NL2009995C2

NL2009995C2 - Compositions.

Info

Publication number: NL2009995C2
Application number: NL2009995A
Authority: NL
Inventors: John Robert Bloor; Christopher Robert Dunk; Richard Michael John Palmer
Original assignee: Norgine Bv
Priority date: 2011-12-23
Filing date: 2012-12-17
Publication date: 2013-09-18
Also published as: FR2984745B3; DK201200198Y4; ES2417408R1; IES86183B2; ES2417408A2; FI10194U1; AU2012101841A4; FR2984745A3; DK201200198U1; IES20120556A2; NL2009995A; ITTO20121118A1; ES2417408B1

Description

Compositions

The present invention relates to compositions comprising cetilistat, including its salts, esters, amides, solvates, polymorphs, and mixtures thereof. The invention also relates to 5 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 2-10 (hexadecyloxy)-6-methyl-4H-3,l-benzoxazin-4-one, and is structurally represented by the compound of Formula I: 0 (i) 15 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.

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

International patent publication number W02010/123047 describes two polymorphs of cetilistat, an A-type crystal and a B-type crystal, and methods for making such crystal forms. 25 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 30 reducing calorie intake by the body. The undigested dietary fat is excreted in the stool, increasing faecal fat content.

2

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 5 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 10 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 15 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 20 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 25 cetilistat in obese patients, defined as BMI greater than or equal to 30kg/m and no comorbidities, or BMI greater than or equal to 28kg/m2 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/m2, with type II diabetes, on metformin).

30

There is a need for simple compositions and formulations of cetilistat, and simple processes to prepare such compositions and formulations.

3

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 5 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 10 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 15 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 W02010/123047 describes compositions of a cetilistat crystal mixed with a pharmacologically acceptable carrier. The pharmacologically acceptable 20 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 25 used. International patent publication number W02010/123047 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, 30 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.

4

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 5 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 10 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.

The present invention relates to compositions comprising cetilistat, including its salts, esters, 15 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. 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 20 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.

25 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 30 (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, 5 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) 5 to (v) in admixture: (i) cetilistat; and (ii) a cellulose; and (iii) sodium lauryl sulphate or cetostearyl alcohol; and (iv) a starch; and 10 (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: 15 (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.

20

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 25 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.

30

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.

6

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 5 (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.

10 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: 15 (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.

20

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 25 (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.

30

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 7 (iii) sodium lauryl sulphate or cetostearyl alcohol; and (iv) a starch; and (v) talc or sodium stearyl fumarate or magnesium stearate.

5 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 10 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 15 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-20 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 25 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). 30

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 8 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.

5 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.

10

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). Sodium starch glycolate is preferred, for example because it releases cetilistat rapidly from the composition upon contact with water (it allows rapid water 15 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 20 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.

25

In another aspect of the invention there is provided a composition comprising components (i) to (v) in admixture: (i) cetilistat; and (ii) microcrystalline cellulose; and 30 (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

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

9

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 5 (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

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

10

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 15 (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

In another preferred aspect of the invention there is provided a unit dose of a composition 20 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 25 (v) talc.

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, and is preferably a hard capsule. The capsule may be clear (transparent 30 or translucent) or opaque, for example white or coloured. Preferably the capsule is an opaque 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. The capsule can be of any convenient size.

10

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 5 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 10 (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.

15 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: 20 (i) cetilistat; and (ii) microcrystalline cellulose; and (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

25

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) microcrystalline cellulose; and 30 (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

11

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 5 (iii) sodium lauryl sulphate; and (iv) sodium starch glycolate; and (v) talc.

Preferably the capsule according to all aspects of the invention is a hard capsule.

10

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 15 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, or from around 120mg to around 150mg. In particularly preferred embodiments, the weight 20 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.

25 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 pack comprising a plurality of unit doses of a composition of the invention. For example, there is provided a kit comprising a pack containing a plurality of 30 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 12 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 a jar or bottle or other container with a 5 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 10 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 15 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, 20 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 25 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).

30 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).

13

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, 5 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 10 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.

15

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, 20 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 25 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; 30 (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.

14

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.

5 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, preblended 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 10 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.

15

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; 20 (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 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. 25 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 30 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 15 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 5 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.

10 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.

15

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 20 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 25 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 30 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 16 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 5 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.

10 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.

