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WO1999036075A1 - Composition orale absorbant l'huile - Google Patents

Composition orale absorbant l'huile Download PDF

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Publication number
WO1999036075A1
WO1999036075A1 PCT/GB1999/000024 GB9900024W WO9936075A1 WO 1999036075 A1 WO1999036075 A1 WO 1999036075A1 GB 9900024 W GB9900024 W GB 9900024W WO 9936075 A1 WO9936075 A1 WO 9936075A1
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WO
WIPO (PCT)
Prior art keywords
oil
sorbing agent
oil sorbing
small
large intestine
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
PCT/GB1999/000024
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English (en)
Inventor
Peter James Watts
Stanley Stewart Davis
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.)
Kyowa Kirin Services Ltd
Original Assignee
Danbiosyst UK Ltd
West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd
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 Danbiosyst UK Ltd, West Pharmaceutical Services Drug Delivery and Clinical Research Center Ltd filed Critical Danbiosyst UK Ltd
Priority to CA002318236A priority Critical patent/CA2318236A1/fr
Priority to JP2000539848A priority patent/JP2003513000A/ja
Priority to AU20643/99A priority patent/AU2064399A/en
Priority to EP99901007A priority patent/EP1045696A1/fr
Publication of WO1999036075A1 publication Critical patent/WO1999036075A1/fr
Priority to NO20003639A priority patent/NO20003639L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/29—Mineral substances, e.g. mineral oils or clays
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material

