(12) Patent Application Publication (10) Pub. No.: US 2009/0301504 A1 Worthen Et Al

Home , Methyl salicylate

US 2009030 1504A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0301504 A1 Worthen et al. (43) Pub. Date: Dec. 10, 2009

(54) METHOD FOR PRODUCING FLAVORED Related U.S. Application Data PARTICULATE SOLD DISPERSIONS (60) Provisional application No. 61/001.225, filed on Oct. 31, 2007. (76) Inventors: David R. Worthen, Lexington, KY (US); David Johnson, Owensboro, Publication Classification KY (US); Patrick P. DeLuca, (51) Int. Cl. Lexington, KY (US); Paolo Blasil, A24B I5/00 (2006.01) Belmonte Picano (IT) (52) U.S. Cl...... 131A274 (57) ABSTRACT Correspondence Address: KREG DEVAULT LLP A method for producing flavoring materials consisting of a ONE INDIANA SQUARE, SUITE 2800 flavor and a simple matrix material that are GRAS or approved for use in food, and that will be stable under INDIANAPOLIS, IN 46204-2079 (US) extremely adverse conditions, greater than 50% moisture, high pH, high temperature stability (60°C.), yet be released in (21) Appl. No.: 12/290,575 the oral cavity; without the use of organic solvents, and with the use of inexpensive materials and unsophisticated equip (22) Filed: Oct. 31, 2008 ment.

Seal 1 g matrix Add specified amount of material (e.g. cetyl methyl salicylate; re alcohol) in glass seal vial vial; immerse in Heat to 65° C water bath while stirring

Assay methyl Remove from heat and salicylate content, allow to cool to room homogeneity, Punch uniform discs temperature while release profile from solidified fusate stirring with brass cork borer Patent Application Publication Dec. 10, 2009 Sheet 1 of 13 US 2009/030.1504 A1

Seal 1 g matrix Add specified amount of material (e.g. cetyl D methyl salicylate, re alcohol) in glass seal vial vial; immerse in Heat to 65° C water bath while stirring

Assay methyl Remove from heat and salicylate content, allow to cool to room homogeneity, Punch uniform discs temperature while release profile from solidified fusate stirring with brass cork borer

Fig. 1

32.73C6ssoci2.sac 1349Jig 20.54Jig

w 20 40 SO 8O OO 120 Patent Application Publication Dec. 10, 2009 Sheet 2 of 13 US 2009/030.1504 A1

35.52C 176.1 JTg

2O 40 SO 8O 1 OO 120 Fig. 2

37.48°C 57.02J/g

20 40 60 80 100 120 Fig. 3 Patent Application Publication Dec. 10, 2009 Sheet 3 of 13 US 2009/030.1504 A1

S s

2O 40 60 BO OO 2O Exo Down Temperature (C) Universal W Fig. 4

2 S. 3 0 62.39°C r 21.8Jfg -2

-4

-8 y r 2O 4O 60 80 100 2O

Fig. 5 Patent Application Publication Dec. 10, 2009 Sheet 4 of 13 US 2009/030.1504 A1

62.67°C

60.78°C 195.7JIg

2O 40 60 8O OO 12O Fig. 6

i52,51C

59.92C 185.5JIg

2O 40. 60 BO OO 120

Fig. 7 Patent Application Publication Dec. 10, 2009 Sheet 5 of 13 US 2009/030.1504 A1

59.73C

S s SS.04C 5 114.6Jig L

20 40 60 80 100 120 Fig. 8

4. 49.29C 2 25, 19°C 1.58C

ab 59.89J/g

s 148.05C 1a 68.39J/g U 8 -2- 134C 4

-6 w w aw w ww or C- or t 2O 40 60 80 100 20 14 SO 18 Exo Down Temperature (C) Universal Fig. 9

Patent Application Publication Dec. 10, 2009 Sheet 7 of 13 US 2009/030.1504 A1

Seal 1 g matrix Add specified amount of material (e.g. cetyl oo methyl salicylate; re alcohol) in glass Seal vial vial; immerse in Heat to 65°C water bath while stirring

Assay methyl Remove from heat and salicylate content, allow to cool to room homogeneity, Grind in glass mortar temperature while release profile and fraction by size stirring using mesh sieves.

Fig.11a

Glass vial containing artificial saliva

Layer of particles, film or tobacco Sandwiched between glass beads

Glass Beads

Fig. 12

Patent Application Publication Dec. 10, 2009 Sheet 11 of 13 US 2009/030.1504 A1

5 O 34. OO

O ------WY ------Y ------7------O 2 22 Particles larger than Particles between Particles between Particles smaller 250 pm 250 and 125 in 125 and 75um than 75 m Fig. 17

s 3.A.

20 30 40 5. s 70 Time (min) Fig. 18 Patent Application Publication Dec. 10, 2009 Sheet 12 of 13 US 2009/030.1504 A1

O 2O 30 40 SO SO 7) Time (min)

Fig. 19 Patent Application Publication Dec. 10, 2009 Sheet 13 of 13 US 2009/030.1504 A1

