WO2014053370A1 - Mousse comestible comprenant un médicament - Google Patents

Mousse comestible comprenant un médicament Download PDF

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Publication number
WO2014053370A1
WO2014053370A1 PCT/EP2013/069909 EP2013069909W WO2014053370A1 WO 2014053370 A1 WO2014053370 A1 WO 2014053370A1 EP 2013069909 W EP2013069909 W EP 2013069909W WO 2014053370 A1 WO2014053370 A1 WO 2014053370A1
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WO
WIPO (PCT)
Prior art keywords
drug
foamed composition
drugs
foam
mixtures
Prior art date
Application number
PCT/EP2013/069909
Other languages
English (en)
Inventor
Salamon Leendert ABRAHAMSE
Peter Arnold
Gustaaf Servaas M.J.E. DUCHATEAU
David Jason Mela
Henricus Petrus F. PETERS
Paul Thomas Quinlan
Jay Philip Tapper
Original Assignee
Unilever N.V.
Unilever Plc
Conopco, Inc., D/B/A Unilever
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 Unilever N.V., Unilever Plc, Conopco, Inc., D/B/A Unilever filed Critical Unilever N.V.
Publication of WO2014053370A1 publication Critical patent/WO2014053370A1/fr

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/54—Mixing with gases
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P30/00—Shaping or working of foodstuffs characterised by the process or apparatus
    • A23P30/40—Foaming or whipping
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams

Definitions

  • the present invention relates to a foamed composition for use in the treatment of administering a drug or mixtures of drugs to an individual.
  • the invention also relates to a method of ingesting a drug or mixture of drugs in the form of or as part of an edible foamed composition.
  • a pharmacologically active component such as e.g. medicaments or drugs having a specific function
  • oral ingestion is commonly in the form of tablets, capsules, drinks, powders and the like.
  • BCS Class I drugs are characterized by a high solubility in combination with a high permeation rate of such drugs across the intestinal wall. This typically results in fast absorption kinetics, resulting a quick peak plasma level (i.e. a short Tmax: time at which the peak plasma concentration is observed) and high concentration at Tmax (i.e. a high Cmax: high peak plasma value).
  • BCS Class II drugs are characterized by a low solubility in combination with a high permeation rate of such drugs across the intestinal wall.
  • BCS Class III drugs are characterised by a rapid dissolution and low permeation across the intestinal wall.
  • BCS Class IV drugs are characterised by a low dissolution and low permeation across the intestinal wall.
  • pharmacologically active components such as drugs are in the form of small solid dosings, such as e.g. pills, tablets or capsules. Oral intake of such small solid dosings is most commonly (physically) facilitated by ingestion of a certain amount of liquid, e.g.
  • PK plasma concentration versus time profile
  • Differences in PK profile could relate to the onset of action or differences in plasma concentrations reached. Avoidance of lag-time effects is especially desired where the onset of action should be fast and absorption be unrestricted (e.g. painkillers, drugs used for spasm and seizures, drugs with stimulating effects).
  • Differences in plasma concentration reached are undesired for drugs with a narrow therapeutic window (warfarin, a BCS class I drug, most anti-cancer drugs, lithium, a BCS Class I drug, phenytoine, a BCS Class II drug) or drugs which have a minimal effective concentration (antibiotics such as doxycycline, a BCS Class I drug).
  • drugs are best taken with food (preferably a controlled amount or composition of food).
  • examples of drugs to be taken with food are all those which give local irritation on the Gl wall (e.g. iron salts, salicylic acid derivatives, and many BCS Class II drugs), or depend on the solubility- enhancing effects of Gl juices (most BCS class II drugs).
  • drugs are usually accompanied with proper instructions for use, consumers may find it difficult to adhere such instructions. It is both desired that the variability in pharmacokinetics is reduced between different subjects, but also within a subject over multiple events the drug is ingested. Hence, reduced variability as a target here covers both.
  • drugs that are preferably taken with no food or only a controlled amount such as for example drugs which should have fast onset of action, all drugs which are vulnerable to gastric acid or pancreatic enzymes (for example but not limited to esters, amides and those with a peptide bond), drugs complexing with common food components such as iron and calcium (e.g. tetracyclines, bisphosphonates), drugs of which the absorption is decreased or delayed such as most antibiotics, beta-blockers, cyclosporine, etc.
  • Drugs not to be taken with acid beverages are e.g. ketoconazole, etc.
  • GB 1 121358 discloses the use of an aerosol foam dosage for the administration of a cough remedy.
  • US 5369131 discloses liquid pharmaceutical compositions which can be administered as a foam. Such foam is disclosed for oral, cutaneous, and intravaginal use.
