WO2003088953A2

WO2003088953A2 - Multiphasic diet

Info

Publication number: WO2003088953A2
Application number: PCT/NL2003/000299
Authority: WO
Inventors: Rene John Raggers; Frederik Gerard Johan Te Hennepe
Original assignee: N.V. Nutricia
Priority date: 2002-04-19
Filing date: 2003-04-22
Publication date: 2003-10-30
Also published as: AU2003224507A1; AU2003224507A8; WO2003088953A3

Abstract

The invention relates to a method for the treatment and/or reduction of overweight, comprising the administration of active ingredients capable of reducing body weight and/or reducing adipose tissue mass. More particularly, the invention relates to such a method comprising administering to a mammal a multiphasic diet which comprises at least 3 successive phases, each phase comprising the administration of an effective amount of one or more active ingredients capable of reducing body weight and/or reducing adipose tissue mass, wherein. - In any given intermediate phase an effective amount is administered of an active ingredient which exerts its weight reducing effect through a different mechanism than any of the active ingredients which are administered in an effective amount in the phases immediately preceding and immediately following said phase; - The multiphasic diet has a total duration of at least 3 successive days; and - Each phase has duration of at least one day. The invention is also concerned with a kit for use in a method as defined above.

Description

MULTIPHASIC DIET

FIELD OF THE INVENTION

The invention relates to a method for the treatment and/or reduction of overweight, comprising the multiphasic administration of active ingredients capable of reducing body weight and/or reducing adipose tissue mass. The present invention further provides a multiphasic weight loss kit, adapted for sequential administration of active ingredients capable of reducing body weight and/or reducing adipose tissue mass.

BACKGROUND OF THE INVENTION

Obesity is very common in nowadays society. Approximately 25% to 35% of the population of the Western world is overweight. Overweight is associated with considerable morbidity and mortality. Obesity is the second preventable death cause in the US and a major risk factor for coronary heart disease, hypertension and diabetes mellitus type II. A reduction of body weight with 10% has shown to decrease the risk for coronary heart disease with 20%. Besides this, overweight and/or excess body fat is generally considered a problem, influencing social satisfaction and perception of health.

Attempts to combat overweight are currently focussed on the prolonged intake of a single drug or combination of active ingredients. However, there is accumulating evidence that prolonged intake of a single active ingredient does not provide the desired weight reduction. The currently used diets often decrease body weight for a limited period of time, followed by a period of marked decrease in efficacy of the active ingredient or drug.

Below several examples are given which illustrate that active ingredients that are currently used to combat obesity loose their efficacy after some time of administration. These examples show that the prolonged administration of active ingredients that combat obesity does not result in the desired lasting weight reducing effect Phlorizin

Treatment of animals with phlorizin (a glucose uptake inhibitor) showed a significant increase in the activity of the disaccharidase, already after 1 day of treatment. At the same time sucrase activity in the upper and central regions of the villus-crypt occurred. Studying the binding of phlorizin to isolated brush border membrane vesicles revealed that besides the increase in enzymatic activity of carbohydrate degrading enzymes, the density/expression of glucose-transporters in the membrane was higher, thereby increasing the glucose-transport potential [Minami, 1993].

Fenflur amine

The mechanism by which fenfluramine suppresses food intake and body weight increase have been linked to its ability to enhance transport of serotonin across serotonin synapses in the brain. During a period of fenfluramine administration, daily food intake was found to drop markedly in the first and second day of treatment, but had returned to pretreatment values by the fifth day. The drug was found to initially lower body weight, however after repeated administration, the body weight no longer decreased. [Choi, 2002]. Steel et al (1973) described that there is no evidence to suggest that mean weight loss can be improved by alternating fenfluramine with phentermine.

CT-II

CT-II, an extract of Nomame Herba, has been described to inhibit intestinal Iipase, thereby reducing the uptake of ingested fat. When obese rats (predisposed to gain weight) were fed with a high-fat diet and treated with CT-II for up to 6 months, body weight initially decreased and thereafter only weight gain was suppressed, indicating that the efficacy of the CT-II decreased in time [Yamamoto, 2000].

Isoproterenol

Activation of adenylyl cyclase by the beta-3 adrenergic receptor (beta-3 AR) plays a main role in adipose tissue homeostasis. The increase in cAMP promotes lipolysis in white adipose tissue; stimulates both thermogenesis and lipolysis in brown adipose tissue (BAT); and induces BAT hypertrophy. Stimulants of beta-3 AR's are often used to combat obesity.

It was found by Jockers (1998) that upon stimulation of the beta-3 AR with isoproterenol, the quantity of beta-3 AR's was down-regulated with a half-life of about 30-40 h. Long term stimulation with both saturating (micromolar) and nonsaturating (nanomolar) concentrations of isoproterenol resulted in a complete desensitization of the beta-3 AR response at the adenylyl cyclase level.

Thus, it will be clear that the prolonged successive administration of various active (weight reducing) ingredients that exert their effect through very different weight reducing mechanisms does not provide a lasting weight reduction. The administration may result in a decrease in body weight initially, but the weight reduction is followed by a period wherein the active ingredient becomes ineffective and weight gain occurs.