ig. 3i US 2009/030 1504 A1 Dec. 10, 2009

METHOD FOR PRODUCING FILAVORED aqueous mixture of a Sugar and starch hydrolysate, together PARTICULATESOLID DISPERSIONS 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 0001. This application claims the benefit of the filing date homogeneous melt, the melt being extruded into a relatively of U.S. Provisional Patent Application Ser. No. 61/001.225, cool solvent, dried and combined with a selected anti-caking filed Oct. 31, 2007, pursuant to 35 U.S.C. S 120. agent to produce the stable, relatively non-hygroscopic par ticulate flavor composition of the invention. The temperature FIELD OF THE INVENTION for the process is preferably maintained at or below a maxi mum of about 126 degrees C. 0002 The present invention relates to particulate flavored 0007. In a family of U.S. patents, including U.S. Pat. Nos. material and more particularly to particulate flavored materi 5,601,865; 5,792,505 and 5,958,502, what has been claimed als comprising a flavor dispersed in or otherwise entrapped is the use of different materials, such as maltodextrins, corn within an edible matrix that can be used to release favors and syrup Solids, maltose syrup Solids, high fructose corn syrup aromas in a controlled manner in consumer products, includ Solids, starches, hydrocolloids, gums, proteins, partially ing tobacco, and methods for preparing and using the same. hydrolyzed proteins, modified proteins, modified hydrocol loids, and modified celluloses, to obtain a liquid melt, heating BACKGROUND OF THE INVENTION and mixing a matrix and a volatile component, to Solidify 0003 Flavor encapsulation is employed to protect flavors thereafter under a pressure sufficient to prevent substantial from degradation, to produce flavoring materials that may be Volatilization of said volatile component. In this invention, dispersed in bulk commodities, and to produce flavoring the dense amorphous, essentially non-crystalline Solid encap materials with modified release characteristics. Volatile oils, Sulant may be described in many cases, but not exclusively by perfumes, food extracts and other flavor modifiers have been those knowledgeable in the art as a glass as characterized by Successfully encapsulated and employed in a variety of con a glass transition temperature. Sumer products. Flavor encapsulation has been achieved 0008 British Patent 767,700 illustrates a method for mak using a number of technologies, including spray drying, pan ing particles comprising inclusions containing a fat-insoluble coating, spray coating, fluidized beds, chemical encapsula vehicle carrying fat-soluble vitamins encased in a moisture tion and comminution. Particulate flavor composites may resistant substance in which the fat insoluble vehicle is consist of shell-core constructs, multi-lamellar vesicles, or as insoluble. dispersions of flavor molecules or droplets in a matrix, as well 0009 U.S. Pat. No. 3,186,909 conveys a method for melt as other types of particles. Other methods include molecular ing a composition containing fatty alcohol esters derived inclusion in cyclodextrin, granulation and coacervation. A from sperm whale oil, adding urea to the composition and variety of materials are employed to encapsulate flavors, dissolving the urea, and adding fish liver oil and Vitamins, including gelatin, mixed lipids and sweeteners (U.S. Pat. No. thereby giving rise to a homogeneous mixture which might be 4,803,082), polymerized acrylic materials (U.S. Pat. No. useful for making particles. 3,520,949) and starches. 0010. The use of the spray-drying technique is claimed in 0004. Many compositions have been proposed for use as U.S. Pat. No. 5,124,162. A mixture of flavor, maltose, malto flavoring materials, and methods have been disclosed for the dextrin and a carbohydrate film former by spray-drying the production of flavor and other core material encapsulation. mixture to form a dense product of at least 0.5 g/cc bulk free Both hydrophilic and hydrophobic compositions have been flow density and less than 20% voids. The invention is reported. Sorbitol, mannitol, Saccharin, Sugar and starch intended to improve the stability against oxidation of the hydrolysate, maltose, malto-dextrin, corn Syrup Solids, mal flavor. tose syrup Solids, high fructose corn syrup Solids, starches, 0011. The production of microparticles useful inaugment hydrocolloids, gums, proteins, partially hydrolyzed proteins, ing, enhancing and/or imparting aroma and/or taste (over modified proteins, modified hydrocolloids, modified cellulo relatively long periods of time in a controllably releasable ses, gelatinized cereal Solids, whey proteins and alginates are manner) to perfume compositions, perfumed articles (e.g., examples of the hydrophilic materials that have been pro deodorancy and antiperspirant sticks), foodstuffs, chewing posed as coating materials in the prior art. On the other hand, gums, beverages and the like is the subject of U.S. Pat. No. paraffin, triglycerides, fatty acids, fatty alcohols, waxes have 6,368.633. The first step reported in the invention is the been proposed as hydrophobic encapsulating materials. adsorption of the olfactory-active material onto silica fol Some of the aforementioned materials have been proposed, lowed by a blending/extrusion step followed by at least one and in Some cases they are currently used in pharmaceutical particularization step. formulation to obtain active controlled release. (0012. The U.S. Pat. No. 3,922,354 describes particulate 0005 U.S. Pat. No. 4,388,328 illustrates a flavor compos free-flowing flavoring compositions utilizing flavoring ite that contains Sorbitol, mannitol, saccharin, and a flavor agents in a cellular matrix of gelatinized cereal Solids and material that may be prepared in the form of Sugar-free can water. Dextrins, mixtures of edible mono and diglycerides of dies, or may be reduced to particles or beads. The procedure higher fatty acids, and coloring agents can also be added to the consists of preparing a eutectic mixture heating the mixture of matrix to provide a free flowing product that exhibits con the components to a temperature of about 200 degrees C. and trolled flavor release characteristics, the aesthetic-appeal of than cooling the same to 70 degrees C. Obviously, the high natural whole or ground spices, and precisely controlled fla temperature employed may adversely affect flavor stability, Vor values and strength. By forming a mixture of partially Volatilization and encapsulation efficiency. gelatinized cereal Solids in water and then heating with agi 0006. In U.S. Pat. No. 4,610,890, a solid essential oil fla tation to a temperature of from about 65 degree to about 100 Vor composition involving preparation of a heated or cooked degree Celsius until gelation takes place. A water content of US 2009/030 1504 A1 Dec. 10, 2009

from about 10 to about 20 percent by weight is achieved. The vored particles that are water-insoluble. U.S. Pat. No. 4,173, patent includes extrusion and grinding of the matter, as well. 492 discloses a process for producing flakes of coated pig A large particle size, high water content and low flavor con ments for dry compounding with polymeric plastics or rubber tent are the disadvantages of the aforementioned invention. materials. Here, the color pigments are encapsulated in a wax, 0013 Encapsulation of a flavor or active agent in a similar Such as hydroxyStearate wax. matrix (i.e., whey protein) is claimed in U.S. Pat. No. 5,756, (0020 U.S. Pat. No. 4,675,236 reveals a process for coating 136. The encapsulation composition that results in the con mono-core type shell-core microcapsules with waxes. The trolled release of the flavor or active agent may be incorpo mono-core type material is formed by spray drying or pulver rated in a yeast-leavened dough without causing a deleterious izing bulk core material, and the core materials are then effect on the rising of the dough. immersed in a wax solution, followed by vacuum drying. The 0014) A number of U.S. patents (e.g., U.S. Pat. Nos. 6,325, product is then introduced together with air or nitrogen gas 859; 6,436,461; 6,929,814; 3,857.964) deal with the use of into a melting and cooling chamber, giving rise to a final acid polysaccharides (e.g., alginates) as embedding materials wax-coated product with a smooth surface and a shape similar once gelified by means of multivalent cation solutions. U.S. to that of the underlying core particle. Pat. No. 6,325,859 claims the encapsulation of flavor, fra (0021 U.S. Pat. No. 3,856,699 describes a process for pro grance, vitamin, and/or coloring materials then to be added to ducing capsules encased in walls of a waxy material. The the food or tobacco products. A similar procedure is described process comprises the dispersion of a waxy material contain in U.S. Pat. Nos. 6,436,461 as well as 6,929,814. ing a core material in an agitated aqueous medium at a tem 0015 U.S. Pat. No. 4,343,826 describes a process for pre perature higher than the melting point of the waxy material, paring beads offat by melting a fat (that contains at least 20% followed by transferring the waxy material into a non-agi solids at a temperature below about 175 degrees F.) and tated aqueous medium at a temperature lower than the melt cooling the melted fat to a temperature about 3 degrees to 8 ing point of the waxy material, thereby inducing the forma degrees F. below the clear point of the fat. The method should tion of solid particles. allow the formation solid drops at least 3 mm in diameter. In (0022 U.S. Pat. No. 3,819,838 describes a particulate solid U.S. Pat. No. 5,460,756, a method and apparatus to entrap composition comprising multiple capsules, each consisting liquids within wax and transforming the wax to a more stable of at least one primary capsule, wherein an active ingredient, crystalline state is claimed. The aim is achieved by placing the Such as a flavor, is encapsulated by a water soluble solid wax/liquid material in a chamber attached to a piston and by encapsulating material, whereupon the primary capsule is applying some force with the piston. re-encapsulated in a water insoluble-solid encapsulating 0016. In U.S. Pat. No. 6,245.366 a fat-coated encapsula material. The inventors note that water soluble encapsulated tion compositions is prepared by mixing an active agent with materials, as described in the prior art, are disadvantageous a moltenfatto obtain a slurry, and cooling the slurry thereafter when mixed with other ingredients, including water or moist to obtain a solid mass in which the active agent is embedded. ingredients. The invention mention also the use of various techniques (i.e., (0023 U.S. Pat. No. 3,764,346 discloses a process for pre spray drying, melt extrusion, coacervation, freeze drying, paring spray dried materials that may be employed as flavor drum drying, belt drying, tray drying, tunnel drying, and enhancers. extrusion) to obtain fat particles. (0024. In U.S. Pat. No. 5,328,684, Morgan et al. describe 0017. An encapsulation system composed of both hydro the encapsulation of flavors, fragrances and related com phobic and hydrophilic material is described in U.S. Pat. No. pounds in fatty alcohols, waxes and in other Substances, such 6,887,493. Solid nanospheres of carnauba wax, candelilla as polymers, in a process employing an apparatus comprising wax, and mixtures thereof, encapsulating a first active agent mixing and feed tanks, gas inlets, heating elements and spray are embedded in micro spheres made of a moisture sensitive nozzles, and related equipment. matrix material (e.g., starch derivative, natural gum, polysac 0025. In U.S. Pat. No. 6,190.722, Wedral et al. describe a charide, protein, hydrocolloid). process for making flavored, free flowing particulates, which 0018 U.S. Pat. No. 3,976,794 describes sweetened coco comprises mixing an oil soluble flavor with a melted edible fat nut products coated with a powdered Sugar further containing in a reaction vessel to form a solution of the oil soluble flavor sugarparticulate enveloped in edible fat. U.S. Pat. Nos. 3,949. in the melted fat, cooling the solution, adding a cooling or 094 and 3,949,096 show a process for preparing various fla Super-cooling agent with agitation to produce solid particles Vorings, colorants, and flavor enhancers coated with a mix having an average diameter of from about 0.1 to 10 cm, or ture of fats and emulsifiers. Here, the process consists of grinding these particles with a Supercooling agent in agrinder spraying flavors and condiments that are intercepted by a or blender to produce substantially free flowing particulate second, impinging spray containing the edible coating mate flavor whose particles have an average diameter of less than 1 rials. These processes require the use of multiple spray con mm. Wedral et al. note that the use of a Super-cooling agent is figurations, and afford relatively low flavor encapsulation necessary to produce particles with an average diameter of efficiency, the particles consisting primarily of excipient less than 1 mm, as the materials are otherwise too sticky and materials. adherent to be properly ground. 0019 U.S. Pat. No. 2,857.281 describes a process of form 0026 U.S. Pat. No. 5,064,669, Tan et al. reveals a method ing a hot, liquid emulsion of a volatile flavoring agent in a for making controlled release flavors. Here, an aqueous fla water soluble, edible sugar matrix. This material is then Voring agent is dispersed in a melted encapsulating or enrob forced through an orifice to form flavored particulates. U.S. ing material. Such as a fat and/or wax and one or more emul Pat. No. 2,785,983 discloses a process for making a flavoring sifiers, mixing one or more water-containing flavor composition by spray-cooling a solution of the desired fla compositions with a texture conditioning agent, then mixing Voring ingredient dispersed in a melted, edible hard fat or the flavor compositions and texture conditioning agent(s) hydrogenated glyceride oil, thereby forming dry, Solid fla with the molten fat or wax to obtain a homogeneous mixture US 2009/030 1504 A1 Dec. 10, 2009