  • EP 362655 discloses foam for oral ingestion, which foam contains high amounts (45 to 78 weight%) of cough syrup, cough drops concentrate, sennoside (senna) syrup, multivitamin syrup, valerian syrup.
  • WO 2010/144865 discloses compositions for treating gastrointestinal disorders, especially but not exclusively of the esophagus. The compositions are for topical treatment of the gastrointestinal tract, as alternative to systemic treatment. The compositions comprise at least one therapeutic agent and are formulated to increase the interaction of the composition comprising said therapeutic agent. Foams are disclosed as an alternative for those having difficulty to swallowing a viscous liquid or solid oral dose.
  • WO 2008/009617 A1 and WO 2008/009623 A1 disclose foams that may contain a functional ingredient. These disclosures are silent about controlled and/or delayed uptake of drugs, and teach that other compounds may be added to the foam to delay or control the uptake of an active additive.
  • WO 2008/046729 A1 discloses foams to increase satiety of a consumer.
  • WO 2008/046699 A1 discloses foams in which the gas bubbles are stabilised by insoluble fibres assembled with surface-active particles. Both references are silent on the uptake of drugs from the foams.
  • pharmacologically active compounds e.g. drugs that belong to BCS Class I, II, III or IV, including mixtures of drugs, in particular for drugs that belong to BCS Class I and II, more in particular for drugs that belong to BCS Class I, and preferably such method should reduce variability in pharmacokinetics with regard to rate of absorption of such drugs in humans, when compared to conventional intake of drugs.
  • pharmacokinetic (PK) variability should be reduced to the smallest possible level in a given experimental design to result in a small variability around the PK parameters which reflect the absorption rate and extent of absorption.
  • the variability in rate of drug absorption (Ka) ("speed" at which a drug enters the central compartment) and/or of Tmax (the time that the highest plasma concentration is achieved) should be small, and preferably smaller than is achieved with existing dosing methods.
  • the ratio between the highest and lowest value of Ka when measured for the same drug in the same dosing in a group of test persons should be less than 10, more preferably less than 6, and preferably the ratio between the highest and lowest value of Tmax when measured for the same drug in the same dosing in a group of test persons should be less than 4, more preferably less than 3.
  • a foamed composition for use in the treatment of administering a drug or mixtures of drugs to an individual, wherein the treatment comprises
  • the invention further relates to a method for administering a drug or mixtures of drugs to an individual, the method comprising
  • the invention further relates to the use of a foamed composition, in the manufacture of a medicament comprising a drug or mixtures of drugs for a therapeutic or prophylactic treatment, which therapeutic or prophylactic treatment comprises
  • the invention further relates to the use of a foamed composition comprising a drug or mixtures of drugs for reducing the variability in the PK profile of said drug, by orally ingesting a dosing of 50 - 600 ml of a foamed composition, and which foamed composition:
  • foamed composition is characterised by a high in-mouth foam stability being evidenced by a reduction in overrun of less than 35% under in-mouth conditions, using the methodology defined in the description.
  • composition, method and use according to the present invention are particularly advantageous for drugs which have a high permeation rate cross the intestinal wall, and which are either easily dissolvable or less well soluble, for reasons given above.
  • drug is a drug of BCS Class I, BCS Class II, BCS Class III or BCS Class IV, preferably of BCS Class I or of Class II, most preferably of BCS Class I. It is preferred (e.g. to distinguish it from food eaten for pleasure) that in the composition, method and use as specified above the drug or mixtures of drugs thereof is a
  • Drug herein comprises the chemical compound as such, as well as its commonly used forms such as its salt(s), oxide, hydrate, complex, ester, or other pharmacologically active form.
  • BCS Class I drug is herein to be understood as all components in the group of Class I as defined by the US Food and Drug Administration in the Biopharmaceutics Classification System.
  • the group of drugs which are BCS Class I drugs herein comprises, but is not limited to:
  • acyclovirb amiloride
  • amitryptyline antipyrine
  • atropine buspironec
  • caffeine captopril
  • chloroquine chlorpheniramine
  • cyclophosphamide desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxepin, doxycycline, enalapril, ephedrine, ergonovine, ethambutol, ethinyl estradiol, fluoxetine, imipramine, ketorolac, ketoprofen, labetolol, levodopajevofloxacin, lidocaine, lomefloxacin, meperidine, metoprolol, metronidazole, midazolam, minocycline, misoprostol, nifedipine, phenobarbital, phenylalanine, prednisolone, primaquine, promazine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, valproic acid, verapamil, zidovudine,
  • amiodarone amiodarone, atorvastatin, azithromycin, carbamazepine, carvedilol, chlorpromazine, cisapride, ciprofloxacin, cyclosporine, danazol, dapsone, diclofenac, diflunisal, digoxin, erythromycin, flurbiprofen, glipizide, glyburide, griseofulvin, ibuprofen, indinavir, indomethacin, itraconazole, ketoconazole, lansoprazole, lovastatin, mebendazole, naproxen, nelfinavir, ofloxacin, oxaprozin, phenazopyridine, phenytoin, piroxicam, raloxifene, ritonavir, saquinavir, sirolimus, spironolactone, tacrolimus, talinolol
  • “Pharmacologically active compound” is herein to be understood as defined by the US Food and Drug Administration as “drug”: (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).
