Combination comprising 5-[4-[2-(n-methyl-n-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione and application thereof

Description of the invention

The present invention relates to a combination comprising 5- [4- [2- (N-methyl-N- (2-pyridyl) -amino) ethoxy] -benzyl] thiazolidine-2,4-dione and its use in the treatment of diabetes mellitus, in particular diabetes mellitus. insulin independent (NIDDM) or type II diabetes mellitus and conditions related to diabetes.

Biguanide antihyperglycemic agents are commonly used to treat NIDDM (or type II diabetes). An example of a biguanide antihyperglycaemic agent is 1,1-dimethylbiguanidine (or metformin).

European patent application EP 0306228 relates to certain thiazolidinedione derivatives described as having antihyperglycemic and hypolipidemic activity. A particular thiazolidinedione disclosed in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione ("Compound I" below).

Certain Compound I salts, including a maleate salt, are described in Example 1 in assembly WO 94/05659.

Compound I exemplifies a class of antihyperglycemic agents known as "insulin sensitisers". 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 Applications, Publication Nos. 92/18501, 93/02079, 93/22445 and US Patent Nos. 5,104,888 and 5,478,852 also describe certain thiazolidinedione insulin sensitisers.

Other groups of compounds generally recognized as having activity as insulin sensitisers are those exemplified by the compounds described in international patent applications, publication numbers WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as "acyclic insulin sensitisers". Other examples of acyclic insulin sensitisers are disclosed in US Patent No. 5,232,945 and International Patent Applications, Publication Nos. WO92 / 03425 and WO91 / 19702.

Examples of other insulin sensitizers are described in European Patent Application Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and US Patent Number 5264451.

The above-disclosed publications are incorporated herein by reference.

European patent application EP 749 751 relates to the use of insulin sensitisers, inter alia, in combination with biguanide compounds. For example, combinations of pioglitazone with other active substances are disclosed. However, the combination of Compound I with biguanide antihyperglycemic compounds is not disclosed.

It has now surprisingly been shown that 2 to 8 mg of Compound I in combination with metformin provides a particularly beneficial effect on glycemic control without the observed adverse effects, so this combination is particularly useful in the treatment of diabetes mellitus, especially type II diabetes and related conditions.

The invention relates to a combination comprising 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -benzyl] thiazolidine-2,4-dione, defined as Compound I, or a pharmaceutically acceptable form thereof. characterized in that it comprises Compound I or a pharmaceutically acceptable form thereof in an amount from 2 to 8 mg and up to 3000 mg metformin, wherein Compound I or a pharmaceutically acceptable form thereof and metformin are in the form of separate pharmaceutical compositions.

Preferably the metformin is in a pharmaceutically acceptable form, which form is metformin hydrochloride.

Preferably the metformin or metformin hydrochloride is present in an amount of 500 mg or 850 mg.

Preferably the combination comprises 2 to 4 mg or 4 to 8 mg of Compound I, or a pharmaceutically acceptable form thereof.

Preferably the combination contains from 2 to 4 mg of Compound I or a pharmaceutically acceptable form thereof.

Preferably the combination contains from 4 to 8 mg of Compound I or a pharmaceutically acceptable form thereof.

Preferably the combination comprises 2 mg of Compound I or a pharmaceutically acceptable form thereof.

Preferably the combination comprises 4 mg of Compound I or a pharmaceutically acceptable form thereof.

Preferably the combination comprises 8 mg of Compound I or a pharmaceutically acceptable form thereof.

PL 195 136 B1

Preferably, Compound I is in the form of the maleate salt.

The invention also relates to the use of from 2 to 8 mg of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -benzyl] thiazolidine-2,4-dione identified as Compound I or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin in the manufacture of a medicament for use in the treatment of diabetes or a diabetic-related condition, wherein Compound I or a pharmaceutically acceptable form thereof and metformin are in the form of separate pharmaceutical compositions.

Preferably the metformin is in a pharmaceutically acceptable form, this form being the hydrochloride salt.

Preferably, Compound I is in the form of the maleate salt.

Preferably, the medicament is for the administration of from 2 to 8 mg of Compound I or its pharmaceutically acceptable form per day.

