Method for producing flavored particulate solid dispersions

Abstract

A method for producing flavoring materials consisting of a flavor and a simple matrix material that are GRAS or approved for use in food, and that will be stable under extremely adverse conditions, greater than 50% moisture, high pH, high temperature stability (60° C.), yet be released in the oral cavity; without the use of organic solvents, and with the use of inexpensive materials and unsophisticated equipment.

Description

This application claims the benefit of the filing date of U.S. Provisional Patent Application Ser. No. 61/001,225, filed Oct. 31, 2007, pursuant to 35 U.S.C. § 120.

FIELD OF THE INVENTION

The present invention relates to particulate flavored-material and more particularly to particulate flavored materials comprising a flavor dispersed in or otherwise entrapped within an edible matrix that can be used to release favors and aromas in a controlled manner in consumer products, including tobacco, and methods for preparing and using the same.

BACKGROUND OF THE INVENTION

Flavor encapsulation is employed to protect flavors from degradation, to produce flavoring materials that may be dispersed in bulk commodities, and to produce flavoring materials with modified release characteristics. Volatile oils, perfumes, food extracts and other flavor modifiers have been successfully encapsulated and employed in a variety of consumer products. Flavor encapsulation has been achieved using a number of technologies, including spray drying, pan coating, spray coating, fluidized beds, chemical encapsulation and comminution. Particulate flavor composites may consist of shell-core constructs, multi-lamellar vesicles, or as dispersions of flavor molecules or droplets in a matrix, as well as other types of particles. Other methods include molecular inclusion in cyclodextrin, granulation and coacervation. A variety of materials are employed to encapsulate flavors, including gelatin, mixed lipids and sweeteners (U.S. Pat. No. 4,803,082), polymerized acrylic materials (U.S. Pat. No. 3,520,949) and starches.

Many compositions have been proposed for use as flavoring materials, and methods have been disclosed for the production of flavor and other core material encapsulation. Both hydrophilic and hydrophobic compositions have been reported. Sorbitol, mannitol, saccharin, sugar and starch hydrolysate, maltose, malto-dextrin, corn syrup solids, maltose syrup solids, high fructose corn syrup solids, starches, hydrocolloids, gums, proteins, partially hydrolyzed proteins, modified proteins, modified hydrocolloids, modified celluloses, gelatinized cereal solids, whey proteins and alginates are examples of the hydrophilic materials that have been proposed as coating materials in the prior art. On the other hand, paraffin, triglycerides, fatty acids, fatty alcohols, waxes have been proposed as hydrophobic encapsulating materials. Some of the aforementioned materials have been proposed, and in some cases they are currently used in pharmaceutical formulation to obtain active controlled release.

U.S. Pat. No. 4,388,328 illustrates a flavor composite that contains sorbitol, mannitol, saccharin, and a flavor material that may be prepared in the form of sugar-free candies, or may be reduced to particles or beads. The procedure consists of preparing a eutectic mixture heating the mixture of the components to a temperature of about 200 degrees C. and than cooling the same to 70 degrees C. Obviously, the high temperature employed may adversely affect flavor stability, volatilization and encapsulation efficiency.

In U.S. Pat. No. 4,610,890, a solid essential oil flavor composition involving preparation of a heated or cooked aqueous mixture of a sugar and starch hydrolysate, together with an emulsifier, is claimed. In this reference the selected essential oil is combined and blended with a mixture in a closed vessel under controlled pressure conditions to form a homogeneous melt, the melt being extruded into a relatively cool solvent, dried and combined with a selected anti-caking agent to produce the stable, relatively non-hygroscopic particulate flavor composition of the invention. The temperature for the process is preferably maintained at or below a maximum of about 126 degrees C.

In a family of U.S. patents, including U.S. Pat. Nos. 5,601,865; 5,792,505 and 5,958,502, what has been claimed is the use of different materials, such as maltodextrins, corn syrup solids, maltose syrup solids, high fructose corn syrup solids, starches, hydrocolloids, gums, proteins, partially hydrolyzed proteins, modified proteins, modified hydrocolloids, and modified celluloses, to obtain a liquid melt, heating and mixing a matrix and a volatile component, to solidify thereafter under a pressure sufficient to prevent substantial volatilization of said volatile component. In this invention, the dense amorphous, essentially non-crystalline solid encapsulant may be described in many cases, but not exclusively by those knowledgeable in the art as a ‘glass’ as characterized by a glass transition temperature.

British Patent 767,700 illustrates a method for making particles comprising inclusions containing a fat-insoluble vehicle carrying fat-soluble vitamins encased in a moisture-resistant substance in which the fat insoluble vehicle is insoluble.

U.S. Pat. No. 3,186,909 conveys a method for melting a composition containing fatty alcohol esters derived from sperm whale oil, adding urea to the composition and dissolving the urea, and adding fish liver oil and vitamins, thereby giving rise to a homogeneous mixture which might be useful for making particles.

The use of the spray-drying technique is claimed in U.S. Pat. No. 5,124,162. A mixture of flavor, maltose, malto-dextrin and a carbohydrate film former by spray-drying the mixture to form a dense product of at least 0.5 g/cc bulk free flow density and less than 20% voids. The invention is intended to improve the stability against oxidation of the flavor.

The production of microparticles useful in augmenting, enhancing and/or imparting aroma and/or taste (over relatively long periods of time in a controllably releasable manner) to perfume compositions, perfumed articles (e.g., deodorancy and antiperspirant sticks), foodstuffs, chewing gums, beverages and the like is the subject of U.S. Pat. No. 6,368,633. The first step reported in the invention is the adsorption of the olfactory-active material onto silica followed by a blending/extrusion step followed by at least one particularization step.

The U.S. Pat. No. 3,922,354 describes particulate free-flowing flavoring compositions utilizing flavoring agents in a cellular matrix of gelatinized cereal solids and water. Dextrins, mixtures of edible mono and diglycerides of higher fatty acids, and coloring agents can also be added to the matrix to provide a free flowing product that exhibits controlled flavor release characteristics, the aesthetic-appeal of natural whole or ground spices, and precisely controlled flavor values and strength. By forming a mixture of partially gelatinized cereal solids in water and then heating with agitation to a temperature of from about 65 degree to about 100 degree Celsius until gelation takes place. A water content of from about 10 to about 20 percent by weight is achieved. The patent includes extrusion and grinding of the matter, as well. A large particle size, high water content and low flavor content are the disadvantages of the aforementioned invention.

Encapsulation of a flavor or active agent in a similar matrix (i.e., whey protein) is claimed in U.S. Pat. No. 5,756,136. The encapsulation composition that results in the controlled release of the flavor or active agent may be incorporated in a yeast-leavened dough without causing a deleterious effect on the rising of the dough.

A number of U.S. patents (e.g., U.S. Pat. Nos. 6,325,859; 6,436,461; 6,929,814; 3,857,964) deal with the use of acid polysaccharides (e.g., alginates) as embedding materials once gelified by means of multivalent cation solutions. U.S. Pat. No. 6,325,859 claims the encapsulation of flavor, fragrance, vitamin, and/or coloring materials then to be added to the food or tobacco products. A similar procedure is described in U.S. Pat. Nos. 6,436,461 as well as 6,929,814.

