Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide

Description of the invention

The invention relates to an antidiabetic pharmaceutical composition and use. The invention will find application in the treatment of diabetes mellitus, especially non-insulin dependent diabetes mellitus (NIDDM), otherwise known as type II diabetes, and pathological conditions associated with diabetes.

Insulin secretagogues are compounds that increase insulin secretion in the beta cells of the pancreas.

Sulfonylureas are well known examples of insulin secretagogues. Sulfonylureas act as antihyperglycemic agents and are used to treat type II diabetes. Examples of sulfonylureas include glibenclamide, glipizide, gliclazide, tolazamide, and tolbutamide.

Biguanide antihyperglycaemic agents are commonly used in the treatment of type II diabetes. An example of a biguanide antihyperglycaemic agent is 1,1-dimethylbiguanidine (Metformin).

In European patent application publication EP 0,306,228 certain thiazolidinedione derivatives having antihyperglycemic and antihyperlipidemic activity are described. One particular thiazolidinedione derivative disclosed in this publication is 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione [hereinafter referred to as "Compound (I)"]. In the international patent application publication WO 94/05659 certain salts of compound (I) are disclosed, inter alia maleate is described.

Compound (I) is an example of a class of antihyperglycaemic agents known as "insulin sensitizers." Especially compound (I) is a thiazolidinedione insulin sensitiser.

Thiazolidinedione insulin sensitisers are also disclosed in European Patent Application Publication Nos. 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0508740, and International Patent Applications 0508740734. Nos. 92/18501, 93/02079 and 93/22445 and in U.S. Patent Nos. 5,104,888 and 5,478,852.

Another series of compounds with known insulin sensitizing activity are those typically represented by the compounds disclosed in WO 93/21166 and WO 94/01420. These compounds are referred to herein as "acyclic insulin sensitisers". Other examples of acyclic insulin sensitizing compounds are those disclosed in US Patent No. 5,232,945 and in WO 92/03425 and WO 91/19702.

Examples of other insulin sensitizers are described in European Patent Application Publication No. 0533933, Japanese Patent Application Publication No. 05271204 and in US Patent No. 5264451.

EP-749751 discloses a huge number of combinations of therapeutic substances that are believed to be useful in the treatment of diabetes. The broadest aspect of this specification discloses a combination comprising an insulin sensitiser and a second therapeutic component selected from an α-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide, statin compounds, a squalene synthase inhibitor, a fubrate compound, an LDL catabolism enhancer, and an angiotensin corventase (ACE) inhibitor. . The specification discloses pioglitazone as an insulin sensitizer, and voglibose as an α-glucosidase inhibitor, and thus different active substances than in the present invention.

It has now surprisingly been found that compound (I) in combination with an insulin secretagogue and a biguanide antihyperglycemic compound has a particularly beneficial effect on blood glucose control. This combination is therefore particularly useful in the treatment of diabetes mellitus, especially type II diabetes and related conditions. Moreover, it turned out that this treatment is accompanied by a minimum of undesirable side effects.

The invention relates to an antidiabetic pharmaceutical composition comprising an insulin sensitizer and other antihyperglycemic agents with mechanisms of action different from the said insulin sensitizer and a pharmaceutically acceptable carrier and / or excipient. which according to the invention contains 2-12 mg of 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} thiazolidine-2,4-dione (compound I) or a pharmaceutically acceptable derivative thereof ; an insulin secretagogue selected from the group consisting of glibenclamide, glipizide, gliclazide, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide,

Glibornuride, glycidone, glisentide, glisolamide, glisoxepid, glyclopyamide, glycylamide or repaglinide; and the biguanide antihyperglycaemic agent which is metformin, buformin or phenformin.

Preferably, the composition according to the invention contains 2-4, 4-8 or 8-12 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 2-4 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 4-8 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 8-12 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 2 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 4 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

Preferably, the composition according to the invention contains 8 mg of Compound (I) or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention is the use of 2-12 mg of 5- {4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl} -thiazolidine-2,4-dione (Compound I) or a pharmaceutically an acceptable derivative; an insulin secretagogue selected from the group consisting of glibenclamide, glipizide, gliclazide, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, glycidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide or repaglinide; and a biguanide antihyperglycaemic agent selected from the group consisting of metformin, buformin and phenformin in the manufacture of a medicament for use in the treatment of type II diabetes and / or conditions associated with type II diabetes.

The invention will find utility in the treatment of diabetes mellitus, especially type II diabetes mellitus and pathological conditions associated with diabetes in mammals, including humans, by administering to the mammal in need of treatment an effective, non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, secretagogue, insulin and a biguanide antihyperglycaemic agent.

