KR20010013845A - Treatment of Diabetes with Thiazolidinedione and Alpha-Glucosidase Inhibitor - Google Patents

Abstract

The present invention comprises administering a pharmaceutically acceptable non-toxic effective amount of an insulin sensitiser and an alpha-glucosidase inhibitor antihyperglycemic agent to a mammal in need thereof. A method of treating diabetes mellitus and a disease associated with diabetes in a mammal.

Description

Treatment of Diabetes with Thiazolidinedione and Alpha-Glucosidase Inhibitor {Treatment of Diabetes with Thiazolidinedione and Alpha-Glucosidase Inhibitor}

Alpha-glucosidase inhibitor antihyperglycemic agents such as Acarbose, Emiglitate and Miglitol are commonly used for the treatment of NIDDM (or Type II diabetes).

European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives disclosed to have antihyperglycemic and antihyperlipidemic activity. One particular thiazolidinedione disclosed in European Patent Application Publication No. EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine -2,4-dione (hereinafter referred to as 'compound (I)'). WO 94/05659 discloses certain salts of compound (I), including maleate, in Example 1 thereof.

Compound (I) is an example of a kind of antihyperglycemic agent known as an 'insinsitiser'. In particular, compound (I) is a thiazolidinedione insulin sensitizer.

European Patent Application Publication No. 0008203, No. 039421, No. 032128, No. 0428312, No. 0489663, No. 055845, No. 0778,1, No. 0206020, No. 0177353, No. 0319189, 0303331, 0332332, 0528734, and 00508740; International Patent Application Publication Nos. 92/18501, 93/02079, 93/22445, and US Pat. Nos. 5,104,888 and 55,547,52 also describe certain thiazolidinedione insulin sensitizers.

Other classes of compounds that are generally recognized to have insulin sensitizing activity are those represented by the compounds described in WO 93/21166 and WO 94/01420. These compounds are referred to herein as 'acyclic insulin sensitizers'. Other examples of acyclic insulin sensitizers are those described in US Pat. No. 52,2945 and WO 92/03425 and WO 91/19702.

Examples of other insulin sensitizers are those described in European Patent Application Publication No. 0533933, Japanese Patent Application Publication No. 05271204 and US Patent No. 5445445.

The aforementioned patent documents are incorporated herein by reference.

The present invention relates to a method of treatment, in particular a method of treating diabetes, in particular insulin independent diabetes (NIDDM) or type II diabetes and diseases associated with diabetes.

Surprisingly, the compound (I) in combination with the alpha-glucosidase inhibitor antihyperglycemic agent provides a particularly beneficial effect on glycemic control with minimal side effects, and therefore, such complexes have diabetes, in particular type II diabetes. And the treatment of diseases associated with diabetes.

Accordingly, the present invention provides a pharmaceutically acceptable non-toxic effective amount of an insulin sensitizer, for example Compound (I) and alpha-, in a mammal, such as a person in need of treatment for diabetes, in particular Type II diabetes and diseases associated with diabetes. Provided is a method of treating diabetes in a mammal, in particular type II diabetes and a disease associated with diabetes, comprising administering a glucosidase inhibitor antihyperglycemic agent.

The present invention provides in another aspect a combination of an insulin sensitizer, eg, compound (I), with an alpha-glucosidase inhibitor antihyperglycemic agent for use in a method of treating diabetes, in particular type II diabetes and a disease associated with diabetes. do.

The methods of the present invention comprise co-administration or sequential administration of insulin sensitizers such as compound (I), and alpha-glucosidase inhibitor antihyperglycemic agents.

Co-administration includes administration of a formulation containing an insulin sensitizer, eg, compound (I) and a biguanide antihyperglycemic agent, or substantially simultaneous administration of separate formulations of each medicament.

In another aspect, the present invention is directed to the preparation of a pharmaceutical composition for treating diabetes mellitus, in particular type II diabetes and diabetes, of insulin sensitizers such as compound (I), and alpha-glucosidase inhibitor antihyperglycemic agents. Provides a use for use.

