WO2013092786A1

WO2013092786A1 - Compositions comprising cetilistat

Info

Publication number: WO2013092786A1
Application number: PCT/EP2012/076265
Authority: WO
Inventors: John Robert BLOOR; Christopher Robert Dunk; Richard Michael John Palmer
Original assignee: Norgine B.V.
Priority date: 2011-12-23
Filing date: 2012-12-20
Publication date: 2013-06-27

Abstract

The present invention relates to compositions comprising cetilistat, including its salts, esters, amides, solvates, polymorphs, and mixtures thereof. The invention also relates to formulations comprising such compositions, to processes for preparation of the compositions and formulations, and to their methods of use for weight management, including weight loss.

Description

COMPOSITIONS COMPRISING CETILISTAT

The present invention relates to compositions comprising cetilistat, including its salts, esters, amides, solvates, polymorphs, and mixtures thereof. The invention also relates to

formulations comprising such compositions, to processes for preparation of the compositions and formulations, and to their methods of use.

Cetilistat is an inhibitor of gastrointestinal (GI) and pancreatic lipases. The compound (also known as ATL-962) has the molecular formula C25H39NO3. Cetilistat has a chemical name 2- (hexadecyloxy)-6-methyl-4H-3,l-benzoxazin-4-one, and is structurally represented by the compound of Formula I:

(I)

European patent publication number EP1143977 describes cetilistat and processes for its manufacture (referred to therein as Compound 18 or 2-hexadecyloxy-6-methyl-4H-3,l- benzoxazin-4-one), as well as salts, esters and amides thereof. The content of European patent publication number EP1143977 is incorporated herein by reference.

European patent publication number EP1897558 describes various specific coated and uncoated tablet formulations of cetilistat.

International patent publication number WO2010/123047 describes two polymorphs of cetilistat, an A-type crystal and a B-type crystal, and methods for making such crystal forms. The crystal can be a non-solvate or a solvate, such as a hydrate (including a deuterate).

Cetilistat binds to lipase contained within the gut contents (for example, within the stomach and/or small intestine). Inhibition of lipase by cetilistat reduces hydrolysis of dietary fats such as dietary triglycerides, limiting absorption of monoglycerides and free fatty acids, thereby reducing calorie intake by the body. The undigested dietary fat is excreted in the stool, increasing faecal fat content. Due to its effect, cetilistat, or a composition or a formulation thereof, may be used to aid weight loss, including both non-medical and medical weight loss.

For example, cetilistat, or a composition or a formulation thereof, may be used for cosmetic weight loss, including improving bodily appearance in general. Cetilistat, or a composition or a formulation thereof, is preferably administered to a subject in need or in desideratum thereof and in a quantity sufficient to maintain a given weight or for cosmetic weight loss.

As a further example, cetilistat, or a composition or a formulation thereof, may also be used for the prevention and/or treatment of obesity or an obesity-related disorder or condition. Obesity- related disorders or conditions include, for example, hyperlipaemia, hyperlipidaemia (for example, hypertriglyceridemia, hypercholesterolemia, low HDL and postprandial

hyperlipidemia), and related diseases such as hyperglycaemia (type II diabetes, impaired glucose tolerance), hypertension, cardiovascular disease, stroke, gastrointestinal disease and gastrointestinal conditions, or complications thereof (for example, complications of type II diabetes, complications of hyperlipidemia and metabolic syndrome). The prevention and/or treatment of any disorder or condition means any effect which mitigates any damage or any medical disorder or condition to any extent, and includes prevention and treatment themselves. The term "treatment" means any amelioration of disorder, disease, syndrome, condition, pain or a combination of two or more thereof.

The published results of two human trials show that cetilistat may produce a clinically and statistically significant weight loss in obese patients, and that cetilistat treatment is well tolerated (Kopelman, P et al, 2007, International Journal of Obesity, 31(3), 494-499: trial of cetilistat in obese patients, defined as BMI greater than or equal to 30kg/m and no co- morbidities, or BMI greater than or equal to 28kg/m with diabetes or hypertension or hypercholesterolaemia that did not require pharmaceutical intervention; Kopelman, P et al, 2010, Obesity Journal, 18(1), 108-115: trial of cetilistat in obese patients, defined as BMI 28- 45kg/m , with type II diabetes, on metformin).

There is a need for simple compositions and formulations of cetilistat, and simple processes to prepare such compositions and formulations. European patent publication number EP1143977 describes compositions comprising any one of a group of 2-oxy-benzoxazinone derivatives (including cetilistat) in combination with a pharmaceutically acceptable carrier or diluent. Examples of possible carriers and/or diluents are listed, but without specifying particularly preferred examples and without specifying a particularly preferred composition. European patent publication number EP1143977 describes administration of the 2-oxy-benzoxazinone derivatives by any convenient method, for example by oral, parenteral, mucosal, rectal or transdermal administration. For oral administration, the compound can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges. As a general example, powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule.

European patent publication number EP1897558 describes various specific uncoated and coated tablet formulations of cetilistat made by granulation, milling and tabletting (followed by film-coating if required), all comprising: (i) cetilistat (7.5, 15, 30 or 60 mg per tablet), and (ii) mannitol or lactose, and (iii) crystalline cellulose, plus various additives.

