WO2001045519A1

WO2001045519A1 - Enhanced ingestible products

Info

Publication number: WO2001045519A1
Application number: PCT/US2000/035517
Authority: WO
Inventors: Alfonso Ganan-Calvo; Reid M. Rubsamen
Original assignee: Universidad De Sevilla; Flow Focusing, Inc.
Priority date: 1999-12-21
Filing date: 2000-12-20
Publication date: 2001-06-28
Also published as: AU2605601A

Abstract

The invention is directed to production of particles for introduction into food using a stable microjet and a monodisperse aerosol formed when the microjet dissociates. A variety of devices and methods are disclosed which allow for the formation of a stream of a first fluid (e.g. a liquid) characterized by forming a stable capillary microjet over a portion of the stream wherein the microjet portion of the stream is formed by a second fluid (e.g. a gas).

Description

ENHANCED INGESTIBLE PRODUCTS

FIELD OF THE INVENTION The mvention relates generally to the field of small particle formation and more specifically to improvement of foods and other ingested items including pharmaceutical drugs by the introduction and/or encapsulation of particles which are very small and uniform m size

BACKGROUND OF THE INVENTION Advances in food technology are improving the foods that are available to consumers and promoting good health both through basic nutation and through enhanced benefits of food products Foods are bemg improved through the reduction or removal of certain components in a food, increasing the amount of certain components normally found m the food, or addmg components to a food which are not normally found in the food Products in which the amount of a component or ingredient naturally or normally present is increased or reduced include breakfast cereals with added bran or dairy products with reduced fat Products with components or ingredients not normally present to any sigmficant extent include fruit juice with added fiber, bread with added fohc acid, and margarine spreads containing fish oils or olive oil

Foods with components not normally present in those foods has become mcreasmgly popular with the mtroduction of "functional foods" A functional food is any non-toxic food or food mgredient that has been altered to provide medical or health benefits, mcludmg the prevention and treatment of disease Functional foods are similar m appearance to conventional foods that are consumed as part of a "normal' diet, but have additives that demonstrate physiological benefits beyond their nutritive content These products include genetically engineered "designer" foods, herbal products, and processed products, such as cereals, soups and beverages Functional food product development reflects a major shift m attitude and an application of current knowledge about diet and health from 'removing the bad¹ (for example, fat, cholesterol and salt) to 'addmg or enhancing the good' (such as calcium, fiber, antioxidants and botanicals) This has, m turn, paralleled consumer interest in healthy eating Hollingsworth, P , Food Technol , 1997, 51, 55-8, Giese, J , & Katz, F , Food Technol , 1997, 51, 58-61 Consumers and their demand for an improved quality of life are bringing worldwide growth to the functional food industry

Currently, a number of functional foods are bemg offered to consumers, mcludmg fortified breads, cereals, juices, and the like For example, juice containing the patented calcium source FruitCal™ (calcium citrate malate), U S Pat No 4,722,8470, which is more readily absorbable m juice (>35%) than calcium from milk or calcium carbonate supplements, is widely marketed These fortified juices provide protection against osteoporosis and promote healthy teeth and bones Certain functional foods are also bemg introduced to prevent, treat or ameliorate physiological conditions such as cardiovascular disease, hypercholesterolemia, and even menopause For example, breakfast cereals with the compound PHYTROL™ added are marketed as foods to control cholesterol

The opportunity for future growth and development of new functional foods worldwide is tremendous Overwhelming evidence supports the link between diet and optimal health, particularly the prevention of degenerative diseases of aging such as cancer, heart disease, osteoporosis, diabetes, arthritis and stroke Given the extended life expectancy for those m developed nations and the commensurate increase in healthcare costs associated with treatmg chrome agemg diseases, there will be more of an emphasis in the future on a preventative rather than a prophylactic approach to healthcare Diet will play a cπtical role m this new paradigm There is thus a new demand for new methods of improving foods by addmg components to these foods to improve nutπent content, reduce the amount or percentage of unwanted components (e g , fats) or provide functional components that increase the physiological response beyond that of conventional food products

SUMMARY OF THE INVENTION The mvention is directed to production of particles for mtroduction mto food using a stable microjet and a monodisperse aerosol of liquid particles formed when the microjet dissociates A variety of devices and methods are disclosed which allow for the formation of a stream of a first fluid (e g a liquid) characteπzed by foπmng a stable capillary microjet over a portion of the stream wherem the microjet portion of the stream is formed by a second fluid (e g a gas) The second fluid is preferably m a different state from the first fluid - - liquid-gas or gas-liquid combinations However, the first and second fluids may be two different fluids immiscible m each other

In preferred embodiments the first fluid is a liquid which forms a food or food additive and the second fluid is a gas which is non-toxic, e g air or nitrogen In a particularly preferred embodiment the first fluid compπsed of material which it would be desirable to have in but which can not be added to food for some reason, e g bad taste or reacts with the food The first fluid is surrounded by a second fluid which is also a liquid, but which can coat and encapsulate the first fluid A third fluid surrounds the second fluid and the third fluid is preferably a gas which focuses the liquid stream to a microjet The jet will break up into particles where the first fluid (liquid food) is coated with the second fluid (liquid carrier coating) The coatmg provided by the second fluid keeps the bad taste or reactive effects of the first fluid from having its undesirable effects

Many preferred embodiments provide a spheric food particle coated with a layer of another mateπal which is non-toxic (e g a polymer which is degraded m the G I ) and may or may not be a food product The coatmg material may be a polymer which is maintained in a flowable liquid form until it coats the internal food particle after which the polymer coating is "cured," polymerized or made non-flowable m some manner, e g by exposure to certain light energy, cuπng agent or a decreased temperature

Although many specific embodiments descnbed here relate specifically to foods those embodiments are applicable to drugs and nutπceuticals and other mateπals Further, the drug embodiments descnbed are applicable to foods, nutπceuticals and other mateπals

The stable capillary microjet compnses a diameter d_} at a given point A in the stream characteπzed by the formula

wherem d_} is the diameter of the stable microjet, « indicates approximately equally to where an acceptable margin of enor is ± 10%, p, is the density of the liquid and AP_g is change m gas pressure of gas surrounding the stream at the pomt A

The microjet can have a diameter m the range of from about 1 micron to about 1 mm and a length m the range of from 1 micron to 50 mm The stable jet is maintained, at least m part, by tangential viscous stresses exerted by the gas on the surface of the jet in an axial direction of the jet The jet is further charactenzed by a slightly parabolic axial velocity profile and still further characteπzed by a Weber number (We) which is greater than 1 with the Weber number bemg defined by the formula

We X - -l≥-

1

wherem the p_g is the density of the gas, d is the diameter of the stable microjet, γ is the liquid-gas surface tension, and V_g ² is the velocity of the gas squared Although the Weber number is greater than 1 when a stable microjet is obtained the Weber number should be less than 40 to obtam a desired monodisperse aerosol Thus, desired results are obtained withm the parameters of 1 < We < 40 Monodisperse aerosols of the invention have a high degree of uniformity in particle size The particles are characterized by having the same diameter with a deviation m diameter from one particle to another in a range of about ±2% or less to about ±30%. preferably about ±3 % or less to about ± 10% and most preferably ±3 % or less The particles in an aerosol will have consistency in size but may be produced to have a size m a range of about 0 1 micron to about 100 microns An object of the invention is to provide a stream of a first fluid (e g a liquid) which stream is characteπzed by foπmng a stable capillary microjet over a portion of the stream wherem this stable capillary microjet portion of the stream is formed by a second fluid (e g a gas) moving at a velocity greater than that of the first fluid Another object of the invention is to provide a monodisperse aerosol of liquid particles in air wherem the particles are charactenzed by havmg the same diameter with a deviation in diameter from one particle to another in a range of from about ±3% to about ±30% wherem the particles are produced as a result of a break up of the stable capillary microjet These particles may be dessicated following dispersion, and then added to food, or may be added to the foods m liquid form An advantage of the invention is that the microjet of liquid flows through an opening surrounded by a focusing funnel of gas so that liquid does not touch the penpheral area of the opening and therefor does not deposit on the opening and cause cloggmg

Another advantage of the invention is that the particles formed are highly uniform m size and are created with a relatively small amount of energy A feature of the invention is that vaπous parameters mcludmg the viscosities and velocities of the fluids can be chosen with consideration to other adjusted parameters to obtain a supercntical flow of liquid which results m the formation of the stable microjet

Another feature of the invention is the production of micronutπents, which are nutπents produced m a precise size range to mcrease the absorption and release of these nutrients m the bloodstream

Another feature of the invention is the ability to coat particles or form hollow spheres, thus maintaining the surface area of a substance while decreasmg the overall amount of the substance (e g , a fiber particle coated with oil or a hollow sphere composed on an antimicrobial) This can also allow introduction of components that are generally incompatible with a food, such as introduction of lactase in milk, by coatmg the component

Yet another feature of the invention is the use production of time-release components that will allow controlled delivery of the contents of the particle, e g , carbohydrates particles coated to allow a systematic release over a twelve hour period

These and other aspects, objects, features and advantages will become apparent to those skilled m the art upon reading this disclosure m combmation with the figures provided

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic view showing the basic components of one embodiment of the mvention with a cylindncal feeding needle as a source of formulation Figure 2 is a schematic view of another embodiment of the mvention with two concentπc tubes as a source of formulation.

Figure 3 is a schematic view of yet another embodiment showing a wedge-shaped planar source of formulation. Figure 3a illustrates a cross-sectional side view of the planar feeding source and the interaction of the fluids. Figure 3b show a frontal view of the openings in the pressure chamber, with the multiple openings through which the atomizate exits the device. Figure 3c illustrates the channels that are optionally formed within the planar feeding member. The channels are aligned with the openings in the pressure chamber.

Figure 4 is a schematic view of a stable capillary microjet being formed and flowing through an exit opening to thereafter form a monodisperse aerosol. Figure 5 is a graph of data where 350 measured values of djd₀ versus QIQ₀ are plotted.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before the present aerosol device and method are described, it is to be understood that this invention is not limited to the particular components and steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a particle" includes a plurality of particles and reference to "a fluid " includes reference to a mixture of fluids, and equivalents thereof known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the prefened methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. DEFINITIONS

The terms "particles", "atomized particles" and "atomized particles of formulation" are used mterchangeably herem and shall mean particles of fluid formulations (preferably liquid food) that have been atomized usmg the device and method of the mvention The particles are generally spheπcal, and may be solid, coated, or hollow spheres

The term "formulation" as used herem refers to any matter which is desired to be atomized A formulation may contain a smgle component to be added to the food, or may contain multiple components The term is also intended to encompass excipients, caπers, and the like, mcludmg compounds to which components are conjugated, as are descnbed in the following sections The terms "air", "particle free air" and the like, are used mterchangeably herem to descπbe a volume of air which is substantially free of other matenal and, m particular, free of particles intentionally added such as particles of formulation The term means that the air does not mclude particles of formulation which have been intentionally added but is not intended to imply that the normal sunoundmg air has been filtered or treated to remove all particles although filtering can take place Air is the preferred gas to use with drug delivery it bemg noted that other gas, e g , C0₂ can be used

The term "food" as used herem means (1) articles used for food (consumed by mouth for nutation) or drink for man or other animals, (2) chewmg gum, and (3) articles used for components of any other such food article Food mcludes articles used by people in the ordinary way most people use food, l e for taste, aroma and/or nutπtive value The term "food" as used herem also is intended to cover food additives (e g condiments) and specialized foods such as infant formula

The term "food additive" as used herem means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, m its becoming a component or otherwise affecting the charactenstics of any food, mcludmg any substance intended for use m producing, manufacturing, packmg, processing, preparmg, treatmg, packaging, transporting, or holding food The term as used herem does not mclude a pesticide chemical or a drug regulated by the Food and Drug Admimstration (as either a prescπption or over the counter (OTC) drug) that has been added to the food Examples of food additives mclude components which, by themselves are not additives such as vitamins, mmerals, color additives, herbal additives (e g , echinacea or St John's Wort), antimicrobials, preservatives, and the like which when added to food are additives