in the form of an emulsion, and finally chilling the flavor size. Additional advantages of the present invention include composition-containing mixture to provide discrete particles the lack of organic Solvents, and the use of inexpensive mate of Solid encapsulated flavoring agent. The process may rials and unsophisticated equipment. require a spray chiller to produce the particles, and produces a composition containing a number of excipients, including BRIEF DESCRIPTION OF THE DRAWINGS emulsifiers and conditioning agents, as well as the flavor 0033 FIG. 1 is a diagram of the fused punch production itself. process of Example 1. 0034 FIG.1a is a differential scanning calorimetry (DSC) SUMMARY OF THE INVENTION thermogram of fused paraffin. 0027. Each of the representative prior art patents, dis 0035 FIG. 2 is a DSC thermogram of fused paraffin and cussed above, has certain disadvantages as compared to the methyl salicylate. production of the materials of the present invention. Several 0036 FIG. 3 is a DSC thermogram of fused cetyl alcohol. of these prior art methods require specialized spray drying, 0037 FIG. 4 is a DSC thermogram of fused cetyl alcohol mixing or extrusion equipment, employ mixtures of several and methyl salicylate. excipients, and may result in the degradation or evaporation 0038 FIG. 5 is a DSC thermogram of fused palmitic acid. of flavors. Still others are limited in the range of particle size 0039 FIG. 6 is a DSC thermogram of fused palmitic acid that may be produced, as well as in flavor loading as a percent and methyl salicylate. of total material weight. The high temperatures required in 0040 FIG. 7 is a DSC thermogram of fused PEG 8000. several of these aforementioned methods may compromise 004.1 FIG. 8 is a DSC thermogram of fused PEG 8000 and flavor stability by thermal degradation and encapsulation effi methyl salicylate. ciency by inducing Volatilization. Further, the extensive use 0042 FIG. 9 is a DSC thermogram of fused cholesterol. of polysaccharides and organic acids as primary matrix and 0043 FIG. 10 is a DSC thermogram of fused cholesterol encapsulation materials may further impact flavor Stability and methyl salicylate. promoting trans-esterification and other degradative pro 0044 FIG. 11 is a graph illustrating methyl salicylate CCSSCS. release from fused punches in artificial saliva at 37° C. 0028. It is an object of the present invention to overcome 0045 FIG.11a is a diagram of the fused punch production these disadvantages by providing a method for producing process Scheme of Example 3. flavoring materials consisting of a flavor and a simple matrix 0046 FIG. 12 is a diagram of glass bead dissolution appa material that are GRAS or approved for use in food, and that ratus for particles and tobacco. will be stable under extremely adverse conditions, greater 0047 FIG. 13 is a graph illustrating methyl salicylate than 50% moisture, high Ph, high temperature stability (60° release from fused particles in artificial saliva at 37°C. C.), yet be released in the oral cavity. 0048 FIG. 14 is a graph illustrating methyl salicylate 0029. It is a further object of the present invention to release from fused particles dispersed in high dark snuff in provide a method of producing Such materials attemperatures artificial saliva at 37° C. Sufficiently low so as to minimize Volatilization and degrada 0049 FIG. 14a is a diagram of the fused punch production tion of the additive components during processing. process Scheme of Example 4. 0030. It is yet another object of the present invention to 0050 FIG. 15 is a graph illustrating methyl salicylate provide a method to produce Such materials that is more release from methyl salicylate-loaded cetyl alcohol particles simple, more scalable and more economical in comparison to dispersed in high dark snuff in artificial saliva at 37° C. the prior art methods. These and other advantages of the 0051 FIG. 16 is a graph illustrating methyl salicylate present invention will become apparent to one skilled in the release from methyl salicylate-loaded cetyl alcohol particles art with reference to the attached. dispersed in methyl salicylate-adsorbed high dark snuff in 0031. The present invention may be practiced using a artificial saliva at 37° C. simple casting and grinding method that does not require 0.052 FIG. 16a is a diagram of the rapid cooling produc chilling, or by a simple aqueous emulsion cooling method tion process scheme of Example 6. using simple agitation equipment. In contrast to previous 0053 FIG. 17 is a bar graph illustrating the particle size of methods, which require several excipients, including plasti Batch H 6. cizers and emulsifiers, the present invention may be prac 0054 FIG. 18 is a graph illustrating in vitro release pro ticed, and desired release characteristics achieved, using a files for formulation 9b. flavor and a single GRAS matrix material. Moreover, in those 0055 FIG. 19 is a graph illustrating in vitro release pro cases where a plasticizer is desired, the plasticizing properties files of formulations reported in Table 5. of methyl salicylate itself might be advantageously used in 0056 FIG. 20 is a color version of optical microscopy of the formulation, further underscoring the simplicity of the Batch SB10(5), magnified 100x in the upper pictures, and present method by obviating the need for additional plasti 200x in the lower pictures. cizing agents. 0032 Particle size may be controlled using simple adjust DETAILED DESCRIPTION OF THE PREFERRED ments to the grinding-sieving process, or by simple alter EMBODIMENTS ations to the aqueous emulsion agitation speed, cooling 0057 The present invention will now be described by way method and emulsifier concentration. Percent flavor loading of certain Examples that illustrate the preferred embodiments is possible across a wide range simply by increasing or of the invention to date. decreasing the amount of flavor incorporated into the molten matrix material. The flavor release rate, and the resistance of Example 1 the particles to water imbibition and hydrolysis, may be con 0.058 Experiments to date have demonstrated a high trolled by changing the matrix material and/or the particle capacity for waxes to absorb and disperse methyl salicylate US 2009/030 1504 A1 Dec. 10, 2009