International patent publication number WO2010/123047 describes compositions of a cetilistat crystal mixed with a pharmacologically acceptable carrier. The pharmacologically acceptable carrier can be various common organic or inorganic carrier substances such as, for example, diluting agents, lubricating agents, binding agents, disintegrating agents, water soluble high polymers, solvent in liquid formulation, solvent aid, suspending agents, isotonizing agents, buffering agents and soothing agents. The usual additives such as anti-corrosion agents, antioxidants, colouring agents, sweeteners, acidifiers, foaming agents and fragrances can also be used. International patent publication number WO2010/123047 lists numerous examples of possible pharmacologically acceptable carriers that could be used in the compositions, but without specifying particularly preferred examples of each carrier type and without specifying a particularly preferred combination of specific carriers or a particularly preferred composition. Example formulations include sugar-coated tablets, film-coated tablets, powder medicine, granules, capsule medicine (including soft capsules), tablets that dissolve in the mouth, film that dissolves in the mouth, liquid medicine, injection, suppository, slow release medicine, adhesive patch, etc. Orlistat (tetrahydrolipstatin) is a known compound which acts as a pancreatic lipase inhibitor and is used for the treatment of obesity and weight loss. Orlistat has a

differing chemical structure to cetilistat, and differs in certain properties. US patent number 6004996 relates to tetrahydrolipstatin-containing compositions, and describes a method to prepare pellets containing specific amounts of tetrahydrolipstatin,

microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate, and

polyvinyl pyrrolidone (povidone). The tetrahydrolipstatin pellets are mixed with

specific amounts of talc and encapsulated in a hard gelatin capsule. US patent number 6004996 also describes a method to prepare granules containing specific amounts of tetrahydrolipstatin, microcrystalline cellulose, sodium starch glycolate, polyvinyl

pyrrolidone and sodium lauryl sulphate. The tetrahydrolipstatin granules are then

filled in a hard gelatin capsule without any other excipients.

formulations comprising such compositions, to processes for preparation of the compositions and formulations, and to their methods of use. Through the selection of specific excipients, the invention provides a useful and effective composition of cetilistat that is a simple dry powder formulation for use in a capsule formulation, that may be prepared by a simple process involving mixing or blending the components of the composition without the need to add water, or to perform a granulation step and/or an extrusion step and/or a spheronisation step during manufacture. Addition of water during a process for preparing a cetilistat composition or formulation may adversely affect the stability of the resulting composition or formulation.

In accordance with the present invention there is provided a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

In all aspects of the invention described herein, particularly preferred compositions do not contain any polyvinyl pyrrolidones (PVPs), also known as povidones. PVPs, include, for example, PVP-K25 or povidone K25, PVP-K29 or povidone K29, PVP- K30 or povidone K30, PVP-K90 or povidone K90.

In another aspect of the invention there is provided a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate;

wherein the composition does not contain a polyvinyl pyrrolidone.

In another aspect of the invention there is provided a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

The composition may be in any suitable form, including a powder, granules, pellets, spheronised particles, or a tabletted composition.

Preferably the composition of the invention is in the form of a powder, and is not in the form of granules, pellets or spheronised particles. This allows easier manufacture of the composition, which may be more cost-effective. A composition of the invention is substantially free from added water, and most preferably free from added water.

Preferably the composition of the invention is administered as a unit dose.

In another aspect of the invention, there is provided a composition suitable for human administration as a unit dose, preferably by oral administration, for example a composition administered as a capsule or as a tablet. Preferably the composition is administered as a capsule formulation. In accordance with the present invention there is also provided a formulation comprising a capsule containing a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

In all aspects of the invention described herein, in particularly preferred formulations the composition does not contain any polyvinyl pyrrolidones (PVPs), also known as povidones. In all aspects of the invention described herein, in particularly preferred formulations the composition is substantially free from added water, and most preferably free from added water.

In another aspect of the invention there is also provided a formulation comprising a capsule containing a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

In a further aspect of the invention there is also provided a capsule containing a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

There is also provided such a capsule wherein the composition does not contain a polyvinyl pyrrolidone.

In a further aspect of the invention there is also provided a capsule containing a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and (ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

In a composition or formulation of the invention, component (i) is acting as a lipase inhibitor. Component (i) may be cetilistat or may be a salt, ester, amide, solvate or polymorph thereof. For example, component (i) may be non-crystalline cetilistat or may be crystalline cetilistat (for example, A-type crystal or B-type crystal or a mixture of A-type and B-type crystal), or may be a mixture of both non-crystalline and crystalline cetilistat. Preferably component (i) is non-crystalline cetilistat or cetilistat A-type crystal, or any mixture thereof.

Salts of cetilistat may be prepared in a conventional manner using methods well known in the art. Examples of salts include those derived from organic acids (such as methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like), or those derived from inorganic bases (such as hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like), or those derived from organic bases (which may include amino acids such as arginine and lysine, mono- , di- or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N- methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N- benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like).

Cetilistat may be a non-solvate or a solvate, such as a hydrate (including a deuterate). For example, the hydrate may be from a 0.5 hydrate to a 5.0 hydrate, preferably a 0.5 hydrate, a 1.0 hydrate, a 1.5 hydrate, a 2.0 hydrate, or a 2.5 hydrate. The 0.5 hydrate, 1.0 hydrate and 1.5 hydrate may be particularly advantageous. Cetilistat can also be a solvate other than a hydrate, such as an alcohol solvate crystal (preferably a Ci_₆ alcohol solvate crystal such as a methanol solvate crystal or an ethanol solvate crystal) and an organic solvent hydrate crystal (preferably a Ci_6 alcohol hydrate crystal such as a methanol hydrate crystal or an ethanol hydrate crystal).

In a composition or formulation of the invention, component (ii) is believed to act

mainly as a bulking agent. Component (ii) is preferably crystalline cellulose, and

most preferably microcrystalline cellulose (MCC). Microcrystalline cellulose is particularly preferred, for example because its particle size is similar to that of

cetilistat. Microcrystalline cellulose is primarily used as a binder/diluent in tablet and capsule formulations in wet-granulation and direct compression processes. In

addition, it can be used as a lubricant and disintegrant.

In a composition or formulation of the invention, component (iii) is believed to act mainly as a wetting agent. Component (iii) is preferably sodium lauryl sulphate (also known as sodium lauryl sulfate or sodium laurilsulfate or sodium laurilsulphate or

SLS). Sodium lauryl sulphate is primarily used as a detergent and wetting agent in formulations.

In a composition or formulation of the invention, component (iv) is believed to act mainly as a disintegrant. Component (iv) is preferably sodium starch glycolate

(SSG), and is most preferably sodium starch glycolate type A. Sodium starch

glycolate (particularly type A) is preferred, for example because it releases cetilistat rapidly from the composition upon contact with water (it allows rapid water

absorption followed by swelling to break up the blend of components). Sodium starch glycolate is primarily used as a disintegrant and tablet compression aid in

formulations.

