EP1082026A1 - Compositions renfermant du phytosterol et/ou du phytostanol a solubilite et dispersibilite ameliorees - Google Patents

Compositions renfermant du phytosterol et/ou du phytostanol a solubilite et dispersibilite ameliorees

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Publication number
EP1082026A1
EP1082026A1 EP99923350A EP99923350A EP1082026A1 EP 1082026 A1 EP1082026 A1 EP 1082026A1 EP 99923350 A EP99923350 A EP 99923350A EP 99923350 A EP99923350 A EP 99923350A EP 1082026 A1 EP1082026 A1 EP 1082026A1
Authority
EP
European Patent Office
Prior art keywords
phytosterols
solubility
phytostanols
fcp
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP99923350A
Other languages
German (de)
English (en)
Inventor
David John Stewart
Radka K. Milanova
Jerzy Zawistowski
Simon Howard Wallis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forbes Medi-Tech Inc
Original Assignee
Forbes Medi-Tech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forbes Medi-Tech Inc filed Critical Forbes Medi-Tech Inc
Publication of EP1082026A1 publication Critical patent/EP1082026A1/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G1/00—Cocoa; Cocoa products, e.g. chocolate; Substitutes therefor
    • A23G1/30—Cocoa products, e.g. chocolate; Substitutes therefor
    • A—HUMAN NECESSITIES
    • A21—BAKING; EDIBLE DOUGHS
    • A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
    • A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
    • A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
    • A21D2/14—Organic oxygen compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
    • A23D7/0056—Spread compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/015—Reducing calorie content; Reducing fat content, e.g. "halvarines"
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
    • A23L7/10—Cereal-derived products
    • A23L7/117—Flakes or other shapes of ready-to-eat type; Semi-finished or partly-finished products therefor
    • A23L7/126—Snacks or the like obtained by binding, shaping or compacting together cereal grains or cereal pieces, e.g. cereal bars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • This present invention relates to the field of phytosterol-based compositions suitable for incorporation into foods, pharmaceuticals, nutraceuticals and the like and to methods of making the same.
  • Sterols are naturally occurring triterpenoids that perform many critical cellular functions.
  • Phytosterols such as campesterol, stigmasterol and beta-sitosterol in plants, ergosterol in fungi and cholesterol in animals are each primary components of cellular and subcellular membranes in their respective cell types.
  • the dietary source of phytosterols in humans comes from plant materials i.e. vegetables and plant oils.
  • the estimated daily phytosterol content in the conventional western-type diet is approximately 60-80 milligrams in contrast to a vegetarian diet which would provide about 500 milligrams per day.
  • Phytosterols have received a great deal of attention due to their ability to decrease serum cholesterol levels when fed to a number of mammalian species, including humans. While the precise mechanism of action remains largely unknown, the relationship between cholesterol and phytosterols is apparently due in part to the similarities between the respective chemical structures (the differences occurring in the side chains of the molecules). It is assumed that phytosterols displace cholesterol from the micellar phase and thereby reduce its absorption.
  • phytosterols in various combinations have been proven to have wide clinical and dietary applications in lowering total and low density lipoprotein cholesterol
  • the key problem now facing researchers in this field is the adaptation of the phytosterol delivery system.
  • Phytosterols are highly hydrophobic, do not dissolve to any significant degree in the micellar phase in the digestive tract and therefore are not capable of efficiently blocking cholesterol abso ⁇ tion. Oils and fats are capable to a limited but not satisfactory degree of dissolving free phytosterols. Since only solubilized phytosterols inhibit the absorption of cholesterol, this "delivery" problem must be adequately addressed.
  • phytostanols the 5 alpha saturated derivatives of phytosterols
  • sitosterols infused into the Gl tract resulted in a 50% reduction in serum cholesterol as opposed to an 85% reduction when sitostanols were infused (9).
  • the advantages of stanols over sterols with respect to inhibition of cholesterol abso ⁇ tion from the Gl tract are two-fold. Firstly, stanols are more chemically stable than their unsaturated counte ⁇ arts in heat and air due to the absence of carbon-carbon bonds in the former. Secondly, stanols are more effective at lowering serum cholesterol on a molecular weight basis than their unsaturated counte ⁇ arts.
  • SA Raision Patent also to Raision Tehtaat Oy AB (hereinafter the "SA Raision Patent") describes a similar composition to that in the Raision Patent but which further contains at least 10% campestanol obtained by hydrogenation of the phytosterol mixture.
  • US Patent No.5,244,887 to Straub discloses a method of making a food additive composition which comprises dissolving a stanol (sitostanol; clionastanol; 22,23- dihydrobrassicastanol; campestanol and mixtures thereof) with an edible solubilizing agent, an anti-oxidant and a carrier or dispersant.
  • a stanol sitostanol; clionastanol; 22,23- dihydrobrassicastanol; campestanol and mixtures thereof
  • the present invention provides a composition suitable for use alone or for inco ⁇ oration into foods, beverages, pharmaceuticals, nutraceuticals and the like which comprises one or more phytosterols, phytostanols or mixtures of both treated to enhance the solubility and dispersability thereof.
  • the present invention further comprises foods, beverages, pharmaceuticals, nutraceuticals and the like which comprise a composition of one or more phytosterols, phytostanols or mixtures of both treated to enhance the solubility and dispersability thereof.
  • formulations include, but are not limited to, the treated composition inco ⁇ orated into edible oils and fat-based foods (such as margarines, butter, mayonnaise, dressing, shortenings, and cheeses), and formed into suspensions, emulsions, microemulsions, liposomes, niosomes and general hydrated lipid phases.
  • the composition additionally may be incorporated into numerous pharmaceutical dosage forms as described in detail below.
  • the present invention further comprises the use of a composition which comprises one or more phytosterols, phytostanols or mixtures of both, treated to enhance the solubility and dispersability thereof, to lower serum cholesterol in animals, including humans.
  • the present invention further comprises methods of making a composition suitable for inco ⁇ oration into foods, beverages, pharmaceuticals, nutraceuticals and the like which comprises enhancing the solubility and dispersability of one or more phytosterols, phytostanols or mixtures of both by any of the techniques described in more detail hereinbelow.
  • composition of the present invention which comprises one or more phytosterols, phytostanols or mixtures of both treated to enhance the solubility and dispersability thereof, has marked advantages over the phytosterol/stanol compositions previously known and described in the art.
  • the composition of the present invention is more soluble and dispersable in both lipid-based and aqueous systems which is critically important due to the fact that only solubilized phytosterols and phytostanols inhibit the abso ⁇ tion of cholesterol in the digestive tract.
  • the techniques described herein to enhance the solubility and dispersability of phytosterol compositions and phytostanol compositions (or mixtures thereof) facilitate the inco ⁇ oration of these compositions into foods, beverages, nutraceuticals and pharmaceuticals. PREFERRED EMBODIMENTS OF THE INVENTION
  • composition suitable for incorporation into foods, beverages, pharmaceuticals, nutraceuticals and the like which comprises one or more phytosterols, phytostanols or mixtures of both treated to enhance the solubility and dispersability thereof.
