SK179399A3 - Use of insulin sensitiser and an insulin - Google Patents

Abstract

A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of Compound (I) and insulin to a mammal in need thereof.

Description

The use of an insulin sensitiser and an insulin pharmaceutical composition

The invention relates to the use of an insulin sensitizer (rosiglitazone compound (i)) and insulin for the manufacture of a medicament for the treatment of diabetes mellitus, in particular non-insulin-dependent diabetes (NIDDM, type II diabetes) and conditions associated with diabetes mellitus.

BACKGROUND OF THE INVENTION

Insulin is the first in a series of agents for the treatment of type I diabetes (or insulin-dependent diabetes). It is also used as an antihyperglycaemic agent in the treatment of NIDDM. European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives which are said to have antihyperglycemic and hypolipidemic effects. One specific thiazolidinedione disclosed in EP 0 306 228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (rosiglitazone), (in hereinafter referred to as Compound (I)). WO94 / 05659 discloses certain salts of compound (I), including the maleate, in Example 1.

International Patent Application WO97 / 05875 describes a method of reducing the amount of exogenous insulin administered to a patient with NIDDM by administering a therapeutically effective amount of a thiazolidinedione derivative and / or related compounds.

It has now surprisingly been shown that a certain amount of Compound (I) in combination with insulin has an exceptionally beneficial effect on glycemic control; such a combination will then be very suitable for the treatment of II. diabetes mellitus and conditions associated with diabetes mellitus.

SUMMARY OF THE INVENTION

The present invention provides the use of an insulin sensitizer, for example rosiglitazone (compound (I)) and insulin to a mammal for the manufacture of a medicament for the treatment of diabetes mellitus, in particular II. type diabetes and conditions associated with diabetes mellitus, in mammals.

The preferred amount of Compound (I) administered is up to 12 mg, especially when administered daily.

Said use comprises co-administration of compound (I) and insulin, or sequential administration of the individual active ingredients.

Co-administration includes administration of a composition consisting of an insulin sensitizer, for example Compound (I) and insulin, or administration, substantially concurrently, of separate formulations of each of said active ingredients.

In one embodiment, the use comprises administering 2 to 12 mg of Compound (I), especially when administered daily.

The use further includes administering 2 to 4, 4 to 8, or 8 to 12 mg of Compound (I) per day.

The use further includes the administration of 2 to 4 mg of Compound (I), especially when administered daily.

The use further includes the administration of 4 to 8 mg of Compound (I), for example more than 4 mg, for example 4.1 mg to 8 mg of Compound (I), especially when administered daily.

The use further includes the administration of 8 to 12 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 2 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 4 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 8 mg of Compound (I), especially when administered daily.

It will be understood that Compound (I) and insulin are administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives, such as pharmaceutically acceptable salts and solvates thereof.

Suitable, pharmaceutically acceptable forms of compound (I) include those described in EP 0 306 228 and WO94 / 05 659, in particular forms of pharmaceutically acceptable salts. A preferred pharmaceutically acceptable salt is maleate.

Suitable, pharmaceutically acceptable solvated forms of compound (I) include the solvate forms described in EP 0 306 228 and WO94 / 05 659, in particular hydrates.

I

Suitable or pharmaceutically acceptable forms of insulin are referred to in basic reference guides such as British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing).

Co.), The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see 31st edition, page 341 and pages cited therein).

Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared by known methods, for example, the methods disclosed in EP 0 306 228 and WO94 / 05 659. EP 0 306 228 and WO94 / 05 659 are hereby incorporated herein by reference. reference.

Compound (I) may exist in one or more tautomeric forms; all such forms are included in the term compound (I) whether they are individual tautomeric forms or mixtures thereof. Compound (I) has a chiral carbon atom and can therefore exist in up to two stereoisomeric forms; the term compound (I) includes all isomeric forms, whether individual isomers or mixtures of isomers, including racemates.

Insulin can be prepared by known methods, for example, methods that can be found or referred to in basic reference guides such as British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) ( for example, see 31st edition, page 341 and pages cited therein).

As used herein, the condition associated with diabetes mellitus means those conditions associated with a pre-diabetic condition, conditions associated with diabetes mellitus itself, and conditions of complications associated with diabetes mellitus.

The term condition associated with self diabetes mellitus includes hyperglycemia, insulin resistance, including acquired insulin resistance and obesity. Other conditions associated with self diabetes mellitus include hypertension and cardiovascular disease, in particular atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid-induced insulin resistance and pregnancy diabetes.

