Treatment of diabetes with thiazolidinedione and metformin

CA 02294582 2005-05-09

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-1TREATMENT OF DIABETES WITH THIAZOLIDINEDIONE AND METFORMIN This invention relates to the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or Type Π diabetes and conditions associated with diabetes mellitus.

Rjgnanwfe antihyperglycaemic agents are commonly used in the treatment of NIDDM (or Type H diabetes). 1,1- Dimethylbiguanidine (or Metformin) is an

Rnrnpftan Patent Application, Publication Number 0,306,228 relates to certain thiazdidincdione derivatives disclosed as having antihyperglycaemic and hypolipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is

5-[4-[2-(N-methyI-N-(2-pyridyI)atnino)ethoxy]benzyl]thiazolidme-2,4-dione . (hereinafter Oompound (1)7- WO94/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.

Compound (I) is an example of a class of anti-hyperglycaemic agents known as insulin sensitisers'- hi particular Compound (I) is a thiazolidinedione insulin sensitiser.

European Patent Applications, Publication Numbers: 0008203,0139421, 0032128,0428312,0489663,0155845,0257781,0208420,0177353,0319189, 0332331,0332332,0528734,0508740; International Patent Application, Publication Numbers 92/18501,93/02079,93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitisers.

Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers WO93/21166 and W094/01420. These compounds are herein referred to as 'acyclic insulin sensitisers': Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.

Examples of other insulin sensitisers are those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.

It is now surprisingly indicated that Compound (I) in combinanon with a biguanide antihypeigtycaemic agent provides a particularly beneficial effect on glycaemic control with no observed adverse effects, such combination is therefore particularly useful for the treatment of diabetes mellitus, especially Type Π diabetes and conditions associated with diabetes mellitus.

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-2Accordingly the present invention provides a combination which comprises from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-

2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof, and up to 3000 mg of metformin or metformin hydrochloride.

In one aspect, the combination comprises from 2 to 4 or 4 to 8 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Typically, the combination comprises from 2 to 4 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Typically, the combination comprises from 8 to 12 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Preferably, the combination comprises 2 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Preferably, the combination comprises 4 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Preferably, the combination comprises 8 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof.

Preferably, the combination of the present invention comprises 500 mg or 850 mg of metformin or metformin hydrochloride.

Preferably, the combination is one wherein Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as a single pharmaceutical composition.

Preferably, the combination is one wherein Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as separate pharmaceutical compositions.

The method of administration of the combination of the present invention comprises either co-administration of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof and metformin or metformin hydrochloride, or the sequential administration thereof.

Co-administration includes administration of a formulation which includes both Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof, and

CA 02294582 2005-05-09

-3metformin or metformin hydrochloride or the essentially simultaneous administration of separate formulations of each agent.

In one embodiment, the present invention provides use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable salt, ester or solvate thereof and up to 3000 mg of metformin or metformin hydrochloride for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal.

In another aspect the present invention provides use of from 2 to 8 mg of 5[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable salt, ester or solvate thereof and up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

Further, the present invention provides use of from 2 to 8 mg of 5-[4-[2-(Nmethyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable salt, ester or solvate thereof in the manufacture of a medicament for use with up to 3000 mg of metformin or metformin hydrochloride in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

Still further the present invention provides use of up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use with from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4dione (Compound (I)) or a pharmaceutically acceptable salt, ester or solvate thereof in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

Typically the amount of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof used is 2 to 4 or 4 to 8 mg.

Typically the amount of Compound (I) or a pharmaceutically acceptable salt, ester of solvate thereof used is 2 to 4 mg.

Typically the amount of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof used 4 to 8 mg.

Preferably the amount Compound (I) or a pharmaceutically acceptable salt, ester or solvate therefore used is 2 mg.

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-4Preferably the amount of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof used is 4 mg.

Preferably the amount of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof used is 8 mg.

Typically the amount of metformin or metformin hydrochloride is 500mg or 850mg.

It will be understood that Compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate. It will be understood that all pharmaceutically acceptable forms of the active agent per se are encompassed by this invention.

Suitable pharmaceutically acceptable salts of Compound (I) include those described in EP 0306228 and WO94/05659, especially pharmaceutically acceptable salted forms. A preferred pharmaceutically acceptable salt is a maleate.