In a composition or formulation of the invention, component (v) is believed to act mainly as a glidant. The choice of a particular component (v), ie talc or sodium

stearyl fumarate or magnesium stearate, may possibly affect the dissolution rate of the composition and/or formulation. Component (v) is preferably talc. Talc is primarily used as a lubricant and diluent in formulations, and also as a dissolution retardant in controlled release formulations, and as an adsorbent.

(i) cetilistat; and

(ϋ) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc. Preferably component (iv) is sodium starch glycolate type A.

There is also provided such a composition wherein the composition does not contain a polyvinyl pyrrolidone. In another aspect of the invention there is provided a unit dose of a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A.

There is also provided such a unit dose wherein the composition does not contain a polyvinyl pyrrolidone.

In a preferred aspect of the invention there is provided a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A. In another preferred aspect of the invention there is provided a unit dose of a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A. In a formulation of the invention, the capsule is acting as a dosing unit. The capsule is preferably suitable for oral administration to humans. The capsule may be a hard or a soft capsule (such as soft gelatin), and is preferably a hard capsule. The capsule may be a hard gelatin capsule (bovine, porcine or fish) or a capsule made from non-animal material, such as a vegetable capsule. The capsule is preferably made from non- animal material (ie material that is not derived from animal origin).

For example, the capsule may be an hydroxypropyl methylcellulose (HPMC) capsule, preferably a hard HPMC capsule. The polymer HPMC is also known as

hypromellose. HPMC capsules are commercially available, and typically the capsule shells comprise HPMC, or HPMC and water. Other components may also be present in the HPMC or other capsule shell (for example, a gelling agent and/or an opacifier and/or a colourant). A range of capsules is available, having varying dissolution profiles. For example, certain grades of capsule are typically used for dietary supplements such as vitamin supplements, while other grades are typically used for pharmaceutical products. Any suitable grade of capsule may be used in a formulation of the invention, and preferably a grade that is typically used for pharmaceutical products. In a formulation of the invention, the functionality of an HPMC capsule is generally equivalent to the functionality of a gelatin capsule. The safety and performance characteristics of cetilistat should be equivalent in HPMC capsule formulations and in hard gelatin capsule formulations. However, a HPMC capsule formulation may show an improved stability profile compared to a hard gelatin capsule containing the same composition. In a formulation of the invention, the properties of HPMC capsules are generally equivalent to hard gelatin capsules with potentially improved stability properties. For example, improved properties may include pH independent dissolution, and/or disintegration, and/or low water vapour permeability. One embodiment is a formulation comprising an HPMC capsule containing a composition wherein component (ii) is microcrystalline cellulose. The

microcrystalline cellulose is acting as a bulking agent, and so forms a relatively large proportion of the composition compared to components (iii), (iv) and (v). HPMC is chemically similar to microcrystalline cellulose and so the two are particularly compatible, thus minimising the chance of interactions between the capsule and this component. Formulations consisting of an HPMC capsule containing a composition of the invention that includes microcrystalline cellulose should show an equivalent or an improved stability profile compared to a hard gelatin capsule containing the same composition.

In a formulation of the invention, the capsule may be clear (transparent or translucent) or opaque, for example white or coloured. The capsule shells can be opacified (for example, with titanium dioxide to produce a white opaque shell) or coloured (for example, with titanium dioxide in combination with pigments). Preferably the capsule is an opaque capsule, most preferably white. For example, the capsule is an opaque HPMC capsule, most preferably white. An opaque capsule can provide protection from light, which may be beneficial if any component in the composition is susceptible to light degradation. In one preferred embodiment of a formulation of the invention, the shell of the capsule comprises titanium oxide, making it a white, opaque capsule.

The capsule can be of any convenient size. Preferably the capsule is size 1 or size 0. Most preferably the capsule is a size 1 capsule.

In another aspect of the invention there is provided a formulation comprising a capsule containing a composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

The components of such a composition were chosen to ensure that the bulk mix would form stable homogeneous mixes with good flow characteristics suitable for semiautomatic encapsulation, and to ensure that the filled capsule shows acceptable disintegration characteristics. Preferably component (iv) is sodium starch glycolate type A, and/or preferably the capsule is made from non-animal material (such as HPMC). There is also provided such a formulation wherein the composition does not contain a polyvinyl pyrrolidone.

In a further aspect of the invention there is also provided a formulation comprising a capsule containing a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A, and/or preferably the capsule is made from non-animal material (such as HPMC).

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

In a preferred aspect of the invention there is also provided a capsule containing a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A, and/or preferably the capsule is made from non-animal material (such as HPMC). Preferably the capsule according to all aspects of the invention is a hard capsule.

In a further aspect of the invention there is also provided a formulation comprising or consisting of an HPMC capsule containing a composition comprising or consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A.

There is also provided such a formulation wherein the composition does not contain a polyvinyl pyrrolidone.

In one embodiment of the invention, there is provided a capsule having a shell comprising HPMC and titanium oxide, the capsule containing a composition consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

Preferably component (iv) is sodium starch glycolate type A.

In a composition or formulation of the invention, the weight of cetilistat may be any suitable weight per unit dose (for example, per capsule). For example, the weight of cetilistat in a unit dose may be from around lmg to around 250mg, lmg to around 240mg (such as 240mg), from around 5mg to around 200mg, from around lOmg to around 150mg (including around: lOmg, 40mg, 50mg, 60mg, 80mg, 120mg, 150mg). The weight of cetilistat in a unit dose is preferably from around lOmg to around 150mg, from around 40mg to around 150mg, from around 50mg to around 150mg, from around 60mg to around 150mg, from around 80mg to around 150mg, from around 120mg to around 150mg. In particularly preferred embodiments, the weight of cetilistat in a unit dose is from around 50mg to around 150mg, from around 60mg to around 150mg, from around 80mg to around 150mg, from around 120mg to around 150mg. For example, the weight of cetilistat in a unit dose may be lOmg, 40mg, 50mg, 60mg, 80mg, 120mg, or 150mg. Preferably the weight of cetilistat in a unit dose is 60mg or 120mg. Most preferably the weight of cetilistat in a unit dose is 120mg.

