CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and incorporates by reference, expressly including any drawings, U.S. provisional application no. 62/321 ,086, which was filed on April 1 1 , 2016.

FIELD

The present invention relates to drug delivery and specifically, in topical applications. BACKGROUND

Delivery systems have been long used in topical products, including cosmetic, over-the-counter (OTC) and prescription products, to help provide the following benefits: 1 ) a sustained release of ingredients to the skin, 2) provide improved protection of the skin care ingredients in formulation, and 3) to help reduce the skin irritation associated with active ingredients that irritate the skin. One particular class of delivery systems that are particularly effective in providing these benefits is known as particulate delivery systems.

There is a continuing need for particulate delivery systems, particularly those for topical applications.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this

specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, and as if each said individual publication, patent, or patent application was fully set forth, including any figures, herein.

However, if a definition provided in any material incorporated by reference herein conflicts with a definition provided herein, the definition provided herein controls. SUMMARY

Embodiments of the present invention include a composition comprising: (a) a natural substrate material such as micro-crystalline cellulose (MCC), (b) an active agent (also referred to as an active compound), and optionally (c) a release modifier. The composition can be used in a personal care formulation or a topical formulation. The personal care formulation or topical formulation may be a semisolid, like a cream or gel, for example; or a liquid, like an emulsion or dispersion, for example. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the cumulative release of several cosmetic products including retinol. DETAILED DESCRIPTION

Use of the singular herein includes the plural and vice versa unless expressly stated to be otherwise. That is, "a" and "the" refer to one or more of whatever the word modifies. For example, "a particle" may refer to one particle, two particles, etc. Likewise, "the compound" may refer to one, two or more compounds. By the same token, words such as, without limitation, "compounds" would refer to one compound as well as to a plurality of compounds unless it is expressly stated or obvious from the context that such is not intended.

As used herein, unless specifically defined otherwise, any words of

approximation such as and without limitation, "about," "essentially," "substantially," and the like mean that the element so modified need not be exactly what is described but can vary from the description. The extent to which the description may vary will depend on how great a change can be instituted and have one of ordinary skill in the art recognize the modified version as still having the properties, characteristics and capabilities of the unmodified word or phrase. With the preceding discussion in mind, a numerical value herein that is modified by a word of approximation may vary from the stated value by ±15% in some embodiments, by ±10% in some embodiments, by ±5% in some embodiments, or in some

embodiments, may be within the 95% confidence interval. As used herein, any ranges presented are inclusive of the end-points. For example, "a temperature between 10 °C and 30 °C" or "a temperature from 10 °C to 30 °C" includes 10 °C and 30 °C, as well as any temperature in between. In addition, throughout this disclosure, various aspects of this invention may be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. As an example, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. Unless expressly indicated, or from the context clearly limited to integers, a description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges 1 .5 to 5.5, etc. , and individual values such as 3.25, etc. that is non-integer individual values and ranges beginning with, ending with or both beginning with and ending with a non-integer value. This applies regardless of the breadth of the range.

As used herein, a range may be expressed as from "about" one particular value and/or to "about" another particular value. When such a range is expressed, another embodiment is included, the embodiment being from one particular value and/or to the other particular value. Similarly when values are expressed as approximations by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As a non-limiting example, if "from about 1 to about 4" is disclosed, another embodiment is "from 1 to 4," even if not expressly disclosed. Likewise, if one embodiment disclosed is a temperature of "about 30 °C," then another embodiment is "30 °C," even if not expressly disclosed. Similarly, if a range is not expressed as from "about" one particular value and/or to "about" another particular value, another embodiment exists including "about" before each end of the range. Likewise, when a particular value is stated, another embodiment exists which is preceded by "about." As a non-limiting example, if "from 1 to 4" is disclosed, another embodiment is "from about 1 to about 4," even if not expressly disclosed. Likewise, if one embodiment disclosed is a temperature of "30 °C," then another embodiment is a temperature of "about 30 °C," even if not expressly disclosed.

As used herein, the use of "preferred," "preferably," or "more preferred," and the like to modify an aspect of the invention refers to preferences as they existed at the time of filing of the patent application.

As used herein, "optional" means that the element modified by the term may or may not be present.

As used herein, the phrase "any combination of" followed by a list joined by the conjunction "and," means any combination of two or more members of the group where the group members are the members of the list joined by the conjunction

"and." As a non-limiting example, "any combination of A, B, C, and D" encompasses the following combinations: A and B; A and C; A and D; B and C; B and D; C and D;

A, B, and C; A, B, and D; A, C, and D; B, C, and D; A, B, C, and D. Similarly, the phrase "A, B, C, D, or any combination thereof" encompasses an individual member (A, B, C, D) or any combination of A, B, C, and D as outlined above. Likewise, the expression "X is selected from the group consisting of A, B, C, D, and combinations thereof means X is an individual member (X is A, X is B, X is C, or X is D), or X is any combination of A, B, C, and D, as outlined above.

As used herein, the phrase "and/or" means a combination or an individual member. As a non-limiting example, "X is A, B, and/or C" encompasses the following possibilities: X is A; X is B; X is C; X is any combination of A, B, and C (A and B; A and C; B and C; A, B, and C).

As used herein, "particle" is a piece of matter held together by physical bonding of molecules, an agglomeration of pieces of matter ("particles") held together by colloidal forces and/or surface forces, a piece of matter which is held together by chemical bonds such as a cross-linked polymer network, a piece of matter formed by ionic interactions, or a piece of matter held together by any combination of agglomeration, surface forces, colloidal forces, ionic interactions, and chemical bonds. For the purposes of this disclosure, a particle will be defined as ranging in size from less than a one tenth of a nanometer to several millimeters in size.

The polydispersity of a plurality of particles represents the distribution of sizes, usually expressed as particle diameters, within a plurality of particles. The average diameter can be a number average diameter, where the number average diameter = ∑i din,/ 1, rij where n, represents the number of particles with a diameter represented by dj. Usually approximations are made and the distribution of particles by diameters is represented as a histogram, or in other words the particles are divided into smaller groups encompassing a smaller range of diameters and each of these groups is assigned a diameter near the center of that range. The surface area average diameter is determined by (∑, fid, ² ) ^{1 2} , and the volume or mass average diameter is determined by (∑, fid, ³ ) ^{1 3} , where f, is n,/∑, n,. Thus, in the case of the surface area average, the weighting factor is the surface area represented by the class of particles of diameter d, while for the volume average diameter, the weighting factor is the volume represented by each class of particles of diameter d,. Since the surface area increases with diameter squared and the volume increases with diameter cubed, the surface area average diameter is greater than the number average diameter. Likewise, the volume average diameter exceeds the surface area diameter. The mass or weight average diameter is the same as the volume average diameter if the density of all of the particles is the same. Similarly, distributions of particle sizes may be based on the number, surface area, or volume of the particles. A weight average or mass average distribution is essentially the same as a volume average distribution if all the particles have the same density.

Another means for determining the average diameter is by the use of dynamic light scattering, which is also called photon correlation spectroscopy, and measures the diffusion of the particles in dispersed in solution or dispersed in air. The method determines the hydrodynamic diameter or the Stokes diameter based on diffusion measurements, and may include solvent associated with the particle. For non- spherical particles, the reported "diameter" is actually the effective diameter, which is the diameter of a sphere with the equivalent hydrodynamic radius. The average diameter determined is the mean hydrodynamic diameter, and is close to the volume-average diameter. One method is outlined in the International Standards Organization ("ISO") 13320.

As used herein, if not otherwise specified, the average particle diameter will refer to the diameter determined by photon correlation spectroscopy. In some embodiments, the average particle diameter will refer to the diameter determined by photon correlation spectroscopy in compliance with ISO 13320:2009, and in some embodiments, the average particle diameter will refer to the diameter determined by the Malvern MASTERS IZER® 3000. The distribution of the particle sizes in a plurality may be represented by the standard deviation, which is a well-known statistical measurement. The standard deviation may be suitable for a narrow particle size distribution. Other measures of polydispersity of a group of particles include the d10 and d90 which refer to the diameters representing the threshold where 10% of the distribution falls below, and 90% of the distribution falls below, respectively. The average may be referred to as a d50. Thus, for a number average, half or 50% of the number of particles have a diameter less than the d50. In other words, the d50 splits the distribution in half. For a volume average diameter, the d50 represents the diameter where half the volume represented by the plurality is in particles having a diameter smaller than d50, or in other words, the intersection of the 50% line on a plot of the cumulative volume of the particles as a function of diameter.

As used herein, "medicinally active compound," "drug," or "therapeutic agent," which will be used interchangeably, refers to any substance that, when administered in a therapeutically effective amount to a patient (an animal, but typically, a human being) suffering from a disease or condition, has a therapeutic beneficial effect on the health and well-being of the patient. A therapeutic beneficial effect on the health and well-being of a patient includes, but is not limited to: (1 ) curing the disease or condition; (2) slowing the progress of the disease or condition; (3) causing the disease or condition to retrogress; and/or, (4) alleviating one or more symptoms of the disease or condition.

As used herein, a medicinally active compound also includes any substance that when administered to a patient, known or suspected of being particularly susceptible to a disease, in a prophylactically effective amount, has a prophylactic beneficial effect on the health and well-being of the patient. A prophylactic beneficial effect on the health and well-being of a patient includes, but is not limited to: (1 ) preventing or delaying on-set of the disease or condition in the first place; (2) maintaining a disease or condition at a retrogressed level once such level has been achieved by a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount; and/or, (3) preventing or delaying recurrence of the disease or condition after a course of treatment with a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount, has concluded. As used herein, "medicinally active compound" also refers to pharmaceutically acceptable, pharmacologically active derivatives of those medicinally active compounds specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, analogs, and the like.

As used herein, "topical administration" is used in its conventional sense to mean delivery of a topical medicinally active compound or pharmacologically active agent to the skin, hair, and/or mucosa, as in, for example, the treatment of various skin disorders. In some embodiments, "topical administration" or a "topical formulation" refers to application to and/or treatment of the skin and/or hair, and in other embodiments, the topical formulation refers to administration to and/or treatment of the skin.

A solid is one of the three states of matter - gas, liquid, and solid. A "solid" as defined by the Merriam Webster dictionary, is a substance that does not flow perceptibly under moderate stress, has "a definite capacity for resisting forces" such as compression or tension "which tend to deform it," and "under ordinary conditions retains a definite shape and size." As used herein, a "solid" can be a substance of definite shape and size and that does not conform to the outline of its container under the force of gravity. As used herein, a solid may be a substance that conforms to the outline of its container by breaking chemical bonds, requires extensive deformation as with a metal, or, if an elastic solid, a substance that conforms with the application of stress, but returns to its prior shape, or substantially its prior shape, when the stress is removed. A substance may be defined to be a solid at a specified temperature and pressure if it has a "viscosity" of greater than 10 ¹² cP (cP = centipoise) at that specified temperature and pressure.

A "fluid," as defined by Merriam Webster dictionary, is a substance that tends to flow or conform to the outline of its container. A fluid is a state of matter that includes gases, liquids, supercritical fluids, and plasma. As used herein, a fluid can be a substance having a viscosity as measured under the temperature and pressure of interest of 10,000 cP or lower. As used herein, a fluid can be a substance that would conform to the shape of its container within a time frame of minutes (up to an hour) under the force of gravity.