  • phytosterol includes all phytosterols without limitation, for example: sitosterol, campesterol, stigmasterol, brassicasterol, desmosterol, chalinosterol, poriferasterol, clionasterol and all natural or synthesized forms and derivatives thereof, including isomers.
  • phytostanol includes all saturated or hydrogenated phytosterols and all natural or synthesized forms and derivatives thereof, including isomers. It is to be understood that modifications to the phytosterols and phytostanols i.e. to include side chains also falls within the purview of this invention.
  • this invention is not limited to any particular combination of phytosterols and/or phytostanols forming a composition.
  • any phytosterol or phytostanol alone or in combination with other phytosterols and phytostanols in varying ratios as required depending on the nature of the ultimate formulation may be treated to enhance the solubility and dispersability as described in the present invention.
  • the composition described in PCT/CA95/00555 which comprises no more than 70% by weight beta-sitosterol, at least 10% by weight campesterol and stigmastanol may be treated by the techniques of the present invention to yield a stable and favourably soluble product for incorporation into foods, beverages, pharmaceuticals and the like.
  • the phytosterols for use in this invention may be procured from a variety of natural sources. For example, they may be obtained from the processing of plant oils (including aquatic plants) such as corn oil and other vegetable oils), wheat germ oil, soy extract, rice extract, rice bran, rapeseed oil, sesame oil and fish oil. Without limiting the generality of the foregoing, it is to be understood that there are other sources of phytosterols such as marine animals from which the composition of the present invention may be prepared.
  • US Patent Serial No. 4,420,427 teaches the preparation of sterols from vegetable oil sludge using solvents such as methanol.
  • phytosterols may be obtained from tall oil pitch or soap, by-products of the forestry practise as described in PCT/CA95/00555, incorporated herein by reference.
  • Such enhancement may be achieved by a number of suitable mans such as, for eample, solubilizing or dispersing the phytosterol or phytostanol composition (or mixture thereof) to form emulsions, solutions and dispersions or self-emulsifying systems; reducing the particle size by mechanical grinding (milling, micronisation etc.), lyophilizing, spray drying, controlled precipitating or a combination thereof; forming solid dispersions, suspensions, hydrated lipid systems; forming inclusion complexations with cyclodextrins; and forming hydrotopes and formulations with bile salts and their derivatives.
  • suitable mans such as, for eample, solubilizing or dispersing the phytosterol or phytostanol composition (or mixture thereof) to form emulsions, solutions and dispersions or self-emulsifying systems; reducing the particle size by mechanical grinding (milling, micronisation etc.), lyophilizing, spray drying, controlled precipitating or a combination thereof; forming solid dispersions
  • the phytosterols and/or phytostanols be isolated from the source and formed into a solid powder through precipitation, filtration and drying, spray drying, lyophilization or by other conventional work-up techniques. This powder form may then be physically modified as described below to enhance the solubility and dispersability of the phytosterol and/or phytostanol in the chosen delivery medium.
  • Emulsions are finely divided or colloidal dispersions comprising two immiscible phases, e.g. oil and water, one of which (the internal or discontinuous phase) is dispersed as droplets within the other (external or discontinuous phase).
  • an oil-in-water emulsion consists of oil as the internal phase, dispersed water as the external phase, the water-in-oil emulsion being the opposite.
  • emulsified systems may be formed which comprise the composition of the present invention including standard emulsions, microemulsions and those which are self-emulsifying (emulsify on exposure to agitated aqueous fluids such as gastric or intestinal fluids).
  • emulsions may include oil and water phases, emulsifiers, emulsion stabilizers and optionally preservatives, flavouring agents, pH adjusters and buffers, chelating agents, antifoam agents, tonicity adjusters and anti-oxidants.
  • Suitable emulsifiers include: anionic surfactants such as alcohol ether sulfates, alkyl sulfates (30-40), soaps (12-20) and sulfosuccinates; cationic surfactants such as quaternary ammonium compounds; zwitterionic surfactants such as alkyl betaine derivatives; amphoteric surfactants such as fatty amine sulfates, difatty alkyl triethanolamine derivatives (16-17); and nonionic surfactants such as the polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated fatty acids and alkyphenols, water-soluble polyethyleneoxy adducts onto polypropylene glycol and alkyl polypropylene glycol, nonylphenol polyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxy-pol
  • emulsion stabilizers include, but are not limited to, lyophilic colloids such as polysaccharides (e.g. acacia, agar, alginic acid, carrageenin, guar gum, karaya gum, tragacanth xanthan gum), amphoterics (e.g. gelatin) and synthetic or semi-synthetic polymers (e.g. carbomer resins, cellulose ethers, carboxymethyl chitin, polyethylene glycol-n (ethylene oxide polymer H(OCH2CH2)nOH); finely divided solids including clays (e.g.
  • lyophilic colloids such as polysaccharides (e.g. acacia, agar, alginic acid, carrageenin, guar gum, karaya gum, tragacanth xanthan gum), amphoterics (e.g. gelatin) and synthetic or semi-synthetic polymers (e.g. carbomer resins
  • Attapulgite bentonite, hectorite, kaolin, magnesium aluminum silicate and montmorillonite), microcrystalline cellulose oxides and hydroxides (e.g. aluminum hydroxide, magnesium hydroxide and silica); and cybotactic promoters/gellants including amino acids, peptides, proteins lecithin and other phospholipids and poloxamers.
  • Suitable anti-oxidants for use in the formation of emulsions include: chelating agents such as citric acid, EDTA, phenylalanine, phosphoric acid, tartaric acid and tryptophane; preferentially oxidized compounds such as ascorbic acid, sodium bisulfite and sodium sulfite; water soluble chain terminators such as thiols and lipid soluble chain terminators such as alkly gallates, ascorbyl palmitate, t-butyl hydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, hydroquinone, nordihydroguaiaretic acid and alpha-tocopherol.
  • Suitable preservatives, pH adjustment agents, and buffers, chelating agents, osmotic agents, colours and flavouring agents are discussed hereinbelow under "Supensions", but are equally applicable with respect to the formation of emulsions.
  • emulsions The general preparation of emulsions is as follows: the two phases (oil and water) are separately heated to an appropriate temperature (the same in both cases, generally 5- 10°C above the melting point of the highest melting ingredients in the case of a solid or semi-solid oil, or where the oil phase is liquid, a suitable temperature as determined by routine experimentation). Water-soluble components are dissolved in the aqueous (water) phase and oil-soluble components are dissolved in the oil phase. To create an oil-in water emulsion, the oil phase is vigorously mixed into the aqueous phase to create a suitable dispersion and the product is allowed to cool at a controlled rate with stirring. A water-in-oil emulsion is formed in the opposite fashion i.e.
  • the water phase is added to the oil phase.
  • hydrophillic colloids are a part of the system as emulsion stabilizers
  • a phase inversion technique may be employed whereby the colloid is mixed into the oil phase rather than the aqueous phase, prior to addition to the aqueous phase.