The invention also relates to the use of 2 to 8 mg of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -benzyl] thiazolidine-2,4-dione identified as Compound I or a compound thereof. a pharmaceutically acceptable form for the manufacture of a medicament for use with metformin in an amount up to 3000 mg in the treatment of diabetes or a diabetic-related condition, wherein Compound I or a pharmaceutically acceptable form thereof and metformin are in the form of separate pharmaceutical compositions.

Preferably, Compound I is in the form of the maleate salt.

Preferably, the medicament is for the administration of from 2 to 8 mg of Compound I or its pharmaceutically acceptable form per day.

The invention also relates to the use of up to 3000 mg of metformin in the manufacture of a medicament for use with 2 to 8 mg of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -benzyl] thiazolidine-2, 4-dione defined as Compound I or a pharmaceutically acceptable form thereof in the treatment of diabetes or diabetes related conditions, wherein Compound I or a pharmaceutically acceptable form thereof and metformin are in the form of separate pharmaceutical compositions.

Preferably the metformin is in a pharmaceutically acceptable form, this form being the hydrochloride salt.

The use of the combination includes either the simultaneous administration of Compound I or its pharmaceutically acceptable form and metformin, or their sequential administration.

The use of the combination includes substantially the simultaneous administration of Compound I, or a pharmaceutically acceptable form thereof, and metformin as separate formulations for each agent.

It is understood that Compound I is administered in a pharmaceutically acceptable form, together with pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters, and solvates thereof, respectively. It should be understood that all pharmaceutically acceptable forms of the active agents per se are included in the present invention.

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

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

A suitable pharmaceutically acceptable form of metformin is an acid addition salt, such as hydrochloride.

Compound I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, can be prepared using known methods, such as those described in EP 0306228 and WO94 / 05659. EP 0306228 and WO94 / 05659 are hereby incorporated by reference.

Compound I can exist in one or more tautomeric forms, all of which are embraced by Compound I as individual tautomeric forms or as mixtures thereof.

Compound I contains a chiral carbon atom and can therefore exist in two stereoisomeric forms and the term Compound I includes all of these isomeric forms, either as individual isomers or as mixtures of isomers including racemates.

Compound I, its pharmaceutically acceptable form, and metformin and metformin hydrochloride are prepared by known methods, and these methods or references to them are found in standard sources such as British Pharmacopoeia, US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, for example, 31st edition page 341 and the pages cited therein) or as described in the publications mentioned above.

PL 195 136 B1

As used herein, the term "conditions associated with diabetes" includes conditions associated with the pre-diabetes period, conditions associated with diabetes itself, and complications associated with diabetes.

As used herein, the term "conditions associated with the pre-diabetes period" includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and blood insulin levels too high.

The "conditions associated with diabetes itself" include hyperglycemia, insulin resistance, including acquired insulin resistance, and obesity. Further conditions associated with diabetes mellitus itself include hypertension and coronary artery disease, particularly arteriosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid-induced insulin resistance, and gestational diabetes.

"Complications of diabetes" include kidney disease, especially type II diabetes related kidney disease, neuropathy, and retinopathy.

Kidney disease associated with Type II diabetes mellitus includes nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal cirrhosis, and end stage renal disease.

As used herein, the term "pharmaceutically acceptable" includes both human and animal uses: for example, the term "pharmaceutically acceptable" includes a veterinary acceptable compound.

In order to avoid confusion, when referring to scalar amounts, including amounts in mg of Compound I in pharmaceutically acceptable form, here it applies to Compound I per se: for example, 2 mg of Compound I in maleate salt form means the amount of maleate salt that is contains 2 mg of Compound I.

Preferably the diabetes is Type II diabetes.

A particularly beneficial effect of the present invention on glycemic control has been shown to be synergistic with the control expected for the sum of the effects of the individual active ingredients.

Glycemic control can be characterized using conventional methods, for example by measuring a commonly used glycemic control index such as fasting plasma glucose or glycosylated hemoglobin (HbAlc). Such indicators are determined using standard methodology, for example as described in Tuescher A., ​​Richterich P., Schweiz med. Wschr. 101 (1971), 345 and 390 and Frank P., "Monitoring the diabetic patent with glycosolated hemoglobin measurements", Clinical products 1988.

In a preferred aspect, the dosage level of each of the active ingredients, when used in accordance with the present invention, will be less than would be required for purely additive effects during glycemic control.

It has also been shown that the use of the present invention will improve the levels of advanced glycosylation end-products (AGEs), leptin and serum lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, over the individual components, together with an improvement in their relationship to each other. and in particular improving the level of serum lipids including total cholesterol, HDL cholesterol, LDL cholesterol, including improving their relationship to one another.