A "semisolid" as defined by Merriam Webster dictionary is "a substance having qualities of both a solid and a liquid; highly viscous." As used herein, a substance can be a "semisolid" at a specific temperature and pressure if it is a fluid having a viscosity greater than 10,000 cP. As used herein, a semisolid can be a substance that would conform to the shape of its container under high stress and/or over a long period of time (months or years).

As used herein, the phrase "wt%" refers to percent by weight.

As used herein, "on a dry basis," refers to not more than 5 weight % water (or other solvent).

Current particulate delivery systems include products which are petroleum derived microparticles that are formed through polymerization reactions of

methacrylate monomers and sold under the trade names of POLY-PORE ^® ,

MICROSPONGE ^® and POLYTRAP ^® Embodiments of the present invention include a composition comprising: (a) a plurality of particles comprising a natural substrate material, such as, but not limited to, cellulose, (b) an active agent, and optionally (c) a release modifier. The plurality of particles may be used to formulate a personal care formulation or a topical formulation, and the formulation may be a semisolid, such as and without limitation, a cream or gel, for example; or a liquid, such as and without limitation, an emulsion or dispersion, for example.

More particularly, the compositions comprise an active agent entrapped by the substrate. As used herein, "entrapped" by the substrate means adsorbed onto the substrate, absorbed into the substrate particles, or a combination thereof. As used herein, with reference to an active agent or active agent composition, "carried by the substrate" or "carried by the particle" also means adsorbed onto the substrate, absorbed into the substrate particles, or a combination thereof. The weight amount of active agent entrapped by the substrate at least equals 1 /100 of the weight of the substrate, and typically is several times the weight of the natural substrate. The active agent can be water soluble or oil soluble. In some embodiments, a release modifier then is applied to the substrate-active agent combination to adsorb onto the substrate, adsorb onto the active agent, absorb into the substrate, coat the

substrate, and/or coat the active agent. If the personal care or pharmaceutical composition to which the plurality of particles to be added is aqueous based, the release modifier preferably is hydrophobic. If the personal care or pharmaceutical composition to which the plurality of particles to be added is oil or hydrophobic solvent based, the release modifier preferably is hydrophilic. Thus, in some embodiments of the present invention, the active agent may be oil soluble and the release modifier may also be oil soluble. As used herein, the term "water-soluble compound" is defined as a compound having a solubility in water of at least 0.5 g per 100 grams of water at 25 °C.

Similarly, "oil-soluble compound" is defined as a compound having a solubility in mineral oil of at least 0.5 g per 100 grams of mineral oil at 25 °C. The terms "water- dispersible" and "oil-dispersible" are defined as compounds having a solubility, at 25 °C , in 100 g of water or mineral oil, respectively, of about 0.1 to about 0.5 g.

In some embodiments, the substrate-active agent or substrate-active agent- release modifier composition can be used in a powder form, such as a component of a cosmetic powder or pharmaceutical powder. In preferred embodiments, the plurality of particles of substrate-active agent or of substrate-active agent-release modifier (or both) may be formulated with other ingredients to provide a semisolid or a liquid composition with a time extended delivery of the active agent. As a non- limiting example, the controlled release composition comprising the substrate-active agent or substrate-active agent-release modifier composition can be applied topically, such that the active ingredient, e.g. , an antioxidant, is slowly released from the natural substrate, over an extended time, to perform its intended function. The preceding description is not limited to the active ingredient being an antioxidant. In some embodiments, the plurality of particles comprising a natural substrate and an active agent, with or without the optional release modifier, are used in a semisolid topical composition such as and without limitation an oil-in-water emulsion, a water- in-oil emulsion, an aqueous gel, or an anhydrous gel.

In some embodiments, the substrate-active agent-release modifier

composition includes about 72 wt% to 76 wt% substrate, such as, and without limitation, microcrystalline cellulose, a cellulose derived from Walnut shells, or a combination thereof, about 6.5 wt% to 8 wt% active agent, such as retinol, a retinoid compound, or a combination thereof, and about 8 wt% to 10 wt% release modifier, such as and without limitation cetyl alcohol, with the remainder being other components and subject to the limitation that the total is not more than 100 wt%.

The individual components of are discussed in more detail below.

Substrates

Preferred substrates are natural materials. As used herein, "natural substrate materials" include cellulose particles, microcrystalline cellulose (MCC), and materials derived from other cellulosic materials including shells such as walnut, hazelnut, acorn, and filbert shells, as well as apricot kernels, pistachio hulls, and macadamia nut hulls. A non-limiting example is WNS Natural Nylon ^® (McKinley Resources, Inc.), which is based on walnuts. Other examples of natural substrates include, without limitation, wood particles, flour, corn cob particles, cotton, and reconstituted cellulose particles such as rayon. Other examples of natural substrates include, without limitation, activated carbon and spider silk. The different types of substrates may be used individually or in combination. In some embodiments, a natural substrate is a substrate which is not created wholly in the laboratory. In some embodiments, a natural substrate is a material that is entirely natural, that may have been purified, but not chemically modified in the laboratory. In some embodiments, chemical modification encompasses attachment of a moiety with a covalent bond.

In some embodiments, the natural substrate is cellulose, and more

specifically, microcrystalline cellulose. Microcrystalline cellulose (MCC) is a cellulose based product formed by removing impurities and amorphous parts of cellulose to produce a crystallite or aggregates of crystallites. The United States

Pharmacopeia/National Formulary (USP/NF) describes microcrystalline cellulose as a "purified, partially depolymerized cellulose obtained by treating alpha (a) cellulose, obtained as a pulp from fibrous plants, with mineral acids." The degree of

polymerization, or the number of repeating units, typically levels off where the level depends upon the cellulose source material used. Source materials are those that include cellulose such as wood, wood pulp, cotton, and other fibers such as ramie. MCC is used in food and pharmaceuticals, and has a monograph in the United States NF.

The surface area for microcrystalline cellulose has been reported to be 1 .35 m ² / gram (European Journal of Pharmaceutics and Biopharmaceutics 48 (1999) 199- 206). This surface area is lower that other materials that have been used as substrates for active compound delivery. Non-limiting examples include

MICROSPONGE ^® 5640, with a surface area (Brunauer-Emmett-Teller (aka BET) nitrogen adsorption method) of 150 - 260 m ² /gram, and for POLY-PORE ^® E200, with a surface area (BET nitrogen adsorption method) of greater than 150 m ² /gram. Example 1

The adsorption capacity of several different microcrystalline cellulose materials and other materials was evaluated by using American Society for Testing and Materials (ASTM) method D281 -12. The oil adsorption capacity was measured using caprylic/capric triglyceride. The triglyceride was added drop wise to the powder and the maximum adsorption capacity was determined when the material could no longer hold anymore of the triglyceride and a glossy sheen was seen on the blend of the two materials. A similar experiment was also run using water as the fluid. The value is reported on the grams of the triglyceride (or water) that could be adsorbed divided by the grams of the microcrystalline cellulose or other material.

Table 1 : Adsorption Capacity of Selected Materials

Not Available Similar to the surface area, the oil adsorption values for the above natural substrate materials are considerably lower than polymeric microparticles, which are the last three entries of Table 1 , MICROSPONGE 5640, POLY-PORE E200, and

POLYTRAP 6603.

PHARMACEL 101 is intended for wet granulation formulations and

PHARMACEL 102 is intended for direct compression formulations. PHARMACEL 101 is a microcrystalline cellulose and PHARMACEL 102 is also a microcrystalline cellulose.

The preferred size of the natural substrate, such as but not limited to micro- crystalline cellulose, is where 90% of the particles fall in the range of 0.7 to 250 microns (micrometers or pm) where the 90% is based on the volume- distribution of diameters. In some embodiments, the natural substrate has an average diameter as determined by laser light scattering, determined for example by an instrument such as the Malvern MASTERSIZER ^® 3000, such that 90% of the particles as determined by the laser-light scattering distribution fall in the range of 0.7 to 250 microns.

Active Agent

In accordance with the embodiments of the present invention, the active agent (which also may be referred to as an active compound, or active ingredient) can be any of a wide variety of compounds, either water soluble or oil soluble. The active agents described herein may be used individually or in combination. In preferred embodiments, the active agent is a topically active compound. The plurality of particles comprising the active agent may be formulated into a controlled release composition, which can be applied to the skin, and the active agent then performs its intended function as it is released from the controlled release composition over time and contacts the skin.

Although the following discussion is directed primarily to topically active compounds, the active agent can be a different type of compound, such as a fragrance, which is control released to act as a room deodorizer, or a pesticide, which is released in a controlled manner for extended insecticidal or herbicidal activity, or similar types of active agents, like drugs and therapeutic agents, that are used in controlled release applications. In some embodiments, the active agent is a water-soluble or water-dispersible compound, i.e., is hydrophilic. However, in other embodiments, the active agent is oil soluble or oil dispersible, i.e., is hydrophobic (also referred to as "oleophilic"). In other embodiments, the active agent is a mixture of compounds, either all

hydrophilic, all oleophilic, or a mixture of hydrophilic and oleophilic compounds. As discussed hereafter, the release modifier also may contribute to the efficacy of the composition.

The active agent is present in the plurality of particles in an amount sufficient to perform its intended function when incorporated into a pharmaceutical or personal care formulation. In some embodiments, the amount of active agent to perform its intended function is about 0.05% to about 30%, by weight, of the composition when in liquid (or fluid) form. In some embodiments, for semisolid forms of pharmaceutical or personal care formulation the amount of active agent to perform its intended function is about 0.05% to about 70%, by weight, of the active agent. Persons skilled in the art are aware of the amount of active agent needed to perform its intended function, and are capable of determining the amount active agent to incorporate into the pharmaceutical or personal care formulation based on the form, e.g., solid, semisolid, or liquid, of the composition.

In some embodiments, the ratio of the weight of the active agent to the weight of the natural substrate material, such as without limitation, MCC, in the plurality of particles is in the range of about 1 : 100 to about 25: 1 , preferably about 1 :20 to about 5: 1 , and most preferably from about 1 : 10 to about 3: 1 .

With respect to topically active agents, such agents are intended to be applied to the skin, or hair, and allowed to remain on the skin for an extended time period to allow a controlled release of the active agent to perform its function. Alternatively, the active ingredients could applied to the skin or the hair in a wash product, such as a shampoo or body wash, where the active agent is delivered during the washing process and some of the active agent remains resident on the skin or hair after the washing process is complete.

The topically active agent, therefore, can be one of, or a mixture of, a cosmetic compound, a medicinally active compound, or any other compound that is useful upon topical application to the skin or hair. Such topically active agents include, but are not limited to, hair-growth promoters, deodorants, skin-care compounds, antioxidants, hair dyes, antibacterial compounds, antifungal compounds, anti-inflammatory compounds, topical anesthetics, sunscreens, and other cosmetic and medicinal topically effective compounds.

A medicinally active compound is described above. In some embodiments, a medicinally active compound is limited to commercially available medicinally active compounds approved by the Food and Drug Administration for use in products requiring a medical doctor's prescription in the United States. In some

embodiments, a medicinally active compound includes commercially available medicinally active compounds approved by the Food and Drug Administration for use in products requiring a medical doctor's prescription in the United States and medicinally active compounds used in commercially available over-the-counter products available in the United States.