  • the oil-based composition of the present invention which is semi-solid, it is preferred to add the composition to the oil phase prior to heating.
  • Microemulsions characterized by a particle size at least an order of magnitude smaller (10-100 nm) than standard emulsions and defined as "a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid" (14), may also be formed comprising the composition of the present invention.
  • the microemulsion comprises a surfactant or surfactant mixture, a co- surfactant, (usually a short chain alcohol) the oil-based composition of the present invention, water and optionally other additives.
  • microemulsions tend to be created spontaneously, that is, without the degree of vigorous mixing required to form standard emulsions. From a commercial perspective, this simplifies the manufacturing process.
  • microemulsions may be sterilized using microfiltration techniques without breaking the microstructure due to the small diameter of the microdroplets.
  • microemulsions are highly thermodynamically stable.
  • microemulsions possess high solubilizing power which is particularly important as they allow for an increased solubilization of the poorly hydrosoluble phytosterols and phytostanols.
  • Surfactant or surfactant mixtures which are suitable for use in the formation of microemulsions can be anionic, cationic, amphoteric or non-ionic and possess HLB (hydrophile-lipophile balance) values within the range of 1-20, more preferably in the ranges 2-6 and 8-17.
  • HLB hydrophile-lipophile balance
  • non-ionic surfactants selected from the group consisting of polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated fatty acids and alkyphenols, water-soluble polyethyleneoxy adducts onto polypropylene glycol and alky polypropylene glycol, nonylphenol polyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxy-polyethoxyethanol, polyethylene glycol, octylphenoxy- polyethoxyethanol, lanolin alcohols, polyoxyethylated (POE) alkyl phenols, POE fatty amides, POE fatty alcohol ethers, POE fatty amines, POE fatty esters, poloxamers (7- 19), POE glycol monoethers (13-16), polysorbates and sorbitan esters.
  • POE polyoxyethylated
  • microemulsions There are many methods known and used by those skilled in the art for making microemulsions.
  • a surfactant, a co-surfactant and the phytosterol, phytostanols or mixtures thereof pre-dissolved in a suitable proportion of an appropriate oil
  • a surfactant, a co-surfactant and the phytosterol, phytostanols or mixtures thereof pre-dissolved in a suitable proportion of an appropriate oil
  • the formation of microemulsions may be achieved by mixing the phytosterols or phytostanols or mixtures thereof with hydrotropic agents and food-grade surfactants (refer to 11 ).
  • Phytosterols or phytostanols or mixtures thereof may be dissolved or dispersed in a suitable oil vehicle and used in this form, for example, in general food usage, in basting meats and fish, and for incorporation into animal feeds.
  • Suitable solubilizing agents include all food grade oils such as plant oils, marine oils such as fish oil and vegetable oils, monoglycerides, diglycerides, triglycerides, tocopherols and the like, and mixtures thereof.
  • Phytosterols or phytostanols or mixtures thereof may be mixed with appropriate excipients, for example, surfactants, emulsion stabilizers (described above) and the like, heated (if necessary) and cooled to form a semi-solid product capable of forming a spontaneous emulsion on mixing with water.
  • This semi-solid product may be used in numerous other forms such as filler material in two-piece hard or soft gelatin capsules, or may be adapted for use in other delivery systems.
  • solid dispersions may typically be prepared by utilizing water-soluble polymers as carriers.
  • these carriers may include, either alone or in combination: solid grade polyethylene glycols (PEG's), with or without the addition of liquid grade PEG's; polyvinylpyrrolidones or their co-polymers with vinyl acetate and cellulose ethers and esters.
  • PEG's solid grade polyethylene glycols
  • Other excipients such as additional members of the glycol family e.g. propylene glycol, polyols,e.g. glycerol etc. may also be included in the dispersions.
  • Solid dispersions may be prepared by a number of ways which are familiar to those in the art. These include, without limitation, the following methods:
  • the molten (fused) dispersion may be sprayed into a stream of cooled air in a spray drier to form solid particles (prilling) or passed through an extruder and spheroniser to form solid masses of a controlled particle size.
  • the molten dispersion is filled directly into two-piece hard gelating capsules;
  • Suspensions which may be used to enhance the solubility and/or dispersability of the phytosterols, phytostanols or mixtures thereof, comprise a solid, perhaps finely divided, internal phase dispersed in an oily or aqueous external phase (the vehicle).
  • the solid internal phase may be added to an emulsion as described above during its' formation to produce a delivery system having properties common to both suspensions and emulsions.
  • a suspension comprises an oily or aqueous vehicle, the dispersed (suspended) internal phase, dispersing and/or wetting agents (surfactants), pH adjustment agents/buffers, chelating agents, antioxidants, agents to adjust ionic strength (osmotic agents) colours, flavours, substances to stabilize the suspension and increase viscosity (suspending agents ) and preservatives.
  • dispersing and/or wetting agents surfactants
  • pH adjustment agents/buffers chelating agents
  • antioxidants agents to adjust ionic strength (osmotic agents) colours
  • flavours substances to stabilize the suspension and increase viscosity (suspending agents ) and preservatives.
  • Appropriate vehicles include, but are not limited to: water, oils, alcohols, polyols, other edible or food grade compounds in which the phytosterol composition is partially or not soluble and mixtures thereof.
  • Appropriate dispersing agents include, but are not limited to: lecithin; phospholipids; nonionic surfactants such as polysorbate 65, octoxynol-9, nonoxynol-10, polysorbate 60, polysorbate 80, polysorbate 40, poloxamer 235, polysorbate 20 and poloxamer 188; anionic surfactants such as sodium lauryl sulfate and docusate sodium; fatty acids, salts of fatty acids, other fatty acid esters, and mixtures thereof.
  • Agents/buffers for pH adjustment include citric acid and its salts, tartaric acid and its salts, phosphoric acid and its salts, acetic acid and its salts, hydrochloric acid, sodium hydroxide and sodium bicarbonate.
  • Suitable chelating agents include edetates (disodium, calcium disodium and the like), citric acid and tartaric acid.
  • Suitable antioxidants include ascorbic acid and its salts, ascorbyl palmitate, tocopherols (especially alpha-tocopherol), butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite and metabisulfite.
  • Suitable osmotic agents include monovalent, divalent and trivalent electrolytes, monosaccharides and disaccharides.
  • Suitable preservatives include parabens (Me, Et, Pr, Bu), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chorhexidine gluconate and phenylethanol. Colours and flavours may be added as desired and may be selected from all nature, natural-identical and synthetic varieties.
  • the solubility/dispersability of phytosterols, phytostanols or mixtures thereof may be enhanced by the formation of phospholipid systems such as liposomes and other hydrated lipid phases, by physical inclusion.
  • This inclusion refers to the entrapment of molecules without forming a covalent bond and is widely used to improve the solubility and subsequent dissolution of active ingredients.
  • Hydrated lipid systems can be prepared using a variety of lipid and lipid mixtures, including phospholipids such as phosphatidylcholine (lecithin), phosphodiglyceride and sphingolipids, glycolipids, cholesterol and the like.
