HEAT-DEHYDRATED EMULSION COMPOSITIONS

Abstract: An improved dehydrated oil-in-water emulsion is prepared from emulsions having oil phase droplets with average diameters of less than about 0.4 microns which dehydrated emulsion, when reconstituted, has essentially the identical characteristics as the original emulsion. The original emulsions are dehydrated at about room temperature or above.

Description: HEAT-DEHYDRATED EMULSION COMPOSITIONS Background of the Invention This invention relates generally to the preparation and composition of dehydrated (dried) oil-in-water emulsions. More specifically, it relates to compositions dried at room tempera¬ ture or above and intended for oral or parenteral use as thera¬ peutics, nutrients, or biologies which are easily reconstituted with water at the time of administration to humans or animals. The compositions and methods of preparation described herein of¬ fer substantial advantages over other methods of preparing dehy¬ drated emulsions for reconstitution. Numerous compositions for oral or parenteral administra¬ tion are desirable in the form of oil-in-water emulsions. These include oral (enteral) feeding systems of edible vegeta¬ ble fats or oils, emulsified using approved emulsifiers, which may also" contain other nutrients such as amino acids, vitamins and sugars in the aqueous phase. Similar preparations based on metabolizable vegetable oils, biocompatible emulsifiers, solu¬ ble nutrients, buffers and water are useful as concentrated cal¬ orie sources in parenteral nutrition. Likewise, such parenter¬ al emulsions of submicron size are used to deliver water-insolu¬ ble, lipid-soluble drugs. Enteral emulsions can also be used to deliver such drugs orally. Such emulsions have potential advantages over other delivery forms which include, but are not limited to, side effect reduction, controlled or sustained re¬ lease, higher activity, improved targeting, enhanced biocompati- bility, increased stability, improved compatibility with other dosage forms, and improved economics. Oil-in-water liquid emulsions for oral and parenteral use have drawbacks which make their preparation, transportation, storage, and administration inconvenient. Liquid emulsions con¬ taining water cannot be employed with drugs which will degrade in the presence of water. Also, the bulk and overall weight of the aqueous phase often makes transportation uneconomic. Liq¬ uid emulsions often have limited shelf life stability due to the tendency of the immiscible phase to separate with time. Concentrations of drugs per unit of fluid are fixed in liquid emulsions. Also, liquid emulsions provide fertile growth media for microorganisms and are difficult both to preserve and to sterilize. One attempt at dehydrating emulsions similar to those of the present invention is disclosed in European Publication 0,211,257 of Abbott Laboratories, published ' February 25, 1987. This publication requires the use of a complex freeze-drying process to dehydrate the emulsion, and then a multi-day period in a lyophilizer slowly increasing the temperature. Even after this extensive and expensive period, reconstitution by the addi¬ tion of water produces particles which are substantially larger than those that were in the original emulsion. Non-protein high stability fat emulsion compositions were prepared in U.S. Pat. No. 4,492,714 (Cooper et al.). The compo¬ sitions contain 10 to 75% edible fat, 0.1 to 3% e ulsifier, 8 to 20% starch, and the remainder filler. They are intended to be dried to . low moisture contents and then rehydrated during use, i.e. as a substitute for cream in coffee. Preparing the Cooper et al. compositions requires, as the critical component, that the starch be a hydrated undextrinized lipophilic starch, predominantly in submicroscopic particle size. As shown by the comparative examples below, the substitution of such a starch for the hydrophilic water-soluble carbohydrate component of the present invention does not produce a rehydratable emulsion. It is an object of the present invention to produce a dehydrated emulsion composition