In a composition or formulation of the invention, the percentage weight of each component compared to the total composition weight may be any suitable percentage weight per unit dose (for example, per capsule). For example, the percentage weights may be in the following ranges:

component (i) : 1-70%, 4-60%, 5-55%; preferably 18-55%;

most preferably 45-55%), particularly 50-55%),

for example 53-54%> (such as 53.5%);

component (ii) : 25-90%>; preferably 30-75%), particularly 35-75%>;

most preferably 30-50%), particularly 30-40%),

for example 36-37%> (such as 36.4%>);

component (iii) : 0.5-3.0%>; preferably 1-2%, for example 1.6%;

component (iv) : 2-6%, 3-6%; preferably 5-6%, for example 5.3%;

component (v) : 1 -4 %; preferably 3-4 %, for example 3.3%.

For example, the percentage weight of each component compared to the total composition weight is shown in the Table below for example compositions A to F:

Most preferably, the percentage weight of each component is:

component (i) : 53-54%, for example 53.3%

component (ii) : 36-37%), for example 36.4% component (iii) : 1-2%, for example 1.6%

component (iv) : 5-6%, for example 5.3%

component (v) : 3-4%, for example 3.3%.

For example, a preferred composition of the invention comprises: cetilistat (around

53.5%) by weight), micro crystalline cellulose (around 36.4% by weight), sodium

lauryl sulphate (around 1.6% by weight), sodium starch glycolate type A (around

5.3%) by weight), talc (around 3.3% by weight).

In a composition or formulation of the invention, the total weight of the composition in a unit dose (for example, the composition contained in a capsule) may be any

suitable weight. For example, the total weight may be from around lOmg to around

450mg, from around lOOmg to around 400mg, from around 150mg to around 330mg

(including around: 150mg, 179mg, 192mg, 225mg, 315mg, or 330mg). Preferably

the total weight of the composition in a unit dose (for example, the composition

contained in a capsule) is 225mg.

In a particularly preferred embodiment, the composition of the invention in a unit dose consists of 120mg cetilistat, 81.9mg of micro crystalline cellulose, 3.6mg of sodium lauryl sulphate, 12.0mg of sodium starch glycolate, and 7.5mg talc.

In one embodiment, the formulation of the invention consists of an HPMC capsule containing 120mg cetilistat, 81.9mg of microcrystalline cellulose, 3.6mg of sodium lauryl sulphate, 12.0mg of sodium starch glycolate, and 7.5mg talc. Preferably the HPMC capsule is a white, opaque capsule. Preferably the HPMC capsule is a size 1 capsule. Preferably the HPMC capsule is a white, opaque, size 1 capsule.

Unit doses of a composition of the invention or the formulations of the invention may be packaged in any convenient fashion, in any convenient pack. For example, the

pack may be a blister, blister pack, tube, jar, bottle, bag, wrapper or other container.

In one aspect of the invention, there is provided a kit comprising a pack comprising a plurality of unit doses of a composition of the invention. For example, there is

provided a pack comprising a plurality of capsules, wherein each capsule is a

formulation of the invention. A plurality of capsules (such as 7, 14, 21, 28, 35, 42, 63, 84, 105; preferably 21, 42 or 84; most preferably 42 or 84, particularly 84) may be packaged in any conventional way. For example, in one preferred embodiment a

plurality of capsules is packaged in a blister pack (for example, 21 capsules per blister in a pack containing from 2 to 10 blisters, preferably 1, 2, 3, 4 or 5 blisters, most

preferably 2 or 4 blisters). For example, the blister may be aluminium foil covered in heat-sealed lacquer layered with PVC or PVdC laminate. Alternatively, a plurality of capsules may be packed in a tube equipped with a removable and replaceable closing means, for example a stopper. Alternatively, the capsules may be provided in ajar or bottle or other container with a removable and replaceable lid or cap (which may be a tamper-proof or tamper-evident lid or cap), or in a bag (such as an aluminium bag) or within a wrapper (for example a foil wrapper). In an embodiment, the capsules are

packaged within a tube, jar, bottle, bag, wrapper or other container without any

wrapping around individual capsules, and a desiccant is preferably also present.

Optionally, individual capsules may have a wrapping. Optionally the kit may be

contained in an outer packaging, such as a carton.

In other embodiments of the invention, there is provided:

(a) a kit comprising a plurality of capsules packaged in a blister or blister pack;

(b) a kit comprising a plurality of capsules packaged in a tube, jar, bottle, bag, wrapper or other container;

(c) a kit comprising a plurality of capsules together with directions or instructions for use;

(d) a kit comprising a plurality of capsules packaged in a blister, blister pack, tube, jar, bottle, bag, wrapper or other container, together with directions or instructions for use;

(e) a kit comprising a plurality of capsules packaged in a blister, blister pack, tube, jar, bottle, bag, wrapper or other container, together with directions or instructions for use, contained in an outer packaging (such as a carton, box, bag or other container or wrapper).

Optionally, the packaging includes one or more tamper-resistant features (for example: a tamper-proof or tamper-evident lid or cap for the container; a film wrapper around the outer packaging, such as a carton). Optionally, the capsule itself may be sealed by tamper-resistant technology (for example, a two-piece hard capsule sealed by any suitable tamper-resistant technology, such as sonic welding, banding, or sealing techniques employing solvents and/or low temperature heating). In one preferred embodiment, there is provided a kit comprising instructions for use and a plurality of capsules packaged in one or more blisters, contained in a carton.

Preferably the kit contains 84 capsules, most preferably presented as a pack

containing four blisters of 21 format (ie 21 capsules per blister). Preferably the blister has an individually perforated format (perforated to allow individual dosing).