The term "color additive" as used herem includes a dye, pigment, or other substance that when added or applied to a food is capable of imparting color thereto

The term "infant formula" as used herem refers to a food which purports to be or is represented for special dietary use solely as a food for infants by reason of its simulation of human milk or its suitability as a complete or partial substitute for human milk The term "improved food" as used herein refers to a food product that is improved over a conventional food product by virtue of the addition of more of a component already present m the conventional counterpart, by reduction of a component present in the conventional counterpart, or by the addition of a component not usually found in the conventional counterpart As used the term encompasses "functional foods", but also mcludes food such as breads with added carbohydrates. cereals with added vitamin and/or mmerals, and foods in which undesirable components are reduced by the addition of other, more desirable components, e g , the replacement of fat with a fat substitute The term "functional food" as used herein refers to designed food with functional additives that effectively combme ingredients not usually found together in a single food source Functional foods have the appearance and structure of conventional foods, but contain sigmficant levels of biologically active components that impart health benefits or desirable physiological effects beyond basic nutation An example of a functional food is a food that is not normally high m fiber or protem to which either fiber or protein are added Another example of a functional food is an infant formula with additives, such as echmacea extract, to boost immunological resistance Yet another example of a functional food is a dairy product with a food additive, such as lactase, to combat lactose mtolerance Yet another example of a functional food is a sports drinks m which the carbohydrates are slowly released m the body so that they supply energy over a prolonged penod

The term "component" as used herem refers to any additive to a food that imparts a positive benefit to a person ingesting the food The term "functional component" as used herein refers to any additive to a functional food that imparts the health benefits and desirable physiological effects of the functional food Examples of such functional components can be seen m Table 1

TABLE 1 EXAMPLES OF FUNCTIONAL COMPONENTS COMPONENT SOURCE POTENTIAL BENEFIT

CAROTENOIDS

PLANT STEROLS

PREBIOTICS/PROBIOTICS

SAPONINS

SOY PROTEINS PHYTOESTROGENS

SULFIDES THIOLS

TANNINS

The term "nutπceutical" as used herem refers to products produced from foods and/or natural sources (e g , herbal extracts) that are sold in medicinal forms such as pills, powders and potions Nutπceuticals impart health benefits or desirable physiological effects that are not generalh associated with food

The terms "vitamins", ' mmerals", "vitamin and mmerals" and the like as used herem generally refer to nutπtive food additives that may be found in or added to a food product As used herem, "vitamin supplements" and "mineral supplements" are considered to be dietary supplements, and as they are separate products they do not fall under the defimtion of "food" per se, but rather are considered to be nutnceuticals for purposes of the present application

The term "drug" as used herein means (1) articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the Umted States, or official National Formulai . or the Physician's Desk Reference (PDR) any supplement to any of them, and (2) articles intended for use m the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, and (3) articles (other than food) mtended to affect the structure or any function of the body of man or other animals, and (4) articles intended for use as a component of any articles specified m (l), (2) or (3)

DEVICE IN GENERAL Different embodiments of the device used to produce particles for addition to food are shown and descnbed herem (see Figures 1, 2 and 3) which could be used in producing the stable capillary microjet and/or a dispersion of particles which are substantially uniform m size Although vanous embodiments are part of the mvention, they are merely provided as exemplary devices which can be used to convey the essence of the invention, which is the formation of a stable capillary microjet and/or uniform dispersion of particles

The basic device for use with the mvention compnses (1) a means for supplymg a first fluid and (2) a pressure chamber supplied with a second fluid which flows out of an exit openmg m the pressure chamber The exit openmg of the pressure chamber is down stream of and preferably aligned with the flow path of the means for supplymg the first flmd The embodiments of Figures 1, 2 and 3 clearly show that there can be a vanety of different means for supplymg the first fluid Other means for supplymg a first fluid flow stream will occur to those skilled m the art upon readmg this disclosure Further, other configurations for forming the pressure chamber around the means for supplymg the first fluid will occur to those skilled m the art upon readmg this disclosure Such other embodiments are mtended to be encompassed by the present invention provided the basic conceptual results disclosed here are obtained, I e a stable microjet is formed and/or a dispersion of particle highly uniform m size is formed To simplify the descnption of the invention, the means for supplymg a first fluid is often referred to as a cylmdπcal tube (see the tube 1 of Figure 1) and the first fluid is generally a liquid, e g liquid food The fluid can be any liquid or gas dependmg on the overall device which the mvention is used within For example, the liquid could be a liquid formulation of a food which is high m nutational value but has an unpleasant taste and as such needs to be coated with a polymer or other mateπal with no taste Further, for purposes of simplicity, the second fluid is generally described herem as being a gas and that gas is often preferably air or a non-toxic gas such as nitrogen However, the first fluid may be a gas and second fluid a liquid or both fluids may be liquid provided the first and second fluid are sufficiently different from each other (immiscible) so as to allow for the formation of a stable microjet of the first fluid moving from the supply means to a downstream exit port of the pressure chamber Notwithstanding these different combmations of gas-liquid, hquid- gas, and liquid-liquid, the mvention is generally descnbed with a liquid formulation being expelled from the supply means and forming a stable microjet due to interaction with surrounding air flow focusmg the microjet to flow out of an exit of the pressure chamber

Formation of the microjet and its acceleration and ultimate particle formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the liquid on passing through an exit oπfice of the pressure chamber which holds the second fluid (1 e the gas) On leavmg the chamber the flow undergoes a large pressure difference between the liquid and the gas. which m turn produces a highly curved zone on the liquid surface near the exit port of the pressure chamber and in the formation of a cuspidal point from which a steady microjet flows, provided the amount of the liquid withdrawn through the exit port of the pressure chamber is replenished Thus, m the same way that a glass lens or a lens of the eye focuses light to a given point, the flow of the gas sunounds and focuses the liquid mto a stable microjet The focusmg effect of the sunoundmg flow of gas creates a stream of liquid which is substantially smaller in diameter than the diameter of the exit onfice of either the liquid pressure supply tube or the pressure chamber This allows liquid to flow out of the pressure chamber oπfice without touching the oπfice, providmg advantages mcludmg (1) cloggmg of the exit onfice is virtually eliminated, (2) contamination of flow due to contact with substances (e g bactena or particulate residue) on the oπfice openmg is virtually eliminated, and (3) the diameter of the stream and the resulting particles are smaller than the diameter of the exit oπfice of the chamber This is particularly desirable because it is difficult to precisely engmeer holes or tubes for extrusion which are very small m diameter Further, m the absence of the focusmg effect (and formation a stable microjet) flow of liquid out of an opening will result m particles which have about twice the diameter of the exit openmg An additional advantage is that the particles are not prone to agglomeration following exit from the chamber

The descnption provided here generally indicates that the fluid leaves the pressure chamber through an exit onfice sunounded by the gas and thereafter enters mto a gaseous surroundmg environment which may be air held at normal atmosphenc pressure However, when the first fluid is a gas and the second fluid is a liquid the fluid present outside of the chamber may also be a liquid This configuration is particularly useful when it is necessary to create very small highly uniform bubbles which are moved mto a liquid sunoundmg exit opening of the pressure chamber The need for the formation of very small highly uniform bubbles mto a gas occurs m a variety of different industrial applications For example, a small air bubble can be uniformly placed in a food product such as a yellow fat (e g butter, margarine, mayonnaise or ice cream By making the air bubbles very small (e g 1-10 microns m diameter) the bubbles are not readily detectable by a person eating the food Further, less product is used and less calories are consumed per volume of the product Those skilled in the art will recognize that variations on the different embodiments disclosed below will be useful in obtaining particularly prefened results Specific embodiments of devices are now descnbed

EMBODIMENT OF FIGURE 1

A first embodiment of the mvention where the supply means is a cylmdncal feedmg needle supplymg liquid mto a pressurized chamber of gas is descnbed below with reference to Figure 1 The components of the embodiment of Figure 1 are as follows 1 Feedmg needle - also referred to generally as a fluid source and a tube 2 End of the feedmg needle used to insert the liquid to be atomized

3 Pressure chamber

4 Oπfice used as gas inlet

5 End of the feedmg needle used to evacuate the liquid to be atomized

6 Oπfice through which withdrawal takes place 7 Atomizate (spray) - also refened to as aerosol

D₀ = diameter of the feedmg needle, d₀ = diameter of the oπfice through which the microjet is passed, e = axial length of the oπfice through which withdrawal takes place, H = distance from the feedmg needle to the microjet outlet, P₀ = pressure mside the chamber, _; = atmosphenc pressure

Although the device can be configured in a vanety of designs, the different designs will all include the essential components shown m Figure 1 or components which perform an equivalent function and obtain the desired results Specifically, a device of the mvention will be compπsed of at least one source of a first flmd (e g , a feedmg needle with an openmg 2) mto which a first fluid such as liquid flowable formulation can be fed and an exit openmg 5 from which the formulation can be expelled The feedmg needle 1, or at least its exit openmg 5, is encompassed by a pressure chamber 3 The chamber 3 has inlet opening 4 which is used to feed a second fluid (e g a gas) mto the chamber 3 and an exit opening 6 through which gas from the pressure chamber and liquid formulation from the feedmg needle 3 are expelled When the first fluid is a liquid it is expelled mto gas to create an aerosol When the first flmd is a gas it is expelled mto a liquid to create bubbles

In Figure 1 the feeding needle and pressure chamber are configured to obtain a desired result of producmg an aerosol wherein the particles are small and uniform in size or bubbles which are small and uniform m size The particles or bubbles have a size which is m a range of 0 1 to 100 microns The particles of any given aerosol or bubbles will all have about the same diameter with a relative standard deviation of ±10% to ±30% or more preferably ±3% to ±10% Stating that particles of the aerosol have a particle diameter in a range of 1 to 5 microns does not mean that different particles will have different diameters and that some will have a diameter of 1 micron while others of 5 microns The particles m a given aerosol will all (preferably about 90% or more) have the same diameter ±3% to ±30% For example, the particles of a given aerosol will have a diameter of 2 microns ±3% to ±10% Such a monodisperse aerosol is created using the components and configuration as descnbed above However, other components and configurations will occur to those skilled m the art The object of each design will be to supply flmd so that it creates a stable capillary microjet which is accelerated and stabilized by tangential viscous stress exerted by the second fluid on the first fluid surface The stable microjet created by the second fluid leaves the pressunzed area (e g , leaves the pressure chamber and exits the pressure chamber onfice) and splits mto particles or bubbles which have the desired size and uniformity

The parameter window used (i e the set of special values for the liquid properties, flow-rate used, feedmg needle diameter, oπfice diameter, pressure ratio, etc ) should be large enough to be compatible with virtually am liquid (dynamic viscosities in the range from 10⁴ to 1 kg m ^!s ^λ). in this way, the capillary microjet that emerges from the end of the feedmg needle is absolutely stable and perturbations produced by breakage of the jet cannot travel upstream Downstream, the microjet splits mto evenly shaped drops simply by effect of capillary instability (see, for example, Rayleigh. "On the instability of jets", Proc London Math Soc , 4-13, 1878), similar in a manner to a laminar capillary jet falling from a half-open tap When the stationary, steady interface is created, the capillary jet that emerges from the end of the drop at the outlet of the feeding pomt is concentπcally withdrawn mto the nozzle After the jet emerges from the drop, the liquid is accelerated by tangential sweeping forces exerted by the gas stream flowing on its surface, which gradually decreases the jet cross-section Stated differently the gas flow acts as a lens and focuses and stabilizes the microjet as it moves toward and mto the exit oπfice of the pressure chamber

The forces exerted by the second fluid flow on the first fluid surface should be steady enough to prevent megular surface oscillations Therefore, any turbulence in the gas motion should be avoided, even if the gas velocity is high, the characteπstic size of the onfice should ensure that the gas motion is laminar (similar to the boundary layers formed on the jet and on the mner surface of the nozzle or hole)

STABLE MICROJET Figure 4 illustrates the interaction of a liquid and a gas to form atomizate using the method of the mvention The feedmg needle 60 has a circular exit opening 61 with an internal radius Ro which feeds a liquid 62 out of the end foπmng a drop with a radius m the range of R^ to RQ plus the thickness of the wall of the needle The exiting liquid forms an infinite amount of liquid streamlines 63 that interact with the sunoundmg gas to form a stable cusp at the interface 64 of the two fluids. The surrounding gas also forms an infinite number of gas streamlines 65, which interact with the exiting liquid to create a virtual focusing funnel 66. The exiting liquid is focused by the focusing funnel 66 resulting in a stable microjet 67, which remains stable until it exits the opening 68 of the pressure chamber 69. After exiting the pressure chamber, the microjet begins to break-up, forming monodispersed particles 70.