  • Effective amount herein is the amount per dosing that gives a therapeutic effect (for the drug stated), when used in an accepted treatment based on the pharmacologically active compound.
  • “Foam”, “foamed composition”, “foam product” and “aerated composition” are herein used interchangeably: they mean herein the same.
  • “Aerated” does not imply that the gas bubbles dispersed in the continuous liquid phase is air or has the same composition as air.
  • An aerated composition like a foam, foam product or foamed composition herein, can have any gas as specified herein dispersed as bubbles in the continuous liquid phase.
  • Aerated or foamed means the presence of a compound in gas phase at temperatures of between 1 and 40°C and atmospheric pressure, wherein the gas can be air but also other gaseous compounds (i.e. aerated can be with other cases than air).
  • "Overrun" of a foamed product is calculated using the following equation:
  • V mix Volume of the same sample after the dispersed gas phase has been removed.
  • foamed systems which are (without containing a drug) known to be able to induce satiety after consumption) can be combined with a drug or mixtures of drugs, which combination can be beneficial for drugs which are preferably not combined with food of substance. This applies to food taken some time before or some time after the drug is ingested. It is believed that the satiety induced by a sufficient amount of foam reduced the tendency of individuals to consume food relatively shortly after consumption of the drug.
  • a minimum amount of foam is required: at least 50 ml, preferably at least 75 ml, more preferably at least 100 ml, and the foam should have sufficient stability as expressed as a high in-mouth foam stability being evidenced by a reduction in overrun of less than 35% under in-mouth conditions, using the methodology defined herein below.
  • the drug or mixtures of drugs is a pharmacologically active compound, and even more preferably that it is present in an effective amount.
  • the concentration of the drug or mixtures of drugs concerned is such that the amount (or concentration) of the drug or mixtures of drugs in the foamed composition is such that 50 ml of said foamed composition comprises an amount of the drug or mixtures of drugs concerned equal to 10 to 300% of the effective amount for said drug or mixtures of drugs. This is preferred as it is believed that at and above 50 ml the effect of reducing variability is achieved (with stronger effects at 100 ml and above).
  • the drug or mixture of drugs is dissolved or dispersed in the continuous aqueous liquid phase of the foamed composition.
  • the benefits of the present invention may be obtained with any type of edible foamed composition as specified for the composition according to this invention and for the method and uses of this invention, as long as it has sufficient foam stability in the mouth. It is believed in the context of this invention (i.e. for the desired effect on variability) that if a foam has sufficient stability in the mouth, such foam will also have sufficient stability in the esophagus and stomach to yield the advantages herein described.
  • “Sufficient foam stability in the mouth” is herein defined as a reduction in overrun of less than 35% when a sample of the product is subjected to a stability test in which conditions of shear are applied that are similar to those observed in the mouth.
  • the in-mouth stability of a foam composition of the present invention and in its methods and uses can be determined by introducing a predetermined volume of an edible aerated product in a glass funnel
  • a peristaltic pump e.g. a Verderflex 2010, Verder Ltd, Leeds, UK
  • the sample is collected in a glass measuring cylinder and the product volume and product weight are measured
  • the foam products in the methods and uses of the present invention typically show a reduction in overrun of less than 30%, preferably of less than 25%, most preferably of less than 22%.
  • known edible foam products such as whipped cream
  • the product obtained from the in-mouth stability test described above still exhibits an overrun of at least 100%, more preferably of at least 120%, and even more preferably at least 150%.
  • Edible foam products that are capable of retaining a high overrun when subjected to conditions of shear that are similar to those observed during mastication and preferably that further exhibit high stability under gastric conditions are extremely useful for the purposes of this invention.
  • the aforementioned criteria are also met by the foam products in the present composition, method and uses of the invention if the shear stability test is conducted at a temperature of 37°C, thus reflecting the prolonged in-mouth stability of the product under conditions of shear that are similar to those exerted during mastication.
  • the foamed composition of the present invention has a physical (foam) stability such that the foam has a half life in the stomach of at least 20 minutes, preferably at least 30 minutes, more preferably of at least 45 minutes.