(e.g., as much as 15% in paraffin). In addition, methyl sali 0065. The fusates were then assayed for methyl salicylate cylate-loaded wax particles have been produced by disper content and homogeneous distribution by randomly sampling sion of a molten wax-methyl salicylate Solution in hot aque round punches with a 6 mm cork borer and dissolving each ous ethanol with rapid agitation and cooling. punch, normalized by weight, in methanol. The methanol 0059. The evaluation of a series of GRAS materials for use Solutions were then assayed for methyl salicylate and Sali as Sustained-release methyl salicylate matrices has led to the cylic acid content by reverse phase HPLC with UV detector. selection of cetyl alcohol and PEG 8000 as promising candi Methyl salicylate content was nearly quantitative (20% w/w) dates. Cetyl alcohol affords steady, reproducible yet delayed in each preparation. Notably, although the scent of methyl methyl salicylate release in artificial saliva. PEG 8000-methyl salicylate was evident, each material appeared to have a high salicylate dispersions lead to a burst of methyl salicylate, with affinity for methyl salicylate. No significant weight loss was a more delayed release when dispersed in tobacco. noted from any fusate, even after 72 hours under reduced 0060 Self-emulsified cetyl alcohol particles prepared pressure. Methyl salicylate remains stable under these pro from aqueous emulsions also give relatively steady, Sustained cessing conditions, as no salicylic acid was detected by HPLC delivery. Flavored cetyl alcohol particles, combined with neat in any fused dispersion. methyl salicylate dispersed in tobacco, offer another alterna 0066. Thermal analysis of solid dispersions is routinely tive flavoring method. performed using differential scanning calorimetry (DSC) for 0061 Fused solid dispersions have been employed both analytical and quality control purposes. DSC may be throughout the food, pharmaceutical and cosmetic industries used to characterize the crystalline and amorphous character in a variety of applications, including the storage and con istics of the materials under study, thereby providing insight trolled release of flavors, fragrances and other actives. Fused into chemical and functional interactions between carrier and dispersions, also referred to as melts or solid solutions, are flavor. This information may be useful for predicting and made by blending a component, such as methyl salicylate, understanding wetting, Solubility, plasticizing effects and into molten GRAS materials at moderate temperatures. The release behavior. DSC is useful for validating the polymor molten solution may be molded, extruded, sprayed as a coat phic character and its reproducible production in Solid dis ing or spray-cooled into particles. The cooled fusate may also persions. The influence of casting, milling and spraying on be molded, punched or milled into particles. Fused disper these dispersion characteristics may also be assessed with sions may be prepared from many self-emulsifying materials, DSC. and require little or no additional solvents or excipients. Since 0067. Accordingly, DSC analysis of the fused carrier con minimal excipients are desirable in any sustained-release fla trols and their corresponding methyl salicylate dispersions Vor preparation, fused dispersions have been explored as a was performed in order to gain an initial appreciation of the possible formulation method. tendency, if any, of methyl salicylate to plasticize or otherwise 0062. A series of GRAS carrier materials were selected interact with each carrier. Fused paraffin (FIG. 1a) melts at and evaluated as potential matrices for producing methyl approximately 60° C., with changes in heat capacity around salicylate-loaded particles for controlled sustained delivery. 40° C. and 60° C. Dental-grade paraffin, cetyl alcohol and its carboxylate ana 0068. The paraffin-methyl salicylate dispersion (FIG. 2) log, palmitic acid, PEG 8000 and cholesterol were employed shows a broadened change in heat capacity and a modest in these initial studies. All of these edible materials are rou melting point reduction, Suggesting a tendency for methyl tinely incorporated into foods and oral preparations. These salicylate to interact with linear aliphatic molecules. materials were selected in order to compare the influence of 0069. A similar change in thermograms was noted for chemical structure, including the presence of hydrogen bond fused cetyl alcohol (FIG. 3), a long chain aliphatic alcohol, donors and/or acceptors, hydrophilic and hydrophobic func and the cetyl alcohol-methyl salicylate dispersion (FIG. 4). tions and the sterol backbone on release performance. All of (0070. In contrast, both fused palmitic acid (FIG. 5), the these materials will mix and melt with methyl salicylate and carboxylate analog of cetyl alcohol, and its corresponding form Solid dispersions. However, at methyl salicylate concen methyl salicylate dispersion (FIG. 6), gave rise to similar trations beyond ca. 20% w/w, the fusates tend to become thermograms, Suggesting less interaction than with the alco tacky, Smearing semi-solids. Accordingly, 20% w/w was cho hol. Sen as the methyl salicylate concentration for the initial par 0071 Based upon these initial DSC data, it is possible that ticle studies. methyl salicylate has a greater tendency to interact with 0063. In a typical experiment to date, 1 gram of carrier hydroxyl-containing compounds than with those containing a material was melted in a glass vial at approximately 65° C. in carboxylate group a water bath. Upon melting, 250 mg of methyl salicylate (20% 0072 Fused PEG 8000 (FIG. 7) and the PEG 8000-methyl w/w) was added with stirring. Since the melting point of salicylate dispersion (FIG. 8) show similar thermal proper cholesterol is ca. 148°C., it was necessary to add 1 mL of ties, with only a very modest change in the heat capacity of dichloromethane to the cholesterol-methyl salicylate mixture PEG 8000, and a modest broadening in the peak, Suggesting in order to produce a liquid dispersion. The vials were imme an interaction between methyl salicylate and PEG. The ten diately sealed and removed from the heat source. The melts dency of methyl salicylate to interact with longer chain ali were then allowed to cool to room temperature. Uniform phatics and hydrogen bond donors, as compared to PEG, a fusates approximately 2 mm in thickness were thus formed on relatively polar, hydrophilic hydrogen bond acceptor, might the bottom of each flat-bottomed vial. No creaming or phase be expected to differ. Although no particular functional or separation was noted in any fusate during or after cooling. structural trend is determined from these data, it appears that The fused dispersions were then dried under reduced pressure methyl salicylate may interact with a variety of matrix mate (330 mm Hg) for 24 hours. rials, suggesting the possibility that methyl salicylate might 0064. A flow diagram of the fusate production process is mix with or otherwise be incorporated into matrices compris shown in FIG. 1. ing certain materials employed in these studies. US 2009/030 1504 A1 Dec. 10, 2009

