Classifications

• • 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
• • 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
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • 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
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent

Definitions

• the present invention relates to pharmaceutical compositions comprising lipase inhibitors.
• lipase inhibitors include lipstatin and orlistat.
• the latter is also known as tetrahydrolipstatin or THL and is derived from a natural product excreted by Streptomyces toxytricini.
• THL tetrahydrolipstatin
• This class of compounds was found to exhibit in vitro as well as in vivo activity against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase, and carboxylester lipase. Its use for the control or prevention of obesity and hyperlipidemia is described, for instance, in U.S. Pat. No, 4,598,089.
• Orlistat is currently administered at doses of 120 mg per meal and dosing is independent of the body mass of the human subject. Orlistat acts locally in the gastrointestinal (GI) tract and prevents lipase from digesting triglycerides and subsequently inhibits the formation of absorbable lipid degradation products. For this reason, systemic availability of the lipase inhibitors is not required and, instead, local residence in the gastrointestinal tract is preferred.
• GI gastrointestinal
• Lipase inhibitor compositions currently administered inhibit around 30% of fat absorption after consumption of a mixed meal; an increase of the lipase inhibitors concentration in the pharmaceutical composition does not increase its clinical efficacy while the intensity of local side effects increases.
• the subject invention provides a pharmaceutical composition comprising at least one lipase inhibitor, at least one surfactant, and at least one dispersant.
• Lipase inhibitors are inhibitors of gastrointestinal and pancreatic lipases, for example orlistat. Such lipase inhibitors are oftentimes present in an amount from 1% to 50% of the total weight of the composition, and more preferably from 5% to 30% of the total weight of the composition.
• dispersants are water-soluble, for example sugars, sugar alcohols, alcohols, effervescents, excipients, capsule disintegrants, tablet disintegrants, and mixtures thereof.
• Preferred dispersants include glucose, sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, glycerol, triacetin, glycofurol, effervescents, and mixtures thereof, and are more favorably sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, glycerol, triacetin, glycofurol, and mixtures thereof.
• Dispersants can also be lipid-soluble compounds that are liquid at body temperature.
• Preferred lipid-soluble compounds include triglycerides, modified triglycerides, diglycerides, modified digliclycerides, monoglycerides, modified monoglycerides, mixtures of modified or non-modified di/mono/triglycerides, vitamin E, tocopherol acetate, terpenes, squalene, and mixtures thereof, more preferably triglycerides, diglycerides, monoglycerides, mixtures of mono/di/triglycerides, vitamin E, tocopherol acetate, and mixtures thereof.
• Favored lipid-soluble compounds include medium chain triglycerides or a mixture of medium chain triglycerides.
• the dispersant usually is present in an amount of at least 5% of the total weight of the composition, for example between 5% and 70% of the total weight of the composition. It is beneficial to use a lipid-soluble compound present in an amount varying between 20 and 90% of the total weight of the composition.
• Preferred surfactants include anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants, and mixtures thereof.
• Favorable surfactants include vitamin E polyethylene glycol 1000 succinate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyglycolyzed glycerides, transesterified and (poly)ethoxylated oils, sorbitan fatty acid esters, poloxamers, fatty acids salts, bile salts, alkylsulfates, lecithins, mixed micelles of bile salts and lecithins, sugar esters, and mixtures thereof.
• surfactants include vitamin E polyethylene glycol 1000 succinate, polyethoxylated castor oil, and polyethylene glycol 40 stearate.
• Surfactant is generally present in an amount of at least 0.1% of the total weight of the composition, and more preferably 0.1% to 90% of the total weight of the composition. Two or more surfactants can be combined.
• inventive pharmaceutical compositions may further comprise pharmaceutically acceptable excipients, such as carbohydrates, antioxidants, co-solvents, as well as thickening agents, preservatives, and lubricants.
• pharmaceutically acceptable excipients such as carbohydrates, antioxidants, co-solvents, as well as thickening agents, preservatives, and lubricants.