  • phospholipids such as phosphatidylcholine (lecithin), phosphodiglyceride and sphingolipids, glycolipids, cholesterol and the like.
  • the lipids may preferably be used in combination with a charge bearing substances such as charge-bearing phospholipids, fatty acids, and potassium and sodium salts thereof in order to stabilize the resultant lipid systems.
  • a typical process of forming liposomes is as follows: 1 ) dispersion of lipid or lipids and the phytosterols or phytostanols or mixtures thereof in an organic solvent (such as chloroform, dichloromethane, ether, ethanol or other alcohol, or a combination thereof).
  • an organic solvent such as chloroform, dichloromethane, ether, ethanol or other alcohol, or a combination thereof.
  • a charged species may be added to reduce subsequent aggregation during liposome formation.
  • Antioxidants such as ascorbyl palmitate, alpha-tocopherol, butylated hydroxytoluene and butylated hydroxyanisole
  • US Patent Serial No. 4,508,703 (also inco ⁇ orated herein by reference) describes a method of preparing liposomes by dissolving the amphiphillic lipidic constituent and the hydrophobic constituent to form a solution and thereafter atomizing the solution in a flow of gas to produce a pulverent mixture.
  • Cyclodextrins are a class of cyclic oiigosaccharide molecules comprising glucopyranose sub-units and having a toroidal cylindrical spatial configuration.
  • Commonly available members of this group comprise molecules containing six (alpha-cyclodextrin), seven (beta-cyclodextrin) and eight (gamma-cyclodextrin) glucopyranose molecules, with the polar (hydrophilic) hydroxyl groups oriented to the outside of the structure and the apolar (lipophilic) skeletal carbons and ethereal oxygens lining the interior cavity of the toroid.
  • This cavity is capable of accomodating (hosting) the lipophilic moiety of an active ingredient (the guest molecule, here the phytosterol or phytostanol or mixture of both) by bonding in a non-covalent manner to form an inclusion complex.
  • the external hydroxyl substituents of the cyclodextrin molecule may be modified to form derivatives having improved solubility in aqueous media along with other desired enhancements, such as lowered toxicity, etc..
  • Examples of such derivatives are: alkylated derivatives such as 2,6-dimethyl-beta-cclodextrin; hydroxyalkylated derivatives such as hydroxypropyl-beta-cyclodextrin; branched derivatives such as diglucosly-beta- cyclodextrin; sulfoalkyl derivatives such as sulfobutylether-beta-cyclodextrin; and carboxymethylated derivatives such as carboxymethyl-beta-cyciodextrin.
  • Other types of chemical modifications, known to those in the art, are also included within the scope of this invention.
  • the cyclodextrin complex often confers properties of improved solubility, dispersability, stability (chemical, physical and microbiological), bioavailability and decreased toxicity on the guest molecule (here, the phytosterols or phytostanols or mixtures thereof).
  • Complexes may be produced, for example, by using the following basic methods: stirring the phytotsterol, phytostanol or mixture thereof into an aqueous or mixed aqueous-organic solution of the cyclodextrin, with or without heating; kneading, slurrying or mixing the cyclodextrin and the phytotsterol, phytostanol or mixture thereof in a suitable device with the addition of an appropriate quantity of aqueous, organic or mixed aqueous-organic liquid, with or without heating; or by physical admixture the cylcodextrin and the phytotsterol, phytostanol or mixture thereof using a suitable mixing device.
  • Isolation of the inclusion complex so formed may be achieved by co- precipitation, filtration and drying; extrusion/spheronisation and drying; subdivision of the moist mass and drying; spray drying; lyophilization or by other suitable techniques depending on the process used to form the cyclodextrin complex.
  • a further optional step of mechanically grinding the isolated solid complex may be employed.
  • cyclodextrin phytosterol complexes enhance the solubility and dissolution rate and increase the stability of the phytosterols or phytostanols or mixtures thereof.
  • cyclodextrin complexation please refer to 16.
  • Bile acids, their salts and conjugated derivatives, suitably formulated, may be used to solubilize phytosterols, phytostanols or mixtures thereof, thereby improving the solubility and dispersion characteristics of these compositions.
  • suitable bile acids include: cholic acid, chenodeoxycholic acid, deoxycholic acid, dehydrocholic acid, and lithocholic acid.
  • suitable bile salts include: sodium cholate, sodium deoxycholate and their other salt forms.
  • suitable conjugated bile acids include: glycochenodeoxycholic acid, glycholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid and their salts.
  • a suitable system for solubilizing phytosterols or phytostanols or mixtures thereof consists of the sterol or stanol component plus one or more bile acids, salts or conjugated bile acids. Further materials may be added to produce formulations having additional solubilization capacity. These materials include, but are not limited to: phospholipids, glycolipids and monoglycerides. These ingredients may be formulated either in the solid phase or by the use of suitable solvents or carrier vehicles, with appropriate isolation and, optionally, particle size reduction using techniques described hereinabove.
  • a suitable enteric coating may be applied to the solid formulation particulates, using techniques known to those skilled in the art.
  • Typical enteric coatings include, inter alia: cellulose acetate phthalate, cellulose acetate trimellitiate, hydroxyproplmethylcellulose phthalate, hydroxyproplmethylcellulose acetate succinate, poly (vinylaceate phthalate), acrylate polymers and their derivatives (e.g. appropriate members of the Eudragit series), ethylcellulose or combinations thereof.
  • Additional excipients may be added to the coating formulation to modify membrane functionality or to aid in the coating process (e.g. surfactants, plasticisers, channeling agents, permeability modifiers and the like).
  • Coating formulation vehicles may comprise aqueous or organic systems, or mixtures of both.
  • hydrotopes Compounds which are capable of opening up the water structure associated with hydrophobic (lipophilic) and other molecules are referred to as hydrotopes. These compounds may be used to enhance the aqueous solubility of poorly water-soluble substances such as phytosterols, phytostanols and their esters.
  • hydrotopes include, inter alia, sodium benzoate, sodium hydroxybenzoates, sodium salicylate, nicotinamide, sodium nicotinate, sodium gentisate, gentisic acid ethanolamide, sodium toluates, sodium aminobenzoates, sodium anthranilate, sodium butylmonoglycolsulfate, resorcinol and the like.
  • Complex formation which is non-covalent in nature, may be achieved by mixing appropriate ratios of the phytosterols or phytostanols or mixtures thereof and the hydrotope or mixtures thereof in a suitable liquid vehicle, which may be aqueous, organic or a combination of both. Additional excipients such as surfactants, polyol, disaccharides etc.. may be added to facilitate complexation or to aid in dispersability.
  • the resultant complex is isolated as a dry powder by any process known in the art (co- precipitation and drying, evaporation of the liquid vehicle, spray drying, lyophilization etc.). Particle size may be reduced by any standard technique such as those described previously herein, if desired.
  • the resultant hydrotope complex may be used without further modification or may be compounded into a variety of other formulations or vehicles as required.