which when reconstituted will yield droplets which are essentially of the same size as those that were in the emulsion prior to the dehydration. It is a further object of this invention to produce such dehydrated emulsions without the use of a freeze-drying procedure and con¬ sequent three-day lyophilization. It is a still further object to produce dehydrated emulsions which will be storage stable for extended periods, easily sterilized, reconstitutable to a variety of concentrations, easily transported, easily preserv¬ ed, and useful for the delivery of lipid-soluble materials, e.g. therapeutics, biologicals, and nutrients, to humans and an¬ imals. It is a still further object to provide a method of pre¬ paring such reconstitutable dehydrated oil-in-water emulsions. Summary of the Invention It has been discovered that an oil-in-water emulsion hav¬ ing a continuous aqueous phase containing therein discontinuous oil phase droplets of less than about 0.4 microns average diam¬ eter may be dehydrated at a temperature of at least about 20*C. and subsequently reconstituted by the addition of water to pro¬ duce an * oil-in-water emulsion wherein the oil phase droplets again have an average diameter of less than about 0.4 microns. The initial emulsion is prepared from a combination of about 0.1 to about 60 weight percent of a lipid-soluble ufaterial, about 0.1 to about 10 weight percent of a oil-in-water emulsi- fier, and about 0.5 to about 70 weight percent of a hydrophilic water-soluble solid carbohydrate, plus water. Description of the Preferred Embodiments The dehydrated emulsions of the present invention are formed by dehydrating a precursor oil-in-water emulsion contain¬ ing all of the desired ingredients. The dehydration is perform¬ ed at a temperature of about room temperature, i.e. at least about 20* C, or above. The resultant dry product contains a minimal amount of moisture and may be reconstituted by the addi¬ tion of water to produce an oil-in-water emulsion having essen¬ tially identical pharmaceutical activity, as the original emul¬ sion before dehydration, as shown by the oil phase droplets hav¬ ing essentially the same size as in the original emulsion. The oil phase droplets in both cases exhibit average diameters less than about 0.4, preferably less than about 0.3, microns. The dehydration and rehydration procedures may cause the oil phase droplets to increase in average diameter, but they still remain smaller than about 0.4 microns and thus essentially completely equivalent in performance to the original emulsion. Normally the increase in average diameter is less than about 50, prefer¬ ably less than about 25, most preferably less than about 10, percent. The precursor oil-in-water emulsion is prepared from a mixture of a lipid-soluble material, an oil-in-water emulsifi- er, a hydrophilic, water-soluble carbohydrate which is solid at room temperature, and water. Generally the mixture will com¬ prise about 0.1 to about 60 weight % lipid-soluble material, about 0.1 to about 10 weight % emulsifier, about 0.5 to about 70 weight % carbohydrate, and about 20 to about 99 weight % water. More preferably, the initial emulsion is prepared from about 1 to about 50 weight % lipid-soluble material, about 0.5 to about 5 weight % emulsifier, about 5 to about 50 weight % carbohydrate, and about 30 to about 95 weight % water. Most preferably, the initial emulsion is prepared from about 5 to about 20 weight % lipid-soluble material, about 1 to about 3 weight % emulsifier, about 5 to about 40 weight % carbohydrate, and about 40 to about 95 weight % water. The emulsions may al¬ so contain such conventional additives as buffers, stabilizers/- preservatives , flavors, colors, and the like, in conventional amounts for pharmaceutical compositions. Any lipid-soluble material may be used in the present in¬ vention. Preferably, the lipid-soluble material will be select¬ ed based upon the dehydration temperature so that it is not de¬ graded by the heat used to dehydrate the emulsion. Examples of suitable lipid-soluble materials include lipids per se. nutri¬ ents, therapeutics, and biologies. Examples of lipids useful herein include, but are not limited to, foods, vegetable and fish oils, triglycerides, synthetic or semi synthetic mono, di, triglycerides, and the like. Lipid-soluble nutrients or drugs useful herein include those active agents which are relatively water-insoluble but are quite oil-soluble. In certain cases, the lipophilic active can also represent the lipid component. Lipid-soluble (lipophilic and amphiphilic) therapeutic and biological agents useful herein are preferably selected from the group consisting of adrenal cortical steroids, adrenal cortical steroid inhibitors, allergens, analeptic agents, anal¬ gesics, anesthetics, anorexics, antialcohol preparations, anti- arthritics, antiasthma, antibacterials, antiseptics, antibiot¬ ics, anticatecholamine synthesis, anticholelithics, anticholin- ergics, inhibitors, anticoagulant antagonist, anticoagulant, an- ticonvulsants, antidepressants, antidiabetics, antidiarrheals, antidiuretics, antidotes, antienuresis, antifibrinolytics, anti- fibrotics, antiflatulents, antifungals, an igonadotropins, anti- herpes, anti-aids, antihistamines, antihyperammonia, antiinfla - matories, antileprosy, antimetabolites, anti igraines, antimo- tion sickness, antinauseants, antineoplastics, antiparasitics, antiparkinsonism, antiplatelet, antiporphyria, antipruritics, antipsychotics, antipyretics, antishock, antispasmodics, anti- vertigo, antiviral, vaccine antigens, globulins, toxoids, bone metabolism regulators, bowel evacuants, bronchial dilators, car¬ diovascular agents, CNS stimulants, chlators, cholesterol, reduc¬ ers, antihyperlipemics, contraceptives, cough and cold prepara¬ tions, decongestants, expectorants, deodorants, dermatologi- cals, diagnostics, dietary supplements, diuretics, depamine re¬ ceptor antagonists, electrolytes, emetics, enzymes, digestants, enzyme inhibitors, ergot derivatives, fertility agents, golucto- linetics, gall stone dissolvers, GI motility regulators, geria¬ tric agents, hematinics, hemostatics, histamine H2 antagonists, antihemorrhoidals, hormones, hyperglycemic agents, hypnotics, immunosuppressives, antiinsect bite agents, laxatives, lipotro- pics, monoclonal antibodies, mouthwashes, mucolytics, muscle relaxants, narcotic antagonists, narcotic detoxifiers, nasal agents, opthalmologicals, otic agents, oxytocics, parasympatho- lytics, parasympathomimetics, penicillin adjuvants, plasma ex¬ tenders, plasma fractions, prostaglandins, psychostimulants, respiratory stimulants, sclerotics, sedatives, antismoking agents, sympatholytics, sympathomimetics, thrombolytics, thy¬ roid preparations, tranquilizers, antituberculars, uricosuries, urinary acidifiers, urinary tract agents, uterine contractants, uterine contraction inhibitors, vaginal preparations, vitamins and x-ray contrast media. The above terms are used in the man¬ ner common to the pharmaceutical sciences as exemplified by the Physicians Desk Reference. 42st edition (Medical Economics Co. NJ, 1988). Lipid-soluble nutrients include, but are not limited to, edible oils from all sources (vegetable, fish, and the like) , vitamins, carbohydrate derivatives, a ino acid derivatives, pro¬ tein derivatives, enzymes, fats, sterols, and all other lipid soluble food additives listed and generally recognized as safe (both currently and in the future since the invention is inde¬ pendent of the particular lipid-soluble material) in 21 CFR 170- 1999 and other parts of the Code of Federal Regulations. (U.S. Government Printing Office, Washington, DC, 1988) The oil-in-water emulsifiers useful herein include, but are not limited to, surface active agents capable of forming oil-in-water emulsions and suitable for use orally or parenter- ally depending on the intended mode of administration. For oral products, examples include those emulsifiers currently listed in 21 CFR 170-199 and other parts of the Code of Federal Regulations which are generally recognized as safe in man or appropriate animals. For parenteral products, useful emulsifi¬ ers include, but are not limited to, natural