• An advantageous group of the subject inventive pharmaceutical compositions include 1% to 50% lipase inhibitor of the total weight of the composition, 5% to 70% of at least one dispersant of the total weight of the composition, and 0.1% to 90% of at least one surfactant of the total weight of the composition. These compositions may further include one or more pharmaceutically acceptable excipients.
• the subject neither provides a pharmaceutical composition containing at least one inhibitor of lipases, at least one surfactant and at least one dispersant.
• Dispersants or “dispersing agents” are materials that facilitate the initial disintegration of the composition and promote further fine distribution in the environment.
• a “surfactant” is a substance such as a detergent that, when added to a liquid, reduces its surface tension between a lipophilic and a hydrophilic phase.
• the surface-active molecule must be partly hydrophilic (water-soluble) and partly lipophilic (soluble in lipids, or oils). It concentrates at the interfaces between bodies or droplets of water and those of oil, or lipids, to act as an emulsifying agent, or foaming agent.
• Preferred surfactants are anionic, cationic, non-ionic and zwitterionic surfactants.
• lipase inhibitor or inhibitor of lipases refers to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases.
• lipase inhibitors for example orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitor of lipases.
• Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin.
• Other lipase inhibitors include a class of compound commonly referred to as panclicins, analogues of orlistat.
• lipase inhibitor refers also to polymer bound lipase inhibitors for example described in International Patent Application W099/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterised in that they have been substituted with one or more groups that inhibit lipases.
• lipase inhibitor also comprises pharmaceutically acceptable salts of these compounds.
• lipase inhibitor preferably refers to orlistat.
• Orlistat is known to be useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat and U.S. Pat. No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123.
• Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day.
• the subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
• the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat.
• treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
• compositions according to the present invention have been found to exhibit very favorable effects when applied orally during meal intake in humans. Surprisingly, an increased efficacy and/or potency compared to the already known compositions was observed. This was unexpected as the compositions according to the invention form, at least in part, micellar or finely dispersed (micron or sub-micron range) materials.
• compositions according to the present invention induce less unpleasant side effects in the single meal test than the already known compositions, despite the greater amount of fat that remains unabsorbed.
• the stools obtained after intake of compositions according to the present invention show less separation of oil from the main stool mass as compared to the conventional compositions. This was unexpected, as equal or higher amounts of fat were present in the collected stools.
• the lipase inhibitor preferably an inhibitor of gastrointestinal and pancreatic lipases, most preferably orlistat, is present in an amount varying from 1 to 50%, preferably 5 to 30%, of the total weight of the composition.
• the presence of at least one surfactant optimizes particle distribution in the stomach.
• the surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants and mixtures thereof.
• surfactants chosen among the group consisting of vitamin E polyethylene glycol 1000 succinate (TPGS), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxyethylene alkyl ethers, polyglycolyzed glycerides, transesterified and (poly)ethoxylated oils, polyoxyethylene castor oils, sorbitan fatty acid esters, poloxamers, fatty acid salts, bile salts, alkylsulfates, lecithins, mixed micelles of bile salts and lecithins, sugar esters and mixtures thereof.
• TPGS vitamin E polyethylene glycol 1000 succinate
• TPGS polyoxyethylene sorbitan fatty acid esters
• polyoxyethylene stearates polyoxyethylene alkyl ethers
• polyglycolyzed glycerides polyglycolyzed glycerides
• transesterified and (poly)ethoxylated oils polyoxyethylene castor
• Polyoxyethylene sorbitan fatty acid esters are commercially available and refer to mono-, di- or tri-ester of sorbitan with fatty acids (C 8 to C 18 ), e.g. POE(20) sorbitan monolaurate (Polysorbate 20), POE(20) sorbitan monopalmitate (Polysorbate 40), POE(20) sorbitan monostearate (Polysorbate 60), POE(20) sorbitan tristearate (Polysorbate 65), POE(6) sorbitan monostearate (PEG-6 Sorbitan Stearate), POE(20) sorbitan monooleate (Polysorbate 80), POE(20) sorbitan monooleate (Polysorbate 80), POE(20) sorbitan trioleate (Polysorbate 85), POE(6) sorbitan monooleate (PEG-6 sorbitan oleate), and POE(20) sorbitan monois
• polyoxyethylene stearates refers to polyoxyethylene glycol esters with stearic acid, e.g. PEG 22 stearate, PEG 32 stearate, and PEG 40 stearate. These compounds are known in the art and commercially available.
