AU2015224466A1 - Water-soluble dietary fatty acids - Google Patents

Abstract

Water-soluble dietary fatty acid formulations, solutions, and methods for increasing the water solubility and/or bioavailability of dietary fatty acids, as well as methods for treating various diseases are disclosed.

Description

WATERSOLUBLE DIETARY FATTY ACIDS BACKGROUND Dietary or nutritional fatty acids are a family of unsaturated fatty acids that include the omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as well as ornega-6 and omega-9 fatty acids. One f the primary sources for the omega-3 fatty acids is fish oil; however, omega-3 10 fatty acids can also be obtained from botanical sources and algae. The cardiovascular and other health benefits of these fatty acids are kno in addition to their general nutritional benefits, Due to the increased awareness of the health benefits of the omega-S class of fatty acids, dietary food supplements of fish oil and flax oil have become popular, and a number of food companies have added 15fish oils to food and beverage products. Until recently. deodorized fish oils with virtually no fishy taste or smell have not been available. However, with the availability of deodorized fish oils, it is now possible to make beverages containing omega-3 fatty acids, or fish oil, but the solubility of the oil in water containing beverages is a problem. Thus, it would be 2 desirable to provide a formulation of nutritional fatty acids that are soluble in water containing beverages, or a water-soluble omega-3 faty acd formulation that could be consumed as a beverage, It would also be desirable to have a clear beverage that is not cloudy or opaque, In addition, it would aiso be desirable to have a process or method of making such formulations. 2$ Furthermore, it is noted that consumption of nutritional or dietary fatty aids have been identified with many health benefits, having the potential to impact numerous diseases such as cardiovascular, neurological. immune unction, and arthritis. In order for any therapeutic molecular substance to be efficiently transported through the gastrointestinal tract, enter the blood, and 0 eventually reach the organs and cells inside the body, the molecule should be dissolvable in the aqueous phase of the ntestinai fluid, Without an acceptable amount of dissolution, the drug would mostly pass through the SI-tract. Fats or oils (lipids) can become more absorbable if they are emulsified in the stomach as part of digestion. This process involves the generation of a lipid-water interface and an interaction between water-soluble lipases and insoluble lipids or fats. The absorption of lipids is enhanced greatly by this process. By already forming a lipid-water complex through a pre-existing water-soluble formulation, the Sbioavailability or absorption of lipids such as dietary fatty acids, can be enhanced. The problem is that nutritional fatty acids such as omega-3 fatty acids are virtually insoluble in water, and if added to beverages as a cloudy emulsion, suspension, or oil in water mixture, they are less than satisfactory to consumers for consumption. 0Due to the many desirable properties of nutritional or dietary fatty acids, it would be advantageous to provide a more water-soluble formulation and/or enhanced bicavailability formulation of these fatty acids for in vivo use. SUMMARY 15 This disclosure relates to unique pharmaceutical compositions comprising water-soluble formulations of dietary or nutritional fatty acids. Specifically, a water-soluble dietary fatty acid gel formulation can comprise from 1 wt% to 75 wt% of dietary fatty acid; and from 25 wt% to 99 wt% of non-ionic surfactant 20 Further, a method of delivering a dietary fatty acid to a subject can comprise administering the water-soluble dietary fatty acd ge formulation to a subject such that the dietary fatty acid is more bioavailable then when the same amount of dietary fatty acid is delivered alone. In another embodiment, a dietary fatty acid solution can comprise from 0,1 25 wt% to 94.9 wt% of water; from 0.1 wt% to 35 wt% of dietary fatty acid; and from 5 wt% to 75 wt% of non-ionic surfactant. In one embodiment, the non-ionic surfactant can be present at a concentration to render the dietary fatty acid water soluble forming a clear solution. Further, a method of delivering a dietary fatty acid to a subject can compnse administering the dietary fatty acid solution to a 30 subject such that the dietary fatty acid is more bioavailable then when the same amount of dietary fatty acid is delivered alone. A method of dissolving dietary fatty acids en water can comprise the steps of combining a dietary fatty acid with a warm, well mixed nonlonic surfactant to form a surfactant-dietary fatty acid mixture; and continuously mixing the su''factant-dietary fatty acid mixture with water at least as slowly as necessary to solubilize the dietary Fatty acid. Additionally a method of enhancing the bioavaiiabiiity of a dietary fatty acid in a subject can comprise dissolving a surfactant-dietarv fatty acid mixture n water s described above. DETAiLED DESCRIPTION 1o The abbrevits used hemin have their conventional eaning vtn the che mical and biological arts. "Dietary fatty acids" as used herein, includes nutritional fatty acids, omega 3 -fatty acids derived from natural sources such as fish, botanical sources such as chia sage or Salvia hispanica, or flax sources derived from linseed, or which are 5 produced synthetically. The following is a list of omega-3 fatty acids (Table 1) followed by a list of botanical extracts of omega-3 fatty acids (Table 2). These Ists are exemplary only, and are not considered to be limiung. Table 1 - List of several common n-3 fatty acids found in nature ---- Lipid Name Chic-Namne --- 6:3-- (-3) all-c , ------- exadecatreno ac AlranOne ni acEid (ALA) 18:3 (n-3) all-ci- 91IZ1I-ocfadecaienoe acid Steandonic acid (STD) :483)5 j al-c/-SO,1Zf5c cdecaebaeincsi ac/la Esosatrienoic acid (ETE) 20:3T(--5- all-c/s-I- 14,1 7--ic-a ie5i-- :cn - E icosatetraenoic acid ( E TA) -i20:4 (n--3) a/i-c/s-8, 14;1117-eicarniniciBa~ Eicosapentaenaic acid (EPA) 20:5 (n-3) all-cis-5 ,11.14, 17-eicosapentaencic acid jflcosapentaencic acid (DP A) 22 5 (n-3) all-cis-7,10, 13.16, 19-docosapentaenc Clupanodonic acid acid Oocosahexaenoic acid (OHBA) 22 5 n-3)} all-cs3-4,7, 10,13,16,1i9-doccoafhexaenci Tabl 2 Sorcs of botanical extracts of omega-S fatty acids - ---- 3 ------ -- Common Name Aternative Name Linnacan Name % n 3 Cha Chia sage-------- 5 ---- nc Kiw'ifruit Chinese gooseberry Actinidia chinens/s 62 eria Sniso ~Perla ftesces- - 51 *Flax Unseed Inum uiaismm 6 Ungonberry CowberryVaccINI/um eane 4 Camnelna Gold--of-pleasure Camelina sativa 36 Pursiard Portulaca - Portuaca o/eracea 35 Black Raspberry - IRubus coccidentai/s 33 Dietary Fatty Acids containing omega-3 fatty acids may also be derived from algae such as Crypthecodinium cchnii and Schizochytriumn, which are rich sources of DHA , or brown 'algae (kelp) for EPA, They may also include 5 conjugated linoleic acid (CLA), ornega-6 fatty acids, and omega-9 fatty acids, such as linolenic acid, linoleic acid (18:2), and gamma linolenic acid (GLA, 18:3). A "non-ionic surfactant " as used herein, is a surface-active agent that tends to be non-ionized (i~e. uncharged) in neutral solutions (e.g. neutral aqueous solutions) 10 The term "treating" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement. remission, diminishing of symptoms; making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline: making the final point of degeneration less 1$ debilitaung; or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination. neuropsychiatric exams, and/or a psychiatric evaluation, Also, treahng includes preventative treatment such as promoting the general health of body systems, such as heart or other organ 20 health.ec. As used herein, the term 'cancer' refers to all types of cancer, neoplasm, or malignant tumors found in mammals, including leukernia, carcinomas and sarcoma, Exemplary cancers include cancer of The brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-smal cell lung, melanoma, mesothelioma, 25 ovary, sarcoma, stomach, uterus and Medulloblastoma. Additional examples ------ ....... ...------------.. ......