U.S. Pat. No. 4,343,826 describes a process for preparing beads of fat by melting a fat (that contains at least 20% solids at a temperature below about 175 degrees F.) and cooling the melted fat to a temperature about 3 degrees to 8 degrees F. below the clear point of the fat. The method should allow the formation solid drops at least 3 mm in diameter. In U.S. Pat. No. 5,460,756, a method and apparatus to entrap liquids within wax and transforming the wax to a more stable crystalline state is claimed. The aim is achieved by placing the wax/liquid material in a chamber attached to a piston and by applying some force with the piston.

In U.S. Pat. No. 6,245,366 a fat-coated encapsulation compositions is prepared by mixing an active agent with a molten fat to obtain a slurry, and cooling the slurry thereafter to obtain a solid mass in which the active agent is embedded. The invention mention also the use of various techniques (i.e., spray drying, melt extrusion, coacervation, freeze drying, drum drying, belt drying, tray drying, tunnel drying, and extrusion) to obtain fat particles.

An encapsulation system composed of both hydrophobic and hydrophilic material is described in U.S. Pat. No. 6,887,493. Solid nanospheres of carnauba wax, candelilla wax, and mixtures thereof, encapsulating a first active agent are embedded in micro spheres made of a moisture sensitive matrix material (e.g., starch derivative, natural gum, polysaccharide, protein, hydrocolloid).

U.S. Pat. No. 3,976,794 describes sweetened coconut products coated with a powdered sugar further containing sugar particulate enveloped in edible fat. U.S. Pat. Nos. 3,949,094 and 3,949,096 show a process for preparing various flavorings, colorants, and flavor enhancers coated with a mixture of fats and emulsifiers. Here, the process consists of spraying flavors and condiments that are intercepted by a second, impinging spray containing the edible coating materials. These processes require the use of multiple spray configurations, and afford relatively low flavor encapsulation efficiency, the particles consisting primarily of excipient materials.

U.S. Pat. No. 2,857,281 describes a process of forming a hot, liquid emulsion of a volatile flavoring agent in a water soluble, edible sugar matrix. This material is then forced through an orifice to form flavored particulates. U.S. Pat. No. 2,785,983 discloses a process for making a flavoring composition by spray-cooling a solution of the desired flavoring ingredient dispersed in a melted, edible hard fat or hydrogenated glyceride oil, thereby forming dry, solid flavored particles that are water-insoluble. U.S. Pat. No. 4,173,492 discloses a process for producing flakes of coated pigments for dry compounding with polymeric plastics or rubber materials. Here, the color pigments are encapsulated in a wax, such as hydroxystearate wax.

U.S. Pat. No. 4,675,236 reveals a process for coating mono-core type shell-core microcapsules with waxes. The mono-core type material is formed by spray drying or pulverizing bulk core material, and the core materials are then immersed in a wax solution, followed by vacuum drying. The product is then introduced together with air or nitrogen gas into a melting and cooling chamber, giving rise to a final wax-coated product with a smooth surface and a shape similar to that of the underlying core particle.

U.S. Pat. No. 3,856,699 describes a process for producing capsules encased in walls of a waxy material. The process comprises the dispersion of a waxy material containing a core material in an agitated aqueous medium at a temperature higher than the melting point of the waxy material, followed by transferring the waxy material into a non-agitated aqueous medium at a temperature lower than the melting point of the waxy material, thereby inducing the formation of solid particles.

U.S. Pat. No. 3,819,838 describes a particulate solid composition comprising multiple capsules, each consisting of at least one primary capsule, wherein an active ingredient, such as a flavor, is encapsulated by a water soluble solid encapsulating material, whereupon the primary capsule is re-encapsulated in a water insoluble-solid encapsulating material. The inventors note that water soluble encapsulated materials, as described in the prior art, are disadvantageous when mixed with other ingredients, including water or moist ingredients.

U.S. Pat. No. 3,764,346 discloses a process for preparing spray dried materials that may be employed as flavor enhancers.

In U.S. Pat. No. 5,328,684, Morgan et al. describe the encapsulation of flavors, fragrances and related compounds in fatty alcohols, waxes and in other substances, such as polymers, in a process employing an apparatus comprising mixing and feed tanks, gas inlets, heating elements and spray nozzles, and related equipment.

In U.S. Pat. No. 6,190,722, Wedral et al. describe a process for making flavored, free flowing particulates, which comprises mixing an oil soluble flavor with a melted edible fat in a reaction vessel to form a solution of the oil soluble flavor in the melted fat, cooling the solution, adding a cooling or super-cooling agent with agitation to produce solid particles having an average diameter of from about 0.1 to 10 cm, or grinding these particles with a supercooling agent in a grinder or blender to produce substantially free flowing particulate flavor whose particles have an average diameter of less than 1 mm. Wedral et al. note that the use of a super-cooling agent is necessary to produce particles with an average diameter of less than 1 mm, as the materials are otherwise too sticky and adherent to be properly ground.

U.S. Pat. No. 5,064,669, Tan et al. reveals a method for making controlled release flavors. Here, an aqueous flavoring agent is dispersed in a melted encapsulating or enrobing material, such as a fat and/or wax and one or more emulsifiers, mixing one or more water-containing flavor compositions with a texture conditioning agent, then mixing the flavor compositions and texture conditioning agent(s) with the molten fat or wax to obtain a homogeneous mixture in the form of an emulsion, and finally chilling the flavor composition-containing mixture to provide discrete particles of solid encapsulated flavoring agent. The process may require a spray chiller to produce the particles, and produces a composition containing a number of excipients, including emulsifiers and conditioning agents, as well as the flavor itself.

SUMMARY OF THE INVENTION

Each of the representative prior art patents, discussed above, has certain disadvantages as compared to the production of the materials of the present invention. Several of these prior art methods require specialized spray drying, mixing or extrusion equipment, employ mixtures of several excipients, and may result in the degradation or evaporation of flavors. Still others are limited in the range of particle size that may be produced, as well as in flavor loading as a percent of total material weight. The high temperatures required in several of these aforementioned methods may compromise flavor stability by thermal degradation and encapsulation efficiency by inducing volatilization. Further, the extensive use of polysaccharides and organic acids as primary matrix and encapsulation materials may further impact flavor stability promoting trans-esterification and other degradative processes.

It is an object of the present invention to overcome these disadvantages by providing a method for producing flavoring materials consisting of a flavor and a simple matrix material that are GRAS or approved for use in food, and that will be stable under extremely adverse conditions, greater than 50% moisture, high Ph, high temperature stability (60° C.), yet be released in the oral cavity.

It is a further object of the present invention to provide a method of producing such materials at temperatures sufficiently low so as to minimize volatilization and degradation of the additive components during processing.

It is yet another object of the present invention to provide a method to produce such materials that is more simple, more scalable and more economical in comparison to the prior art methods. These and other advantages of the present invention will become apparent to one skilled in the art with reference to the attached.

The present invention may be practiced using a simple casting and grinding method that does not require chilling, or by a simple aqueous emulsion cooling method using simple agitation equipment. In contrast to previous methods, which require several excipients, including plasticizers and emulsifiers, the present invention may be practiced, and desired release characteristics achieved, using a flavor and a single GRAS matrix material. Moreover, in those cases where a plasticizer is desired, the plasticizing properties of methyl salicylate itself might be advantageously used in the formulation, further underscoring the simplicity of the present method by obviating the need for additional plasticizing agents.