Suitable thiazolidinedione insulin sensitizers are compound (I).

Other suitable thiazolidinedione insulin sensitizers are (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzo Pyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2 , 4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5- [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone).

Suitable alpha-glucosidase inhibitor antihyperglycemic agents are acarbose.

Other suitable alpha-glucosidase inhibitor antihyperglycemic agents are emiglytate and miglytol.

In one particular aspect, the methods of the present invention comprise administering from 2 to 12 mg of compound (I), especially when administered per day.

In particular, the methods of the invention comprise administering 2 to 4 mg, 4 to 8 mg or 8 to 12 mg of insulin sensitizer, for example compound (I) per day.

In particular, the methods of the invention comprise administering 2 to 4 mg of compound (I), especially when administered per day.

In particular, the methods of the present invention comprise administering from 4 to 8 mg of compound (I), especially when administered per day.

In particular, the method of the invention comprises administering 8 to 12 mg of compound (I), especially when administered per day.

Preferably, the method of the invention comprises administering 2 mg of compound (I), especially when administered per day.

Preferably, the methods of the present invention comprise administering 4 mg of compound (I), especially when administered per day.

Preferably, the method of the invention comprises administering 8 mg of compound (I), especially when administered per day.

Insulin sensitizers, such as compound (I), and alpha-glucosidase inhibitor antihyperglycemic agents, respectively, are suitably pharmaceutically acceptable salts, esters and solvates thereof, as appropriate for the relevant pharmaceutical actives. It will be understood that it will be administered in a pharmaceutically acceptable form, including derivatives. In some instances, the name used for the relevant alpha-glucosidase inhibitor herein may be related to the specific pharmaceutical form of the active agent concerned: It is understood that all pharmaceutically acceptable forms of the active agent are themselves included in the present invention. Will be.

Suitable pharmaceutically acceptable forms of insulin sensitizers include those described in the patent document.

Suitable pharmaceutically acceptable chloride forms of compound (I) include those described in European Patent Application Publication No. EP 0306228 and International Patent Application Publication No. WO94 / 05659. Preferred pharmaceutically acceptable salts are maleates.

Suitable pharmaceutically acceptable solvate forms of compound (I) include those described in European Patent Application Publication No. EP 0306228 and International Patent Application Publication No. WO94 / 05659, in particular hydrates.

Suitable pharmaceutically acceptable forms of the alpha-glucosidase inhibitor antihyperglycemic agents depend on the particular medicament used, but include known pharmaceutically acceptable forms of the particular compound selected. Such derivatives are described in standard references, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (eg, 31st Edition 341). Pages and pages mentioned here).

Insulin sensitizers can be prepared using known methods, such as those described in the above-mentioned patent documents, which are incorporated herein by reference.

Compound (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof can be prepared using known methods, for example those described in EP 0306228 and WO94 / 05659. The disclosures of EP 0306228 and WO 94/05659 are incorporated herein by reference.

Compound (I) may exist in one of several tautomeric forms, all of which are included in the term compound (I) as individual tautomeric forms or as mixtures thereof. Since compound (I) contains chiral carbon atoms, it may exist in up to two stereoisomeric forms, and the term compound (I) includes both of these isomeric forms as individual isomers or as a mixture of isomers including racemates. do.

Selected alpha-glucosidase inhibitor antihyperglycemic agents are prepared according to known methods, which are standard references, such as the British and US Pharmacopeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and literature. Found or referred to in Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, page 31, 341, and pages cited therein).

As used herein, the term 'disease associated with diabetes' includes diseases associated with prediabetes conditions, diseases associated with diabetes itself and complications associated with diabetes.

As used herein, the term 'diseases associated with pre-diabetic conditions' includes diseases such as insulin resistance (including genetic insulin resistance), impaired glucose tolerance, obesity and hyperinsulinemia.