Co-administration includes administration of a formulation containing an insulin sensitizing compound, an insulin secretagogue, and a biguanide antihyperglycemic compound, or substantially simultaneous administration of separate formulations of the individual compounds.

A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser.

A suitable thiazolidinedione insulin sensitiser is compound (I).

Other thiazolidinedione insulin sensitisers include: (+) - 5 - {[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl ) methoxy] phenyl] methyl} thiazolidine-2,4-dione (troglitazone), 5- {4 - [(1-methylcyclohexyl) methoxy] benzyl} thiazolidine-2,4-dione (ciglitazone), 5- {4- [ 2- (5-ethylpyridin-2-yl) ethoxy] benzyl} thiazolidine-2,4-dione (pioglitazone) and 5 - [(2-benzyl-2,3-dihydro-benzo-pyran) -5-ylmethyl) -thiazolidine- 2,4-dione (englitazon).

Suitable insulin secretagogues include sulfonylureas.

Suitable sulfonylurea derivatives include glibenclamide, glipizide, gliclazide, tolazamide and tolbutamide.

Other sulfonylureas include acetohexamide, carbutamide (carbutamide), chlorpropamide, glibornuride, glycidon (gliquidone), glisentide (glisentide), glisolamide (glisolamide), glisoxepide (glisoxepide), glyclopyamide (glyclopyamide (glycylamide) and glycylamide.

Yet another insulin secretagogue is repaglinide.

A suitable biguanide antihyperglycaemic agent is metformin, buformin or phenformin, especially metformin.

It is understood that both the insulin sensitizing compound, such as compound (I), the insulin secretagogue, and the biguanide antihyperglycemic compound are administered in pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters or solvates of these compounds. suitable for a specific relationship. As used herein, in some instances, the names of insulin secretagogues and biguanide antihyperglycemic compounds may refer to a particular form of

Of the respective active compound. It is understood that all these pharmaceutically acceptable forms of the active compounds are as such within the scope of the invention.

Suitable pharmaceutically acceptable salt forms of insulin sensitizing compounds such as compound (I) include those which, for compound (I), are described in European patent publication EP 0306228 and in international patent application publication WO 94/05659. A preferred pharmaceutically acceptable salt of compound (I) is maleate.

Suitable pharmaceutically acceptable solvate forms of insulin sensitizing compounds such as compound (I) include solvates, especially hydrates, which for compound (I) are described in European patent publication EP 0306228 and international patent application publication WO 94/05659.

The choice of the appropriate pharmaceutically acceptable forms of the insulin secretagogue and the biguanide antihyperglycemic compound depends on the specific compound used, however, these forms include the known pharmaceutically acceptable forms of the particular compound selected. Such derivatives are described in standard reference texts such as British Pharmacopoeia, American Pharmacopoeia, Encyclopedias "Remington's Pharmaceutical Sciences" (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g. XXXI edition, pp. 341 and the pages cited therein).

An insulin sensitizing compound such as compound (I), a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof may be prepared in a known manner, e.g. as disclosed for compound (I) in European Patent Publication EP 0306228 and International Patent Application Publication No. WO 94/05659.

Compound (I) may exist in one of several tautomeric forms.

The selected insulin secretagogue and the biguanide antihyperglycemic agent are prepared in a known manner, e.g. by one of the methods described in standard reference texts such as the British Pharmacopoeia, American Pharmacopoeia, "Remington's Pharmaceutical Sciences" (Mack Publishing Co.), Martindale Theaters. Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g., XXXI edition, p. 341 and the pages cited therein).

The term "diabetic pathological conditions" herein includes conditions associated with diabetes itself and complications associated with diabetes. Conditions associated with diabetes also include conditions associated with pre-diabetes.

The term "conditions associated with pre-diabetes" includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and hyperinsulinemia.

Conditions associated with diabetes itself include hyperglycemia, insulin resistance, including acquired insulin resistance. Other conditions associated with diabetes itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include Stein-Leventhal syndrome, steroid-induced insulin resistance, and gestational diabetes.

Complications associated with diabetes include kidney disease, especially type II diabetes related kidney disease, neuropathy, and retinopathy.

Kidney diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerulosclerosis, renal sclerosis in hypertension, and end-stage renal disease. An additional kidney disease associated with type II diabetes is nephrotic syndrome.

For the avoidance of doubt, it is clarified that when the amounts are expressed in scalar terms, including mg of compound (I) in pharmaceutically acceptable form, the stated amount relates directly to compound (I) as such. For example, 2 mg of compound (I) in maleate form means that amount of the maleic acid salt contains 2 mg of compound (I).

The term "diabetes" means diabetes mellitus type II.