  • "Foam half life in the stomach” herein is the gastric retention time where 50% of the foam volume ingested remains present as a foam in the stomach.
  • the presence of a foam in the stomach, and thus the half life can be determined by visualisation techniques as known in the medical profession. Of these, Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) scanning are preferred techniques, as they directly show the presence of foam, air and liquid.
  • MRI Magnetic Resonance Imaging
  • CT Computer Tomography
  • Ultrasound imaging can also be used for this, but due to differences in image quality and the interpretation of it a large enough set of test persons would be needed, as a person skilled in the art of ultrasound imaging would know. Also, with ultrasound imaging a foamed composition in the stomach as such cannot be visualised using ultrasound imaging, but the presence of foam can be derived from the reappearance of antral motility and ultrasound signal after the foam has left the stomach. Also, these imaging techniques can also be used to determine whether a foamed composition has a sufficient stability to pass the mouth and be present for some time as an aerated composition.
  • the foamed compositions of the present invention include in its uses and methods, have a very high gastric stability.
  • Such high gastric stability of the foamed product can be apparent from the time (t 1 ⁇ 2 ) needed to achieve a reduction in overrun of 50% under simulated gastric conditions.
  • the foamed product of the present invention exhibits a t 1 ⁇ 2 of more than 30 minutes.
  • the aforementioned parameter t 1 ⁇ 2 is determined in a gastric stability test involving transferring 400 ml of an aerated edible product to a vessel of a United States Pharmacopeia (USP) dissolution model II apparatus (VanKel VK 7000), of which the temperature of the water bath is set to 37.5 °C and slow shear in the stomach is simulated with a special paddle at a stirring rate of 1.2 s-1 (72 rpm).
  • USP United States Pharmacopeia
  • t 1 ⁇ 2 exceeds 45 minutes, even more preferably it exceeds 60 minutes, even more preferably it exceeds 90 minutes and most preferably t 1 ⁇ 2 exceeds 120 minutes.
  • compositions of the present invention and in the method and uses herein are such that they have an overrun of at least 100%.
  • the edible foamed product of the present invention has an overrun of at least 120%, more preferably of at least 150%, and even more preferably between 150% and 800%.
  • the gas phase in the present product can comprise air or any other gas that is considered safe for food applications.
  • the foam in the compositions, method and uses of the present invention is a pourable or spoonable aerated composition.
  • the product is non- pourable (i.e. spoonable).
  • Such a spoonable product typically exhibits spoonable rheology defined as follows: yield value of >50 Pa, when extrapolating from shear rates between 100 and 300 s "1 , a Bingham viscosity ⁇ 500 mPa.s between shear rates of between 100 and 300 s "1 , a failure at stress at a strain of ⁇ 0.5 Radians.
  • the yield stress is determined at a temperature of 20 °C using a Haake VT550 viscometer.
  • the edible foam product is pourable.
  • a pourable product offers the advantage that it can be drunk. If the product is drunk rather than eaten, the chance of undesirable density increase as a result of mastication is minimised - for example bread is high overrun product, but practically all air is lost during mastication.
  • the foam in the compositions, methods and uses of the present invention is not a mousse and is not sponge-like.
  • a mousse is herein to be understood as having a continuous phase that is a gelled phase, and this is to be distinguished from the currently used pourable and spoonable aerated compositions, in which the continuous phase of the aerated composition is not a gelled phase (but a liquid phase).
  • the foam in the compositions, methods and uses of the present invention is preferably non-frozen when ingested, as frozen compositions like ice cream tend to melt in the mouth and/or upper gastro-intestinal tract and following that lose their foam stability.
  • the foam in the compositions, methods and uses of the present invention preferably comprises by weight 50-99.5% water, a foaming agent and a stabiliser (next to the pharmacologically active component).
  • the foaming agent preferably comprises, for a good foamed
  • composition one or more of:
  • HLB HLB value of at least 8, preferably at least 9, more preferably at least 12, a food grade protein
  • food grade amphiphatic particles having a contact angle at air/water interface between 70 and 120 degrees, and preferably having a volume weighted mean diameter of 0.02 to 10 micron ( ⁇ ).
  • Preferred food grade proteins in this connection comprise dairy proteins such as whey protein and/or casein protein and sources thereof, as well as vegetable proteins like soy protein, meat- and fish derived protein, and egg protein like albumin. When used as sole foaming agent, such food grade proteins are preferably used in an amount of from 1 to 7% by weight.
  • Preferred food grade amphiphatic particles herein comprise one or more of cocoa particles.
  • the stabiliser e.g. to give the product sufficient physical stability, e.g. to allow some time between preparation of the foamed composition, it is preferred that the stabilizer comprises a dietary fibre or a sucrose ester. Preferred amounts in this context are: from 0.1 to 5% by weight. Too little may not provide the desired stability, too much may make foaming difficult.
