Knot Extract, Pomegranate, Potassium Ascorbyl Tocopheryl Phosphate, Potassium Sulphite, Propyl gallate, pyridoxine hydroxybenzoate, pyridoxine hydroxycitrate, quercetin, resveratrol, retinyl formyl aspartame, rosmarinic acid, rosemary flower extract, rosemary leaf extract, rutin, rutin hydrate, sodium ascorbate, sodium ascorbyl /Cholesteryl phosphate, sodium ascorbyl phosphate, sodium hydrogen sulfite, sodium erythobate, sodium metabisulfite, SOD, peroxide oxidase, sodium sulfite, sodium tocopheryl phosphate, stearyl gallate, tetrahexyldecyl ascorbate , tetrahicucumin, tetrahydrocurcumin diacetate, thioctic acid (alpha lipoic acid), thioglycolamide, thiodiglycolic acid, thiolactic acid, thiotaurine, tocopherol, tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate , Tocopheryl Retinoate, Tocopheryl Succinate, Tocoquinone, Trisodium Ascorbyl Isopalmitate Phosphate, Ubiquinol, Ubiquinone (Co Q-10), Grape Juice Extract, Grape Seed Extract, Zinc Adenosine Triphosphate, Zinc Ascorbate.

As discussed above, a given antioxidant component may consist of a single antioxidant or two or more different antioxidants, eg, three or four or more, five or more antioxidants. In some examples, the antioxidant component comprises two antioxidants.

Where the antioxidant component includes two or more antioxidants, any convenient combination may be used.

For example, BHT and ascorbyl palmitate, thioctate (alpha lipoic acid) and calcium ascorbate, tocopherol (e.g. mixed tocopherol) and thioctic acid (alpha lipoic acid) and resveratrol, tocopherol and thioctic acid (alpha lipoic acid) ) can be used. When two or more antioxidants are included, the weight ratio of antioxidants may vary, and the weight ratio may be the same, for example 1:1, in the range from 0.1:5 to 5:0.1, for example from 1:2.5 to 2.5 It may be different by :1.

In a given amount of the dry particulate composition, the weight percentage of the total antioxidant component (eg, consisting of one or more antioxidants, as described above) may vary. In some examples, the weight percent is from 1 to 50 weight percent, such as 5 to 30 weight percent, such as 5 to 25 weight percent, 5 to 20 weight percent, 15 to 20 weight percent.

It should be noted that the antioxidant compositions as described herein are not limited for use with, for example, titanium dioxide (TiO2) activators. The disclosed antioxidant systems can be used with a variety of other activators when used in combination with calcium particles, and such compositions are described, for example, but not limited to, in U.S. Patent No. 8,445,002, the disclosure of which is It is incorporated herein by reference.

solvent system

The solvent system may be composed of a single solvent or two or more different solvents, and the specific solvent or solvents constituting the solvent system may be selected based on the properties of the active agent to be combined with the particles. In some instances, the solvent system is aqueous and may be 100% water, and may be used as needed with one or more additional solvents, including organic or inorganic, polar and non-polar solvents. In another example, the solvent system may be non-polar.

Fabrication of dry particle activators

In the preparation of a dry particle active according to an embodiment of the present invention, as outlined above, the active agent(s), nanoporous calcium phosphate particles and a solvent system are combined to form a calcium phosphate particle/active agent mixture. The various components may be combined using any convenient protocol. In some instances, the active agent(s) is first dissolved in a solvent system and the resulting active agent solution is combined with the calcium phosphate particles. In another example, calcium phosphate particles are first combined with a solvent system and then an activator is added to form a calcium phosphate particle/active agent mixture.

The active agent(s) and solvent system may be combined using any protocol sufficient to produce the desired mixed solution. In some cases, the active agent(s) and solvent system are combined by stirring. Stirring can be provided using any convenient protocol, for example, a stir bar, stir blade, propeller, and the like. The temperature at which the active agent binds and dissolves with the solvent system may vary and may be below room temperature, at room temperature or above room temperature. The particular temperature at which the combination of the active agent and solvent is carried out may be based on the properties of the solvent system, such as melting point, boiling point, etc., as well as the properties of the active agent selected (e.g. the temperature is selected so as not to inactivate the active agent). . In some cases the temperature range is only in the range of 0°C to 200°C. In some examples, the temperature ranges from 4 to 25°C, for example from 5 to 10°C. In some examples, the temperature is at least room temperature, such as 35 to 60 °C, such as 40 to 45 °C, 50 to 55 °C, or higher. In some examples, the temperature is between 65 and 150° C., such as between 70 and 85° C., between 90 and 105° C., between 120 and 135° C. or higher. In some examples, the temperature is between 5 and 80°C, such as between 5 and 75°C, such as between 10 and 65°C, such as between 20 and 60°C.

