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WO2003009840A1 - Composition renfermant au moins un inhibiteur de la lipase ainsi que de la carnitine - Google Patents

Composition renfermant au moins un inhibiteur de la lipase ainsi que de la carnitine Download PDF

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Publication number
WO2003009840A1
WO2003009840A1 PCT/EP2002/007812 EP0207812W WO03009840A1 WO 2003009840 A1 WO2003009840 A1 WO 2003009840A1 EP 0207812 W EP0207812 W EP 0207812W WO 03009840 A1 WO03009840 A1 WO 03009840A1
Authority
WO
WIPO (PCT)
Prior art keywords
carnitine
lipase inhibitor
vitamine
orlistat
composition
Prior art date
Application number
PCT/EP2002/007812
Other languages
English (en)
Inventor
Andrea Schaffhauser
Elmar Zurbriggen
Paula Gaynor
Original Assignee
Lonza Ag
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 Lonza Ag filed Critical Lonza Ag
Publication of WO2003009840A1 publication Critical patent/WO2003009840A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • composition comprising at least one lipase inhibitor and carnitine
  • the present invention relates to compositions comprising lipase inhibitors and carnitine and to oral dosage forms comprising said compositions.
  • a further object of the present invention is the use of carnitine to enhance the absorption of at least one lipophilic vitamins, in particular of
  • Vitamines D and E during treatment of a person with lipase inhibitors and/or the use of carnitine for the manufacture of pharmaceutical preparations suitable therefore.
  • Another object of the invention is a produce, comprising a lipase inhibitor and carnitine as a combinatorial medicine for simultaneous, separate or temporally staggered application.
  • a further object of the present invention is the use of carnitine to enhance loss of body fat upon treatment with orlistat and/or the use of carnitine for the manufacture of phramaceutical preparations suitable therefore.
  • Intestinal lipase inhibitors applied orally, are effective slimming agents used to treat obesity.
  • Orlistat is the most prominent intestinal lipase inhibitor drug and is marketed under the trade name Xenical ®. Orlistat is a lipophilic substance that is a highly efficient inhibitor of pancreatic lipase and drastically reduces the uptake of dietary fat, i.e. triglycerides by inhibiting the lipase- promoted release of free fatty acids in the gut.
  • Lipase inhibitors such as Orlistat reduce the calorific value of the diet that is available to the organism. It concomittantly reduces serum levels of Cholesterol (M. Davidson et al., Weight control and risk factor reduction in obese subjects treated for 2 years with Orlistat, JAMA, 281, 235-243). It must be taken continously over extended periods of time and might be taken as a prophylactic measure continously.
  • the increased fat content of the non-digested dietary broth in the gut's lumen that is going to be excreted also entails a different partitioning of other fat-soluble substances in the gut, in particular the lipophilic Vitamins such as Vitamins E, D and A or of essential unsatured fatty acids.
  • composition comprises Carnitine or an Acyl-Carnitine or a salt thereof and a lipase inhibitor.
  • lipase inhibitor in the context of the present invention, any known, pharmaceutically acceptable inhibitor of intestinal lipases is to be understood.
  • Sucft lipases may also be termed pancreatic lipases since they are excreted from the pancreas. Examples comprises Orlistat, Lipstatin, FL-386, WY- 121898, Bay-N-3176, Valilactone, Esterastin, Ebelactone A, Ebelactone B oder RHC 80267 or mixtures thereof. These compounds are known to the expert in the field.
  • the lipase inhibitor is Orlistat.
  • Orlistat is N-formyl-L-leucine-(S)-l-[[(2S,3S)-3-hexyl- 4-oxooxetan-2-yl] -methyl] dodecylester as described in Chemical Abstracts under the Registry Number 96829-58-2.
  • (-)-Tetrahydrolipstatin refering to the naturally occuring compound Lipstatin which has the same lipase-inhibiting, but less potent effect. Its molecular weight is 495.74 and its molecular formular is C 2 9H 53 N0 5 . It is highly lipophilic, having a solubility in water at 23°C of ⁇ lmg/lOOml. Die compassion supplidis, etc.