  • any phytosterol or phytostanol or mixture thereof, treated as described herein to form a composition of enhanced solubility/dispersability, may be used as an effective agent to lower serum cholesterol in animals, particularly humans. It is to be understood, however, that this composition is equally suited for administration to other animals, for example, in the form of veterinary medicines and animal foods. There are numerous modes or "vehicles" of delivery of this composition, accordingly, this invention is not intended to be limited to the following delivery examples.
  • composition of the present invention may be incorporated into various conventional pharmaceutical preparations and dosage forms such as tablets (plain and coated) for use orally, bucally or lingually, capsules (hard and soft, gelatin, with or without additional coatings) powders, granules (including effervescent granules), pellets, microparticulates, solutions (such as micellar, syrups, elixirs and drops), lozenges, pastilles, ampuls, emulsions, microemulsions, ointments, creams, suppositories, gels, and transdermal patches, modified release dosage forms together with customary excipients and/or diluents and stabilizers.
  • tablets plain and coated
  • bucally or lingually capsules (hard and soft, gelatin, with or without additional coatings) powders, granules (including effervescent granules), pellets, microparticulates, solutions (such as micellar, syrups, elixir
  • composition of the present invention adapted into the appropriate dosage form as described above may be administered to animals, including humans, orally, by injection (intra-venously, subcutaneously, intra-peritoneally, intra-dermally or intra-muscularly), topically or in other ways. Although the precise mechanism of action is unclear, the composition of the present invention, administered intra-venously, lowers serum cholesterol.
  • the phytosterol composition may have, in addition to the role as an inhibitor of cholesterol absorption in the intestine, a systemic effect on cholesterol homeostasis through bile acid synthesis, enterocycte and biliary cholesterol excretion, bile acid excretion and changes in enzyme kinetics and cholesterol transport between various compartments within the body (PCT/CA97/00474 which was published on January 15, 1998). See also paper to Peter Jones (under publication). 2) Foods/Beverages/Nutraceuticals:
  • composition of the present invention may be inco ⁇ orated into foods, beverages and nutraceuticals, including, without limitation, the following:
  • Dairy Products such as cheeses, butter, milk and other dairy beverages, spreads and dairy mixes, ice cream and yoghurt;
  • Fat-Based Products such as margarines, spreads, mayonnaise, shortenings, cooking and frying oils and dressings;
  • Confectionaries such as chocolate, candies, chewing gum, desserts, non-dairy toppings (for example Cool WhipTM), sorbets, icings and other fillings;
  • composition of the present invention may be incorporated directly and without further modification into the food, nutraceutical or beverage by techniques such as mixing, infusion, injection, blending, immersion, spraying and kneading.
  • the composition may be applied directly onto a food or into a beverage by the consumer prior to ingestion.
  • Solubility and dispersability of any phytosterol or phytostanol mixture may be enhanced via the formation of emulsions and microemulsions which may readily be incorporated into margarines, butter, spreads, mayonnaise, dressings, yoghurt and the like.
  • Patents covering the preparation of margarines and yellow spreads include: US Patent Serial Nos: 5,118,522; 5,536,523; 5,409,727; 5,346,716; 5,472,728; and 5,532,020, all of which are inco ⁇ orated herein by reference.
  • An aqueous ethanolic vehicle was prepared by mixing water and ethanol in the ratios of water (9 parts - 1 part) to ethanol (1 part - 9 parts) and the temperature was adjusted to 20-50°C.
  • 2-dydroxypropyl-beta-cylcodextrin was dissolved in the mixture to give a concentration of 10-50% w/v, with stirring.
  • a slight calculated excess of a phytosterol composition comprising beta-sitosteroi, campesterol and stigmastanol was added in fine powder form to the mixture and the vessel sealed. The mixture was stirred for 2-48 hours under a maintained reaction temperature.
  • the resultant mixture was filtered and the filtrate allowed to attain an appropriate temperature.
  • the complex was then isolated by spraying drying at 39-90°C over an appropriate time cycle and yielded a free-flowing powder of small and regular particle size.
  • the mixture was prepared in accordance with the protocol outlined in Example 1 up to and including the stage of filtration.
  • 0.1-1% w w of colloidal silicone dioxide (based on the calculated solids content of the filtrate) was added to the filtrate while stirring.
  • the complex was then isolated by spray drying at 30-90°C over an appropriate time cycle and yielded a free-flowing powder of small and regular particles size.
  • An aqueous ethanolic vehicle was prepared by mixing water and ethanol in the ratios of water (9 parts - 1 part) to ethanol (1 part - 9 parts) and the temperature was adjusted to 20-50°C. Calculated amounts of sodium cholate and sodium taurocholate were dissolved to give a combined concentration of 30-60% w/v. the ratios of sodium cholate to sodium taurocholate were between 1 part - 9 parts to 9 parts - 1 part. A slight calculated excess of a phytosterol composition comprising beta-sitosterol, campesterol and stigmastanol was added in fine powder form, the vessel sealed, and the mixture gently stirred for 2-24 hours.
  • the mixture was filtered and a calculated quantity of soybean lecithin (0.5-30% w/w based on the solids content of filtrate) was added with gentle stirring. Stirring was continued for a period up to 4 hours and the mixture allowed to attain a suitable temperature.
  • the mixture was spray dried at 30-90°C over a suitable time cycle to yield an isolated solid complex as a free flowing powder of small and irregular particle size.
  • An enteric coating solution was prepared comprising a mixture of EudragitTM L 100/ Eudragit TM S 100 (enteric film formers) 6+1.2% w/w composite concentration, triethylcitrate (plasticiser) 0.6+1.12% w/w, talc (anti-tack agent) 3+0.6% w/w, water (vehicle) 5+1% w/w, isopropyl alcohol (vehicle) to 100% w/w.
  • the powder, prepared as described above was spray coated using equipment and methodology known in this field, to a percentage weight increase (based upon input weight of powder) sufficient to ensure an effective enteric barrier. The resultant coated powder product was then collected.
  • the mixture was prepared in accordance with the protocol outlined in Example 3 up to and including the addition of soybean lecithin, stirring and cooling.
  • 0.1- 1% w/w of colloidal silicone dioxide (based on the calculated solids content of the filtrate) was added to the filtrate while stirring.
  • the mixture was spray dried at 30-90°C over a suitable time cycle to yield an isolated solid complex as a free flowing powder of small and irregular particle size.
  • the enteric coating solution was then prepared and applied as described in Example 3.
  • the mixture was prepared in accordance with the protocol outlined in Example 3 up to and including the step of spray drying to form the free flowing powder.
  • a water-soluble film former here, hydroxypropylmethylcellulose formulated in a hydroalcoholic vehicle along with a plasticiser and ant-tack agent
  • Gentisic acid anhydride (10-40% w/v) was dissolved in appropriate volume of water, containing 5-20% v/v ethanol at 20-60°C.
  • a calculate slight excess of a phytosterol composition comprising beta-sitosterol, campesterol and stigmastanol in fine powder form was added, the vessel sealed and the mixture stirred vigorously for 2-24 hours. The mixture was then filtered and the filtrate allowed to attain a suitable temperature.