include, Hodgkin's Disease, Nor-Hodgkin's Lymphoma, multiple myeloma, euroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary rmacroglobulinemlia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin 5 lesions, testicular cancer, lymphomas. thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine and exocrine pancreas, and prostate cancer. "Patient" or "subject" refers to a mammalian subject, including human, 10 As used herein. the term "titration or "titrate" means the slow addition of a compound or solution to a liquid while mixing. The rate at which the compound or solution is added should not exceed a certain threshold, or the clear nature and viscosity of the solute is lost, Slow addition can be as a drizzle or drop by drop, but in no case should equal large volumes. Slow addition can be specified as a 15 percent of the volume it is being added to per second or per minute, for example 5 mL per second to 100 mL water, or 5 wt% addition per second or minute of the content being added to water or water containing beverage. As used herein, the term "clear aqueous solution" in reference to a solution containing dietary fatty acid means a water containing solution (e.g. a beverage) 20 that is free of visible particles of undissolved dietary fatty acid. In accordance with some embodiments, the clear aqueous solution is not a dispersion, and not a suspension, and remains clear upon sitting undisturbed for 1 hour or nore. Often, very small micelles are formed that are not visible, and thus, the solution is clear. 25 The term "water-soluble herein refers to the solubilization or very fine dispersion of dietary fatty acids so that they are not visible to the naked eye in solution, Often, in the formulations of the present disclosure, the fatty acids can form micelles in water with a nondonic surfactant barrier, and the micelles can be smaller than about 100 nm in size, and often are about 15 nm to about 30 nm in 30 sze, Thus, whether the dietary fatty acids are strictly dissolved or merely so finely dispersed that the solution they form within is clear, this is still considered to be "water-soluble" in accordance with embodiments of the present disclosure.