  • Suitable dietary fibres in this context are one or more of the group consisting of: carrageenan, xanthan, cellulose, gellan, locust bean gum, with xanthan being the most preferred stabiliser (as it provides stabilising without too much viscosity increase).
  • Fat may be present in the compositions, methods and uses according to this invention, but such is preferably kept at a low level, so as not to induce too much calories to the composition. Also, fat may act detrimental on the stability of the aerated compositions. Hence, in the compositions in the methods and uses herein, the edible foamed
  • composition comprises fat in an amount of less than 2% by weight, preferably less than 1.8% by weight, more preferably between 0 and 1.8% by weight, even more preferably between 0 and 1 .5% by weight, even more preferably form 0.01 to 1.5% by weight.
  • stabiliser water and optionally fat
  • other components that may be present include carbohydrates, (non-caloric) sweeteners, flavouring components.
  • the edible foamed compositions of the present invention can be prepared by any suitable means.
  • the foamed compositions may be manufactured, packed and marketed in a foamed form, but it is also possible to prepare a non-aerated product which is packed and marketed, which is then foamed some time or immediately before consumption, either by the individual or at a point of sale or distribution.
  • a convenient way (and one which can easily give foamed compositions of high stability) to offer such to users is when the composition according to this invention and for use in the method and uses of this invention is packed as a non- aerated (e.g. liquid) composition in a pressurised container in a liquid form.
  • the pressurised container can hold the edible liquid (non-aerated) composition and a propellant, which liquid composition can be released from the container by activating a valve (on the container) to produce an edible foamed product.
  • the invention further relates to the use in the composition, method and uses of the present invention of a pressurised container further comprising a propellant, and wherein the pressurised container is equipped with a valve, wherein the liquid can be released from the pressurised container by activating said valve to produce the aerated composition for the compositions, methods and uses according to this invention.
  • the edible aerated product thus obtained has a density that is much lower (e.g. 40% lower) than that of the liquid composition in the container.
  • the edible foamed product produced upon activation of the valve has the same composition as the edible liquid composition (gas phase not being included).
  • Suitable propellants in this include compressed gases, especially liquefied gasses.
  • the propellant employed is selected from N 2 0, N 2 , C0 2 , air and combinations thereof. Most preferably, the propellant employed is selected from N 2 0, N 2i C0 2 and combinations thereof.
  • the propellant contained in the pressurised container has a pressure of at least 2 bar, more preferably at least 3 bar. Usually, said pressure does not exceed 12 bar.
  • the foamed composition in the compositions, methods and uses as set out herein is packaged in a pressurised container or not, it is preferred in the present invention that the foamed composition is prepared by the user from a composition which is packaged as a liquid. This liquid is then to be turned into the aerated composition before being consumed.
  • the foam of the present invention may also be prepared by whipping a suitable liquid using, for instance, a standard kitchen mixer. By this, an amount of the liquid is added to the bowl of the mixer and mixed at high speed to aerate the
  • the edible aerated product thus obtained has a density that is much lower (e.g. 40% lower) than that of the liquid composition.
  • the gas bubbles contained within the edible foamed composition in the compositions, methods and uses according to this invention can vary widely in size.
  • the air bubbles in the product have a volume weighted mean diameter in the range of 5-500 ⁇ , preferably of 10-200 ⁇ .
  • the volume weighted mean diameter of the gas bubbles is suitably determined by means of optical microscopy.
  • the stability of the edible foamed product is affected by the composition of the gas that is retained within the foamed product.
  • a gas that has limited water-solubility Air, for instance, is not particularly suitable as e.g. oxygen has a relatively high solubility in water.
  • the edible foamed product in the present invention contains a gas that is less soluble in water than air (at a temperature of 37°C.
  • the gas contained in foam product contains elevated levels of one or more of the following gasses: N 2 , N 2 0, C0 2 , He, 0 2 .
  • elevated means that the concentration of at least one of said gasses is at least 10% higher than in air.
  • the foam can be designed to contain calories or not, depending on the drug, the desired effect and the use. When only a satiety effect is desired for the drug(s) concerned, then the foam is preferably designed as a low calory foam.
  • the composition for use in the current method is has a low caloric density.
  • Caloric density of the aerated composition used in the current methods herein is digestible (for humans) calories per volume (or weight, depending on what is specified) of aerated compositions.
  • the aerated composition has a caloric density of less than 5 kcal/ml, preferably less than 2 kcal/ml, more preferably less than 0.5 kcal/ml of aerated composition (ready for consumption).
  • sucrose and glucose do not count as drugs.
