NZ518076A - 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (BRL49653) for treating non-insulin dependent diabetes (NIDDM) - Google Patents

Abstract

A combination comprises from 2-12 mg of 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4- dione) or a pharmaceutically acceptable form and insulin. The combination can be used in the manufacture of a medicament for the treatment of diabetes mellitus.

Description

New Zealand Paient Spedficaiion for Paient Number 518076 1 8 0 7 6 intellectual property office of N.Z. 2 8 MAR 2002 Received NEW ZEALAND PATENTS ACT, 1953 No: Divided out of No. 501259 Date: Dated 15 June 1998 COMPLETE SPECIFICATION TREATMENT OF DIABETES WITH ROSIGLITAZONE AND INSULIN We, SMITHKLINE BEECHAM P.L.C., of New Horizons Court, Brentford, Middlesex TW8 9EP, Great Britain, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) TREATMENT OF DIABETES WITH ROSIGLITAZONE AND INSULIN This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or 5 Type II diabetes and conditions associated with diabetes mellitus.

Insulin is a front line treatment agent for Type I diabetes (or Insulin Dependent Diabetes). It is also used as an antihyperglycaemic agent in the treatment ofNIDDM.

European Patent Application, Publication Number 0,306,228 relates to certain 10 thiazolidinedione derivatives disclosed as having antihyperglycaemic and hypolipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)'). W094/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.

International Patent Application, publication number W097/05875 discloses a method for reducing the amount of exogenous insulin administered to a patient having NIDDM by administering a therapeutically effective amount of a thiazolidinedione derivative and/or a related compound.

It is now surprisingly indicated that a specific amount of Compound (I) in 20 combination with insulin provides a particularly beneficial effect on glycaemic control, such combination is therefore particularly useful for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus.

Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus 25 in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of Compound (I) and insulin, to a mammal in need thereof.

Preferably, the amount of Compound (I) administered is up to 12 mg, especially when administered per day.

The method comprises either co-administration of Compound (I) and insulin or the sequential administration thereof.

Co-administration includes administration of a formulation which includes both an insulin sensitiser, such as Compound (I), and insulin or, more suitably, the essentially simultaneous administration of separate formulations of each 35 agent In one particular aspect, the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day. -la- Particularly, the method comprises the administration of 2 to 4 , 4 to 8 or 8 to 12 mg of Compound (I) per day.

Particularly, the method comprises the administration of 2 to 4mg of Compound (I), especially when administered per day.

Particularly, the method comprises the administration of 4 to 8mg, such as greater than 4 for example 4.1, to 8 mg, of Compound (I), especially when administered per day.

Particularly, the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.

Preferably, the method comprises the administration of 2 mg of Compound (I), especially when administered per day.

Preferably, the method comprises the administration of 4 mg of Compound (I), especially when administered per day.

Preferably, the method comprises the administration of 8 mg of Compound 15 (I), especially when administered per day.

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

Suitable pharmaceutically acceptable salted forms of Compound (I) include 20 those described in EP 0306228 and W094/05659. A preferred pharmaceutically acceptable salt is a maleate.

Suitable pharmaceutically acceptable solvated forms of Compound (I) include those described in EP 0306228 and W094/05659, in particular hydrates.

Suitable pharmaceutically acceptable forms of insulin are referred to in 25 standard reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).

Compound (I) or, a pharmaceutically acceptable salt thereof, or a 30 pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP 0306228 and W094/05659. The disclosures of EP 0306228 and W094/05659 are incorporated herein by reference.

Compound (I) may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures 35 thereof. Compound (I) contains a chiral carbon atom, and hence can exist in one or more stereoisomeric forms, the term Compound (I) encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.

Insulin is prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st 5 Edition page 341 and pages cited therein).

When used herein the term 'conditions associated with diabetes' includes conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.

'Conditions associated with diabetes mellitus itself include hyperglycaemia, 10 insulin resistance, including acquired insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and gestational diabetes. 15 'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy.

Renal diseases associated with Type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.

For the avoidance of doubt, when reference is made herein to scalar amounts, including mg amounts, of Compound (I) in a pharmaceutically acceptable form, the 25 scalar amount referred to is made in respect of Compound (I) per se: For example 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I).

Diabetes mellitus is preferably Type II diabetes.

The particularly beneficial effect on glycaemic control provided by the 30 treatment of the invention is indicated to be a synergistic effect relative to the control expected for the sum of the effects of the individual active agents.

Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are 35 determined using standard methodology, for example those 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 agents when used in accordance with the treatment of the invention will be less than would have been required from a purely additive effect upon glycaemic control.

In the method of the invention, the active medicaments are preferably 5 administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.

In the treatment of the invention, insulin is usually administered by injection or by other known methods, for example those described in the reference texts mentioned herein. Thus the following comments relating to compositions, 10 formulations and methods of administration suitably refer to the compositions, formulations and administration of Compound (I).

Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration. 15 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 consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be 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, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example 25 starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. 30 Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water 35 or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring 5 agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial 10 or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I)s suspended in the vehicle instead of being 15 dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions may contain from 0.1% to 99% by weight, preferably from 20 10-60% by weight, of the active material, depending upon the method of administration.

Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

The compositions are formulated according to conventional methods, such as 25 those disclosed herein and in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra Pharmacopoeia (London The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).

The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.

Suitable dosages including unit dosages of the Compound of formula (I) comprise 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).

In the treatments the two medicaments may be administered from 1 to 6 35 times a day, but most preferably 1 or 2 times per day.

Suitable dosages of insulin, including unit dosages, include those described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The* ;Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein). ;A range of 2 to 4mg includes a range of 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 4mg. ;A range of 4 to 8mg includes a range of 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 8mg. ;A range of 8 to 12 mg includes a 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 12mg. ;No adverse toxicological effects have been established for the compositions or methods of the invention in the abovementioned dosage ranges. ;The following example illustrates the invention but does not limit it in any way. ;COMPOUND (I) COMPOSITIONS ;A Concentrate Preparation ;5 Approximately two thirds of the lactose monohydrate is passed through a suitable screen and blended with the milled maleate salt of Compound (I). ;Sodium starch glycollate, hydoxypropyl methylcellulose, microcrystalline cellulose and the remaining lactose are passed through a suitable screen and added to the mixture. Blending is then continued. The resulting mixture is then wet ;10 granulated with purified water. The wet granules are then screened, dried on a fluid bed drier and the dried granules are passed through a further screen and finally homogenised. ;% COMPOSITION OF GRANULAR CONCENTRATE ;15 ;Ingredient ;Quantity (%) ;Milled Compound (I) as maleate salt ;13.25 (pure maleate salt) ;Sodium Starch Glycollate ;5.00 ;Hydoxypropyl Methylcellulose 5.00 ;2910 ;Microcrystalline Cellulose ;20.0 ;Lactose Monohydrate, regular to 100 grade ;Purified water ;* Removed during processing.

Claims (17)

5 1 8 0 7 6 B Formulation of the concentrate into tablets. The granules from above are placed into a tumble blender. Approximately two thirds of the lactose is screened and added to the blender. The microcrystalline 5 cellulose, sodium starch glycollate, magnesium stearate and remaining lactose are screened and added to the blender and the mixture blended together. The resulting mix is then compressed on a rotary tablet press to a target weight of 150mg for the 1,2 and 4mg tablets and to a target weight of 300mg for the 8mg tablets. 10 The tablet cores are then transferred to a tablet coating machine, pre-warmed with warm air (approximately 65°C) and film coated until the tablet weight has increased by 2.0% to 3.5%. Quantity (mg per Tablet) Tablet Strength l.Omg 2.0mg 4.0mg 8.0mg Active Ingredient: Compound (I) maleate Concentrate granules 10.00 20.00 40.00 80.00 Other Ingredients: Sodium Starch Glycollate 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 Total Weight of Tablet Core 150.0 150.0 150.0 300.0 Aqueous film coating material 4.5 4.5 4.5 9.0 Total Weight of Film Coated Tablet 154.5 154.5 154.5 309.0 15 -8- Claims

1. A combination which comprises from 2 to 12 mg of 5-[4-[2-(N-methyl-N-(2--pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically 5 acceptable form thereof, and insulin.

2. A combination according to claim 1, which comprises from 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I) or a pharmaceutically acceptable form thereof. 10

3. A combination according to claim 1 or claim 2, which comprises from 2 to 4 mg of Compound (I) or a pharmaceutically acceptable form thereof.

4. A combination according to claim 1 or claim 2, which comprises from 4 to 8 mg of Compound (I) or a pharmaceutically acceptable form thereof. 15

5. A combination according to claim 1 or claim 2, which comprises from 8 to 12 mg of Compound (I) or a pharmaceutically acceptable form thereof.

6. A combination according to any one of claims 1 to 3, which comprises 2 mg of 20 Compound (I) or a pharmaceutically acceptable form thereof.

7. A combination according to any one of claims 1 to 4, which comprises 4 mg of Compound (I) or a pharmaceutically acceptable form thereof. 25

8. A combination according to any one of claims 1, 2, 4 and 5, which comprises 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.

9. A combination according to any one of claims 1 to 8, wherein Compound (I) or a pharmaceutically acceptable form thereof and insulin are formulated as a single 30 pharmaceutical composition.

10. A combination according to any one of claims 1 to 8, wherein Compound (I) or a pharmaceutically acceptable form thereof and insulin are formulated as separate pharmaceutical compositions. 35 -9- office OF n.z 1 7 OCT 2003 RECEIVED 10

11. A combination according to any one of claims 1 to 10, for the treatment of diabetes mellitus and conditions associated with diabetes mellitus.

12. A pharmaceutical composition comprising from 2 to 12 mg of 5-[4-[2-(N-methyl-N--(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof, insulin and a pharmaceutically acceptable carrier therefor.

13. Use of from 2 to 12 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof and insulin in the manufacture of a medicament for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

14. Use of from 2 to 12 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)-ethoxy]-benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for use with insulin in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.

15. A combination according to any one of claims 1 to 11 and substantially as hereinbefore described.

16. A pharmaceutical composition according to claim 12 and substantially as 25 hereinbefore described.

17. Use according to claim 13 or claim 14 and substantially as hereinbefore described. 15 20 30 -10- 1 o DEC 2003 JjECEjypn