  • Carnitine according to the present invention may be (DL)-Carnitine or, preferably, essentially pure L-Carnitine.
  • Such Carnitine may as well be Acyl-Carnitine, in particular 2-Acetyl-Carnitine.
  • Such Carnitine may be employed either as an inner salt or as a simple or complex salt together with other ionic substances such as, but not limited to, chloride, fumarate, tartrate, citrate, isocitrate, (-)-hydroxycitrate, magnesium, calcium, cholin, either alone or in suitable combinations, particularly as non-hygroscopic complex salts, e.g.
  • Carnitine-magnesium- citrate L-Carnitine-magnesium-hydroxycitrate or L-Carnitine-cholin-tartrate.
  • Carnitine according to the present invention is either L-Carnitine- tartrate, L-Carnitine-magnesium-citrate or L-Carnitine-magnesium-(-)-hydroxycitrate.
  • Carnitine is, in its L-form, a naturally occurring substance involved in energy metabolism in mitochondria that is widely used as a nutritional supplement, e.g. for slimming and is a well-known substance without adverse effects.
  • L-Carnitine in admixture with at least (-)-hydroxycitrate is a further prefered embodiment of the present invention since hydroxycitrate acts as a non-metabolizable analogue of citrate and has an additional slimming effect, as is well known.
  • Hydroxycitrate is a naturally occurring substance and activates Carnitin-Palmitoyl-Transferase I (CPT).
  • CPT Carnitin-Palmitoyl-Transferase I
  • the latter enzyme is crucial for effective, carnitine-mediated import of fatty acids into mitochondria for the purpose of energy-generating breakdown of fatty acids. Even more preferably, it is a complex salt.
  • a complex salt comprising L-Carnitine, (-)-hydroxycitrate and an earth alkali metal such as Magnesium or Calcium in stoechiometric amounts is a non-hygroscopic, easily storable substance well-suited for nutraceutical or pharmaceutical formulations.
  • a lipase inhibitor such as e.g. Orlistat
  • a lipase inhibitor such as e.g. Orlistat
  • Vitamin E alpha-Tocopherol
  • Vitamin D Calcitriol and/or Cholecalciferol
  • Vitamin K Meenachinon and/or Menadion
  • Vitamin Q10 Ubichinon
  • Provitamin A Carotenoids
  • Vitamin A Retinol, Retinal, Retinoic acid and/or 3-Dehydroretinol
  • the abso ⁇ tion rate is understood in this context as the abso ⁇ tion of a lipophilic Vitamine, preferably of Vitamine E, from the lumen of the the intestine. Due to enhanced abso ⁇ tion, the blood serum levels of lipophilic Vitamins, particularly of Vitamine E, are increased in humans upon combination therapy with carnitine and a lipase inhibitor such as e.g. orlistat as compared to lipase inhibitor treatment alone. In rat studies, the liver content of Vitamin E is also found to be enhanced in case of carnitine plus orlistat feeding as compared to a control group treated with orlistat without concomitant administration of carnitine.
  • Vitamine E content from a suitably prepared sample may be determined e.g. by the method of
  • Vitamine E is required in a daily dose of approx. 10 mg/day for an adult, which is a rather elevated dose as compared to other Vitamins which are only required in smaller quantities (Vit D: 0.005 mg, Vit A: 1-2 mg). Vitamine E has been shown to reduce singificantly the risk of coronary heart disease by retarding the oxidation of serum lipoproteins and inhibiting the proliferation of vascular smooth muscle cells (Chan, A. et al.
  • Vitamin E and artherosclerosis J.Nutr. 128: 1593-1596, 1998 and Motoyama, T. etal., Vitamin E administration improves impairment of endothelium-dependent vasodilation in pateints with coronary spasmic angina, J. Am. Coll. Cardiol. 32: 1672-1679, 1998).
  • a positive side effect of such concomitant administration of carnitine during treatment with lipase inhibitors is the additional slimming effect of carnitine that contributes to the ultimate goal of lipase inhibitor therapy, loss of body fat and general decrease in body weight. Due to its stimulating action of beta-oxidation of fatty acids, Carnitine promotes reduction in body weight and the loss of body fat. In addition, probands reported feeling less hungry and fewer cravings for sugar which enabled them to adhere easier to a certain diet regimen as upon treatment of obesity (Kaats, G.R. (1992) Cur. Ther. Res.51:261). Such effects are perfectly in line with the objective of a lipase inhibitor-based phrophylactic or therapeutic treatment.