SUMMARY OF THE INVENTION

The present inventors have found an effective method to overcome the above disadvantageous effects, which occur after prolonged administration of weight reducing active ingredient(s). The present invention provides a multiphasic diet, which results in a lasting weight reduction during the duration of the diet. Additionally, the present diet can be used for a prolonged period of time, to prevent significant weight gain from occurring.

The present inventors believe that the mammalian body is "programmed" to gain weight. This can be explained from an evolutionary point of view. Mammals have seldom, if ever, been exposed to unlimited amounts of (high caloric) foodstuff. In fact, periods of food deprivation and starvation often occurred. From a Darwinistic point of view, mammals better adapted to survive these periods of limited food availability had improved chances of propagation. Over millions of years, mammals improved their capabilities to store energy in the form of adipose tissue and developed physiological mechanisms that prevent the loss of those tissues so as to enhance their chance of survival. The most efficient way to store energy in the body is through the generation of adipose tissue. The body has many physiological mechanisms that are highly efficient in generating adipose tissue in time of availability of vast amounts of (high caloric) foodstuff. Additionally, as exemplified above, the body has many mechanisms that prevent the loss of adipose tissue upon exogenous stimuli. Physiological mechanisms within the body will thus quickly counteract each stimulus to reduce adipose tissue mass. Hence, prolonged stimulation of a single mechanism involved in weight reduction will only initially result in a decrease of body weight and/or adipose tissue mass, because the body will initiate feedback mechanisms that counteract this effect.

The present invention provides a method for the treatment and/or prevention of overweight, which overcomes the above disadvantages that inevitably result from the prolonged administration of an active (weight reducing) ingredient. The present method comprises administering to a mammal a multiphasic diet, wherein in each phase, an effective amount of a different active ingredient capable of reducing body weight and/or adipose tissue mass is administered. The alternating administration of active ingredients, which act on different weight reducing mechanisms and a limited number of consecutive days of administration of the same active ingredients, as provided in the present method, prevents that the body develops mechanisms that counteract the action of the active ingredient. The present method is thus designed to provide the body insufficient stimuli for inducing or further developing physiological feedback mechanisms, which reduce the efficacy of the weight-reducing active ingredients.

DETAILED DESCRIPTION OF PREFFERED EMBODIMENTS Accordingly, the present invention relates to a method for the treatment or prevention of overweight, said method comprising administering to a mammal a multiphasic diet which comprises at least 3 successive phases, each phase comprising the administration of an effective amount of one or more active ingredients capable of reducing body weight and/or reducing adipose tissue mass, wherein • in any given intermediate phase an effective amount is administered of an active ingredient which exerts its weight reducing effect through a different mechanism than any of the active ingredients which are administered in an effective amount in the phases immediately preceding and immediately following said phase; • the multiphasic diet has a total duration of at least 3 successive days; and

• each phase has a duration of at least one day.

The term "active ingredient" refers to a component or composition capable of reducing bod)? weight and/or reducing adipose tissue mass. The active ingredient may suitably be a single ingredient known or suspected to reduce body weight or compositions that aid in the reduction of body weight, such as meal replacement products containing preferably less than 250 kcal per serving, more preferably less than 200 kcal/serving. The term "phase" as used in the present invention is the period wherem an effective amount of active ingredient(s) that exert(s) their weight reducing effect through the same mechanism(s) are administered. Each phase has a duration of at least one day.

The term "intermediate phase" refers to a phase that is immediately preceding and immediately following another phase.

The term "mechanism" refers to a process in the mammalian body involved in the regulation of body weight and/or adipose tissue mass, which can be influenced with an exogenously administered active ingredient(s).

The term "diet" as used in the present invention refers to a plurality of active ingredient containing compositions intended for sequential enteral or parenteral administration to a mammal.

The term "feedback mechanism" as used in the present invention refers to a reactive process in the mammalian body which develops upon influencing a mechanism with exogenously administered active ingredient(s) and that counteracts the (initial) mechanism(s) induced by the administration of these exogenous active ingredient(s). The term "unit dosage" refers to a physically discrete dosage form, containing a predetermined amount of one or more active ingredients. The term "daily unit dosage" refers to one or more unit dosages, which are to be administered within a single day to deliver a predetermined daily dosage of active ingredient(s).

Phases

In order to prevent development and/or initiation of one or more feedback mechanisms, active ingredients should be administered for a limited number of consecutive days. The duration of a phase is therefore limited. Preferably the duration of a phase does not exceed 50 days, more preferably does not exceed 30 days, more preferably does not exceed 14 days, even more preferably does not exceed 7 days, most preferably does not exceed 4 days.

The present method preferably comprises at least three, more preferably at least 4, even more preferably at least 5 phases, wherein a different unique ingredient is administered.

The results achieved with the present method generally improve with an increasing number of phases. The present method therefore preferably comprises at least 3, more preferably at least 4, even more preferably at least 5 phases, most preferably at least 10 phases. Preferably the method does not exceed 1000 phases, more preferably does not exceed 100 phases, even more preferably does not exceed 50 phases, most preferably does not exceed 25 phases.