  • the mixture was spray dried at 30-90°C over a suitable time cycle and a solid hydrotropic complex isolated in free-flowing powder form, of small and regular particle size.
  • the mixture was prepared in accordance with the protocol outlined in Example 6 up to and including the stage of filtration.
  • 0.1-1% w/w of colloidal silicone dioxide (based on the calculated solids content of the filtrate) was added to the filtrate while stirring.
  • the complex was then isolated by spray drying at 30-90°C over an appropriate time cycle and a solid hydrotropic complex isolated in free-flowing powder form, of small and regular particle size.
  • FCP-3P2 Batch FM-P2-63 (composition: campestanol, 19.16%; sitostanol, 76.99%; campesterol, 0.13%; beta- sitosterol, 0.07%) was used in formulation work. Content uniformity data was referenced to the total phytostanol content of the batch, i.e. 96.15%.
  • Example 8 Solutions and Dispersions (Oil-based)
  • FCP-3P2 In order to determine the lipophilicity of FCP-3P2 the compound was evaluated in a selection of test systems. Solubility in fixed oils, the octanol / water partition coefficient and solubility in pH 5 aqueous buffer were chosen as relevant characteristics. Knowledge of these parameters would also act as guidance in future formulation efforts. FCP-3P2 was represented by Batch FM-P2-48 (composition: campestanol, 20.03%; sitostanol, 75.12%, campesterol, 3.19%).
  • the octanol / water partition coefficient was assessed by dissolving 5mg of test compound in 5mL of 1 -octanol (oil phase), adding 15mL of pH 5.0 phosphate buffer and equilibrating by vortexing (VWR Multi-Tube Vortexer, setting 2) at 21 C for 30 seconds, followed by static storage at 21 C for 16 hours, in 20mL closed glass scintillation vials. It was observed that the two phases were completely transparent and no filtration step was necessary prior to analysis. The vials were then independently sampled for analysis from the aqueous and octanol phases. Analysis was by GC-Mass Spectrometry.
  • FCP-3P2 is substantially lipophilic in character, having negligible solubility in simple aqueous media.
  • the data is consistent with comparable testing on steroids, which bear some significant structural similarities to the sterols and stanols.
  • the formulation of an oil-based solution of the active represents a feasible delivery system. If the quantity of FCP-3P2 exceeds it's solubility in the oily vehicle, a combination solution / dispersion will result. In this event, the active particle size distribution may be reduced, if desired, by homogenisation, e.g. using a high-shear device such as the Microfluidics Microfluidizer Model M-110Y or large-scale equivalent.
  • Example 9 Emulsions (Macroemulsions)
  • a 10% w/v solution of FCP-3P2 was prepared by adding 5.062g of material to 45.248g of soybean oil and heating to 63 C, to give a clear solution. 10mL of this solution was taken and 0.748g of Span 60 [polyoxyethylene-(20)-sorbitan monostearate] dissolved in it. This constituted the oil phase.
  • the surfactant has a Hydrophile-Lipophile
  • HLB Balance
  • Tween 40 has an HLB value of 15.6 +/-
  • Analytical assessment of the emulsion included visual examination for phase separation over 5 days, optical microscopic evaluation of oil droplet size, pH measurement and
  • this dosage delivery system has successfully enhanced both FCP-3P2 solubility and dispersibility.
  • a self-emulsifying drug delivery system is one that readily undergoes emulsification in aqueous media under low or modest shear (agitation) conditions. Elevated temperature is not necessarily required. This ideally translates to a spontaneous in vivo emulsification and subsequent dispersion following oral administration. Furthermore, it is desirable for the SEDDS to form a microemulsion on exposure to aqueous media, thereby affording an additional enhancement of dispersibility and an increased surface area for absorption (smaller droplet size distribution than a macroemulsion).
  • a SEDDS may be utilised in a variety of ways. For example, it is suited to filling into a soft gelatin capsule (softgel), or other suitable dosage form, for oral administration, or it may be further processed into a microemulsion prior to administration.
  • soft gelatin capsule softgel
  • microemulsion prior to administration.
  • SEDDS SEDDS
  • it's subsequent compounding into a microemulsion is noted below.
  • Capmul MCM (a proprietary blend of medium chain glycerides), 5.30g, and Tween 80
  • ком ⁇ онент 80 is a high-HLB (15.0 +/- 1.0) surfactant emulsifier.
  • the measured pH of the system was 5.72.
  • a cosolvent mixture consisting of 125mL chloroform and 125mL ethanol, was prepared in a 500mL round-bottom flask.0.49g FCP-3P2 and 2.007g Benecel (a grade of hydroxypropylmethylcellulose) were added and the mixture was stirred at ambient temperature until a clear solution resulted. Solvent was removed by rotary evaporation under vacuum at 40 C and the resultant film was vacuum dried for a period at ambient temperature, following which the temperature was increased to 45 C and drying continued to achieve a total residual solvent level of less than 200 ppm (GC-headspace analysis). The dried film was cooled to ambient temperature and carefully scraped from the flask wall.
  • FCP-3P2 did not form a complete molecular dispersion in the Benecel matrix, following evaporation of the solvent vehicle.
  • the complex film was visibly opaque and optical microscopic examination revealed rounded particulates, ranging from 20-200 microns in size, within the matrix.
  • Untreated FCP-3P2 generally exhibits a rod-like crystal habit and a significantly larger overall mean particle size and distribution. Modification of the crystallisation process (crystal habit and size) by polymeric and surfactant materials has been documented in the literature, so this observation is not unexpected.
  • hydrophobic (lipophilic) FCP-3P2 in this preparation was of a markedly smaller overall particle size than the original material and is embedded in a hydrophilic water-soluble matrix, some improvement in aqueous dispersibility might reasonable be anticipated.
  • DSC is widely employed to assess specific thermal properties of single materials and formulated systems. Examples would include determination of melting point and melting behaviour, identification of polymorphic forms, differentiation between amo ⁇ hous and crystalline forms of a material and, in this case, evaluation of potential solid dispersion formation. Whilst characteristic melting endotherms for the individual components of a solid dispersion should be readily identifiable, conversion to a true solid dispersion would be expected to cause significant changes in their DSC thermograms. In the case of an active material, substantial modification or complete elimination of the specific melting endotherm(s) for that substance are commonly observed.
  • DSC scans were run on FCP-3P2, Benecel and the FCP-3P2/Benecel formulation, using a Dupont Model 91 OS Differential Scanning Calorimeter, calibrated against an indium standard, with helium gas purging. A scan rate of 10 C/minute, over a temperature range of 20-200 C, was utilised. Sample sizes varied from 3.98-4.60mg and powders were run in crimped aluminium cups.
  • FCP-3P2 typically shows one major melting endotherm, with a peak value of approximately 143.3 C. Benecel exhibited no significant endo- or exo-therms over the test temperature range.
  • the FCP-3P2/Benecel formulation showed a single endotherm at 142.6 C, corresponding to free FCP-3P2 and the area under the endotherm curve equated to the loading level of the FCP-3P2 in the matrix. Thus, we may say that a true molecular dispersion has not formed between these two substances.