The gas flow, which affects the liquid withdrawal and its subsequent acceleration after the jet is formed, should be very rapid but also uniform in order to avoid perturbing the fragile capillary interface (the surface of the drop that emerges from the jet). Liquid flows out of the end of a capillary tube and forms a small liquid drop at the end. The tube has an internal radius R-. The drop has a radius in a range of from R- to R. plus the structural thickness of the tube as the drop exits the tube, and thereafter the drop nanows in circumference to a much smaller circumference as is shown in the expanded view of the tube (i.e. feeding needle) 5 as shown in Figures 1 and 4. As illustrated in Figure 4, the exit opening 61 of the capillary tube 60 is positioned close to an exit opening 68 in a planar surface of a pressure chamber 69. The exit opening 68 has a minimum diameter D and is in a planar member with a thickness L. The diameter D is refened to as a minimum diameter because the opening may have a conical configuration with the nanower end of the cone positioned closer to the source of liquid flow. Thus, the exit opening may be a funnel-shaped nozzle although other opening configurations are also possible, e.g. an hour glass configuration. Gas in the pressure chamber continuously flows out of the exit opening. The flow of the gas causes the liquid drop expelled from the tube to decrease in circumference as the liquid moves away from the end of the tube in a direction toward the exit opening of the pressure chamber.

In actual use, it can be understood that the opening shape which provokes maximum gas acceleration (and consequently the most stable cusp and microjet with a given set of parameters) is a conically shaped opening in the pressure chamber. The conical opening is positioned with its nanower end toward the source of liquid flow.

The distance between the end 61 of the tube 60 and the beginning of the exit opening 68 is H. At this point it is noted that R-, D, H and L are all preferably on the order of hundreds of microns. For example, R- = 400/im, D = 150_/_m, H = 1mm, L = 300μm. However, each could be 1/100 to lOOx these sizes.

The end of the liquid stream develops a cusp-like shape at a critical distance from the exit opening 68 in the pressure chamber 69 when the applied pressure drop ΔP_g across the exit opening 68 overcomes the liquid-gas surface tension stresses γ/R^* appearing at the point of maximum curvature — e g 1/R^* from the exit opening

A steady state is then established if the liquid flow rate Q ejected from the drop cusp is steadily supplied from the capillary tube This is the stable capillary cusp which is an essential characteπstic of the mvention needed to form the stable microjet More particularly, a steady, thin liquid jet with a typical diameter d, is smoothly emitted from the stable cusp-like drop shape and this thin liquid jet extends over a distance in the range of microns to millimeters The length of the stable microjet will vary from very short (e g 1 micron) to very long (e g 50 mm) with the length dependmg on the (1) flow-rate of the liquid and (2) the Reynolds number of the gas stream flowing out of the exit opening of the pressure chamber The liquid jet is the stable capillary microjet obtained when supercntical flow is reached This jet demonstrates a robust behavior provided that the pressure drop ΔP_g applied to the gas is sufficiently large compared to the maximum surface tension stress (on the order of γ/d,) that act at the liquid-gas interface The jet has a slightly parabolic axial velocity profile which is. m large part, responsible for the stability of the microjet The stable microjet is formed without the need for other forces, l e without addmg force such as electncal forces on a charged fluid However, for some applications it is preferable to add charge to particles, e g to cause the particles to adhere to a given surface The shapmg of liquid exiting the capillary tube by the gas flow forming a focusmg funnel creates a cusp-like meniscus resultmg in the stable microjet This is a fundamental characteπstic of the invention The fluid stream flowing from the tube has substantially more density and develops substantially more inertia as compared to the gas, which has lower viscosity than the liquid These charactenstics contnbute to the formation of the stable capillary jet The stable capillary microjet is maintained stably for a sigmficant distance in the direction of flow away from the exit from the tube The liquid is. at this pomt. undergoing "supercritical flow " The microjet eventually destabilizes due to the effect of surface tension forces Destabilization results from small natural perturbations moving downstream, with the fastest growing perturbations bemg those which govern the break up of the microjet, eventually creatmg a monodisperse (a uniform sized) aerosol 70 as shown m Figure 4

The microjet. even as it lmtially destabilizes, passes out of the exit onfice of the pressure chamber without touching the penpheral surface of the exit opening This provides an important advantage of the invention which is that the exit openmg 68 (which could be refened to as a nozzle) will not clog from residue and/or deposits of the liquid Clogging is a major problem with very small nozzles and is generally dealt with by cleaning or replacing the nozzle When fluid contacts the surfaces of a nozzle opening some fluid will remain m contact with the nozzle when the flow of fluid is shut off The liquid remaining on the nozzle surface evaporates leaving a residue After many uses over time the residue builds up and clogging takes place The present mvention substantially reduces or eliminates this cloggmg problem

MATHEMATICS OF A STABLE MICROJET Cylmdπcal coordinates (r.z) are chosen for making a mathematical analysis of a stable microjet, 1 e liquid undergomg "supercntical flow " The cusp-like meniscus formed by the liquid coming out of the tube is pulled toward the exit of the pressure chamber by a pressure gradient created by the flow of gas

The cusp-like meniscus formed at the tube's mouth is pulled towards the hole by the pressure gradient created by the gas stream From the cusp of this meniscus, a steady liquid thread with the shape of radius r = ξ is withdrawn through the hole by the action of both the suction effect due to ΔP_g, and the tangential viscous stresses τ_s exerted by the gas on the jet's surface m the axial direction The averaged momentum equation for this configuration may be wntten

where Q is the liquid flow rate upon exiting the feeding tube, P_{ is the liquid pressure, and p_! is the liquid density, assuming that the viscous extensional term is negligible compared to the kmetic energy term, as will be subsequently justified In addition, liquid evaporation effects are neglected The liquid pressure ] is given by the capillary equation

where γ is the liquid-gas surface tension As shown m the Examples, the pressure drop ΔP_g is sufficiently large as compared to the surface tension stress γ/ξ to justify neglecting the latter m the analysis This scenano holds for the whole range of flow rates in which the microjet is absolutely stable In fact, it will be shown that, for a given pressure drop AP_g, the minimum liquid flow rate that can be sprayed in steady jet conditions is achieved when the surface tension stress γ/ξ is of the order of the kmetic energy of the liquid pιβ²/(2π²ξ⁴) since the surface tension acts like a "resistance" to the motion (it appears as a negative term m the right-hand side term of Eq (1)) Thus,

For sufficiently large flow rates Q compared to Q_mm. the simplified averaged momentum equation m the axial direction can be expressed as

where one can identify the two dπving forces for the liquid flow on the nght-hand side This equation can be mtegrated provided the following simplification is made if one uses a thin plate with thickness L of the order or smaller than the hole's diameter D (which minimizes downstream perturbations in the gas flow), the pressure gradient up to the hole exit is on the average much larger than the viscous shear term 2τ_s/ξ owning to the surface stress On the other hand, the axial viscous term is of the order 0[μ²Q/D²d_s ²], since the hole diameter D is actually the characteristic distance associated with the gas flow at the hole's entrance m both the radial and axial directions This term is very small compared to the pressure gradient m real situations, provided that ΛP_g » μ²/D²p₁ (which holds, e g , for liquids with viscosities as large as 100 cpoises, using hole diameters and pressure drops as small as D ~ 10 μm and AP_g ≥ lOO mbar) The neglect of all viscous terms in Eq (4) is then justified Notice that m this limit on the liquid flow is quast-tsentropic in the average (the liquid almost follows Bernoulli equation) as opposed to most micrometac extensional flows Thus, integratmg (4) from the stagnation regions of both fluids up to the exit, one obtains a simple and universal expression for the jet diameter at the hole

8p, d. Q ^' (5)

Π²ΔP

which for a given pressure drop ΛP_g is independent of geometncal parameters (hole and tube diameters, tube-hole distance, etc ), liquid and gas viscosities, and liquid-gas surface tension This diameter remains almost constant up to the breakup pomt since the gas pressure after the exit remains constant

MONODISPERSE PARTICLES

Above the stable microjet undergoing "supercntical flow" is descnbed and it can be seen how this aspect of the mvention can be made use of in a vaπety of mdustnal applications — particularly where the flow of liquid through small holes creates a clogging problem An equally important aspect of the invention is obtamed after the microjet leaves the pressure chamber

When the microjet exits the pressure chamber the liquid pressure P_x becomes (like the gas pressure _°_g) almost constant m the axial direction, and the jet diameter remains almost constant up to the point where it breaks up by capillary instability Defining a Weber number We = (P_gV_g ²-/,)/ γ - 2

(where v_g is the gas velocity measured at the oπfice), below a certain expeπmental value We_c ~ 40 the breakup mode is axisymmetnc and the resultmg droplet stream is characterized by its monodispersity provided that the fluctuations of the gas flow do not contnbute to droplet coalescence (these fluctuations occur when the gas stream reaches a fully developed turbulent profile around the liquid jet breakup region) Above this We_c value, smuous nonaxisymmetnc disturbances, coupled to the axisymmetnc ones, become apparent For larger We numbers, the nonlinear growth rate of the smuous disturbances seems to overcome that of the axisymmetnc disturbances The resulting spray shows sigmficant polydispersity m this case Thus, it can be seen that by controlling parameters to keep the resulting Weber number to 40 or less, allows the particles formed to be all substantially the same size The size vanation is about ±3 % to ±30% and move preferably ±3 % to ± 10% These particles can have a desired size e g 0 1 microns to 50 microns

The shed vorticity influences the breakup of the jet and thus the formation of the particles Upstream from the hole exit, in the accelerating region, the gas stream is laminar Typical values of the Reynolds number range from 500 to 6000 if a velocity of the order of the speed of sound is taken as charactenstic of the velocity of the gas Downstream from the hole exit, the cylindrical mixing layer between the gas stream and the stagnant gas becomes unstable by the classical Kelvin-Helmholtz instability The growth rate of the thickness of this layer depends on the Reynolds number of the flow and ring vortices are formed at a frequency of the order oϊvJD, where D is the hole diameter Typical values of v_g and D as those found in our expeπmental technique lead to frequencies or the order of MHZ which are comparable to the frequency of drop production (of order of t_h ')

Given the liquid flow rate and the hole diameter, a resonance frequency which depends on the gas velocity (or pressure difference dnving the gas stream) can be adjusted (tuned) in such a way that vortices act as a forcmg system to excite perturbations of a determined wavelength on the jet surface Expeπmental results obtained clearly illustrates the different degree of couplmg between the two gas- liquid coaxial jets In one set of expeπmental results the particle sizes are shown to have a particle size of about 5 7 microns with a standard deviation of 12% This results when the velocity of the gas has been properly tuned to minimize the dispersion m the size of droplets resulting from the jet breakup In this case, the flow rate of the liquid jet and its diameter are 0 08 l s ' and 3 μm. respectively Data have been collected using a MASTERSIZER from MALVERN Instruments As the degree of couplmg decreases, perturbations at the jet surface of different wavelengths become excited and, as it can be observed from the size distnbutions, the dispersion of the spray mcreases