The amount of active agent dissolved in the solvent system may be selected based on the solubility of the active agent in the solvent system and/or the amount of calcium phosphate particles used. In some cases, the relative amount of active agent to calcium phosphate particles is 0.1% by weight or more, such as 10% by weight or more, such as 20% by weight or more, such as 30% by weight or more, such as 40% by weight or more, such as 60% by weight or more. , such as 70% by weight or more, such as 80% by weight or more, such as 90% by weight or more, including 100% by weight or more, including 1000% by weight or more. In some instances, the weight ratio of active agent(s) to calcium phosphate particles ranges from 0.01:10, 0.1:1,1:1 and 1:0.1. In some instances, the weight ratio of calcium particle active(s) to calcium phosphate particles is between 0.5:1.0 and 5:1, and in particular in some cases the ratio is 1:1.

For example, as described above, for the preparation of an active agent solution, a suitable amount of calcium phosphate particles (as mentioned above, which may or may not be pretreated, for example) is combined with the solution. In some instances, the calcium phosphate particles combined with the active agent solution are dried. In some instances, the method includes initially wetting the nanoporous calcium phosphate particles with a solvent system, wherein the solvent system is the same or different from the solvent system used to prepare the active agent solution, eg, as described above. .

The particles (dried or wetted, as described above) can be combined with a solution of the active agent in a solvent system, e.g., as described above to prepare a liquid composition comprising the particles and the active agent(s) in a solvent system. have. The composition herein may be referred to as an active agent mixture. To prepare a liquid composition comprising an active agent and particles in a solvent system, the active agent solution and particles (dried or wetted, as described above) can be subjected to any convenient protocol, for example, by stirring (as described above). can be used to mix. The mixing step lasts a time sufficient to produce the desired mixture and in some cases ranges from 1 minute to 600 minutes, for example from 5 minutes to 300 minutes. In some cases, the nanoporous calcium phosphate particles and the active agent(s) solution are combined under negative pressure. For bonding under negative pressure, the required pressure may vary, in some cases including 0.001 Torr to 1 Torr, such as 0.1 Torr to 0.01 Torr, and 0.5 Torr to 0.05 Torr.

Following preparation of the mixture, the solvent system is dried off from the active agent mixture to produce the desired dry particulate. Drying may be accomplished using any convenient protocol, including, but not limited to, specific protocols such as, but not limited to, drying methods maintained at an elevated temperature sufficient to evaporate the solvent. Drying methods include drying by heat conduction, such as spray drying, air drying, fluidized bed drying and superheated steam drying, or drying by thermal convection, such as vacuum drying, freeze drying, rotary drum drying and rotary vacuum drying or thermal radiation. drying, such as, but not limited to, infrared thermal drying, microwave drying, or other drying by electromagnetic and thermal radiation or supercritical drying. If necessary, various protocols can be used in combination. After separation of the solvent, the obtained dry matter is further processed, if necessary, for example by grinding (eg, via a ball mill, hammer mill, jet impact mill, wet impact mill, etc.), sieving (with or without vibration, air flow or jet stream fractionation), etc. to produce a dry particulate active.

As noted above, the active compositions of the present invention may have a single active agent associated with a given calcium particle, or two or more active agents associated with the same calcium particle (e.g., three or more active agents, four or more, five or more different active agents). activator).

As a result of the above manufacturing protocol, particulate titanium dioxide (TiO2) of the present invention is obtained. The resulting dry powder active agent is covalently or ionic in the interior of the particle and/or on the particle, and/or on the surface of the particle, and/or is tightly and/or loosely linked with the particle. The amount of active agent component (consisting of one or more distinct active agents) bound or associated with the calcium phosphate particles may vary depending on the particular active agent(s). The particle size distribution of the resulting active particles, in some instances, is such that the majority (such as 60% or more, 75% or more, 90% or more, 95% or more) of the particles are 0.01 to 100 μm, such as 0.01 to 20 μm. μm, for example 0.1 to 10 μm, and a diameter distribution comprising the range of 0.1 to 2 μm.