  • a further beneficial side effect of carnitine administration is the reduction of serum cholesterol levels based on metabolic effects (Cacciatore, L. et al., (1991), Drugs Exp. Clin. Res. 18, 355 ff.), thereby complementing the lowered availability of dietary cholesterol upon lipase inhibitor treatment. This further promotes a patient's health. Given the deplenishing effect of carnitine for Cholesterol, the replenishing effect in case of lipophilic Vitamines such as Vitamine E or D is even more su ⁇ rising.
  • the composition in accordance with the present invention comprises at least 50 mg to 8000 mg carnitine per 100 mg of lipase inhibitor, more preferably at least 100-500 mg carnitine per 100 mg of lipase inhibitor.
  • the lipase inhibitor may amount to between 10 to 1000 mg, preferably between 20 to 250 mg, in suitable oral dosage forms comprising the composition.
  • a daily dose for Orlistat can be 50-300 mg for an average adult and is achieved by multiple oral intake of a capsule or tablet, preferably upon meals.
  • Carnitine may amount to between 50 to 8000 mg in suitable oral dosage forms of the composition.
  • a vitamine abso ⁇ tion increasing effective amount is an amount of Carnitine, preferably L-Carnitine, which increases the intestinal abso ⁇ tion of the lipophilic vitamines, such as Vitamines D, A and in particular Vitamine E.
  • the dose of carnitine preferably amounts to 0.5 to 8 g.
  • the combinatorial slimming effect has been observed to be not merely additive, but synergistic in respect of lipase inhibitor and carnitine action, respectively.
  • composition according to the present Invention may be added to foodstuff, i.e. the diet, or swallowed as a freshly prepared suspension.
  • the composition may be added to low- calorific cereal or chocolate bars or similiar snacks comprising a certain amount of fat.
  • Dispersible powders and granules comprising the composition according to the present invention are a prefered embodiment.
  • Such powders or granules may be suitable for preparation of an aqueous suspension by the addition of water and may provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • the composition is prepared as an oral dosage form and may comprises further, pharmaceutically acceptable exciepients.
  • excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch and alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated with known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone or with a wax may be employed.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch and alginic acid
  • binding agents such as starch, gelatin or a
  • oral dosage forms such as tablets, capsules or microbeads are coated with an enteric coating which prevents dissolution in the acidic environment of the stomach. Instead, this coating dissolves in the small intestine at a more neutral pH.
  • enteric coated compositions are described by Bauer et al.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Oil suspensions may be formulated by suspending the active ingredients in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agent such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by an added antioxidant such as ascorbic acid.
  • Additional excipients for example sweetening, flavoring and coloring agents, may also be present. It is also possible to add further slimming agents such as glycosidase inhibitors, e.g. acarbose, whose function is to hinder breakdown of carbohydrates such as starch in the intestine. This further reduces the calorific value of the diet.
  • further slimming agents such as glycosidase inhibitors, e.g. acarbose, whose function is to hinder breakdown of carbohydrates such as starch in the intestine. This further reduces the calorific value of the diet.
  • the composition of the present invention further comprises one or several lipophilic vitamins such as Vitamine A, Vitamine D or Vitamine E, preferably in an amount of 8-800 mg per dosage form or per 100 mg lipase inhibitor.