Definitions

  • the present invention relates generally to a composition for use in the management of obesity. More particularly, the present invention relates to a composition which is adapted to absorb unwanted dietary fat in the small and/or large intestine of a patient, especially dietary fat which is either non-metabolizable or which has not been metabolized owing to treatment of the patient with drugs that inhibit the enzymatic conversion of the fats.
  • Obesity is a major problem in many Western countries with an estimate of over 30% of adults defined as clinically obese. Weight reduction can be achieved by the use of diet or pharmacological agents. Unfortunately, both approaches can lead to unpleasant side effects such as fat "leakage” or "spotting".
  • Olestra is known commercially as OleanTM and is available from Procter and Gamble (New Eng. J. Med. 334, 984 (1996)).
  • the material is a polyester of sucrose and six or nine triglycerides and can be used to replace both vegetable and animal fats.
  • Olestra adds the necessary texture and taste characteristics of fat, but is not metabolized in the intestine by the dietary Upases and, as a consequence, is not absorbed. However, if large quantities of food containing Olestra are consumed, then the excess fat can leak from the anal sphincter causing embarrassment and soiling of clothes. (Anon. Univ. California at Berkeley Wellness Lett. 12, 1-2 (986)).
  • fats In the body, fats (triglycerides) are converted enzymatically to fatty acids and diglycerides and these materials are then solubilised by bile salt micelles and subsequently absorbed.
  • One pharmacological treatment of obesity may involve the use of drugs that inhibit the enzymatic conversion of the fats to fatty acids and diglycerides, and a number of drugs are in development that act in this way.
  • the mechanism can be one of preferential binding with lipases to prevent their interaction with dietary lip ids.
  • the compound Orlistat, Merck Index, 12, Edition P.6998 is a good example of a pancreatic lipase inhibitor (Obes. Res. 3 Suppl. 4, 6235, 1995).
  • Olestra the impaired metabolism of the dietary fat, e.g. by the administration of a lipase inhibitor, can result in anal leakage of fat material.
  • chitosan as a food additive or as a pharmaceutical preparation to reduce the absorption of lipids is described in US-4,233,023.
  • US-4,233,023 There is no suggestion in US-4,233,023 that chitosan could be delivered to the terminal ileum or the colon in a coated single unit dosage form.
  • the examples given in US-4,233,023 describe food products and a powder that is dispersed in water or a flavoured vehicle before administration.
  • composition that delivers an oil sorbing agent to the small and/or large intestine of man, especially the terminal ileum and/or proximal and transverse colon.
  • a composition comprising an oil sorbing agent characterised in that the composition is adapted to deliver the oil sorbing agent to the small or large intestine of a mammal, especially man.
  • an oil sorbing delivery system comprising an oil sorbing agent characterised in that the system is adapted to deliver the oil sorbing agent to the small or large intestine of a mammal, especially man.
  • oil sorbing agent we mean a material that when in contact with oil, either as oil alone or as oil dispersed in an aqueous medium at a pH between 5 and 8 or thereabouts, will sorb between 0.5 and 25 ml of oil per g thereof.
  • the oil sorbing agent will be capable of sorbing between 1 and 20 ml of oil, more preferably between 2 and 10 ml of oil per g thereof.
  • oil includes fats and dietary fats, fatty acids, tryglycerides, non metabolizable oils and fats.
  • the oil sorbing agent that is released into the small and/or large intestine, especially the terminal ileum and/or the proximal and transverse colon, to interact with dietary fat can be various in nature.
  • dietary fat we mean any oleaginous material that is not absorbed in the small intestine and is a component of a food stuff.
  • the term includes Olestra as well as vegetable and animal fats.
  • Suitable oil sorbing agents include calcium silicate, microcrystalline cellulose (AvicelTM), dried aluminium hydroxide gels, microcrystalline chitosan ( as described by Struszczyk, J. Appl. Polymer Sci. 33, 177 1987 and available from Novasso OY, Finland), charcoal and porous carbon adsorbants such as the product AST- 120 (available from Kurela Chemical Industry Co. Ltd. , Japan and described in J. Pharm. Pharmac. 49 657, (1997)).
  • a suitable quantity of oil sorbing agent for administration to the patient is in the range of from 1 to 10 g per day. More preferably, from 1 to 5 g per day is administered on a fasted stomach.
  • Calcium silicate is a particularly preferred oil sorbing agent.
  • a porous calcium silicate that sorbs oil is known as Florite and is available from Eisai Co. Ltd. , Japan. This material is stated to sorb 5 ml of oil per g of sorbant.
  • Calcium silicate is a material that is used in both pharmaceuticals and foods.
  • An especially preferred oil sorbing agent is microcrystalline chitosan.
  • composition/delivery system of the invention may be a suitably coated single unit dosage form.
  • the single unit dosage form is a tablet having a core comprising the oil sorbing agent and an outer coating or layer which surrounds the core and comprises a material which prevents release or any substantial release of the oil sorbing agent until the tablet reaches the small or large intestine.
  • the coating is adapted to prevent release of the oil sorbing agent in both the stomach and the upper regions of the small intestine, by which we mean the duodenum and jejunum, so that release of the oil sorbing agent does not take place until the tablet reaches the terminal ileum or the large intestine, e.g. colon.
  • Tablets can be produced by direct compression of the oil sorbing agent (which is normally in powder, form) or by processes involving granulation in which the powder is wetted with a granulating agent, e.g. water, alcohol or a sugar solution, and the wet mass passed through a sieve to produce wet granules that are then dried, e.g. in a hot-air oven, prior to compression to form a tablet.
  • a granulating agent e.g. water, alcohol or a sugar solution
  • Dispersion or disintegration aids e.g.