0073. Similarly, an examination of the DSC thermograms proof of concept model for flavor release from an individual of fused cholesterol (FIG.9) and the cholesterol-methyl sali reservoir. Flavor-loaded matrix particles, which might be dis cylate mixture (FIG.10) reveals a greater tendency for methyl persed into loose, tinned Snuff offer another option for Sus salicylate to interact with hydroxyl-containing aliphatics. In tained-release delivery. Size, color and texture could be opti fact, a depression of about 10°C. was observed with choles mized for flavor delivery and consumer acceptance. The terol after blending with methyl salicylate. These data may be larger Surface area-to-volume ratio of particles may offer useful for the rational selection of matrix materials and opti more rapid flavor release. In addition, several methods are mization of methyl salicylate formulations. available for the production of such particles, including com minution of a solid dispersion, spraying molten solutions and Example 2 various emulsion technologies. 0078. A series of methyl salicylate particles were pro 0074 Individual flavor reservoirs or some other type of duced by grinding the cooled solid dispersions previously flavor-pak might be included in a snuff can or in a snuff described in a glass mortar and pestle, then passing the par pouch for sustained flavor release. Alternatively, snuff might ticles through standard testing sieves. Light microscopy be incorporated directly into such a flavored matrix in order to revealed that the particles that were ground and sieved to a make a buccal pellet. Such a reservoir or pellet might be fraction between 75 and 250 um in size were generally frac comprised of a tablet, a punch or some other flavor-matrix tured and irregular in shape. The particles were assessed for mass. Accordingly, an initial evaluation of the release char methyl salicylate content and homogeneity by HPLC. The acteristics of methyl salicylate from the Solid dispersions was grinding did not affect the properties of the particles. performed using fused punches. These punches, rather simi 0079. As the material tended to smear and clog the lar to a tablet, were prepared by removing a uniform, 6 mm screens, the cholesterol-methyl salicylate fusate could not be diameter disc from a 2 mm thick Solid dispersion produced as described in the scheme of FIG. 1. The punches, uniform in comminuted and sieved into discrete particles. Thus, it was size and Surface area, were homogeneous in methyl salicylate not further evaluated as a particle matrix. Instead, a 1:1 w/w content (20% w/w). Normalized for weight, the punches were mixture of two of the other matrix materials, cetyl alcohol and placed in a 20 mL. glass vial, and 10 mL artificial saliva (see PEG 8000, was used instead. p. 30, para. 3; Na et al.) was gently added with slow stirring at 0080 A flow diagram of the flavored particle production 37°C. At the indicated time point, a 1 mL aliquot part of the process is provided in the scheme of FIG. 11a. artificial saliva was removed for assay and replaced with 1 mL I0081 Dissolution studies, analogous to those described of fresh artificial saliva, thereby simulating a sink condition. for the punches, were then performed. Because the particles The sample was dissolved in 4 mL 50% methanol to ensure are buoyant, and in order to model the cheek and gum dissolution, and then assayed for methyl salicylate content by structure of snuff held in the mouth, the particles (50 mg, 10 HPLC, and cumulative release was calculated after correcting mg methyl salicylate equivalent) were first Sandwiched for Volume. As a control, an amount of neat methyl salicylate between two layers of inert glass beads (1 mm): The beads equivalent to that contained in the pellets was dispersed on the tended to keep the particles in place in a defined layer. At the bottom of control vials, and its dissolution was analogously same time, artificial saliva freely flowed through the Plateau assayed. The results of this study, presented as the meaniSD border channels between the beads on both sides of the par of three independent experiments, are summarized in FIG. ticle layer, in a manner analogous to saliva flow in the buccal 11. pouch. These dissolution apparatuses, illustrated in FIG. 12, 0075. The PEG 8000 pellet, primarily comprised of a were also used for the tobacco studies and flash melt film hydrophilic polymer, rapidly dissolved into a wet mass in the studies described in later sections. vial. Not Surprisingly, methyl salicylate release was most I0082. The dissolution apparatus consists of a 20 mL. glass rapid from the PEG 8000 punch. A burst of flavor release was vial containing 10 mL artificial saliva and two 1 gram layers noted within the first few minutes of dissolution. PEG, a of glass beads, between which may be sandwiched a layer of well-known hydrotrope and wetting agent with significant particles, a flash melt film, a wad of tobacco, or another Surface active properties, may be useful for providing a flavor dosage form. burst in a methyl salicylate formulation, or as a burst coating I0083 Methyl salicylate release from the fused particles, as on a delayed-release composition. compared to an equivalent amount of neat methyl salicylate 0076. As compared to the control, the more hydrophobic distributed between the beads, is summarized in FIG. 13. matrices all retarded the release of methyl salicylate. Since I0084. The results are expressed as the meant-SD of three these punches were solid castings, release was likely a func independent experiments. Once again, PEG 8000 produced a tion of solubilization of methyl salicylate located on the rapid methyl salicylate burst. Cetyl alcohol displayed consis punch surface, as well as diffusion and solubilization of tently slower release as compared to the methyl salicylate methyl salicylate trapped in the interior. Cetyl alcohol, which control. Palmitic acid gave mixed results, with release has modest Surface activity, is a major component of com approximating that of methyl salicylate early on, followed by mercial self-emulsifying waxes. Cetyl alcohol also gave the slower release, perhaps due to depletion of surface methyl steadiest release profile. Given these characteristics, cetyl salicylate and/or the formation of a stagnant film. Cetyl alco alcohol may be among the more promising matrix materials hol gave its characteristically steady, retarded release profile tested so far. throughout the experiment. Since it has surfactant and self emulsifying properties, it may form a stagnant film that tends Example 3 to retard methyl salicylate release. Notably, the cetyl alcohol PEG 8000 composite afforded an initial burst of methyl sali 0077. As stated, the punches described in the previous cylate, followed by release that was slower than methyl sali Example afford both an initial assessment of methyl salicy cylate itself. This combination may be particularly useful for late release from the various matrix materials, as well as a manufacturing composite particles with both characteristics. US 2009/030 1504 A1 Dec. 10, 2009

It may be possible to minimize the use of additional excipi tants employed during the emulsification process, uniform, ents simply by manufacturing these composite particles in spherical particles are readily and reproducibly manufac various cetyl alcohol/PEG ratios. tured. 0085. In order to model particle performance when dis I0088 Sophisticated flavor emulsions and microencapsu persed in tobacco, as well as to examine the effect of tobacco lated systems have been manufactured using a variety of dispersion on methyl salicylate release, an analogous set of emulsion techniques. However, one goal of the research com experiments was performed in which the particles (50 mg, 10 pleted to date has been to produce sustained-release flavor mg methyl salicylate equivalent) were first dispersed in 500 matrices while using a minimum of excipients. Thus, the mg of high dark snuff, then sandwiched between the bead GRAS materials employed in the previous Examples were layers in the dissolution vials, as shown in FIG. 12. Assays assessed for their capacity to form flavor-loaded particles revealed that the particles were uniformly dispersed. In addi using the melting-cooling emulsion technique without addi tion, no methyl salicylate was detected in extracts of the tional excipients. PEG was not evaluated in these aqueous tobacco itself, which is known to synthesize methyl salicylate emulsion studies, as it is readily dissolved in water. Future as a chemical signal when stressed. Methyl salicylate release PEG emulsion studies may be performed in an appropriate from the fused particles dispersed in tobacco, as compared to antisolvent. an equivalent amount of neat methyl salicylate adsorbed on I0089. In a typical melting cooling emulsion experiment, 1 tobacco, is summarized in FIG. 14. gram of matrix material (cetyl alcohol, paraffin, palmitic acid I0086) Neat methyl salicylate release, as well as methyl or cholesterol wetted with dichloromethane) was melted at salicylate release from the palmitic acid and cetyl alcohol 65° C. As soon as the material was melted, serial amounts of particles, was not significantly affected by dispersion in methyl salicylate were added, vigorous agitation on a stirring tobacco. This suggests that artificial saliva and methyl sali plate was commenced, and 100 mL of deionized water, pre cylate diffusion are not significantly altered by the presence viously heated to 65°C., was added over 60 seconds. The heat of tobacco. In addition, the presence of any Surface or chemi was removed, and the emulsion, consisting of melted matrix cally active tobacco components, if any, did not alter the methyl salicylate droplets dispersed in water, was allowed to dissolution characteristics of methyl salicylate itself. This is particularly important in light of the vast change in methyl cool to room temperature. After the droplets formed hard salicylate release noted with the PEG 8000 particles. While microcapsules, they were collected using a 10 um filter, the punch and free particle experiments revealed a tendency washed with 10 mL cold water, and air-dried overnight. The for PEG 8000 to produce a rapid methyl salicylate burst, when resulting particles were spherical in shape, generally free dispersed in tobacco, the PEG 8000 and, to a lesser extent, the flowing and non-adherent. FIG. 14a provides a diagram of the PEG 8000-cetyl alcohol particles, manifested a distinct procedure employed for producing flavored particles from reduction in release rate. It is not likely that the chemical aqueous dispersions. stability or surface activity of PEG, a non-ionic poly-ether, 0090 Cetyl alcohol was the only matrix material that are going to be adversely affected in the presence of tobacco. formed Suitable particles under these minimal conditions. The DSC experiments suggest that methyl salicylate does not The others tended to form large agglomerates and sheets that appreciably interact with PEG. One possible explanation for varied Substantially in size and shape. Thus, cetyl alcohol was the reduction in release rate may be that, in lieu of any elec chosen as the model emulsion matrix material. In order to trostatic interaction, dispersion and confinement in the determine the maximum loading capacity of cetyl alcohol, tobacco matrix may induce the formation of a PEG hydrogel analogous experiments were conducted using increasing or stagnant film. The film may cause a diffusion rate limited amounts of methyl salicylate. As Summarized in Table 1, release of methyl salicylate. The observation that PEG methyl salicylate incorporation into the cetyl alcohol par tobacco dispersions may retard flavor release has potential in ticles was nearly quantitative up to about 33% w/w, beyond more advanced Sustained-release applications. At the same time, PEG provides a formulation challenge, as its high affin which the material became soft and gel-like. ity for water, and the high water content of tobacco (55%). may compromise particle integrity, and thus flavor encapsu TABLE 1 lation, on product storage. Production of methyl salicylate-loaded cetyl alcohol particles by melting-cooling in an aqueous oil-in-water dispersion. Example 4 Methyl Salicylate Content Methyl Salicylate Encapsulation 0087. The mechanical comminution of solid dispersions is (mg) % by Weight % Yield Theoretical Actual a ready way to produce particles. However, mechanically 1OO 9 94.5 9 9.2 processed particles may be irregular in shape, as demon 2OO 16.7 96.O 16.7 12.8 strated in the previous Example. In addition, polymorphic 250 2O 93.1 2O 19.9 500 33 90.2 33 31.3 changes may be induced during the size reduction process. 750 43 34.O 43 30.9 Solid dispersions produced by cooling melted matrix emul 1OOO 50 O (gel) 50 O (gel) sions may be another useful means for producing methyl salicylate-loaded particles. When dispersed in aqueous media, lipophilic compounds tend to minimize interfacial 0.091 The particles were rather large, perhaps due to the Surface area and Surface free energy by spontaneously form lack of an emulsifier and high-shear mixing. ing spheres. Upon cooling, the liquid oil phase droplets 0092. The particles were also polydisperse in size, as Solidify, producing discrete spherical particles. Depending shown in Table 2. The 33% w/w methyl salicylate emul upon the temperature, shearing method and auxiliary Surfac sion system gave rise to Smaller particles. US 2009/030 1504 A1 Dec. 10, 2009