It is highly desirable in a number of different mdustπal applications to have particles which are uniform m size or to create aerosols of liquid particles which are uniform m size For example, particles of a liquid formation contammg a pharmaceutically active drug could be created and designed to have a diameter of about 2 microns ±3% These particles could be inhaled mto the lungs of a patient for lntrapulmonary drug delivery Moreover, particle size can be adjusted to target a particular area of the respiratory tract

The gas flow should be laminar m order to avoid a turbulent regime - turbulent fluctuations in the gas flow which have a high frequency and would perturb the hquid-gas mterface The Reynolds numbers reached at the oπfice are v d_r. Re = -£-! ~ 4000

where v_g is the kmematic viscosity of the gas Even though this number is quite high, there are large pressure gradients downstream (a highly convergent geometry), so that a turbulent regime is very unlikely to develop The essential difference from existmg pneumatic atomizers (which possess large Weber numbers) and the present mvention is that the aim of the present invention is not to rupture the quid-gas mterface but the opposite, I e to increase the stability of the mterface until a capillary jet is obtained The jet, which will be very thm provided the pressure drop resulting from withdrawal is high enough, splits into drops the sizes of which are much more uniform than those resulting from disorderly breakage of the quid-gas interface m existmg pneumatic atomizers

The proposed atormzation system obviously requires delivery of the liquid to be atomized and the gas to be used m the resulting spray Both should be fed at a rate ensuring that the system lies within the stable parameter wmdow Multiplexing is effective when the flow-rates needed exceed those on an individual cell More specifically, a plurality of feedmg sources or feeding needles may be used to mcrease the rate at which aerosols are created The flow-rates used should also ensure the mass ratio between the flows is compatible with the specifications of each application

The gas and liquid can be dispensed by any type of continuous delivery system (e g a compressor or a pressunzed tank the former and a volumetric pump or a pressunzed bottle the latter) If multiplexing is needed, the liquid flow-rate should be as uniform as possible among cells, this may entail propulsion through several capillary needles, porous media or any other medium capable of distπbutmg a uniform flow among different feeding pomts Each individual atomization device should consist of a feeding point (a capillary needle, a point with an open microchannel, a microprotuberance on a contmuous edge, etc ) 0 002-2 mm (but, preferentially 0 01-0 4 mm) m diameter, where the drop emerging from the microjet can be anchored, and a small orifice 0 002-2 mm (preferentially 0 01-0 25 mm) in diameter facing the drop and separated 0 01-2 mm (preferentially 0 2-0 5 mm) from the feedmg pomt The oπfice commumcates the withdrawal gas around the drop, at an mcreased pressure, with the zone where the atomizate is produced, at a decreased pressure The atomizer can be made from a vaπety of materials (metal, polymers, ceramics, glass)

Figure 1 depicts a tested prototype where the liquid to be atomized is inserted through one end of the system 2 and the propelling gas in mtroduced via the special mlet 4 m the pressure chamber 3

The prototype was tested at gas feeding rates from 100 to 2000 mBar above the atmosphenc pressure P_a at which the atomized liquid was discharged The whole enclosure around the feeding needle 1 was at a pressure P₀ > P_a The liquid feedmg pressure, P_h should always be slightly higher than the gas propelling pressure, P₀ Dependmg on the pressure drop in the needle and the liquid feedmg system, the pressure difference ( , - P₀ > 0) and the flow-rate of the liquid to be atomized, Q, are linearly related provided the flow is laminar - which is mdeed the case with this prototype The cntical dimensions are the distance from the needle to the plate (H), the needle diameter (D ₀), the diameter of the orifice through which the microjet 6 is discharged (d₀) and the axial length, e, of the onfice (J e the thickness of the plate where the onfice is made) In this prototype, H was vaπed from 0 3 to 0 7 mm on constancy of the distances (D₀ = 0 45 mm, d₀ - 0 2 mm) and e - 0 5 mm The quality of the resultmg spray 7 did not vary appreciably with changes in// provided the operating regime (i e stationary drop and microjet) was maintained However, the system stability suffered at the longer H distances (about 0 7 mm) The other atomizer dimensions had no effect on the spray or the prototype functioning provided the zone around the needle (its diameter) was large enough relative to the feedmg needle As explained further below it is possible to obtam a stable capillary microjet which does not disassociate into a monodisperse aerosol However, by adjustmg parameters which relate to the Weber number a stable microjet is formed which disassociates to monodisperse aerosol

WEBER NUMBER Adjusting parameters to obtain a stable capillary microjet and control its breakup mto monodisperse particle is governed by the Weber number and the hquid-to-gas velocity ratio or α which equal VJV_g The Weber number or "We" is defined by the following equation

* . . ----_ wherem p_g is the density of the gas, d is the diameter of the stable microjet, γ is the hquid-gas surface tension, and V² is the velocity of the gas squared

When carrying out the invention the parameters should be adjusted so that the Weber number is greater than 1 m order to produce a stable capillary microjet However, to obtain a particle dispersion which is monodisperse (I e each particle has the same size ±3 to ±30%) the parameters should be adjusted so that the Weber number is less than 40 The monodisperse aerosol is obtained with a Weber number in a range of about 1 to about 40 when the breaking time is sufficiently small to avoid non- symmetric perturbations ( 1 < We < 40)

OHNESORGE NUMBER

A measure of the relative importance of viscosity on the jet breakup can be estimated from the Ohnesorge number defined as the ratio between two characteπstic times the viscous time t_v and the breaking time t_h The breaking time t_b is given by [see Rayleigh (1878)]

Perturbations on the jet surface are propagated mside by viscous diffusion m times t_v of the order of

where μ is the viscosity of the liquid Then, the Ohnesorge number, Oh, results

μ. Oh = ^λ (4)

(P_tj )

If this ratio is much smaller than unity viscosity plays no essential role m the phenomenon under consideration Since the maximum value of the Ohnesorge number m actual experiments conducted is as low as 3 7* 10², viscosity plays no essential role during the process of jet breakup

EMBODIMENT OF FIGURE 2

A vaπety of configurations of components and types of fluids will become apparent to those skilled in the art upon readmg this disclosure These configurations and fluids are encompassed by the present invention provided the can produce a stable capillary microjet of a first fluid from a source to an exit port of a pressure chamber contammg a second fluid The stable microjet is formed b \ the first fluid flowing from the feedmg source to the exit port of the pressure chamber bemg accelerated and stabilized by tangential viscous stress exerted by the second fluid m the pressure chamber on the surface of the first fluid forming the microjet The second fluid forms a focusmg funnel when a vaπety of parameters are correctly tuned or adjusted For example, the speed, pressure, viscosity and miscibility of the first and second fluids are chosen to obtam the desired results of a stable microjet of the first flmd focused mto the center of a funnel formed with the second fluid These results are also obtained by adjustmg or tuning physical parameters of the device, mcludmg the size of the openmg from which the first fluid flows, the size of the openmg from which both fluids exit, and the distance between these two openings The embodiment of Figure 1 can, itself, be ananged m a vaπety of configurations Further, as mdicated above, the embodiment may include a plurality of feedmg needles A plurality of feedmg needles may be configured concentπcally in a smgle construct, as shown in Figure 2

The concentrically positioned feeding needle preferable extrude liquids which are not misable in each other, e g oil and water The feedmg needles can be designed and have fluid flowing through them so as to result m the creation of a plurality of concentncal spheres, l e a sphere mside a sphere mside another sphere etc The stability of the concentncal spheres can be maintained by a number of procedures For example , the concentncal spheres are blown mto a cuπng tube The spheres move through the tube and are inadiated by energy which cures, hardens or polymeπzes sphere coating which then prevent the liquids held in the different coatmg spheres from mterrmxmg An internal solid sphere of lactose could be coated with a polymer coatmg which would not dissolve m a dairy product (e g milk or ice cream) but would dissolve m the G I tract Thus, the lactose of the dairy product would combine with the lactase enzyme after bemg consumed This would make it possible for lactose intolerant individuals to eat dairy products

The internal sphere could be gas (e g air or mtrogen) held by a polymer coatmg shell The shell could have a coatmg which is high m fat , flavor, sweet taste etc thereon By spreadmg the coatmg over a large area, the effect of it is amplified when the particles are dispersed uniformly m a food product

The components of the embodiment of Figure 2 are as follows 21 Feedmg needle - tube or source of fluid 22 End of the feedmg needle used to insert the liquids to be atomized

23 Pressure chamber

24 Oπfice used as gas mlet

25 End of the feeding needle used to evacuate the liquid to be atomized

26 Oπfice through which withdrawal takes place 27 Atomizate (spray) or aerosol

28 First liquid to be atomized (inner core of particle)

29 Second liquid to be atomized (outer coatmg of particle)

30 Gas for creation of microjet 31 Internal tube of feedmg needle

32 External tube of feeding needle

D = diameter of the feeding needle, d = diameter of the oπfice through which the microjet is passed, e = axial length of the oπfice through which withdrawal takes place, H = distance from the feeding needle to the microjet outlet, g=surface tension, P₀ = pressure mside the chamber, P_a = atmosphenc pressure The embodiment of Figure 2 is preferably used when attempting to form a sphencal particle of one substance coated by another substance, e a sweet tasting substance surrounding a bitter tastmg substance The device of Figure 2 is compnsed of the same basic component as per the device of Figure 1 and further mcludes a second feedmg source 32 which is positioned concentncally around the first cylmdncal feedmg source 31 The second feeding source may be sunounded by one or more additional feedmg sources with each concentπcally positioned around the precedmg source The outer coating may be used for a variety of purposes, including coatmg particles to prevent small particles from sticking together, to obtain a sustained release effect of the active compound (e g a pharmaceutically active drug) mside, and or to mask flavors, and to protect the stability of another compound (e g a pharmaceutically active drug) contamed therein

The process is based on the microsuction which the hquid-gas or liquid-liquid mterphase undergoes (if both are immiscible), when said mterphase approaches a point beginning from which one of the fluids is suctioned off while the combined suction of the two fluids is produced The mteraction causes the fluid physically surrounded by the other to form a capillary microjet which finally breaks mto spherical drops If mstead of two fluids (gas-liquid), three or more are used that flow in a concentric manner by injection using concentac tubes, a capillary jet composed of two or more layers of different fluids is formed which, when it breaks, gives πse to the formation of spheres composed of several approximately concentnc spherical layers of different fluids The size of the outer sphere (its thickness) and the size of the inner sphere (its volume) can be precisely adjusted This can allow the manufacture of coated particles for a variety of end uses For example the thickness of the coating can be vaπed m different manufacturing events to obtain coated particles which have gradually decreasing thicknesses to obtam a controlled release effect of the contents, e g a nutntional food or a pharmaceutically active drug The coatmg could merely prevent the particles from degrading, reacting, or sticking together The method is based on the breaking of a capillary microjet composed of a nucleus of one liquid or gas and sunounded by another or other liquids and gases which are in a concentnc manner mjected by a special injection head, m such a way that they form a stable capillary microjet and that they do not mix by diffusion durmg the time between when the microjet is formed and when it is broken When the capillary microjet is broken mto sphencal drops under the proper operatmg conditions, which will be descnbed m detail below, these drops exhibit a sphencal nucleus, the size and eccentacity of which can be controlled

