WO2003009840A1

WO2003009840A1 - Composition comprising at least one lipase inhibitor and carnitine

Info

Publication number: WO2003009840A1
Application number: PCT/EP2002/007812
Authority: WO
Inventors: Andrea Schaffhauser; Elmar Zurbriggen; Paula Gaynor
Original assignee: Lonza Ag
Priority date: 2001-07-24
Filing date: 2002-07-13
Publication date: 2003-02-06

Abstract

Composition comprising at least one lipase inhibitor and Carnitine or an Acyl-carnitine or a salt thereof and a method of enhancing the absorption of lipophilic vitamins, particularly Vitamine E, during therapeutic or prophylactic treatment of a person with a lipase inhibitor by administering Carnitine.

Description

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.

The intact, undigested triglycerides thus remain in the gut and are excreted. Dietary fat content is the most common reason for obesiety in industrialized countries and may account for typical civilisatory diseases such as cardiovascular disease, diabetes mellitus or even certain types of cancer (Bray, G.A., Health hazards of obesity, Endocrinol. Metab. Clin. North Am., (1996) 25:

655-660).

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. However, 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. It is the same effect that accounts for beneficial decrease of serum cholesterol and the adverse event of reduced vitamin-intake. The unwanted side-effect of phrophylactic or therapeutic treatment with Orlistat, particularly over extended periods of time, is the reduced capacity of the body to obtain essential lipophilic vitamins such as Vitamin D and E from the normal, ingested diet (M. Davidson et al., Weight control and risk factor reduction in obese subjects treated for 2 years with Orlistat, JAMA, 281, 235-243). Equally, the effectiveness of orally ingested vitamine supplements comprising such vitamins is decreased thereupon. Other routes of administration, e.g. by means of injection, are costly and discomfortable as a routine measure.

It is an object of the present invention to overcome this disadvantage of lipase inhibitor treatment of a person and to enhance the absorption rate of lipophilic vitamins. It is a another object of the present invention to further enhance loss of body fat upon orlistat treatment of a person.

This object is solved by a composition according to claim 1. The composition comprises Carnitine or an Acyl-Carnitine or a salt thereof and a lipase inhibitor. Under 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.

Preferably, 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. Optional, it is named (-)-Tetrahydrolipstatin as 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 C₂9H₅₃N0₅. It is highly lipophilic, having a solubility in water at 23°C of < lmg/lOOml. Die Herstellung dieser Substanz ist im Stand der Technik beschrieben.

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. L-Carnitine-magnesium- citrate, L-Carnitine-magnesium-hydroxycitrate or L-Carnitine-cholin-tartrate. hi even more preferred embodiments, 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). 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.

Surprisingly, upon concomitant treatment with a lipase inhibitor such as e.g. Orlistat, such a composition enhances the intestinal absorption rate of lipophilic Vitamins such as Vitamin E (alpha-Tocopherol), Vitamin D (Calcitriol and/or Cholecalciferol), Vitamin K (Menachinon and/or Menadion), Vitamin Q10 (Ubichinon), Provitamin A (Carotenoids) or Vitamin A (Retinol, Retinal, Retinoic acid and/or 3-Dehydroretinol) from the ingested diet. The absoφtion rate is understood in this context as the absoφtion of a lipophilic Vitamine, preferably of Vitamine E, from the lumen of the the intestine. Due to enhanced absoφtion, 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. hi rats, absoφtion may be directly measured by lymph duct cannulation of the mesenteric lymph duct and collection of labelled vitamine compounds that have been infused into the gastrointestinal system. Vitamine E content from a suitably prepared sample may be determined e.g. by the method of

Zaspel et al. (Anal. Biochem. 130: 146-150; 1983). Such an effect of Carnitine, that is known to function as a transporter molecule for long-chain acyl rests in the mitochondrial membrane, is new. In particular 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 suφrising.

Preferably, 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. According to the present invention, 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. For example, 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. Preferably, it amounts to between 250 to 450 mg for the puφose of enhancing the absoφtion of Vitamins. A vitamine absoφtion increasing effective amount is an amount of Carnitine, preferably L-Carnitine, which increases the intestinal absoφtion of the lipophilic vitamines, such as Vitamines D, A and in particular Vitamine E.

However, if a concomitant and pronounced slimming effect of carnitine is to be achieved as well, 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.

The composition according to the present Invention may be added to foodstuff, i.e. the diet, or swallowed as a freshly prepared suspension. For example, 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. Preferably, the composition is prepared as an oral dosage form and may comprises further, pharmaceutically acceptable exciepients.

Such 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 absoφtion 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. In another preferred embodiment, 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. Complex organic molecules such as lipase inhibitors, in particular lipstatin, are susceptible in varying degrees to acid hydrolysis. Such enteric coated compositions are described by Bauer et al.