In some cases, the relative amount of active agent to calcium particles ranges from 1 wt% or less to 500 wt% or more by weight, and in some cases 50 wt% or more, such as 60 wt% or more, such as 70 wt% or more. % or more, such as 80% by weight or more, such as 90% by weight or more, such as 100% by weight or more, such as 150% by weight or more, such as 500% by weight or more, including 1000% by weight or more. do. In some instances, the weight ratio of active agent(s) to calcium particles is 0.5:1.0 to 5:1, for example, in some cases the ratio is 1:1.

Depending on the nature of the resulting active agent to be employed, the protocol may or may not include coating the resulting active powder. Coating materials (which may include one or more coating materials) are those that maintain the association of the active agent with the calcium phosphate particles in various formulations, eg, formulations for topical application to the skin. Suitable coatings include those that are physiologically acceptable, are solid at room temperature, and are suitable for application to the skin. The coating component may be a single material or a combination of two or more materials, the combination providing one or more desirable properties. Materials used as the coating material include, but are not limited to, wax, butter, and the like. Coating materials and methods of use thereof are disclosed in US Patent Application No. 12/565,687, published as US2010-0086606, the disclosure of which is incorporated herein by reference.

topical preparations

The present invention includes topical formulations configured for application to a topical site on a human subject.

The composition of the present invention is intended for action on the keratinized skin surface or mucosal surface of a mammalian subject, for example a human subject. The mucosal surface refers to the location of an object comprising the mucous membrane, for example, the inside of the mouth, the inside of the nose, and the like. By keratinized skin surface is meant the location of the skin of an individual, ie the location of the external covering or integument of the animal's body. Because the dermal delivery formulations of the present invention are formulated for delivery to a topical location, these formulations are formulated to be physiologically compatible with the topical location of interest. Thus, when contacted with the keratinized skin surface or mucosal surface of the target of interest, these delivery compositions do not elicit substantial physiological responses (eg, inflammation or irritation) that render their use unsuitable for topical application. The topical formulations of the present invention include: (a) an active agent (which may or may not be stable); and (b) topical delivery vehicles.

As noted above, topical compositions include an amount of the dry particulate active agent present in a topical delivery vehicle.

The amount of dry particulate active agent present in the delivery composition and associated with the delivery vehicle can vary widely. In some embodiments, the amount of dry particulate active agent present in the delivery vehicle is between 0.01 mg/g and 500 mg/g, such as between 0.01 mg/g and 250 mg/g, such as between 0.1 mg/g and 200 mg/g, such as between 1 mg/g and 100 mg. /g, and includes 10 to 50 mg/g. In some instances, the dry particulate active agent present in the composition is at least about 0.001% by weight, such as 0.01%, 0.05%, or 1% or more, 5% or more, 10% or more, 15% or more, 25% or more, 30% or more, 50% or more. In certain embodiments, the dry particulate active is added directly to the delivery vehicle (ie, the dry particulate active is not wetted prior to mixing/combining with the delivery vehicle). That is, the dry particulate active agent and the delivery vehicle are combined to form a topical composition.

By delivery vehicle (ie, topical delivery component) is meant that portion of the topical composition that is not the dry particulate active. Delivery vehicles include, but are not limited to, compositions suitable for application via one or more oral, topical, implantable, ocular, otic, rectal, vaginal, etc. routes. In certain embodiments, the vehicle is formulated to be applied to a topical area or surface of a subject, eg, a keratinized skin surface. Compositions may be formulated, for example, as stable solutions or suspensions of the ingredients in an aqueous solvent. If desired, the ingredients are combined with the carrier materials to form solutions, suspensions, gels, lotions, creams, ointments, aerosol sprays, roll-ons, foam products, mousses, powders, sticks, and the like. In certain embodiments, it is an aqueous vehicle, ie, an aqueous vehicle comprising an amount of water. Examples of aqueous carriers include hydrogels, sprays, serums, and the like.