VWater-sokubfe Formuations It has been discovered that non-ionic surfactants can be used to increase the solubility and/or biavailabilty of dietary fatty acids when combined appropriately. Thus, non-Ionic surfactants can be used to form fatty acid gel Sformulations that are highly water-soluble. In one aspect, the present disclosure provides a water-soluble formulation including a dietary fatty acid, and a non-ionic surfactant, In some embodiments, the water-soluble formulation does not include a vegetable oil suspension or visible macro-micelles (micellvisiisible to the naked eye) in water. In other 10 embodiments, the water-soluble formulation does not include an alcohol (e.g. the dietary fatty acid is not first dissolved in alcohol and then added to water) or other additives that would otherwise enhance the solubility of the dietary fatty acids. In accordance with this, a water-soluble dietary fatty acid gel formulation can comprise or consist essentially of from 1 wt% to 75 wt% of dietary fatty acid; 15 and from 25 wt% to 99 wt% of non-Ionic surfactant, In one embodiment, the gel formulation can be soluble in water and forms a clear solution at a weight ratio of 1:3 (gel to water). In another embodiment, the gel formulaton can be soluble in water and forms a clear solution at a weight ratio of 1:1. In still another embodiment, the dietary fatty acid can be present at from 5 wt% to 60 wt%, and 2 the non-ionic surfactant can be present at from 40 wt% to 95 wt%. A dietary fatty acd solution can also comprise or consist essentially of from 0.1 wt% to 94.9 wt% of water; from 0.1 wt% to 35 wt% of dietary fatty acid; and from 5 wt% to 75 wt% of non-ionic surfactant. In one embodiment, the water can be present at afrom15 wt% to 75 wt%; the dietary fatty acid can be present at from 2 wt% to 20 wt%, and the non-ionic surfactant can be present atfronm 20 wt% to 50 wt%, in one embodiment the non-ionic surfactant can be present at a concentration to render the dietary fatty add water-soluble forming a clear solution, In accordance with these embodiments the dietary fatty acids can be 30 nutritional fatty acids, omega-3 fatty acids derived from natural sources such as fish, botanical sources such as chic sage or Salvia hispanica, or flax sources derived from linseed, or which are produced synthetically. Exemplary omega-3 fatty acids are set forth in Table 1, and a list of botanical extracts of omega-S fatty f0 acids are set forth in Table 2. Furthermore, it is noted that dietary fatty acids containing omega-3 fatty acids may also be derived from algae such as Crypthecodinium cohnii and Schizochytrium, which are rich sources of DHA , or brown algae (kelp) for EPA, They may also include conjugated linoleic acid (CL A), omega-6 fatty acids, and omega-9 fatty acids, such as linolenic acid. linolec acid (18:2). ano gamma linolenic add (GLA, 18:3). Other dietary fatty acids not listed herein can also be used, depending on the desired result to be achieved. Useful non-ionic surfactants That can be used include, for example, non ionic water-soluble mono-, di and t glycerides; non-ionic water-soluble mono and di- fatty acid esters of polyethylene glycol; non-ionic water-soluble sorbitan fatty acid esters (e.g. sorbitan monooleates such as SPAN SQ and TWEEN 20 (polyoxyethylene 20 sorbitan monooleate)); polyglycolyzed glycerides; non-ionic water-soluble triblock copolymers (e.g. poly(ethyleneoxide)ipoly (propyleneoxide)/ poly(ethyleneoxide) triblock copolymers such as poloxamer 406 (PLURONIC F-127), and derivatives thereof Examples of non-ionic water-soluble mono-, di- and tri- glycerides include propylene glycol dicarpylate/dicaprate (e.g. liglyol 840), medium chain mono and diglycerides (e.g, Capmul and lmwitoR 72), medium-chain triglycerides (e.g. caprylic and capric triglycerides such as LAVRAFAC, MIGLYOL 810 or 812, CRODAMOL GTC-PN, and SOFTISON 378), long chain monoglycerides (e.g, glyceryl rmonooleates such as PECEOL, and glyceryl monolinoleates such as MAISINE), polyoxyl castor oil (e.g. macrogoiglycerol ricinoleate, macrogolgiycerol hydroxystearate, macrogjol cetostearyl ether), polyethylene glycol 660 25 hyd roxystearate, and derivatives thereof. Non-ionic water-soluble mono- and d fatty acid posters of polyethylene glycol include d-a-tocophery polyethyleneglycol 1000 succinate (TPGS) poyethyleneglycol 660 12-hydroxystearate (SOLUTOL MS 15), polyoxy oleate and stearate (e.g. PEG 400 monostearate and PEG 1750 monostearate), and 30 derivatives thereof. 100011 Polyglycolyzed glycerides include polyoxyethylated oleic glycerides. polyoxyethylated linole c glycerides, polyoxyethylated ceprylic/capric glycerides and derivatives thereof Specific examples include Labrafil M 944CS, Labrafil M-21 25C,abraso SOFN, and GELUIRE in some embodIments, the non-ionic surfactant Is a glycerol-polyethylene glycol oxystearate, or derivative thereof These compounds may be synthesized by reacting either castor oil or hydrogenated castor oi with varying amounts of ethyene oxide, Macrogolglycerol ricinoleate is a mixture of 83 wt% relatively hydrophobic and 17 wt% relatively hydrophilic components. The major component of the relatively hydrophobic portion is glycerol polyethylene glycol ricinoleate, and the major components of the relatively hydrophilic portion are 0 polyethylene glycols and glycerol ethoxylates. Macrogolglycerol hydroxystearate (glycerol-polyethylene glycol oxysterate) is a mixture of approximately 75 wt% relatively hydrophobic of which a najor portion is glycerol polyethylene glycol 12 oxystearate. In some embodiments, the water-soluble formulations include the dietary 15 fatty acid, and glycerol-polyethylene glycol oxystearate, to form a transparent water-soluble formulation, which means that the formulation can be clearly seen through with the naked eye, but may be optionally colored. The transparent water-soluble formulation can be solvated in water to form a clear solution. in some embodiments, the transparent water-soluble formulations do not contain 20 particles (e.g. particles of undissolved dietary fatty acid) visible to the naked eye. In certain embodiments, light may be transmitted through the transparent water soluble formulations without diffusion or scattering. Thus, in some embodiments, the transparent water-soluble formulations are not opaque, cloudy or milky-white. In some embodiments, the water-soluble formulation is a non-alcoholic 25 formulation, which indicates that the formulation that does not include (or includes only in trace amounts) methanol lethal, , propanol or butanoL In other embodiments, the formulation does not include (or includes only in trace amounts) ethanol. In some embodiments, the formulation can be a non-aprotic solvated 30 formulation, meaning that water-soluble aprotic solvents are absent or are included only in trace amounts. Water-soluble aprotic solvents are water-soluble non-surfactant solvents in which the hydrogen atoms are not bonded to an oxygen or nitrogen and therefore cannot donate a hydrogen bond.

in some embodiments, the water-soluble forrnuiation does not include (or includes only in trace amounts) a polar aprotic solvent. Polar aprotic solvents are aprotic solvents whose molecules exhibit a molecular dipole moment but whose hydrogen atoms are not bonded to an oxygen or nitrogen atom, Examples of polar aprotic solvents include aldehydes, ketones, dimethyl sulfoxide (DM80), and dimethyl formamide (DF). In other embodiments, the water-soluble formulation does not include (or includes only in trace amounts) dimethyl sulfoxide. Thus, in some embodiments, the water-soluble formulation does not include DM30, in a related embodiment, the water-soluble formulation does not include DM3 or ethanol. in still other embodiments, the water-soluble formulation does not include (or includes only in trace amounts) a non-polar aprotic solvent. Non-polar aprotic solvents are aprotic solvents whose molecules exhibit a molecular dipole of approximately zero. Examples include hydrocarbons, such as alkanes, alkenes, and alkynes. The water-soluble formulation of the present invention includes formulabons dissolved in water (i.e. aqueous formulations). In some embodiments, the water-soluble formulation forms a transparent water-soluble formulation when added to water. Thus. in accordance with some embodiments 20 of the present disclosure, because of the nature of the water-soluble dietary fatty acid gel formulations prepared herein, often, only water and optionally a small amount of a stabilizing agent is all that is used to form the dietary fatty acid solutions of the present disclosure, e~g.. alcohol, aprotic solvents (polar or non polar), etc. are not required for solvating the dietary fatty acids, In some ombodiments. the water-soluble formulation consists essentially of dietary fatty acid and a non-ionic surfactant Whore a water-soluble formulation "consists essentially of" dietary fatty acid and a nor-onic surfactant, the formulation includes the dietary fatty acid, the non-ionic surfactant, and optionally additional components widely known in the art to be useful in 0 neutraceutical formulations, such as preservatives, taste enhances, colors, buffers, water, etc, which do not impact the basic solubility of the formulation i.e. no additional organic solvauing soiven tsare required.