For example, a skin conditioner can be the active agent of a composition of the present invention. Skin conditioning agents include, but are not limited to, humectants, such as fructose, glucose, glycerin, propylene glycol, glycereth-26, mannitol, and urea, pyrrolidone carboxylic acid, hydrolyzed lecithin, coco-betaine, cysteine hydrochloride, glucamine, PPG-15, sodium gluconate, potassium aspartate, oleyl betaine, thiamine hydrochloride, sodium laureth sulfate, sodium hyaluronate, hydrolyzed proteins, hydrolyzed keratin, amino acids, amine oxides, water-soluble derivatives of vitamins A, E, and D, amino-functional silicones, ethoxylated glycerin, alpha-hydroxy acids and salts thereof, fatty oil derivatives, such as PEG-24 hydrogenated lanolin (PEG is polyethylene glycol), almond oil, grape seed oil, and castor oil, and mixtures thereof. Other skin conditioning agents include, but not limited to, Vitamins such as Vitamin A (retinol, retinal, retinoic acid and other derivatives such as esters and ethers), Vitamin C (ascorbic acid and hydrophobic and hydrophilic modified versions of ascorbic acid), Vitamin E (tocopherol, tocopherol acetate and other modified versions of tocopherol) and Vitamin K.

Numerous other skin conditioners are listed in the International Cosmetic Ingredient Dictionary and Handbook, Fifteenth Ed., J. Nikitakis, H. P. Breslawec, eds. , Personal Care Product Council (2014), (hereafter PCPC Handbook), Volume 3 pages 4186- 4260, incorporated herein by reference.

In addition, the topically active agent can be a hair dye, such as, but not limited to, m-aminophenol hydrochloride, p-aminophenol sulfate, 2,3-diaminophenol hydrochloride, 1 ,5-naphthalene-diol, p-phenylenediamine hydrochloride, sodium picramate, cationic dyes, anionic dyes, FD&C dyes, like Blue No. 1 , Blue No. 2, Red No. 3, Red No. 4, or Red No. 40, D&C dyes, like Yellow No. 10, Red No. 22, or Red No. 28, and pyrogallol. Numerous other hair dyes are listed in the PCPC Handbook, pages 4439-4445, incorporated herein by reference.

The topically active agent also can be an antioxidant, like ascorbic acid or erythorbic acid, or a fluorescent whitening agent or optical brightener, like a distyrylbiphenyl derivative, stilbene or a stilbene derivative, a pyralozine derivative, or a coumarin derivative. In addition, a self-tanning compound, like dihydroxy acetone, or a hair growth promoter can be the topically active agent.

The topically active agent also can be a deodorant or antiperspirant compound, such as an astringent salt or a bioactive compound. The astringent salts include, without limitation, organic and inorganic salts of aluminum, zirconium, zinc, and mixtures thereof. The anion of the astringent salt can be, for example and without limitation, sulfate, chloride, chlorohydroxide, alum, formate, lactate, benzyl sulfonate, or phenyl sulfonate. Non-limiting exemplary classes of antiperspirant astringent salts include aluminum halides, aluminum hydroxyhalides, zirconyl oxyhalides, zirconyl hydroxyhalides, and mixtures thereof.

Exemplary aluminum salts include, but are not limited to, aluminum chloride and the aluminum hydroxyhalides having the general formula AI ₂ (OH) _x Q _y XH ₂ 0, wherein Q is chlorine, bromine, or iodine; x is about 2 to about 5; x+y is about 6, wherein x and y are not necessarily integers; and X is about 1 to about 6. Exemplary zirconium compounds include, but are not limited to, zirconium oxy salts and zirconium hydroxy salts also referred to as zirconyl salts and zirconyl hydroxy salts, and represented by the general empirical formula ZrO(OH) ₂ -nzLz, wherein z varies from about 0.9 to about 2 and is not necessarily an integer; n is the valence of L; 2- nz is greater than or equal to 0; and L is selected from the group consisting of halides, nitrate, sulfamate, sulfate, and mixtures thereof.

Exemplary deodorant compounds, therefore, include, but are not limited to, aluminum bromohydrate, potassium alum, sodium aluminum chloro-hydroxy lactate, aluminum sulfate, aluminum chlorohydrate, aluminum-zirconium tetrachlorohydrate, an aluminum-zirconium polychlorohydrate complexed with glycine, aluminum- zirconium trichlorohydrate, aluminum-zirconium octachlorohydrate, aluminum sesquichloro-hydrate, aluminum sesquichlorohydrex PG (propylene glycol), aluminum chlorohydrex PEG, aluminum zirconium octachlorohydrex glycine complex, aluminum zirconium pentachlorohydrex glycine complex, aluminum zirconium tetrachlorohydrex glycine complex, aluminum zirconium trichlorohydrex glycine complex, aluminum chlorohydrex PG, zirconium chlorohydrate, aluminum dichlorohydrate, aluminum dichlorohydrex PEG, aluminum dichlorohydrex PG, aluminum sesquichlorohydrex PG, aluminum chloride, aluminum zirconium

pentachlorohydrate, chlorophyllin copper complex, numerous other useful

antiperspirant compounds listed in the PCPC Handbook at page 56, incorporated herein by reference, and mixtures thereof. In the above list, PG is propylene glycol, and PEG is polyethylene glycol. The active agent also can be a fragrance that acts as a deodorizer by masking malodors. Numerous fragrance compounds are listed in the PCPC Handbook, pages 4373-4376, incorporated herein by reference.

In addition, other compounds can be included as the topically active agent in an amount sufficient to perform their intended function. For example, if the composition is intended to be a sunscreen, then compounds such as benzophenone- 3, trihydroxy-cinnamic acid and salts, tannic acid, uric acids, quinine salts, dihydroxy naphtholic acid, an anthranilate, diethanolamine methoxycinnamate, p-aminobenzoic acid, phenyl-benzimidazole sulfonic acid, PEG-25, p-aminobenzoic acid, or triethanolamine salicylate can be used as the active agent.

Further, sunscreen compounds such as dioxybenzone, ethyl 4-[bis(hydroxy- propyl)]amino-benzoate, glyceryl aminobenzoate, homosalate, methyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, red petrolatum, titanium dioxide, 4-menthylbenzylidene camphor, benzophenone-1 , benzophenone-2, benzophenone-6, benzophenone-12, isopropyl dibenzoyl methane, butyl methoxydibenzoylmethane, zotocrylene, or zinc oxide can be used as the active agent. Other sunscreen compounds are listed in PCPC Handbook, pages 4273 and 4274, incorporated herein by reference.

Similarly, topically active drugs, like antifungal compounds, antibacterial compounds, anti-inflammatory compounds, topical anesthetics, skin rash, skin disease, and dermatitis medications, and anti-itch and irritation-reducing compounds can be used as the active agent in the compositions of the present invention. For example, analgesics such as benzocaine, dyclonine hydrochloride, aloe vera, and the like; anesthetics such as butamben picrate, lidocaine hydrochloride, xylocaine, and the like; antibacterials and antiseptics, such as povidone-iodine, polymyxin b sulfate-bacitracin, zinc-neomycin sulfate-hydrocortisone, chloramphenicol, ethylbenzethonium chloride, erythromycin, and the like; antiparasitics, such as lindane; essentially all dermatologicals, like acne preparations, such as benzoyl peroxide, erythromycin benzoyl peroxide, clindamycin phosphate, 5,7-dichloro-8- hydroxyquinoline, and the like; anti-inflammatory agents, such as alclometasone dipropionate, betamethasone valerate, and the like; burn relief ointments, such as o- amino-p-toluenesulfonamide monoacetate, and the like; depigmenting agents, such as monobenzone; dermatitis relief agents, such as the active steroid amcinonide, diflorasone diacetate, hydrocortisone, and the like; diaper rash relief agents, such as methylbenzethonium chloride, and the like; emollients and moisturizers, such as mineral oil, PEG-4 dilaurate, lanolin oil, petrolatum, mineral wax, and the like;

fungicides, such as butocouazole nitrate, haloprogin, clotrimazole, and the like; herpes treatment drugs, such as 0-[(2-hydroxymethyl)methyl]guanine; pruritic medications, such as alclo-metasone dipropionate, betamethasone valerate, isopropyl myristate, and the like; psoriasis, seborrhea, and scabicide agents, such as anthralin, methoxsalen, coal tar, and the like; steroids, such as 2-(acetyloxy)-9- fluoro-1 ', 2', 3', 4'-tetrahydro-1 1 -hydroxypregna-1 ,4-dieno-[16, 17-b]naphthalene- 3,20-dione and 21 -chloro-9-fluoro-1 ', 2', 3', 4'-tetrahydro-1 1 b-hydroxypregna-1 ,4- dieno-[16, 17-b]naphthalene-3,20-dione. Any other medication capable of topical administration, like skin bleaching agents, skin protestant, such as allantoin, and antiacne agents, such as salicylic acid, also can be incorporated in a composition of the present invention in an amount sufficient to perform its intended function. Other topically active compounds are listed in Remington's Pharmaceutical Sciences, 17 ^th Ed. , Merck Publishing Co. , Easton, Pa. (1985), pages 773-791 and pages 1054- 1058, incorporated herein by reference.

In some embodiments, the active agent is glycolic acid, tea tree oil, or a combination thereof.

In some embodiments, the active agent is a retinoid compound. As used herein, the term "retinoid compound" denotes both naturally occurring and synthetic compounds bearing the general structure of vitamin A (retinol) and variations on that structure which bear similarities to retinol in terms of biological activity. Non-limiting examples included among this class are: retinol: 3,7-dimethyl-9-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-2,4,6,8-nonatetraen-1 -ol (all trans) retinyl palmitate retinyl acetate retinyl linoleate dehydroretinol: 3,7-dimethyl-9-(2,6,6-trimethyl-1 ,3-cyclohexadien-1 -yl)-2, 4,6,8- nonatetrae n-1 -ol retinal (aldehyde form of retinol)

13-cis-retinoic acid etretinate: (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4 ,6,8-nonatetra enoic acid ethyl ester etretin: (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4 ,6,8-nonatetra enoic acid motretinide: N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona -2,4,6,8- tetra en-1 -oic acid ethyl amide

(E, E)-9-(2,6-dichloro-4-methylphenyl)-3,7-dimethyl-2,4,6,8-tetr aen-1 -oic acid ethyl ester

(E, E)-4-[2-methyl-4-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-1 ,3-butadienyl]benzoic acid

(E)-4-[4-methyl-6-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-1 ,3,5-hexatrienyl]benzoic acid (all-E)-3,7-dimethyl-9-(3-thienyl)-2,4,6,8-nonatetraenoic acid

(E, E, E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-nap hthalenyl) -2,4,6- octatrienoic acid (E, E)-6-[2,6,6-trimethyl-1 -cyclohexen-1 -yl)ethenyl]-2-naphthalenecarboxylic acid

(E,E,E)-7-(2,3-dihydro-1 , 1 ,3,3-tetramethyl-1 H-inden-5-yl)-3-methyl-2,4,6-oc tatrienoic acid

(E)-4-[2-(2,3-dihydro-1 , 1 ,3,3-tetramethyl-1 H-inden-5-yl)-1 -propenyl]benzoic acid

(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth alenyl)-1 -propenyl ]benzoic acid

(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl -2-naphthalenyl)-1 - propenyl]benzoic acid

(E)-1 ,2,3,4-tetrahydro-3-methyl-1 ,1 ,4,4-tetramethyl-6-(1 -methyl-2-phenyleth enyl)naphthalene

(E)-1 ,2,3,4-tetrahydro-1 , 1 ,4,4-tetramethyl-6-naphthyl-2-naphthalenecarboxylic acid

(E)-6-{2-[4-(ethylsulfonyl)phenyl]-1 -methylethenyl}-1 ,2,3,4-tetrahydro-1 , 1 , 4,4- tetramethylnaphthalene-4-[(5,6,7,8-tetrahydro-5,5,8,8-tetram ethyl-2-naphtha- lenyl)ethynyl]benzoic acid

(E)-2-(1 , 1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl)-1 -[4-(tetrazol-5-yl)phenyl]-1 - propene

(E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethy l-2-naphthalenyl)- 1 - propenyl]benzyl alcohol

Preferred retinoids are retinol, retinal, retinoic acid, retinyl palmitate, retinyl acetate, and retinyl linoleate. More preferred are retinol, retinal, retinyl palmitate, retinyl acetate, and retinyl linoleate, and the most preferred is retinol. Another preferred retionid is retinaldehyde.

Some active agents may fall in more than one category. In some embodiments, the active agent is a topically active compound. In some embodiments the topically active compound is a skin-care compound, an antioxidant, or a mixture thereof. In some embodiments, the active agent is a topically active compound selected from the group consisting of aloe vera, PEG-4 dilaurate, lanolin oil, petrolatum, mineral wax, salicyclic acid, and mixtures thereof. In some embodiments, the active agent is a topically active compound selected from the group consisting of silicones, isopropyl myristate, vitamin E, vitamin E acetate, retinol, and mixtures thereof. Active agents which may irritate the skin may benefit from the embodiments of the present invention. Some non-limiting examples of active agents which are known to be irritating to the skin or are expected to be irritating to the skin include benzoyl peroxide, capsicum, menthol, menthyl lactate, witch hazel, ethanol, synthetic and natural fragrances.

Release Modifier

The substrate-active agent combination may have limited controlled release capabilities. In some embodiments, a release modifier is added to the particles of the substrate-active agent combination.

Preferably, the release modifier is hydrophobic when the plurality of substrate- active agent particles is to be included in an aqueous based product. Conversely, the release modifier preferably is hydrophilic when the plurality of substrate-active agent particles is to be included in an oil based formulation.

The release modifier is adsorbed onto the substrate, or penetrates into the substrate, and also coats the substrate and the active agent.

In some embodiments, the release modifier is adsorbed onto the substrate, and in some embodiments, the release modifier is absorbed into the substrate, and in some embodiments, the release modifier is both adsorbed onto the substrate and absorbed into the substrate. The release modifier may also coat the active agent and/or surround the active agent.

The amount of release modifier present in the substrate-active agent-release modifier composition is about 0.5% to about 50%, and preferably about 0.5% to about 35%, by weight of the composition where the residual solvent from

manufacture comprises not more than 2 wt%, preferably not more than 0.5 wt%. In some embodiments, the release modifier is present in an amount of about 2% to about 25%, or about 4% to about 15%, by weight of the substrate-active agent- release modifier composition where the residual solvent from manufacture comprises not more than 2 wt%, preferably not more than 0.5 wt%. Residual solvent refers to a solvent that is used in the manufacture but it not intended as part of the final composition.

In some embodiments, the ratio of the weight of the release modifier to the weight of the natural substrate material, such as without limitation, MCC, is in the range of about 1 :25 to about 1 :2, preferably about 1 :20 to about 1 :4. In some embodiments, the ratio of the weight of the release modifier to the weight of the active agent is in the range of about 1 :4 to about 4: 1 , preferably about 3: 1 to about 1 :3.

The identity of the release modifier is not particularly limited. However, it is preferred that the release modifier is water insoluble, i.e. , has a water-solubility of 0.1 g (gram) or less in 100 ml (milliliter) of water at 25 °C , when the plurality of particles is to be formulated in an aqueous based formulation. It is also preferred that the release modifier is oil insoluble, i.e. , has an oil-solubility of 0.1 g or less in 100 ml of mineral oil at 25 °C, when the plurality of particles is to be formulated in an oil based formulation. However, release modifiers having oil or water solubility up to 20 g in 100 ml of mineral oil or water, respectively, can be used with particles intended to be used in an aqueous based formulation or an oil-based formulation, respectively. As used herein, "mineral oil" refers to USP/NF grade mineral oil.

The release modifier is selected such that it does not adversely affect the active agent, e.g. , is nonreactive and noninteractive with the active agent. The release modifier can be a solid at room temperature, i.e. , 25 °C, or it can be a liquid. A liquid release modifier has a low volatility, i.e. , has a boiling point of above 150 °C at one atmosphere (760 mmHg (millimeters of Mercury)). In many embodiments, the release modifier has cosmetic or medicinal properties which perform in conjunction with the active agent.

Accordingly, one class of useful release modifiers is the fatty alcohols, i.e. , alcohols having eight through twenty carbon atoms (Cs - C2o)- Fatty alcohols ethoxylated with one to three moles of ethylene oxide also are useful hydrophobic compounds. Examples of fatty alcohols and ethoxylated fatty alcohols include, but are not limited to, behenyl alcohol, caprylic alcohol, cetyl alcohol, cetaryl alcohol, decyl alcohol, lauryl alcohol, isocetyl alcohol, myristyl alcohol, oleyl alcohol, stearyl alcohol, tallow alcohol, steareth-2, ceteth-1 , cetearth-3, and laureth-2. Sterols, like lanolin alcohol, also can be used as the release modifier. Additional fatty alcohols and sterols are listed in the PCPC Handbook, pages 4007, incorporated herein by reference.

Another useful class of release modifiers is the Cs - C20 fatty acids, including, but not limited to, stearic acid, capric acid, behenic acid, caprylic acid, lauric acid, myristic acid, tallow acid, oleic acid, palmitic acid, isostearic acid, and additional fatty acids listed in the PCPC Handbook, pages 4006 and 4007, incorporated herein by reference.

The release modifier also can be a hydro-carbon, like mineral oil, 1 -decene dimer, a poly-decene, paraffin, petrolatum, or an isoparaffin, for example. Another class of release modifiers is the waxes, like mink wax, montan wax, carnauba wax, and candelilla wax, for example, and synthetic waxes, like silicone waxes, polyethylene, and polypropylene. Additional hydrocarbons and waxes are listed in the PCPC Handbook, pages 4019 and 4020, incorporated herein by reference.

Fats and oils also are useful release modifiers. Examples of fats and oils include, but are not limited to, lanolin oil, linseed oil, coconut oil, olive oil, menhaden oil, castor oil, soybean oil, tall oil, rapeseed oil, palm oil, and neatsfoot oil. Glyceryl esters of fatty acids also can be used as the release modifier, as can lanolin derivatives, such as hydrogenated lanolin, oleyl lanolate, lanolinamide DEA, and similar lanolin derivatives. Similarly, essential oils, like eucalyptus oil, peppermint oil, rose oil, clove oil, lemon oil, pine oil, and orange oil, can be used as the release modifier. Such essential oils also can serve as a fragrance. Additional fats, oils, and essential oils are listed in the PCPC Handbook, pages 4003 - 4006, incorporated herein by reference.

An especially useful class of release modifiers is the silicone oils, like dimethicone, and the functional silicone oils, like dimethicone copolyol. The silicone oils have a viscosity of about 10 centipoise (cP) to about 600,000 cP, and typically about 350 cP to about 10,000 cP, at 25 °C. Examples of silicone oils include dimethicone, dimethicone copolyol, dimethiconol, simethicone, phenyl trimethicone, stearoxy dimethicone, tri-methylsilylamodinethicone, an alkyl dimethicone copolyol, and a dimethicone having polyoxyethylene and/or polyoxypropylene side chains. Other classes of useful release modifiers include poly(acids), like poly(lactic acid); polymeric ethers, both homo and block copolymers, like poly(ethylene oxide-b- propylene oxide); polyols, like sorbitol, ascorbic acid, and mannitol; salts of Cs - C20 fatty acids, e.g. , sodium, potassium, aluminum, calcium, and magnesium salts of fatty acids; alkanolamides; and synthetic polymers, like a urea/-formaldehyde resin, a polyethyleneimine, a poly-acrylamide, a polyacrylic acid and salts thereof, polyvinylpyrrolidone and copolymers thereof, a polyisoprene, or a polystyrene, for example. Additional polymeric ethers, alkanolamides, and synthetic polymers are listed in the PCPC Handbook, pp. 4064 - 4075, incorporated herein by reference.

The release modifier also can be a water-insoluble ester having at least 10 carbon atoms, and preferably 10 to about 32 carbon atoms. Suitable esters include those comprising an aliphatic alcohol having about eight to about twenty carbon atoms and an aliphatic or aromatic carboxylic acid including from two to about twelve carbon atoms, or conversely, an aliphatic alcohol having two to about twelve carbon atoms with an aliphatic or aromatic carboxylic acid including about eight to about twenty carbon atoms. The ester is either straight-chained or branched. Suitable esters, therefore, include, for example, but are not limited to: (a) aliphatic monohydric alcohol esters, including, but not limited to: myristyl propionate, isopropyl isostearate, isopropyl myristate, isopropyl palmitate, cetyl acetate, cetyl propionate, cetyl stearate, isodecyl neopentanoate, cetyl octanoate, isocetyl stearate; (b) aliphatic di- and tri-esters of polycarboxylic acid, including, but not limited to: diisopropyl adipate, diisostearyl fumarate, dioctyl adipate, and triisostearyl citrate; (c) aliphatic polyhydric alcohol esters, including, but not limited to: propylene glycol dipelargonate; (d) aliphatic esters of aromatic acids, including, but not limited to: C12 - C15 alcohol esters of benzoic acid, octyl salicylate, sucrose benzoate, and dioctyl phthalate.

Numerous other esters are listed in the PCPC Handbook, at pages 3989 through 4000, incorporated herein by reference.

The release modifier also can be a biological polymer, a gum, a salt or derivative of a gum, or a carbohydrate. Examples of such release modifiers include, but are not limited to, hyaluronic acid, potato starch, corn starch, rice starch, sodium hyaluronate, locust bean gum, tragacanth gum, xanthan gum, methylcellulose, hydroxy-ethylcellulose, karaya gum, carboxymethylcellulose, sucrose, sucrose laurate, dextrin, corn syrup, pectin, methyl gluceth-10, gelatin, algin, carrageenan, and mixtures thereof. Additional biological polymers, carbohydrates, gum, and salts and derivatives of gums are listed in the PCPC Handbook, at pp. 4013 - 4014, incorporated herein by reference.

Another class of release modifiers is the sorbitan derivatives, like PEG-10 sorbitan laurate, PEG-20 sorbitan isostearate, PEG-3 sorbitan oleate, polysorbate 40, sorbitan stearate, and sorbitan palmitate, for example, where PEG refers to polyethylene glycol. Other sorbitan derivatives are listed in the PCPC Handbook, at page 4059 - 4060, incorporated herein by reference.

In some embodiments, the release modifier is selected from the group consisting of poly(acid)s, polyols, salts of Cs - C20 fatty acids, alkanolamides, water- soluble polymers, biological polymers, gums, carbohydrates, cellulose derivatives, sorbitan derivatives, and mixtures thereof.

In preferred embodiments, the release modifier is a fatty alcohol such as cetyl alcohol, stearyl alcohol or a combination of cetyl alcohol and stearyl alcohol as well as cetyl alcohol in combination with another release modifier.

For clarity, the release modifiers described herein may be used individually, or in combination with other release modifiers, including, but not limited to, those release modifiers described herein.

Optional Ingredients

The controlled release compositions of the present invention also may include optional ingredients traditionally included in cosmetic, medicinal, and other such compositions. These optional ingredients include, but are not limited to, surfactants, humectants, dyes, fragrances, preservatives, antioxidants, detackifying agents, and similar types of compounds. The optional ingredients are included in the

composition in an amount sufficient to perform their intended function. Optional ingredients may be used individually or in combination.

Examples of optional ingredients include, but are not limited to, polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80, butylated hydroxy- toluene (BHT), butylated hydroxyanisole (BHA), and propyl gallate. Polysorbates are a group of oleate esters of sorbitol and its' anhydrides condensed with polymers of ethylene oxide. Polysorbates are used as emulsifiers and surfactants in food, pharmaceuticals and cosmetics. Polysorbates 20, polysorbate 60, and polysorbate 80 have a specification listed in the United States Pharmacopeia/National Formulary (USP/NF). With respect to antioxidants, both water-soluble and oil-soluble antioxidants may be used. Non-limiting examples of water-soluble antioxidants are ascorbic acid (vitamin C), isoascorbic acid, imidazoline urea, methyl paraben, sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, thioglycerol, thiosorbitol, thiourea, thioglycolic acid, cysteine

hydrochloride, and 1 ,4-diazabicyclo-(2,2,2)-octane. Examples of oil-soluble antioxidants are butylated hydroxytoluene (BHT), butylated hydroanisole (BHA), a- tocopherol (vitamin E), ascorbyl palmitate, phenyl-a-naphthylamine, hydroquinone, propyl gallate, roxmarinum officinalis (Rosemary) leaf extract, Octadecyl Di-t-butyl-4- hydroxyhydrocinnamate, Tetrabutyl Ethylidinebisphenol, Pentaerythrityl Tetra-di-t- butylHydroxyhydrocinnamate, and nordihydro-guiaretic acid. The amount of antioxidant can vary and is not critical to the embodiments disclosed herein. In some embodiments, the weight: weight ratio of antioxidant to active agent is from 1 : 1000 to 1 : 1 , preferably from 1 : 100 to 1 :2.

Another type of additional ingredient is a chelating agent to serve as a scavenger for trace metals. Non-limiting examples of chelating agents suitable for use in the embodiments disclosed herein are ethylenediamine tetraacetic acid (EDTA) and derivatives and salts of EDTA, dihydroxyethylglycine, citric acid, and tartaric acid. The amount of chelating agent can likewise vary and is not critical to the embodiments disclosed herein.

In some embodiments, the optional ingredients, such as an antioxidant, may also be an active agent (active ingredient) as well as performing a second function. Similarly, some release modifiers may be used as an "optional ingredient," that is the substance may have a secondary function as well as acting as a release modifier. One of skill in the art will be able to determine which substances have dual (or even more than two) uses, and for which use(s) the substance is being added to the formulation.

The ratio of the weight of the sum of all the optional ingredients to the weight of the active agent (or sum of active agents) may be in the range of 10: 1 to 1 : 100, and preferably in the range of 3: 1 to 1 :10. In some embodiments, the only ingredients are used the active agent(s), the substrate(s), and the release

modifier(s). In some embodiments, the active agent-substrate composition is only one or more active agents and one or more substrates, while in other embodiments, the sum of all active agents and substrates comprises not less than 99 wt% of the active agent-substrate composition. In determining the ratios above, one of skill in the art will be able to determine if a particular substance, for example, an antioxidant, is an "additional ingredient," or an "active agent." As a non-limiting example, in some embodiments of an active agent-substrate composition including an antioxidant and a retinoid, the retinoid is the "active agent" and the antioxidant is an "additional ingredient."

Manufacture of the Compositions

Typically, the active agent is entrapped by the substrate prior to adding the optional release modifier. However, in some embodiments, the optional release modifier can be added to the natural substrate simultaneously with the active agent. In some embodiments, the release modifier is added both simultaneously with the active agent, and an additional quantity of release modifier, which may be the same release modifier or a different release modifier, may be added after the substrate- active agent combination has been made.

One manner of entrapping the active agent is to dissolve, disperse, or partially dissolve and partially disperse the active agent into a solvent, optionally with other ingredients. In preferred embodiments, the active agent as well as the optional other ingredients are in a true solution (dissolved). A solvent can refer to one chemical compound, or a mixture of chemical compounds.

Non-limiting examples of such solvents which may be used in preparing the compositions described herein are liquid petrolatum, polysorbate ether, petroleum ether, alcohols (e.g., methanol, ethanol, isopropanol, propylene glycol and higher alcohols), aromatics (e.g., benzene and toluene), alkanes (e.g., pentane, hexane and heptane), ketones (e.g., acetone and methyl ethyl ketone), chlorinated

hydrocarbons (e.g., chloroform, carbon tetrachloride, methylene chloride, and ethylene dichloride), and oils (e.g., isopropyl myristate, diisopropyl adipate, mineral oil, and silicone oils).

The resulting mixture of solvent, active agent, and optional ingredients, is added to the substrate (contacted with the substrate), and mixed until uniform. The active agent may be from 2 wt% to 90 wt% of the mixture, and preferably from 5 wt% to 40 wt% of the mixture. The other ingredients may be 2 wt% to 90 wt% of the mixture, and preferably from 5 wt% to 40 wt% of the mixture. Of course, the total of the solvent, active agent, and other ingredients sum to 100 wt%. The ratio of the weight of the mixture of solvent, active agent, and optional ingredient to the weight of substrate ranges from about 1 :4 to about 4: 1 , and preferably about 3: 1 to about 1 :2.

The mixture of solvent, active agent, and optional ingredient is added to the substrate and blended. In some embodiments, the blending is accomplished with a low shear mixing apparatus, such as a plow mixer made by Littleford. Alternatively, the mixture of the solvent, active agent, and optional ingredient may be sprayed onto the substrate. It may be sprayed onto the substrate in a granulator (pan granulator, pan coater, blender, mixer, or the like) and blended, or it may be sprayed onto the substrate in a fluid bed, where the fluid bed may include or may not include a

Wurster insert. The combination of the active agent and the substrate is preferably not made by spray drying.

The mixture of the solvent, active agent, and optional ingredient is mixed or blended with the substrate until a uniform blend is achieved.

After the mixture of active agent, optional ingredients, and solvent are blended with the substrate, the solvent used for the entrapment of the active agent may be substantially removed. In some embodiments, the solvent may remain as part of the final composition. However, in most embodiments, ideally all of the solvent is removed, but in practice 100 wt% removal is not possible. Thus, in some

embodiments, the residual solvent is not more than 100 ppm (parts per million by weight), not more than 0.01 wt%, not more than 0.1 wt% or not more than 1 wt% of the final composition or an intermediate composition. In some embodiments, substantially removed is 99.9 wt% or more removed, and in other embodiments, substantially removed is 90 wt% or more removed. One of skill in the art will be able to determine if the solvent is the type that is intended to be part of the final formulation rather than be removed.

Solvent removal encompasses allowing the solvent to evaporate from the particles of substrate-active agent over time, which may be at room temperature (about 18 °C to about 25 °C, preferably about 20 °C to about 22 °C). Solvent removal also encompasses placing the material in an environment at a temperature above room temperature, such as without limitation between about 26 °C to about 90 °C, preferably about 30 °C to about 65 °C, in an environment of reduced pressure (less than 760 mmHg (millimeters of Mercury), such as without limitation less than 100 mmHg), or both. Solvent removal may be accomplished in a forced air or natural convection oven, a tray drier, a fluid bed drier, or any combination thereof. In some embodiments, the above process of adding a mixture of the solvent, active agent, and optional ingredients to the natural substrate with solvent removal may be executed on more than one occasion to reach a desired amount of active agent entrapped by the substrate. The solvent may be only partially removed between successive occurrences of the addition with a tighter specification on the residual solvent after the last repetition, for example 90 wt% removal between repetitions but not less than 95 wt% after the final addition process.

The release modifier may be added by similar techniques that are used to add and/or combine the active agent with the substrate - that is the use of a blender, mixer, or granulator to add a mixture of the release modifier and a solvent (and optionally other ingredients) to the active agent-substrate combination with removal of the solvent. In addition, depending upon the specific release modifier, the material may be melted and added to the active agent-substrate combination. Similar to the situation with active entrapment, several repetitions of the addition, with solvent removal if needed, may be executed to achieve a desired addition of release modifier addition.

Characteristics of the Composition and Use in Pharmaceutical and Personal Care Compositions

With respect to all compositions described herein, it is understood that the active agent "as received" may include impurities and therefore, may not assay at 100%, or at the stated purity or label claim (such as, for example, 50 wt%). As a result, the quantity of one or more ingredients may be adjusted to account for any changes in potency of the active agent while maintaining a specific wt% in the final composition. Alternatively, the percent by weight of the active agent in the active agent-substrate composition and/or the active agent-substrate-release modifier composition may vary.

It is also understood that the weight percent, for the optional ingredients and substrates, is determined by the quantity of the materials added to the formulation. Thus, the calculated %ingredient can also include impurities, moisture, residual solvents (from manufacture), or a combination thereof included with the ingredient as added to the composition. As a non-limiting example, if 10 g of microcrystalline cellulose were to be added to a controlled release composition of a total weight of 20 g, the weight percent micro-crystalline cellulose would be 50%, even if the

microcrystalline cellulose contained 5 wt% water.

Typically, the weight percent of the active agent is determined by assay of the final composition which may or may not include a release modifier, or of the intermediate, active agent-substrate combination.

In some embodiments, the active agent-substrate-release modifier

composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and further optionally including a release modifier, where the average particle diameter is about 60 microns, and preferably in the range of about 1 to about 150 microns as measured by laser light scattering, or as determined from a volume- distribution of diameters. In some embodiments, the active agent-substrate-release modifier composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and further including a release modifier, where the polydispersity of the particles as determined by D90/D10, based on the volume distribution or approximated with a distribution determined by laser light scattering, is in the range of 4 to 8. In some embodiments, the active agent-substrate-release modifier composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and further including a release modifier, where the volume average diameter and the polydispersity based on the volume average distribution falls within the ranges in the immediately preceding two sentences.

In some embodiments, the active agent-substrate composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and without a release modifier, where the polydispersity of the particles as determined by D90/D10, based on the volume distribution or

approximated with a distribution determined by laser light scattering, is in the range of 4 to 8. In some embodiments, the active agent-substrate composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and without a release modifier, where the volume average diameter and the polydispersity based on the volume average distribution falls within the ranges in the immediately preceding two sentences.

In some embodiments, the active agent-substrate-release modifier

composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and without a release modifier, where the average particle diameter is about 60 microns, and preferably in the range of about 1 to about 150 microns as measured by laser light scattering, or as determined from a volume- distribution of diameters. In some embodiments, the active agent-substrate- release modifier composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and without a release modifier, where the polydispersity of the particles as determined by D90/D10, based on the volume distribution or approximated with a distribution determined by laser light scattering, is in the range of 4 to 8. In some embodiments, the active agent- substrate-release modifier composition is a plurality of particles, the particles including a natural substrate with active agent entrapped by the substrate, and further including a release modifier, where the volume average diameter and the polydispersity based on the volume average distribution falls within the ranges in the immediately preceding two sentences.

The composition, whether particles of active agent-substrate or particles of active agent-substrate-release modifier or a combination of both, may be

incorporated in fluid, semisolid, or solid composition for preparations for personal care or pharmaceutical use. In some embodiments, the plurality of particles of active agent-substrate or active agent-substrate-release modifier may be used in a preparation (or formulation) commonly used for skin treatment. These preparations include pastes, gels, creams, lotions, ointments, sprays, powders, oils, and sticks. Preferred preparations for the inclusion of the plurality of particles of active agent- substrate or active agent-substrate-release modifier are aqueous fluid compositions such as oil-in-water and water-in-oil emulsions, gels, creams, lotions, ointments and sprays. In some embodiments, the composition, a plurality of particles, is dispersed in an aqueous medium. Regardless of the preparation, however, the medium in which the composition, a plurality of particles, is dispersed can contain additional ingredients for any of a variety of cosmetic, therapeutic or preventive effects. Such ingredients are well known to those skilled in the art.

Ointments, as is well known in the art of pharmaceutical formulation, are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum active compound delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like. As with other substrates or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa. : Mack Publishing Co. , 1995), at pages 1399-1404, ointment bases may be grouped in four classes: oleaginous bases;

emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, see Remington: The

Science and Practice of Pharmacy for further information.

Creams, as also well known in the art, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not

necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceutical formulation, gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. An aqueous gel is a gel in which the carrier liquid is 50 wt% or more water. An anhydrous gel is one that is free of water, or, in some embodiments, one that comprises not more than 5 wt% water. Preferred "organic macro- molecules," i.e. , gelling agents, are crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g. , carboxypolyalkylenes that may be obtained commercially under the CARBOPOL® trademark. Also preferred are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene

copolymers (some of which are sold under the trade name PLURONIC® and some of which are poloxamers as defined by the USP/NF) and polyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose;

gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin may be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

Lotions, which are preferred for delivery of cosmetic agents, are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids. In some

embodiments, lotions comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium

carboxymethyl-cellulose, or the like.

Pastes are semisolid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gels. The base in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base.

As noted above, the composition, whether particles of active agent-substrate or particles of active agent-substrate-release modifier or a combination of both, may be incorporated in fluid, semisolid, or solid composition for preparations for personal care or pharmaceutical use. When incorporated, the plurality of particles are dispersed into fluid or semisolid compositions, such as and without limitation, pastes, gels, ointments, creams, and lotions, the particles largely (not less than 95 wt%) exist as individual particles dispersed homogeneously or substantially

homogeneously throughout the composition. In some embodiments, the particle size (diameter) in the composition, such as pastes, gels, ointments, creams, and lotions, is small enough to exhibit a non-gritty, smooth cosmetically acceptable lotion feel. In some embodiments, a "small enough" particle diameter is where 95% of the particles, as determined from the volume-average particle diameter distribution or a laser-light scattering particle diameter distribution, have a diameter in the range of 0.75 to 220 microns (micrometers or pm),

When the composition, the substrate-active agent optionally including a release modifier, is added to a preparation or formulation, such as a topical composition, forming a controlled release composition, the formulation releases the active agent over a time frame longer than 8 hours, which is not more than 80 wt% of the active agent is released at 4 hours after administration. In some embodiments, not more than 50 wt% of the active agent in the controlled release composition is released at 2 hours after administration, and in some embodiments, not more than 30 wt% of the active agent in the controlled release composition is released at 2 hours after administration. In some embodiments, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the active agent is released within 8 hours. In some

embodiments, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the active agent is released within 12 hours, and in some embodiments, at least 90 wt%, at least 95 wt%, or at least 99 wt% of the active agent is released within 24 hours. The release rate can be determined by standard in-vitro models.

In some embodiments, a gel comprising the plurality of particles comprising the active agent and the natural substrate, without a release modifier, exhibits a measurably lower release of the active agent, and in some embodiments, the release is lower by at least 5%, than the release of active agent over the same time period of an equivalent gel comprising the active agent without the natural substrate when the time period is the time frame at which 20 wt%, 30 wt%, 50 wt%, or 75 wt% of the active agent has been released from the gel without the natural substrate. As used herein, "an equivalent gel" means the same gel is formed and a quantity of active agent composition is added to the gel that is equivalent to the amount of active agent composition carried by the plurality of particles added to the initial gel. In some embodiments the measurably lower release of the active agent, which may be at least 5% lower release of the active agent, occurs when the gel is an aqueous gel of about 0.1 - 2 wt% carbomer, for example and without limitation about 0.2 wt% carbomer, with pH adjustment to be in the range of about 6.5 and an active agent concentration of 0.05 to 0.5 wt% in the gel. Carbomer is the USP name for a cross- linked polyacrylic acid polymer where there are several different types of Carbomer depending upon the cross-linking monomer. In some embodiments, the active agent-substrate-release modifier composition, when used in a formulation, reduces irritation, including cumulative irritation, when compared to using the same active agent in the same formulation, but in the absence of the substrate and release modifier. In other words, the use of the active agent-substrate-release modifier composition in a formulation, such as a topical formulation, reduces irritation as compared to use of "free" active agent. In some embodiments, "free" active agent is active agent as received which may include other ingredients. In some embodiments, "free" active agent is active agent without any other optional ingredients.

In some embodiments is a pharmaceutical composition, the composition being an aqueous solution, an oil-in-water emulsion, a water-in-oil emulsion, an aqueous gel, or an anhydrous gel, the composition comprising water-insoluble particles of a natural substrate comprising an active agent composition comprising an active agent; wherein the water-insoluble particles comprising the active agent composition comprise between about 0.01 % and about 5.0% by weight of the pharmaceutical composition; and wherein the pharmaceutical composition causing lower irritancy when applied than a composition containing the same concentration of active agent in a non-particle formulation. In some embodiments, the water- insoluble particles are formed of cellulose, and in some embodiments, the cellulose is a microcrystalline cellulose. In some embodiments, the active agent composition of the water insoluble particles comprises from about 5% to about 60% by weight of retinol, from about 1 % to about 75% by weight of an antioxidant, optionally from about 0.01 % to about 1 % by weight of a chelating agent, and a surfactant, subject to the limitation that the sum of the components does not exceed 100 %. In preferred embodiments, the pharmaceutical composition is an oil-in-water emulsion, the oil-in- water emulsion comprising, by weight, about 75% to about 81 % water, 0.5% magnesium aluminum silicate, 3.0% glycerin, 3.5% emulsifying esters, 2.5% cholesterol/lanosterol esters, 1 .0% stearic acid, 3.0% cetyl alcohol, 4.0% emulsifying wax, 2.0% silicone fluid, 0.5% soya sterol ethoxylates, 0.3% triethanolamine, 0.06- 0.3% BHT, and 0-1 .0% diazolidinylurea.

In some embodiments are pharmaceutical compositions for topical administration of an active agent, the pharmaceutical composition comprising an oil- in-water emulsion comprising, suspended in the emulsion, a plurality of particles of a natural substrate and an active agent, the composition causes lower irritancy when applied than a composition containing the same concentration of active agent in an oil-in-water, the oil-in-water emulsion being the same as the oil-in-water emulsion in which the plurality of particles is suspended (except that the particles are not suspended in the emulsion).

In some embodiments are pharmaceutical compositions for topical

administration of an active agent, the pharmaceutical composition being an oil-in- water emulsion comprising, suspended in the emulsion, solid water-insoluble microscopic particles and a retinoid composition comprising retinol carried by the particles, and the pharmaceutical composition comprising between about 0.001 % and about 20.0% by weight of the retinoid composition, the pharmaceutical composition causing lower irritancy when applied than a composition containing the same concentration of retinol in a non-(microscopic particle) formulation. In some embodiments, the pharmaceutical composition described comprises between about 0.01 % and about 5.0% by weight of the retinoid composition. In some embodiments, the retinoid composition comprises from about 1 % to about 90% by weight of retinol. In some embodiments, the retinoid composition comprises from about 5% to about 60% by weight of retinol. In some embodiments, the retinoid composition further comprises from about 0.01 % to 1 % by weight of a chelating agent. In some embodiments, the retinoid composition further comprises from about 1 % to about 75% by weight of an antioxidant. In some embodiments, the retinoid composition further comprises a surfactant.

Some non-limiting embodiments of the present invention are described in the following numbered embodiments:

Embodiment 1 : A composition comprising a plurality of particles, the particles comprising:

(a) a natural substrate; and

(b) an active compound, said active compound adsorbed onto, absorbed into, or both adsorbed onto and absorbed into said natural substrate, wherein the active compound is present in a weight amount at least one hundredth and up to three times greater than the weight amount of the natural substrate.

Embodiment 2: In some embodiments of the present invention, such as but not limited to those described in embodiment 1 , the plurality of particles when dispersed in a fluid not less than 95 weight% exist as individual particles dispersed homogeneously or substantially homogeneously throughout the composition.

Embodiment 3: In some embodiments of the present invention, such as but not limited to those described in embodiment 2, the fluid is a paste, a gel, an ointment, a cream, or a lotion.

Embodiment 4: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 3, the composition further comprises a release modifier, said release modifier coated and adsorbed onto said natural substrate and said active compound.

Embodiment 5: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 4, wherein the fluid is a paste, a gel, or an ointment.

Embodiment 6: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 4, wherein the fluid is a cream, or a lotion.

Embodiment 7: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 6, the active compound is oil soluble.

Embodiment 8: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 6, the active compound is water soluble.

Embodiment 9: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 8, the active compound is a medicinally active compound.

Embodiment 10: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 9, the natural substrate material is cellulose.

Embodiment 1 1 : In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 9, the natural substrate material is microcrystalline cellulose.

Embodiment 12: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 9, the natural substrate material is derived from walnut. Embodiment 13: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 12, the active compound is a topically active compound.

Embodiment 14: In some embodiments of the present invention, such as but not limited to those described in embodiment 13, the topically active compound is selected from the group consisting of skin-care compounds, antioxidants, and mixtures thereof.

Embodiment 15: In some embodiments of the present invention, such as but not limited to those described in embodiment 13, the topically active compound is selected from the group consisting of aloe vera, PEG-4 dilaurate, lanolin oil, petrolatum, mineral wax, salicyclic acid, and mixtures thereof.

Embodiment 16: In some embodiments of the present invention, such as but not limited to those described in embodiment 13, the topically active compound is selected from the group consisting of silicones, isopropyl myristate, vitamin E acetate, retinol, and mixtures thereof.

Embodiment 17: In some embodiments of the present invention, such as but not limited to those described in embodiment 13, the topically active compound is selected from the group consisting of aloe vera, glycolic acid, tea tree oil, lanolin oil, petrolatum, mineral wax, salicyclic acid, and mixtures thereof.

Embodiment 18: In some embodiments of the present invention, such as but not limited to those described in embodiment 13, the topically active compound is selected from the group consisting of silicones, isopropyl myristate, vitamin E acetate, retinol, retinoic acid, retinaldehyde, and mixtures thereof.

Embodiment 19: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 18, the particles of the

composition further comprise a release modifier in an amount of about 0.5% to about 30% by weight of composition.

Embodiment 20: In some embodiments of the present invention, such as but not limited to those described in embodiment 19, the release modifier is selected from the group consisting of poly(acid)s, polyols, salts of Cs - C20 fatty acids, Cs - C20 fatty alcohols, alkanolamides, water-soluble polymers, biological polymers, gums, carbohydrates, cellulose derivatives, sorbitan derivatives, and mixtures thereof. Embodiment 21 : In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 20, the release rate of the active compound from a 2 weight% carbomer aqueous gel, the gel comprising the plurality of particles comprising the active compound and the natural substrate, in an amount such that the active compound comprises 0.05 wt% to 0.5 wt% of the gel, is measurably lower than the release of active compound over the same time period of an equivalent gel comprising the same amount of active compound without the natural substrate.

Embodiment 22: In some embodiments of the present invention, such as but not limited to those described in embodiments 1 - 20, the release rate of the active compound from a 2 weight% carbomer aqueous gel, the gel comprising the plurality of particles comprising the active compound and the natural substrate, in an amount such that the active compound comprises 0.05 wt% to 0.5 wt% of the gel, is lower by at least 5 % than the release of active agent over the same time period of an equivalent gel without the natural substrate.

Embodiment 23: In some embodiments of the present invention, such as but not limited to those described in embodiment 21 , the time period over which release is determined is the time point at which 70 wt% of the active compound has been released from the gel without the natural substrate.

Embodiment 24: In some embodiments of the present invention, such as but not limited to those described in embodiment 22, the time period over which release is determined is the time point at which 70 wt% of the active compound has been released from the gel without the natural substrate.

Embodiment 25: In some embodiments of the present invention, such as but not limited to those described in embodiment 19, the release rate of the active compound from a 2 weight% carbomer aqueous gel, the gel comprising the plurality of particles comprising the active compound, natural substrate, and release modifier, in an amount such that the active compound comprises 0.05 wt% to 0.5 wt% of the gel, is measurably lower than the release of active compound over the same time period of an equivalent gel comprising the active compound without the particles.

Embodiment 26: In some embodiments of the present invention, such as but not limited to those described in embodiment 19, the release rate of the active compound from a 2 weight% carbomer aqueous gel, the gel comprising the plurality of particles comprising the active compound, natural substrate, and release modifier, is lower by at least 5% than the release of active compound over the same time period of an equivalent gel comprising the active compound without the particles.

Embodiment 27: In some embodiments of the present invention, such as but not limited to those described in embodiment 25, the time period over which release is determined is the time point at which 70 wt% of the active compound has been released from the gel without the particles.

Embodiment 28: In some embodiments of the present invention, such as but not limited to those described in embodiment 26, the time period over which release is determined is the time point at which 70 wt% of the active compound has been released from the gel without the particles.

Embodiment 29: A personal care or pharmaceutical composition, the composition being an aqueous solution, an oil-in-water emulsion, a water-in-oil emulsion, an aqueous gel, or an anhydrous gel, the pharmaceutical or personal care composition comprising a sub composition, such as but not limited to, any of those described in embodiments 1 - 28.

Embodiment 30: A pharmaceutical composition, the composition being an aqueous solution, an oil-in-water emulsion, a water-in-oil emulsion, an aqueous gel, or an anhydrous gel, the composition comprising water-insoluble particles of a natural substrate comprising an active agent composition comprising an active agent; wherein the water-soluble particles comprising the active agent composition comprise between about 0.01 % and about 5.0% by weight of the pharmaceutical composition; and wherein the pharmaceutical composition causing lower irritancy when applied than a composition containing the same concentration of active agent in a non-particle formulation.

Embodiment 31 : In some embodiments of the present invention, such as but not limited to those described in embodiment 30, the water-insoluble particles are formed of cellulose.

Embodiment 32: In some embodiments of the present invention, such as but not limited to those described in embodiment 31 , the cellulose is a microcrystalline cellulose.

Embodiment 33: In some embodiments of the present invention, such as but not limited to those described in embodiments 30 - 32, the active agent composition of the water insoluble particles comprises from about 5% to about 60% by weight of retinol, from about 10% to about 75% by weight of an antioxidant, and optionally from about 0.01 % to about 1 % by weight of a chelating agent, and a surfactant.

Embodiment 34: In some embodiments of the present invention, such as but not limited to those described in embodiments 13 - 20, the pharmaceutical composition is an oil-in-water emulsion, the oil-in-water emulsion comprising, by weight, about 75% to about 81 % water, 0.5% magnesium aluminum silicate, 3.0% glycerin, 3.5% emulsifying esters, 2.5% cholesterol/lanosterol esters, 1 .0% stearic acid, 3.0% cetyl alcohol, 4.0% emulsifying wax, 2.0% silicone fluid, 0.5% soya sterol ethoxylates, 0.3% triethanolamine, 0.06-0.3% BHT, and 0-1 .0% diazolidinylurea.

Embodiment 35: A pharmaceutical composition for topical administration of an active agent, the pharmaceutical composition comprising an oil-in-water emulsion comprising, suspended in the emulsion, a plurality of particles of a natural substrate and an active agent, the composition causing lower irritancy when applied than a composition containing the same concentration of active agent in an oil-in-water, the oil-in-water emulsion being the same as the oil-in-water emulsion in which the plurality of particles is suspended.

Embodiment 36: A pharmaceutical composition for topical administration of an active agent, the pharmaceutical composition being an oil-in-water emulsion comprising, suspended in the emulsion, solid water-insoluble microscopic particles and a retinoid composition comprising retinol carried by the particles, and the pharmaceutical composition comprising between about 0.001 % and about 20.0% by weight of the retinoid composition, the pharmaceutical composition causing lower irritancy when applied than a composition containing the same concentration of retinol in a non-(microscopic particle) formulation.

Embodiment 37: In some embodiments of the present invention, such as but not limited to that described in embodiment 36, the the pharmaceutical composition comprises between about 0.01 % and about 5.0% by weight of the retinoid

composition.

Embodiment 38: In some embodiments of the present invention, such as but not limited to that described in embodiment 37, the retinoid composition comprises from about 1 % to about 90% by weight of retinol.

Embodiment 39: In some embodiments of the present invention, such as but not limited to that described in embodiment 37, where the retinoid composition comprises from about 5% to about 60% by weight of retinol. Embodiment 40: In some embodiments of the present invention, such as but not limited to those described in embodiments 36 - 39, the retinoid composition further comprises from about 10% to about 75% by weight of an antioxidant.

Embodiment 41 : In some embodiments of the present invention, such as but not limited to those described in embodiments 36 - 40, the retinoid composition further comprises a surfactant.

Embodiment 42: In some embodiments of the present invention, such as but not limited to those described in embodiments 36 - 41 , the retinoid composition further comprises from about 0.01 % to 1 % by weight of a chelating agent.

Examples

The following examples are given to aid in understanding the invention, but it is to be understood that the invention is not limited to the particular materials or procedures of the examples.

Example 2: Retinol-Microcrvstalline cellulose combination

A combination of retinol entrapped by microcrystalline cellulose was made. The source of the retinol for the combination can either be BASF 50C ^® or Nicolas Piramal 50WM ^® . Both products are a mixture of Retinol, Polysorbate 20, butylated hydroxy-toluene (BHT) and butylated hydroxyanisole (BHA) where the retinol concentration in this product is approximately 50 wt%. The specific composition of these products (BASF 50C ^® or Nicolas Piramal 50WM ^® ) is Retinol 42.75 - 49.5 wt%; BHT 3.15 - 3.5 wt%; BHA 0.9 - 1 .10 wt%; and Polysorbate 20 45.9 - 53.2 wt%. The solvent used was acetone. To 10 g of acetone was added 0.165 g BHT and 0.047 g BHA, 0.003 Propyl Gallate, and 10 g retinol source (BASF 50C) and the solution was stirred until a homogeneous solution formed. Under a nitrogen stream, the retinol solution was added to 10 g of MCC (DFE PHARMACEL ^® 101 ) and mixed by hand with a spatula until uniform. There was no pre-treatment or washing of the MCC which was used "as received." The mixture was then placed in a vacuum oven (at about 20 inches of mercury or fewer inches of mercury) set at 35 °C and dried until more than 90 wt% of the acetone was removed (less than 10 wt% of the amount added remained in the product) as judged by a moisture balance. A preferred particle diameter of the natural substrate is one in which 95% of the particles as determined from the particle diameter distribution, either a volume- particle diameter distribution or a laser-light scattering particle diameter distribution, fall within the diameter range of 0.75 micrometers to 220 micrometers. The composition of this product is provided in Table 2 where the wt% excludes solvent added during the manufacture:

Table 2: Composition of the Retinol-MCC Combination

The total is less than 100 wt% due to rounding errors, and to 4 significant figures, the sum is 100.0 wt%. In the above formulation, both BHT and BHA are antioxidants. Although the active agent in the active agent-natural substrate may be an

antioxidant, in this formulation the BHT and BHA are added as "optional ingredients" to prevent the degradation of the active agent, retinol.

Example 3: Formation of a Modified Release Composition

A controlled release composition is made by adding cetyl alcohol to the active agent - substrate combination of Example 2. A solution of 15 wt% solution of cetyl alcohol is made by adding 3 g of cetyl alcohol to methanol which dissolves the cetyl alcohol. The cetyl alcohol solution is added to the combination of Example 2 (active agent-substrate combination) and mixed until uniform. The combination of the active agent-substrate-release modifier is then dried in the vacuum oven (at about 20 inches of mercury or fewer inches of mercury) at 35 °C until less than 1 wt% solvent remains in the composition. The oven at 35 °C means the temperature of the air in the oven is 35 °C (within normal variability). The composition of the product is shown below in Table 3:

Table 3: Composition of the Modified Retinol-MCC Combination

Example 4: Formation of a Second Modified Release Composition

The addition of more cetyl alcohol to the active agent - substrate -release modifier composition of Example 3 results in a second modified release composition. Another solution of 15 wt% cetyl alcohol in methanol including 3 g of cetyl alcohol is made and is added to the composition of Example 3 and mixed until uniform. The active agent - substrate -release modifier composition is then dried in the vacuum oven (at about 20 inches of mercury or fewer inches of mercury) at 35 °C until less than 1 wt% solvent remains in the composition. The composition of the second modified release product is: Table 4: Composition of the Modified Retinol-MCC Combination

Example 5: Formation of a Third Modified Release Composition

The addition of a third quantity of cetyl alcohol to the active agent - substrate

-release modifier composition of Example 4 results in a third modified release composition. Another solution of 15 wt% cetyl alcohol in methanol including 3 g of cetyl alcohol is made and is added to the composition of Example 4 and mixed until uniform. The active agent - substrate -release modifier composition is then dried in the vacuum oven (at about 20 inches of mercury or fewer inches of mercury) at 35 °C until less than 1 wt% solvent remains in the composition. The composition of the third modified release product is:

Table 5: Composition of the Modified Retinol-MCC Combination

Example 6: Formation of another Modified Release Composition

Similar to the procedure of Example 1 , a retinol-substrate combination was made by preparing an acetone solution that contained 13 g acetone, 13 g Nicolas Piramal 50WM BHA Free (a source of retinol), 0.04 g Propyl Gallate, and 2.7 g BHT, which was added to 50 g of the Pharmacel 101 MCC (see Example 1 ). The acetone solution was added to the MCC and mixed until homogeneous under an inert atmosphere, and then the acetone was removed under vacuum and heating. To the product of the previous step, 3 g of Cetyl Alcohol was dissolved in 19.8 g of acetone, added to the retinol-substrate combination and then the acetone was removed under vacuum and heating. The process was repeated another time using the same quantity of cetyl alcohol and acetone which after drying under vacuum and heating gave a product with the following composition. Table 6: Composition of the Modified Retinol-MCC Combination

Example 7: Formation of another Modified Release Composition

Similar to the procedure of Example 1 , a retinol-substrate combination was made by preparing an acetone solution that contained 10.4 g acetone, 10.4 g Nicolas Piramal 50WM (a source of retinol), 0.029 g Propyl Gallate, 1.4 g BHT, and 0.40 g BHA, which was added to 137 g of the Natural Nylon (see Example 1 ). The acetone solution was added to the Natural Nylon and mixed until homogeneous under an inert atmosphere, and then the acetone was removed under vacuum and heating. The process of adding the same concentration of retinol and optional ingredients in the acetone solution and then drying the product was repeated three more times to give an active agent - substrate combination with 15 wt% retinol. Example 8: Release of Retinol from Formulated Products

To evaluate the extended release of an active agent from the delivery system to the surface of the skin, a Franz diffusion cell is used. In the operation of a Franz diffusion cell, a finished cosmetic product (lotion, cream or gel) is applied to a membrane which is placed on top of liquid receptor phase which is a good solvent for the active agent. The active agent diffuses across the membrane and enters the stirred receptor phase which is periodically sampled and then the sampled receptor phase is analyzed, such as by using High Pressure Liquid Chromatography (HPLC), for the content (or concentration) of the cosmetic active agent. A plot of the amount of active released as a function of time allows the comparison between cosmetic or medicinally active compounds that are free in the finished product in comparison to those actives that have been entrapped in the delivery system. For the following samples, an aqueous gel was formed by adding 0.2 wt% Carbopol ^® Ultrez 10 (Lubrizol) (a cross-linked polyacrylic acid polymer used for rheology modification) to nitrogen-sparged deionized (Dl) water and then neutralizing the gel to pH 6.5. The retinol source was then added into the gel under nitrogen and yellow lights to make a product that contained 0.2 wt% retinol in the finished product. Three products were made: 1 ) gel that contained only "free" retinol (Retinol source of BASF 50C); 2) gel that contained an MCC-retinol combination (a composition of Example 2); and 3) gel that contained an MCC-retinol-cetyl alcohol combination (a composition of Example 4). Approximately 0.5 g of cosmetic product was placed on top a silicone elastomer membrane for six diffusion cells where there are six cells per formulation and the average of the six cells is reported. The cells were then filled with a 60/40 (by volume) blend of ethanol and Dl water taking care to make sure that no air bubbles were trapped on the surface of the membrane. The cells were stirred using a flea stir bar and the temperature of the cells was controlled to be at 37 °C. Receptor phase solution was removed from the diffusion cell at 1 , 2, 4, 6 and 8 hours. The cumulative amount of retinol released (micrograms) is shown in Table 6 below as well as in Figure 1 .

Table 6: Cumulative Release of Retinol

Example 9: Clinical Study Cumulative Irritation

A 14-day cumulative cutaneous irritation potential study using human volunteers can be used to help compare the acute irritation potential between a number of formulated products. This cross-over study was run by Inovapotek Pharmaceutical Research and Development (Porto, Portugal) using 44 human volunteers (subjects) who met the enrollment criteria. For each of the test products and controls, the product was occulsively placed on the subject's back using an 8 mm Finn Chamber (SmartPractice, Denmark) using Scanpor adhesive tape

(Actavis). The product was kept on the subject's back for 23 hours and 30 minutes. After this period of time, the chamber was removed, and the cutaneous irritation potential was evaluated thirty minutes after removal of the chamber using a 6-point scale shown in Table 7 below. The product was then applied again and this processed was repeated nine additional times over a 14 day period of time.

Table 7: Scoring for Clinical Study

The clinical score for the cutaneous irritation potential was obtained by summing together each of the individual results. If the score on any individual analysis reach a 3 or 4, the product was no longer applied to the back of the subject and the score was recorded as either a 3 or 4 for the subsequent timepoints.

For this study, three products were evaluated: 1 ) a retinol lotion containing a retinol-substrate-release modifier of the composition of Example 4; 2) the same lotion but with neither retinol nor retinol-substrate-release modifier composition in it (placebo formula); and 3) a market retinol product (ROC Retinol Correxion Deep Wrinkle Night Cream, Johnson and Johnson Company). The two retinol containing products contained different amounts of retinol with the product containing the retinol-substrate-release modifier composition was analyzed and had having 0.17 % retinol, while the ROC product contained 0.1 % retinol (label claim).

The formulation for the retinol-substrate-release modifier composition is listed below in Table 8. The placebo product contained the same materials except that the retinol-substrate-release modifier composition of Example 4 was replaced by water.

Table 8: Clinical Formulation

The cumulative irritation results are shown in Table 9 below: Table 9: Cumulative Irritation Results from the Clinical Study

Both the Retinol-Substrate-Release Modifier containing product and the ROC product were found to be more irritating than the placebo product. The cumulative irritation score for both the Retinol-Substrate-Release Modifier product and the ROC product were equivalent from a statistical standpoint (Student T-Test), but when the scores were normalized to take into account that the Retinol-Substrate-Release Modifier product contained 70 % greater amount of retinol, the Retinol-Substrate- Release Modifier product was found to statistically less irritating than the ROC product (Student T Test, p < 0.01 ).

Example 10: Cumulative Irritation Study of Retinol-Substrate-Release Modifier with

Different Substrates

In the same cumulative irritation study as discussed above in Example 9, the irritation potential of three additional products was compared. A lotion was formulated that has the following ingredient list where the retinol source was either MICROSPONGE ^® C1 16A Retinol (U.S. Patent 5,851 ,538), a retinol-substrate- release modifier formulation using a polymer substrate, or the retinol-substrate- release modifier formulation using microcrystalline cellulose from Example 4 above (retinol-substrate-release modifier composition). For the Placebo product, no retinol delivery system was added to the product. The product using MICROSPONGE C1 16A had a final retinol concentration of 0.17 wt% retinol while the product made from the retinol-substrate-release modifier composition of Example 4 contained 0.17 wt% retinol. The ingredients used in the retinol cream were as follows: Water, Caprylic/Capric Triglyceride, Glycerin, Cetearyl Alcohol, C10-30

Cholesterol/Lanosterol Esters, Dimethicone, Cetyl Ricinoleate, Cetyl Alcohol, Polysorbate 60, Phenoxyethanol, Stearic Acid, Cyclopentasilxane, PEG-10 Soy Sterol, Magnesium Aluminum Silicate, Cyclohexasiloxane, Chlorphenesin, Disodium EDTA, Xanthan Gum, BHT, Ethylhexylglycerin, Bisabolol, Sodium Hydroxide, and Ascorbyl Palmitate. The cumulative irritation results are listed in the Table 10 below:

Table 10: Cumulative Irritation Results from the Second Clinical Study

Both the retinol-substrate-release modifier composition containing product and the Microsponge® retinol product were found to be more irritating than the placebo product. The cumulative irritation score for both the retinol-substrate- release modifier composition product was statistically lower than that for the

Microsponge® Retinol (Student T-Test) with a p < 0.01 . Example 1 1 : Active Agent-Substrate with Salicylic Acid

A solution was prepared from 5 g of USP grade salicylic acid and 15 g of acetone. This solution was added to 50 g of MCC, specifically, Pharmacel 101 (see Example 1 above for description), and blended. After the solution was uniformly loaded onto the MCC, the product was placed in vacuum oven at 40 °C until the acetone was removed. This process was repeated three additional times to give an active agent-substrate combination (Salicylic acid-MCC) that contained 28 wt% salicylic acid in the final composition. Example 12: Active Agent Substrate with Glycolic Acid

Thirty-four (34) grams of Glycolic acid solution (70 wt% glycolic acid in water) was added to 66 grams of MCC, specifically, Pharmacel 101 (see Example 1 above for description), and blended until a uniform mixture was obtained. The blend was then placed in vacuum oven (at about 20 inches of mercury or fewer inches of mercury) at 50 °C until most of the water was removed from the product which resulted in a product that contained 25 wt% glycolic acid. As used in this and the following examples, a vacuum oven refers to an oven at about 20 inches of mercury or fewer inches of mercury.

Example 13: Active Agent Substrate with Ascorbic Acid

Fifty (50) grams of Ascorbic Acid (USP grade, 325 mesh (U.S. standard sieve)) was added to 150 g of Dl water. After a clear solution was obtained, the ascorbic acid solution was added to 200 g of MCC, specifically Pharmacel 101 . The mixture was then dried in vaccum oven at 40 - 45 °C until the weight of the product was constant and the moisture remaining in the product was less than 0.5 wt%. The concentration of Ascorbic Acid in the composition was found to be 25 wt%.

Example 14: Clinical Study using Retinol Entrapment

An 84 day clinical trial was completed using a lotion that was formulated using the Modified Retinol-MCC combination of Example 4. The 33 panelists (subjects) involved in the trial applied the product either once (evening) or twice (morning and evening) a day to their face, depending on their tolerance for the retinol lotion. All of the panelists applied a SPF 55 sunscreen to their face in the morning. If they also used the retinol product, they applied the sunscreen on top of the retinol product. The perioribital area around the eye was evaluate by a trained evaluator for the depth of the wrinkle using the Fitzpatrick wrinkle score which is a score that ranges in values from 1 - 9 with a value of 1 signifying very faint and fine wrinkles to a score of 9 signifying deep wrinkles which may include redundant skin folds. The evaluation took place at days 7, 28, 56 and 84 after application of the product.

The formulation used in this study is same one as listed in Table 8 above. The results for clinical study are listed in Table 1 1 . Table 11 : Clinical Study Results

For time points, 56 and 84 days, the clinical study shows that a statistically significant reduction in the mean Periorbital Wrinkle score as compared to the initial time point was seen at a > 95 % confidence interval. This shows that a finished product containing the Retinol-MCC-Release Modifier combination of Example 4 is able to effective delivery retinol to the skin.

While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention. Moreover, although individual aspects or features may have been presented with respect to one embodiment, a recitation of an aspect for one embodiment, or the recitation of an aspect in general, is intended to disclose its use in all embodiments in which that aspect or feature can be incorporated without undue experimentation. Also, embodiments of the present invention specifically encompass embodiments resulting from treating any

dependent claim which follows as alternatively written in a multiple dependent form from all prior claims which possess all antecedents referenced in such dependent claim (e.g. each claim depending directly from claim 1 should be alternatively taken as depending from any previous claims).