Preferably the blister comprises a PVC/PVdC blister laminate (for example, layers of PVC /PVdC, such as 250 micron PVC and 60 gsm PVdC, that is suitable for

perforation) and lidding foil (for example, aluminium foil, such as 20 micron hard temper aluminium foil with 6-8 gsm PVC compatible Heat seal lacquer). Optionally, text and/or symbols and/or any other visual representations may be printed on the

lidding foil (for example, in up to four colours, preferably up to three colours, most preferably one colour). The carton may be any suitable design (for example, it may be a side opening, aeroplane/reverse tuck format). The carton may have any suitable dimensions; for example, for a kit containing 84 capsules, the carton may typically bel32mm (face) x 41mm (side) x & 98mm (height). Preferably, text and/or symbols and/or any other visual representations may be printed on the carton (for example, in up to four colours, preferably up to three colours, most preferably two colours) and at least key information (such as the product name) may also be expressed in Braille.

Preferably, tamper evident stickers are applied to the carton.

In a further aspect of the invention, there is provided a process for making a composition according to the invention comprising mixing components (i) to (v) together in powder form.

A composition of the invention may be made according to standard manufacturing processes, comprising blending (usually preceded by sieving and dispensing of the components into the required quantities). Components may be added, pre-blended and/or blended in any suitable order by any suitable means. Any suitable blending process may be used, including a stage blending process. An advantage of the composition of the invention is that it is not necessary to add water, or to perform a granulation step and/or an extrusion step and/or a spheronisation step during its manufacture. A composition of the invention is substantially free from added water, and most preferably free from added water.

In one embodiment of the invention, the process for making a composition comprises:

(a) blending components (i), (iii) and (iv) together; (b) adding component (ii) to the blend produced in step (a), followed by further blending;

(c) adding component (v) to the blend produced in step (b), followed by final blending.

In a further aspect of the invention, there is provided a process for making a formulation according to the invention comprising mixing components (i) to (v) together in powder form, and filling a capsule with the resulting composition.

A formulation of the invention may be made according to standard manufacturing processes for capsule presentations, comprising blending and filling (usually preceded by sieving and dispensing of the components into the required quantities). Components may be added, pre- blended and/or blended in any suitable order by any suitable means. Any suitable blending process may be used, including a stage blending process. An advantage of the formulation of the invention is that it is not necessary to add water, or to perform a granulation step and/or an extrusion step and/or a spheronisation step during manufacture of the composition to be filled into the capsule, although it is possible to include granulation and spheronisation (optionally preceded by extrusion) in the manufacturing process if desired. A formulation of the invention is substantially free from added water, and most preferably free from added water.

For example, an embodiment of the invention may be made by the following process:

(a) Pre -blend the components cetilistat, sodium starch glycolate and sodium lauryl sulphate together in a suitable vessel or mixer (such as an intermediate bulk container or IBC);

(b) Add microcrystalline cellulose to the pre-blended components, and perform the main blend;

(c) Add talc to the blended materials, and perform the final blend to produce a blended powder;

(d) Encapsulate the blended powder into capsules, according to the correct filling quantity.

In capsule filling trials using HPMC capsules from different suppliers, evaluations showed comparable and satisfactory ease of filling and accuracy of filling (correct filling quantity).

In further aspects, there are provided methods of using the compositions or formulations of the invention for weight management, and compositions or formulations for use in those methods. A composition or formulation of the invention is taken by a subject, preferably orally, and is useful for weight management in that subject. In particular, a composition or formulation of the invention may be used for weight management in a mammal (for example: humans, rats, mice, cats, dogs, rabbits, cattle, swine, hamsters, sheep and monkeys), preferably in a human. Weight management encompasses, for example, weight loss, weight maintenance, prevention or amelioration of weight gain (including reducing the risk for weight regain after prior weight loss). Weight loss includes medical and non-medical weight loss: for example, assisting or promoting weight loss to achieve a healthy weight (which may provide medical benefits to the subject), and cosmetic weight loss. The compositions or formulations of the invention may be used in weight loss (to cause, promote or aid weight loss of all kinds). In particular, a composition or formulation of the invention is used for aiding weight loss.

A composition or formulation of the invention works by decreasing the amount of fat from food absorbed by the subject's body. It does this by blocking the enzymes (lipases) inside the gut which digest fat. This changes the content of the digestive tract by preventing some of the fat that is eaten from being digested, so reducing total calorie intake. The undigested fat is eliminated in the faeces. In one preferred embodiment, a composition or formulation of the invention is used to prevent fat digestion.

In another preferred embodiment, a composition or formulation of the invention is used to increase fat elimination in the faeces.

In a further preferred embodiment, a composition or formulation of the invention is used to help manage a subject's weight. For example, a composition or formulation of the invention may be used to help a subject lose weight. As a further example, a composition or formulation of the invention may be used to help a subject maintain weight, or to prevent or ameliorate weight gain.

In another preferred embodiment, a composition or formulation of the invention is used to help a subject lose weight if the subject is overweight or obese. A composition or formulation of the invention is used for aiding weight loss, in particular for helping an overweight or obese subject lose weight. There are a number of health benefits to being a healthy weight. Achieving a healthy weight promotes a feeling of well being and reduces the risk of diseases associated with being overweight or obese, such as heart disease, diabetes, osteoarthritis, some cancers, respiratory disease and reproductive health problems. A composition or formulation of the invention may help a subject achieve one or more of these benefits.

In further aspects, there is provided a kit according to the invention for use in weight management, for helping a subject manage the subject's weight, for use in weight loss, for aiding weight loss, and/or for helping an overweight or obese subject lose weight.

The compositions or formulations of the inventions are optionally taken in

conjunction with one or more of the following, preferably with at least one of the

following:

o Reduced calorie diet

o Reduced or low fat diet

o Healthy lifestyle strategies, such as taking regular exercise.

Preferably a composition or formulation of the invention is used with a reduced calorie, low fat diet. More preferably a composition or formulation of the invention is used with a reduced calorie, low fat diet and other healthy lifestyle strategies such as taking regular exercise. Most preferably a composition or formulation of the invention is used with a reduced calorie, low fat diet and taking regular exercise.