15

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 20 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/m2 as overweight, a human adult with BMI greater than or equal to 30kg/m2 as obese, and a human adult with BMI less than or equal to 18.5kg/m2 as underweight. Subjects suffering from an obesity-related disorder or condition, or subjects with an increased likelihood of developing an obesity-related disorder or 25 condition (for example, due to family history or lifestyle), typically may have a BMI greater than or equal to 28kg/m2 or at one time may have had a BMI greater than or equal to 28kg/m2. However, such subjects may also have a BMI less than 28kg/m2, 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/m2 and particularly in 30 humans with BMI greater than 18.5kg/m2 (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/m2, more preferably in subjects with BMI greater than or equal to 28kg/m2, and most preferably in 17 subjects with BMI greater than or equal to 30kg/m2. In preferred embodiments, a composition or formulation or kit of the invention is used in humans having a BMI greater than 18.5kg/m2.

To use compositions or formulations of the invention for weight management (including 5 weight loss), the preferred doses of cetilistat are: from lOOmg to 450mg per day, for example from 150mg to 380 mg per day, from 180mg to 360mg per day, such as 180mg per day or 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 10 15 Omg of 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 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 15 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 20 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; 25 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 30 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 18 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).

5

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 10 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.

15 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 in 24 hours. If the appropriate daily dose of 20 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).

25 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: 30 (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; 19 (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

5 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 10 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; 15 (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.

20 The following example illustrates but does not limit the invention.

Example 1: Capsule containing a cetilistat composition

The following cetilistat composition and formulation were made by the following process: (a) cetilistat, sodium starch glycolate and sodium lauryl sulphate were pre-blended in an 25 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; 30 (d) the blended powder was filled into a capsule according to the correct filling quantity.

The resulting formulation was a capsule containing a composition consisting of cetilistat, microcrystalline cellulose, sodium lauryl sulphate, sodium starch glycolate, and talc in admixture.

Claims

A composition comprising a mixture of components (i) - (v): (i) cetilistat; and 5 (ii) microcrystalline cellulose; and (iii) sodium lauryl sulfate; and (iv) sodium starch glycolate; and (v) talk.

A composition according to claim 1, which composition does not contain polyvinylpyrrolidone.

3. A composition according to claim 1 or claim 2 consisting of a mixture of components (i) - (v): (i) cetilistat; and (ii) microcrystalline cellulose; and (iii) sodium lauryl sulfate; and (iv) sodium starch glycolate; and (v) talk.

A capsule containing a composition according to any one of claims 1-3.

A capsule according to claim 4 comprising a composition consisting of a mixture of components (i) - (v): (i) cetilistat; and (ii) microcrystalline cellulose; and (iii) sodium lauryl sulfate; and (iv) sodium starch glycolate; and (v) talk. 30

The capsule according to claim 4 or claim 5, wherein the capsule contains 10 mg, 40 mg, 50 mg, 60 mg, 80 mg, 120 mg, or 150 mg of cetilistat.

The capsule according to any of claims 4-6, wherein the capsule is a hard capsule.

A kit comprising a package containing a plurality of capsules, wherein each capsule is a capsule according to any of claims 4-7. 5

The kit of claim 8, wherein the package is a blister, blister package, tube, jar, bottle, bag, wrap or other container.

A composition according to any one of claims 1-3 or a capsule according to any one of claims 4-7, for use in weight control.

A composition or capsule according to claim 10 for assisting a patient in controlling the patient's weight.

A composition or capsule according to claim 10 or claim 11, for use in people who have a BMI higher than 18.5 kg / m2.

A composition according to any of claims 1-3 or capsule according to any of claims 4-7, for use in weight loss. 20

A composition or capsule according to claim 13 for promoting weight loss.

15. A composition or capsule according to claim 14, for assisting an overweight or obese patient in losing weight.

A composition or capsule according to any one of claims 13 to 15, for use in people with a BMI higher than 18.5 kg / m2.

A capsule for use in weight control, wherein the capsule contains a composition consisting of a mixture of components (i) - (v): (i) cetilistat; and (ii) microcrystalline cellulose; and (iii) sodium lauryl sulfate; and (iv) sodium starch glycolate; and (v) talk.

A capsule for use in weight loss, wherein the capsule contains a composition consisting of a mixture of components (i) - (v): (i) cetilistat; and (ii) microcrystalline cellulose; and (iii) sodium lauryl sulfate; and (iv) sodium starch glycolate; and (v) talk.

A composition substantially as described herein with reference to Example 1. 15

20. A capsule substantially as described herein with reference to Example 1. 20 25