were perceived when in the mouth and an oily sensation was TABLE 2 also felt. This would cause acceptability problems for cus tomers. The increase of the flavor content up to 10-20% was Size range of isolable methyl salicylate-loaded cetyl alcohol particles. believed to be useful to reduce the amount of particulate Particle Type >500 um 250-500 um 75-2SO um &75um material in the final product (e.g., tobacco) and to optimize the process and to reduce the overall cost, as well. 20% Methyl 19.4 75.9 4.6 O Salicylate 0098. In a typical experiment of the previous Examples, 33% Methyl O 89.8 7.6 2.5 the needed amount of methyl salycilate was added to 1 g of Salicylate 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 0093 Methyl salicylate remained stable throughout the while under vigorous agitation. The dispersion was cooled to process, as no salicylic acid was detected when the particles room temperature, and the formed particles were collected by were assayed for methyl salicylate content and homogeneity. filtration, were washed with cold water and were air-dried Clearly, more sophisticated emulsion methods could be overnight. employed to produce Smaller, more uniform particles. Nev ertheless, these initial studies demonstrate that spherical methyl salicylate-cetyl alcohol particles may be reproducibly Example 5 manufactured without excipients using the simplest tech 0099. The main improvements focused on how the inter niques. Methyl salicylate release from the emulsified cetyl nal phase is dispersed into the external phase and the agitation alcohol particles is summarized in FIG. 15. procedure. In the modified method the melted internal phase 0094. The influence of methyl salicylate loading (20 or (2 g of CA and the needed amount of methyl salycilate) are 33% w/w) and particle size (75-250 nm or 250-500 nm sieve injected via a plastic syringe into 400 mL of deionized water fractions) were evaluated. Using the aforementioned glass (with or without surfactant) heated at 65° C. and agitated with bead release apparatus described in FIG. 12, the particles (10 mechanical stirring. After injection the heating was discon mg methyl salicylate equivalent) or the neat methyl salicylate tinued and the dispersion was allowed to cool at room tem control were placed between the glass bead layers, and perature. Particles were recovered by filtration, were washed release studies in artificial saliva at 37°C. were performed as with 3 L of deionized water and were dried under vacuum described in the previous sections. Methyl salicylate release overnight (15 mm Hg). The different preparations performed from the emulsified cetyl alcohol particles was slower than with Example 5 are reported in Table 3, while the particle size neat methyl salicylate dissolution, regardless of particle load of the batch number 6 is shown in FIG. 17. ing or size. This Suggests that cetyl alcohol remains a viable 0100 Not all the performed preparations gave rise to par choice for sustained flavor release. As would be expected, ticle formation (Table 3). The optimal stirring rate was found release was faster from the smaller particles, which have a to be 1000 rpm when deionized water was used as the external much higher surface area to volume ratio. Particle size phase, while 500 rpm when 0.35% of poly (vinyl alcohol) was appears to have a greater influence on methyl salicylate added. Batch #2 formed very large particles clearly visible, release than percent loading, as release from the smaller 20% most likely in the range between 500 and 1000 um; therefore W/w particles was significantly faster than that from the larger not suitable for their particle size. Preparation #4 provided 33% w/w particles. Smaller particles and this preparation was repeated adding 0095 Tobacco is currently flavored by maceration and methyl salicylate (23.1% of target loading). The preparation coating with methyl salicylate. Combining this method with a was performed in triplicate (batches #6, 7 and 8 in Table 3). Sustained-release preparation has produce Superior flavor The particle recovery was satisfactory (~80%), while the release in experiments completed to date. In one experiment mean encapsulation efficiency (~35%) and the methyl salicy 250-500 um cetyl alcohol particles (20 or 30% w/w, 10 mg late content (8%) were considered too low (Table 3). The methyl salicylate equivalent) were dispersed in 500 mg high particle size of these three batches was considered satisfac dark snuff with or without 10 mg free methyl salicylate and tory (FIG. 17). The low active content was ascribed to the the neat control, and the release experiment was repeated. The evaporation of the volatile methyl salicylate during the time results of these experiments are shown in FIG. 16. that the dispersion was allowed to cool at room temperature 0096 Methyl salicylate release from the particles dis without any external cooling. persed in tobacco was little changed from that released from 0101 Flavor lost during encapsulation has been reported the equivalent, free particles, as summarized in FIG. 15 and to be an issue. In fact some prior art processes (i.e., U.S. Pat. previously discussed. Methyl salicylate release from the Nos. 5,601,865; 5,792.505 and 5.958.502) have employed a tobacco containing both free and encapsulated methyl salicy pressure sufficient to prevent substantial volatilization of the late approximated the sum of that released from the particles Volatile component. alone plus that released from the neat control. These data Suggest that methyl salicylate release is simply additive when Example 6 both encapsulated and free methyl salicylate are dispersed in tobacco. 0102. In order to achieve higher actual content, to reduce 0097. It was a further object of the research completed to to a minimum the flavor Volatilization, and to achieve Smaller date to further modify the aforementioned flavored particle more desirable particles with a narrower size range without production methods in order to optimize the liposphere par the need for grinding, the above reported method was further ticle size, to possibly ~100 um or smaller, and to increase the modified. drug content up to 10-20%. These two characteristics were 0103) In the modified method, the cooling process has determined to be of fundamental significance after the in vitro been accelerated in order to decrease the loss of the volatile assay of the previously produced batches. Large particles flavor during this phase. Practically, after the internal phase US 2009/030 1504 A1 Dec. 10, 2009

injection the emulsion was held at 65° C. for 5 min and was then transferred to an ice bath always under stirring. The other TABLE 4-continued steps were unchanged. The scheme of FIG. 16a provides a diagram of the procedure. The results obtained are reported in Preparations made with the method of Example 6 Table 4. Encapsu 0104 Batch9 differs from Batches 6, 7 and 8 only in the lation Actual processing (Example 6 instead of Example 5). The rapid Batch Internal Methyl Recovery Efficiency Content cooling in ice bath Substantially increases the encapsulation i Phase Salicylate (%) (%) (%) efficiency up to ~60%, leading to an actual content close to 11a Cetyl Alcohol 1.5 g (75%) 83.4 34.4 15.1 15%. Assays were made to enhance the active content even (2 g) though 15% can be considered suitable. By increasing the 11b Cetyl Alcohol 1.5 g (75%) 79.7 38.4 16.8 target loading, it was possible to achieve an actual loading of (2 g) -23% (batch 10 in Table 4). 0105 Batches 9, 10, and 11 were performed in a replicate 0106. In vitro release of the Batch 9b was performed in of 3 and the results are shown in Table 4. The three formula triplicate. In order to respect the infinite sink conditions, the tions gave mean methyl salicylate contents of 10.8, 15.0 and miscibility of methyl salicylate with artificial saliva and 18.2%, respectively. The method yield was about 80% for deionized water at 37° C. were assessed. The miscibility almost all the preparations (Table 4). Particles from Batches resulted to be 0.77 and 0.79 mg/mL, respectively. 6-10 did not give any oily sensation in the mouth or in the 0107 The following in vitro release method was used. A hands. weighed amount of particles was placed in a 20 mL Scintil