and synthetic phos- pholipids, egg and soy lecithins, block copolymers of ethylene oxide and propylene oxide (Pluronics tm , Tetronics tm - BASF Corp.), straight chain POE derivatives (Tweens tm - ICI Ameri¬ ca) , sσrbitan esters (Arlacels tm - ICI America) , cholic acid derivatives, and the like. Carbohydrates useful herein are those carbohydrates which are both hydrophilic and water-soluble. The carbohydrate is thus one which is capable of being dehydrated to a dry solid (so that the lipid-soluble materials have a place on which to deposit during the drying operation) . The specific carbohy¬ drate used should also be biocompatable with the intended use of the specific emulsion. Examples of such hydrophilic water- soluble carbohydrates include mono, di, oligo, and polysaccha- rides and sugar alcohols. More specifically, useful herein are dextrose, sucrose, fructose, galactose, sorbitol, mannitol, xy- litol, trehalose, inositol, lactose, maltose, dextrin, and wa¬ ter-soluble starch derivatives are suitable carbohydrates. Any other hydropohilic, water-soluble carbohydrate which either now or in the future becomes generally recognized as safe for food use may .be used herein. While any suitable source of water may be used both in preparing the initial emulsions as well as in reconstituting the dehydrated ones, generally the purity of the water "will de¬ pend upon the specific use intended for the product. The aque¬ ous phase may also contain, but not necessarily dissolved there¬ in, other components known to the art to be appropriate for the intended route of administration, e.g. water-soluble materials such as buffers, chelates, electrolytes, flavors, colors, essen¬ tial elements, salts, amino acids, water soluble vitamins, pre¬ servatives, stablilizers, combinations thereof, and the like. The precursor oil-in-water emulsion is conventionally pre¬ pared by (i) dissolving all lipid-soluble active materials, emulsifiers and additives into a lipid phase, (ii) dissolving all water-soluble or water-dispersible emulsifiers, carbohy¬ drates, and additives into an aqueous phase, and (iii) forming an oil-in-water emulsion of the two phases wherein the oil phase droplets have average diameters of less than about 0.4 microns . Heat may be used, where appropriate, to achieve dissolu¬ tion for either or both of the phases, provided that none of the components is subject to rapid heat-degradation. Critical to the successful rehydration of the subsequent¬ ly dehydrated emulsion is the preparation of a precursor liquid emulsion with a submicron average droplet size (i.e. less than about 0.4 microns) and also, preferably, a narrow size distribu¬ tion. The average diameter of the droplets is measured by quas- ielastic laser light scattering instrumentation. Preferably, the average droplet size is less than 0.3 microns with a size distribution less than +/- 50%. Conventional mixing technology is seldom able to achieve such size and size distribution with¬ out employing unacceptably high levels of surface active agents or requiring the presence of undesirable cosolvents such as al¬ cohols and the like. The preferable droplet size range may be readily achieved by employing a process exemplified by Microflu- technology. Microfluidizer equipment is commercially available from Microfluidics Corp. , Newton, MA, and is describ¬ ed in U.S. Pat. No. 4,533,254, the subject matter of which is hereby incorporated by reference. To utilize the Microfluidizer equipment and technology, a crude emulsion is prepared by slowly adding one phase to the other, preferably the lipid phase to the aqueous phase, with low energy mixing provided by such as a conventional propeller stirrer. The crude emulsion is then processed through the ul¬ tra high energy Microfluidizer equipment to produce a superfine emulsion of submicron size and within the preferable average droplet size range. The precursor liquid emulsion exhibits ex¬ cellent storage stability with regard to retaining its initial average size and size distribution. The precursor oil-in-water emulsions are formed into the dehydrated compositions of this invention by dehydrating the precursor liquid emulsion. The dehydration can be performed at ambient or elevated temperature with or without vacuum. The drying temperature is generally as high as possible provided that it is not so high that any component is degraded thereby. Examples of suitable dehydration methods include spray drying, tray drying, drum drying, oven drying, falling ball drying, flu¬ id bed drying, flash drying and the like. In a preferred embod¬ iment, it is desireable to minimize the length of exposure of the precursor liquid emulsion to both the atmosphere and to heat due to the sensitive nature of many of the ingredients em¬ ployed and to minimize, preferably prevent, any degradation or agglomeration of the resulting dehydrated emulsion. Moreover, the drying process should provide an economic incentive rela¬ tive to more costly processes such as lyophilization and pro¬ vide a dehydrated emulsion that rehydrates into a liquid pro¬ duct similar to the precursor liquid emulsion. It has been dis¬ covered that spray drying combines all the aforementioned desir¬ able elements. Spray drying entails creating droplets of the liquid emulsion using a nozzle or cetrifugal atomizer within a large chamber into which heated air is flowed. As the droplets encounter the hot air, the water evaporates and the resulting dry powder may be isolated by a cyclone or bag collector. Resi¬ dence times are normally extremely short in a spray dryer, thus minimizing any deleterious contact with heat and air. General¬ ly the spray drying will be performed at exit temperatures less than about 100'C. The droplet size of the original lipid phase, and not the size of the atomized emulsion droplet, has been found to determine the size of the droplets in the result¬ ing emulsion on reconstitution of the dehydrated emulsion. After spray drying, the dehydrated emulsions may be sub¬ jected to further manipulations such as sieving, sterilization and packaging as are well known in the art. The practice of this invention is illustrated by, but not limited to, the following examples in which all parts and per- cents are by weight unless otherwise specified: EXAMPLE I A. Precursor Liquid Emulsion Preparation In a suitable container, 7.2 gm of egg phospholipid (par¬ enteral grade; Pfanstiehl, Waukegan, IL) is added to 200 ml of water for injection, USP (Baxter, Morton Grove, IL) with propel¬ ler mixing until the phospholid is fully hydrated (1 hr.). Stirring continues while 60.0 gm of soybean oil, USP, superefin- ed (Welch, Holme & Clarke, S. Plainfield, NJ) is added drop- wise. In another container, 30.0 gm of sucrose, USP (Mallin- krodt, St. Louis, MO) is dissolved in 300 ml of water for injec¬ tion, USP. The sucrose solution is slowly added, with propel- lar mixing, to the coarse emulsion of soybean oil, water and phospholipid described above and the total combined volume is then adjusted to 600 ml with water for injection, USP. The re¬ sulting coarse emulsion (droplet size 2 to 25 microns) is then adjusted to pH = 7.4 with either hydrochloric acid solution (reagent grade) or sodium hydroxide solution (reagent grade) . This material is them processed through a Microfluidiz- er^- M-110 (Microfluidics Corp., Newton, MA) four times at 12,000 psi operating pressure and a flow rate of 200 ml/min¬ ute. The resulting droplet size of the microemulsion was meas¬ ured using a quasi-elastic laser light scattering particle size determination instrument (Brookhaven Instruments, Model BI-90, Brookhaven, NY). The average droplet size was 0.19 microns with a size distribution of +/- 35%. B. Dehydration of Emulsion The precursor liquid emulsion described in (A) was dehy¬ drated by spray drying using a Buchi Laboratory Model 190 spray dryer (Brinkmann Instruments, Westbury, NY). Flow rate, inlet heating, pump and aspirator rates were adjusted to achieve an outlet air temperature of 43 β C. Dry product was collected for examination and analysis. It was white-light tan in color and showed acceptable flow characteristics. Analysis indicated a residual moisture content of 1.0%. C. Reconstitution of Dehydrated Emulsion The dehydrated emulsion of (B) was weighed into vials (0.21 gm per vial) which were then sealed with rubber diaphrams and metal closures. Using a syringe, 1.3 ml of water for injec¬ tion was added to several of the vials which were then shaken for five seconds by hand. A white, fluid homogeneous appearing emulsion resulted in each case. Analysis of the emulsions for average droplet diameter showed that they were 0.21 microns with a size distribution of +/- 34%. Reconstituted emulsions showed no separation or meaningful change in average droplet size after storage for one week at room temperature. EXAMPLE II Precursor liquid emulsion was prepared as in Example I using an additional 30 gm of sucrose. Droplet size measurement after Microfluidizer^ processing was 0.20 microns with a size distribution of +/- 30%. This emulsion was dehydrated under the same drying conditions as Example I and similarly rehydrat- ed. The rehydrated emulsion showed an average droplet size of 0.22 microns with a size distribution of +/- 28%. EXAMPLE III Precursor liquid emulsion of Example II was dehydrated by spray drying with conditions adjusted so as to achieve an out¬ let air temperature of 48°C. The dehydrated emulsion, rehy¬ drated as in Example I, showed a droplet size of 0.23 microns with a size distribution of +/- 27%. EXAMPLE IV Precursor liquid emulsion of Example II was dehydrated by spray drying with conditions adjusted so as to achieve an out¬ let air temperature of 59'C. The dehydrated emulsion, reconsti- tuted as in Example I, showed a droplet size of 0.21 microns with a size distribution of +/- 29%. EXAMPLE V The following precursor liquid emulsion was prepared as in Example I: Soybean Oil 30.0 gm Egg Phospholipid 7.2 gm Sucrose 30.0 gm Water for injection qs. to 600 ml The pH was adjusted to 7.4. A droplet size determination of this precursor liquid emulsion was 0.21 microns with a size distribution of +/- 29%. This emulsion was then dehydrated by spray drying with conditions adjusted so as to achieve an out¬ let air ^ temperature of 45"C. the dehydrated emulsion, reconsti¬ tuted as in Example I, showed a droplet size of 0.19 microns with a size distribution of +/- 43%. EXAMPLE VI Precursor liquid emulsion was formulated and prepared as in Example V using an additional 30 gm of sucrose. A droplet size determination on this precursor liquid emulsion showed a size of 0.18 microns with a size distribution of +/- 30%. The emulsion was dehydrated as in Example V. Upon rehydration, size measurement of the droplets showed 0.18 microns with a size distribution of +/- 38%. After three months storage at room temperature, this sample measured 0.16 microns with a size distribution of +/- 47%. EXAMPLE VII The following precursor emulsion was prepared as in Exam¬ ple I: Soybean Oil 500 gm Egg Phospholipid 60 gm Sucrose 750 gm Water qs to 5000 ml A droplet size determination was made of the oil phase droplets in this precursor liquid emulsion and they were found to average 0.18 microns with a size distribution of +/- 35%. This emulsion was then dehydrated by spray drying using an APV Anhydro Dryer-Type SI using an inlet air temperature of 200"C. and an outlet air temperature of 90"C. The dehydrated emul¬ sion, upon reconstitution, showed droplets having an average size of 0.26 microns +/- 45%. EXAMPLE VIII The following precursor emulsion was prepared: Metronidazole 3 gm Soybean Oil 60 gm Egg Phospholipid 7.2 gm Sucrose 90 gm Water for injection qs 600 ml . Metronidazole, a therapeutic agent, is dissolved in the soybean oil by means of a propeller mixer. Egg phospholipid is added to the water and fully hydrated (1 hr) using propeller mixing. Mixing is continued and the sucrose is added slowly until complete dissolution is achieved at which time the oil phase is added forming coarse emulsion. This emulsion is then processed through a Microfluidizer M-110 three times at 14,000 psi operating pressure. The resulting precursor liquid emul¬ sion, which contains oil phase droplets measuring 0.19 microns with a size distribution of +/-26% was dehydrated using a Buchi Laboratory Model 190 spray dryer. Upon reconstitution, the re¬ sulting emulsion showed an average droplet size of 0.27 microns with a size distribution of +/" 3% - COMPARATIVE EXAMPLE A The basic procedure of Example I was repeated except that the hydrophilic, water-soluble starch, i.e. sucrose, was replac- ed by the hydrated undextrinized lipophilic starch of U.S. Pat. No. 4,492,714, i.e. National Starch # 1817. The specific compo¬ sition prepared contained the following components: Egg phospholipid 1.2 gm Soybean oil 10.0 gm National Starch #1817 7.0 gm Water for injection qs 100 ml The composition was processed through the Microfluidizer as in Example I. The resultant precursor emulsion was not suf¬ ficiently stable to be dehydrated since it separated into two distinct phases within an hour of its preparation. As such, it is not suitable to produce a homogeneous dehydrated product which can be rehydrated to an essentially identical product. COMPARATIVE EXAMPLE B The basic procedure of Example I was repeated with a dif¬ ferent composition which, on a solids basis, is within the scope of U.S. Pat. No. 4,492,714. The specific composition evaluated was: Egg phospholipid ("emulsifier") 0.3 gm Soybean oil ("fat") 7.5 gm National Starch #1817 1.5 gm Sucrose ("edible filler") 0.4 gm Water for injection qs 100 ml The composition was processed into an oil-in-water emul¬ sion in which the average droplet size was found to be about 0.5 microns with a size distribution of +/- 50%. The emulsion was dehydrated by tray drying at a maximum temperature of 50" C., which is essentially the actual temperature of the corre¬ sponding material that exits the spray drier in Example I. Attempts to reconstitute the dehydrated emulsion by the addition of water were unsuccessful. The resulting liquid sep¬ arated into two phases immediately upon cessation of shaking.

Claims: WHAT IS CLAIMED IS: 1. An oil-in-water emulsion from which the water has been removed, which dehydrated material is prepared from an oil-in-water emulsion containing a continuous aqueous phase with discontinuous oil phase droplets dispersed therein and having an average diameter of less than about 0.4 microns, com¬ prising (a) a oil-in-water emulsion from which the water is remov¬ ed being prepared from a combination of: (i) about 0.1 to about 60 weight percent of a lipid- soluble material, (ii) about 0.1 to about 10 weight percent of an oil- in-water emulsifier, (iii) about 0.5 to about 70 weight percent of a hy¬ drophilic, water-soluble carbohydrate, and (iv) about 20 to about 99 weight percent water, (b) the water is removed at a temperature of at least 20° C; wherein the addition of water to reconstitute the origi¬ nal emulsion produces an oil-in-water emulsion having oil phase droplets having an average diameter of less than 0.4 microns. 2. The product of Claim 1 wherein the lipid-soluble ma¬ terial is a lipid. 3. The product of Claim 1 wherein the lipid-soluble ma¬ terial is a human or animal food product. 4. The product of Claim 1 wherein the lipid-soluble ma¬ terial is an oil selected from the group consisting of vegeta¬ ble and fish oils. 5. The product of Claim 1 wherein the lipid-soluble ma¬ terial is a glyceride selected from the group consisting of syn¬ thetic and semi-synthetic mono-, di-, tri-glycerides. 6. The product of Claim 1 wherein the lipid-soluble ma¬ terial is a lipid-soluble nutrient selected from the group con¬ sisting essentially of edible vegetable oils, edible fish oils, vitamins, carbohydrate derivatives, a ino acid derivatives, pro¬ tein derivatives, enzymes, fats, and sterols. 7. The product of Claim 1 wherein the lipid-soluble ma¬ terial is any lipid-soluble food additive identified in the U.S. Code of Federal Regulations as generally recognized as safe for human consumption. 8. The product of Claim 1 wherein the lipid-soluble ma¬ terial is a combination of a lipid and at least one other lipid- soluble material. <?. The product of Claim 8 wherein the other lipid-solu¬ ble material is a nutrient. 