Topical compositions may contain other physiologically acceptable excipients or other auxiliary additives, particularly those relating to organoleptic properties, such as also fragrances, dyes, buffers, refreshing agents (eg menthol), coatings and the like. Excipients and auxiliary additives may be present in customary amounts, for example, in the range of about 0.001% to 5% by weight, such as 0.001-2%, in some cases not exceeding 10% by weight total.

Lotions (as well as other topical formulations) may contain one or more of the following components: water, viscosity modifiers, humectants, vegetable oils and hydrogenated vegetable oils, emollients, conditioning, emulsifiers, glycerin esters of fatty acids, silicones, C1-C30 mono esters and polyesters of sugars, conditioning agents, preservatives, etc. Depending on the topical formulation, additional components may be included: abrasives, adsorbents, antibacterial and antifungal agents, astringents, anti-acne agents, anti-wrinkle agents, antioxidants, antimicrobial agents, binders, biologically active agents, buffers, bulking actives, chelating agents, Chemical additives, external analgesics, film formers, opacifiers, pH adjusters, reducing agents, colorants, perfumes, cosmetic soothing agents, tanning actives and accelerators, skin improvement/whitening agents, sunscreens, surfactants, skin conditioning agents, vitamins, etc.

As noted above, semi-solid delivery compositions such as gels, creams and ointments can be formulated. Such compositions may be mixtures of (in addition to the active agent) water, water soluble polymers, preservatives, alcohols, polyhydric alcohols, emulsifiers, wetting agents, waxes, solvents, thickening agents, plasticizers, pH adjusting agents, water-retaining agents, and the like. In addition, such compositions may also contain other physiologically acceptable excipients or other minor additives such as fragrances, dyes, emulsifiers, buffers, coatings, and the like.

It can also be made into a solid formulation, for example, a topical patch formulation. Topical patch formulations can be made quite versatile. Topical patch formulations may include an active agent layer, a supportive and release liner. The active agent layer may include one or more of physiologically acceptable excipients or other minor additives such as fragrances, dyes, buffers, coatings, and the like. The support layer may be made of a flexible material suitable for the movement of the human body, including, for example, plastic films, various non-woven fabrics, textiles, spandex, and the like. A variety of inert coatings can be used, including the various materials that can be used in salves, described below. Alternatively, non-woven or textile coverings may be used, in particular resilient coverings, which allow heat and vapor transport. These coatings allow cooling of the painful area, which provides greater comfort while protecting the gel from mechanical removal. The release liner may be made of any convenient material, wherein representative release films include polyesters such as PET or PP, and the like.

When present in the delivery vehicle, a high weight percent active agent associated with calcium particles remains in the initial dry particulate composition. In some instances, the remaining active agent associated with the calcium particles (and thus not free from delivery vehicle) comprises, by weight, at least 40%, such as at least 50%, at least 60%, at least 70%. The remaining active agents associated with the calcium particles can be transported with the particles to the skin for delivery in the skin's acidic environment.

Usefulness

The topical formulations of the present invention are used in a method of delivering an active agent to a topical location in a subject, wherein the topical location may be a skin surface location or a mucosal location. In delivering an active agent to a topical location in a subject, the formulations of the present invention are capable of delivering the active agent to a subcutaneous location that is at least below the skin surface of the subject. Accordingly, embodiments of the present invention include methods for delivering active agent/calcium particle complexes to the deep stratum corneum of a subject, wherein these methods may result in delivery of the complex into the deep stratum corneum and/or dermis of a subject. "Deep stratum corneum" means at least one cell layer below the skin surface, such as 2 or more cell layers, for example 5 or more cell layers below the skin surface, or 10 or more cell layers below the skin surface. means the realm. In some cases, the active agent/calcium particle complex is delivered to an area of the stratum corneum of 2 μm or more, such as 5 μm or more, or 15 μm or more, below the surface of the skin.

