KR20010013843A - Treatment of Diabetes with Rosiglitazone and Insulin - Google Patents

Abstract

Provided is a method of treating diabetes and diabetes related diseases in a mammal comprising administering a pharmaceutically acceptable non-toxic effective amount of Compound (I) and insulin to a mammal in need thereof. do.

Description

Treatment of diabetes with rosiglitazone and insulin {Treatment of Diabetes with Rosiglitazone and Insulin}

Insulin is the first line treatment for type I diabetes (or insulin dependent diabetes). It is also used as an antihyperglycemic agent in the treatment of NIDDM.

European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycemic and hypolipidemic activity. One particular thiazolidinedione described 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)'). International Patent Application Publication No. WO94 / 05659 discloses certain salts of Compound (I), including maleate, in Example 1 thereof.

WO97 / 05875 discloses a method for reducing exogenous insulin dosage in a patient of NIDDM by administering a therapeutically effective amount of a thiazolidinedione derivative and / or related compound.

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.

It has now been surprisingly found that certain amounts of Compound (I) in combination with insulin provide a very beneficial effect on glycemic control, and therefore such complexes have been shown to be particularly useful in the treatment of diabetes, in particular type II diabetes and diseases associated with diabetes. .

Thus, the present invention comprises administering a pharmaceutically acceptable non-toxic effective amount of Compound (I) and insulin to a mammal, such as a person in need of treatment of diabetes, in particular Type II diabetes and a disease associated with diabetes. Methods of treating diabetes in animals, in particular Type II diabetes and diseases associated with diabetes, are provided.

Preferably, the dosage of compound (I) is 12 mg or less, especially when administered per day.

The method of the present invention comprises coadministration of compound (I) and insulin or sequential administration thereof.

Co-administration includes administration of an insulin sensitizer, such as compound (I), and a formulation containing both insulin, or more suitably, simultaneous administration of separate formulations of each medicament.

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 method of the present invention comprises administering 2 to 4 mg, 4 to 8 mg or 8 to 12 mg of 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 invention comprise administering from 4 to 8 mg, for example at least 4 mg (eg 4.1 mg) 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.

It will be understood that Compound (I) and Insulin are each administered in a pharmaceutically acceptable form comprising pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts and solvates for Compound (I).

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 insulin are described in the British and US Pharmacopoeia, 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).

Compound (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof can be prepared by known methods, for example, described in European Patent Application Publication No. EP 0306228 and International Patent Application Publication No. WO94 / 05659. It can be prepared using the method. The disclosures of European Patent Application Publication No. EP 0306228 and International Patent Application Publication No. WO94 / 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 one or more stereoisomeric forms, and the term compound (I) includes both of these isomeric forms as individual isomers or as a mixture of isomers including racemates.

Insulin is prepared according to known methods, which methods are described in the UK and US pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g. (See p. 31, p. 341 and the page cited therein).

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

'Diseases associated with diabetes itself' include hyperglycemia, insulin resistance (including acquired insulin resistance) and obesity. Another disease associated with diabetes itself includes hypertension and 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' encompasses veterinary acceptable compounds.

For the sake of clarity, when referring to a scalar amount including the mg amount of a compound (I) in pharmaceutically acceptable form, the scalar amount mentioned is for compound (I) itself: ie 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 treatment methods 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 conventionally used blood glucose control indexes, such as conventionally fasting blood glucose or glycosylated hemoglobin (HB A1c). Such indices are standard methods, for example, 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 active agent when used in accordance with the treatment methods of the invention will be less than necessary to exhibit a pure additive effect on glycemic control.

In the methods of the invention, the active agents are preferably administered in the form of pharmaceutical compositions. As noted above, such compositions may include both drugs or only one of the two drugs.

In the method of treatment of the invention, insulin is generally administered by injection or by other known methods, for example the methods described in the references mentioned above. Accordingly, the following description of the compositions, formulations and methods of administration suitably describes the compositions, formulations and administration of compounds (I).

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

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 form 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, sugar, 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.

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, 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 (eg 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, the fluid unit dosage forms may be prepared using the compound and sterile vehicle and may be suspended or dissolved in the vehicle, depending on the concentration used. In the preparation of solutions, the compounds may be dissolved in water for injection, sterile filtered and then filled and sealed in suitable vials or ampoules. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. To enhance stability, the composition can be filled into a vial and freeze after removing the 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 are described in the methods and standard references described herein, such as the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see For example, see page 31, page 341, and pages cited therein) and according to conventional methods such as those described by Harry's Cosmeticology (Leonard Hill Books).

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

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

At the time of treatment, both medications may be administered 1 to 6 times a day, most preferably once or twice a day.

Suitable dosage forms, including unit dosage forms of insulin, include the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, 31). Edition 341 and pages cited therein).

The range of 2-4 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. Include.

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 toxicological 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.

Composition of Compound (I)

A. Concentrate Preparation

About ⅔ 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 20.0 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 (15)

A method of treating diabetes mellitus and a disease associated with diabetes, comprising administering a pharmaceutically acceptable non-toxic effective amount of Compound (I) and insulin to a mammal in need thereof. The method of claim 1 comprising administering up to 12 mg of compound (I). The method of claim 1 or 2 comprising administering 2 to 12 mg of compound (I). The method of any one of claims 1 to 3 comprising administering from 2 to 4 mg, 4 to 8 mg or 8 to 12 mg of compound (I). The method of any one of claims 1 to 3, comprising administering 2 to 4 mg of compound (I). The method of any one of claims 1 to 3 comprising administering from 4 to 8 mg of compound (I). The method of any one of claims 1 to 3 comprising administering 8 to 12 mg of compound (I). The method of any one of claims 1 to 3 comprising administering 2 mg of compound (I). The method of any one of claims 1 to 3 comprising administering 4 mg of compound (I). The method of any one of claims 1 to 3 comprising administering 8 mg of compound (I). A pharmaceutical composition comprising compound (I), insulin and a pharmaceutically acceptable carrier. The composition of claim 11, wherein said insulin sensitizer is compound (I). 13. A composition according to claim 11 or 12 containing up to 12 mg or 2 to 12 mg of compound (I). A pharmaceutical composition for use as an active therapeutic agent, containing compound (I), insulin and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating diabetes and diseases associated with diabetes, comprising compound (I), insulin and a pharmaceutically acceptable carrier.