It is advantageous to administer the active substances in the form of a pharmaceutical composition. As indicated above, such active ingredients are in the form of separate pharmaceutical compositions.

Generally, such compositions are adapted for oral administration. However, they may be adapted to other modes of administration, for example parenteral, sublingual or transdermal administration.

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

In order to obtain a suitable consistency for administration, it is preferred that the composition is in the form of a unit dose.

A unit dose for oral administration may be in the form of tablets and capsules, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrators, e.g. starch, polyvinylpyrrolidone, starch glycolate PL 195 136 B1

-sodium or microcrystalline cellulose; or also pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

It is preferred that the compositions are in the form of a dosage unit in an amount appropriate to the daily dose used.

Particular dosages of Compound I are 2 mg / day, 4 mg / day, including 2 mg twice daily, and 8 mg / day, a total of 4 mg twice daily.

Suitable unit doses of a Compound of formula I contain 2, 3, 4, 5, 6, 7, or 8 mg of Compound I.

The combination of the present invention may be administered from 1 to 6 times daily, but most preferably 1 or 2 times daily.

Suitable dosages of Compound I or metformin include known dosages of these compounds as described or referenced in sources such as British Pharmacopoeia and US Pharmacopoeia, Remington Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press). (see, for example, 31st edition, page 341 and the pages cited therein) or the above-mentioned publications.

Suitable dosages of metformin include up to 3000 mg / day in unit doses, or 500 mg (e.g., two or three times a day) or 850 mg (e.g., twice a day), one example of a metformin dosage being 500 mg once to five times a day.

Thus, one example involves the administration of 4 to 8 mg of Compound I (2 mg twice daily, or 4 mg twice daily, respectively) and 1000 mg or 2500 mg of metformin (500 mg twice daily or 500 mg five times daily, respectively).

Solid oral compositions may be prepared in a conventional manner by mixing, filling, or tableting. Multiple mixing operations involving large amounts of fillers can be used to distribute the active agent in these compositions. Such operations are, of course, typical in this field. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular by means of enteric coatings.

Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or they may be presented as a dry product for constitution 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, hydroxyethyl cellulose, carboxymethyl cellulose, gel aluminum stearate, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may contain edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol esters; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if necessary, conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle and, depending on the concentration used, may be suspended or dissolved in the vehicle. In preparing solutions, the compound may be dissolved in water for injection and filtered on a sterile filter before filling into a suitable vial or ampoule and sealing. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To improve the stability, the composition can be frozen after filling the vials and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that Compound I is suspended in the vehicle instead of dissolving, and sterilization cannot be accomplished by filtration. The compound can be sterilized by treating it with ethylene oxide before suspending in the sterile vehicle. To facilitate uniform distribution of the compound, it is preferable to include a surfactant or wetting agent in the composition.

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

The compositions may, if desired, be in the form of a tampon accompanied by written or printed instructions for use.

The compositions are formulated according to conventional methods such as those described in standard sources, for example, British Pharmacopoeia, US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press (see, for example, 31st edition). page 341 and the pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).

PL 195 136 B1

The range of 2 to 4 mg covers the range 2.1 to 4, 2.2 to 4, 2.3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2 , 8 to 4, 2.9 to 4, or 3 to 4 mg.

The range of 4 to 8 mg covers the range 4.1 to 8, 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.5 to 8 4.6 to 8 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8, 6 to 8 or 7 to 8 mg.

At the aforementioned dosage ranges, no adverse toxicological effects were found for the composition or use of the present invention.

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

E xample

The present studies evaluated the pharmacokinetics (PK) of Compound I and metformin (M) administered alone and in combination. Sixteen female volunteers, 22 to 55 years of age, received Compound I (2 mg Q12h), M (500 mg Q12h) or the combination orally for 4 days each. Plasma collected on day 4 for each route of administration was assessed for the concentration of Compound I and M. Oral doses of Compounds I and M were safe and well tolerated alone and in combination. There were no cases of hypoglycaemia and concomitant administration did not increase the concentration of lactic acid in the blood.