Diseases associated with diabetes itself include hyperglycemia, insulin resistance, including acquired insulin resistance, and obesity. Another disease associated with diabetes itself includes high blood pressure, cardiovascular disease, especially those associated with atherosclerosis and insulin resistance. Diseases associated with insulin resistance include polycystic ovary syndrome and steroid induced insulin resistance and gestational diabetes.

'Diabetes-related complications' include kidney disease, in particular kidney disease, neuropathy and retinopathy associated with type II diabetes.

Renal diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive neurosis and late stage kidney disease.

As used herein, the term 'pharmaceutically acceptable' includes both human and veterinary uses, for example the term 'pharmaceutically acceptable' includes veterinary acceptable compounds.

For the sake of clarity, when referring herein to a scalar amount comprising an mg amount of a compound (I) in a pharmaceutically acceptable form, the scalar amount mentioned is for compound (I) itself: for example, male 2 mg of compound (I) in acid form is the amount of maleate containing 2 mg of compound (I).

Diabetes is preferably type II diabetes.

Particularly beneficial effects on glycemic control provided by the methods of treatment of the present invention appear to be synergistic compared to the expected control over the sum of the effects of the individual active agents.

Glucose control can be characterized by measuring conventional indices of glycemic control typically used, such as fasting blood glucose or glycosylated hemoglobin (Hb A1c). Such indices are standard methods such as those in Tuescher A., Richterich, P., Schweiz. med. Wschr. 101 (1971), 345, and 390, and Frank P., Monitoring the Diabetic Patient with Glycosylated Hemoglobin Measurements, Clinical Products 1988.

In a preferred aspect, when used in accordance with the treatment methods of the present invention, the dosage level of each active agent will be less than necessary to exhibit a pure additive effect on glycemic control.

In addition, the treatment methods of the present invention will improve levels of serum lipids, including total cholesterol, HDL-cholesterol, LDL-cholesterol, including improved glycosylation end products (AGEs), leptin, and proportions over individual drugs. , In particular, serum cholesterol, including total cholesterol, HDL-cholesterol, LDL-cholesterol, including improvement in proportions.

In the methods of the invention, the active agent is preferably administered in the form of a pharmaceutical composition. As indicated above, such compositions may contain both drugs or only one of the two drugs.

Thus, in one aspect of the invention there is provided a pharmaceutical composition comprising an insulin sensitizer, for example Compound (I) in particular 2-12 mg, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. .

Such compositions can be prepared by mixing insulin sensitizers, for example Compound (I) in particular 2-12 mg, alpha-glucosidase inhibitor antihyperglycemic agents and pharmaceutically acceptable carriers.

In general, the composition is suitable for oral administration. However, it may be suitable for other modes of administration, for example, parenteral, sublingual or transdermal.

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

In order to achieve consistency of administration, the compositions of the present invention are preferably in unit dosage form.

Unit dosage forms for oral administration may be tablets and capsules, and may include binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers such as lactose, sugars, corn starch, calcium phosphate, sorbitol or glycine; Tableting lubricants such as magnesium stearate; Disintegrants such as starch, polyvinylpyrrolidone, sodium glycolate starch or microcrystalline cellulose; Or pharmaceutically acceptable wetting agents, for example conventional excipients such as sodium lauryl sulfate.

The composition is preferably in unit dosage form for an appropriate daily administration.

Suitable dosage forms comprising unit doses of the compound of formula (I) contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I).

At the time of treatment, the medicament may be administered 1 to 6 times per day, but most preferably, 1 or 2 times per day.

Particular dosages of compound (I) are 2 mg / day, 4 mg / day including 2 mg twice daily, and 8 mg / day including 4 mg twice daily.

Suitable dosage forms, including unit dosage forms of insulin sensitizers and alpha-glucosidase inhibitor antihyperglycemic agents, are standard reference literature, such as the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Known dosages and units for Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, page 31, page 341 and pages mentioned herein) or those compounds described or referred to in the above publications. Dosage.