(Coated Pharmaceutical Dosage Forms: Fundamentals, Manufacturing Techniques,

Biopharmaceutical Aspects, Test Methods and Raw Materials, CRC Press, Washington, D.C.,

1998) .

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.

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.

In another preferred embodiment, 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. In a more preferred embodiment, 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-

1596 (1998), Motoyama et al., vitamin E administration improves impairment of endothelium- dependent vasodilation in patients with coronary spasmic angina, J. Am. Coll. Cardiol. 32: 1672-

1679 (1998)). Upon treatment of a person with a lipase inhibitor, only concomitant administration of carnitine ensures efficient use, i.e. intestinal absoφtion, of supplementary

Vitamin E .

It is a further object of the present invention to provide a method to enhance the absoφtion of lipophilic Vitamins, in particular of Vitamin E, during prophylactic or therapeutic treatment of a person with a lipase inhibitor, in particular with orlistat, by administration of Carnitine as essentially described in the preceding sections. It is possible to achieve this puφose not only by ingesting compositions combining carnitine and a lipase inhibitor as described above, but as well by injecting pharmaceutical preparations of carnitine concomitant with oral ingestion of said lipase inhibitor or by ingesting stepwise separately prepared formulations of carnitine and said lipase inhibitor, respectively. It is also possible to saturate the body's need for carnitine once a day by a certain dose of carnitine, effective amounts being described above, whilst ingesting e.g. orlistat repeatedly concomitant with the ingestion of diet. This means shortly before, during or after meals. However, it is equally possible to employ retard-capsules or -tablets which continously release the lipase inhibitor over a prolonged period of time, thus abolishing the need of timing the ingestion of the lipase inhibitors with the meals.

It is also possible to prepare dosage forms combining , according to the present invention, a lipase inhibitor and Carnitine whilst not bringing them physically in admixture. 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. In such a double-walled capsule, 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. Even more generally, a produce 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 is an object of the present invention. Such items a generally termed kits-of-parts and may e.g. consist of separate blister bags comprised in a single package.

It is possible to provide a kit 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 puφose of either solely alleviating Vitamine deficiency or additionally enhancing slimming. Suitable doses and dosage forms have been described in the preceding sections.

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. It has been found that, for reasons unknown, the replenishing effect of carnitine on absoφtion of lipophilic vitamins such as Vitamine E is more pronounced and thus the co-treatment with carnitine and a lipase inhibitor is even more effective in case of this group of humans with regard to the absoφtion of Vitamin E.

It is another object of the present invention to provide a method for enhancing the loss of body fat by use of carnitine during treatment with orlistat. The above given details for working the invention apply hereto as well. However, as already said above, 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. Suφrisingly, 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. Example 1

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 μm. 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:

L-Carnitine (Carnitine-Mg-Citrate, Lonza Ltd.) 300 mg

Orlistat 40 mg

Sodium-stearate 1.5 mg microcrystalline cellulose 20

Vitamine E 2 mg Lactose 37 mg

Talcum 4.5 mg

Sodium-Carboxymethyl-starch 8.5 mg

Polyvinylpolypyrrolidon 8.5 mg

Acarbose 25.0 mg

Example 2

Use of Carnitine to alleviate the vitamine deplenishing effect of orlistat treatment

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

Use of Carnitine to enhance slimming and alleviate the vitamine deplenishing effect

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 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.

Claims

1. Composition comprising at least one lipase inhibitor and carnitine or an Acyl-carnitine or a salt thereof.

2. Composition according to claim 1, characterised in that the composition further comprises a pharmaceutically acceptable excipient .

3. Composition according to one of the preceding claims, characterised in that the lipase inhibitor is orlistat.

4. Composition according to one of the preceding claims, characterised in that the ratio of Carnitine:lipase inhibitor is 10 to 8000 mg L-Carnitine per 100 mg of lipase inhibitor.

5. Composition according to one of the preceding claims, characterised in that the composition further comprises a supplementary amount of at least a lipophilic vitamine.

6. Composition according to one of the preceding claims, characterised in that the lipophilic vitamine is Vitamine E.

7. Produce 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.

8. Oral dosage form comprising a composition according to claim 1.

9. Dosage form according to claim 8, characterised in that it is a tablet or a capsule.

10. Use of carnitine for manufacturing a medicine for enhancing the absoφtion of at least one lipophilic vitamine during therapeutic or prophylactic treatment of a person with a lipase inhibitor.

11. Use of carnitine for manufacturing a medicine for enhancing loss of body fat during treatment with Orlistat b administering carnitine at least in a dose of 0.5 g per day to a human. carnitine-(-)-hydroxycitrate or Calcium-carnitine-(-)-hydroxycitrate.

13. Method for enhancing the absoφtion of at least one lipophilic vitamine during therapeutic or prophylactic treatment of a person with a lipase inhibitor which comprises orally administering Carnitine.

14. Method for enhancing loss of body fat during treatment with Orlistat which comprises administering carnitine at least in a dose of at least 0.5 g per day to a human.