10. The product of Claim 8 wherein the other lipid-solu¬ ble material is a therapeutic. 11. The product of Claim 8 wherein the other lipid-solu¬ ble material is a biologic. 12. The product of Claim 1 wherein the emulsifier is sel¬ ected from the group consisting essentially of phospholipids, egg and soy lecithins, block copolymers of ethylene oxide and propylene oxide, straight chain polyoxyethylene derivatives, sorbitan esters, and cholic acid derivatives. 13. The product of Claim 1 wherein the emulsifier compris¬ es a phospholipid-containing emulsifier derived from eggs. 14. The product of Claim 1 wherein the emulsifier compris¬ es a phospholipid-containing emulsifier derived from soybeans. 15. The product of Claim 1 wherein the carbohydrate is se¬ lected from the group consiting essentially of mono, di, oligo, and polysaccharides and sugar alcohols. 16. The product of Claim 15 wherein the carbohydrate is selected from the group consisting essentially of dextrose, su¬ crose, fructose, galactose, sorbitol, annitol, xylitol, trehal- ose, inositol, lactose, maltose, dextrin, starch derivatives, and mixtures thereof. 17. The product of Claim 1 wherein the water further con¬ tains at least one water-soluble material selected from the group consisting essentially of buffers, chelates, electro¬ lytes, flavors, colors, essential elements, salts, a ino acids, water-soluble vitamins, preservatives, and stablilizers. 18. The product of Claim 1 wherein the oil phase droplets of the emulsion from which the water is removed are less than about 0.3 microns in average diameter. 19. The product of Claim 18 wherein after reconstitution by the addition of water the oil phase droplets are less than about 0.3 microns in average diameter. 20. The product of Claim 1 wherein the oil-in-water ini¬ tial emulsion is prepared from about 1 to about 50 weight % lip¬ id-soluble material, about 0.5 to about 5 weight % emulsifier, about 5 to about 50 weight % hydrophilic water-soluble carbo¬ hydrate, and about 30 to about 95 weight % water. 21. The product of Claim 1 wherein the oil-in-water ini¬ tial emulsion is prepared from about 5 to about 20 weight % lip¬ id-soluble material, about 1 to about 3 weight % emulsifier, about 5 to about 40 weight % hydrophilic water-soluble carbo¬ hydrate, and about 40 to about 95 weight % water. 22. The product of Claim 1 wherein the water is removed from the emulsion by means of a spray dryer. 23. The product of Claim 22 wherein the spray dryer is op¬ erated at a maximum exit temperature of less than about 100"C. 24. A method of preparing a oil-in-water emulsion product from which the water has been removed and which may be reconsti¬ tuted by the addition of water to produce an emulsion wherein the oil phase droplets are less than about 0.4 microns in aver¬ age diameter which comprises (i) forming a crude precursor oil- in-water emulsion from a mixture of a lipid-soluble material, an oil-in-water emulsifier, a hydrophilic water-soluble carbohy¬ drate which is solid at room temperature, and water, (ii) pro¬ cessing the crude precursor emulsion to form a microemulsion wherein .the oil phase droplets have average diameters less than about 0.4 microns, and (iii) removing the water from the microe¬ mulsion at- a temperature from above about 20*C. to a maximum temperature which is below that at which any component in the mixture will substantially degrade. 25. The method of Claim 24 wherein the oil phase droplets of the microemulsion before water removal have average diame¬ ters less than about 0.4 microns. 26. The method of Claim 24 wherein the oil phase droplets of both the microemulsion before removal of the water and after reconstituted of the emulsion by the addition of water have average diameters less than about 0.3 microns. 27. The method of Claim 24 wherein the water removal is performed by means of a spray dryer.

Inventors: SICILIANO ARTHUR A, TABIBI ESMAIL, SICILIANO, ARTHUR, A., TABIBI, ESMAIL
Applicants: MEDICONTROL CORP, MEDICONTROL CORPORATION
Application year: 1989
Main classification: A23D7
IPC codes: A23K1, A61K9, A61K47, B01J13