• polyoxyethylene alkyl ethers refers to ether composed of polyoxyethylene and alkyl groups, e.g. POE(7) C12-14 alkyl ether, POE(9) C12-14 alkyl ether, POE(3)C12-14 alkyl ether, and POE(9)C12-14 alkyl ether.
• Transesterified and (poly)ethoxylated oils are surfactants that have been chemically modified by a) a saponification reaction and b) a re-esterification with fatty acids and/or polyethylenglycol (PEG).
• PEG polyethylenglycol
• polyglycolyzed glycerides refer to glycerides that are partially esterified with fatty acids and polyethylenglycol (PEG). Examples are polyglycolyzed glycerides, 44/14, saturated polyglycolyzed glycerides, 50/13, and saturated polyglycolyzed glycerides, 53.
• polyoxyethylene castor oils refers to castor oil that has been esterified with polyethyleneglycol, e.g. polyoxyl 35 castor oil (Cremophor EL), PEG-30 castor oil, PEG-40 castor oil, PEG-25 hydrogenated castor oil, and PEG-40 hydrogenated castor oil.
• fatty acid salts refers to pharmaceutically acceptable salts of C 12 to C 18 fatty acids, preferably natural fatty acids, e.g. Mg-stearate.
• alkyl sulfates refers to C 12 to C 18 alkylsulfates, e.g. sodium dodecylsulfate.
• sorbitan fatty acid esters refers to esters of C 12 to C 18 fatty acids, preferably natural fatty acids, like sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan tristearate, sorbitan trioleate, etc.
• lecithin refers to natural or synthetic lecithin.
• a lecithin has the following structure:
• R 1 and R 2 are fatty acids as defined herein (see definition for fatty acid salts).
• Lecthins may be chosen from the group consisting of natural lecithin, synthetic lecithin, soya lecithin, egg lecithin, synthetic dipalmitinlecithin, partially or fully hydrogenated lecithin and mixtures thereof.
• bile salts refers to pharmaceutically acceptable salts, e.g. sodium salts, of bile acids, e.g. cholanic acid, etc.
• sugar esters refers to esters of sugars with fatty acids, e.g. C 12 -C 18 fatty acids, e.g. fatty acids of sucrose like sucrose stearate or sucrose palmitate.
• polystyrene resin refers to a co-polymer of polyethylenglykols and polypropylenglykols, e.g. of general formula
• pharmaceutically acceptable means that the buffer or salts are acceptable from a toxicity viewpoint.
• Preferred surfactants may be selected from the group consisting of vitamin E polyethylene glycol 1000 succinate, e.g. TPGS, Eastman Chemicals; polyethoxylated castor oil, e.g. Cremophor El, BASF; and polyethylene glycol 40 stearate, Myri 52, Serva, Crodet S40 Croda.
• the surfactants are usually present in an amount of at least 0.1% of the total weight of the composition, preferably in an amount of 0.1 to 90%, more preferably in an amount of 1 to 20%.
• Dispersants can be chosen from water and lipid soluble compounds. They are usually present in an amount of at least 5% of the total weight of the composition, preferably in amounts varying between 5 and 70% of the total weight of the composition.
• One embodiment of the present invention refers to water-soluble dispersants.
• Suitable water soluble dispersing agents can be found in the group consisting of sugars, sugar alcohols, alcohols, effervescents, excipients, capsule disintegrants, tablet disintegrants and mixtures thereof. More preferred dispersants may be chosen from the group consisting of glucose, sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, glycerol, triacetin, glycofurol, effervescents, like effervescents, e.g. NaHCO 3 /acid mixtures, e.g.