  • Such composition may further comprise essential fatty acids such as linolic acid, linolenic acid or 6-omega- polyunsatured fatty acids.
  • the composition comprises Vitamine E. Supplemental Vitamine E has been shown to reduce singificantly the risk of coronary heart disease by retarding the oxidation of serum lipoproteins and inhibiting the proliferation of vascular smooth muscle cells (Chan et al., Vitamin E and atherosclerosis, J. Nutr. 128: 1593-
  • Vitamin E isoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe .
  • Such pharmaceutical dosage forms might be e.g. gelatine capsules having a partitioning wall or double walled capsules consisting essentially of two separate capsules one being inserted into the other.
  • a compound such as lipstatin may be comprised a solution in oil, thereby being well protected from the action of atmospheric oxygen, whilst carnitine is comprised in a solid preparation made up as a powder and being stored in a separate compartment.
  • Such dosage forms merely combining carnitine and a lipase inhibitor are a further object of the present invention.
  • kits-of-parts comprising a lipase inhibitor and carnitine or an Acyl-carnitine or a salt thereof as a combinatorial medicine for simultaneous, separate or temporally staggered application.
  • Such items a generally termed kits-of-parts and may e.g. consist of separate blister bags comprised in a single package.
  • kits comprising a base dose of a lipase inhibitor, e.g. in a capsule, and a blister package of carnitine, the latter allowing for individual, customary dosing of carnitine depending on the pu ⁇ ose of either solely alleviating Vitamine deficiency or additionally enhancing slimming.
  • a lipase inhibitor e.g. in a capsule
  • a blister package of carnitine e.g. in a capsule
  • a blister package of carnitine e.g. a blister package of carnitine
  • Combination therapy with carnitine and a lipase inhibitor according to the present invention is applicable to persons of all ages, expediently adolescents and adults, h a preferred embodiment, the person being administered carnitine concomittantly with treatment with a lipase inhibitor is a woman, in an even more preferred embodiment a woman who has already passed to the menopause, the latter approximately corresponding to an age of >35-40 years, whereby this must be understood as an estimate, not as a limiting feature in the context of this embodiment.
  • the daily dose of Carnitine should amount to at least 0.5 g per day, preferably to 0.5 to 8 g per day, in order to achieve a pronounced slimming effect upon administration of Carnitine.
  • concomitant use of orlistat led to a more than simply additive decrease in body fat content expressed as % of total body weight.
  • the synergistic effect was observed to be limited to adminstration of orlistat, since another type of lipase inhibitor used as a control showed no such effect.
  • Composition and pharmaceutical dosage form comprising Carnitine (commercial L-Carnitine, Lonza Ltd.) and Orlistat.
  • a hard gelatine capsule is filled with approx. 447 mg of a powder mixture.
  • the particle size is ⁇ 0.8 ⁇ m.
  • the powder has been mixed by addition of the fine-milled, solid compounds- in a conventional knedding machine.
  • the composition of the powder mixture is given below:
  • An obese adult receives a daily dose of 120 mg Orlistat during a 4-week period.
  • the dosage form is a gelatine capsule as described in the preceding example.
  • a capsule is ingested three times a day, at meals.
  • Blood serum levels of Vitamin E are measured daily and stably rise after the first week of treatment. The elevated level is maintained over the entire period of treatment that is remaining.
  • Example 3
  • the dosage form is a gelatine capsule as described in the preceding example that is ingested three times a day, before meals, plus an extra dose of a drinking solution made up from an effervescent tablet containing 1 g of Carnitine before every meal. Changes in Vitamine E levels are observed as described in the preceding example.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