In the case of spheres containing two materials, the injection head 25 consists of two concentric tubes with an external diameter on the order of one millimeter Through the internal tube 31 is mjected the mateπal that will constitute the nucleus of the imcrosphere, while between the internal tube 31 and the external tube 32 the coatmg is mjected The fluid of the external tube 32 joms with the fluid of tube 31 as the fluids exit the feedmg needle, and the fluids (normally liquids) thus injected are accelerated by a stream of gas that passes through a small oπfice 24 facmg the end of the injection tubes When the drop in pressure across the orifice 24 is sufficient, the liquids form a completely stationary capillary microjet, if the quantities of liquids that are injected are stationary This microjet does not touch the walls of the oπfice, but passes through it wrapped in the stream of gas or funnel formed by gas from the tube 32 Because the funnel of gas focuses the liquid, the size of the exit onfice 26 does not dictate the size of the particles formed

When the parameters are correctly adjusted, the movement of the liquid is uniform at the exit of the oπfice 26 and the viscosity forces are sufficiently small so as not to alter either the flow or the properties of the liquids, for example, if there are biochemical molecular specimens having a certain complexity and fragility, the viscous forces that would appear in association with the flow through a micro-oπfice might degrade these substances

Figure 2 shows a simplified diagram of the feedmg needle 21, which is comprised of the concentnc tubes 30, 31 through the internal and external flows of the fluids 28, 29 that are going to compose the microspheres comprised of two immiscible fluids. The difference m pressures P₀ - P_; (P₀ > ?ι) through the onfice 26 establishes a flow of gas present m the chamber 23 and which is gomg to sunound the microjet at its exit The same pressure gradient that moves the gas is the one that moves the microjet in an axial direction through the hole 26, provided that the difference m pressures P₀ - P, is sufficiently great in comparison with the forces of surface tension, which create an adverse gradient m the direction of the movement

In any operation of the device, the exit hole may be supplemented with (1) a temperature control means (e g a heater) and/or (2) a vibrational energy generating means The heater could, for example, prevent the formulation of unwanted condensation on the openmg hole 26 The vibrational energy generatmg means could serve to break up the stable microjet into smaller and more uniform particles than would form without the vibrational energy The frequency of the vibration can be set to obtam a desired particle size and the heater temperature can be adjusted

There are two limitations for the minimum sizes of the mside and outside jets that are dependent (a) on the surface tensions gl of the outside liquid 29 with the gas 30 and g2 of the outside liquid 29 with the mside liquid 28, and (b) on the difference m pressures DP = P₀ - P_α through the onfice 26 In the first place, the jump in pressures DP must be sufficiently great so that the adverse effects of the surface tension are minimized This, however, is attained for very modest pressure increases for example, for a 10 micron jet of a liquid havmg a surface tension of 0 05 N/m (tap water), the necessary minimum jump in pressure is in the order of 0 05 (N/m) / 0 00001 m = DP= 50 mBar But, m addition, the breakage of the microjet must be regular and axilsymmetπc, so that the drops will have a uniform size, while the extra pressure DP cannot be greater than a certain value that is dependent on the surface tension of the outside liquid with the gas gl and on the outside diameter of the microjet It has been experimentally shown that this difference in pressures cannot be greater than 20 times the surface tension gl divided by the outside radius of the microjet

Therefore, given some mside and outside diameters of the microjet, there is a range of operatmg pressures between a minimum and a maximum, nonetheless, experimentally the best results are obtained for pressures in the order of two to three times the minimum

The viscosity values of the liquids must be such that the liquid with the greater viscosity m^ venfies, for a diameter d of the jet predicted for this liquid and a difference through the oπfice DP , the inequality ϊi < D Pd²D

Q

With this, the pressure gradients can overcome the extensional forces of viscous resistance exerted by the liquid when it is suctioned toward the oπfice

Moreover, the liquids must have very similar densities m order to achieve the concentncity of the nucleus of the microsphere, since the relation of velocities between the liquids moves accordmg to the square root of the densities vl/v2 = (r2/rl)^1/2 and both jets, the mside jet and the outside jet, must assume the most symmetncal configuration possible, which does not occur if the liquids have different velocities (Figure 2) Nonetheless, it has been expenmentally demonstrated that, on account of the surface tension g2 between the two liquids, the nucleus tends to migrate toward the center of the microsphere. withm prescπbed parameters

When two liquids and gas are used on the outside, the distance between the planes of the mouths of the concentnc tubes can vary, without the charactenstics of the jet bemg substantially altered, provided that the internal tube 31 is not introduced mto the external one 32 more than one diameter of the external tube 32 and provided that the internal tube 31 does not project more than two diameters from the external tube 32 The best results are obtamed when the internal tube 31 projects from the external one 32 a distance substantially the same as the diameter of the internal tube 31 This same criterion is valid if more than two tubes are used, with the tube that is sunounded (inner tube) projectmg beyond the tube that sunounds (outer tube) by a distance substantially the same as the diameter of the first tube

The distance between the plane of the internal tube 31 (the one that will normally project more) and the plane of the orifice may vary between zero and three outside diameters of the external tube 32, dependmg on the surface tensions between the liquids and with the gas, and on their viscosity values Typically, the optimal distance is found experimentally for each particular configuration and each set of liquids used

The proposed atomizmg system obviously requires fluids that are gomg to be used m the resultmg spray to have certain flow parameters Accordmgly, flows for this use must be

- Flows that are suitable so that the system falls withm the parametnc window of stability Multiplexing (l e several sets of concentric tubes) may be used, if the flows required are greater than those of an individual cell

- Flows that are suitable so that the mass relation of the fluids falls withm the specifications of each application Of course, a greater flow of gas may be supplied externally by any means m specific applications, since this does not interfere with the functioning of the atomizer - If the flows are varied, the charactenstic time of this variation must be less than the hydrodynamic residence times of liquid and gas in the microjet, and less than the inverse of the first natural oscillation frequency of the drop formed at the end of the injection needle

Therefore, any means for continuous supply of gas (compressors, pressure deposits, etc ) and of liquid (volumetric pumps, pressure bottles) may be used If multiplexing is desired, the flow of liquid must be as homogeneous as possible between the vanous cells, which may require impulse through multiple capillary needles, porous media, or any other medium capable of distπbutmg a homogeneous flow among different feeding points

Each atomizing device will consist of concentnc tubes 31, 32 with a diameter ranging between 0 05 and 2 mm, preferablv between 0 1 and 0 4 mm, on which the drop from which the microjet emanates can be anchored, and a small orifice (between 0 001 and 2 mm in diameter, preferably between 0 1 and 0 25 mm), facing the drop and separated from the point of feeding by a distance between 0 001 and 2 mm. preferably between 0 2 and 0 5 mm The oπfice puts the suction gas that sunounds the drop, at higher pressure, m touch with the area in which the atomizing is to be attained, at lower pressure EMBODIMENT OF FIGURE 3 The embodiments of Figures 1 and 2 are similar in a number of ways. Both have a feeding piece which is preferably in the form of a feeding needle with a circular exit opening. Further, both have an exit port in the pressure chamber which is positioned directly in front of the flow path of fluid out of the feeding source. Precisely mamtaining the alignment of the flow path of the feeding source with the exit port of the pressure chamber can present an engineering challenge particularly when the device includes a number of feeding needles. The embodiment of Figure 3 is designed to simplify the manner in which components are aligned. The embodiment of Figure 3 uses a planar feeding piece (which by virtue of the withdrawal effect produced by the pressure difference across a small opening through which fluid is passed) to obtain multiple microjets which are expelled through multiple exit ports of a pressure chamber thereby obtaining multiple aerosol streams. Although a single planar feeding member as shown in Figure 3 it, of course, is possible to produce a device with a plurality of planar feeding members where each planar feeding member feeds fluid to a linear array of outlet orifices in the surrounding pressure chamber. In addition, the feeding member need not be strictly planar, and may be a curved feeding device comprised of two surfaces that maintain approximately the same spatial distance between the two pieces of the feeding source. Such curved devices may have any level of curvature, e.g. circular, semicircular, elliptical, hemi-elliptical, etc. The components of the embodiment of Figure 3 are as follows: 41. Feeding piece. 42. End of the feeding piece used to insert the fluid to be atomized.

43. Pressure chamber.

44. Orifice used as gas inlet.

45. End of the feeding needle used to evacuate the liquid to be atomized.

46. Orifices through which withdrawal takes place. 47. Atomizate (spray) or aerosol.

48. first fluid containing material to be atomized.

49. second fluid for creation of microjet.

50. wall of the propulsion chamber facing the edge of the feeding piece.

51. channels for guidance of fluid through feeding piece. d_j = diameter of the microjet formed; p_A= liquid density of first fluid (48); p_B= liquid density of second fluid (49). v_A= velocity of the first liquid (48); v_B=velocity of the second liquid (49); e = axial length of the orifice through which withdrawal takes place; H = distance from the feeding needle to the microjet outlet; P₀ = pressure inside the chamber;

flow rate The proposed dispersing device consists of a feeding piece 41 which creates a planar feeding channel through which a where a first fluid 48 flows The flow is preferably directed through one or more channels of umform bores that are constructed on the planar surface of the feedmg piece 41 A pressure chamber 43 that holds the propelling flow of a second liquid 49. houses the feedmg piece 41 and is under a pressure above maintained outside the chamber wall 50 One or more orifices, openings or slots (outlets) 46 made in the wall 52 of the propulsion chamber face the edge of the feeding piece Preferably, each bore or channel of the feeding piece 41 has its flow path substantially aligned with an outlet 46

Formation of the microjet and its acceleration are based on the abrupt pressure drop resulting from the steep acceleration undergone by the second fluid 49 on passmg through the onfice 46, similarly to the procedure descnbed above for embodiments of Figures 1 and 2 when the second fluid 49 is a gas

When the second fluid 49 is a gas and the first fluid 48 is a liquid, the microthread formed is quite long and the liquid velocity is much smaller than the gas velocity In fact, the low viscosity of the gas allows the liquid to flow at a much lower velocity, as a result, the microjet is actually produced and accelerated by stress forces normal to the liquid surface, I e pressure forces Hence, one effective approximation to the phenomenon is to assume that the pressure difference established will result m the same kinetic energy per unit volume for both fluids (liquid and gas), provided gas compressibility effects are neglected The diameter d_} of the microjet formed from a liquid density P] that passes at a volumetac flow-rate Q through an orifice across which a pressure difference AP_g exists will be given by

8p_; d / * β * π²ΔP

See Ganan-Calvo, Physical Review Letters. 80 285-288 (1998)

The relation between the diameter of the microjet, d_p and that of the resultmg drops, d, depends on the ratio between viscous forces and surface tension forces on the liquid on the one hand, and between dynamic forces and surface tension forces on the gas on the other (i e on the Ohnesorge and Weber numbers, respectively) (Hinds (Aerosol Technology, John & Sons, 1982), Lefevre (Atomization and Sprays, Hemisphere Pub Corp , 1989) and Bayvel & Orzechowski (Liquid Atomization Taylor & Francis 1993)) At moderate to low gas velocities and low viscosities the relation is roughly identical with that for capillanty instability developed by Rayleigh d = 1 89d_j Because the liquid microjet is very long, at high liquid flow-rates the theoretical rupture pomt lies m the turbulent zone created by the gas jet. so turbulent fluctuations in the gas destabilize or rupture the liquid microjet m a more or less uneven manner As a result, the benefits of drop size uniformity are lost

On the other hand, when the second fluid 49 is a liquid and the first fluid 48 is a gas, the facts that the liquid is much more viscous and that the gas is much less dense virtually equalize the fluid and gas velocities The gas microthread formed is much shorter, however, because its rupture zone is almost mvaπably located in a laminar flowing stream, dispersion in the size of the microbubbles formed is almost always small At a volumetric gas flow-rate Q_g and a liquid overpressure ΔP the diameter of the gas microjet is given by

8_P/

Q π²ΔR,

The low liquid velocity and the absence of relative velocities between the liquid and gas lead to the Rayleigh relation between the diameters of the microthread and those of the bubbles (i e d = \ 89_/) The above equation applies accurately when the inner fluid is liquid and the outer fluid is gas However, when the inner fluid is gas and the outer fluid is a liquid, the above equation may not apply for a number a reasons For example, the liquid does not move faster than the gas being focused to a microjet However, the mvention does make it possible to nanowly focus a stream of gas usmg a sunoundmg pressunzed liquid Further, the focused stream of gas does break up to form small bubbles which are substantially umform in size The bubbles are smaller and more umform than if the outer liquid were not present

If both fluids 48. 49 are liquid and scarcely viscous, then their relative velocities will be given by

The diameter of a microjet of the first liquid at a volumetric flow-rate of A Q_A and an overpressure of AP_B will be given by

At viscosities such that the velocities of both fluids 48, 49 will rapidly equilibrate m the microjet, the diameter of the microjet of the first liquid will be given by

The proposed atomization system obviously requires delivery of the fluids 48, 49 to be used in the dispersion process at appropriate flow-rates. Thus:

(1) Both flow-rates should be adjusted for the system so that they lie within the stable parameter window. (2) The mass ratio between the flows should be compatible with the specifications of each application. Obviously, the gas flow-rate can be increased by using an external means in special applications (e.g. burning, drug inhalation) since this need not interfere with the atomizer operation. (3) If the flow-rates are altered, the characteristic time for the variation should be shorter than the hydrodynamic residence times for the liquid and gas in the microjet, and smaller than the reciprocal of the first natural oscillation frequency of the drop formed at the end of the feeding piece. (4) Therefore, the gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). (5) The atomizer can be made from a variety of materials (metal, polymers, ceramics, glass).