• NaHCO 3 /citric acid NaHCO 3 /citric acid, and mixtures thereof.
• Most preferred water soluble dispersants are sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, e.g. polyethylenglycol 100-10000, more preferably polyethylenglycol 400-6000, e.g. polyethylenglycol 400, glycerol, triacetin, glycofurol and mixtures thereof
• effervescent mixtures NaHCO 3 /citric acid
• HPMC hydroxypropylmethylcellulose
• compositions of the invention comprising lipid soluble compounds as dispersion agents are known as Self-Emulsifying Drug Delivery Systems (SEDDS).
• SEDDS have the particular characteristic of emulsifying under conditions of gentle agitation and can be termed microemulsions in case they contain water.
• a description of compositions of SEDDS can be found for instance in C. W. Pouton, Advanced Drug Delivery Reviews, 25, (1997), 47-58. It has been observed that, after dispersion in aqueous environment, compositions of a lipase inhibitor in SEDDS separate into a clear micellar phase and in lipid droplets, wherein the lipase inhibitor is present in both phases.
• compositions as described above comprising at least one dispersant which is a lipid soluble compound and is liquid at the body temperature.
• the lipid soluble dispersing agent is preferably applied in amounts varying between 20 and 90% of the total weight of the compositions and must be liquid at the body temperature (i.e. >37° C.).
• the dispersants can be chosen among the group consisting of triglycerides, modified triglycerides, diglycerides, modified diglycerides, monoglycerides, modified monoglycerides, mixtures of modified or non-modified di/mono/triglycerides, vitamin E, tocophero acetate, terpenes, squalene and mixtures thereof, more preferably the lipid soluble compound is chosen from the group consisting of triglycerides, diglycerides, monoglycerides, modified monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocopherol acetate, and mixtures thereof.
• compositions according to the present invention may further comprise an additional surfactant (co-surfactant).
• glycolide ester refers to an ester of glycerol with fatty acids with 2 to 7 (short; short chain glycerides), 8 to 12 (medium; medium chain glycerides) and >12 (long; long chain glycerides) carbon atoms.
• examples are glyceryl trilaurate, glyceryl tristearate, etc.
• Examples for diglycerides are glyceryl dilaurate, glyceryl distearate, ect.
• monoglycerides are glyceryl monolaurate and glyceryl monostearate.
• the invention also comprises the corresponding mixtures of mono-, di- and triglycerides.
• modified in this context refers to modified glycerides, e.g. wherein one or more fatty acids have been replaced by other fatty acids or wherein the fatty acid moieties have been chemically modified.
• compositions according to the present invention can be administered using conventional dosage forms such as hydroxypropylmethylcellulose (HPMC) capsules, soft gelatin capsules, hard gelatin capsules, starch capsules, tablets, chewable tablets and capsules, syrups, etc.
• HPMC hydroxypropylmethylcellulose
• the invention is useful with any inhibitor of lipases, but is especially useful for inhibitors of the gastric and pancreatic lipase and, in particular, for the active compound orlistat.
• a preferred composition of the present invention comprises
• the lipase inhibitor e.g. orlistat
• the surfactant in an amount of 1-20%.
• the present invention relates also to a process for preparing pharmaceutical compositions as described above, which process comprises mixing at least one inhibitor of lipases with at least one surfactant and at least one dispersant.
• a further aspect of the present invention is to provide a method for controlling or preventing obesity comprising the step of administering to a patient a pharmaceutical composition as described above.
• the invention also relates to the use a composition as defined above for the preparation of a medicament for the prevention and treatment of obesity.
• Capsules containing 60 mg orlistat in the above composition were applied to human volunteers during a single meal test.
• Human subjects consumed a meal consisting of 130 g hamburger meat, 10 g butter and 100 g French fries (fried in peanut oil) and containing overall about 35 g fat.