Thus, typical daily doses of acarbose range from 50 to 600 mg, for example 100 to 200 mg per day.

Solid oral compositions can be prepared by conventional blending, filling or tableting methods. The blending operation can be repeated to distribute the active agent throughout the composition using a large amount of filler. Such work is of course common in the art. Tablets may be coated according to methods well known in standard pharmaceutical practice, in particular with enteric coatings.

Oral liquid compositions may be in the form of emulsions, syrups or elixirs, for example, or may be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations include suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hardened edible fats; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional additives such as conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are prepared using compounds and sterile vehicles and can be suspended or dissolved in the vehicle depending on the concentration used. In preparing the solution, the compound may be dissolved in water for injection, sterile filtered and then filled into a suitable vial or ampoule and sealed. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. To enhance the stability, the composition can be frozen in a vial and freed of water under vacuum. Parenteral suspensions are prepared in substantially the same manner except that compound (I) is suspended instead of dissolved in the vehicle and cannot be sterilized by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound.

The composition may contain 0.1 to 99% by weight, preferably 10 to 60% by weight of active substance, depending on the method of administration.

If desired, the composition may be in the form of a pack with written or printed instructions for use.

The compositions may be prepared by conventional methods, such as standard references, such as the British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (eg See, eg, page 31, page 341 and the pages cited therein and Harry's Cosmeticology (Leonard Hill Books).

In another aspect, the invention also provides a pharmaceutical composition for use as an active therapeutic agent, containing Compound (I), in particular 2 to 12 mg, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. .

In particular, the present invention provides a pharmaceutical for treating diabetes, in particular type II diabetes and diseases associated with diabetes, comprising compound (I) in particular 2-12 mg, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. To provide a composition.

The range of 2 to 4 mg ranges from 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. It includes.

The range of 4 to 8 mg is 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 in the range of 7 to 8 mg.

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

No toxic side effects were seen in the above-mentioned dosage ranges for the compositions or methods of the present invention.

The following examples illustrate the invention but do not limit it in any way.

In this study, we investigated whether administration of acarbose (A) altered the PK of coadministered compound (I). Sixteen healthy volunteers (aged 24-24) received a single oral dose (8 mg) of compound (I) on day 1, followed by repeated dosing with A up to 7 days (three times daily with meals). 100 mg). On day 8, a single oral dose of compound (I) was co-administered with the morning dose of A. The PK profiles after administration of compound (I) on days 1 and 8 were compared. Co-administration of compounds (I) and A is well cited. Compound (I) + A: PK data and point evaluation [95% confidence interval] for compound (I) alone were analyzed.

Parameter [unit] Compound (I) only Compound (I) + A AUC (0-inf) [ng.h / ml] 2793 (581) 2502 (755) C _max [ng / ml] 428 (86) 451 (141) T_max* [city] 1.48 (0.97-5.95) 1.24 (0.95-3.98) T1 / 2 [hour] 4.93 (0.78) 3.79 (0.78) * Data presented as midpoint (range)

Compound (I) absorption (C _max and T _max ) is not affected by co-administration with A, but exposure to compound (I) (AUC [0-inf]) is the mean upon co-administration of compound (I) + A. 12% decrease (PE 0.88 [0.79, 0.98]) and at the same time T1 / 2 decreased about 1 hour. Thus, acarbose appears to slightly increase the clearance of compound (I), but the change is small and does not seem to be clinically relevant. In conclusion, compound (I) may be co-administered with acarbose without adversely affecting the pharmacokinetics of compound (I) and / or its potential clinical benefit.

Composition of Compound (I)

A. Concentrate Preparation

About IX of lactose monohydrate was passed through a suitable screen and blended with maleate of milled compound (I). Sodium glycolate starch, hydroxypropyl methylcellulose, microcrystalline cellulose and the remaining lactose were passed through a suitable screen and added to the mixture. Then blending was continued. The resulting mixture was then wet granulated with purified water. The wet granules were then screened, dried on a fluid bed dryer, the dried granules passed through another screen and finally homogenized.