  • the single unit dosage form is a capsule having a casing which encloses a compartment containing the oil sorbing agent and a barrier coating or layer on the outer surface of the casing which comprises a material which prevents release or any substantial release of the oil sorbing agent until the capsule reaches the small or large intestine.
  • the coating is adapted to prevent release of the oil sorbing agent in both the stomach and the upper regions of the small intestine, by which we mean the duodenum and jejunum, so that release of the oil sorbing agent does not take place until the tablet reaches the terminal ileum or the large intestine, e.g. colon.
  • any of the capsules which have been fabricated to deliver medicaments to the human body may be employed. Suitable capsules include those made of hard gelatin, starch or hydroxypropylmethyl cellulose.
  • Starch capsules e.g. as described in the United States Pharmacopoeia (USP), are preferred since these offer advantages in coating, i.e. in the storage and stability of the coating layer.
  • Starch capsules having an outer coating of a material which is resistant to the conditions prevailing in the stomach and the upper regions of the small intestine such that release of the oil sorbing agent contained in the capsule is prevented or substantially prevented until the capsule reaches the terminal ileum and/or colon are preferably used in the present invention.
  • Such capsules are described in PCT/GB95/01458.
  • starch capsules we include capsules made from starch as well as capsules made from modified starches or starch derivatives.
  • derivatives we particularly mean esters and ethers of the parent compound that can be unfunctionalised or functionaiised to contain, for example, ionic groupings.
  • Suitable starch derivatives include hydroxy ethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, succinate derivatives of starch and grafted starches.
  • Such starch derivatives are well known and described in the art (for example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)).
  • the starches used should be of food or pharmaceutical quality.
  • the starch capsules can be made by an injection moulding process and typically comprise a body and a cap. The body is filled with the oil sorbing agent and the cap is then attached and sealed. Methods for making starch capsules are well known and are described, for example, in EP-A-118240, WO-90/05161 , EP-A-0304401 , WO-92/04408 and GB- 2187703.
  • the oil sorbing agent may thus be filled into the various known delivery systems intended for targeting the ileocaecal and colonic regions, including those described in the above references.
  • the oil sorbing delivery system may take the form of a capsule containing granules or pellets of the oil sorbing agent which have been provided with an outer coating comprising a material which prevents release or any substantial release of the oil sorbing agent until the granules/pellets reach the small or large intestine.
  • the coating/layer in the above described delivery systems may be formed from an enteric material such as an enteric polymer that slowly dissolves within the small intestine to allow exposure of the oil sorbing agent to the liquid in the terminal ileum and/or colon.
  • the coating/layer may be formed from a polymeric material that is not degraded until it meets the specific conditions found in the colon. Such degradation may be through direct chemical decomposition, e.g. the degradation of disulphide bonds under reducing conditions, or the result of the microflora found within the colon which can bring about the degradation of polysaccharide materials.
  • enteric coating materials for targeting the ileocaecal or colonic regions which may be used to coat capsules, tablets or pellets are those which dissolve at a pH of 4.5 or above, e.g. a pH of 5.0 or above. In this way, the coatings only begin to dissolve once they have left the stomach and have entered the small intestine.
  • a thick layer of coating is thus preferably provided which will dissolve in about 2 to 5 hours, thereby allowing the capsule shell or tablet core underneath to break-up only when it has reached the terminal ileum and/or the colon.
  • Such coatings can be made from a variety of polymers such as cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), poly vinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac, as described by Healy in his article "Enteric Coatings and Delayed Release” , Chapter 7 in Drug Delivery to the Gastrointestinal Tract, eds. Hardy et al, Ellis Horwood, Chichester, 1989.
  • a thickness of 150 to 300 ⁇ m is suitable for coatings of the polymers.
  • enteric materials are polymers comprising methyl methacrylate residues, such as methyl methacrylate homopolymers and copolymers of metliyl methacrylate and methacrylic acid. Copolymers of methyl methacrylate and methacrylic acid are available as EudragitTM enteric polymers (Rohm Pharma, Darmstadt. Germany).
  • Preferred compositions are based on Eudragit LI 00 and Eudragit SI 00 as described in PCT/GB95/01458.
  • Eudragit L100 dissolves at pH 6 and upwards while Eudragit SI 00 dissolves at pH 7 and upwards.
  • Preferred coating compositions are based on Eudragit LI 00 and Eudragit SI 00 in the range 100 parts LI 00:0 parts SI 00 to 20 parts LI 00: 80 parts SI 00.
  • the most preferable range is 70 parts LI 00: 30 parts SI 00 to 80 parts LI 00: 20 parts S100.
  • the thickness necessary to achieve colon specific delivery decreases.
  • a coat thickness of the order 150-200 ⁇ m is preferable. This is equivalent to 70-
  • a coat thickness of the order 80 to 120 ⁇ m is preferable, which is equivalent to 30 to 60 mg coating for a size 0 capsule.
  • the colonic region has a large population of microbial anaerobic organisms providing reducing conditions.
  • the coating may suitably comprise a material which is redox sensitive.
  • Such coatings may comprise azopolymers which may, for example, consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesised by free radical polymerisation (the azopolymer being broken down enzymatically and specifically in the colon), or disulphide polymers (see PCT/BE91/00006 and Van den Mooter, Int. J. Pharm, 87, 37 (1992)).
  • amylose or a complex thereof Another material which may be used to provide release in the colon is amylose or a complex thereof.
  • a coating composition can be prepared by mixing an amylose-butan-1-ol complex (glassy amylose) with an ethyl cellulose aqueous dispersion (EthocelTM) (Milojevic et al. , J. Control. Rel. , 38, 75 (1996)).