Although not preferred in the present method, between the phases or between diet cycles, there may be a period wherein no active ingredient is administered. Preferably this period is kept to a minimum length, i.e. preferably less than 10 days, more preferably less than 5 days, even more preferably less than 2 days, most preferably 0 days. The phase preceding and following a period wherein no active ingredient is administered are considered successive phases, i.e. phases following the other phase. Active ingredients administered in a phase

During each intermediate phase of the present method, an effective amount of an active ingredient is administered, which exerts its weight reducing effect through a different mechanism than any of the active ingredients which are administered in an effective amount in the phases immediately preceding and immediately following said intermediate phase (herein referred to as "unique ingredients)"). Consequently, in the present method, each intermediate phase comprises the administration of at least one unique ingredient. Other active ingredients) capable of reducing weight maybe coadministered with the unique ingredient(s), either simultaneously or on separate occasions during the day. However, administration of an effective amount of an active ingredient for a prolonged period of time has been proven ineffective. The successive (i.e. uninterrupted) administration of an effective amount of one or more active ingredients which exert their weight reducing effects upon the same mechanism is therefore preferably limited to a maximum of 50 days, preferably 30 days, even more preferably 14 days, most preferably 7 days, with the proviso that this limitation preferably does not relate to active ingredients that reduce the intestinal absorption of dietary fat, in particular orlistat™. Orlistat™ is an inhibitor of gastro-intestinal lipase. In combination with a hypocaloric diet, orlistat has been shown to improve weight loss when compared to placebo in the first year of usage [Sjostrom, 1998]. It is the inventors believe that the body cannot quickly initiate feedback mechanisms upon administration of orlistat. Hence, a preferred embodiment of the present invention comprises the coadministration of an effective amount of an active ingredient, which reduces the intestinal absorption of dietary fats in at least 50% of the phases of the present method, preferably in at least 75% of the phases, more preferably in all of the phases.

For reasons similar to those described above, i.e. the ineffectiveness of successive administration of an effective amount of an active ingredient for a prolonged period, the administration of effective amounts of the same (or functionally similar) active ingredients is preferably separated by one or more phases. Increasing the number of days and/or phases between the administration of the same active ingredient or ingredients which exert their weight reducing effects through the same weight reducing mechanism, provides a prolonged period of absence of the stimulus that initiates or stimulates the development of a particular feedback mechanism. Lengthened absence of stimuli also causes the down-regulation of any feedback mechanisms that may have been initiated by earlier administration of active ingredients. The repeated administration of an effective amount of an active ingredient after a relatively long administration-free interval will thus exert an improved weight reducing effect compared to a situation wherein an effective amount of the active ingredient is administered continuously, or is recommenced shortly after it was stopped. The administration of an effective amount of the same active ingredient or active ingredients which exert their weight reducing effect through the same weight reducing mechanism is therefore preferably separated by at least two phases, even more preferably at least three phases. In a particularly preferred embodiment, each phase consists of the administration of a single unique ingredient. Furthermore, a period of successive administration of an effective amount of a particular active ingredient and a latter period of administration of an effective amount of the same active ingredient, or active ingredient which exerts its weight reducing effect through the same weight reducing mechanism, is preferably separated by a period of at least 4 day, more preferably by a period of at least 6 days, even more preferably by a period of at least 10 days.

Increasing the number of unique ingredients generally enhances the long term efficacy of the present method. The number of unique ingredients administered in the present method thus preferably exceeds 3, more preferably exceeds 4, even more preferably exceeds 5, most preferably exceeds 6. Preferably the amount of unique ingredients administered in the present method does not exceed 1000, more preferably does not exceed 100, even more preferably does not exceed 50, most preferably does not exceed

10.

In a preferred embodiment, the present method comprises the repeated administration of the same unique sequence of phases, i.e. the same active ingredients are re-administered in the same sequence with the same duration of the phases. The combination of phases which together forms an unique sequence of phases within an administration regimen is hereinafter referred to as "diet cycle".

The complexity and costs for a multiphasic diet may be minimised by employing a multiphasic diet that comprises a plurality of diet cycles. The present method therefore preferably comprises at least two diet cycles, more preferably at least three diet cycles, even more preferably at least 4 diet cycles, most preferably a least 5 diet cycles. A diet cycle has a preferred duration of at least 3 days, more preferably at least 5 days, even more preferably at least 7, most preferably at least 15 days. The duration of a diet cycle preferably does not exceed 100 days, more preferably does not exceed 50 day, even more preferably does not exceed 35 days, most preferably does not exceed 20 days. Table 1 gives the most preferred duration of a diet cycle in the present method as a function of the number of unique ingredients employed within the diet. Although the inventors believe that the number of unique ingredients administered in the present method is not bound to a limit, for practical reasons the number of unique ingredients is preferably below 50, more preferably below 10.