% Composition of granular concentrate

ingredient Volume (%) Compound (I) as milled maleate 13.25 (pure maleate) Sodium glycolate starch 5.00 Hydroxypropyl methylcellulose 2910 5.00 Microcrystalline cellulose 20.00 Lactose Monohydrate, Rule Grade Up to 100 Purified water * * Removed during machining

B. Formulation of Concentrates into Tablets

The granules obtained above were placed in a tumble blender. About ⅔ of lactose was screened and added to the blender. Microcrystalline cellulose, sodium glycolate starch, magnesium stearate and the remaining lactose were screened and added to the blender and the mixture blended together. The resulting mixture was then compressed on a rotary tablet press to a target weight of 150 mg for 1, 2 and 4 mg tablets and a target weight of 300 mg for 8 mg tablets.

The tablet cores were then transferred to a tablet coater previously warmed to warmth (about 65 ° C.) and film coated until the tablet weight increased from 2.0% to 3.5%.

Amount (mg / tablet) Tablet concentration 1.0 mg 2.0 mg 4.0 mg 8.0 mg Active Ingredients: Compound (I) Maleate Concentrate Granule 10.00 20.00 40.00 80.00 Other ingredients: Sodium glycolate starch microcrystalline cellulose lactose monohydrate magnesium stearate 6.9627.85104.440.75 6.4625.8596.940.75 5.4621.8581.940.75 10.9243.70163.881.50 Total weight of tablet core 150.0 150.0 150.0 300.0 Water based film cladding 4.5 4.5 4.5 9.0 Total weight of film coated tablets 154.5 154.5 154.5 309.0

Claims (21)

Administering a pharmaceutically acceptable non-toxic effective amount of an insulin sensitiser and an alpha-glucosidase inhibitor antihyperglycemic agent to a mammal in need thereof. Method of treating diabetes and diseases associated with diabetes. The method of claim 1, wherein said alpha-glucosidase inhibitor antihyperglycemic agent is acarbose, emiglytate or miglytol. The method of claim 1, wherein the alpha-glucosidase inhibitor antihyperglycemic agent is acarbose. The method according to any one of claims 1 to 3, wherein the insulin sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine- 2,4-dione (compound (I)). The method of any one of claims 1 to 4 comprising administering from 2 to 12 mg of compound (I). 6. The method of claim 1, comprising administering 2-4 mg, 4-8 mg or 8-12 mg of compound (I). 7. The method of any one of claims 1 to 6 comprising administering 2 to 4 mg of compound (I). The method of any one of claims 1 to 6, comprising administering 4-8 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 8 to 12 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 2 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 4 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 8 mg of compound (I). The method of claim 1, wherein the insulin sensitizer is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzo Pyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2 , 4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5- [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone); Or a pharmaceutically acceptable form thereof. A pharmaceutical composition comprising an insulin sensitizer, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. 15. The composition of claim 14, wherein said alpha-glucosidase inhibitor antihyperglycemic agent is acarbose, emiglitate or miglitol. 16. The composition of claim 14 or 15, wherein said alpha-glucosidase inhibitor antihyperglycemic agent is acarbose. The composition according to any one of claims 14 to 16, wherein said insulin sensitizer is compound (I). 18. The composition according to any one of claims 14 to 17, which contains 2 to 12 mg of compound (I). A pharmaceutical composition for use as an active therapeutic agent comprising an insulin sensitizer, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating diabetes and diseases associated with diabetes, comprising an insulin sensitizer, an alpha-glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. The method of claim 14, 19 or 20, wherein the insulin sensitizer is selected from (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5, 7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclo Hexyl) methoxy] benzyl] thiazolidine-2,4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine- 2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone); Or a pharmaceutically acceptable form thereof.