  • the final coating may comprise an inner layer of glassy amylose and an outer layer of cellulose or acrylic polymer material (All wood et al. , GB9025373.3).
  • Other suitable coating materials include calcium pectinate (Rubenstein et al. , Pharm. Res.
  • pectin - a polysaccharide which is totally degraded by colonic bacterial enzymes (Ashford et al. , Br. Pharm. Conference, 1992 Abstract 13); chondroitin sulphate (Rubenstein et al. , Pharm. Res. 9, 276, 1992); dextran hydrogels (Hovgaard and Br ⁇ ndsted, 3rd Eur. Symp. Control. Drug Del. , Abstract Book, 1994, 87); modified guar gum, such as borax modified guar gum (Rubenstein and Gliko-Kabir, S.T.P Pharma Sciences 5, 41 (1995)); p-cyclodextrin (Sie ke et al.
  • saccharide containing polymers including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, raffinose and stachyose and saccharide- containing natural polymers including modified mucopolysaccharides such as cross-linked chondroitin sulfate and metal pectin salts, for example calcium pectate (Sintov and Rubenstein; PCT/US91/03014); methacrylate galactomannan (Lehmann and Dreher, Proc. Int. Int. Symp. Control. Rel. Bioact. Mater.
  • compositions/systems of the invention may also be adapted to deliver therapeutic agents, such as drugs that inhibit the enzymatic conversion of fats to fatty acids and diglycerides, to the small or large intestine of the gastrointestinal tract, e.g. to the terminal ileum or the colonic region, especially the proximal colon.
  • therapeutic agents such as drugs that inhibit the enzymatic conversion of fats to fatty acids and diglycerides
  • a means is provided to prevent release of the drug until the formulation reaches the colonic region
  • Example 1 Measurement of the in vitro fat binding properties of the oil sorbing agent calcium silicate
  • the binding studies were conducted on the oil sorbing agent dosed into the buffer system as a powder as well as in the form of an uncoated single unit system such as a tablet or capsule that subsequently disperse into the buffer svstem.
  • Example 2 Measurement of the in vitro fat binding properties of the oil sorbing agent microcrystalline chitosan
  • Example 3 Measurement of the in vitro fat binding properties of the oil sorbing agent microcrystalline chitosan (high viscosity environment)
  • an aqueous solution containing 1.6% hydroxypropyl methylcellulose was prepared: 400 ml of water was heated to 80°C and 16 grams of Methocel E10M grade HPMC was added (Colorcon, Orpington, UK). The HPMC was dispersed into the hot water and the dispersion transferred to an ice bath. Stirring was continued until a viscous gel had formed. The mixture was removed from the ice bath and adjusted to 1000 ml with water. 200 ml of HPMC solution and 20 ml of sunflower oil was added to each of two glass beakers.
  • HPMC hydroxypropyl methylcellulose
  • microcrystalline chitosan (see Example 2) was added to one of the beakers. The contents of each beaker were stirred thoroughly and then left to stand overnight. In the sample containing no microcrystalline chitosan, the oil formed a clear layer on top of the HPMC solution. In the sample containing microcrystalline chitosan, there was no free oil visible at the surface of the beaker. The upper half of the beaker content had a yellow colouration, suggesting that the oil resided in dispersed form in this portion of the sample.
  • Faeces were obtained from three female cross-bred pigs and pooled. The following formulations were evaluated in duplicate.
  • the effect of the oil sorbing agent on the faecal excretion of fat in rats fed on high fat diet can be measured using the method described by Deuchi et al. Biosci. Biotech. Biochem. 59 781 (1995). In this method the oil sorbing agent is included in the experimental diet that contains corn oil and lard (40%). The animals are fed the diet for 13 days. Faecal lip ids are measured gravimetrically by a standard method (e.g. Saxon) (see Richterich and Colombo, Clinical Chemists, Wiley 1981). An apparent fat digestability value is obtained.
  • a standard method e.g. Saxon
  • the ability of a single unit dosage form and the oil sorbing agent contained therein to effect fat adsorption in vivo is determined using a fistulated pig.
  • the pig has a fistula in the intestines in the region of the terminal ileum. This allows direct access to the large intestine and is, therefore, a suitable model for the evaluation of a system that targets a material to the colon or ileocaecal junction of man.
  • the model used is described by Garner et al. J. Pharm. Pharmac. 48, 689, (1996).
  • Uncoated single units are placed into the colon through the ileal fistula where they are able to break up to release their contents.
  • Pigs are provided with a diet to provide steatorrhoea. The faeces are collected for O 99/36075
  • the faecal fat content of treated and untreated animals is measured using a standard assay for fat content (see for example Richterich and Colombo, Clinical Chemistry, Wiley, 1981).
  • a tablet system was prepared by the direct compression of 500 mg microcrystalline chitosan containing 25 mg of croscarmellose sodium as a dispersing agent.
  • the tablets were made using a Manesty F3 machine with 20 mm x 8 mm oblong concave punches.
  • the tablets were coated with a layer of enteric polymer (3: 1 ratio of Eudragit L:S with plasticiser and talc in isopropanol) to provide a thickness equivalent to a 90 mg increase in average tablet weight.
  • the tablets were coated by a standard method of spray coating using an Aeromatic STREA-1 coater (standard column) drying temperature 25 °C, fan speed 6, atomization pressure 1 bar.
  • a pan coater could also be used.
  • the ability of the tablets to remain intact at an acid pH (stomach conditions) and release their contents after 2 hours in alkaline conditions (to simulate transit in the small intestine and release of the adsorbent in the distal colonic region) was determined using a standard USP Dissolution apparatus (Type 1) employing buffers at pH 2 and pH 6.8. The tablets were exposed to acid conditions for 2 hours and remained in tact. After exposure to the alkaline conditions, the coating dissolved and the tablets released their contents.
  • Starch capsules (USP) were obtained from Capsugel, Switzerland. The capsules were filled with 500 mg of calcium silicate (Florite). The capsules were then coated as in Example 3 to provide a weight gain of 90 mg.