FORMULATION COMPOSITION OF PARTICLES OF THE INVENTION

A number of different components can be added to foods using the technology of the present invention. The following are exemplary components that may be added to the formulations of the particles to be added to foods. The functional components may be used alone or in combination in the particles, which can be designed and sized for increased bioavailablity of the particles. In addition, functional components may be found in the center of a coated particle, as a layer in a multi-layered particle, or as the coating of a particle or hollow sphere.

Formulation components may also be inert materials that serve to coat a functional particle, provide controlled release of the functional components of a particle, or provide a filler as a template to be coated with a composition containing a functional particle. The descnbed components are not mtended to be all-mclusive, and it is well withm the skill of one m the art to identify other components that may be used in the mvention upon readmg the present specification

Herbal Extracts

The passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) has stimulated the inclusion of a variety of herbs and botanicals mto numerous functional food products, mcludmg beverages, chewmg gums and sports bars Herbal extracts and/or the functional components of such may be added to foods using the device of the invention This mcludes herbal extracts purported to stimulate mental acuity, such as ginkgo biloba, those that provide energy, such as ginseng and guarana. those that build lean muscle mass, such as chromium picolrnate and creatme, those that promote weight loss, such as caffeine, ephednne and Ma Huang, and those that stimulate the immune system, such as echmacea Additional extracts include, but are not limited to bilberry extract, pme bark extract, garlic extract, green tea extract, turmeric, yeast extract, algae extract, royal jelly extract, tea extract, caffeine, kola nut extract, zinc, grape seed extract, flavonoids, yohimbe, milk thistle extract, bee pollen, etc

Functional Components

Scientists have recently turned their attention to the health benefits of non-nutritive food components, such as those m plant foods, as non-nutntive dietary components for use m disease prevention Although much of the research focus on these phytocheπucals has been directed at their cancer chemoprevention properties, biologically-active plant components may be important m reducmg nsk for other chronic diseases, mcludmg osteoporosis and heart disease Phytochemicals and or other functional components that provide beneficial physiological results can be incorporated mto functional food to bring these benefits to consumers

In one example, sitostanol ester added to yellow fats has been shown to reduce cholesterol New Englan J Med 1995 Other bioactive ingredients such as omega-3 -fatty acids, and bifidogenic dietary fibers (e g Raftiline) may be used m yellow fats to lower cholesterol and/or fight cardiovascular disease In yet another example, functional components may ease the symptoms of menopause, such as mght sweats and hot flashes The addition of 'phytoestrogens' to food helps to reduce hot flashes and mght sweats m women These functional components can be added to foods to help ease these symptoms m women suffeπng from such discomfort

Additional exemplary functional components can be found in Table 1, and mclude carotenoids. collagen hydrolysate, dietary fiber, fatty acids, flavonoids, glucosinolates, mdoles, lsothiocyanates, phenols, plant sterols, prebiotics/ probiotics, saponms, soy proteins, sulfides. thiols, tannms, etc

Pharmaceutical Additives In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like m the liquid formulation, or earners such as starches, sugars, diluents, granulating agents, lubncants. bmders. disintegrating agents and the like m the coatmg Such components can be found, for example, m Remington's Pharmaceutical Science, 15th Ed , Mack Pubhshmg Company, Easton, PA (1980), which is mcorporated herein by reference Because of their ease in administration and production using the methods of the present invention, capsules represent the most advantageous oral dosage unit form

Excipient Matenal Formulations of the mvention may comprise different amounts and ratios of food components and excipient matenal Numerous different excipients can be used Upon readmg the disclosure those skilled m the art will come to understand the general concepts of the invention and will recognize that other excipients. amounts, ratios and combmations might be used to obtain the results first shown here A typical formulation of the mvention will contain about 50% to 100% by weight of food component and a particularly prefened formulation will comprise 80% by weight of the food component Assuming a formulation with 80% by weight of food component with the remaining 20% bemg excipient mateπal there are a number of possible components which could be used to make up that 20% Those skilled m the art and readmg this disclosure will recognize that there are endless possibilities m terms of formulations Even if the formulations are limited to the relatively few compounds shown above the formulation could be changed m Imutless ways by adjusting the ratios of the components to each other

Controlled Release Formulations

One necessary characteπstic of a controlled release formulation is that it does not release all of the active mgredient at one time but rather releases the active ingredient gradually over time This is particularly important when (1) the component has a relatively short half life and (2) a desired level of the component m blood serum must be mamtained over a long penod to obtain the desired effect If all of the component is released at once it will all enter the circulatory system at once and be metabolized m the liver thereby causmg the serum level to drop below the desired level

Controlled release withm the scope of this invention can be taken to mean any one of a number of extended release dosage forms The following terms may be considered to be substantially equivalent to controlled release, for the purposes of the present mvention contmuous release, controlled release, delayed release, depot, gradual release, long-term release, programmed release, prolonged release, proportionate release, protracted release, repository, retard, slow release, spaced release, sustained release, time coat, tuned release, delayed action, extended action, layered-time action, long actmg. prolonged action, repeated action, slowing actmg, sustained action, sustained- action medications, and extended release Further discussions of these terms may be found in Lesczek Krowczynski, Extended-Release Dosage Forms, 1987 (CRC Press, Inc )

The various controlled release technologies cover a very broad spectrum of drug dosage forms Controlled release technologies include, but are not limited to physical systems and chemical systems Physical systems include, but are not limited to, reservoir systems with rate-controlling membranes, such as microencapsulation, macroencapsulation, and membrane systems, reservoir systems without rate-controlling membranes, such as hollow fibers, ultra microporous cellulose tnacetate, and porous polymenc substrates and foams, monolithic systems, mcludmg those systems physically dissolved in non-porous, polymenc, or elastomeπc matrices (e g , nonerodible, erodible, environmental agent mgression, and degradable), and mateπals physically dispersed m non-porous, polymenc, or elastomenc matrices (e g , nonerodible. erodible, environmental agent mgression. and degradable), laminated structures, including reservoir layers chemically similar or dissimilar to outer control layers, and other physical methods, such as osmotic pumps, or adsorption onto ion-exchange res s and such system may be lngestable, implantable implants, transdermal devices, etc Chemical systems include, but are not limited to, chemical erosion of polymer mataces

(e g , heterogeneous, or homogeneous erosion), or biological erosion of a polymer matax (e g , heterogeneous, or homogeneous) Additional discussion of categories of systems for controlled release may be found m Agis F Kydonieus, Controlled Release Technologies Methods, Theory and Applications, 1980 (CRC Press, Inc ) Controlled release drug delivery systems may also be categoπzed under their basic technology areas, mcludmg, but not limited to. rate-preprogrammed drug delivery systems, activation- modulated drug delivery systems, feedback-regulated drug delivery systems, and site-targetmg drug delivery systems

In rate-preprogrammed drug delivery systems, release of drug molecules from the delivery s . stems "preprogrammed" at specific rate profiles This may be accomplished by system design, which controls the molecular diffusion of drug molecules in and/or across the barrier medium within or sunounding the delivery system. Fick's laws of diffusion are often followed.

In activation-modulated drug delivery systems, release of drug molecules from the delivery systems is activated by some physical, chemical or biochemical processes and/or facilitated by the energy supplied externally. The rate of drug release is then controlled by regulating the process applied, or energy input.

In feedback-regulated drug delivery systems, release of drug molecules from the delivery systems may be activated by a triggering event, such as a biochemical substance, in the body. The rate of drug release is then controlled by the concentration of triggering agent detected by a sensor in the feedback regulated mechanism.

In a site-targeting controlled-release drug delivery system, the drug delivery system targets the active molecule to a specific site or target tissue or cell. This may be accomplished, for example, by a conjugate including a site specific targeting moiety that leads the drug delivery system to the vicinity of a target tissue (or cell), a solubilizer that enables the drug deliver}' system to be transported to and preferentially taken up by a target tissue, and a drug moiety that is covalently bonded to the polymer backbone through a spacer and contains a cleavable group that can be cleaved only by a specific enzyme at the target tissue.

There are a number of controlled release formulations that are developed preferably for oral administration. These include, but are not limited to, osmotic pressure-controlled gastrointestinal delivery systems; hydrodynamic pressure-controlled gastrointestinal delivery systems; membrane permeation-controlled gastrointestinal delivery systems, which include microporous membrane permeation-controlled gastrointestinal delivery devices; gastric fluid-resistant intestine targeted controlled-release gastrointestinal delivery devices; gel diffusion-controlled gastrointestinal delivery systems; and ion-exchange-controlled gastrointestinal delivery systems, which include cationic and anionic drugs. Additional information regarding controlled release drug delivery systems may be found in Yie W. Chien, Novel Drug Delivery Systems, 1992 (Marcel Dekker, Inc.). some of these formulations will now be discussed in more detail.

Enteric coatings are applied to tablets to prevent the release of drugs in the stomach either to reduce the risk of unpleasant side effects or to maintain the stability of the drug which might otherwise be subject to degradation of expose to the gastric environment. Most polymers that are used for this purpose are polyacids that function by virtue or the fact that their solubility in aqueous medium is pH-dependent, and they require conditions with a pH higher then normally encountered in the stomach.