The exact Body Mass Index (BMI) ranges within which a subject is classified as healthy weight, overweight, obese, or underweight may vary from subject to subject. In addition, individual health authorities may define overweight, obese and underweight according to local standards, based on the typical BMI and health of their particular national populations. As a general guideline to a healthy weight for humans, the World Health Organisation generally defines a human adult with BMI greater than or equal to 25kg/m as overweight, a human adult with BMI greater than or equal to 30kg/m as obese, and a human adult with BMI less than or equal to 18.5kg/m as underweight. Subjects suffering from an obesity-related disorder or condition, or subjects with an increased likelihood of developing an obesity-related disorder or condition (for example, due to family history or lifestyle), typically may have a BMI greater

_{2 2} than or equal to 28kg/m or at one time may have had a BMI greater than or equal to 28kg/m . However, such subjects may also have a BMI less than 28kg/m , and may never have had a higher BMI. The compositions or formulations of the invention may be used for weight management in humans with BMI greater than or equal to 18.5kg/m and particularly in 2

humans with BMI greater than 18.5kg/m (preferably in subjects with an increased likelihood of becoming overweight and/or of developing obesity and/or of developing an obesity-related disorder or condition), preferably in subjects with BMI greater than or equal to 25kg/m , more preferably in subjects with BMI greater than or equal to 28kg/m , and most preferably in

2

subjects with BMI greater than or equal to 30kg/m . In preferred embodiments, a composition

2 or formulation or kit of the invention is used in humans having a BMI greater than 18.5kg/m .

To use compositions or formulations of the invention for weight management (including weight loss), the preferred doses of cetilistat are: from lOOmg to 450mg per day, preferably from 150mg to 380 mg per day, more preferably from 180mg to 360mg per day, particularly 180mg per day or 360mg per day, most preferably 360mg per day. Preferably the total cetilistat dose per day is provided in divided doses (for example, 1 , 2 or 3 or 4 doses per day, particularly 2 or 3 or 4 doses per day, preferably 2 or 3 doses per day, most preferably 3 doses per day; each divided dose containing from 50mg to 150mg of cetilistat, preferably 60mg or 120mg of cetilistat, most preferably 120mg cetilistat).

In one preferred embodiment, a composition or formulation of the invention wherein the daily dose of cetilistat administered is at least 150mg cetilistat per day (and preferably 360mg per day) is used to cause or aid weight loss of more than or equal to 2% from the baseline weight of the subject within 12 weeks, and preferably more than or equal to 3% from the baseline weight of the subject within 12 weeks.

A unit dose of a composition or formulation of the invention (preferably a capsule

formulation) is taken orally by a subject. A composition or formulation of the

invention is preferably taken with fluid such as water, and preferably with a meal

containing fat or within one hour of a meal containing fat. A composition or

formulation of the invention works if dietary fat is present, so need not be taken if a meal is missed or if a meal does not contain any fat. In this case, the total cetilistat dose per day may be reduced accordingly (to zero if no fat is consumed that day) as the number of divided doses taken may be reduced (one dose per fat-containing meal;

zero dose if no fat is consumed that day). Optionally the subject may take additional fluid (such as water, fruit juice, or another solution of electrolytes), such as up to three litres (for example, about two litres) of fluid per day. Since some vitamins are absorbed with fats, a subject may optionally take a daily vitamin supplement to ensure such a subject continues to absorb sufficient fat- soluble vitamins (these are vitamins A, D, E and K). A subject may optionally take a daily multivitamin supplement comprising one or more of the fat-soluble vitamins and/or may optionally take one or more single fat-soluble vitamin supplements daily.

Preferably the supplement is taken as long as possible after a meal (for example, as long as possible after the evening meal). Preferably the supplement is taken at bedtime. For example, a subject may take a daily multivitamin supplement comprising vitamins A, D, E and K, preferably the supplement is taken as long as possible after a meal (for example, at bedtime).

When taking a composition or formulation of the invention, any unwanted GI effects, if present, tend to be mild and occur for a short time. Most subjects do not find the unwanted effects to be troublesome. The most common unwanted effects result from blocking fat digestion in the gut which reduces fat absorption in the gut (which is how cetilistat contributes to weight loss). Unwanted effects may include diarrhoea and fatty stools. A subject eating very high fat meals whilst taking a composition or formulation of the invention may experience more GI effects, such as diarrhoea, since more fat is passed in the faeces or stools. Diet related side-effects can be minimised or avoided by eating low fat meals.

A subject takes an appropriate daily dose of cetilistat, preferably in the form of one or more unit doses. For example, a subject may take up to three unit doses of a composition in 24 hours (such as up to three capsules in 24 hours). For example, a subject may take up to three capsules each containing 120mg cetilistat in 24 hours (total daily dose of cetilistat 120mg, 240mg or preferably 360mg). If the appropriate daily dose of cetilistat is exceeded, a subject may in some cases experience side- effects such as severe diarrhoea. These side-effects may be alleviated by avoiding fatty food for 24 hours. A subject experiencing severe diarrhoea may also take fluid and electrolyte replacement (such as fruit juice).

In a further aspect, there is provided a composition or formulation or kit according to the invention for use in weight management, for helping a subject manage the subject's weight, for use in weight loss, for aiding weight loss, and/or for helping an overweight or obese subject lose weight, wherein the use includes one or more of the following:

(a) use in conjunction with reduced calorie diet and/or reduced or low fat diet

and/or healthy lifestyle strategies such as taking regular exercise;

(b) taking up to three unit doses (such as up to three capsules) in 24 hours;

(c) taking the unit dose (such as the capsule) with or after a meal containing fat,

or within one hour of a meal containing fat;

(d) taking the unit dose (such as a capsule) with fluid such as water;

(e) taking additional fluid such as water, fruit juice, or another solution of

electrolytes;

(f) taking a daily vitamin supplement, such as one or more of vitamins A, D, E

and/or K.