In some embodiments, the water-soluble formulation is a watersohubiized formulation, meaning that the dietary fatty acid and a non-ionic surfactant are admired with water (ekg. a water containing liquid) to form the solutions of the present disclosure, but does not include organic solvents (eg. ethanol or other 5 alcohol or solvating solvent). In some embodiments, the water solubilized formulation a transparent water-soluble formulation. Method In another aspect of the present invention is described a method of 0 producing the water-soluble fatty acid formulations, Simply warming and mixing the dietary fatty acids with a non-ionic surfactant (such as glycerol-polyethylene glycol oxystea rate or other similar non-ionic surfactant) will not result in a clear water-soluble solution unless it is added appropriately. Instead, a semi-solid gel like cloudy or milky, high viscosity solution is obtained by simple mixing, This 5 waxy, cloudy, high viscosity gel is not suitable for forming clear solutions in water or beverages. It becomes a solidified milky white mass. By slowly titrating or adding the dietary fatty acid into the warm non-ionic surfactant while mixing, a clear solution can be obtained, More specifically, a method of dissolving dietary fatty acids in water can 20 comprise the steps of combining a dietary fatty acid with a warm, well mixed non ionic surfactant to form a surfactant-dietary fatty acid mixture; and continuously mixino the surfactant-dietary fatty acid mixture with water at least as slowly as necessary to solubilize the dietary fatty acid. In certain specific embodiments, the warm, well mixed non-ionic surfactant is prepared by the preliminary step of 25 heating the surfactant to a temperature of about 90 *F to about 200 *F while mixing until clear. In another specific embodiment, the combining step includes adding the dietary fatty acid to the non-ionic surfactant slowly and stirring until thoroughly mixed. The dietary fatty acid can be sufficiently dispersed or dissolved in the surfactant so that a resultant solution contains no visible micelles 30 or particles of dietary fatty acid. For example, the mixing step can include slowly adding the surfactant-dietary fatty acid mixture to warm water at a rate not to exceed 5 voi% of the water per second. Furthermore, the step of hearing the water-soluble nonionic surfactant can ncluda the step of stirnng or mixing during the heating step. The rate at which the dietary fatty acid is added to the warm surfactant, and the temperature of the surfactant can be aided by carrying out the process S appropriately for a desired result, e.g. forming a clear solution. For example. in sorne embodiments, the surfactant should not be below a certain temperature or above a certain temperature, Likewise, if the dietary fatty acid gel mixture is added to the water too fast, a solid gel-like mass will result. The non-ionic surfactant should typically also be stirred thoroughly to remove bubbles (oxygen). 10 and until clear. Once the dietary fatty acid has been added to the surfactant, it is stirred for at least 10 minutes. or more, and typically for about 1 hour. In further detail, when adding the water-soluble dietaryfatty acid gel formulation to water, the foratiotion should be added at a rate not to exceed 5 mL per second to a volume of water of 100 mL, or not more than 5 vol% of the 15 water per second of the volume of water it is being added to. The rate of addition depends on the volume of water, Further, the water can be stirred continuously while the addition of the dietary fatty acid gel is being slowly added. The solution may be heated to increase solubility, if desired or necessary, That being said, the heating temperature is typically selected to avoid chemical breakdown of the 20 dietary fatty acid and/or non-ionic surfactant The temperature of the dietary fatty acid gel (dietary fatty acid/non-ionic surfactant) should not typically exceed 200 *F, and the water temperature should also not typically exceed 200 *F. Ideally, the temperature of both should be maintained at from 100 to 150 UF. and in one embodiment, the water can optionally be maintained at about 100 *F while slowly 25 adding the dietary fatty acid gel mixture, In some embodiments, the resulting solution is a water-soluble formulation or transparent water-soluble formulation as described above. For example, the resulting solution may be a water-soluble formulation that is a crystal clear solution, with no particles visible to the naked eye. The present disclosure also provides a method of delivering a dietary fatty acid to a subjec composing administering the formulation or solution described herein to a subject such that the dietary fatty acid is more bioavailable than when the same amount of dietary fatty acid is delivered alone. Administration routes 1 * will be descrbed in detail hereinafter, but suffice it to say that nay administration route can be used that is effective for treating a disease or providing a heath benefit, e.g. oral mucosal ocular, parenteral or topical delivery. Thus, the present disclosure can provide a method of treating cancer, 5 obesity, diabetes, cardiovascular disease. dyslipidaemia, age-related macular degeneration (e.g. vision loss associated with age-related macular degeneration) high cholesterol retinopathy (eg, diabetic retinopathy), or a neurological disease in subject in need of such treatment. The method includes administering to the subject an effective amount of the water-soluble formulations disclosed herein. It 1 0 is noted that thought these diseases are provided in a common list, they are not equivalent diseases and should be considered herein as if each are listed separately. In another aspect, the present invention provides a method for enhancing the bioavailability of dietary fatty acid. The method includes combining dietary 1 fatty, and a non-ionic surfactant to form a surfactant-diatary fatty acid mixture The surfactant-dietary Fatty acid mixture may be administered to the subject thereby enhancing the bioavailabiity of the dietary fatty acid. The bioavailability is enhanced compared to the bioavailability of dietary fatty acid in the absence of non-ionic surfactant. Dosages and Dosage Forus The amount of dietary fatty acid adequate to treat a disease or provide a health benefit can be defined as a "therapeutically effective dose," The dosage schedule and amounts effective for this use, Le. the "dosing regimen," will 25 depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient's physical status, age and the like, ln calculating the dosage regimen for a patient, the mode of administration also is taken into consideration. The dosage regimen also takes into consideration oharmacokinetics 30 parameters well known in the art, Le the rate of absorption, bicavailability, metabolism, clearance, and the like (see. e.g. Hidalgo-Aragones (1996) J. Steroid Biocem, Mol, Biot 58:611-617 Groning (196) Pharmazie 51:337-341: Fotherby (1996) Contraception 54:59-69: Johnson (1995)J. Pharm. SL 12 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:i03-108; the latest Remington's, supra). The state of the art allows the clnian to determine the dosage regimen for each individual patient and disease or condo ton treated. Single or multiple administrations of dietary fatty acid formulations can be administered de pending on the dosage and frequency as required and tolerated by the patient. The formulations should provide a sufficient quantity of active agent to effectively treat the disease state, or to provide the appropriate health benefit. Lower dosages can be used, particularly when the dietary fatty acid is 0 administered to an anatomically secluded site in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ. Higher dosages can be used in topical administration. Actual methods for preparing parenterally administrable dietary fatty acid formulations will be known or apparent to those skilled in the art and are described in more detail in such 15 publications as Remington's. supra. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al- eds. De Gruyter, New York (1987). in some embodiments, the dietary fatty acid is present in the water-soluble dietary gel formulation at a concentration of 1 wt% to 75 wt%, or alternatively, at fror 5 wt% to 50 wt%, 10 wt% to 35 wt/, or 20 wt% to 25 wt%, The dietary fatty 20 acd may also be present as a solution in a ready to drink beverage formulation at a concentration from 0.1 mg/mL to 10 mg/mL, or alternatively, from 0.5 mg/mL to 5 mg/m, If making a concentrate to be added to additional water, the concentration can be from 10 to 125 mrg/mL, for example. These ranges are not intended to be limiting, but rather provide guidelines for preparing ready to drink 25 formulations, as well as concentrates. It is noted that there can be a maximum concentration for achieving a crystal clear solution, if a clear solution is desired, The water-soluble formulation can also be in the form of a pharmaceutical composition, The pharmaceutical composition may include dietary fatty acid, a non-ionic surfactant, and a pharmaceutically acceptable recipient. After a pharmaceutical composition including dietary fatty acid of the present disclosure has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition For administration of dietary fatty acid, such labeling would include, for example, instructions concerning the amount, frequency and method of administration, Any appropriate dosage form is useful for administration of the water soluble formulation of the present disclosure, such as oral, parenteral, mucosal Secular, and topical dosage forms, Oral preparations include tablets, pills, powder, dragees, capsules (e.g. soft-gel capsules) liquids, lozenges, gels, syrups, slurries, beverages, suspensions, etc. suitable for ingestion by the patient, Examples of liquid formulations include drops, sprays, aerosols, emulsions, lotions, suspensions, drinking solutions, gargles, and inhalants. The formulations 10 of the present disclosure can also be administered by injection, that is, intravenously, intranuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the formulations described herein can be administered by inhalation, for example, intranasally. Additionally, the formulations of the present invention can be administered topically, such as 5 transdermally. The formulations can also be administered by intraocular, intravaginal, and iarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi J. Clin. Pharmacol. 35.1187-1193, 1995: Tjwa, Ann. Allergy Asthma Immunol. 75:1 07 ili, 1995). For preparing pharmaceutical compositions from the formulations of the present disclosure. phanraceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders. tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's"). Suitable carriers include magnesium carbonate, magnesium stearate, talc, 30 sugar, lactose, pectin, dextrin, starch (from corn, wheat, rice, potato, or other plants), gelatin, tragacanth, a low melting wax, cocoa butter, sucrose, mannitol, sorbitol, cellulose (such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylceilulose), and gums (including arabic and tragacanth), as I14 well as proteins such as gelatin and colagen. if desired, disintegrating or co solubilizing agents may be added, such as the cross-Iinked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. n tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, 10 carbopol gel polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigrments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, push-it 1 capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol Push-fit capsules can contain dietary fatty acid Mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, dietary fatty acid may be dissolved or suspended in suitable liquids, such as fatty oils, 2 iquid paraffin, or liquid polyethylene glycol with or without stabilizers, or alternatively, may be encapsulated as the water-soluble dietary fatty acid gel formulation (prior to addition of water). For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, can be first melted and the active component 25 dispersed homogeneously therein, such as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify. Liquid form preparations include solutions, suspensions, beverages, and emulsions, for example, water or water/propylene glycol solutions. For parenteral 0 injection, liquid preparations can be forrmulated in solution in aqueous polyethylene glycol solution or other suitable solution for injection, Aqueous solutions and beverages suitable for oral use can be prepared by dissolving the water-soluble dietary fatty acid gel formulation in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous solutions or suspensions suitable for oral use can be made by dispersing the active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose hydroxypropvlmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g, heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g, polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from Fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring age one one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity, Also included are solid form preparations, which may be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms 20 include solutions, suspensions, and emulsions. These preparations may contain, n addition to the dietary fatty acid, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners. dispersants, thickeners. solubilizing agents, and the like. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol sorbitol or sucrose, These formulations can be preserved by 25 the addition of an antioxidant such as ascorbic acid..As an example of an injectable oil vehicle, see Minto, J Pharmacol. Exp. Thor. 281:93-102, 1997. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatioes, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides. such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as poiyoxyethylene sorbitan mono-olate, The emulsion can also contain sweetening agents and flavoring agents, as in the 16 formulation of syrups and elixirs., Such formulations can also contain a demulcent, a preservative, or a colonng agent. The formulations of the invention can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jelies, paints, powders, and aerosols. The formulations can also be delivered as microspheres for slow release in the body. For example, nicrospheres can be administered via intradermal njection of drug -containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym Ed. 7:623-645, 1995: as biodegradable and injectable gel formulations (see, el., Gao Pherm. Res. 12:857-863, 1995): or as mcrospheres for oral administration (see, e.g, Eyles, J, Pharm, PharmacoL 49:669-674, 1997), Both transdermal and intradermal routes afford constant delivery for weeks or months. The formulations of the invention can be provided as a salt and can be 15 formed with many acids, including but not hmited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases. the preparation may be a lyophilized powder in I mM-50 mM histidine, 0,1 wt% to 2 wt% sucrose, 2 'wt% to 7 wt% mannitol at a pH range of 4,5 to 5,5, that 20 is combined with buffer prior to use, In another embodiment, the formulations of the invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e. by employing ligands attached to the liposorne, or attached directly to the oligonucleotide. that bind to surface membrane protein receptors or 25 the cel resulting in endocytosis, By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the dietary fatty acid, dietary fatty acid metabolite or slat thereof into the target cells in vivo, (See, e.g., Al-Muhammed, J. Microencapsul, 13:293-306, 1996: Chcnn, Curr. Opin, Biotechnol 6:98-708, 1995; Ostro, Am. J, Hosp. Pharm, 46:1576 1587, 1989), The formulations may be administered as a unit dosage form. In such forn the preparation is subdivided into unit doses containing appropriate 17 quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantties of preparation, such as picketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component, The composition can, if desired, also contain other compatible therapeutic agents. Assays Subject non-ionic surfactants may be assayed for their ability to solubliize dietary fatty acid using any appropriate method. Typically, a non-ionic surfactant is warmed and contacted with the dietary fatty acid and mixed mechanically 15 and/or automatically using a shaker, vortex, or sonicator device. Water may be optionally added, for example, where the dietary fatty acid and/or surfactant are in powder form. The solution is heated to increase solubility. The heating temperature is selected to avoid chemical breakdown of the dietary fatty acid or non-ionic surfactant. The surfactant or dietary fatty acid should typically not be 20 heated above 200 *F, and preferably not more than 150 *F. The resulting solution may be visually inspected for colloidal particles to determine the degree of solubility of the dietary fatty acid, Alternatively, the solution may be filtered and analyzed to determine the degree of solubiity, For example, a spectrophotometer may be used to determine the concentration of 25 dietary fatty acid present in the filtered solution. Typically, test solution is compared to a positive control containing a series of known quantities of pre filtered dietary fatty acid solutions to obtain a standard concentration versus tV/vLs absorbance curve. Alternatively, high performance liquid chromatography may be used to determine the amount of dietary fatty acid in solution. High throughput solubility assay methods are well known in the art. Typically, these methods involve automated dispensing and mixing of solutions with varying amounts of non-ionic surfactants, dietary fatty acid, and optionally other co-solvents. The resulting solutions may then be analyzed to determine the degree of solubility using any appropriate method as discussed above. The Millipore MultiScreen Solubility filter plate with modified track-etched polycarbonate, 0.4 pm membrane is a single-use, 96-well product assembly that includes a filter plate and a cover. The device s intended for processing aqueous solubility samples in the 10-300 piL volume range. The vacuum filtration design is compatible with standard, microtiter plate vacuum manifolds. The plate is also designed to fit with a standard, 96-well microtiter receiver plate for use in filtrate collection. The MultiScreen Solubility filter plate has been 10 developed and QC tested for consistent filtration flow-time (using standard vacuum). low aqueous extractable compounds, high sample filtrate recovery, and its ability to incubate samples as required to perform solubility assays. The low binding membrane has been specifically developed for high recovery of dissolved organic compounds in aqueous media. 15 The aqueous solubility assay allows for the determination of dietary fatty acid solubility by mixing, incubating and filtering a solution in the MultiScreen Solubility filter plate. After the filtrate is transferred into a 96-well collection plate using vacuum filtration, it is analyzed by UV/vis spectroscopy to determine solubiity. Additionally, LC/MAIS or HPLC can be used to determine compound 20 solubility. especially for compounds with low UV/Vis absorbance and/or compounds with lower purity. For quantificaton of aqueous solubility, a standard calibration curve may be determined and analyzed for each compound prior to dtening aqueous solubiity Test solutions may be prepared by adding an aiquot of concentrated a 25 given compound. The solutions are mixed in a covered 96-well MultiScreen Solubility flter plate for 1.5 hours at room temperature. The solutions are then vacuum filtered into a 96-well, polypropylene, V-bottomed collection plate to remove any insoluble precipitates. Upon complete filtration, 160 pL/well are transferred from the collection plate to a 96-well UV analysis plate and diluted 3 with 40 pL/well of acetonitrle. The UV/vis analysis plate is scanned from 260 500 nm with a UV/vis microplate spectrometer to determine the absorbance profile of the test compound Thus, one skilled in the art may assay a wide variety of non-ionic surfactants to determine their ability of solubilize dietary fatty acid compounds in accordance with embodiments of the present disclosure. The terms and expressions which have been employed herein are used as terms of description and not of imitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible within the scope of the invention claimed. Moreover, any one or more features of any embodimenof f the invention may be combined with any one or I0 more other features of any other embodiment of the invention, without departing from the scope of the invention, For example, the features of the formulations are equally applicable to the methods of treating disease states described herein, All publications, patents, and patent applications cited herein are hereby incororated by reference in their entirety for all purposes. EXAM PLES The examples below are meant to illustrate certain embodiments of the disclosure, and are intended not to limit the scope of the invention. It is noted 20 that Lucifer Yellow is from Molecular Probes (Eugene, OR). Hanks buffer and all other chemicals are obtained from Sigma-Aldrich (St Louis, MO). E xample 1 -~ Preparation of onega-3 gel formulations (fish7 oil) and subsequent aqueous solutions of omega-3 fatly acids 29 Water-soluble compositions of omega-3 fatty acids are formulated using the non-ionic surfactant nmacrogolglycerol hydroxystearate (Glycerol-Polyethylene glycol oxystearate). First, the non-ionic surfactant is heated to about 115 "F and stirred until clear and virtually no bubbles are apparent. A deodorized omega-S fatty acid fish oil, containing 30 wt% omega-S fatty acids at room temperature is 30 very slowly added or titrated into the warm macrogolglycerol hydroxystearate until a clear slightly viscous solution is formed containing dissolved omega-3 fatty acids (or "omega-3 gel formulation" or "fatty acid gel formulation"). The omega-S gel formulation thus comprises $0 g of the macrogolglycerol hydmoxystearate and j o . Sic 10 g of omega-3 fatty acids, representing about 17 wt% of the omega-S fatty acids gel formulation. The omega-S fatty gel formulation is slowly titrated at a rate of about 1 m-L per second to 100 mL of warm water maintained as a mixing vortex with a stirrer at 100 RPM, and maintained ate temperature of about 110 1 *F until a crystal clear solution is formed. The water is continuously stirred during the addition phase and shortly thereafter after. As can be seen from the above example. an aqueous solution of solubilized omega-3 fatty acids is achieved by adding the omega-3 fatty acid gel formulation to the warm water, thereby making a water-soluble beverage. More 0 specifically, the aqueous omega-3 fatty acid gel formulation is prepared by maintaining the gel formulation at a temperature of about 115 *F and titrating or adding drop by drop the gel mixture to warm water to form a clear aqueous solution (or very fine dispersion that is vsually clear) of omega-S fatty acids. This aqueous omega-S fatty acid formulation will not have an undesirable flavor. The 15 aqueous omega-S fatty acid formulation included water (100 mL), macrogolgyceroi hydroxystearate 40 (50 mL), and a deodorized, 30 wt% onega 3 fatty acid fish oil (10 mL), a concentration of omega-S fatty acids in the aqueous dietary fatty acid formulation is about 6.6 wt% (water containing beverage). A visual inspection confirmed that the solution will be crystal-clear with no visible 20 particles. The aqueous omega-3 fatty acid formulation is analyzed by HPLC to verify its contents, Example 2 The solubility of the omega-3 fatty acids in pH 7.4 Hank's Balanced Salt Solution (10 mM HEPES and 15 mM glucose) is compared to the omega-3 gel formulation. At least 1 mg omega-3 fatly acid oil (SO wt% omega-3) as well as 100 mg of omega-S gel formulation is combined with 1 mL. of buffer to make a cl mg/nt omega-3 oil mixture and a 1 mg/mL omega-S gel formulation mixture, respectively. The respective mixtures are shaken for 2 hours using a benchtop vortexer and left to stand overnight at room temperature. After vortexing and standing overnight, the omega-S oil mixture is then filtered through a 0.45-am nylon syringe filter (Whatman. CaWt 6789-0404) that is first saturated with the sample. 21 After vortexing and standig overnight, the omega-3 gel formulation mixture is centrifuged at 14,000 rpm for 10 minutes, The filtrate orsupernatant is sampled twice, consecutively, and diluted 10 0, and 10,000-fold in a mixture of 50:50 assay buffer:acetonitrile prior to analysis, Both mixtures are assayed by LC/MS/MS using electrospray ionization against the standards prepared in a mixture of 50:50 assay buffer:acetonitrile. Standard concentrations ranged from 1 .0 pM down to 3,0 nM. Results would indicate a significant difference in solubility between the two formulations. Example 3 To test the permeability of dietary fatty acids across Caco-2 cell monolayers, Caco-2 cell monolayers are grown to confluence on collagen coated, microporous, polycarbonate membranes in 12-well Costar Transwelk@ 15plates, The test aricle is the aqueous dietary fatty acids formulation, and the dosing concentration is 2 piM in the assay buffer (HBSSg) as in the previous example, Cell rnonolayers are dosed on the apical side (A-to-B) or basolateral side (Bto-A) and incubated at 37 C with 5 % CO 2 in a humidified incubator. 20 Samples are taken from the donor chamber at 120 minutes, and samples from the receiver chamber are collected at 60 and 120 minutes, Each determination is performed in duplicate. Lucifer yellow permeability is also measured for each monolayer after being subjected to the test article to ensure no damage is inflicted to the cell monolayers during the permeability experiment. Permeability 5 of samples of atenolol, propranolol and dioxin are also measured to compare with the permeability of the dietary fatty acids sample. Ail samples are assayed for dietary fatty acids, or corresponding comparative compounds, by LC/MS/MS using electrospray ionization. The apparent permeability (Papp) and percent recovery are calculated as is known in the art, Dietary fatty acids permeability 3 results can be presented as by reporting the permeability (106 cm/s) and recovery of Dietary fatty acids across Caco~2 cell monolayers. All monolayers pass the post-experiment integrity control with Lucifer yellow Papp <0,8 x 10 cmts.