One preferable type of oral controlled release structure is enteric coating of a solid or liquid dosage form. Enteric coatings promote the compounds remaining physically incorporated in the dosage form for a specified penod when exposed to gastπc juice Yet the enteπc coatmgs are designed to dismtegrate m intestinal fluid for ready absorption Delay of absorption is dependent on the rate of transfer through the gastromtestmal tract, and so the rate of gastπc emptying is an important factor Some mvestigators have reported that a multiple-unit type dosage form, such as granules, may be supenor to a smgle-unit type Therefore, m one embodiment, a functional components or active mgredient may be contained in an entencally coated multiple-unit dosage form In a more preferable embodiment, the active mgredient dosage form is prepared by producing particles havmg an active ingredient-enteπc coatmg agent solid on an inert core material These granules can result m prolonged absorption of the drug with good bioavailabihty Typical enteric coatmg agents mclude, but are not limited to, hydroxypropylmethylcellulose phthalate, methacryclic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthaJate and cellulose acetate phthalate Akihiko Hasega a, Application of solid dispersions ofNifedipine with enteric coating agent to prepare a sustained-release dosage form, Chem Pharm Bull 33 1615- 1619 (1985) Various enteπc coatmg matenals may be selected on the basis of testmg to achieve an enteric coated dosage form designed ab initio to have a preferable combmation of dissolution time, coatmg thicknesses and diametral crushing strength S C Porter et al ,The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate, J Pharm Pharmacol 22 42p (1970)

On occasion, the performance of an enteπc coatmg may hmge on its permeability S C Porter et al , The Permeability of Enteric Coatings and the Dissolution Rates of Coated Tablets, J Pharm Pharmacol 34 5-8 (1981) With such oral delivery systems, the component release process may be initiated by diffusion of aqueous fluids across the enteπc coating Investigations have suggested osmotic dπven/ruptuπng effects as important release mechanisms from enteπc coated dosage forms Roland Bodmeier et al , Mechanical Properties of Dry and Wet Cellulosic and Acrylic Films Prepared from Aqueous Colloidal Polymer Dispersions used in the Coating of Solid Dosage Forms, Pharmaceutical Research, 11 882-888 (1994)

The selection of the earner may have an influence on the dissolution charactenstics of the dispersed component in a liquid because the dissolution rate of a component from a surface may be affected by other components m a multiple component mixture For example, a water-soluble earner may result m a fast release of the drug from the matrix, or a poorly soluble or msoluble carrier may lead to a slower release of the drug from the matrix The solubility of the active ingredient may also be increased owmg to some mteraction with the earners

The controlled release properties may be provided by a combmation of hydrophilic polymers In certain cases, a rapid release of the component may be desirable in order to facilitate a fast onset of therapeutic affect Hence one layer of the tablet may be formulated as an immediate release granulate By contrast, the second layer of the tablet may release the drug m a controlled manner, preferably through the use of hydrophilic polymers This controlled release may result from a combmation of diffusion and erosion through the hydrophilic polymer matπx The food components of the invention can be mcorporated mto any one of the aforementioned controlled released dosage forms, or other conventional dosage forms The amount of components contained in each dose can be adjusted, to meet the needs of the individual patient, and the indication One of skill m the art and readmg this disclosure will readily recognize how to adjust the level of component and the release rates in a controlled release formulation, m order to optimize delivery of the component and its bioavailabihty

EXEMPLARY USES OF EMBODIMENTS 1 and 3 OF THE PRESENT INVENTION

Embodiments 1 and 3 can be used for the production of improved products mcludmg pharmaceuticals and foods of the present invention when used to produce small, uniform particles of a smgle formulation The formulation may contain more than one nutaent or active mgredient, either as separate compounds and/or as conjugated compounds For example, a single formulation may contam carbohydrate and an excipient that provides controlled release of the carbohydrate In another example, the formulation may contam a nutaent such as a mineral conjugated to an excipient (such as a protem, ammo acid, salt, etc ) that provides better absorption of the molecule In yet another example, the nutrients themselves may be provided in a form that can be better absorbed mto the gastromtestmal system, e g as "micronutaents"

Formulations to Increase Bioavailabihty

Bioavailabihty is defined as the efficiency with which a natural or manufactured source of an element delivers the element to storage or supplies it to metabolically active tissue or to a protem The methods of the mvention can improve bioavailabihty of ceratin drugs and nutaents by providing them m an improved form for mgestion from a formulation with drugs or food, by providing the mam active component (e g drugs) with other components that mcrease the bioavailabihty of the mam active component, or by providmg the mam active component m a time release formulation Certain nutaents, e g minerals, can be conjugated to proteins, ammo acids, salts, etc to mcrease the bioavailabihty, and these conjugates can be particularized using the methods of the mvention See e g , Wapmr, Am J Chn Nutr 67 1054S-60S (1998) The presence of these conjugates as discrete particles can also increase the bioavailabihty of the particles, as the bioavailabihty of many minerals in vivo is limited by their ability to form strongly bound compounds which are not absorbed by the body By providing discrete conjugates that are absorbed before agglomeration of the nutaent, the bioavailabihty of a nutaent may be significantly mcreased

A number of nutaents display unproved absorption m the presence of other food components For example, absorption of calcium and magnesium can be stimulated by co-mgestion of sugars such as lactulose and ohgofructose Brommage et al , J Nutr 123 2186-2194 (1993), Delzenne et al , Life Sci , 57 1579-1587 (1995), Ohta et al , Int J Vitam Nutr Res 64 316-323 ( 1994) The addition of these components in food m an amount that increases mineral absorption but that does not overly affect the flavor or texture of food can be accomplished using the methods of the present mvention which are sizmg and coatmg of particles to obtam a desired result

Infant formulas

Infant formulas are a special food category that must meet the special needs of infants The present mvention can be used to add numerous additives or functional components to infant formulas that would optimize the growth and/or health of infants For example, babies fed on commercial formulas do not receive the same immune protection as babies receiving human breast milk Infant formula of the invention could be enhanced to contain physical and/or chemical immune boosters, such as echmacea extract, or antibodies agarnst certain pathogens that they would normally receive m breast milk Babies with certain medical needs could also have drugs such as antibiotics added to the formula to prevent or treat infection while allowing ease of administering these drugs to the infants

In addition, there are no commercially available infant formulas suitable for low birth weight and preterm formulas Such formulas need to compensate for the increased nutntional needs of premature, low weight, and very low weight infants The devices and methods of the mvention could mcrease the overall nutntional value of the formulas by providmg these nutaents with better bioavailabihty, or combmations of nutrients not currently available with conventional technology, e g due to chemical interactions m the formulation

EXEMPLARY USES OF EMBODIMENT 2 OF THE PRESENT INVENTION

Embodiment 2 of the device of the present invention provides methods of coatmg one formulation with another formulation by providmg fluids from concentnc needles This allows the production of multi-layered particles (e g , if separate liquids are delivered m the concentnc needles) or hollow particles (e g , if the innermost fluid is a gas) This methods allows the introduction of a number of components to pharmaceutical or food products, mcludmg multi-layered functional components, hollow food and drug additives, and the like, as descnbed in more detail below Foods with Coated Functional Particles that Enhance Flavor. Taste and or Texture

The methods of the invention can be used to coat functional components with a substance havmg a desirable quality for food flavor or texture (e g , spices, seasonings, natural flavorings, essential oils, fats, oleoresms, natural extracts, sugar, artificial sweeteners, salt, sour, or bitter flavors or mixtures thereof, etc ) This effectively allows a reduction m the use of the coating substance, and increase m the amount of the desirable component to be coated Thus, a food product can be made contammg a particle that contains a functional component such as fiber, protem, or a desirable compound that positively affects physiology, where the coated particle gives the food the sensation of having additional amounts of the substance that enhances flavor and/or texture Recent guidelines from the US Department of Agnculture (US DA) recommend 6-11 servings per day of gram products for overall good health while the National Cancer Institute recommends a daily intake of 20-30g of fibre per day for cancer risk reduction The methods of the invention can be used to produce food products having greater fiber content, while still maintaining the texture and taste of their conventional counterparts, by coatmg fiber particles with a desirable substance that enhances the flavor, texture, etc of the food For example, the technology of embodiment 2 can be used to coat a fiber particle, e g , a. bran particle, with a second substance, e g , a fat, oil, or sugar The coated particles can be produced to mimic the size of a normal particle found m the foods, e g , a fat-coated bran particle can be produced to mimic the normal size of a fat globule in the food This will preserve the flavor and/or feel of the food, mcrease the amount of dietary fiber, and decrease the amount of the substance used to coat the fiber This may be especially helpful m creatmg foods that are lower m fat, e g foods designed to decrease cardiovascular disease, or foods lower in sugar, such as foods for diabetics, without sacπficmg the taste or texture of the food product

The RDA of protem per day for an adult is 0 8 grams/kg For many people, and especially people with limited diets such as vegetarians and vegans, it can be difficult not only to consume the needed amount of protem, but also to consume "complete" protem, l e all of the essential ammo acids The device of the mvention can be used to "coat" proteins and/or specific ammo acids in foods to make the foods higher m protem (or in "complete protem"). but with a more desirable taste and/or texture due to the substance that is coatmg the protem

Coatmg of other filler molecules, such as methylcellulose, casern, starch soybean meal, and the like, is also mtended to be encompassed m this embodiment of the present mvention The use of such filler compositions, which preferably do not add to the calonc nature of a food, will be apparent to one skilled m the art upon reading the present disclosure This will also result in a reduction m the substance coatmg the filler particle in the food products without sacnficing the desirable qualities of that coating substance Food with Components Having Food Additive Coatings

The actual amount of a number of food additives may be decreased using the technology of the mvention. For example, if the effectiveness of a food additive is due to its surface area, then coating a filler particle with a food additive will allow use of less of the additive overall, while maintaining the effectiveness of the additive. For example, color additives that are added to food products may be modified by coating a filler particle, e.g., methylcellulose, which will allow the creation of a particle that is composed of mostly filler but that has the properties of a larger particle of the color additive. This will allow maintenance of the color of a food or drink product while limiting the actual amount used in the product. In another example, antimicrobial additives may be used to coat a filler particle, such as starch, to provide a molecule with higher surface area of the antii-iicrobial while reducing the actual amount of antimicrobial used.

Alternatively, the amount of food additive may be decreased by introduction of hollow spheres composed of the additive, for example a hollow sphere composed of a coloring additive. As with coating a filler, the use of hollow spheres will decrease the overall amount of the additive while maintaining the surface area of the additive.

Food additives that may be used to coat a particle include, but are not limited to: Acidifiers, Adjuvants of flavor, alkalies, anti-browning agents, anti-caking agents, anti-microbial agents, antistalling agents, binders, buffers, sequesters and chelators, coating agents, color agents, surfactants, emulsifiers, extenders, flavors, flavor enhancers, maturing agents (i.e. dough conditioners), sweeteners, and the like.

Foods with Time-release Pharmaceutical Particles

Foods having components that are preferably control-released can be coated with any number of compositions that will allow the component to be released at various times or intervals following ingestion. Using excipients as described in the preceding section on controlled release formulations, particles can be produced which have an internal core of a desired drug (either prescription or OTC), and an outer core of the excipient. Alternatively, particles can be produced which have an external core of a desired drug and an excipient coated around an inert core. The thickness of the outer coating may determine the length of time for release, and so the outer coating of the particles can be varied to provide release over a period of time. For example, particles having a core with functional component can be covered by an excipient coat of varying thickness can be introduced into a single food to allow release over a desired time period. In another example, the particles can have a coatmg of a uniform thickness to provide delivery of a component at a specific time period, e.g. delivery of insulin following ingestion of the food. Foods with Incompatible Components

Foods havmg functional components that are incompatible with the other mgredients of the food product may also be coated us g the technology of Embodiment 2 to allow addition of the incompatible component to the functional food One example of this would be the addition of coated particles of lactase to a dany product such as milk, cheese or ice cream The lactose can be delivered with these lactose-containing products to aid in the digestion of the product by people afflicted with lactose intolerance This would preclude the need for additional supplements, and would provide the proper amount of lactase with the lactose-containing product Another example of the addition of an enzyme incompatible with the food product is the addition of coated amylase particles to certain high- fiber foods such as such as canned beans to aid in digestion In yet another example of a compound which blocks the uptake of undesirable components (e g fats) could be combined with foods containing those undesirable components Foe example, a drug such as Xemcal™ which blocks fat absorption is combmed with a high fat food such as hamburger

The addition of incompatible food components is particularly useful in infant formulas Lactose is the primary carbohydrate in breast and cow milk Some infants are deficient in the enzyme, especially premature and lactase-deficient infants Soy protems are not as nutntious as milk protems and calcium is not as easily absorbed from soy formulas as from cow-milk formulas For infants havmg such problems, addition of a component contammg lactase to break down the lactose would allow the formulas to be based upon cow's milk, but would allow the infants to properly digest the formula