The particularly favorable effect on blood glucose in the treatment method according to the invention is shown in a synergistic effect compared to the control expected for the sum of the effects of the individual active ingredients.

Suitably the insulin sensitizer is a drug to be used as a primary drug.

Blood glucose control can be determined by known methods, for example, by determining a commonly used index of glycemic control such as fasting plasma glucose or glycosylated hemoglobin (HbA1c) levels. These indicators are determined by standard methods, for example the method described by Tuescher A. and Richterich P. in Schweiz.

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Med. East 101: 345 and 390 (1971) and by Frank P: "Monitoring the Diabetic Patient with Glycosolated Hemoglobin Measurements", Clinical Products (1988).

In a preferred aspect, the dosage level of each of the active ingredients when used in a treatment regimen will be less than that required for a purely additive effect of these ingredients in blood glucose control.

There is also an indication that, compared to treatment with individual medications, treatment gives better results in indices of advanced glycosylation (AGE) end products, leptin, and serum lipids, including total cholesterol, HDL-cholesterol, LDL-cholesterol levels, and improved ratios. between these indicators, especially it gives an improvement in the level of serum lipids, including improvement in the level of total cholesterol, HDL-cholesterol, LDL-cholesterol and improving the relative proportions of these levels.

The term "pharmaceutically acceptable" as used herein includes both human and veterinary use. For example, the term "pharmaceutically acceptable" includes a compound that is approved for veterinary use.

In the process according to the invention, the active compounds are preferably administered in the form of a pharmaceutical composition. As noted above, such compositions may contain all or only one of the drugs.

Accordingly, in one aspect, the invention relates to a pharmaceutical composition containing an insulin sensitizing compound such as compound (I), especially an amount of 2 mg to 12 mg of this compound, an insulin secretagogue, a biguanide antihyperlycemic compound and a pharmaceutically acceptable compound. carrier.

These compositions can be prepared by mixing an insulin sensitiser such as compound (I), especially an amount of 2 mg to 12 mg of this compound, an insulin secretagogue, a biguanide antihyperglycaemic agent and a pharmaceutically acceptable carrier.

In general, the compositions are adapted for oral administration. They can also be adapted to other routes of administration, for example, for parenteral, sublingual or transdermal administration.

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

In order to ensure consistency in use, it is preferred that the composition according to the invention is in the form of a dosage unit.

The presentation of the dosage unit for oral use may be tablets and capsules containing the usual adjuvants such as binders, e.g. syrup, acacia gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, tablet lubricants, e.g. magnesium stearate, disintegrants, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

These compositions are preferably formulated in unit dosage forms containing appropriate amounts of the active ingredient to ensure the proper daily dosage.

Suitable dosages for insulin sensitizers are those disclosed in the above-mentioned patent publications and patent applications.

A suitable dose range including the dose unit range for Compound (I) is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg compound (I).

During treatment, these drugs can be taken from 1 to 6 times daily and most preferably once or twice daily.

A specific dosage of Compound (I) is 2 mg / day, 4 mg / day, including 2 mg twice daily, and 8 mg / day, including 4 mg twice daily.

Suitable dosages comprising unit doses of an insulin secretagogue such as a sulfonylurea derivative or a biguanide antihyperglycemic agent are known dosages, including unit doses prescribed for these compounds, given or cited in texts such as the British Pharmacopoeia, American Pharmacopoeia, encyclopedias: "Remington's Pharmaceutical Sciences "(Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g. XXXI edition, p. 341 and pages cited therein).

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Thus, for sulfonylureas, typical daily doses of glibenclamide are in the range 2.5 mg to 20 mg, e.g. 10 mg twice daily or 20 mg once daily, typical daily doses of glipizide are 2.5 mg to 40 mg, typical daily doses of glipizide are 40 to 320 mg, typical daily doses of tolazamide are 100 mg to 1000 mg , typical daily doses of tolbutamide are from 1000 mg to 3000 mg, typical daily doses of chlorpropamide are from 100 mg to 500 mg and typical daily doses of glycvidone are from 15 mg to 180 mg.

Repaglinide can be used in amounts generally in the range of 0.5 mg to 4 mg, usually with meals, up to a typical maximum daily dose of 16 mg.

With regard to the biguanide antihyperglycaemic agents, the corresponding doses of metformin are up to 3000 mg per day. The drug is administered in unit doses of 500 mg (for example two or three times a day) or 850 mg (for example twice a day). An example of a metformin dosage is the administration of 500 mg once to 5 times daily.

Oral solid compositions can be prepared by known compounding, filling, or tabletting methods. Multiple mixing operations can be used to evenly distribute the active ingredient throughout those compositions using large amounts of fillers. Such operations are of course known. The tablets may be coated by methods well known in normal pharmaceutical practice, especially enteric coating.

