Method for producing flavored particulate solid dispersions   

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

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

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

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.

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.

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.

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.

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