  • uptake of drugs can be sustained or controlled by the addition of a material to the drug that causes a delayed or sustained release of such drug.
  • a drug may be coated with a material which degrades slowly in the intestinal tract, to sustain release of the drug.
  • the drug may be coated with a material which is insoluble under the acidic conditions of the stomach, in order to control uptake of the drug in the intestines.
  • the drug may be coated with a material which is soluble in the stomach, in order to facilitate the uptake of the drug in the stomach.
  • One of the advantages of the current invention is that addition of materials which normally delay or control uptake of drugs are not required to be used in the current compositions of the invention. Therefore preferably the foamed compositions of the present invention are free from a biopolymer or a bioengineered composition or a polymer for providing a sustained or delayed release of a medicinal or nutritive component.
  • Exemplary aerated edible product formulations with BSC class I drugs are illustrated.
  • Table 1 Compositions of formulations for producing aerated edible products with BSC class I drugs.
  • the liquid formulations were prepared as follows. All ingredients are added to water and mixed until fully dispersed.
  • Exemplary aerated edible product with BSC class I drug is illustrated in FIG. 1 .
  • formulation B Three hundred gram of formulation B (example 1 ) was poured into a pressurisable dispenser (cream whipper "Gourmet Whip", 0.5 I, iSi GmbH). The dispenser was closed and a N 2 0 gas charger was mounted on the dispenser until gas was released therefrom. The dispenser was vigorously shaken for about 20 seconds, following which the contents are released yielding an aerated edible product.
  • a pressurisable dispenser cream whipper "Gourmet Whip", 0.5 I, iSi GmbH
  • Exemplary aerated edible product with BSC class I drug is illustrated in FIG. 1 .
  • formulation B (example 1 ) gram was weighed in the metal bowl of a kitchen machine (Kenwood, model chef classic KM330). The liquid was mixed at maximum speed for 1 min after which an overrun of 250% is achieved.
  • Samples of the aerated edible product and drained liquid were collected and analysed for paracetamol content.
  • 5 ml of each sample was weighed into a 50-ml volumetric flask and 25 ml acetonitrile was added for precipitation of the proteins.
  • the samples were vortexed for 30 sec and then placed in an ultrasonic bath for 10 min. After cooling down the flasks were filled to the mark with acetonitrile, homogenized, and centrifuged at 3000 rcf for 10 min.
  • Supernatants were diluted prior to HPLC analysis. All samples were analyzed in duplicate.
  • This example shows a paracetamol-containing foam having a good bench-top stability.
  • aerated edible product from example 3 Four hundred ml of aerated edible product from example 3 was put into a glass funnel (diameter 100 mm, neck length 100 mm and a neck diameter of 10 mm). The funnel was connected to a silicone tube with a length of 400 mm and a diameter of 12x8 mm. The middle part of the silicone tube was inserted into a peristaltic pump (Watson-Marlow model 501 ) and operating at 60 rpm. Aerated edible product pumped through the silicone tube was collected in a previously weighed vessel. The impact of the simulated oral cavity test is determined by observing the start (400 mL) and end volume. The simulated oral cavity test reduced the overrun of the aerated edible product by less than 5%.
  • Figure 1 shows the stability of the aerated edible product from example 5 under simulated gastric conditions. Less than 40% of aerated edible product is digested within 60 min under the conditions used in this test. The t 1 ⁇ 2 is 55 minutes.
  • the volunteers were recruited from local area of Nottingham. Selection criteria were: age 18-60 years, Body Mass Index (BMI, kg/m2) >20 and ⁇ 35, apparently healthy (measured by questionnaire) and not using medicines judged likely to influence the study results. Only normal and low restraint eaters (Federoff et al, 2003; Polivy et al. 1978) were included. Any subjects with tendencies toward diagnosable eating disorders (anorexia nervosa or bulimia) were excluded
  • Subjects were scanned at baseline to ensure their stomach was empty. They then consumed 150g of one of the products instead of breakfast and MRI measurements were conducted at several time points (up to 4 hours after consumption of the test product) to measure gastric behaviour. The subjects were blind to aerated test product type.
  • the subjects were instructed not to use alcohol or play sports. They were asked to refrain from consuming any food or drink other than non-caloric beverages from 22.00 until arrival at the test facility.
  • the volunteers were instructed to avoid high intensity physical activity and direct contact with food. Volunteers were not allowed to eat and drink anything else during the study. Subjects were asked about their mode of transportation together with food consumption the evening before the test day and drinks consumed from 10 pm till the next morning.
  • test products were equicaloric (1 10kcal) and their nutritional composition is detailed in Table 5.