Upon reaching the target skin location, the uniform, hard, round, nanoporous particles are subjected to acidic conditions, such as pH 5.5 or less, such as pH 5 or less, such as 4.5 or less. Upon dissolution under conditions below, or 4.3 or below, e.g., physiologically acidic conditions of the stratum corneum, the active agent/calcium particle complex releases their active agent "payload" and begins to degrade (e.g., the skin by dissolution induced by the pH gradient of The time required for dissolution of the particles within the deep stratum corneum may vary from a few minutes to several days, for example in the range of 1 minute to 24 hours, such as 10 minutes to 12 hours, or 30 minutes to 3 hours. and over this period the active agent is released from the dry particulate active agent. The proportion of active agent released from the active agent/calcium particle complex can vary, in some cases 0.01% or greater, such as 0.1% or greater, 1% or greater, such as 10% or greater, 50% or greater, 75% or greater, and 100% or greater. includes

For this reason, the methods of the present invention result in delivery of the active agent at least into the stratum corneum of a subject. Additional target locations include, but are not limited to, additional epidermal regions such as stratum lucidum, stratum granulosum, stratumspinusom, stratum basale, and dermis. In certain embodiments, the active agent is delivered to the dermal region. In certain embodiments, the active agent is delivered into the subdermal region, eg, subcutaneous tissue.

In practicing the methods of the present invention, a topical formulation is applied to a topical area of a subject and, as previously described, held in the topical area for a time sufficient to effect the desired delivery of the active agent to the subject. The topical area is, in certain embodiments, a keratinized skin area. Keratinized skin areas, including hair follicles, sweat glands, and sebaceousglands, can be located in a variety of locations, for example hands and feet, arms, legs, torso, for example, rib cage, back, stomach; head, for example. For example, neck, face, etc. In certain embodiments, the region will be a head region, eg, a facial region, eg, forehead, larynx region, near the mouth, and the like. The topical area to which the composition is applied may, in certain embodiments, vary in an area ranging ^{from 1 mm 2} to 20,000 cm ² or more, such as from 1 to 50 cm ² , or from 3 to 10 cm ^{2 .}

After application, the topical formulation is maintained at the site of application for a period of time sufficient to produce the desired therapeutic outcome, eg, relief of symptom(s), reduced dryness, eg, site of application. This period of time, in certain embodiments, varies from an instant to several days, for example, from 1 minute to at least 24 hours, from 30 minutes to 12 hours, and includes from 1 hour to at least 12 hours.

In practicing the methods of the invention, the subject may be administered in a single dose or in two or more dosage units over a period of time. can be administered to the subject in one or more dosage units, e.g., two or more dosage units, three or more dosage units, four or more dosage units, two or more dosage units, etc. It may be administered on a unit, daily basis, several times a day, with a rest period in between, for example, 4 hours, 6 hours, 12 hours, 1 day, 3 days, 7 days, and the like.

The methods and compositions of the present invention may be used in a number of different animals, wherein these animals are typically "mammals", where the term is used in carnivores (eg, dogs and cats), rodents (eg, mice, guineas). It is widely used to describe organisms in the classes of mammals, including pigs and rats), Lepidoptera (eg, rabbits), and Primates (eg, humans, chimpanzees, and monkeys). In certain embodiments, the subject or patient is a human.

The topical formulations of the present invention are used in applications requiring the delivery of a titanium dioxide (TiO2) active agent.

In certain embodiments, topical formulations are used to treat skin conditions. "Treatment" means that at least alleviation of the symptoms associated with the condition afflicting the subject is obtained, and the term alleviation in the broadest sense means that at least a reduction in a parameter associated with the symptom being treated, eg, a syndrome, is achieved. Thus, treatment is, e.g., complete suppression, e.g., preventing the occurrence, or cessation, e.g., of a symptom, or at least a syndrome associated therewith, such that the subject no longer suffers from the symptom, or at least a syndrome associated therewith. including the non-existent state. In certain embodiments, the subject may be a patient diagnosed with the disease for which the topical formulation is prescribed to the patient suffering from the disease.

The practice of the method of the present invention can improve the improvement results on the skin, and there is a noticeable reduction in the amount of wrinkles, roughness, dryness, relaxation, paleness, or pigment spots. Methods for measuring improvement in skin condition are well known in the art (see, e.g., Olsen er al, J. Amer. Acad. Dermatol 26:215-24, 1992), or a patient or a third party, e.g. For example, it may include a subjective evaluation by the treating physician. The objective method is described in Grove er al, J. Amer. skin topography measurements such as those described in Acad. Dermatol 21:631-37 (1989). In skin topography measurements, a silicone rubber replica is made into a small area of skin, for example a circular area with a diameter of 1 cm. The silicone mockup captures the fine lines and wrinkles of the skin. These specimens are analyzed using computerized digital image processing to provide an objective measure of skin topography. Skin topography measurements generated after digital image processing are described in Olsen eral, J. Amer. Acad. Dermatol 37:217-26, 1997 using the values Ra and Rz. where Ra denotes the area of deviation below and above the average centerline of the skin surface, and Rz denotes the difference between the maximum and minimum heights within five identical segments of the skin surface profile. A statistically significant decrease in R (eg, Po0.05) in the Ra and Rz values of skin treated according to the invention compared to untreated skin indicates improvement in skin.