TABEL 1

Coadministration of active ingredients

During each phase two or more active ingredients may be administered. However, the number of different active ingredients, administered within a single phase, that exert their weight reducing effects on a different mechanism is preferably limited, because it can reduce the efficacy of the present method. Preferably, the number of active ingredients, administered within the same phase, that exert an effect on different mechanisms, is below 5, more preferably below 4, even more preferably below 3. Duration of multiphasic diet

The multiphasic diet has a duration of at least 3 successive days, however, in order to achieve a considerable reduction of overweight, e.g. a considerable reduction in adipose tissue mass, the present method should have a duration of at least 7 successive day, preferably at least 10 successive days, more preferably at least 14 successive days, most preferably at least 30 successive days. . It is the inventors belief that the diet can be taken as long as weight reduction or prevention of body weight increase is desired.

Mechanisms of weight reduction An effective amount of an active ingredient used in the present method is capable of reducing bodyweight and/or reducing adipose tissue mass by exerting an effect on at least one mechanism. The mechanism may be stimulated or inhibited, depending on the specific mechanism. The exogenously administered active ingredient preferably inhibits or stimulates a weight reducing mechanism through one or more of: a) changing the (local) in vivo availability of precursors of biologically active molecules involved in the mechanism outside the gastrointestinal tract (e.g. by administering precursors of biologically active molecules) b) stimulation or inhibition of the in vivo release and/or availability of biological active molecules involved in the mechanism; c) metabolizing biological active molecules involved in the mechanism d) influencing the expression, sensitivity or activity of biologically active molecules involved in the mechanism (e.g. agonistic or antagonistic stimulation of receptors).

According to a particularly preferred embodiment of the present invention, a. multiphasic diet or a diet cycle comprises the administration of at least 2, preferably at least 3, even more preferably at least 4, unique active ingredients, which exert their weight reducing effects (either direct or indirect) through at least one mechanism selected from:

a. inhibition of intestinal glucose absorption, e.g. inhibiting the action of intestinal glucose transporters b. stimulation of the intestinal formation of complex carbohydrates from glucose (e.g. fructose or sparingly digestible di-, tri-, or polysaccharides). c. inhibition of intestinal amylase activity d. inhibition of intestinal glycosidase activity e. inhibition of intestinal disaccharidase activity f. inhibition of intestinal lipase activity g. inhibition of intestinal fatty acids and (monoacyl)glycerol absorption (e.g. inhibiting the action of intestinal fatty acids and (monoaeyl)glycerol transporters) h. stimulation of the formation of sparingly digestible or unabsorbable intestinal complexes containing one or more of fatty acids, (monoacyl) glycerol and triglycerides. i. agonistic stimulation of gastric mechano-receptors (e.g. through inhibition of gastric emptying) j. agonistic stimulation of a beta adrenergic receptor (beta AR) and/or stimulation of beta AR expression, preferably the beta-3 adrenergic receptor k. reduction of alpha-adrenergic receptor (alpha- AR) stimulation or inhibition of alpha-

AR expression 1. stimulation of intracellular adenylate cyclase activity m. inhibition of intracellular phosphodiesterase activity n. stimulation of intracellular cAMP concentration increase via a mechanism different from those mechanisms described under j. to m.) o. reduction of intracellular calcium concentrations in adipocytes p. stimulation of the activity of hormone sensitive lipase (HSL), e.g. by stimulation translocation of HSL to the intracellular environment of the adipocyte q. inhibiting the activity of catechol-O-methyl transferase r. stimulation of lipolysis via a mechanism other than those described above under j-q s. inhibition of intracellular citrate lyase (e.g. ATP citrate lyase) t. stimulation of serotonin levels in nerve tissue, e.g. by inhibiting serotonin re-uptake or administering a precursor of serotonin. u. agonistic stimulation of dopamine receptor and/or stimulation of the expression of dopamine receptors v. increase leptin concentration, agonistic stimulation of the leptin receptors and/or stimulation of the expression of leptin receptors w. increase cholecystokinin (CCK) concentrations, agonistic stimulation of the CCK receptors and/or stimulation of the expression of CCK receptors x. reduction of ghrelin concentration, antagonistic stimulation of ghrelin receptors and/or inhibition of the expression of the ghrelin receptor

y. inhibition of appetite via a mechanism other than those described above under s-y z. stimulation of the activity or expression of (mitochondrial) uncoupling proteins aa. inhibition or prevention of the formation of in vivo energy carriers (e.g. ATP) from mitochondrial oxidation processes (e.g.mitochondrial uncoupling) bb. increasing insulin sensitivity cc. antagonistic stimulation, decreasing the sensitivity and/or inhibition of the expression of the adinosine receptor dd. increase thyroid hormone levels and/or ratios, agonistic stimulation of the thyroid hormone receptor and/or stimulation of the thyroid hormone receptor expression ee. antagonistic stimulation, decreasing the sensitivity and/or inhibition of the expression of the cannaboid receptors ff. stimulation of increase in growth hormone levels gg. stimulation of the increase of gamma-aminobutyric acid (GAB A) concentrations, preferably in the brain, hh. stimulation of adrenaline release from nerve tissue ( e.g. calcium antagonists)

According to a particularly preferred embodiment the present method comprises the administration of at least 2, preferably at least 3, even more preferably at least 4, unique active ingredients, which exert their weight reducing effects through at least one mechanism selected from the group consisting of a,b,c,d,e,f,g,j,l,m,o,s and y as described above. Table 2 gives examples of active ingredients and their mechanisms through which they exert (at least part) of their weight reducing effect