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 reconstitution with water or other suitable vehicle before use. These liquid preparations may contain the usual adjuvants such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats, emulsifying agents, e.g. lecithin, sorbitan monooleate or acacia gum, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol, preservatives, e.g. methyl or propyl p-hydroxybenzoate or sorbic acid and, if appropriate, flavoring or coloring agents.

For parenteral administration, liquid dosage unit forms are made using the active compound and a sterile vehicle. Depending on the concentration used, this compound can either be suspended or dissolved in the vehicle. In preparing solutions, the active compound can be dissolved in water for injection and filter sterilized before filling into suitable vials or ampoules and sealing them. Conveniently, additives such as a local analgesic, preservative, and buffering agent can also be dissolved in the carrier. To increase the stability, the composition can be frozen after filling into 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 being dissolved, and sterilization is not performed by filtration. The compound may be sterilized with ethylene oxide before suspending in the sterile vehicle. A surfactant or wetting agent is preferably added to the composition to facilitate uniform distribution of the active compound.

Depending on the intended method of application, these compositions may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of the active ingredient.

If desired, the compositions may be packaged with attached, written or printed instructions for use.

These compositions are prepared and made into finished formulations using common methods such as those described in standard reference texts such as British Pharmacopoeia, American Pharmacopoeia, Encyclopedias: "Remington's Pharmaceutical Sciences" (Mack Publishing Co.) , Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g., XXXI Edition, p. 341 and the pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).

The invention also relates to a pharmaceutical composition for use as a medicament, comprising an insulin sensitizing compound, such as compound (I), especially an amount of 2 mg to 12 mg of this compound, an insulin secretagogue, a biguanide antihyperglycaemic compound and a pharmaceutically acceptable carrier.

The invention also relates to the use of an insulin sensitizing compound, such as compound (I), in particular an amount of 2 mg to 12 mg of this compound, a stimulant compound.

The secretion of insulin and a biguanide antihyperglycemic compound in the manufacture of a medicament for the treatment of diabetes and related conditions.

The invention relates in particular to a pharmaceutical composition containing an insulin sensitizing compound, such as compound (I), in particular an amount of 2 mg to 12 mg of this compound, an insulin secretagogue, a biguanide antihyperglycaemic compound and a pharmaceutically acceptable carrier for use in the treatment of diabetes and medical conditions. pathology associated with diabetes.

The range of 2 mg to 4 mg is ranges of 2.1 to 4 mg, 2.2 to 4 mg, 2.3 to 4 mg,

2.4 to 4 mg, 2.5 to 4 mg, 2.6 to 4 mg, 2.7 to 4 mg, 2.8 to 4 mg, 2.9 to 4 mg and 3 to 4 mg .

The range of 4 mg to 8 mg is 4.1 to 8 mg, 4.2 to 8 mg, 4.3 to 8 mg,

4.4 to 8 mg, 4.5 to 8 mg, 4.6 to 8 mg, 4.7 to 8 mg, 4.8 to 8 mg, 4.9 to 8 mg, 5 to 8 mg , from 6 to 8 mg and from 7 to 8 mg.

The range of 8 mg to 12 mg is from 8.1 to 12 mg, 8.2 to 12 mg, 8.3 to 12 mg, 8.4 to 12 mg, 8.5 to 12 mg, 8.6 to 12 mg, 8.7 to 12 mg, 8.8 to 12 mg, 8.9 to 12 mg, 9 to 12 mg, 10 to 12 mg and 11 to 12 mg.

No toxicological effects have been found for the compositions according to the invention in which the above-mentioned dosage ranges are used. Composition for the compound (I)

Preparation of the concentrate:

The tablet concentrate was prepared with the following ingredients

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

<td>Ground Compound (I) as maleate Sodium starch glycolate Hydroxypropylmethylcellulose 2910 Microcrystalline cellulose (Avicel PH102) Lactose monohydrate, general purpose grade Purified Water</td><td>13.25 (pure maleate 5.00 5.00 20.0 up to 100 *</td>

* - deleted during the process

The above concentrate is formed into tablets using the following substances:

<td></td><td colspan="4">Amount (mg in one tablet)</td>

<td>The content of active compound in a 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: Granular maleate concentrate of compound (I)</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>(Avicel PH102) Lactose monohydrate</td><td> 104,44</td><td> 96,94</td><td> 81,94</td><td> 163,88</td>

<td>(Pharmatose DCL15) 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 material</td><td> 4,5</td><td> 4,5</td><td> 4,5</td><td> 9,0</td>

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

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