Cette invention concerne une composition renfermant au moins un inhibiteur de la lipase ainsi que de la carnitine ou de l'acylcarnitine ou un sel de celle-ci, ainsi qu'une méthode permettant de renforcer l'absorption de vitamines lipophiles, en particulier la vitamine E, lors d'un traitement thérapeutique ou prophylactique d'une personne au moyen d'un inhibiteur de la lipase par l'administration de carnitine.
PCT/EP2002/007812 2001-07-24 2002-07-13 Composition renfermant au moins un inhibiteur de la lipase ainsi que de la carnitine WO2003009840A1 (fr)

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EP01117965.2 2001-07-24
EP01117965 2001-07-24

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010042499A1 (fr) * 2008-10-06 2010-04-15 Banner Pharmacaps, Inc. Solutions stables d'orlistat pour formes galéniques pharmaceutiques
US20100221326A1 (en) * 2007-09-12 2010-09-02 Mader S.R.L. Pharmaceutical compositions for oral use for treating patients affected by obesity
WO2011033356A1 (fr) * 2009-09-18 2011-03-24 World-Trade Import-Export Wtie, Ag Composition pharmaceutique amaigrissante et procédé permettant d'obtenir une telle composition
JP2018501310A (ja) * 2014-12-17 2018-01-18 エンプロス ファーマ エービーＥｍｐｒｏｓ Ｐｈａｒｍａ Ａｂ 肥満症及び関連代謝障害の治療用のオルリスタット及びアカルボースの放出調節組成物
CN119859108A (zh) * 2025-03-21 2025-04-22 辽宁科硕营养科技股份有限公司 一种2-羟基柠檬酸复合盐及其制备方法与应用

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2001068075A2 (fr) * 2000-03-10 2001-09-20 Hill's Pet Nutrition Procede pour augmenter l'absorption intestinale des vitamines solubles dans la graisse chez les femmes post-menopausiques et les animaux

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2001068075A2 (fr) * 2000-03-10 2001-09-20 Hill's Pet Nutrition Procede pour augmenter l'absorption intestinale des vitamines solubles dans la graisse chez les femmes post-menopausiques et les animaux

Non-Patent Citations (3)

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Title
DAVIDSON M H ET AL: "WEIGHT CONTROL AND RISK FACTOR REDUCTION IN OBESE SUBJECTS TREATED FOR 2 YEARS WITH ORLISTAT A RANDOMIZED CONTROLLED TRIAL", JAMA THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, CHICAGO,IL, US, vol. 281, no. 3, 20 January 1999 (1999-01-20), pages 235 - 242, XP000984679, ISSN: 0098-7484 *
GAYNOR P.: "L-carnitine: a naturally occurring vitamin-like nutrient for dietary enrichment", FOOD MARKETING AND TECHNOLOGY, vol. 13, no. 6, 1999, pages 6 - 7, XP001117760 *
JAYAPRAKAS V ET AL: "Influence of dietary L-carnitine on growth and lipid metabolism in pearlspot, Etroplus suratensis (Bloch).", INDIAN JOURNAL OF EXPERIMENTAL BIOLOGY, vol. 36, no. 10, October 1998 (1998-10-01), pages 1044 - 1048, XP001117581, ISSN: 0019-5189 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100221326A1 (en) * 2007-09-12 2010-09-02 Mader S.R.L. Pharmaceutical compositions for oral use for treating patients affected by obesity
WO2010042499A1 (fr) * 2008-10-06 2010-04-15 Banner Pharmacaps, Inc. Solutions stables d'orlistat pour formes galéniques pharmaceutiques
US8309107B2 (en) 2008-10-06 2012-11-13 Banner Pharmacaps, Inc. Stable solutions of orlistat for pharmaceutical dosage forms
WO2011033356A1 (fr) * 2009-09-18 2011-03-24 World-Trade Import-Export Wtie, Ag Composition pharmaceutique amaigrissante et procédé permettant d'obtenir une telle composition
JP2018501310A (ja) * 2014-12-17 2018-01-18 エンプロス ファーマ エービーＥｍｐｒｏｓ Ｐｈａｒｍａ Ａｂ 肥満症及び関連代謝障害の治療用のオルリスタット及びアカルボースの放出調節組成物
US11975105B2 (en) 2014-12-17 2024-05-07 Empros Pharma Ab Modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders
CN119859108A (zh) * 2025-03-21 2025-04-22 辽宁科硕营养科技股份有限公司 一种2-羟基柠檬酸复合盐及其制备方法与应用

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