In a further aspect, there is provided a kit according to the invention further comprising instructions for use wherein the instructions for use specify one or more of:

(a) use of the capsule in conjunction with reduced calorie diet and/or reduced or

low fat diet and/or healthy lifestyle strategies such as taking regular exercise;

(b) taking up to three capsules in 24 hours;

(c) taking the capsule with or after a meal containing fat, or within one hour of a

meal containing fat;

(d) taking the capsule with fluid such as water;

(e) taking additional fluid such as water, fruit juice, or another solution of

electrolytes;

(f) taking a daily vitamin supplement, such as one or more of vitamins A, D, E

and/or K.

Orlistat (tetrahydrolipstatin) is a known compound which acts as a pancreatic lipase inhibitor and is used for the treatment of obesity and weight loss. Orlistat has a differing chemical structure to cetilistat, and differs in certain properties. Various GI adverse events (or side effects) have been associated with the use of orlistat. These side effects generally result from the passage of undigested fats through the GI tract.

A particular benefit of using a composition or formulation according to the invention for weight management is that cetilistat has an improved side effect profile compared to orlistat, whilst retaining at least an equivalent efficacy and safety profile. This may help to improve compliance with use, particularly long-term use, of a weight management product. Bryson, A et al, 2009 [Br J Clin Pharmacol, 67(3):309-315] and Kopelman, P et al, 2010 [Obesity Journal, 18(1), 108-115] provide the results of trials using formulations of cetilistat according to the invention, although details of the composition are not disclosed. Bryson, A et al [2009] describe the reduction of dietary fat absorption by the lipase inhibitor cetilistat in a healthy volunteer study which included orlistat as a comparator. The incidence and frequency of steatorrhoea was compared with faecal fat excretion, and the tolerability of cetilistat appeared to be improved relative to orlistat. There was no evidence of a direct relationship between lipase inhibition per se and intolerable GI side effects, which suggested other factors may determine the incidence of GI events (such as the chemical structure and particular properties of the individual compounds). Kopelman, P et al, 2010 [Obesity Journal, 18(1), 108-115] describe a trial of cetilistat in obese patients (BMI 28-45kg/m ) with type II diabetes on metformin, using orlistat as a comparator. Discontinuation in the group taking the orlistat product was significantly worse than discontinuation in the group taking the cetilistat products, showing a clear difference between cetilistat and orlistat. The results again suggested there is no direct correlation between lipase inhibition and the nature and frequency of GI adverse events. Padwal, R, 2008 [Curr Opinion in Investigational Drugs, 9(4):414-421] reviewed cetilistat as a new lipase inhibitor for the treatment of obesity, and stated that a major differentiating feature and potential advantage of cetilistat over orlistat relates to the lower frequency of GI adverse events, suggesting that cetilistat may be better tolerated by subjects taking the product. Thus subjects may be more likely to persist taking a cetilistat composition or formulation, complying with use for the entire time required for appropriate weight management.

The following examples illustrate but do not limit the invention. Example 1: HPMC capsule containing a cetilistat composition (120mg)

The following cetilistat composition and formulation was made by the following process:

(a) cetilistat, sodium starch glycolate type A and sodium lauryl sulphate were pre -blended in an intermediate bulk container;

(b) microcrystalline cellulose was added to the pre -blended components, and the mixture was blended;

(c) talc was added to the blended materials, and the mixture was further blended to produce a blended powder;

(d) the blended powder was filled into the capsule, according to the correct filling quantity.

Name of component Weight per capsule (mg)

Cetilistat 120.0

Microcrystalline cellulose (Avicel PHI 01) 81.9

Sodium lauryl sulphate 3.6

Sodium starch glycolate Type A 12.0

Talc 7.5

Total content weight 225mg

Capsule

HPMC, white opaque capsule shell Size 1

Example 2: Hard gelatin capsules containing a cetilistat composition (lOmg, 40mg, 50mg, 60mg, 80mg, 120mg, 150mg)

The following cetilistat compositions and formulations were made according to the process described in Example 1.

Name of component Weight per Weight per Weight per

capsule (mg) capsule (mg) capsule (mg)

Cetilistat 80.0 120.0 150.0

Microcrystalline cellulose 54.6 81.9 150.0

Sodium lauryl sulphate 2.4 3.6 6.0

Sodium starch glycolate Type A 8.0 12.0 15.0

Talc 5.0 7.5 9.0

Total content weight 150.00 225.00 330.00

Capsule

Hard gelatin, white opaque Size 1 Size 1 Size O

Example 3: HPMC capsules containing a cetilistat composition (lOmg, 40mg, 50mg, 60mg, 80mg, 150mg)

The following cetilistat compositions and formulations are made according to the following process:

(a) cetilistat, sodium starch glycolate and sodium lauryl sulphate are pre-blended;

(b) microcrystalline cellulose is added to the pre-blended components, and the mixture is blended;

(c) talc is added to the blended materials, and the mixture is further blended to produce a blended powder;

(d) the blended powder is filled into the capsule, according to the correct filling quantity.

Name of component Weight per Weight per Weight per

capsule (mg) capsule (mg) capsule (mg)

Cetilistat 60.0 80.0 150.0

Microcrystalline cellulose 232.14 54.6 150.0

Sodium lauryl sulphate 3.6 2.4 6.0

Sodium starch glycolate 12.0 8.0 15.0

Talc 7.5 5.0 9.0

Total content weight 315.24 150.00 330.00

Capsule

HPMC, white opaque capsule Size O Size 1 Size O

shell Example 4: Capsules containing a cetilistat composition ( lOmg, 40mg, 50mg, 60mg, 80mg, 120mg, 150mg)

The following cetilistat compositions and formulations are made by the following process:

(a) cetilistat, sodium starch glycolate and cetostearyl alcohol are pre -blended in an intermediate bulk container;

(c) sodium stearyl fumarate or magnesium stearate is added to the blended materials, and the mixture is further blended to produce a blended powder;

Name of component Weight per Weight per Weight per

capsule (mg) capsule (mg) capsule (mg)

Cetilistat 80.0 120.0 150.0

Microcrystalline cellulose 54.6 81.9 150.0

Cetostearyl alcohol 2.4 3.6 6.0

Sodium starch glycolate 8.0 12.0 15.0

Sodium stearyl fumarate or 7.5

5.0 9.0

Magnesium stearate

Total content weight 150.00 225.00 330.00

Capsule

HPMC, white opaque Size 1 Size 1 Size O

or Hard gelatin, white opaque

Claims

1. A composition comprising components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

2. A composition as claimed in claim 1 wherein the composition does not contain a

polyvinyl pyrrolidone.