The use of the compositions and methods of the present invention provides significant advantages. In some instances, topical formulations (e.g., creams and lotions) comprising particulate titanium dioxide (TiO2) compositions are storage stable, and composition and/or active agent properties such as color, viscosity, activity of the active agent and the like are substantially unchanged at room temperature and elevated temperature, e.g., 40 °C or higher, 50 °C or higher, over a long period of time, e.g., 1 week or more, 2 weeks or more, 1 month or more, 6 months or more, 1 year or more. . In some cases, topical formulations (eg, creams and lotions) comprising particulate titanium dioxide (TiO2) compositions exhibit at least 2-fold, such as 5-fold, 10-fold or more increased bioavailability compared to controls. In some instances, topical formulations (e.g., creams and lotions) comprising particulate titanium dioxide (TiO2) compositions exhibit sustained release of the active agent, wherein the sustained release of the active agent is at least 6 hours of an amount required for treatment, e.g., 12 It means sustained release for at least 18 hours, for example, at least 24 hours, for example, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days. In some instances, topical formulations (e.g., creams and lotions) comprising particulate titanium dioxide (TiO2) compositions exhibit synergistic effects on the skin health activity of titanium dioxide (TiO2) and calcium, resulting in synergistic effects of treatment outcomes. The size is greater than would be expected from the additive activity of each of these two formulations.

The following examples are provided by way of illustration and not limitation.

Experiment

I. Preparation of Titanium Dioxide-Hydroxysomes® Calcium Phosphate Particle Composition

a. A composition of 50 to 80 wt% of Hydroxysomes® calcium phosphate particles (Laboratory Skin Care, South San Francisco), 10 to 30 wt% of titanium dioxide powder and 5 to 50 wt% of titanium dioxide-Hydroxysomes® calcium phosphate particles was prepared. Titanium dioxide was dissolved in 200 to 600 ml of ethanol until it became a clear solution, and Hydroxysomes® calcium phosphate particles were added to combine the dry ingredients. The mixture was mixed at room temperature for 30 minutes and dried until no more ethanol remained.

b. 50-80% by weight of Hydroxysomes® calcium phosphate particles (Laboratory Skin Care, South San Francisco), 10-30% by weight of titanium dioxide powder and 5-50% by weight, such as 5-20% by weight of one or more antioxidants A titanium dioxide-Hydroxysomes® calcium phosphate particle composition was prepared. Dissolve the antioxidant component in 200 to 600 ml of ethanol until a clear solution, add titanium dioxide to the ethanol until a clear solution, and add Hydroxysomes® calcium phosphate particles to combine the dry components. The mixture was mixed at room temperature for 30 minutes and dried until no more ethanol remained. The antioxidant component used includes one or more of the following antioxidants, such as two or more, three or more: tocopherol, mixed tocopherols (eg, eg δ-tocopherol, γ-tocopherol, α-tocopherol, β-tocopherol a combination of two or more tocopherols such as ), alpha lipoic acid, butylated hydroxytoluene, and ascorbyl palmitate.

II. Characteristics of Titanium Dioxide-Hydroxysomes® Calcium Phosphate Particle Composition

a. The shelf life stability of the compositions prepared by the methods described in I.a and I.b above was tested. The product was observed to be stable for 24 months at room temperature, 3 months at 40°C, and 1 month at 50°C, as measured using the HPLC protocol.

In addition, several formulations of the composition were tested as aqueous topical formulations. Using HPLC analysis, the product was observed to be stable as a formulation for 1 month at 50° C., and the decrease in active agent was less than 2.5. In addition, several formulations of compositions with antioxidant components were tested as aqueous topical formulations. A result was obtained that a formulation comprising a complex having an antioxidant component showed stability under accelerated stability test conditions.

b. When the Hydroxysomes® calcium phosphate particle composition was used in combination with various antioxidant components, the resistance of titanium dioxide to linearization was analyzed and evaluated. Results were obtained in which formulations comprising complexes with antioxidant components exhibited stability under accelerated stability testing conditions.