  • Stable Aerated 490 150 1 10 0.2 7.2 20.2 18.6 0.8 c edible product
  • d contains 0.2 g xanthan gum
  • Both aerated edible products were produced by aerating the beverage with air as described in example 3. All test products' overrun was measured and amounted 247% ⁇ 7% for the stable and 254% ⁇ 3% less stable aerated edible products. For both test products, the simulated oral cavity test as described in example 6 reduced the overrun of the aerated edible products by less than 5%.
  • Magnetic resonance imaging (MRI) Magnetic resonance imaging
  • the subjects were supine on the scanner bed. They were kept tilted with their left side slightly raised on the scanner bed using a folded towel to help avoiding the possibility that floating layers of the test meals could empty first through the pylorus, which would be different from what happens during normal upright digestion.
  • Gastric aerated edible product volume was measured from the balanced gradient echo (also called balanced turbo field echo or BTFE).
  • BTFE balanced turbo field echo
  • 2D slices of the abdomen were acquired. Every data set from each time point was then recalled on a UNIX workstation for analysis.
  • commercial specialistic software (Analyze 9, Biomedical Imaging Resources, Mayo Clinic, Rochester, MN) was used to trace manually on each 2D slice around the region of interest (ROI) of the aerated edible product in the stomach on each slice.
  • ROI region of interest
  • FIG. 1 shows examples of ROIs drawn intragastrically for a Stable Aerated edible product and a Less Stable Aerated edible product at different time points. These were plotted in Microsoft Excel to allow for observations on the time courses of intragastric volumes.
  • the study used a random allocation, parallel design, with treatments balanced across test days.
  • Each subject group was given a single exposure to a single volume of an aerated edible product, each portion having a volume of 10, 25, 50, 100, 150 or 250 ml.
  • This0 product was given as a mid-morning snack (at 10.30 am) following a fixed 250 kcal breakfast given at 08.00 am.
  • Self-reported eating motivation ratings (6 scales) were collected regularly from 155 minutes prior to consumption of the test product and for 3 hours afterwards.
  • the 144 participating subjects were randomized into groups of 24 subjects per treatment, with groups matched for gender mix, age and body weight (mean within 5 yr and 5 kg). Ten subjects were withdrawn from the study for reasons unrelated to the study products. Characteristics of the remaining 133 subjects (91 females, 42 males) were: age: 35.8 (range 18 - 60) y; BMI: 24.8 (range 21.0 - 34.6) kg/m 2 . Study products
  • Each subject was given a single exposure to a single portion of an aerated edible product at a specified volume at 10.30 following a fixed breakfast at 08.00.
  • Six aerated edible products were evaluated varying in total volume.
  • the test products consisted of Slim-Fast Optima high protein ready-to-drink meal replacement shakes (190 kcal/325 ml when not aerated), aerated on site with N 2 0 (from an iSi dispenser and using an iSi N 2 0 disposable gas filled cylinder) (Slim-Fast is a trademark of Unilever PLC, United Kingdom and Unilever NV, Netherlands; iSi is a tradename of iSi GmbH).
  • An ingredients list of the non-aerated SlinvFast high protein chocolate RTD shake base is shown in Table 7.
  • the liquid formulation used was the same as the commercial product identified above, but with a different chocolate flavouring component. The overrun of the product was approximately 200%.
  • the content of one 325ml can of Slim-Fast high protein chocolate shake was poured into the stainless steel iSi bottle and the device head was screwed onto the stainless steel bottle
  • One iSi N 2 0 gas filled cylinder was inserted into the cylinder holder and the cylinder holder was screwed to the device head until all of the content of the cylinder was released into the bottle. Thereafter the device was vigorously shaken for 20 seconds.
  • the foam was then dispensed by turning the device upside down with the decorator tip in the vertical position and gently pressing the lever. The entire amount ( ⁇ 900ml) was dispensed 5 against the inside edge of a large glass container and then the required foam volumes was poured into glasses which had been pre-marked with the required volume. The weight of the foam was subsequently measured.
  • the study was a product benchmarking study, aimed to generate a dose-response profile for satiety effects, focused on identifying lower volume limits for potential consumer concepts.
  • Curves of Least Square means (LSmeans) were produced based on the 25 measurements, and based on these curves a time-to-return-to-baseline (TTRTB) was calculated by using a modeling technique based on the Weibull distribution (Schuring et al 2008). This Weibull method also turned out to be the most suitable, non-parametric model to estimate TTRTB for these satiety curves.
  • the 50 ml and 100 ml contained only 10 and 19 kcal per serving respectively, yet showed meaningful effects on appetite.
  • the effects on appetite observed here are greater (and persist for longer) than shown in literature for beverages having either no caloric content or a caloric content which is higher than the foams now tested, at the same volume.
  • Peters et al. (201 1 ) for instance tested a 100 ml minidrink as a snack and effects on hunger and appetite were comparable or even smaller compared to the effects seen here for the 50 or 100 ml foam, yet the 100 ml minidrink contained considerably more energy (80 kcal).
  • Example 11 study using foam containing paracetamol.
  • This study was an open-label, randomized, single-centre, explorative, cross-over design.
  • the study consisted of a screening visit and two intervention periods. Treatments were separated by a wash-out period of 1 week.
  • the study itself i.e. after screening) covered 12 subjects.
  • Test product will be administered at approximately 8:00 h.
  • composition of the formulations were the following:
  • Vitamin B6 2.4 mg 1.9 mg
  • Plasma paracetamol concentrations were quantified using a rapid UPLC-MS/MS-based method developed at URDV. Paracetamol concentrations can be quantified within a range of 0.1 to 10 ⁇ . For accuracy the following values were found: between 90-105% with an average of 98%.
  • DBS dried blood sampling
  • the primary study parameter was the Gastric Empying half time (GE50). Secondary study parameters were all parameters that describe the PK profile of paracetamol, e.g. area- under the plasma concentration time curve, absorption- and elimination rates.
  • GE curves were constructed from the PK data based on Wagner-Nelson deconvolution method (Sanaka et al 1998, Nakada et al 1999). The following PK data were calculated 1 ) partial areas under the plasma concentrations time profile (AUC 0" ') using non- compartmental analysis and 2) K e i , l iqui d and total predicted area under the plasma concentration time curve (AUC° " ⁇ ) using compartmental analysis. The GE half time (GE50) was intrapolated from the individual curves with accuracy of 1 min or less.
  • GE50 is not normal distributed and needed to be log transformed.
  • LS mean GE50 for foam is 26.9 min and for liquid 24.2 min (range respectively 19.6-36.9 min and 17.9-32.8 min) and descriptive GE50 for foam is 27.2 ⁇ 1 1.4 min and for liquid 29.8 ⁇ 19.5 min. There is no significant difference between the treatments on GE50.
  • Figure 2 Comparison of the behaviour of the aerated edible products in the stomach. The intensity scales are increased for better visualisation of the aerated edible product.

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Abstract

La présente invention concerne une mousse comprenant un médicament ou un mélange de médicaments, ladite mousse étant composée d'une phase liquide continue et d'une phase gazeuse dispersée, et présentant une bonne stabilité en bouche et un taux d'expansion d'au moins 50 %, et étant dosée en une quantité de 50 à 600 mL.
PCT/EP2013/069909 2012-10-05 2013-09-25 Mousse comestible comprenant un médicament WO2014053370A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018158195A1 (fr) * 2017-02-28 2018-09-07 Lument Ab Agent de contraste négatif destiné à une ingestion orale pour tomodensitométrie (tdm) abdominale

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009623A1 (fr) * 2006-07-17 2008-01-24 Nestec S.A. Appareil à membrane cylindrique pour former de la mousse
WO2008009617A1 (fr) * 2006-07-17 2008-01-24 Nestec S.A. Produits contenant de la mousse intelligente et procédé de fabrication
WO2008046729A1 (fr) * 2006-10-17 2008-04-24 Unilever N.V. Produit de type mousse comestible pour le traitement ou la prévention de l'obésité
WO2008046699A1 (fr) * 2006-10-17 2008-04-24 Unilever N.V. Produit alimentaire aéré et son procédé de préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009623A1 (fr) * 2006-07-17 2008-01-24 Nestec S.A. Appareil à membrane cylindrique pour former de la mousse
WO2008009617A1 (fr) * 2006-07-17 2008-01-24 Nestec S.A. Produits contenant de la mousse intelligente et procédé de fabrication
WO2008046729A1 (fr) * 2006-10-17 2008-04-24 Unilever N.V. Produit de type mousse comestible pour le traitement ou la prévention de l'obésité
WO2008046699A1 (fr) * 2006-10-17 2008-04-24 Unilever N.V. Produit alimentaire aéré et son procédé de préparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018158195A1 (fr) * 2017-02-28 2018-09-07 Lument Ab Agent de contraste négatif destiné à une ingestion orale pour tomodensitométrie (tdm) abdominale
EP3900744A1 (fr) * 2017-02-28 2021-10-27 Lument AB Poudre pour agent de contraste négatif destiné à une ingestion orale
US11179483B2 (en) 2017-02-28 2021-11-23 Lumentab Per-oral negative contrast agent for abdominal CT
JP7146788B2 (ja) 2017-02-28 2022-10-04 ルメント アーベー 腹部ｃｔ用経口陰性造影剤

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