TABLE 2

above under s-y stimulation of adrenaline release from nerve tissue benidipine inhibition or prevention of the formation of in vivo energy carriers (e.g. curcumin

ATP) from mitochondrial oxidation processes (e.g.uncoupling) increasing insulin sensitivity chromium antagonistic stimulation, decreasing the sensitivity and/or inhibition of caffeine the expression of the adinosine receptor increase thyroid hormone levels and/or ratios, agonistic stimulation of phosphates the thyroid hormone receptor and/or stimulation of the thyroid hormone receptor expression antagonistic stimulation, decreasing the sensitivity and/or inhibition of SR141716A (Di Marzo, 2000) the expression of the cannaboid receptors stimulation of increase in growth hormone levels 1-DOPA stimulation of the increase of gamma-aminobutyric acid (GABA) topimarate concentrations, preferably in the brain. stimulation of the activity or expression of (mitochondrial) uncoupling phytanic acid proteins, delaying gastric emptying

Administration

The effective amount(s) of active ingredient(s) administered during a particular phase are preferably administered in the form of a daily unit dosage. A daily unit dosage may comprise one or more unit dosages, which may be administered simultaneously or on separate occasions during the day. To prevent complexity of the administration regime, the amount of unit dosages forming a daily unit dosage is preferably below 4. More preferably, a daily dosage consists of a single unit dosage. The unit dosages are preferably administered within the period between 60 minutes before and 60 minutes after a meal. The unique ingredients are preferably administered enterally, even more preferably orally.

Overweight

The present method can be used in the prophylactic and/or curative treatment of overweight. The term overweight as used in the present invention refers to a bodyweight and/or an adipose tissue mass that is above the desired bodyweight and or desired adipose tissue mass. The present method can thus suitably be used to reduce or prevent an increase in adipose tissue mass, e.g. a method for increasing lean body mass. The present method can both be used to treat or prevent overweight in a medical sense and/or for the cosmetic treatment or prevention of overweight. Preferably the present method is used to prevent or treat overweight in pets, farm animals or humans. The method is particularly suitably for humans. In the present method, the active ingredients are preferably administered in the form of unit dosages, which contain at least a pharmaceutically acceptable excipient. The unit dosages can be suitably provided in the form of nutritional supplements and/or pharmaceuticals.

Article of manufacture

The present invention also provides an article of manufacture comprising a packaging with two or more different series of daily dosages, in which said article bears a label indicating that the series should be administered sequentially to a subject desiring to lose weight.

The term "series of daily dosages" refers to one or more daily dosages that contain the same active ingredient(s). Preferably a series of daily dosages comprises at least 2, more preferably at least 3, even more preferably at least 5, most preferably at least 7, especially at least 10 daily dosages. Preferably a series of daily dosages contains less than 100 daily dosages, more preferably less than 50 daily dosages, even more preferably less than 25 daily dosages.

Preferably the article contains at least 10, more preferably at least 25, even more preferably at least 40, most preferably at least 50 daily dosages. The article preferably contains less than 1000, more preferably less than 100 daily dosages.

The article contains at least two, more preferably at least 3, even more preferably at least 4, most preferably at least 5, especially at least 6 different series of daily dosages. Although not prerequisite to the present article, the series of daily dosages are preferably separately identifiable, e.g. by means of accompanying instructions or by physical separation. Alternatively the series of daily dosages may be visually distinct from each other. Kit adapted for sequential administration

The present invention also provides a multiphasic weight loss kit, adapted for sequential oral administration of series of daily unit dosages, which comprises at least three daily unit dosages, each comprising an effective daily dosage of at least one active ingredient capable of reducing body weight, wherein the kit comprises at least 2 different series of daify unit dosages, each series containing an effective daily dosage of an active ingredient which exerts its effect via a different weight reducing mechanism than an active ingredient contained in an effective daily dosage in at least one of the other series, and wherein the series are intended for administration in an alternating fashion, wherein administration of one or more daily unit dosages of one series is followed by administration of one or more daily unit dosages of another series and so forth.

Preferably, in the multiphase weight loss kit, the sequence of intended administration of the series of daily dosage units is predetermined. More preferably, the unit dosages are arranged within the kit in a sequential manner so as to facilitate administration in accordance with the desired regimen. Each intermediate series preferably consists of one or more daily dosage units that contain an effective daily dosage of an active ingredient which exerts its effect via a different weight reducing mechanism than any active ingredient contained in an effective daily dosage in a series immediately preceding and immediately following said intermediate series. The present multiphasic weight loss kit is preferably adapted for carrying out the above described method.

Additionally the kit preferably comprises at least 3, more preferably at least 7, even more preferably at least 14 daily unit dosages, which each comprise at least an effective amount of an active ingredient capable of reducing body weight. For practical purposes, the number of daily dosages of the kit may be limited to 100, preferably to 30. The kit contains at least 2, preferably at least 3, even more preferably at least 5 different series of daily unit dosages, wherein each series of daily unit dosage contains an effective amount of an active ingredient, which exerts its effect via a different weight reducing mechanism than an active ingredient contained in the series immediately preceding and immediately following said intermediate series, preferably via a different weight reducing mechanism than any of the other series. According to a preferred embodiment the kit contains at least 3, more preferably at least 4, even more preferably at least 5 series of daily dosage units.