Exame4 - Preparation of omega-? gel formulations (f/ax seed oil) and subsequent aqueous solutons of omega-3 fatty acids Five (5) grams of flax seed oil is dissolved in 50 mL of warm Polyethylene 5 Glycol 660 Hydroxystearate by mixing until a dear gel is formed (omega-3 gel formulation" The omega-3 gel formulation is then very slowly added to 100 mL of varm distilled water while continuous mixing (e.g, with a paddle suspended and rotating at 100 RPM by slowly adding as a drizzle, or drop-by-drop using a titration apparatus) The omega-3 gel formulation with flax seed oil is added very Slowly to the mixing water to avoid solidification of the liquid into a solid gel, or cloudy' wite mass (e.g., at a rate of 1 mL every 10 seconds or more whie stirring continues, A clear solution is formed ith no visible particles or micelles, Example 5 - Preparation of omega-3 gel formulations (fish oil) and subsequent 15 aqueous solutions of omega-S fatty acids 30 grams of fish oil is dissolved in 50 mL of warm macrogolglycerol hydroxystearate (Glycerol-Polyethyiene glycol oxystearate) by mixing unti a gel is formed (omega-3 gel formulation"). The omega-3 gel formulation is then very slowly added to 200 mL of warm distilled ater while continuous mixing (e.g., 20 with a paddle suspended and rotating at 100 RPM by slowly adding as a drizzle, or drop-by-drop using a titration apparatus), The omega-3 gei formulation with fish oil is added very slowly to the mixing water to avoid solidification of the liquid into a solid gel, or cloudy white mass (e.g. at a rate of 1 mL every 10 seconds or more while stirring continues). A clear solution is formed with no visible particles 25 or micelles.