Suitable pharmaceutically acceptable solvated forms of Compound (I) include those described in EP 0306228 and WO94/05659, in particular hydrates.

Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP 0306228 and WO94/05659.

Compound (I) may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures thereof. Compound (I) contains a chiral carbon atom, and hence can exist in up to two stereoiosmeric forms, the term Compound (I) encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.

Compound (I), pharmaceutically acceptable forms thereof, metformin and metformin hydrochloride are prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition on page 341 and pages cited therein) or as described in the abovementioned publications.

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Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or. glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described in: Tuescher A, Rjchterich, Schweiz, med. Wschr. 101 (1971), 345 and 390 and Frank P.»

Clinical Products 1988.

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-6In a preferred aspect, the dosage level of each of the active agents when used in accordance with, the treatment of the invention will be less than would have been required from a purely additive effect upon, glycaemic control.

There is also an indication that the treatment of the invention will effect an improvement, relative to the individual agents, in the levels of advanced glycosylation end products (A GF-?), leptin and serum, lipids including total cholesterol, HDLcholesterol, LDL-cholesterol including improvements in the ratios thereof, in particular an improvement in serum lipids including total cholesterol, HDLcholesterol, LDL-cholesterol including improvements in the ratios thereof:

The active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.

Accordingly, in one aspect on the invention there is provided a pharmaceutical composition comprising from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound I)) or a pharmaceutically acceptable salt, ester or solvate thereof, up to 3000 mg of metformin or metformin hydrochloride and a pharmaceutically acceptable carrier therefor.

Such compositions may be prepared by admixing from 2 to 8 mg of Compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof, metformin or metformin hydrochloride and a pharmaceutically acceptable carrier therefor.

Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdennal administration.

The compositions may be in the form of tablets, capsules, powders, grannley, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

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capsules and may contain conventional excipients such as binding agente, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starchy calcium phosphate, sorbitol or glycine;

CA 02294582 2005-05-09 tabletting lubricants, for example magnesium stearate; disinlegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The compositions are preferably in a unit dosage form in an amount

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6, 7 or 8 mg of Compound (I).

The composition of the invention may be administered from 1 to 6 tim»c a day, but most preferably 1 or 2 times per day.

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Suitable dosages of metformin or metformin hydrochloride include up to 3000mg per day, in unit doses of 500mg (for example two or three times per day) or 850mg (for example two times per day), one example of a dosage for metformin is 500mg once building to five times per day.

Thus, one example of administration of the combination of the present invention is 4 or 8mg of Compound (I) (at 2mg twice per day or 4mg twice per day respectively) and lOOOmg or 2500mg of metformin (at 500mg twice per day or 500mg five times per day respectively).

The solid oral compositions may be prepared by conventional methods of

Wending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitoL, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymetfayicdlulose, afaminiurn stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan.

CA 02294582 2005-05-09 monooleate, or acacia; non-aqueous vehicles (which may inchide edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be other suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before tilling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the etahifity, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I)s suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to

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Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.

Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

The compositions are formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Exira Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) and Harry's Cosmeticoiogy (Leonard Hill Books).

A range of 2 to 4mg includes a range of 2.1 to 4,22 to 4, 23 to 4,2.4 to 4, 23 to 4,26 to 4,2.7 to 4,2.8 to 4,2.9 to 4 or 3 to 4mg.

A range of 4 to 8mg includes a range of 4.1 to 8,4.2 to 8, 43 to 8,4.4 to 8, 43 to 8,4.6to 8,4.7to 8,4.8 to 8,4.9 to 8,5 to 8,6to 8 or7to 8mg.

No adverse toxicological effects have been established for the corr^ngfrfo+nr methods of the invention in the abovementioned dosage ranges. '

The following example illustrates the invention but does not limit it in any way.

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Example

This study evaluated the pharmacokinetics (PK) of Compound (I) and metformin (M) administered alone and in combination. Sixteen male volunteers, aged 22 to 55 years, received oral Compound (I) (2 mg Q12h), M (500 mg Q12h), or the combination, each for 4 days. Plasma collected on day 4 of each regimen was assayed for Compound (I) and M concentrations. Oral doses of Compound (I) and M were safe and well tolerated alone or in combination. There were no episodes of hypoglycaemia and co-âdministration did not result in an increase in blood lactic acid concentration.