Each series of daily dosage unit may contain a single active ingredient or a combination of active ingredients. However, the number of different active ingredients that exert their weight reducing effects on a different mechanisms in one type of daily unit dosage is preferably limited, because it may reduce the length of effective use of the present kit. Preferably the amount of different active ingredients that exert their weight reducing effects on a different mechanisms in one type of daily unit dosage is below 5, more preferably below 4, even more preferably below 3.

The present multiphasic weight loss kit can be suitably used in the present method for the treatment of overweight. In fact, the multiphasic weight loss kit may be adapted for an administration regimen of any preferred embodiment of the present method as described above. It will be clear from the context of the description of the present method, which preferred embodiments of the multiphasic weight loss kit are described. For this purpose, for example, wherever the term "phase" is used to describe the present method, replacement of this term by the term "series" generally provides the description of preferred embodiments of the multiserial weight loss kit. Although the form of the kit may be adapted for sequential administration in any form, preferred forms include:

- A means for dispensing individual dosages, which releases a single unit dosage per action, wherein the sequence of release of the unit dosages is predetermined. Said means is preferably accompanied by an indication of the recommended frequency of intake of the unit dosage (e.g. a tube like tablet dispenser) - A blister card (or push-through packaging) provided with an indication of the sequence of administration of the unit dosages (e.g. date indications or other sorts of indications which denote the sequence in which the unit dosages should be taken).

Suitable blister cards are for example described in EP0391459, which is herein incorporated by reference. In the present blister card, each unit dosage is preferably sealed is a separate compartment. Container(s) containing unit dosages, wherein the unit dosages and or containers are provided with a marking (e.g. color or number), which enables the recognition of a particular unit dosage or group of unit dosages, accompanied with instruction to ingest a particular unit dosage or one or more of a group of unit dosages in a particular frequency and/or in a particular order.

LITERATURE

Minami H, Kim JR, Tada K, et al. Inhibition of glucose absorption by phlorizin affects intestinal functions in rats. Gastroenterology 1993; 105:692-7.

Choi S, Jonak EM, Simpson L, Patil V, Fernstrom JD. Intermittent, chronic fenfluramine administration to rats repeatedly suppresses food intake despite substantial brain serotonin reductions. Brain Res 2002; 928:30-9.

Yamamoto M, Shimura S, Itoh Y, Ohsaka T, Egawa M, Inoue S. Anti-obesity effects of lipase inhibitor CT-II, an extract from edible herbs, Nomame Herba, on rats fed a high-fat diet. Int J Obes Relat Metab Disord 2000; 24:758-64. Jockers R, Issad T, Zilberfarb V, de Coppet P, Marullo S, Strosberg AD. Desensitization of the beta-adrenergic response in human brown adipocytes. Endocrinology 1998; 139:2676-84.

Steel JM, Munro JF, Duncan LJP. A cornparitive trial of different regimens of fenfluramine and phentermine in obesity. Practitioner 1973; 211: 232-236

Sjostrom, L., A. Rissanen, et al. (1998). "Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group." Lancet 352(9123): 167-72.

Dickinson, K., T. J. North, et al. (2001). "Determination of body composition in conscious adult female Wistar utilising total body electrical conductivity." Physiol Behav 74(4-5): 425-33. EXAMPLES

Example 1:

A multiphasic weight loss diet cycle which has a duration of 7 days wherein the active ingredients are orally administered according to the scheme given in Table 4.

TABLE 4

Example 2: A multiphasic weight loss diet cycle which has a duration of 30 days wherein the active ingredients are orally administered according to the scheme given in Table 5.

TABLE 5

Example 3:

A multiphasic weight loss diet cycle which has a duration of 30 days wherein the active ingredients are administered according to the scheme given in Table 5, and on each day of the multiphasic diet 360 mg Orlistat (120 milligrams (mg) three times a day with meals) is coadministered.

Example 4

A packaged weight loss product comprising the following daily dosages: series A. 20 daily dosages containing 50 mg benzphetamine (Didrex™) series B. 20 daily dosages containing 100 mg caffeine series C. 20 daily dosages of Tunuate™

The weight loss product contains instructions to ingest the daily dosages in the following order (in 6 phases and two diet-cycles): day 1-10: 10 daily dosages series A day 11-20 10 daily dosages series B day 21-30 10 daily dosages series C day 31-40 10 daily dosages series A day 41-50; 10 daily dosages series B day 51-60 10 daily dosages series C

Example 5 A weight loss product comprising the following daily dosages for oral ingestion: series A. 20 daily dosages containing 50 mg benzphetamine (Didrex™) series B. 20 daily dosages containing 100 mg caffeine series C. 20 daily dosages of Tunuate™ series D. 5 reconstitutable meal replacement powders (Slimfast™ Powder Shake) The weight loss product contains instruction to ingest the daily dosages in the following order: day 1-10: 10 daily dosages series A day 11: 1 daily dosage series D day 12-21: 10 daily dosages series B day 22: 1 daily dosage series D day 23-32: 10 daily dosages series C day 33: 1 daily dosage series D day 34-43: 10 daily dosages series A day 44: 1 daily dosage series D day 45-54: 10 daily dosages series B day 55: 1 daily dosage series D day 56-65: 10 daily dosages series C