• Stools were collected from day-1 (a day before eating the single meal) until day 5 after the test meal. The first and the last stools were employed to assess background fat excretion.
• Stools were stored frozen and extracted for total lipid according to Bligh and Dyer (Bligh, E. G., and Dyer, W. J., Can. J. Biochem. Physiol., 37, (1959), 911). Background excretion of lipids was subtracted to obtain the amount of fat excreted due to the orlistat treatment. The excreted fat was quantified by gravimetry and expressed as percentage of the fat content of the test meal.
• a composition consisting of 180 mg Cremophor EL (polyethoxylated castor oil, BASF), 60 mg MCT, 60 mg orlistat and 200 mg of finely milled effervescent vitamin C tablets was obtained according to the preparation described in example 1. Hydroxypropylmethylcellulose capsules containing each 60 mg orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• a composition consisting of 450 mg Gelucire 44/14 (lauroyl macrogol-32 glycerides, Gattefosse, France), 90 mg MCT, 60 mg orlistat and 200 mg of finely milled effervescent vitamin C tablets was obtained according to the preparation described in example 1. Hydroxypropylmethylcellulose capsules containing each 60 mg of orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• Example 1 The composition of example 1 was prepared, except that instead of an effervescent mixture, 200 mg finely milled glucose was used as an additional excipient. Hydroxypropylmethyl-cellulose capsules containing each 30 mg of orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• a composition consisting of 1700 mg TPGS and 300 mg orlistat were added to a planet-mixer in which the metal beaker was warmed to 60° C. After melting, the mixture was stirred and 10 g of solid sorbitol was added while continuously stirring at 150 rpm. The stirring was continued for 30 minutes during which time the preparation cooled down to room temperature. Afterwards, the solid mixture was sieved through a 2 mm sieve. Hydroxypropyl-methylcellulose capsules containing each 30 mg of orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• polyethylene glycol 400 PEG 400, Clariant
• 300 mg glycerol 30 mg polyethylene glycol 40 stearate (Myrj 52, Serva Germany; Crodet S40, Croda UK) were added.
• the mixture was heated to 60 ° C. and subsequently cooled down to room temperature under stirring.
• 60 mg orlistat were than added to the so obtained suspension and stirred till homogeneity.
• the so obtained composition was filled into hydroxypropylmethylcellulose capsules. Capsules containing 60 mg orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• 340 mg glycerol were mixed with 30 mg polyethylene glycol 40 stearate. The mixture was heated to 60° C. and subsequently under stirring cooled down to room temperature. 30 mg orlistat, 100 mg polyethylene glycol 400 (PEG 400) and 100 glucose were then added to the so obtained solution and stirred till homogeneity. Hydroxypropylmethylcellulose capsules containing 30 mg orlistat in the above composition were applied to human volunteers according to the method described in example 1.
• compositions according to the present invention are much higher than that of conventional formulations.
• Compositions according to the invention containing just the half or even a quarter of the lipase inhibitor of the known composition are much more efficacious and/or potent.
• Table 1 shows also the number of stool samples containing free oil for each of the above compositions. Stool samples obtained after intake of compositions according to the present invention show no or just occasional separation of oil from the main stool mass. The positions according to the present invention enable therefore to minimize or copletely suppress anal leakage of oil which is one of the most undesired side effect of the prior art compositions.

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  • 2002-03-12 NO NO20021204A patent/NO331906B1/no not_active IP Right Cessation
• 2003
  • 2003-03-25 HK HK03102148A patent/HK1049966A1/xx not_active IP Right Cessation
  • 2003-04-21 US US10/419,346 patent/US20030181512A1/en not_active Abandoned
• 2004
  • 2004-03-05 US US10/794,123 patent/US8012494B2/en not_active Expired - Lifetime
• 2006
  • 2006-09-29 CY CY20061101416T patent/CY1106180T1/el unknown
• 2011
  • 2011-07-19 US US13/185,558 patent/US20110275706A1/en not_active Abandoned

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