<td rowspan="2"> Parameter [nnits| </td><td colspan="2"> M</td><td colspan="2"> Compound (I)</td>

<td> Alone</td><td> Comte</td><td> Alone</td><td> Comte</td>

<td> AUC(0-12) [ngh/mL]</td><td> 626 (494-866)</td><td> 629 (418-912)</td><td> 6508 (4694-8705)</td><td> 6575 (4773-9230)</td>

<td> Cmax [ng/mL]</td><td> 105 (785-1502)</td><td> 104 (763-1392)</td><td> 901 (620-1251)</td><td> 918 (635-1344)</td>

<td> Tmax [horns]</td><td> 3.0 (2.0-4.0)</td><td> 33 (15-4.0)</td><td> 3.0 (1.0-6.0)</td><td> 33 (15-6.0)</td>

<td> Tl/2 [hems]</td><td> • 322 (2.45-5.01)</td><td> 321 (236-4.64)</td><td> 324 (236-4.19)</td><td> 3.41 (2.64-438)</td>

Combo “ Compound (I) + M coadministratian

Coadministration of Compound (I) and M did not affect the steady-state pharmacokinetics (AUC(0-12), Cmax, Tmax, or Tl/2) of either drug. Because M plasma concentrations were unaffected, coadministration or Compound (I) will not accentuate the concentrationdependent toxicides of M.

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-10COMPOUND (I) COMPOSITIONS

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Concentrate Preparation

Approximately two thirds of the lactose monohydrate is passed through a suitable screen and blended with the milled maleate salt of Compound (I). Sodium starch glycollate, hydoxypropyl methylcellulose, microcrystallme cellulose and the remaining lactose are passed through a suitable screen and added to the mixture Blending is then continued. Thé resulting mixture is then wet granulated with purified water. The wet granules are then screened, dried on a fluid bed drier and the dried granules are passed through a further screen and

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% COMPOSITION OF GRANULAR CONCENTRATE

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Quantity (%)

Milled Compound (I) as maleate salt

13.25 (pure maleate salt)

Sodium Starch Glycollate

5.00

Hydoxypropyl Metfaylcelhilose 5.00 2910

20.0

Microcrystalline Cellulose

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to 100

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Purified water

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-11B Formulation of the concentrate into tablets.

The granules from above are placed into a tumble blender. Approximately two thirds of the lactose is screened and added to the blender. The microcrystalline cellulose, sodium starch glycollate, magnesium stearate and remaining lactose are screened and added to the blender and the mixture blended together. The resulting mix is then compressed on a rotary tablet press to a target weight of 150mg for the 1,2 and 4mg tablets and to a target weight of 300mg for the 8mg tablets.

The tablet cores are then transferred to a tablet coating machine, pre-warmed with warm air (approximately 65°C) and film coated until the tablet weight has increased by 2.0% to 33%.

Quantity (mg per Tablet)

<td> Tablet Strength</td><td> l.Omg</td><td> XOmg</td><td> 4.0mg</td><td> 8.0mg</td>

<td> Active Ingredient:</td><td></td><td></td><td></td><td></td>

<td> Compound (I) maleate Concentrate granules</td><td> 10.00</td><td> 20.00</td><td> 40.00</td><td> 80.00</td>

<td> Other Ingredients:</td><td></td><td></td><td></td><td></td>

<td> Sodium Starch Glycollate</td><td> 6.96</td><td> 6.46</td><td> 5.46</td><td> 1032</td>

<td> Microcrystaliine Cellulose</td><td> 27.85</td><td> 25.85</td><td> 21.85</td><td> 43.70</td>

<td> Lactose monohydrate</td><td> 104.44</td><td> 9654</td><td> 8134</td><td> 163.88</td>

<td> Magnesium Stearate</td><td> 0.75</td><td> 0.75</td><td> 0.75</td><td> 130</td>

<td> Total Weight of Tablet Core</td><td> 150.0</td><td> 150.0</td><td> 150.0</td><td> 300.0</td>

<td> Aqueous film coating material</td><td> 43</td><td> 43</td><td> 43</td><td> 9.0</td>

Total Weight of Film Coated Tablet

1543 1543 1543 309.0