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Abstract

L'invention concerne un système d'administration d'agent absorbant l'huile, qui renferme un agent absorbant l'huile et qui peut administrer ledit agent à l'intestin grêle ou au gros intestin chez un mammifère. L'agent en question peut être un silicate de calcium ou un chitosane microcristallin.
PCT/GB1999/000024 1998-01-17 1999-01-15 Composition orale absorbant l'huile Ceased WO1999036075A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002318236A CA2318236A1 (fr) 1998-01-17 1999-01-15 Composition orale absorbant l'huile
JP2000539848A JP2003513000A (ja) 1998-01-17 1999-01-15 経口油吸収組成物
AU20643/99A AU2064399A (en) 1998-01-17 1999-01-15 Oral oil sorbing composition
EP99901007A EP1045696A1 (fr) 1998-01-17 1999-01-15 Composition orale absorbant l'huile
NO20003639A NO20003639L (no) 1998-01-17 2000-07-14 Oral oljeabsorberende blanding

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GBGB9800912.9A GB9800912D0 (en) 1998-01-17 1998-01-17 New composition
GB9800912.9 1998-01-17

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WO1999036075A1 true WO1999036075A1 (fr) 1999-07-22

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EP (1) EP1045696A1 (fr)
JP (1) JP2003513000A (fr)
AR (1) AR014422A1 (fr)
AU (1) AU2064399A (fr)
CA (1) CA2318236A1 (fr)
GB (1) GB9800912D0 (fr)
NO (1) NO20003639L (fr)
WO (1) WO1999036075A1 (fr)
ZA (1) ZA99327B (fr)

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FR2838026A1 (fr) * 2003-04-18 2003-10-10 Netlab Dispositif a complement alimentaire
WO2003013471A3 (fr) * 2001-08-08 2007-11-08 Paolina Galvao Composition pharmaceutique a enrobage enterique comprenant du chitosane
EP2016946A1 (fr) * 2007-07-18 2009-01-21 The Jordanian Pharmaceutical Manufacturing Co. Composition de coprécipité de chotisane et de dioxyde de silicium pour une utilisation en tant qu'agent thérapeutique
US7498038B2 (en) 2001-08-16 2009-03-03 Cmp Therapeutics Limited Chitin microparticles and their medical uses
CN103756782A (zh) * 2014-02-12 2014-04-30 中国农业科学院油料作物研究所 一种制取植物油的方法
US20140178505A1 (en) * 2012-12-21 2014-06-26 National Health Research Institutes Mesoporous silica nanoparticles for oil absorption

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WO1995035100A1 (fr) * 1994-06-21 1995-12-28 Danbiosyst Uk Limited Composition destinee a administrer un medicament dans le colon
US5540917A (en) * 1992-06-24 1996-07-30 Hoffmann-La Roche Inc. Biomass lipase inhibitor useful for treating adiposity
EP0775450A2 (fr) * 1995-11-24 1997-05-28 Ar Trade-Invest SA Compositions diététiques contenant du chitosan
WO1998034625A1 (fr) * 1997-02-06 1998-08-13 Novasso Oy Substance aux fins de la reduction de teneurs en lipides et en cholesterol et technique afferente
JPH10306028A (ja) * 1997-05-06 1998-11-17 Koji Haraguchi 脂質消化吸収阻害整腸剤

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US4432968A (en) * 1980-10-20 1984-02-21 The Dow Chemical Company Weight control with fat imbibing polymers
US5540917A (en) * 1992-06-24 1996-07-30 Hoffmann-La Roche Inc. Biomass lipase inhibitor useful for treating adiposity
WO1995035100A1 (fr) * 1994-06-21 1995-12-28 Danbiosyst Uk Limited Composition destinee a administrer un medicament dans le colon
EP0775450A2 (fr) * 1995-11-24 1997-05-28 Ar Trade-Invest SA Compositions diététiques contenant du chitosan
WO1998034625A1 (fr) * 1997-02-06 1998-08-13 Novasso Oy Substance aux fins de la reduction de teneurs en lipides et en cholesterol et technique afferente
JPH10306028A (ja) * 1997-05-06 1998-11-17 Koji Haraguchi 脂質消化吸収阻害整腸剤

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003013471A3 (fr) * 2001-08-08 2007-11-08 Paolina Galvao Composition pharmaceutique a enrobage enterique comprenant du chitosane
US7498038B2 (en) 2001-08-16 2009-03-03 Cmp Therapeutics Limited Chitin microparticles and their medical uses
US8551501B2 (en) 2001-08-16 2013-10-08 Mucovax Inc. Chitin microparticles and their medical uses
FR2838026A1 (fr) * 2003-04-18 2003-10-10 Netlab Dispositif a complement alimentaire
EP2016946A1 (fr) * 2007-07-18 2009-01-21 The Jordanian Pharmaceutical Manufacturing Co. Composition de coprécipité de chotisane et de dioxyde de silicium pour une utilisation en tant qu'agent thérapeutique
US20140178505A1 (en) * 2012-12-21 2014-06-26 National Health Research Institutes Mesoporous silica nanoparticles for oil absorption
CN104955446A (zh) * 2012-12-21 2015-09-30 财团法人卫生研究院 用于吸收油脂的中孔洞硅奈米粒子
US9185928B2 (en) * 2012-12-21 2015-11-17 National Health Research Institutes Mesoporous silica nanoparticles for oil absorption
CN103756782A (zh) * 2014-02-12 2014-04-30 中国农业科学院油料作物研究所 一种制取植物油的方法

Also Published As

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NO20003639D0 (no) 2000-07-14
AU2064399A (en) 1999-08-02
JP2003513000A (ja) 2003-04-08
AR014422A1 (es) 2001-02-28
GB9800912D0 (en) 1998-03-11
EP1045696A1 (fr) 2000-10-25
ZA99327B (en) 2000-09-08
CA2318236A1 (fr) 1999-07-22
NO20003639L (no) 2000-09-04

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