TABLE 3 Preparations made with the method of Example 5 Batch Internal Methyl External Phase Stirring Encapsulation Actual Active i Phase Salicylate 400 mL. (rpm) Recovery Efficiency Content Notes 1 Cetyl Alcohol Water 500 No particle (2 g) formation 2 Cetyl Alcohol Water 1OOO Particles (2 g) 3 Cetyl Alcohol Water 12508 Coagulate (2 g) 4 Cetyl Alcohol Water -- 0.35% 500 87% (1.87 g) Particles (2 g) PVA 5 Cetyl Alcohol Water -- 0.35%. 1 OOO 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.

lation vial filled with 10 mL of artificial saliva and stirred with TABLE 4 a magnetic bar. At predetermined time points, 1 mL of media was carefully withdrawn using a 1 mL Syringe provided with Preparations made with the method of Example 6 a 0.2 um filter. The fresh media was added through the same Encapsu filter in order to recoverall the particles previously stopped on lation Actual the filter. The filter was validated before utilization. Release Batch Internal Methyl Recovery Efficiency Content i Phase Salicylate (%) (%) (%) was performed at 37° C. at a stirring rate of 150 rpm. 0108. The artificial saliva was composed of the following: 9 Cetyl Alcohol 0.6 g (30%) 97.2 61.7 14.2 (2 g) Sodium chloride, 0.844 g; potassium chloride, 1.200 g. cal 9a Cetyl Alcohol 0.6 g (30%) 846 40.9 9.45 cium chloride dihydrate, 0.193 g; magnesium chloride (2 g) hexahydrate, 0.111 g; potassium phosphate dibasic, 0.342 g; 9b Cetyl Alcohol 0.6 g (30%) 85.5 37.4 8.60 and water to make to 1000 ml. The pH was adjusted with (2 g) hydrochloric acid solution to pH 5.7+0.1. 10 Cetyl Alcohol 1.0 g (50%) 6S.O 39.8 13.2 (2 g) 0109 An example of the release profile of the particles of 10a Cetyl Alcohol 1.0 g (50%) 80.2 53.1 17.7 Batch 9b is given in FIG. 18. The in vitro release study was (2 g) performed in triplicate. The 3 release profiles are practically 1Ob Cetyl Alcohol 1.0 g (50%) 81.7 42.6 14.2 (2 g) overlaying one another, proving a good reproducibility of the 11 Cetyl Alcohol 1.5 g (75%) 89.8 51.9 22.8 employed method and an homogeneity of the particles in the (2 g) Batch. Only about 50% of the initial content was found in the release media. This may be explained by hypothesizing some US 2009/030 1504 A1 Dec. 10, 2009 methyl salicylate loss during the sampling process that could 0115 FIG. 19 shows the release profiles (performed in be avoided using more appropriate headspace sampling tech duplicate) of the 5 Batches reported in Table 5 that were niques (i.e., static or dynamic headspace sampling). obtained using the release method previously described. 0110. After a positive panel evaluation of the 3 Batches (9. 0116. The release profiles demonstrate a low intra- and 10, and 11) (Table 4), Batch 10 was chosen as the best for inter-batch variation, again confirming the good method mulation mainly on the basis of the intermediate flavor con reproducibility. As previously observed, the appearance of tent. Moreover, the formulation of Batch 9 looked to be not the flavor in the release media was limited to the 40-50% of very reproducible and the content was still too low, while the the total amount employed for the study (FIG. 19). In order to formulation of Batch 11 showed some stability issue during confirm the loss of the volatile matter, mass balance studies storage at room temperature. Methyl salicilate was found to were performed. Together with the 2 samples employed in the be localized on the surface of the particles, rendering a “wet release study, 2 extra samples for each batch were placed in appearance at the glass vial wall. The high flavor content may the same conditions and kept closed. Only one sampling was explain this behavior. done at the 60 minute time point. Then the samples (micro particles and release media, 10 mL) were mixed with 30 mL 0111 Cethyl alcohol crystals should be less ordered in the of methanol to dissolve all the methyl salicylate (flavor left in particles with respect to the raw material because of the the particles and present in the release media) and assayed at addition of methyl salicylate behaving as an impurity in the the HPLC. Results of this study are reported in Table 6. The crystal lattice. The storage allows crystals to reorganize bet samples in a closed container released always higher amounts ter, provoking a squeezing effect on the encapsulated flavor. offlavors at 60 minutes (about 70%) (Tab. 6). The amount lost The partial localization of the flavor on particle surface, due to was estimated to be lower for the samples assayed only once, the high active content, should be accounted for, as well. The never higher than ~20%, while the other samples showed a same behavior was not observed for formulations of Batches loss always around 30-40% of the initial amount. This con 9 and 10. firms the previous hypothesis. Example 7 TABLE 6 0112 The first attempt to scale up was to a batch size of 15 Results of the mass balance study. g. 10 g of cetyl alcohol and 5 g of methyl salicylate were Amount melted (65° C) and injected into 2 L of deionized water, Amount Amount left in the Amount containing 0.35% of poly (vinyl alcohol), heated at 65° C. Sample released after recovered microparticles lost under agitation with mechanical stirring (500 rpm).5 minutes l8le Sample 60 minutes (%) (%) (%) (%) after injection the heating was discontinued and the disper SB10(1) a S2.9 56.0 3.1 44 b* 52.4 49.6 SO4 sion was cooled using an ice bath. Particles were recovered by c* * 71.4 86.7 15.3 13.3 filtration, washed with 6L of deionized water and dried under ** 72.2 79.8 7.6 2O2 SB10(2) a 39.2 61.4 22.2 38.6 vacuum overnight (15 mm Hg). Characteristics of the b* 39.1 59.7 20.6 40.3 obtained particles are reported in Table 5. c* * 69.0 91.5 22.5 8.5 0113 Particles showed a mean flavor content of 13.8+1. ** 60.6 82.5 21.9 17.5 1% and an encapsulation efficiency of 41.6+3.2%; while the SB10(3) a 45.7 60.7 15 39.3 b* 45.7 60.1 14.4 39.9 preparation method had a yield of 86.9-2.8%. The high c* * 72.4 86.O 13.6 14 reproducibility of the method is proven by the low standard ** 71.7 92.6 20.9 7.4 deviations obtained for both the encapsulation efficiency and SB10(4) a 49.1 69.9 20.8 30.1 the product yield (Table 5). b* 46.1 66.3 2O2 33.7 c* * 70.4 91.3 20.9 8.7 0114 For the 5 preparations, 90% of the particles were ** 70.2 91.4 21.2 8.6 smaller than 90 um and 50% were in the 40-48 um range. SB10(5) a 44.2 S4.O 9.8 46 Similar particle size is another indication of good method b* 44.9 56.0 11.1 44 reproducibility.

TABLE 5 Characteristics of the particles obtained with the scaled up method. Methyl salicylate Encapsulation Batch content efficiency Method yield Particle size l8le (%) (%) (%) D(v, 0.1) D(v, 0.5) D(v, 0.9) 10(1) 13.7 41.O 83.0 (12.452 g) 13.4 m 44.5 m 85.7 m 10(2) 15.7 47.0 87.7 (13.158 g) 14.9 m 47.9 m 87.2 m 10(3) 13.0 39.0 86.8 (13.026 g) 12.6 m 40.7 m 83.5 m 10(4) 13.1 39.4 86.2 (12.925 g) 17.5 m 48.0 m 86.6 m 10(5) 13.8 41.4 90.7 (13.607 g) 18.4 m 47.7 m 86.2 m *Target load 33.33%; Batch size 15 grams. D(v, 0.1), D(v, 0.5), D(v, 0.9) represent 10, 50,90% of particles smaller than that size. US 2009/030 1504 A1 Dec. 10, 2009 10