Other components that, when added to a food, may cause the food to change in nature of texture can also be added to a food by coatmg the particle for release dunng digestion For example, gelatm has been associated with the promotion of healthy bones and joints The addition of gelatin mto a beverage, however, changes the nature of the beverage because it begms to gel The gelatm may be coated and added to the beverage to provide the benefits of the gelatin while maintaining the fluid nature of the beverage

Foods Fortified with Components that Alter Taste

The device of the mvention can also be used to introduce components to food while masking negative effects of the component on the food For example, a number of functional components and additives, e g mmerals such as iron, may alter the taste of a food product Where it is desirable to mtroduce a component that affects the flavor of a food, the flavor of the component may be masked by a coatmg that has either a neutral flavor or a flavor that actively enhances the food product Some research has shown that omega-3 fatty acids, found m fish such as salmon and mackerel as well as in soybean and canola oil lower both LDL-cholesterol and tπglyceπde ley els in the blood Similarly, garlic extract has been touted as reducmg blood cholesterol levels Since both of these components strongly (and generally negatively) influence the flavor of a food, coatmg these components can allow them to be added to a wide vaπety of foods, e g , energy bars or baked goods

Packagmg Mateπals

The packing material of food e g cookies can be impregnated with particles which encapsulate a gas which includes a desired smell e g fresh baked cookie smell When the package is torn open the particles are opened releasing the desired smell The encapsulated food smells could also be used m product advertising

Controlled Release Formulations

Any food, food additives, drug, nutntional or other desired matenal can be formulated usmg different aspects of the invention to obtam a desired controlled release profile One means of obtaining a controlled release profile is to make a formulation which mcludes particle size increasing from a first known size to a second larger know size, etc If the size of each group (e g 2-10) group of particles has a known well defined size with a nanow size distnbution in that group then the release rate of mateπals from that group of particles can be determined The smaller the particles m a group, the faster the rate of release Thus, by producmg a formulation of several groups of particles of different sizes, the rate of release of the formulation as a whole can be controlled This can be done, for example, to control the rate in which sugar m a food is released to a diabetic patient to aid m controlling glucose levels This could be done with a drug to (a) quickly obtain a therapeutic level with a first quick release drug, and (b) obtained a constant level of the drug thereafter over a given penod of time by balancing the rate of release of subsequent groups against the rate at which the drug is cleared from the body Although the use of groups of particles of different sizes m a formulation may obtain the desired results, it may not be possible to obtain the desired results with all materials For example, some mateπals will dissolve too quickly to obtain the desired controlled release result only by usmg particles of different sizes m different groups

In such a situation, the desired controlled release results can be obtained by coatmg particles In one embodiment, the core particles are all the same size as obtamable via the present invention The formulation compnses a plurality of groups of particles wherein all the particles of a given group have a coatmg which is substantial the same size and thickness However, the coatmg thickness differs from one group to another

A first group may include a very thin coatmg or no coatmg at all Each subsequence group will compnse particles with thicker and thinner coatmgs The rate of release of a drug from particles in any group can be determined By knowing the rate of release of each group a desired formulation can be produced with the desired rate of release

A prefened formulation will quickly release enough drug to obtam a therapeutic level of drug in the patient, e g m blood Thereafter, that level of drug will be maintained m a desired therapeutic range over a desired period of time, e g hours, days, weeks, months, etc

The embodiments of figures 2 and 3 can be combined and used to more rapidly produce controlled release formulations on a commercial scale In figure 3C there are a plurahty of semicircular grooves 51 which form a plurality of extrusion tubes which are equivalent to the feedmg tube 1 of figure 1 or tube 21 of figure 2 Each of the tubes formed by the two parts of the channels or grooves 51 can have an inner feedmg tube inserted therein such as the inner tube 31 of figure 2 The inner feedmg tube (not shown in figure 3) is used to supply a liquid food or drug and the outer tube formed usmg the channels 51 are used to supply the coating material, e g a polymer matenal generally used in connection with a controlled release formulations such as methylcellulose The device is modified so that different groups of tubes formed by the channels 51 have different diameters For example, a first group of channels 51 form tubes with a diameter of 10 microns and each have an mner feedmg tube with a diameter of 5 microns The inner feedmg tube supplies the active component such as a pharmaceutical active drug The inner tubes may have different diameters but preferably all have the same diameter A second group of channels 51 form tubes with a diameter of 11 microns and each has an inner feedmg tube with a diameter of 5 microns Each successive group of channels 51 has a larger diameter but mcludes an inner feedmg tube havmg the same diameter When the device is operated, active mateπal (e g drug or food) is supplied to the inner feeding tube and a coatmg mateπal (e g an inactive, non-toxic polymer) is supplied to the outer groups of channels 51 The operation results m forming groups of particles wherem all groups have an inner core sphere of the same size but where the coatmg of each group of particles is larger than the coatmg of the previous group Thus, a formulation of controlled release particles of different groups with different rates of release can be simultaneously produced

While the present invention has been descnbed with reference to the specific embodiments thereof, it should be understood by those skilled m the art that vanous changes may be made and equivalents may be substituted without departing from the true spirit and scope of the mvention In addition, many modifications may be made to adapt a particular situation, matenal, composition of matter, process, process step or steps, to the objective, spiπt and scope of the present mvention All such modifications are mtended to be withm the scope of the claims appended hereto

Claims

What is claimed is:

1. A method for producing food particles, comprising the steps of: forcing a liquid food through a channel of a feeding source in a manner which causes the liquid to be expelled from an exit opening; forcing a gas through a pressure chamber in a manner which causes the gas to exit the pressure chamber from an exit orifice down stream of a flow path of the liquid expelled from the exit opening of the feeding source; wherein a stable first liquid-gas interface is maintained and the liquid forms a stable jet focused on the exit orifice of the pressure chamber by the gas.

2. The method of claim 1 , wherein the particles formed have the same diameter with a deviation of about ±3% to about ±30%.

3. The method of claims 1 or 2, further comprising: dispersing the food particles in a food composition.

4. A method for producing encapsulated particles, comprising the steps of: forcing a first liquid through a channel of a first feeding source in a manner which causes the first liquid to be expelled from an exit opening; forcing a second liquid through a channel of a second feeding source in a manner which causes the second liquid to be expelled from an exit opening, wherein said second liquid sunounds said first liquid as said first liquid moves from the first feeding source; and forcing a gas through a pressure chamber in a manner which causes the gas to exit the pressure chamber from an exit orifice down stream of a flow path of the first and second liquids expelled from the exit opening of the feeding sources; wherein a stable liquid-gas interface is maintained between the second liquid and the gas, and the first and second liquids are immersible and form a stable capillary jet focused on the exit orifice of the pressure chamber by the gas.

5. The method of claim 4, wherein the first liquid is a food and the second liquid is a polymer material which encapsulates particles which form when the jet leave the pressure chamber.

6 The method of claim 4, where the first liquid is a pharmaceutically active agent and the second liquid is a polymer material which encapsulates particles which form when the jet leave the pressure chamber

7 A method, compnsmg feedmg a first fluid from a first cyhndncal feedmg source, simultaneously feedmg a second fluid from a second cylmdncal feeding source which is concentπcally positioned around the first feedmg source, and forming a stable microjet of the first fluid sunounded by the second fluid by a sunoundmg gas flowing m a direction with the first and second fluids

8 The method of claim 7, wherem the microjet compnses a diameter d_} at a given pomt A in the stream characterized by the formula

wherem d_} is the diameter of the stable microjet, ~ mdicates approximately equal to where an acceptable margin of error is ± 10%, p, is the density of the liquid and ΔP_g is change m gas pressure of gas sunoundmg the stream at the pomt A, and Q the liquid flow rate

9 The method of claims 7 or 8, wherem the microjet breaks up mto sphencal droplets m approximately concentnc spherical layers of the first fluid and the second fluid

10 A food composition, compnsmg a base food matenal compnsmg 90 percent or more of the composition, and sphencal particles compnsmg 10 percent or less of the composition, wherem the particles are characterized by having a diameter m a range of from about 0 1 micron to about 100 microns and wherem the particles have the same diameter with a deviation m diameter from one particle to another of less than about ± 30 % and the particles are comprised of a material not naturally present in the base food mateπal

11 The food composition of claim 8, wherem the particles have a deviation m diameter from one particle to another of less than about ± 10 %

12 The food composition of claims 10 or 11. wherem the particles are gas filled spheres

13 A controlled release formulation, compnsmg a first group of coated particles compnsed of an mner core of a first active compound and a coatmg layer of a first thickness, a second group of coated particles compnsed of an inner core of a second active compound and a coatmg layer of a second thickness which is greater than the first thickness, and a container holding the first group and the second group of coated particles

14 The formulation of claim 13, further compnsmg a third group of coated particles compnsed of an inner core of a third active compound and a coatmg layer of a third thickness which is greater than the second thickness

15 The formulation of claims 13 or 14, wherem the active compounds are the same

16 A method of producmg coated particles of a drug, compnsmg the steps of forcmg a liquid formulation compnsmg a first ingestible substance mcludmg food for pharmaceutically active drug through a channel of a first feedmg source m a manner which causes a stream of the liquid drug to be expelled from a first exit opening at a first velocity, forcmg a liquid comprising a coatmg matenal through a second channel concentncally positioned around the first channel m a manner which causes a stream of the liquid coatmg mateπal to be expelled from a second exit openmg at a velocity which is substantially the same as the first velocity whereby the stream of coatmg mateπal is concentπcally positioned around the stream of first ingestible substance, forcmg a gas through a pressure chamber m a manner which causes the gas to exit the pressure chamber from an exit orifice positioned downstream of the concentπcally positioned streams of liquid ingestible substance and coatmg material, wherem the density of the liquid foimulation compnsmg the ingestible substance is substantially the same (±30%) as the density of the liquid compnsing the coatmg matenal, and the gas focuses the concentncally positioned streams to a stable jet of two concentnc jets which flows out of the chamber exit orifice and breaks up into coated particles of ingestible substance coated with the coatmg mateπal

17 The method of claim 16, wherem the stable jet compnsed of two concentnc jets compnses a diameter d_} at a given point A m the stream charactenzed by the formula

wherem d_} is the diameter of the stable jet. ^s indicates approximately equally to where an acceptable margm of enor is ± 10%, _l is the average density of the liquid of the jet compnsed of two concentnc jets and ΛP_g is change m gas pressure of gas sunoundmg the stream at the pomt A and Q is the total flow rate of the two concentnc jets

18 The method of claim 17, wherem d_i is a diameter m a range of about 1 micron to about 1 mm

19 The method of claim 17, wherem the stable j et compnsed of two concentnc j ets has a length m a range of from about 1 micron to about 50 mm

20 The method of claim 17, wherem the stable jet compnsed of two concentric jets is maintained, at least in part, by tangential viscous stresses exerted by the gas on a surface of the jet m an axial direction of the jet

21 The method of claim 17, wherem the stable jet compnsed of two concentric jets is further characteπzed by a slightly parabolic axial velocity profile

22 The method of claim 17, wherem the particles of ingestible substance coated with coatmg mateπal are characterized by havmg the same diameter with a deviation in diameter from one particle to another in a range of from about ±3% to about ±30%

23 The method of claim 22, wherem the deviation m diameter from one particle to another is m a range of from about ±3% to ±10%

24 The method of claim 16. wherem a given coated particle has a diameter m a range of about 0 1 micron to about 100 microns and other particles produced have the same diameter as the given particle with a deviation of about ±3% to about ±30%

25. The method of claim 16, wherein ΔP is equal to or less than twenty times the surface tension of the liquid of the coating material with the gas divided by the radius of the single stable jet.