Although the foregoing invention has been described by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain modifications may be made in light of the teachings of the invention without departing from the spirit or scope of the appended claims. something to do.

Accordingly, the foregoing is merely illustrative of the principles of the present invention. It will be appreciated that those skilled in the art will be able to make various implementations, although not explicitly described or shown herein, which embody the principles of the invention and are included within the spirit and scope thereof. Moreover, all examples and conditions recited herein are primarily intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors in the advancement of the art, and are intended to assist the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art, and these specific examples and conditions It is not limited to conditions. Moreover, all statements herein reciting principles, aspects and implementations of the invention, and specific embodiments thereof, are intended to cover both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, that is, any element developed to perform the same function, regardless of structure. For this reason, it is intended that the scope of the present invention not be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention are embodied by the appended claims.

Claims (17)

Drying, characterized in that the composition comprises a titanium dioxide (TiO2) active agent present in the interior and/or particle surface of the nanoporous calcium particles and/or loosely connected with the particles, wherein the weight percent of the titanium dioxide (TiO2) active agent in the composition is from 0.001 to 100. Particulate titanium dioxide (TiO2) composition. The dry particulate titanium dioxide (TiO2) composition according to claim 1, wherein the nanoporous calcium particles are nanoporous calcium phosphate particles. The dry particulate titanium dioxide (TiO2) composition according to claim 2, wherein the nanoporous calcium particles are nanoporous calcium phosphate particles. 4. Dry particulate titanium dioxide (TiO2) composition according to claim 3, wherein the uniform, hard, spherical, nanoporous calcium phosphate particles are ceramic. Dry particulate titanium dioxide (TiO2) composition according to any one of claims 1 to 4, characterized in that the uniform, hard, spherical, nanoporous calcium phosphate particles have a diameter of 1 to 10 μm. The dry particulate titanium dioxide (TiO2) composition according to claim 5, wherein the uniform, hard, spherical, and nanoporous calcium phosphate particles have a diameter of 2 μm or less. 7. Dry particulate titanium dioxide (TiO2) composition according to any one of claims 1 to 6, characterized in that the nanoporous calcium phosphate particles comprise pores having a size of 2 nm to 100 nm. 8. Dry particulate titanium dioxide (TiO2) composition according to any one of the preceding claims, characterized in that the titanium dioxide (TiO2) activator is retinaldehyde. 9. Dry particulate titanium dioxide (TiO2) composition according to any one of the preceding claims, characterized in that the composition further comprises an antioxidant component. 10. The dry according to claim 9, wherein the antioxidant component is at least one selected from the group consisting of BHT, ascorbyl palmitate, thioxane (alpha lipoic acid), calcium ascorbate, tocopherol, mixed tocopherol composition, and resveratrol. Particulate titanium dioxide (TiO2) composition. 11. The method of claim 10, wherein the antioxidant component is BHT and ascorbyl palmitate, thioxane (alpha lipoic acid) and calcium ascorbate, mixed tocopherol and thioxane (alpha lipoic acid) and resveratrol, and mixed tocopherol and thioxane Dry particulate titanium dioxide (TiO2) composition, characterized in that at least one selected from the group consisting of (alpha lipoic acid). The dry particle titanium dioxide (TiO2) composition of any one of claims 1 to 11; and
topical delivery vehicle
A topical formulation comprising a. 13. The topical formulation of claim 12, wherein the topical vehicle is an aqueous topical vehicle. (a) the dry particle titanium dioxide (TiO2) composition of any one of claims 1-11; and
(b) topical delivery vehicles
A topical formulation comprising: topically applying a titanium dioxide (TiO2) active agent to a subject to be delivered;
A method of delivering a titanium dioxide (TiO2) activator to a subject. (a)
(i) nano-porous calcium particles including pores constituting the inner space; and
(ii) a titanium dioxide (TiO2) activator;
are combined in the presence of a solvent to form a mixture;
(b) a process for preparing a dry particulate titanium dioxide (TiO2) composition by removing the solvent from the mixture. 16. The method of claim 15, wherein the method is a method of preparing the composition of any one of claims 1-15. 17. The method of claim 16, wherein the particles and the titanium dioxide (TiO2) activator are bonded under negative pressure.