  • a model system was established in an attempt to ascertain whether specific formulation approaches could yield potential improvements in the dispersibility of FCP- 3P2 in the gastric environment.
  • a USP dissolution apparatus equipped with paddles (Apparatus II) and domed vessels was employed.
  • Stirring rate and medium volume were selected by experimentation to give efficient mixing without turbulence.
  • a 60 minute overall assessment period was set.
  • Untreated FCP-3P2 is hydrophobic in nature. Material (50mg) added to the surface of the stirred test medium, did not wet and persisted as floating particles for up to 60 minutes, when the test was terminated.
  • the FCP-3P2 Benecel formulation sample was prepared by gently grinding in a mortar and passage through a 25 mesh sieve. Sieved material (100mg) was taken and added to the surface of the stirred test medium. Over the course of the 60 minute test period, material was observed to hydrate and commence dispersal into the medium. Whilst the dispersal process was not completed within this time, the test medium became noticeably opalescent. Optical microscopic examination of samples withdrawn from the bulk medium confirmed the presence of small particulates, as noted under 4.1. Based upon this data, it would appear that the aqueous dispersibility of FCP-3P2 has been enhanced by this formulation approach. Wettability may be improved upon in future experiments, using a number of potential means.
  • a suitable surfactant for example, addition of a suitable surfactant to the formulation, pre-suspension of the formulation in a quantity of an appropriate water-miscible liquid vehicle, substitution of spray drying for rotary evaporation as a process for isolating a more uniform dried product, etc.
  • FCP-3P2 was assayed by GC-FID, using a cholestane internal standard.
  • the x-ray diffraction pattern of a substance can be used to evaluate it's internal structure and gives useful information as to whether a material is amo ⁇ hous or crystalline in nature.
  • the technique can also be used to demonstrate the influence of added substances on the pre-existing internal molecular arrangement of a particular material. As such, it constitutes a complimentary procedure to DSC investigations and was employed for this purpose in the current experimental work.
  • FCP-3P2 showed a characteristic pattern that indicated a reasonable degree of crystallinity. Benecel also demonstrated a characteristic pattern, with little evidence of crystallinity. The physical mixture produced a composite pattern, containing elements of the individual components. FCP-3P2/Benecel solid dispersion showed a pattern which was quite similar to that of the physical mixture, but in addition appeared to indicate a reduced degree of FCP-3P2 crystallinity.
  • Carbopol 971 P (a proprietary grade of Carbomer 941 USNF), 0.51 g, was added to water, 75mL, and mixed to create a smooth lump-free suspension.
  • Analytical evaluation included: visual assessment of sedimentation, optical microscopic appearance, pH check and FCP-3P2 content uniformity determination. Test methods were as per Emulsions, unless otherwise stated.
  • This characteristic was evaluated using an optical microscope equipped with a calibrated eyepiece.
  • the suspension was examined in the undiluted form, by placing a suitable quantity on a microscope slide and fitting a cover slip, at 400x magnification and ranged from approximately 2.5 to 25 microns in particle size (major axis).
  • the measured pH of the system was 6.0 (initial) and 5.9 at the 5 day test point of the sedimentation test.
  • a liposomal dispersion was evaluated as an example of a hydrated lipid system.
  • a solution was prepared containing the following materials: phospholipids- dimyristoyiphosphatidylcholine, 2.832g, dimyristoylphosphatidylglycerol, 1.392g; FCP- 3P2, 0.782g; dichloromethane, to 50mL. Sonication of the mixture for 30 minutes at 40 C yielded a slightly opalescent solution, which was subsequently clarified by passage through a 0.5 micron filter.
  • the particle size and lamellarity of the LMVs was reduced by passing 250 uL quantities of dispersion (at 40 C) through an Avanti Mini Extruder, fitted with a 0.08 micron filter, for a total of 11 passes, to give a dispersion of small unilamellar vesicles (SUVs).
  • SSVs small unilamellar vesicles
  • Analytical assessment of the formulation included: liposomal particle size evaluation, pH measurement and FCP-3P2 content uniformity determination. Testing methodologies were as per Emulsions, unless otherwise stated.
  • the SUV dispersion was examined under 400x magnification and in the phase contrast mode. A uniform dispersion of discrete liposomes having diameters of less than 1 micron was observed.
  • the measured pH of the system was 6.45.
  • This formulation approach has enhanced both the solubility and dispersibility of the active in aqueous media.
  • the FCP-3P2/2-HPB sample was prepared by gentle grinding in a mortar and easily reduced to a fine powder.
  • This formulation approach has enhanced the dispersibility of the active in aqueous media.
  • Sodium deoxycholate was chosen as a typical example of a human bile salt.
  • a cosolvent mixture consisting of 100mL ethanol and 50mL DCM, was added to a 500mL round-bottom flask.
  • Solvent was removed by rotary evaporation under vacuum at 40-50 C, to yield a white powder mass. Further vacuum drying at ambient temperature reduced residual solvent to workable levels (DCM less than 200 ppm, ethanol greater than 200 ppm- limit testing employed; GC-headspace analysis). The product was free of residual solvent odour.
  • Analytical investigation of product included: DSC assessment, XRD evaluation, aqueous dispersibility testing and FCP-3P2 content uniformity determination. Testing methods were as per Solid Dispersions, unless otherwise stated. DSC Evaluation
  • thermogram for the test formulation showed two consecutive melting endotherms, peaking at 136.3 C and 141.8 C, separated by a small exothermic peak.
  • FCP-3P2 typically has a melting endotherm peaking at 143.3 C. Thus, these thermal events are probably due to the active.
  • FCP-3P2 may exist in a metastable state in the formulation, initially melting at 136.3 C, recrystallising to the stable form and then re-melting at 141.8 C. It was noted that the area under the 141.8
  • SDC showed a pattern that is indicative of a non-crystalline material.
  • test formulation scan was essentially a composite of the patterns for the two components and the degree of crystallinity of the FCP-3P2 has been little affected by it's combination with SDC. These observations support the DSC data.
  • test formulation presented as a fine powder and was used as received.
  • pH 5 phosphate buffer was used as the test medium, since the bile acid is present as it's sodium salt, which possesses a significantly greater aqueous solubility than the parent acid.
  • the medium initially chosen for dispersibility testing would cause conversion to the acid form and substantially inhibit dispersion of the complex. This consideration necessitates the design of a dosage form which releases it's contents upon reaching the upper regions of the small intestine and is protected from exposure to the acidic gastric fluid, i.e. an enteric coated system. Since bile salts are known to cause gastric irritation and emesis upon oral administration, these would be further reasons to prevent premature release in the stomach.
  • test formulation had substantially wetted and appeared as a fine particulate dispersion in the test medium, with a small proportion of material floating at the surface.
  • trace of material was present at the surface, the majority being present as a uniform particulate suspension.
  • This formulation approach has improved FCP-3P2 dispersibility and wettability in aqueous media. Since the bile salts perform a solubilising function in vivo (they are surfactants), it is also possible that oral bioavailability will be enhanced.