Example 6:

A packaged weight loss product comprising the following daily dosages: series A: 20 patches of "Curb your cravings™ weight loss patches (Curb Your

Cravings™, Bellmore) series B: 20 daily dosages of Dermalin-Apg™, a transdermal gel formulation series C: 20 daily dosages of Total Lean™ (GNC)

The weight loss product contains instruction to apply the daily dosages in the following order: day 1-10: topically apply 10 daily dosages series A day 11-20: topically apply 10 daily dosages series B and 10 daily dosages of series C day 21-30: topically apply 10 daily dosages series A and ingest 10 daily dosages series C day 31-40: topically apply 10 daily dosages series B Example 7: Multiphasic program in rats

20 male Wistar rats (age 10 weeks at the start of the experiments) were housed individually in a temperature controlled room (± 21 °C) with lights on from 8 am to 8 pm. Animals had free access to water throughout the study and received ad lib food during the first part of the study. Food intake was monitored and/or controlled throughout the study. At arrival, animals were housed individually and fed a semisynthetic high fat (HF) diet for a run-in period of 2.5 weeks (35 energy % fat, 52 energy % carbohydrate, 13 energy % protein). On day 0, the animals were divided into 2 groups of 10 animals. Each group had comparable average + s.e.m. body weight.

Group A received the HF-diet without additions (control).. Group B received a cyclic diet pattern (multiphasic). Each cycle consisted of 3 phases of 4 days each. During phase 1 of each cycle, the rats received HF-diet with Fenfluramine™ (150 mg/kg HF-diet); during phase 2, the rats received HF-diet with Ephedrine (600 mg/kg HF-diet); and during phase 3, the rats received HF-diet with Orlistat™ (250 mg/kg HF-diet). The multiphasic treatment consisted of 4 cycles.

The concentrations of active ingredients in the HF-diet were aimed to result in 7.5 mg Fenfluramine™ per kg body weight per day, 30 mg Ephedrine per kg body weight per day and 5 mg Orilistat™ per animal per day. Fenfluramine™ is a serotonin-reuptake inhibitor resulting in reduced food intake. Ephedrine is a compound which increases energy expenditure, and Orlistat (Xenical ®) is a lipase inhibitor resulting in reduced intestinal fat absorption.

During the experiment the body weight and food intake were determined every 4 days. Body Fat percentage was determined at regular intervals using Total Body Electrical Conductivity (TOBEC, EM-Scan SA 3000, BioTech, Engeland) according to the method decribed by Dickinson et al. (2001).

After two cycles (i.e. 24 days), an adjustment in the experiment was made, based on interim results. Animals in the multiphasic diet-group appeared to overeat during the phase when orlistat was administered. This does not reflect the situation in Orlistat™-treated humans. Therefore, the food availability for the rats on the multiphasic diet in the phase in which Orlistat™¹ was administered, was restricted to the level of the control animals.

Figure 1 depicts the body weight of rats that received either control diet or the multiphasic diet. Figure 1 shows that the multiphasic diet causes a significantly and prolonged reduced body weight increase compared to control. These results are indicative for the body weight reducing properties of the present multiphasic diet and method.

Figure 2 depicts the percentage body fat of rats that received either control diet or the multiphasic diet. Figure 2 shows that the multiphasic diet causes a significantly reduced body fat increase compared to control. These results are indicative for the advantageous body fat reduction achieved by the present method.

Figure 3 depicts the food intake of rats that received either control diet or the multiphasic diet. The recurring significant reduction of food intake by the rats receiving the multiphasic diet during the phases wherein fenfluramine was administered shows that the multiphasic diet effectively prevents the development of tolerance to fenfluramine™.

Claims

1. A cosmetic method for the treatment or prevention of overweight, said method comprising administering to a mammal a multiphasic diet which comprises at least 3 successive phases, each phase comprising the administration of an effective amount of one or more active ingredients capable of reducing body weight and/or reducing adipose tissue mass, wherein in any given intermediate phase an effective amount is administered of an active ingredient which exerts its weight reducing effect through a different mechanism than any of the active ingredients which are administered in an effective amount in the phases immediately preceding and immediately following said phase; the multiphasic diet has a total duration of at least 3 successive days; and each phase has a duration of at least one day.

2. Use of active ingredients capable of reducing body weight and/or reducing adipose tissue mass for the preparation of a multiphasic diet for use in a method for the treatment and/or prevention of overweight, the method comprising administering to a mammal said multiphasic diet, which comprises at least 3 successive phases, each phase comprising the administration of an effective amount of one or more active ingredients capable of reducing body weight and/or reducing adipose tissue mass, wherein in any given intermediate phase an effective amount is administered of an active ingredient which exerts it weight reducing effect through a different mechanism than any of the active ingredients which are administered in an effective amount in the phases immediately preceding and immediately following said phase; - the multiphasic diet has a total duration of at least 3 successive days; and each phase has a duration of at least one day.