Claims (27)

1. A water--soluble dietary fatty add gelformulaton, comprsing fom 1y% to 75 vt f d etarfaty acd and Rom5 wt Mto 99 wt% of nnnic surf acnt 10

2. The fomulation of lain 1,wherein the gel frmulation s so n water and forms a clear solution at a weh ratio of 3

3. The formulation of claim 1, wherein the gel formulation is soluble in 15 water and forms a clear solution at a weight ratio of 1:1, 4 The formulation of claim 1, wherein the dietary fatty acid is an omega-3 fatty acid.

05. The formulation of claim 4, wherein the omega-3 fatty acid is icosapen taenoic acid (EPA), docosahexaenoic acid (DHA), or a mixture thereof

6. The formulation of claim 1, wherein the dietary fatty acid is present at a concentration of at least 20 wt%.

7. The formulation of claim 1, wherein the non-ionic surfactant is a non-ionic water-soluble mono-, di or tri glyceride; non-ionic water-soluble mono- or di- fatty acid ester of poiyethyelene glycol: non-ionic water-soluble sorbitan fatty acid ester; polyglycolyzed glyceride: non-ionic water-soluble triblock copolymers: derivative thereof; or combinations thereof, 8, The formulation of claim 1, wherein the non-ionic surfactant i-s a non-ionic water-soluble mono-, di-, or tri- glyceride.

9. The formulation of claim 1, wherein the non-ionic su factant is g lyce rol-po lyethyAene g lycol oxysteara te, S10 The formulation of claim 1, wherein the non-ionic surfactant is macrogolglycerol ricinoleate, macrogolglycerol hydroxystearate, polyethylene glycol 660 hydroxy'stearate, or a mixture thereof.

11. The formulation of claim 1, wherein the non-ionic surfactant is 10 polyethylene glycol 660 hydroxystearate. 1. The formulation of claim 1, wherein the formulation is an oral formulation 15 13. The formulation of claim 1, wherein the formulation is a mucosal, parenteral, ocular, or topical formulation, 14, The formulation of claim 1, wherein the dietary fatty acid is present at from 5 wt% to 60 wt%, and the non-ionic surfactant is present at from 40 % ?w to 95 wt%.

15. The formulation of lai 1 herein the dietary fatty acidis denied from a fish, algae, or vegetable source. 25 16. The formulation of claim 1 further comprising a pharmaceutically acceptable excipient or stabilizer. 7 The formulaton ofclaim 1, insisting essentialy of the dietary aty acid and the non-ioni suradant 18, A method of delivering a dietary fatty acid to a subject, comprising administering the formulation of claim 1 to a subject such that the dietary fatty acid is more bioavailable than when the same amount of dietary fatty acid is delivered alone.

19. The method of cain8 when the step of dminisrngsy 5 ral. mucosal, oclar, parenteral, or topical deliery.

20. The method of claim 18, wherein the administering is a result of the subject being treated for cancer, obesity, diabetes, cardiovascular disease dyslipidaemia, age-related macuar degeneration, high cholesterol, retinopathy, or a neurological disease.

21. A dietary attyacid sui coprsi from 0. Iwt% to 94 .w of water from 0. wt% to 35 wt% of detary fatty acid and Sfron 5 wt% to 75 vt% of non-ionic surfactant

22. The soluion of daim 21, wherein the water is present at fromis wt%io 75 w%;he dietary fattyacii present at from 2 wlM to 20 wt% and the non-ioni s urfactantds present at from 20 wt% to 50 wt%. 200

23. The solution of clair 21. wherein the non-ionic surfactant is present at a concentration to render the dietary fatty acid water-soluble, forming a clear solution, 25 24. The solution ofdlairm 21, wherein the dietary fatty acid is an ome a

25. The soluton of caimc4, wherein he eae fatty acid is eiNosapentaenoin acid (EPA docosahexeenoc acid (DH A or a mturehereof. 26, The solution of claim 21 wherein the frmulation is a nomalDholic forumon, 26

27. The solution of claim 21, wherein the formulation is a non-aprotic isolated fomulation

28. The solution of claim 21, wherein the dietary fatty acid is present at > a concentration of at least 0,1 mg/mL.

29. The solution of claim 21. wherein the dietary fatty acid is present at a concentration of at least 1 mg/nL. 10 30, The solution of claim 21, wherein the dietary fatty acid is present at a concentration from 0.1 mg/mL to 10 rng/rnL. 31, The solution of claim 21, wherein the dietary fatty acid is present at a concentration from 10 to 125 mg/mL. 15 32, The solution of claim 21, wherein the non-ionic surfactant is a non ionic water-soluble mono-, di-, or tri- giyceride; non-ionic water-soluble mono- or di- fatty acid ester of polyethylene glycol; non-ionic water-soluble sorbitan fatty acid ester; polyglycoyzed glyceride; non-ionic water-soluble triblock copolymers; 20 derivative thereof; or combinations thereof. 33, The solution of claim 21, wherein the non-ionic surfactant is a non ionic water-soluble mono-, di- or tri- g yceride. 25 34, The solion of dam 21, wheri the non-ionic surfatant i glycedpolyethylene glycol xystearate .35. Thesuion of daim 2 wherein the nor-ionic surfactant is raerogolgycol icieatemacrogoglycerdhydroxyeatepolyethylene 30 glycol 660 hydroxystearat or a mixe e reof

36. The solution of claim 21, whereIn the non-ionic surfactanti polyehylene glycol 660 hydroxysearate. 7 The solution of claim 21 wherein the formulation is an oral formulation. .3 33. The solution of claim 37, wherein the ora formulation s a beverage. 3. The solution ofim7 wherein the ral formulation is pray r a tablet, 0 40. The solution of claim 37, wherein the oral formulation is present in a soft gel capsule, and the water content is less than about 10 wt%.

41. The solution of claim 21, wherein the formulation is a mucosat parenteral, ocular or topical formulation.

42. The solution of claim 21 wherein the dietary fatty acid is derived from a fish, algae, or vegetable source,

43. The solution of claim 21, further comprising a pharmaceutically 0 acceptable excipient or stabilizer. 44, The solution of claim 21 consisting essentially of the dietary fatty acid, the non-ionic surfactant, and the water. 25 45. A method of delivering a dietary fatty acid to a subject, comprising administering the formulation of claim 21 to a subject such that the dietary fatty acid is more Oioavaiiable than when the same amount of dietary fatty acid is delivered alone. 30 46. The method of claim 45. whberein the step of administering is by oral, mucosal, ocular. parenteral or topical delivery.

47. The method of claim 45, wherein the administering is a result of the subject being treated for cancer, obesity, diabetes, cardiovascular disease, dyslipidaemia, age-related macular degeneration, high cholesterol retinopathy, or a neurological disease. A method of dissolving dietary fatty acids in water comprising the steps of: combining a dietary fatty acid with a warm, well rnixed non-ionic surfactant to form a surfactant-dietary fatty cod mixture; and 10 coninuously mixing the surfactant-dietary fatty acid mixture with water at least as slowly as necessary to solubilize the dietary fatty acid.

49. The method of claim 48, wherein said non-ionic surfactant is a glycerol-polyethylene glycol oxystearate, ethoxylated castor oil, polyethylene 15 glycol 660 hydroxystarate, or a mixture thereof, 50, The method of claim 48, wherein the warm, well mixed non-ionic surfactant is prepared by the preliminary step of heating the surfactant to a temperature of about 90 TF to about 200 *F while mixing until clear.

51. The method of claim 48, wherein the combining step includes adding the dietary fatty acid to the non-ionic surfactant slowly and stirring until thoroughly mixed so as to constitute from 1 wt% to 75 wt% dietary fatty acid and from 25 wt% to 99 wt% surfactant wherein the dietary fatty acid is sufficiently dispersed or dissolved in the surfactant so that the gel composition contains no visible miceles or particles of dietary fatty acid.

52. The rnethod of claim 48, wherein the mixing step includes slowly adding the surfactant-dietary fatty acid mixture to warm water at a rate not to 30 exceed vol% of the water per second. 53 A method as in claim 48, where the step of heating the water soluble non-ionic surfactant includes the step of stirring or mixing during the heating step,

54. A method of enhancing the bioavailability of a dietary fatty acid in a subject, said rnethod comprising dissolng a surfactantdietary fatty acid mixture in water as in claim 48