Complications associated with diabetes mellitus include kidney diseases, especially kidney diseases associated with diabetes II. type, neuropathy and retinopathy.

- Kidney diseases associated with II. Types of diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and last degree of kidney disease.

The term pharmaceutically acceptable is used herein to include both human and veterinary use; for example, the term pharmaceutically acceptable includes a veterinarily acceptable compound.

To avoid misunderstanding of the expression of scalar quantities, including mg amounts of compound (I) in a pharmaceutically acceptable form, the scalar amount refers to compound (I) per se; for example, 2 mg of Compound (I) as a maleate (addition salt) is an amount of the maleate salt of Compound (I) containing 2 mg of Compound (I).

Diabetes mellitus is preferably II. type diabetes.

The particularly favorable effect in controlling glycemia by the treatment according to the invention, found in comparative trials, appears to be a synergistic effect, the effect being greater than the sum of the effects of the individual active substances.

Glycemic control can be characterized by conventional methods, for example, by determining the glycemic index typically used, for example, dietary plasma sugar or glycosylated hemoglobin (Hb A 1c). These parameters are determined by conventional procedures, for example those described by Tuescher A., Monitoring the Diabetic Patient with Glycosylated Hemoglobin Measurements, Clinical Products 1988.

In a preferred embodiment, the dosage level of each of the active ingredients when used for the treatment of the present invention is lower than would be required for the same control of blood glucose for only the sum of the effects of the individual substances.

In the method of the invention, the active ingredients are preferably administered in the form of pharmaceutical compositions. As mentioned above, the pharmaceutical compositions may comprise both or just one of the drugs.

In the treatment of the invention, insulin is generally administered by injection or other known means, for example, the methods set forth in the above-mentioned manuals. The following relates to pharmaceutical compositions, formulations and routes of administration, suitably it relates to pharmaceutical compositions, formulations and routes of administration of compound (I).

I

The pharmaceutical composition is usually formulated to be suitable for oral administration. However, it may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.

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

In order to achieve reliability in drug delivery, it will be appreciated that the pharmaceutical composition of the invention will be in unit dosage form.

Unit dosage forms for oral administration may be tablets or capsules and the pharmaceutical composition may contain commonly used excipients and additives 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 such as magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, for example sodium lauryl sulfate.

Solid oral pharmaceutical compositions may be prepared by conventional methods of mixing, filling or tabletting. When a large proportion of fillers is used, the mixing operation can be repeated to mix the active ingredient in the pharmaceutical composition. These operations are known in the art. The tablets may be coated by methods well known in the pharmaceutical art; in particular, the tablets may be coated with coatings which dissolve in the intestinal tract.

Oral liquid drug preparations may take the form of, for example, emulsions, syrups or elixirs, or may be in the form of dry preparations for reconstitution (prior to use) in water or other suitable carrier. These liquid preparations may contain conventional additives such as dispersants, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol, or ethanol; preservatives, for example

-6-methyl or propyl p-hydroxybenzoate or sorbic acid; if desired, they may contain commonly used flavorings and / or colorants or pigments.

Liquid unit dosage forms for parenteral administration are prepared from said active compounds and a sterile carrier; depending on the concentration chosen, the active compounds may be dissolved or suspended in a carrier. In preparing solutions, the active compound is dissolved in water for injection; sterilize by filtration before filling into a suitable ampoule or vial and before sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffers may be dissolved in the carrier. To enhance stability, the pharmaceutical compositions may be freeze-dried after filling and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, but compound (I) is suspended in the carrier instead of being dissolved and sterilization cannot be accomplished by filtration. Before dispersion in a sterile carrier, compound (I) can be sterilized by the action of ethylene oxide. Preferably, a surfactant is included in the carrier to facilitate uniform distribution of the compound in the suspension.

The pharmaceutical compositions may contain from 0.01% to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient, depending on the mode of administration.

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

Pharmaceutical compositions are formulated in accordance with general principles, such as those disclosed 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 31 ^st Edition page 341 and pages therein) or in Cosmeticology (Harry, Leonard Hill Books).

Said pharmaceutical compositions are preferred in unit dosage form in an amount corresponding to the respective daily dose.

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

The compounds of the invention may be administered 1 to 6 times daily, most preferably once or twice daily.