Particle size may be controlled using simple adjustments to the grinding-sieving process, or by simple alterations to the aqueous emulsion agitation speed, cooling method and emulsifier concentration. Percent flavor loading is possible across a wide range simply by increasing or decreasing the amount of flavor incorporated into the molten matrix material. The flavor release rate, and the resistance of the particles to water imbibition and hydrolysis, may be controlled by changing the matrix material and/or the particle size. Additional advantages of the present invention include the lack of organic solvents, and the use of inexpensive materials and unsophisticated equipment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of the fused punch production process of Example 1.

FIG. 1a is a differential scanning calorimetry (DSC) thermogram of fused paraffin.

FIG. 2 is a DSC thermogram of fused paraffin and methyl salicylate.

FIG. 3 is a DSC thermogram of fused cetyl alcohol.

FIG. 4 is a DSC thermogram of fused cetyl alcohol and methyl salicylate.

FIG. 5 is a DSC thermogram of fused palmitic acid.

FIG. 6 is a DSC thermogram of fused palmitic acid and methyl salicylate.

FIG. 7 is a DSC thermogram of fused PEG 8000.

FIG. 8 is a DSC thermogram of fused PEG 8000 and methyl salicylate.

FIG. 9 is a DSC thermogram of fused cholesterol.

FIG. 10 is a DSC thermogram of fused cholesterol and methyl salicylate.

FIG. 11 is a graph illustrating methyl salicylate release from fused punches in artificial saliva at 37° C.

FIG. 11a is a diagram of the fused punch production process scheme of Example 3.

FIG. 12 is a diagram of glass bead dissolution apparatus for particles and tobacco.

FIG. 13 is a graph illustrating methyl salicylate release from fused particles in artificial saliva at 37° C.

FIG. 14 is a graph illustrating methyl salicylate release from fused particles dispersed in high dark snuff in artificial saliva at 37° C.

FIG. 14a is a diagram of the fused punch production process scheme of Example 4.

FIG. 15 is a graph illustrating methyl salicylate release from methyl salicylate-loaded cetyl alcohol particles dispersed in high dark snuff in artificial saliva at 37° C.

FIG. 16 is a graph illustrating methyl salicylate release from methyl salicylate-loaded cetyl alcohol particles dispersed in methyl salicylate-adsorbed high dark snuff in artificial saliva at 37° C.

FIG. 16a is a diagram of the rapid cooling production process scheme of Example 6.

FIG. 17 is a bar graph illustrating the particle size of Batch # 6.

FIG. 18 is a graph illustrating in vitro release profiles for formulation 9b.

FIG. 19 is a graph illustrating in vitro release profiles of formulations reported in Table 5.

FIG. 20 is a color version of optical microscopy of Batch SB10(5), magnified 100× in the upper pictures, and 200× in the lower pictures.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described by way of certain Examples that illustrate the preferred embodiments of the invention to date.

Example 1

Experiments to date have demonstrated a high capacity for waxes to absorb and disperse methyl salicylate (e.g., as much as 15% in paraffin). In addition, methyl salicylate-loaded wax particles have been produced by dispersion of a molten wax-methyl salicylate solution in hot aqueous ethanol with rapid agitation and cooling.

The evaluation of a series of GRAS materials for use as sustained-release methyl salicylate matrices has led to the selection of cetyl alcohol and PEG 8000 as promising candidates. Cetyl alcohol affords steady, reproducible yet delayed methyl salicylate release in artificial saliva. PEG 8000-methyl salicylate dispersions lead to a burst of methyl salicylate, with a more delayed release when dispersed in tobacco.

Self-emulsified cetyl alcohol particles prepared from aqueous emulsions also give relatively steady, sustained delivery. Flavored cetyl alcohol particles, combined with neat methyl salicylate dispersed in tobacco, offer another alternative flavoring method.

Fused solid dispersions have been employed throughout the food, pharmaceutical and cosmetic industries in a variety of applications, including the storage and controlled release of flavors, fragrances and other actives. Fused dispersions, also referred to as ‘melts’ or ‘solid solutions’, are made by blending a component, such as methyl salicylate, into molten GRAS materials at moderate temperatures. The molten solution may be molded, extruded, sprayed as a coating or spray-cooled into particles. The cooled fusate may also be molded, punched or milled into particles. Fused dispersions may be prepared from many self-emulsifying materials, and require little or no additional solvents or excipients. Since minimal excipients are desirable in any sustained-release flavor preparation, fused dispersions have been explored as a possible formulation method.

A series of GRAS carrier materials were selected and evaluated as potential matrices for producing methyl salicylate-loaded particles for controlled sustained delivery. Dental-grade paraffin, cetyl alcohol and its carboxylate analog, palmitic acid, PEG 8000 and cholesterol were employed in these initial studies. All of these edible materials are routinely incorporated into foods and oral preparations. These materials were selected in order to compare the influence of chemical structure, including the presence of hydrogen bond donors and/or acceptors, hydrophilic and hydrophobic functions and the sterol backbone on release performance. All of these materials will mix and melt with methyl salicylate and form solid dispersions. However, at methyl salicylate concentrations beyond ca. 20% w/w, the fusates tend to become tacky, smearing semi-solids. Accordingly, 20% w/w was chosen as the methyl salicylate concentration for the initial particle studies.

In a typical experiment to date, 1 gram of carrier material was melted in a glass vial at approximately 65° C. in a water bath. Upon melting, 250 mg of methyl salicylate (20% w/w) was added with stirring. Since the melting point of cholesterol is ca. 148° C., it was necessary to add 1 mL of dichloromethane to the cholesterol-methyl salicylate mixture in order to produce a liquid dispersion. The vials were immediately sealed and removed from the heat source. The melts were then allowed to cool to room temperature. Uniform fusates approximately 2 mm in thickness were thus formed on the bottom of each flat-bottomed vial. No creaming or phase separation was noted in any fusate during or after cooling. The fused dispersions were then dried under reduced pressure (330 mm Hg) for 24 hours.

A flow diagram of the fusate production process is shown in FIG. 1.

The fusates were then assayed for methyl salicylate content and homogeneous distribution by randomly sampling round ‘punches’ with a 6 mm cork borer and dissolving each ‘punch,’ normalized by weight, in methanol. The methanol solutions were then assayed for methyl salicylate and salicylic acid content by reverse phase HPLC with UV detector. Methyl salicylate content was nearly quantitative (20% w/w) in each preparation. Notably, although the scent of methyl salicylate was evident, each material appeared to have a high affinity for methyl salicylate. No significant weight loss was noted from any fusate, even after 72 hours under reduced pressure. Methyl salicylate remains stable under these processing conditions, as no salicylic acid was detected by HPLC in any fused dispersion.

Thermal analysis of solid dispersions is routinely performed using differential scanning calorimetry (DSC) for both analytical and quality control purposes. DSC may be used to characterize the crystalline and amorphous characteristics of the materials under study, thereby providing insight into chemical and functional interactions between carrier and flavor. This information may be useful for predicting and understanding wetting, solubility, plasticizing effects and release behavior. DSC is useful for validating the polymorphic character and its reproducible production in solid dispersions. The influence of casting, milling and spraying on these dispersion characteristics may also be assessed with DSC.

Accordingly, DSC analysis of the fused carrier controls and their corresponding methyl salicylate dispersions was performed in order to gain an initial appreciation of the tendency, if any, of methyl salicylate to plasticize or otherwise interact with each carrier. Fused paraffin (FIG. 1a) melts at approximately 60° C., with changes in heat capacity around 40° C. and 60° C.

The paraffin-methyl salicylate dispersion (FIG. 2) shows a broadened change in heat capacity and a modest melting point reduction, suggesting a tendency for methyl salicylate to interact with linear aliphatic molecules.

A similar change in thermograms was noted for fused cetyl alcohol (FIG. 3), a long chain aliphatic alcohol, and the cetyl alcohol-methyl salicylate dispersion (FIG. 4).

In contrast, both fused palmitic acid (FIG. 5), the carboxylate analog of cetyl alcohol, and its corresponding methyl salicylate dispersion (FIG. 6), gave rise to similar thermograms, suggesting less interaction than with the alcohol.

Based upon these initial DSC data, it is possible that methyl salicylate has a greater tendency to interact with hydroxyl-containing compounds than with those containing a carboxylate group

Fused PEG 8000 (FIG. 7) and the PEG 8000-methyl salicylate dispersion (FIG. 8) show similar thermal properties, with only a very modest change in the heat capacity of PEG 8000, and a modest broadening in the peak, suggesting an interaction between methyl salicylate and PEG. The tendency of methyl salicylate to interact with longer chain aliphatics and hydrogen bond donors, as compared to PEG, a relatively polar, hydrophilic hydrogen bond acceptor, might be expected to differ. Although no particular functional or structural trend is determined from these data, it appears that methyl salicylate may interact with a variety of matrix materials, suggesting the possibility that methyl salicylate might mix with or otherwise be incorporated into matrices comprising certain materials employed in these studies.

Similarly, an examination of the DSC thermograms of fused cholesterol (FIG. 9) and the cholesterol-methyl salicylate mixture (FIG. 10) reveals a greater tendency for methyl salicylate to interact with hydroxyl-containing aliphatics. In fact, a depression of about 10° C. was observed with cholesterol after blending with methyl salicylate. These data may be useful for the rational selection of matrix materials and optimization of methyl salicylate formulations.

Example 2

Individual flavor reservoirs or some other type of ‘flavor-pak’ might be included in a snuff can or in a snuff pouch for sustained flavor release. Alternatively, snuff might be incorporated directly into such a flavored matrix in order to make a buccal pellet. Such a reservoir or pellet might be comprised of a tablet, a punch or some other flavor-matrix mass. Accordingly, an initial evaluation of the release characteristics of methyl salicylate from the solid dispersions was performed using fused punches. These punches, rather similar to a tablet, were prepared by removing a uniform, 6 mm diameter disc from a 2 mm thick solid dispersion produced as described in the scheme of FIG. 1. The punches, uniform in size and surface area, were homogeneous in methyl salicylate content (20% w/w). Normalized for weight, the punches were placed in a 20 mL glass vial, and 10 mL artificial saliva (see p. 30, para. 3; Na et al.) was gently added with slow stirring at 37° C. At the indicated time point, a 1 mL aliquot part of the artificial saliva was removed for assay and replaced with 1 mL of fresh artificial saliva, thereby simulating a sink condition. The sample was dissolved in 4 mL 50% methanol to ensure dissolution, and then assayed for methyl salicylate content by HPLC, and cumulative release was calculated after correcting for volume. As a control, an amount of neat methyl salicylate equivalent to that contained in the pellets was dispersed on the bottom of control vials, and its dissolution was analogously assayed. The results of this study, presented as the mean±SD of three independent experiments, are summarized in FIG. 11.

The PEG 8000 pellet, primarily comprised of a hydrophilic polymer, rapidly dissolved into a wet mass in the vial. Not surprisingly, methyl salicylate release was most rapid from the PEG 8000 punch. A burst of flavor release was noted within the first few minutes of dissolution. PEG, a well-known hydrotrope and wetting agent with significant surface active properties, may be useful for providing a flavor burst in a methyl salicylate formulation, or as a burst coating on a delayed-release composition.

As compared to the control, the more hydrophobic matrices all retarded the release of methyl salicylate. Since these punches were solid castings, release was likely a function of solubilization of methyl salicylate located on the punch surface, as well as diffusion and solubilization of methyl salicylate trapped in the interior. Cetyl alcohol, which has modest surface activity, is a major component of commercial self-emulsifying waxes. Cetyl alcohol also gave the steadiest release profile. Given these characteristics, cetyl alcohol may be among the more promising matrix materials tested so far.

Example 3

As stated, the punches described in the previous Example afford both an initial assessment of methyl salicylate release from the various matrix materials, as well as a proof of concept model for flavor release from an individual reservoir. Flavor-loaded matrix particles, which might be dispersed into loose, tinned snuff, offer another option for sustained-release delivery. Size, color and texture could be optimized for flavor delivery and consumer acceptance. The larger surface area-to-volume ratio of particles may offer more rapid flavor release. In addition, several methods are available for the production of such particles, including comminution of a solid dispersion, spraying molten solutions and various emulsion technologies.

A series of methyl salicylate particles were produced by grinding the cooled solid dispersions previously described in a glass mortar and pestle, then passing the particles through standard testing sieves. Light microscopy revealed that the particles that were ground and sieved to a fraction between 75 and 250 μm in size were generally fractured and irregular in shape. The particles were assessed for methyl salicylate content and homogeneity by HPLC. The grinding did not affect the properties of the particles.

As the material tended to smear and clog the screens, the cholesterol-methyl salicylate fusate could not be comminuted and sieved into discrete particles. Thus, it was not further evaluated as a particle matrix. Instead, a 1:1 w/w mixture of two of the other matrix materials, cetyl alcohol and PEG 8000, was used instead.

A flow diagram of the flavored particle production process is provided in the scheme of FIG. 11a.

Dissolution studies, analogous to those described for the punches, were then performed. Because the particles are buoyant, and in order to model the ‘cheek and gum’ structure of snuff held in the mouth, the particles (50 mg, 10 mg methyl salicylate equivalent) were first sandwiched between two layers of inert glass beads (1 mm): The beads tended to keep the particles in place in a defined layer. At the same time, artificial saliva freely flowed through the Plateau border channels between the beads on both sides of the particle layer, in a manner analogous to saliva flow in the buccal pouch. These dissolution apparatuses, illustrated in FIG. 12, were also used for the tobacco studies and flash melt film studies described in later sections.

The dissolution apparatus consists of a 20 mL glass vial containing 10 mL artificial saliva and two 1 gram layers of glass beads, between which may be sandwiched a layer of particles, a flash melt film, a wad of tobacco, or another dosage form.

Methyl salicylate release from the fused particles, as compared to an equivalent amount of neat methyl salicylate distributed between the beads, is summarized in FIG. 13.

The results are expressed as the mean±SD of three independent experiments. Once again, PEG 8000 produced a rapid methyl salicylate burst. Cetyl alcohol displayed consistently slower release as compared to the methyl salicylate control. Palmitic acid gave mixed results, with release approximating that of methyl salicylate early on, followed by slower release, perhaps due to depletion of surface methyl salicylate and/or the formation of a stagnant film. Cetyl alcohol gave its characteristically steady, retarded release profile throughout the experiment. Since it has surfactant and self-emulsifying properties, it may form a stagnant film that tends to retard methyl salicylate release. Notably, the cetyl alcohol-PEG 8000 composite afforded an initial burst of methyl salicylate, followed by release that was slower than methyl salicylate itself. This combination may be particularly useful for manufacturing composite particles with both characteristics. It may be possible to minimize the use of additional excipients simply by manufacturing these composite particles in various cetyl alcohol/PEG ratios.

In order to model particle performance when dispersed in tobacco, as well as to examine the effect of tobacco dispersion on methyl salicylate release, an analogous set of experiments was performed in which the particles (50 mg, 10 mg methyl salicylate equivalent) were first dispersed in 500 mg of high dark snuff, then sandwiched between the bead layers in the dissolution vials, as shown in FIG. 12. Assays revealed that the particles were uniformly dispersed. In addition, no methyl salicylate was detected in extracts of the tobacco itself, which is known to synthesize methyl salicylate as a chemical signal when stressed. Methyl salicylate release from the fused particles dispersed in tobacco, as compared to an equivalent amount of neat methyl salicylate adsorbed on tobacco, is summarized in FIG. 14.

Neat methyl salicylate release, as well as methyl salicylate release from the palmitic acid and cetyl alcohol particles, was not significantly affected by dispersion in tobacco. This suggests that artificial saliva and methyl salicylate diffusion are not significantly altered by the presence of tobacco. In addition, the presence of any surface or chemically active tobacco components, if any, did not alter the dissolution characteristics of methyl salicylate itself. This is particularly important in light of the vast change in methyl salicylate release noted with the PEG 8000 particles. While the punch and free particle experiments revealed a tendency for PEG 8000 to produce a rapid methyl salicylate burst, when dispersed in tobacco, the PEG 8000 and, to a lesser extent, the PEG 8000-cetyl alcohol particles, manifested a distinct reduction in release rate. It is not likely that the chemical stability or surface activity of PEG, a non-ionic poly-ether, are going to be adversely affected in the presence of tobacco. The DSC experiments suggest that methyl salicylate does not appreciably interact with PEG. One possible explanation for the reduction in release rate may be that, in lieu of any electrostatic interaction, dispersion and confinement in the tobacco matrix may induce the formation of a PEG hydrogel or stagnant film. The film may cause a diffusion rate limited release of methyl salicylate. The observation that PEG tobacco dispersions may retard flavor release has potential in more advanced sustained-release applications. At the same time, PEG provides a formulation challenge, as its high affinity for water, and the high water content of tobacco (55%), may compromise particle integrity, and thus flavor encapsulation, on product storage.

Example 4

The mechanical comminution of solid dispersions is a ready way to produce particles. However, mechanically processed particles may be irregular in shape, as demonstrated in the previous Example. In addition, polymorphic changes may be induced during the size reduction process. Solid dispersions produced by cooling melted matrix emulsions may be another useful means for producing methyl salicylate-loaded particles. When dispersed in aqueous media, lipophilic compounds tend to minimize interfacial surface area and surface free energy by spontaneously forming spheres. Upon cooling, the liquid oil phase droplets solidify, producing discrete spherical particles. Depending upon the temperature, shearing method and auxiliary surfactants employed during the emulsification process, uniform, spherical particles are readily and reproducibly manufactured.

Sophisticated flavor emulsions and microencapsulated systems have been manufactured using a variety of emulsion techniques. However, one goal of the research completed to date has been to produce sustained-release flavor matrices while using a minimum of excipients. Thus, the GRAS materials employed in the previous Examples were assessed for their capacity to form flavor-loaded particles using the melting-cooling emulsion technique without additional excipients. PEG was not evaluated in these aqueous emulsion studies, as it is readily dissolved in water. Future PEG emulsion studies may be performed in an appropriate antisolvent.

In a typical melting cooling emulsion experiment, 1 gram of matrix material (cetyl alcohol, paraffin, palmitic acid or cholesterol wetted with dichloromethane) was melted at 65° C. As soon as the material was melted, serial amounts of methyl salicylate were added, vigorous agitation on a stirring plate was commenced, and 100 mL of deionized water, previously heated to 65° C., was added over 60 seconds. The heat was removed, and the emulsion, consisting of melted matrix-methyl salicylate droplets dispersed in water, was allowed to cool to room temperature. After the droplets formed hard microcapsules, they were collected using a 10 μm filter, washed with 10 mL cold water, and air-dried overnight. The resulting particles were spherical in shape, generally free-flowing and non-adherent. FIG. 14a provides a diagram of the procedure employed for producing flavored particles from aqueous dispersions.

Cetyl alcohol was the only matrix material that formed suitable particles under these minimal conditions. The others tended to form large agglomerates and sheets that varied substantially in size and shape. Thus, cetyl alcohol was chosen as the model emulsion matrix material. In order to determine the maximum loading capacity of cetyl alcohol, analogous experiments were conducted using increasing amounts of methyl salicylate. As summarized in Table 1, methyl salicylate incorporation into the cetyl alcohol particles was nearly quantitative up to about 33% w/w, beyond which the material became soft and gel-like.

TABLE 1
Production of methyl salicylate-loaded cetyl alcohol particles
by melting-cooling in an aqueous oil-in-water dispersion.
Methyl Salicylate Content	Methyl Salicylate Encapsulation
(mg)	% by Weight	% Yield	Theoretical	Actual
100	9	94.5	9	9.2
200	16.7	96.0	16.7	12.8
250	20	93.1	20	19.9
500	33	90.2	33	31.3
750	43	34.0	43	30.9
1000	50	0 (gel)	50	0 (gel)

• • The particles were rather large, perhaps due to the lack of an emulsifier and high-shear mixing.
  • The particles were also polydisperse in size, as shown in Table 2. The 33% w/w methyl salicylate emulsion system gave rise to smaller particles.

TABLE 2
Size range of isolable methyl salicylate-loaded cetyl alcohol particles.
Particle Type	>500 um	250-500 um	75-250 um	<75 um
20% Methyl	19.4	75.9	4.6	0
Salicylate
33% Methyl	0	89.8	7.6	2.5
Salicylate

Methyl salicylate remained stable throughout the process, as no salicylic acid was detected when the particles were assayed for methyl salicylate content and homogeneity. Clearly, more sophisticated emulsion methods could be employed to produce smaller, more uniform particles. Nevertheless, these initial studies demonstrate that spherical methyl salicylate-cetyl alcohol particles may be reproducibly manufactured without excipients using the simplest techniques. Methyl salicylate release from the emulsified cetyl alcohol particles is summarized in FIG. 15.

The influence of methyl salicylate loading (20 or 33% w/w) and particle size (75-250 nm or 250-500 nm sieve fractions) were evaluated. Using the aforementioned glass bead release apparatus described in FIG. 12, the particles (10 mg methyl salicylate equivalent) or the neat methyl salicylate control were placed between the glass bead layers, and release studies in artificial saliva at 37° C. were performed as described in the previous sections. Methyl salicylate release from the emulsified cetyl alcohol particles was slower than neat methyl salicylate dissolution, regardless of particle loading or size. This suggests that cetyl alcohol remains a viable choice for sustained flavor release. As would be expected, release was faster from the smaller particles, which have a much higher surface area to volume ratio. Particle size appears to have a greater influence on methyl salicylate release than percent loading, as release from the smaller 20% w/w particles was significantly faster than that from the larger 33% w/w particles.

Tobacco is currently flavored by maceration and coating with methyl salicylate. Combining this method with a sustained-release preparation has produce superior flavor release in experiments completed to date. In one experiment 250-500 μm cetyl alcohol particles (20 or 30% w/w, 10 mg methyl salicylate equivalent) were dispersed in 500 mg high dark snuff with or without 10 mg free methyl salicylate and the neat control, and the release experiment was repeated. The results of these experiments are shown in FIG. 16.

Methyl salicylate release from the particles dispersed in tobacco was little changed from that released from the equivalent, free particles, as summarized in FIG. 15 and previously discussed. Methyl salicylate release from the tobacco containing both free and encapsulated methyl salicylate approximated the sum of that released from the particles alone plus that released from the neat control. These data suggest that methyl salicylate release is simply additive when both encapsulated and free methyl salicylate are dispersed in tobacco.

It was a further object of the research completed to date to further modify the aforementioned flavored particle production methods in order to optimize the liposphere particle size, to possibly ˜100 μm or smaller, and to increase the drug content up to 10-20%. These two characteristics were determined to be of fundamental significance after the in vitro assay of the previously produced batches. Large particles were perceived when in the mouth and an oily sensation was also felt. This would cause acceptability problems for customers. The increase of the flavor content up to 10-20% was believed to be useful to reduce the amount of particulate material in the final product (e.g., tobacco) and to optimize the process and to reduce the overall cost, as well.

In a typical experiment of the previous Examples, the needed amount of methyl salycilate was added to 1 g of melted (65° C.) cetyl alcohol (CA) and 100 mL of deionized water, which were heated at the same temperature, and were the poured over a 60 second time period onto a stirring plate while under vigorous agitation. The dispersion was cooled to room temperature, and the formed particles were collected by filtration, were washed with cold water and were air-dried overnight.

Example 5

The main improvements focused on how the internal phase is dispersed into the external phase and the agitation procedure. In the modified method the melted internal phase (2 g of CA and the needed amount of methyl salycilate) are injected via a plastic syringe into 400 mL of deionized water (with or without surfactant) heated at 65° C. and agitated with mechanical stirring. After injection the heating was discontinued and the dispersion was allowed to cool at room temperature. Particles were recovered by filtration, were washed with 3 L of deionized water and were dried under vacuum overnight (15 mm Hg). The different preparations performed with Example 5 are reported in Table 3, while the particle size of the batch number 6 is shown in FIG. 17.

Not all the performed preparations gave rise to particle formation (Table 3). The optimal stirring rate was found to be 1000 rpm when deionized water was used as the external phase, while 500 rpm when 0.35% of poly (vinyl alcohol) was added. Batch # 2 formed very large particles clearly visible, most likely in the range between 500 and 1000 μm; therefore not suitable for their particle size. Preparation #4 provided smaller particles and this preparation was repeated adding methyl salicylate (23.1% of target loading). The preparation was performed in triplicate (batches #6, 7 and 8 in Table 3). The particle recovery was satisfactory (˜80%), while the mean encapsulation efficiency (˜35%) and the methyl salicylate content (8%) were considered too low (Table 3). The particle size of these three batches was considered satisfactory (FIG. 17). The low active content was ascribed to the evaporation of the volatile methyl salicylate during the time that the dispersion was allowed to cool at room temperature without any external cooling.

Flavor lost during encapsulation has been reported to be an issue. In fact some prior art processes (i.e., U.S. Pat. Nos. 5,601,865; 5,792,505 and 5,958,502) have employed a pressure sufficient to prevent substantial volatilization of the volatile component.

Example 6

In order to achieve higher actual content, to reduce to a minimum the flavor volatilization, and to achieve smaller more desirable particles with a narrower size range without the need for grinding, the above reported method was further modified.

In the modified method, the cooling process has been accelerated in order to decrease the loss of the volatile flavor during this phase. Practically, after the internal phase injection the emulsion was held at 65° C. for 5 min and was then transferred to an ice bath always under stirring. The other steps were unchanged. The scheme of FIG. 16a provides a diagram of the procedure. The results obtained are reported in Table 4.

Batch 9 differs from Batches 6, 7 and 8 only in the processing (Example 6 instead of Example 5). The rapid cooling in ice bath substantially increases the encapsulation efficiency up to ˜60%, leading to an actual content close to 15%. Assays were made to enhance the active content even though 15% can be considered suitable. By increasing the target loading, it was possible to achieve an actual loading of ˜23% (batch 10 in Table 4).

Batches 9, 10, and 11 were performed in a replicate of 3 and the results are shown in Table 4. The three formulations gave mean methyl salicylate contents of 10.8, 15.0 and 18.2%, respectively. The method yield was about 80% for almost all the preparations (Table 4). Particles from Batches 6-10 did not give any oily sensation in the mouth or in the hands.

TABLE 3
Preparations made with the method of Example 5
Batch	Internal	Methyl	External Phase	Stirring		Encapsulation	Actual Active
#	Phase	Salicylate	400 mL	(rpm)	Recovery	Efficiency	Content	Notes
1	Cetyl Alcohol	—	Water	500	—	—	—	No particle
	(2 g)							formation
2	Cetyl Alcohol	—	Water	1000	—	—	—	Particles
	(2 g)
3	Cetyl Alcohol	—	Water	1250*	—	—	—	Coagulate
	(2 g)
4	Cetyl Alcohol	—	Water + 0.35%	500	87% (1.87 g)	—	—	Particles
	(2 g)		PVA
5	Cetyl Alcohol	—	Water + 0.35%	1000	—	—	—	Coagulate
	(2 g)		PVA
6	Cetyl Alcohol	0.6 g (30%)	Water + 0.35%	500	84.9% (2.206 g)	30.2%	7.5%	Particles
	(2 g)		PVA
7**	Cetyl Alcohol	0.6 g (30%)	Water + 0.35%	500	87% (2.003 g)	37.5%	8.8%	Particles
	(2 g)		PVA
8**	Cetyl Alcohol	0.6 g (30%)	Water + 0.35%	500	77% (2.289 g)	36.8%	8.4%	Particles
	(2 g)		PVA
*Stirring was kept to 1250 upon until the suspension temperature dropped to 30° C., when it was lowered to 500 rpm.
**Batches # 7 and 8 are replicates of Batch # 6.

TABLE 4
Preparations made with the method of Example 6
				Encapsu-
				lation	Actual
Batch	Internal	Methyl	Recovery	Efficiency	Content
#	Phase	Salicylate	(%)	(%)	(%)
9	Cetyl Alcohol	0.6 g (30%)	97.2	61.7	14.2
	(2 g)
9a	Cetyl Alcohol	0.6 g (30%)	84.6	40.9	9.45
	(2 g)
9b	Cetyl Alcohol	0.6 g (30%)	85.5	37.4	8.60
	(2 g)
10	Cetyl Alcohol	1.0 g (50%)	65.0	39.8	13.2
	(2 g)
10a	Cetyl Alcohol	1.0 g (50%)	80.2	53.1	17.7
	(2 g)
10b	Cetyl Alcohol	1.0 g (50%)	81.7	42.6	14.2
	(2 g)
11	Cetyl Alcohol	1.5 g (75%)	89.8	51.9	22.8
	(2 g)
11a	Cetyl Alcohol	1.5 g (75%)	83.4	34.4	15.1
	(2 g)
11b	Cetyl Alcohol	1.5 g (75%)	79.7	38.4	16.8
	(2 g)

In vitro release of the Batch 9b was performed in triplicate. In order to respect the infinite sink conditions, the miscibility of methyl salicylate with artificial saliva and deionized water at 37° C. were assessed. The miscibility resulted to be 0.77 and 0.79 mg/mL, respectively.

The following in vitro release method was used. A weighed amount of particles was placed in a 20 mL scintillation vial filled with 10 mL of artificial saliva and stirred with a magnetic bar. At predetermined time points, 1 mL of media was carefully withdrawn using a 1 mL syringe provided with a 0.2 μm filter. The fresh media was added through the same filter in order to recover all the particles previously stopped on the filter. The filter was validated before utilization. Release was performed at 37° C. at a stirring rate of 150 rpm.

The artificial saliva was composed of the following: Sodium chloride, 0.844 g; potassium chloride, 1.200 g; calcium chloride dihydrate, 0.193 g; magnesium chloride hexahydrate, 0.111 g; potassium phosphate dibasic, 0.342 g; and water to make to 1000 ml. The pH was adjusted with hydrochloric acid solution to pH 5.7±0.1.

An example of the release profile of the particles of Batch 9b is given in FIG. 18. The in vitro release study was performed in triplicate. The 3 release profiles are practically overlaying one another, proving a good reproducibility of the employed method and an homogeneity of the particles in the Batch. Only about 50% of the initial content was found in the release media. This may be explained by hypothesizing some methyl salicylate loss during the sampling process that could be avoided using more appropriate headspace sampling techniques (i.e., static or dynamic headspace sampling).

After a positive panel evaluation of the 3 Batches (9, 10, and 11) (Table 4), Batch 10 was chosen as the best formulation mainly on the basis of the intermediate flavor content. Moreover, the formulation of Batch 9 looked to be not very reproducible and the content was still too low, while the formulation of Batch 11 showed some stability issue during storage at room temperature. Methyl salicilate was found to be localized on the surface of the particles, rendering a “wet” appearance at the glass vial wall. The high flavor content may explain this behavior.

Cethyl alcohol crystals should be less ordered in the particles with respect to the raw material because of the addition of methyl salicylate behaving as an impurity in the crystal lattice. The storage allows crystals to reorganize better, provoking a squeezing effect on the encapsulated flavor. The partial localization of the flavor on particle surface, due to the high active content, should be accounted for, as well. The same behavior was not observed for formulations of Batches 9 and 10.

Example 7

The first attempt to scale up was to a batch size of 15 g. 10 g of cetyl alcohol and 5 g of methyl salicylate were melted (65° C.) and injected into 2 L of deionized water, containing 0.35% of poly (vinyl alcohol), heated at 65° C. under agitation with mechanical stirring (500 rpm). 5 minutes after injection the heating was discontinued and the dispersion was cooled using an ice bath. Particles were recovered by filtration, washed with 6 L of deionized water and dried under vacuum overnight (15 mm Hg). Characteristics of the obtained particles are reported in Table 5.

Particles showed a mean flavor content of 13.8±1.1% and an encapsulation efficiency of 41.6±3.2%; while the preparation method had a yield of 86.9±2.8%. The high reproducibility of the method is proven by the low standard deviations obtained for both the encapsulation efficiency and the product yield (Table 5).

For the 5 preparations, 90% of the particles were smaller than 90 μm and 50% were in the 40-48 μm range. Similar particle size is another indication of good method reproducibility.

TABLE 5
Characteristics of the particles obtained with the scaled up method.
	Methyl salicylate	Encapsulation
Batch	content	efficiency	Method yield	Particle size b
name	(%) a	(%)	(%)	D(v, 0.1)	D(v, 0.5)	D(v, 0.9)
10(1)	13.7	41.0	83.0 (12.452 g)	13.4 μm	44.5 μm	85.7 μm
10(2)	15.7	47.0	87.7 (13.158 g)	14.9 μm	47.9 μm	87.2 μm
10(3)	13.0	39.0	86.8 (13.026 g)	12.6 μm	40.7 μm	83.5 μm
10(4)	13.1	39.4	86.2 (12.925 g)	17.5 μm	48.0 μm	86.6 μm
10(5)	13.8	41.4	90.7 (13.607 g)	18.4 μm	47.7 μm	86.2 μm
a Target load 33.33%; Batch size 15 grams.
b D(v, 0.1), D(v, 0.5), D(v, 0.9) represent 10, 50, 90% of particles smaller than that size.

FIG. 19 shows the release profiles (performed in duplicate) of the 5 Batches reported in Table 5 that were obtained using the release method previously described.

The release profiles demonstrate a low intra- and inter-batch variation, again confirming the good method reproducibility. As previously observed, the appearance of the flavor in the release media was limited to the 40-50% of the total amount employed for the study (FIG. 19). In order to confirm the loss of the volatile matter, mass balance studies were performed. Together with the 2 samples employed in the release study, 2 extra samples for each batch were placed in the same conditions and kept closed. Only one sampling was done at the 60 minute time point. Then the samples (microparticles and release media, 10 mL) were mixed with 30 mL of methanol to dissolve all the methyl salicylate (flavor left in the particles and present in the release media) and assayed at the HPLC. Results of this study are reported in Table 6. The samples in a closed container released always higher amounts of flavors at 60 minutes (about 70%) (Tab. 6). The amount lost was estimated to be lower for the samples assayed only once, never higher than ˜20%, while the other samples showed a loss always around 30-40% of the initial amount. This confirms the previous hypothesis.

TABLE 6
Results of the mass balance study.
				Amount
		Amount	Amount	left in the	Amount
Sample		released after	recovered	microparticles	lost
name	Sample	60 minutes (%)	(%)	(%)	(%)
SB10(1)	a*	52.9	56.0	3.1	44
	b*	52.4	49.6	—	50.4
	c**	71.4	86.7	15.3	13.3
	d**	72.2	79.8	7.6	20.2
SB10(2)	a*	39.2	61.4	22.2	38.6
	b*	39.1	59.7	20.6	40.3
	c**	69.0	91.5	22.5	8.5
	d**	60.6	82.5	21.9	17.5
SB10(3)	a*	45.7	60.7	15	39.3
	b*	45.7	60.1	14.4	39.9
	c**	72.4	86.0	13.6	14
	d**	71.7	92.6	20.9	7.4
SB10(4)	a*	49.1	69.9	20.8	30.1
	b*	46.1	66.3	20.2	33.7
	c**	70.4	91.3	20.9	8.7
	d**	70.2	91.4	21.2	8.6
SB10(5)	a*	44.2	54.0	9.8	46
	b*	44.9	56.0	11.1	44
	c**	68.0	79.6	11.6	20.4
	d**	67.1	81.0	13.9	19
*Samples employed in the release study
**Samples assessed for the release only at 60 minutes

Since the particles will have to release their content in the mouth, a “non-closed system,” the release conditions used for the release (FIG. 6) should mimic more closely the real life situation (flavor dissolved in the saliva as well as flavor volatilized reaching the olfactory neuroepithelium). Due to the fact that flavor perception is generally described as a combination of taste and smell, the overall yield of a flavor is very difficult to predict even if appropriate headspace sampling techniques (i.e., static or dynamic headspace sampling) are used. In fact, the most straightforward approach is through evaluation by an olfactive panel. Panel evaluations can be carried out directly with the desired consumer product and do not require complex analytical methods. If a sufficient number of panelists is used, the statistical significance of the experiment can be determined.