3. Use according to claim 1 or 2, wherein each phase has a duration of 1 to 14 days.

4. Use according to any one of the preceding claims, wherein the time interval between each of the phases is less than 2 days.

5. Use according to any one of the preceding claims, wherein successive phases do not comprise the administration of an effective amount of active ingredients that exert their effect through the same weight reducing mechanism.

6. Use according to any one of the preceding claims, wherein the different mechanisms include at least 2 of: inhibition of intestinal glucose absorption stimulation of the intestinal formation of complex carbohydrates from glucose inhibition of intestinal amylase activity • inhibition of intestinal glycosidase activity inhibition of intestinal disaccharidase activity inhibition of intestinal lipase activity inhibition of intestinal fatty acids and (monoacyl)glycerol absorption stimulation of the formation of sparingly digestible or unabsorbable intestinal complexes containing one or more of fatty acids, (monoacyl)glycerol and triglycerides.

• inhibition of gastric emptying

• agonistic stimulation of a beta adrenergic receptor (beta AR) and/or stimulation of beta AR expression, preferably the beta-3 adrenergic receptor • reduction of alpha-adrenergic receptor (alpha- AR) stimulation or inhibition of alpha- AR expression

• stimulation of intracellular adenylate cyclase activity

• inhibition of intracellular phosphodiesterase activity

• stimulation of intracellular cAMP concentration increase via a mechanism different from those mechanisms described under j . to m.

• reduction of adipocyte intracellular calcium concentrations • stimulation of the activity of hormone sensitive lipase (HSL)

• inhibiting the activity of catechol-O-methyl transferase

• stimulation of lipolysis via a mechanism other than those described above under j toq

• inhibition of intracellular citrate lyase • stimulation of serotonin levels in synaptic fluid in the brain, e.g. by inhibiting serotonin re-uptake or administering a precursor of serotonin.

• agonistic stimulation of dopamine receptor and/or stimulation of the expression of dopamine receptors

• increase leptin concentration, agonistic stimulation of the leptin receptors and/or stimulation of the expression of leptin receptors

• increase cholecystokinin (CCK) concentrations, agonistic stimulation of the CCK receptors and/or stimulation of the expression of CCK receptors

• reduction of ghrelin concentration, antagonistic stimulation of ghrelin receptors and/or inhibition of the expression of the ghrelin receptor • inhibition of appetite via a mechanism other than those described above under s-y

• stimulation of the activity or expression of (mitochondrial) uncoupling proteins

• inhibition or prevention of the formation of in vivo energy carriers (e.g. ATP) from mitochondrial oxidation processes

• increasing insulin sensitivity • antagonistic stimulation, decreasing the sensitivity and or inhibition of the expression of the adinosine receptor

• increase thyroid hormone levels and/or ratios, agonistic stimulation of the thyroid hormone receptor and/or stimulation of the thyroid hormone receptor expression

• antagonistic stimulation, decreasing the sensitivity and/or inhibition of the expression of the cannaboid receptors

• stimulation of increase in growth hormone levels

• stimulation of the increase of gamma-aminobutyric acid (GAB A) concentrations, preferably in the brain.

7. Use according to any one of the preceding claims, wherein the multiphasic diet is administered for a duration of at least 7 successive days, preferably at least 14 successive days.

8. Use according to any one of the preceding claims, wherein on each day during the multiphasic diet at least one unit dosage is administered.

9. Use according to any one of the preceding claims, wherein the multiphasic diet comprises at least 5 successive phases.

10. A multiphasic weight loss kit, adapted for sequential oral administration of series of daily unit dosages, which comprises at least three daily unit dosages, each comprising an effective daily dosage of at least one active ingredient capable of reducing body weight, wherein the kit comprises at least 2 different series of daily unit dosages, each series consists of one or more daily unit dosages that contain an effective daily dosage of an active ingredient which exerts its effect via a different weight reducing mechanism than an active ingredient contained in an effective daily dosage in at least one of the other series, and wherein the series are intended for administration in an alternating fashion, wherein administration of one or more daily unit dosages of one series is followed by administration of one or more daily unit dosages of another series and so forth.

11. Multiphasic weight loss kit according to claim 10, wherein the sequence of intended administration of the series of daily dosage units is predetermined.

12. Multiphasic weight loss kit according to claim 11, wherein each intermediate series contains an effective daily dosage of an active ingredient which exerts its effect via a different weight reducing mechanism than any active ingredient contained in an effective daily dosage in a series immediately preceding and immediately following said intermediate series.

13. A multiphasic weight loss kit according to claims 10-12, wherein the unit dosages are arranged within the kit in a sequential manner so as to facilitate administration in accordance with the desired regimen.

14. A multiphasic weight loss kit according to claims 10-13, adapted for carrying out the method according to any of claims 1-9.

15. An article of manufacture comprising a packaging with two or more different series of daily dosages containing one or more active ingredients capable of reducing bod]/ weight and/or reducing adipose tissue mass, in which said article bears a label indicating that the series should be administered sequentially to a subject desiring to lose weight.