polyethylene glycol, alginic acid, a phospholipid, lecithin, TABLE 6-continued cholic acid, desoxycholic acid, diacetyl tartaric acid esters of mono- and diglycerides, glycocholic acid, mono- and diglyc Results of the mass balance study. erides and their monosodium phosphate derivatives, propy Amount lene glycol, ox bile extract, taurocholic acid, gum arabic, Amount Amount left in the Amount agar-agar, ammonium alginate, calcium alginate, carobbean Sample released after recovered microparticles lost gum, chondrus extract, ghattigum, guar gum, potassium algi l8le Sample 60 minutes (%) (%) (%) (%) nate, sodium alginate, Sterculia gum, tragacanth, hydroxypro c:* * 68.0 79.6 11.6 20.4 pylmethylcellulose, any other water soluble derivatives of * * 67.1 81.0 13.9 19 cellulose, and mixtures thereof.\ *Samples employed in the release study We claim: **Samples assessed for the release only at 60 minutes 1. A method of producing edible flavored particulate solid dispersions, comprising the steps of 0117 Since the particles will have to release their content melting an edible matrix material and homogenously in the mouth, a "non-closed system, the release conditions incorporating therein one or more edible flavoring used for the release (FIG. 6) should mimic more closely the agentS, real life situation (flavor dissolved in the saliva as well as cooling the flavored melted matrix material to achieve a flavor volatilized reaching the olfactory neuroepithelium). Solid dispersion having a flavor within an edible matrix, Due to the fact that flavor perception is generally described as and a combination of taste and smell, the overall yield of a flavor grinding the solid dispersion into particles and sieving the is very difficult to predict even if appropriate headspace Sam resulting particles to achieve edible flavored particulate pling techniques (i.e., static or dynamic headspace sampling) Solid dispersions of a desired size. are used. In fact, the most straightforward approach is through 2. A method of producing edible flavored particulate solid evaluation by an olfactive panel. Panel evaluations can be dispersions, comprising the steps of carried out directly with the desired consumer product and do melting an edible matrix material and homogenously not require complex analytical methods. If a Sufficient num incorporating therein one or more edible flavoring ber of panelists is used, the statistical significance of the agentS, experiment can be determined. cooling the flavored melted matrix material to achieve a 0118. An example of particle morphology is given in FIG. solid dispersion having a flavor within an edible matrix, 20, which reports optical microscopy pictures of the particles and of Batch SB10(5) (Table 5). Optical microscopy show a simi cutting or pressing one or more punches from the Solid lar morphology for the particles of the five scaled Batches. dispersion to achieve edible flavored particulate solid Pictures show a capsule-like morphology that is likely dispersions in the form of punches of a desired size. obtained when oil is encapsulated. 3. A method of producing edible flavored particulate solid 0119) An evaluation of the five of methyl salicylate cetyl dispersions, comprising the steps of alcohol microparticles of the scaled up Batches was con melting an edible matrix material and homogeneously ducted by a panel of tobacco industry experts and was com incorporating therein one or more flavoring agents, pletely positive from the point of view of flavor content and mixing with high shear the flavored melted matrix material yield when mixed with snuff. The particle size was consid with an aqueous solution to create an agitated aqueous ered optimal to avoid an oily taste in the mouth as well an oily dispersion, and sensation in the hands. cooling the agitated aqueous dispersion to a temperature 0120. Among the edible matrix materials that would be below the melting point of the flavored matrix material Suitable for use in the present invention area wax, a fat, a fatty to produce edible flavored particulate solid dispersions alcohol, a sterol, cetyl alcohol, Stearyl alcohol, paraffin, poly having a flavor within an edible matrix that are recover ethylene glycol, a fatty acid, a polyunsaturated fatty acid, able by filtration, flotation, centrifugation or vibro-sepa rudua fatty acid ester, palmitic acid, Stearic acid, oleic acid, ration. lauric acid, myristic acid, behenic acid, a triglyceride, poly 4. The method according to claims 1, 2 or 3, wherein the ethylene glycol, cholesterol, lecithin, a phospholipids, and matrix material is selected from the group consisting of a mixtures thereof. wax, a fat, a fatty alcohol, a sterol, cetyl alcohol, Stearyl 0121 Among the flavoring agents that would be suitable alcohol, paraffin, polyethylene glycol, a fatty acid, a polyun for use in the present invention are a volatile oil, an essential saturated fatty acid, rudua fatty acid ester, palmitic acid, oil, a botanical extract, methyl salicylate, ethyl salicylate, Stearic acid, oleic acid, lauric acid, myristic acid, behenic cinnamic acid, cinnamon oil, peppermint oil, spearmint oil, acid, a triglyceride, polyethylene glycol, cholesterol, lecithin, wintergreen oil, acetaldehyde, acetoin, aconitic acid, aneth a phospholipid, and mixtures thereof. ole, benzaldehyde, N-butyric acid, d- or 1-carvone, cinnama 5. The method according to claims 1, 2 or 3, wherein the ldehyde, citral, decanal, diacetyl, ethyl acetate, ethyl flavoring agent is selected from the group consisting of a butyrate, ethyl Vanillin, eugenol, geraniol, geranyl acetate, Volatile oil, an essential oil, a botanical extract, methyl sali glycerol tributyrate, limonene, linalool, linallyl acetate, cylate, ethyl salicylate, cinnamic acid, cinnamon oil, pepper 1-malic acid, methyl anthranilate, 3-methyl-3 phenylglycidic mint oil, spearmint oil, wintergreen oil, acetaldehyde, acid ethyl ester, piperonal, Vanillin, citrus flavoring, berry acetoin, aconitic acid, anethole, benzaldehyde, N-butyric flavoring, and mixtures thereof. acid, d- or 1-carvone, cinnamaldehyde, citral, decanal, 0122) Among the suitable surfactants that would be suit diacetyl, ethyl acetate, ethylbutyrate, ethylvanillin, eugenol, able for use in the present invention are an alcohol, a fatty geraniol, geranyl acetate, glycerol tributyrate, limonene, lina alcohol, a fatty acid, a fatty acid ester, polyvinyl alcohol, lool, linallyl acetate, 1-malic acid, methyl anthranilate, 3-me US 2009/030 1504 A1 Dec. 10, 2009 thyl-3-phenyl glycidic acid ethyl ester, piperonal, Vanillin, paddles, propellers, impellers, or gas agitation using air, citrus flavoring, berry flavoring, and mixtures thereof nitrogen, argon, helium, or another Suitable gases, or by com binations thereof. 6. The method according to claim 1, wherein the grinding 10. The method according to claims 1, 2 or 3, wherein the step includes grinding in a blender, or oscillator, or mill, or flavored particulate solid dispersions have a particle or punch grinder, without freezing the flavored solid dispersion. size in the range of about 10 nm to about 300 microns in 7. The method according to claim 3, wherein the aqueous diameter. Solution contains a surfactant selected from the group con 11. The method of claim 10, wherein the flavored particular sisting of an alcohol, a fatty alcohol, a fatty acid, a fatty acid solid dispersions contain from about 1 to about 80% weight in ester, polyvinyl alcohol, polyethylene glycol, alginic acid, a weight flavoring agents within the edible matrix. phospholipid, lecithin, cholic acid, desoxycholic acid, 12. The method according to claims 1, 2 or 3, and further diacetyl tartaric acid esters of mono- and diglycerides, gly comprising the step of adding one or more colorants to the cocholic acid, mono- and diglycerides and their monosodium flavored particulate Solid dispersions prior to formation, dur phosphate derivatives, propylene glycol, Ox bile extract, tau ing formation, or after formation to impart thereto a desired rocholic acid, gum arabic, agar-agar, ammonium alginate, coloration. calcium alginate, carob bean gum, chondrus extract, ghatti 13. The method according to claims 1, 2 or 3 and further gum, guar gum, potassium alginate, sodium alginate, Stercu comprising the step of dispersing the flavored particulate lia gum, tragacanth, hydroxypropylmethylcellulose, any Solid dispersions withina consumer product selected from the group consisting of tobacco, moist Snuff, dry Snuff, individu other water soluble derivatives of cellulose, and mixtures ally wrapped Snuff pouches, Snuff pouch paper, edible films, thereof. coffee, tea, chewing gum, confections, candy, or other food 8. The method according to claim 7, wherein the concen products. tration of the surfactant ranges from about 0.1 percent to 14. A flavored particulate solid dispersion produced by the about 30% weight to volume. method of claims 1, 2 or 3. 9. The method according to claim 3, wherein the mixing with high shear is accomplished by stirring, blending, c c c c c