  • Sodium gentisate (SG) was selected as a model hydrotrope.
  • the resultant solution was transferred to a 250mL round bottom flask and solvent removed by vacuum rotary drying at 60 C, to give a damp mass. Further vacuum drying at ambient temperature yielded a dry powder mass.
  • Analytical testing included: DCS assessment, XRD evaluation, aqueous dispersibility testing and FCP-3P2 content uniformity determination. Test methods were as per Solid Dispersions, unless otherwise stated.
  • the SG thermogram showed two melting endotherms, peaking at 89.7 C and 169.6 C.
  • test formulation thermogram showed a similar pattern to that for the SDC (Bile Salt) complex, consisting of a minor melting endotherm peaking at approximately 135 C, followed by a small exotherm, leading to a sharp endotherm peaking at 141.5 C
  • test formulation showed little evidence of crystallinity, indicating that some definite physical interaction has occurred between the two substances. This observation is consistent with the DSC evaluation data.
  • pH 5.0 phosphate buffer was substituted for 0.1N HCI, since the sodium salt of gentisic acid was present in the formulation.
  • Material initially floats on the surface of the test medium, with some particulates dispersing into the bulk liquid. A visible film forms at the surface, indicating some dissolution of the SG carrier. At 60 minutes, there was a slight increase in the level of dispersed particles, but the majority of the material remained at the surface and the SG film persisted.
  • Phytrol® which consists of campesterol, campestanol, ⁇ -sitosterol and sitostanol was mixed with nonfat milk powder in the ratio of 1 :7 to 1:8. About 6 L of milk mix was prepared from whole milk, skimmed milk and phytrol containing milk powder. Milk was standardized to 0.75 - 1 % fat, 12 - 13% solids and 0.5-1% phytrol using the Pearsons Square method (Hyde, K.A. and Rothwell, J., 1973, In Ice Cream, Churchill Livingstone Ltd., London, U.K.).
  • Milk mix was permitted to remain at room temperature for 30 minutes to re-hydrate powder milk and than it was homogenized using a high sheer batch mixer (Ultra-Turrax T50 equipped with the dispersing element S50N, IKA Works Inc., Wilmington, NC, USA).
  • Other devices such as a single-stage homogeniser, a two- stage homogeniser or a high-pressure microfluidizer may alternatively be used for homogenization of the milk mix.
  • milk mix was pasteurized at 69oC (156oF) for 30 minutes (batch/vat), cooled to 44oC and hold at this temperature for up to 15 minutes.
  • Phytrol® consisted of campesterol campestanol, ⁇ -sitosterol and sitostanol was mixed with multipurpose flour (1% and 2%, w/w) using Hobart mixer (Model N50). Alternatively, Phytrol was mixed with milk using a high-pressure microfluidizer. Subsequently, all other ingredients were mixed in proportions indicated below.
  • Phytrol® consisted of campesterol, campestanol, ⁇ - sitosterol and sitostanol was dissolved in partially hydrogenated vegetable oil in elevated temperature (40-80oC).
  • the oil/Phytrol blend was cooled to 30oC and emulsified using a high sheer batch mixer (Ultra-Turrax T50 equipped with the dispersing element S50N, IKA Works Inc., Wilmington, NC, USA). Subsequently, two oil blends (9.4% and 18.8% of Phytrol) were further emulsified using a high-pressure microfluidizer at 20,000 PSI.
  • Cereal bars were produced by combining binder (40%), water (5%) and edible particles (55%). Below two typical examples of binder used for making a cereal bar.
  • Glycerin 3% Sucrose in water /glucose syrup was heated to 10OoC while Phytrol containing fat was liquefied at 40-80oC. Hot sugar solution was placed in the bowl (Hobart mixer, Model N50) and fat was added followed by adding all remaining binder ingredients. All ingredients were thoroughly and vigorously mixed. After cooling down to 40oC, edible particles are added while thorough, non-vigorous mixing was carried out. Following edible particles were typically incorporated into the cereal bars.
  • Example 21 Chocolate
  • Phytrol® consisted of campesterol, campestanol, ⁇ -sitosterol and sitostanol was mixed with soybean oil using a high sheer batch mixer (Ultra-Turrax T50 equipped with the dispersing element S50N, IKA Works Inc., Wilmington, NC, USA). The blend (20% Phytrol) was subsequently emulsified using a high-pressure microfluidizer at 20,000 PSI. Chocolate was composed of an outer shell (42 wt%, no Phytrol) and a center (69%, Phytrol).
  • Chocolate outer shell was made by mixing sugar (45%), whole milk powder (20%), cocoa butter (23%), cocoa mass (12%), soy lecithin (0.3%) and pure vanilla (0.1%) in a heating tank. All ingredients were melted, tempered and deposited into molds. Center was prepare my mixing sugar, cocoa butter, whole milk powder, cocoa mass, soy lecithin and pure vanilla in the proportions as for outer shell. The mix was melted and tempered. Consequently, Phytrol/soybean oil blend was mixed with chocolate in the 1:1 ratio and deposited into molds previously filled with chocolate without Phytrol. Chocolate pieces were than cooled, wrapped and packed into the boxes. Using the molding system, 10-12 g chocolate pieces were produced.

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  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nutrition Science (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Cette composition propre à être incorporée à des aliments, des boissons, des médicaments, des aliments fonctionnels et analogue, renferme un ou plusieurs phytostérols et phytostanols ou des mélanges de ces deux substances, lesquelles substances ont subi un traitement visant à améliorer leur solubilité et leur dispersibilité.
EP99923350A 1998-06-05 1999-06-07 Compositions renfermant du phytosterol et/ou du phytostanol a solubilite et dispersibilite ameliorees Ceased EP1082026A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9249798A 1998-06-05 1998-06-05
US92497 1998-06-05
PCT/CA1999/000512 WO1999063841A1 (fr) 1998-06-05 1999-06-07 Compositions renfermant du phytosterol et/ou du phytostanol a solubilite et dispersibilite ameliorees

Publications (1)

Publication Number Publication Date
EP1082026A1 true EP1082026A1 (fr) 2001-03-14

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EP99923350A Ceased EP1082026A1 (fr) 1998-06-05 1999-06-07 Compositions renfermant du phytosterol et/ou du phytostanol a solubilite et dispersibilite ameliorees

Country Status (7)

Country Link
EP (1) EP1082026A1 (fr)
JP (1) JP2002517418A (fr)
AU (1) AU771960B2 (fr)
BR (1) BR9910950A (fr)
CA (1) CA2334449A1 (fr)
NZ (1) NZ508645A (fr)
WO (1) WO1999063841A1 (fr)

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Also Published As

Publication number Publication date
JP2002517418A (ja) 2002-06-18
WO1999063841A1 (fr) 1999-12-16
AU4027599A (en) 1999-12-30
AU771960B2 (en) 2004-04-08
BR9910950A (pt) 2002-02-13
NZ508645A (en) 2003-10-31
CA2334449A1 (fr) 1999-12-16

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