3. A composition as claimed in either claim 1 or claim 2 consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) a cellulose; and

(iii) sodium lauryl sulphate or cetostearyl alcohol; and

(iv) a starch; and

(v) talc or sodium stearyl fumarate or magnesium stearate.

4. A composition as claimed in any of claims 1 to 3 wherein component (ii) is crystalline cellulose or microcrystalline cellulose.

5. A composition as claimed in claim 4 wherein component (ii) is microcrystalline cellulose.

6. A composition as claimed in any of claims 1 to 5 wherein component (iii) is sodium lauryl sulphate.

7. A composition as claimed in any of claims 1 to 6 wherein component (iv) is sodium starch glycolate.

8. A composition as claimed in claim 7 wherein component (iv) is sodium starch glycolate type A.

9. A composition as claimed in any of claims 1 to 8 wherein component (v) is talc.

10. A composition as claimed in claim 1 consisting of components (i) to (v) in admixture:

(i) cetilistat; and

(ii) microcrystalline cellulose; and

(iii) sodium lauryl sulphate; and

(iv) sodium starch glycolate; and

(v) talc.

11. A composition as claimed in any of claims 1 to 10 wherein the percentage weight of each component is:

component (i) : 53-54%,

component (ii) : 36-37%,

component (iii) : l-2%>,

component (iv) : 5-6%>,

component (v) : 3-4%>.

12. A composition as claimed in claim 1 1 wherein the percentage weight of each component is:

(i) cetilistat : 53-54%,

(ii) microcrystalline cellulose : 36-37%,

(iii) sodium lauryl sulphate : 1-2%,

(iv) sodium starch glycolate type A : 5-6%,

(v) talc : around 3-4%>.

13. A capsule containing a composition as claimed in any of claims 1 to 12.

14. A capsule as claimed in claim 13 wherein the capsule is a hard capsule.

15. A capsule as claimed in claim 13 or claim 14 wherein the shell of the capsule comprises titanium oxide.

16. A capsule as claimed in any of claims 13 to 15 wherein the capsule contains lOmg to 150mg of cetilistat.

17. A capsule as claimed in claim 16 wherein the capsule contains lOmg, 40mg, 50mg, 60mg, 80mg, 120mg, or 150mg of cetilistat.

18. A capsule as claimed in claim 17 wherein the capsule contains 120mg of cetilistat.

19. A capsule as claimed in any of claims 13 to 18 wherein the total weight of the composition contained in the capsule is from around 150mg to around 330mg.

20. A capsule as claimed in claim 19 wherein the total weight of the composition contained in the capsule is around 150mg, 179mg, 192mg, 225mg, 315mg, or 330mg.

21. A capsule as claimed in claim 20 wherein the total weight of the composition contained in the capsule is 225mg.

22. A capsule as claimed in claim 21 wherein the capsule contains a composition consisting of 120mg cetilistat, 81.9mg of microcrystalline cellulose, 3.6mg of sodium lauryl sulphate, 12.0mg of sodium starch glycolate, and 7.5mg talc.

23. A kit comprising a pack containing a plurality of capsules, wherein each capsule is a

capsule as claimed in any of claims 13 to 22.

24. A kit as claimed in claim 23 wherein the pack is a blister, blister pack, tube, jar, bottle, bag, wrapper or other container.

25. A kit as claimed in claim 24 wherein the pack is a blister or blister pack.

26. A kit as claimed in any one of claims 23 to 25 further comprising instructions for use.

27. A kit as claimed in any of claims 23 to 286 which is contained in an outer packaging.

28. A composition as claimed in any of claims 1 to 12 for use in weight management.

29. A composition as claimed in claim 28 for helping a subject manage the subject's weight.

30. A composition as claimed in either claim 28 or claim 29 for use in humans having a BMI greater than 18.5kg/m .

31. A composition as claimed in any of claims 1 to 12 for use in weight loss.

32. A composition as claimed in claim 31 for aiding weight loss.

33. A composition as claimed in claim 32 for helping an overweight or obese subject lose weight.

34. A composition as claimed in any of claims 31 to 33 for use in humans having a BMI greater than 18.5kg/m .

35. A capsule as claimed in any of claims 13 to 22 for use in weight management.

36. A capsule as claimed in claim 35 for helping a subject manage the subject's weight.

37. A capsule as claimed in either claim 35 or claim 36 for use in humans having a BMI

2

greater than 18.5kg/m .

38. A capsule as claimed in any of claims 13 to 22 for use in weight loss.

39. A capsule as claimed in claim 38 for aiding weight loss.

40. A capsule as claimed in claim 39 for helping an overweight or obese subject lose weight.

41. A capsule as claimed in any of claims 38 to 40 for use in humans having a BMI greater than 18.5kg/m².

42. A kit as claimed in any of claims 23 to 27 for use in weight management.

43. A kit as claimed in claim 42 for helping a subject manage the subject's weight.

44. A kit as claimed in either claim 42 or claim 43 for use in humans having a BMI greater than 18.5kg/m².

45. A kit as claimed in any of claims 23 to 27 for use in weight loss.

46. A kit as claimed in claim 45 for aiding weight loss.

47. A kit as claimed in claim 46 for helping an overweight or obese subject lose weight.

48. A kit as claimed in any of claims 45 to 47 for use in humans having a BMI greater than 18.5kg/m².

49. A process for making a composition as claimed in any of claims 1 to 12 or 29 to 34

comprising mixing components (i) to (v) together in powder form.

50. A process for making a formulation which is a capsule as claimed in any of claims 13 to 22 or 35 to 41 comprising mixing components (i) to (v) together in powder form, and filling a capsule with the resulting composition.