Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-08-10
2002-03-19
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S464000, C424S400000, C514S057000
Reexamination Certificate
active
06358522
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions containing an inhibitor of gastrointestinal lipases, one (or more) additive(s) of the group consisting of substantially non-digestible, substantially non-fermentable, hydrophilic and/or hydrocolloidal food grade thickeners and emulsifiers, and excipients.
An example of an inhibitor of gastrointestinal lipases is orlistat, previously known as tetrahydrolipstatin or THL. Orlistat reduces the absorption of dietary fat. Its use for the control or prevention of obesity and hyperlipidaemia is described in U.S. Pat. No. 4,598,089. Orlistat is the N-formyl-L-leucine ester with (3S,4S)-3-hexyl-4-[(2S)-2-hydroxy-tridecyl]-2-oxetanone.
Anal leakage of oil (oily spotting) is an adverse effect which is occasionally observed in patients treated with lipase inhibitors. This phenomenon reflects physical separation of some liquid unabsorbed dietary fat from the bulk of unabsorbable solids in the lower large intestine. This physical separation and thus anal leakage of oil can be prevented with the pharmaceutical compositions of the present invention.
In the U.S. Pat. No. 5,447,953 it has been demonstrated that by combining a lipase inhibitor with substantial amounts of water-insoluble crude fibers, the inhibiting effect on fat absorption can be increased. This synergistic effect is likely attributable to acceleration of gastrointestinal transit of food by the water-insoluble fiber component. The consequent shortening of the time period available for fat digestion combined with the reducing effect on lipase activity intensifies the inhibitory effect on fat absorption.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that the separation of unabsorbed oil from the feces and thus anal oil leakage can be reduced or prevented, when a lipase inhibitor such as orlistat is administered in combination with low amounts of one or more substantially non-digestible, substantially non-fermentable, hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers.
It is an object of the present invention to use substantially non-digestible, substantially non-fermentable hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers for the combined simultaneous, separate or chronologically spaced administration with lipase inhibitors, e.g. orlistat, in the treatment of obesity and hyperlipaemia.
It is another object of the present invention to provide pharmaceutical compositions containing substantially non-digestible, substantially non-fermentable hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers and lipase inhibitor for administration to a patient in unit dosage form to prevent anal oil leakage.
The invention is further concerned with the use of the above thickeners and/or emulsifiers for treating or preventing the syndrome of anal leakage of oil occurring after the administration of a lipase inhibitor, such as orlistat, or after ingestion of food containing poorly absorbable or non-absorbable fats or oils or undigestible oily fat substitutes. Methods for preventing anal oil leakage in patients comprising administering to the patients compositions containing a lipase inhibitor and thickeners and/or emulsifiers are described herein.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, substantially non-digestible, substantially non-fermentable hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers are administered with lipase inhibitors, e.g. orlistat, to treat or prevent anal oil leakage. The substantially non-digestible, substantially non-fermentable hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers can be administered with the lipase inhibitor either simultaneously or sequentially. The present invention provides pharmaceutical compositions containing lipase inhibitor and substantially non-digestible, substantially non-fermentable hydrophilic and/or hydrocolloidal food grade thickeners and/or emulsifiers for administration to patients in unit dosage form to treat or prevent anal oil leakage. The compositions of the present invention also preferably contain auxiliary excipients such as binders, diluents, and lubricants. A preferred lipase inhibitor is orlistat. Orlistat is the N-formyl-L-leucine ester with (3S,4S)-3-hexyl-4-[(2S)-2-hydroxy-tridecyl]-2-oxetanone. Further examples of lipase inhibitors which can be used in the scope of the present invention are lipstatin, panclicins, hesperidin, ebelactones, esterastin and their derivatives, and valilactone.
In accordance with the present invention, the term “food grade”thickener or emulsifier is any conventional thickener or emulsifier used in foods.
Preferred thickeners for use with the present invention are water soluble natural, synthetic or semisynthetic polysaccharides, such as methylcellulose, xanthan gum, psyllium seed, ispaghula husk, plantago ovata seeds, karaya gum and mixtures of such compounds.
Methyl cellulose is the methyl ether of cellulose. It is slowly soluble in water, giving a viscous, colloid solution.
Xanthan gum is a biosynthetic hydrocolloidal high molecular weight exopolysaccharide produced by pure culture fermentation of Xanthomonas campestris. It contains D-glucose, D-mannose, and D-glucuronic acid as the dominant hexose units and is manufactured as the sodium, potassium, or calcium salt.
Psyllium seed husk, seed coat is a source of soluble fibre. It comprises cellulose containing walls of endosperm, and mucilage containing epidermis of small dried ripe seeds. A colorless transparent mucilage forms upon contact with water.
Ispaghula husk is
psyllium
hydrophilic mucilloid. It comprises the epidermis and collapsed adjacent layer of Plantago species, e.g.
Pl. psyllium
. It swells rapidly upon contact with water to form a stiff mucilage.
Plantago ovata seeds (seed husk and seed coat) is a source of soluble fibre. It comprises cellulose containing walls of endosperm, and mucilage containing epidermis of small dried ripe seeds. A colorless transparent mucilage forms upon contact with water.
Karaya gum is a hydrocolloidal exudate or gum from Sterculia species. It forms a homogenous adhesive gelatinous mass upon contact with water.
Examples of these types of thickeners are contained in over-the-counter (OTC) products and/or food additives, such as:
METHOCEL A4M, a trademark of Dow Chemical Co. for a high viscosity methyl cellulose,
KELTROL TF, a trademark of Merck & Co. Inc., Rahway N.J., for xanthan gum,
MUCILAR; psyllium seed (
Psyllii seminis testa
), a product of Spirig AG, CH-4622 Egerkingen,
METAMUCIL, ispaghula husk (
Ispaghulae testae pulvis
) a product of Procter & Gamble, CH-1211 Geneve 2,
AGIOCUR, plantago ovata seeds, a product of Madaus AG, D-5000 Köln 91,
NORMACOL MITE, a trademark of Norgine Ltd., Great Britain, for karaya gum,
POLY-KARAYA, a trademark of Delalande for karaya gum of Interdelta SA, CH-1701 Fribourg.
A further example of a thickener is FIBERCON (polycarbophil), a trademark of Lederle Laboratories Division, American Cyanamid Co., Pearl River N.Y., for the calcium salt of a synthetic loosely crosslinked hydrophilic resin of the polycarboxylate type.
As emulsifiers which can be utilized in the compositions of the invention, there can be cited saccharose polyesters, such as Ryoto Sugar Esters, e.g. Ryoto Sugar Ester S-170. Ryoto Sugar Esters are a trade name of Mitsubishi-Kasi Foods Corp., Chuo-Ku, Tokyo 104, for sucrose fatty acid esters. Ryoto Sugar Ester S-170 contains sucrose stearic acid polyesters.
Examples of excipients which can be used in the pharmaceutical compositions of the invention are binders, diluents and lubricants, such as AVICEL, polyvinyl pyrrolidone (povidone), talc, stearic acid and sodium stearyl fumarate; sweeteners, such as sorbitol, glucose, saccharose, saccharine-sodium salt and sodium cyclamate; flavour agents, such as passion fruit, citron and limette; flavour enhancers, such as citric acid, monosodium citrate, sodium chloride and chinine sulfate; ef
Hug Manuela
Märki Hans-Peter
Meier Marcel
Hoffmann-La Roche Inc.
Johnston George W.
Jones Dameron L.
Parise John P.
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