<td rowspan="2">Parameter [units]</td><td colspan="2">M.</td><td colspan="2">Relationship I</td>

<td>Alone</td><td>Komb.</td><td>Alone</td><td>Komb.</td>

<td>AUC (0-12)</td><td> 626</td><td> 629</td><td> 6508</td><td> 6575</td>

<td>[ng.h / ml]</td><td> (494-866)</td><td> (418-912)</td><td> (4694-8705)</td><td> (4773-9230)</td>

<td>Cmax</td><td> 105</td><td> 104</td><td> 901</td><td> 918</td>

<td>[ng / md]</td><td> (78,9-150,2)</td><td> (76,5-139,2)</td><td> (620-1251)</td><td> (635-1344)</td>

<td>Tmax</td><td> 3,0</td><td> 3,5</td><td> 3,0</td><td> 3,5</td>

<td>[hours]</td><td> (2,0-4,0)</td><td> (1,5-4,0)</td><td> (1,0-6,0)</td><td> (1,5-6,0)</td>

<td>T1 / 2</td><td> 3,22</td><td> 3,21</td><td> 3,24</td><td> 3,41</td>

<td>[hours]</td><td> (2,45-5,01)</td><td> (2,56-4,64)</td><td> 2,56-4,19</td><td> (2,64-4,58)</td>

Comb. = Co-administration of Compound I + M

Co-administration of Compound I and M had no effect on the steady-state pharmacokinetics (AUC (0-12), Cmax, Tmax, or T1 / 2 of both drugs. Since there was no effect on plasma M concentrations, co-administration of Compound I would not increase the concentration-dependent effect of the drug. the toxicity of M.

Compositions of Compound I.

A. Receiving the concentrate

About two-thirds of the lactose monohydrate is passed through a suitable sieve and mixed with the ground maleate salt of Compound I. Sodium starch glycolate, hydroxypropyl methylcellulose, microcrystalline cellulose, and residual cellulose are passed through a suitable sieve and added to the mixture. Stirring continues. The resulting mixture is then wet granulated with purified water. The wet granules are then screened, dried in a fluid bed dryer, and the dried granules are passed through a further sieve and finally homogenized.

% Composition of the granular concentrate

<td>Ingredient</td><td>Amount (%)</td>

<td>Ground Compound I as maleate salt</td><td>13.25 (pure maleate salt)</td>

<td>Sodium starch glycolate</td><td> 5,00</td>

<td>Hydroxypropylmethylcellulose 2910</td><td> 5,00</td>

<td>Microcrystalline cellulose</td><td> 20,00</td>

<td>Lactose monohydrate, homogeneous</td><td>up to 100</td>

<td>Purified water</td><td> *</td>

* Deleted during the process

B. Tablet concentrate formulation

PL 195 136 B1

The granules from the above are placed in a tumble mixer. About two-thirds of the lactose is screened and added to the blender. Microcrystalline cellulose, sodium starch glycolate, magnesium stearate and the remaining lactose are screened and added to the blender and the mixture is blended together. The resulting mixture is then compressed on a rotary tablet press to a final weight of 150 mg for 1.2 and 4 mg tablets and to a final weight of 300 mg for 8 mg tablets.

The tablet cores are then transferred to a tablet coater, pre-warmed with warm air (about 65 ° C) and film coated until a tablet weight gain of 2.0% to 3.5% is obtained.

<td rowspan="2">The power of the tablet</td><td colspan="4">Amount (mg per tablet</td>

<td>1.0 mg</td><td>2.0 mg</td><td>4.0 mg</td><td>8.0 mg</td>

<td>Active ingredient: Concentrated Compound I maleate granules</td><td> 10,00</td><td> 20,00</td><td> 40,00</td><td> 80,00</td>

<td>Other ingredients: Sodium starch glycolate</td><td> 6,96</td><td> 6,46</td><td> 5,46</td><td> 10,92</td>

<td>Microcrystalline 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> 96,94</td><td> 81,94</td><td> 163,88</td>

<td>Magnesium stearate</td><td> 0,75</td><td> 0,75</td><td> 0,75</td><td> 1,50</td>

<td>Total weight of the tablet core</td><td> 150,0</td><td> 150,0</td><td> 150,0</td><td> 300,0</td>

<td>Coating film containing water</td><td> 4,5</td><td> 4,5</td><td> 4,5</td><td> 9,0</td>

<td>Total weight of the film coated tablet</td><td> 154,5</td><td> 154,5</td><td> 154,5</td><td> 309,0</td>

Patent claims