An example of particle morphology is given in FIG. 20, which reports optical microscopy pictures of the particles of Batch SB10(5) (Table 5). Optical microscopy show a similar morphology for the particles of the five scaled Batches. Pictures show a capsule-like morphology that is likely obtained when oil is encapsulated.

An evaluation of the five of methyl salicylate cetyl alcohol microparticles of the scaled up Batches was conducted by a panel of tobacco industry experts and was completely positive from the point of view of flavor content and yield when mixed with snuff. The particle size was considered optimal to avoid an oily taste in the mouth as well an oily sensation in the hands.

Among the edible matrix materials that would be suitable for use in the present invention are a wax, a fat, a fatty alcohol, a sterol, cetyl alcohol, stearyl alcohol, paraffin, polyethylene glycol, a fatty acid, a polyunsaturated fatty acid, rudua fatty acid ester, palmitic acid, stearic acid, oleic acid, lauric acid, myristic acid, behenic acid, a triglyceride, polyethylene glycol, cholesterol, lecithin, a phospholipids, and mixtures thereof.

Among the flavoring agents that would be suitable for use in the present invention are a volatile oil, an essential oil, a botanical extract, methyl salicylate, ethyl salicylate, cinnamic acid, cinnamon oil, peppermint oil, spearmint oil, wintergreen oil, acetaldehyde, acetoin, aconitic acid, anethole, benzaldehyde, N-butyric acid, d- or l-carvone, cinnamaldehyde, citral, decanal, diacetyl, ethyl acetate, ethyl butyrate, ethyl vanillin, eugenol, geraniol, geranyl acetate, glycerol tributyrate, limonene, linalool, linalyl acetate, 1-malic acid, methyl anthranilate, 3-methyl-3 phenyl glycidic acid ethyl ester, piperonal, vanillin, citrus flavoring, berry flavoring, and mixtures thereof.

Among the suitable surfactants that would be suitable for use in the present invention are an alcohol, a fatty alcohol, a fatty acid, a fatty acid ester, polyvinyl alcohol, polyethylene glycol, alginic acid, a phospholipid, lecithin, cholic acid, desoxycholic acid, diacetyl tartaric acid esters of mono- and diglycerides, glycocholic acid, mono- and diglycerides and their monosodium phosphate derivatives, propylene glycol, ox bile extract, taurocholic acid, gum arabic, agar-agar, ammonium alginate, calcium alginate, carob bean gum, chondrus extract, ghatti gum, guar gum, potassium alginate, sodium alginate, sterculia gum, tragacanth, hydroxypropylmethylcellulose, any other water soluble derivatives of cellulose, and mixtures thereof.\

Claims

1. A method of producing edible flavored particulate solid dispersions, comprising the steps of

melting an edible matrix material and homogenously incorporating therein one or more edible flavoring agents,

cooling the flavored melted matrix material to achieve a solid dispersion having a flavor within an edible matrix, and

grinding the solid dispersion into particles and sieving the resulting particles to achieve edible flavored particulate solid dispersions of a desired size.

2. A method of producing edible flavored particulate solid dispersions, comprising the steps of

melting an edible matrix material and homogenously incorporating therein one or more edible flavoring agents,

cooling the flavored melted matrix material to achieve a solid dispersion having a flavor within an edible matrix, and

cutting or pressing one or more punches from the solid dispersion to achieve edible flavored particulate solid dispersions in the form of punches of a desired size.

3. A method of producing edible flavored particulate solid dispersions, comprising the steps of

melting an edible matrix material and homogeneously incorporating therein one or more flavoring agents,

mixing with high shear the flavored melted matrix material with an aqueous solution to create an agitated aqueous dispersion, and

cooling the agitated aqueous dispersion to a temperature below the melting point of the flavored matrix material to produce edible flavored particulate solid dispersions having a flavor within an edible matrix that are recoverable by filtration, flotation, centrifugation or vibro-separation.

4. The method according to claims 1, 2 or 3, wherein the matrix material is selected from the group consisting of a wax, a fat, a fatty alcohol, a sterol, cetyl alcohol, stearyl alcohol, paraffin, polyethylene glycol, a fatty acid, a polyunsaturated fatty acid, rudua fatty acid ester, palmitic acid, stearic acid, oleic acid, lauric acid, myristic acid, behenic acid, a triglyceride, polyethylene glycol, cholesterol, lecithin, a phospholipid, and mixtures thereof.

5. The method according to claims 1, 2 or 3, wherein the flavoring agent is selected from the group consisting of a volatile oil, an essential oil, a botanical extract, methyl salicylate, ethyl salicylate, cinnamic acid, cinnamon oil, peppermint oil, spearmint oil, wintergreen oil, acetaldehyde, acetoin, aconitic acid, anethole, benzaldehyde, N-butyric acid, d- or l-carvone, cinnamaldehyde, citral, decanal, diacetyl, ethyl acetate, ethyl butyrate, ethyl vanillin, eugenol, geraniol, geranyl acetate, glycerol tributyrate, limonene, linalool, linalyl acetate, 1-malic acid, methyl anthranilate, 3-methyl-3-phenyl glycidic acid ethyl ester, piperonal, vanillin, citrus flavoring, berry flavoring, and mixtures thereof

6. The method according to claim 1, wherein the grinding step includes grinding in a blender, or oscillator, or mill, or grinder, without freezing the flavored solid dispersion.

7. The method according to claim 3, wherein the aqueous solution contains a surfactant selected from the group consisting of an alcohol, a fatty alcohol, a fatty acid, a fatty acid ester, polyvinyl alcohol, polyethylene glycol, alginic acid, a phospholipid, lecithin, cholic acid, desoxycholic acid, diacetyl tartaric acid esters of mono- and diglycerides, glycocholic acid, mono- and diglycerides and their monosodium phosphate derivatives, propylene glycol, ox bile extract, taurocholic acid, gum arabic, agar-agar, ammonium alginate, calcium alginate, carob bean gum, chondrus extract, ghatti gum, guar gum, potassium alginate, sodium alginate, sterculia gum, tragacanth, hydroxypropylmethylcellulose, any other water soluble derivatives of cellulose, and mixtures thereof.

8. The method according to claim 7, wherein the concentration of the surfactant ranges from about 0.1 percent to about 30% weight to volume.

9. The method according to claim 3, wherein the mixing with high shear is accomplished by stirring, blending, paddles, propellers, impellers, or gas agitation using air, nitrogen, argon, helium, or another suitable gases, or by combinations thereof.

10. The method according to claims 1, 2 or 3, wherein the flavored particulate solid dispersions have a particle or punch size in the range of about 10 nm to about 300 microns in diameter.

11. The method of claim 10, wherein the flavored particular solid dispersions contain from about 1 to about 80% weight in weight flavoring agents within the edible matrix.

12. The method according to claims 1, 2 or 3, and further comprising the step of adding one or more colorants to the flavored particulate solid dispersions prior to formation, during formation, or after formation to impart thereto a desired coloration.

13. The method according to claims 1, 2 or 3 and further comprising the step of dispersing the flavored particulate solid dispersions within a consumer product selected from the group consisting of tobacco, moist snuff, dry snuff, individually wrapped snuff pouches, snuff pouch paper, edible films, coffee, tea, chewing gum, confections, candy, or other food products.

14. A flavored particulate solid dispersion produced by the method of claims 1, 2 or 3.