I

Suitable insulin doses, including unit doses, include those as described herein or as determined in basic manuals such as British and US

Pharmacopoieas, Remington's Pharmaceutical Sciences (Mack Publishing Co.),

Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 ^st Edition page 341 and pages cited therein).

The range 2 to 4 mg includes 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 4-8 mg includes the range 4.1-8, 4.2-8, 4.3-8, 4.4-8, 4.5-8, 4.6-8, 4.7-8.4. , 8 to 8, 4.9 to 8, 5 to 8, 6 to 8, or 7 to 8 mg.

The range of 8 to 12 mg includes the range of 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 adverse toxicological effects were noted in the dosage ranges of the pharmaceutical compositions of the present invention.

The following example illustrates the invention in more detail, but does not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example

Pharmaceutical Compounds of Compound (I)

A) Preparation of concentrate

Approximately 2/3 of the lactose monohydrate was sieved through a suitable sieve and mixed with the ground maleate of compound (I). The sodium starch glycolate, hydroxypropyl methylcellulose, microcrystalline cellulose and the rest of the lactose were sieved through a suitable sieve and added to the mixture. The mixture was stirred vigorously. The resulting mixture was wet granulated with purified water. The wet granulate was then sieved and dried in a fluid-bed dryer, and the dried granulate was sieved through another screen and finally homogenized.

-8The composition of the granular concentrate;

Pharmaceutical composition component Quantity (%) Grind compound (I) as a maleic acid salt 13.25 (pure maleate) sodium starch glycolate 5.00 hydroxypropyl methylcellulose 2910 5.00 Microcrystalline cellulose 20.0 Lactose monohydrate, normal grade to 100 purified water *

* water escapes during processing

B) Formulation of the concentrate into tablets

The granulate prepared in A) was placed in a mixer. About 2/3 of the sieved lactose was added to the blender; Microcrystalline cellulose, sodium starch glycolate, magnesium stearate and the rest of the lactose were sieved through a suitable sieve and added to the mixer. The mixture was thoroughly mixed. The resulting mixture was then compressed on a rotary die to a weight of 150 mg for 1, 2 and 4 mg tablets and to a weight of 300 mg for 8 mg tablets.

The prepared tablet core was then transferred to a tablet wrapper. The material was prewarmed with warm air (approximately 65 ° C) and film coated to increase the tablet weight by 2-3%.

tablet strength (pharmacologically) 1.0 mg 2.0 mg 4.0 mg 8.0 mg active ingredient: compound (I), maleate granulate concentrate amount (mt j on tablet) 10.00 20.00 40.00 80.00 other ingredients: sodium starch glycolate 6.96 6.46 5.46 10.92 microcrystalline cellulose 27.85 25.85 21.85 43.70 lactose monohydrate 104.44 96.94 81.94 163.88 magnesium stearate 0.75 0.75 0.75 1.50 weight of the tablet core together 150.0 150.0 150.0 300.0 aqueous coating material 4.5 4.5 4.5 9.0 total weight of coated tablet 154.5 154.5 154.5 309.0

Claims (14)

PATENT CLAIMS Use of an insulin sensitizer - compound (I) and insulin for the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in mammals. The use of claim 1, which comprises administering up to 12 mg of Compound (I). Use according to claim 1 or 2, which comprises administering 2 to 12 mg of compound (I). Use according to any one of claims 1 to 3, which comprises administering 2 to 4, 4 to 8, or 8 to 12 mg of compound (I). Use according to any one of claims 1 to 3, which comprises administering 2 to 4 mg of compound (I). Use according to any one of claims 1 to 3, which comprises administering 4 to 8 mg of compound (I). The use according to any one of claims 1 to 3, which comprises administering 8 to 12 mg of compound (I). The use according to any one of claims 1 to 3, which comprises administering 2 mg of compound (I). The use of any one of claims 1 to 3, which comprises administering 4 mg of Compound (I). The use of any one of claims 1 to 3, which comprises administering 8 mg of Compound (I). 1. A pharmaceutical composition comprising an insulin sensitizer, insulin and a pharmaceutically acceptable carrier therefor. Pharmaceutical composition according to claim 11, characterized in that the insulin sensitizer is compound (I). Pharmaceutical composition according to claim 11 or 12, characterized in that it contains up to 12 mg or 2 to 12 mg of compound (I). The pharmaceutical composition of claim 11 for use as an active therapeutic agent. The pharmaceutical composition of claim 11 for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus.