Title of Invention

NOVEL METHOD OF TREATMENT

Abstract A method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a mammal which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser and a biguanide antihyperglycaemic agent, to a mammal in need thereof and a pharmaceutical composition comprising an insulin sensitiser and a biguanide antihyperglycaemic agent.
Full Text 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 Type II diabetes and conditions associated with diabetes mellitus.
Insulin secretagogues are compounds that promote increased secretion of insulin by the pancreatic beta cells.
The sulphonylureas are well known examples of insulin secretagogues. The sulphonylureas act as hypoglycaemic agents and are used in the treatment of NIDDM (or Type II diabetes). Examples of sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic 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)1). WO94/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.
Compound (I) is an example of a class of anti-hyperglycaemic agents known as 'insulin sensitisers'. In particular Compound (I) is a thiazolidinedione insulin sensitiser.
European Patent Applications, Publication Numbers: 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitisers.
Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers WO93/21166 and WO94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.
txampies ot other insulin sensitisers are those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
The above mentioned publications are incorporated herein by reference. It is now surprisingly indicated that Compound (I) in combination with an insulin secretagogue 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. The treatment is also indicated to proceed with minimum side effects.
Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, such as Compound (I), and an insulin secretagogue, to a mammal in need thereof.
In another aspect the invention provides an insulin sensitiser, such as Compound (I), together with an insulin secretagogue for use in a method for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus.
The method comprises either co-administration of an insulin sensitiser, such as Compound (I), and an insulin secretagogue or the sequential administration thereof.
Co-administration includes administration of a formulation which includes both an insulin sensitiser, such as Compound (I), and a biguanide antihyperglycaemic agent or the essentially simultaneous administration of separate formulations of each agent.
In another aspect the invention provides the use of an insulin sensitiser, such as Compound (I), and an insulin secretagogue for use in the manufacture of a composition for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus.
Suitable insulin secretagogues include sulphonylureas.
Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
Further sulphonylureas include acetohexamide, carbuttimide, chlorpropamide, glibornuride, gltquidone, gliscntide, glisolamide, g)iso Furtlier suitable insulin secretagogues include repaglinide A suitable thiazolidinedione insulin sensitiser is Compound (I). Other suitable thiazolidinedione insulin sensitisers include (+) - >-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tctramethyl-2H-l-benzopyran-2-yl)melhu\y]phenyl]methyl]-2,4-thtazolidincdionc (or troglitozone), 5 [ I [(1 mei-hylcydohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazcne), 5-[4-[2-l'5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or piogl tazone) or
englitazonu).
In one particular aspect, the method comprises the administrat on of 2 to 12 mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to S 4 to 8 or 8 to 12 mg of Compound (I) per day.
Particularly, the method comprises the administration of 2 to Piirticularly, the method comprises the administration of 4 to i'mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 8 to 2 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg f 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 (I), especially when administered per day.
II will be understood that the insulin sensitiser, such as Comp >uttd Q) and the insulin secretagogue ctre each administered in a pharm;iceutica ly acceptable form, including pharmaceutically acceptable derivatives su';h as pharmaceutically acceptable salts, esters and solvates thereof, us appse prijitef appropriate of the relevant pharmaceutically active agent. In certain ir stances herein the names used for the relevant insulin sccretagogues may relat ;toa particular pharmaceutical form of the relevant active agent: It will be inderstppd
thai; all pharmaceutically acceptable forms of the activeagents per seju 5 encompassed by this invention.
Suitable pharmaceutically acceptable salted forms of Compou id (I) include those described in EP 03062:28 and W094/05659. A pireferrec pharmaceutically acceptable salt is a maleate.
Suitable pharmaceutically acceptable solvated forms of Comp )und (I) include those described in EP 0306228 and WO94/05659, in particular hydrates.
Suitable pharmaceutical!y acceptable forms of the insulin sensitiser and the insulin secretagogue depend upon the particular secretagogue used but include known phsirmaceutically acceptable forms of the particular secretagogi e chosen. Such derivatives are found or are referred to 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 3 41 and lages cited therein) or the above mentioned publications.
Compound (I) or, a pharmaceutically acceptable salt thereof, (* a pharmaceutical ly acceptable solvate thereof, may be prepared using kn own methods, for example those disclosed in EP 0306228 and WO94/0565'). The disclosures of EP 0306228 and W094/05659 are incorporated herein ty reference.
Compound (I) may exist in one of several tautomeric forms, all of which arc; encompassed by the term Compound (I) as individual tautomeric frms or as mixtures thereof. Compound (I) contains a crural carbon atom, and he ice can exist in up to two stereotsomeric fbtms, the term Compound (I) encorr passes all of these isomeric forms whether as individual isomers or as mixtures c f isomers, including racemates.
The insulin secretagogue of choice is prepared according to kn nvn methods, such methods are foujid or are referred to in standard referen :.e texts,
such as ths British and US Pharmacopoeias, Remington's Pharmaceuti :al Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages citedjheroin) or the above mentioned publications.
When used herein the term 'conditions associated with diabete;' includes those conditions associated with dis.betes mellitus itself and ccmplicat ons associated with diabetes mellitus.
'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 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 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 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 administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.
Accordingly, in one aspect the present invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) especially 2 to 12 mg thereof, an insulin secretagogue and a pharmaceutically acceptable carrier therefor.
There is also an indication that the treatment of the invention wi ,1 effect
an improvement, relative to the individual agents, in the levels of advan ocd glycosylation end products (AGEs), leptin and serum lipids including t( *al cholesterol, HDL-cholesterol, LDL-cholesterol including imprcivement: in the
ratios thereof, in control particular an improvement in serum lipids in iludtng
total cholesterol, HDL-cholestcroI, LDL-cholestcrol including improve nents in the ratios thereof.
In the method of the invention, the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, suuh compositions can include both medicaments or one only of the medicai lents.
Accordingly, in one jispect the present invention also provides a phiirmaceutical composition comprising an insulin scnsitiser, such as C ampound (I) especially 2 to 12 mg thereof, an insulin secretagogue and a pharma :eutically acceptable carrier therefor.
Such compositions may be prepared by admixing an insulin sc nsitiser, such as Compound (I) especially 2 to 12 mg thereof, the insulin secrets gogue and a p'harmaceutically acceptable carrier therefor.
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.
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 thai a composition of the invention is in trie form of a unit dose.
Unit dose presentation forms for oral administration may be t* ble :s and capsules and may contain conventional excipients such as binding age? ts, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrol: done; fillers, for example lactose, sugar, maize-starch, calcium phosphate, so 'bitol or glycine; tabletting lubricants, for example magnesium stearate;, disinte; ;niij,ts, for example starch, polyvinylpyrrolidone, sodium starch glycollati; or microcrystalline cellulose; or pharmaceutically acceptable wetting age its such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an a nount appropriate for the relevant daily dosage.
Suitable dosages including unit dosages of the Compound of ft »rmula (I) comprise 1,2, 3, 4, 5, 6, 7, S, 9,10, 11 or 12 mg of Compound (I).
In the treatment the medicaments may be administered from 1 to Particular dosages of Compound (I) are 2mg/day, 4mg/day, in Suitable dosages including unit dosages of the insulin sensitise r or the insulin secretagogue, such as the sulphonyl urea, include the known do sages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmac jutical Sciences (Mack Publishing Co.), Mtirtindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications.
Thus: a typical daily dosage of glibcnclamide is in the range o:" from 2.5 to 4&4»g#0 mg, for example IQmg twice per day or 20mg once per da /i a typical daily dosage of glipizide is in the range of from 2.5 to 40 mg; a typical daily dosage of gliclazide is in the range of from 40 to 320 mg; a typical daily dosage of tolazamide is in the range of from 100 to 1000 mg; a typical daily dosage of tolbutamide is in the range of from 1000 to 3000 mg; a typical daily d >sage of chlorpropiimlde is in the range of from 100 to 500 mg; and atypical dsily dotage of gliquidone is in the range of from 15 to 180 mg.
^Aji example of a treatment of the inyentioncomprises the adrt imstration of 4 mg of Compound (I), for example taken as 2mg twice per day, an Repaglinide may be taken in amount!-, usually in the range of from O.Smg to 4mg and usually with meals, up to a typical, maximum daily dosage of 16mg per day.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be i sed to distribute the active agent throughout those compositions employing 1; jge quantities of fillers. Such operations are of course conventional in the ait. The tablets may be coated according to methods well known in normal ph? rmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, 01 elixirs, or may be presented as a dry product for reconstituti 311 with
water or other suitable vehicle before use. Such liquid preparations ma> contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulosi, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, fcr example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which rr ay include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl -alcohol; preservat ves, for example methyl or propyl p-hydroxytaenzoate or sorbic acid; and if desi -ed conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms fire preps red utilizing the compound and a sterile vehicle, and, depending on the com entration used, can be cither suspended or dissolved in the vehicle. In preparing ! olutions
the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adj wants such as a local anaesthetic, a preservative and buffering agent can be di: solved in the vehicle. To enhance the stability, the composition can be frozen arW filling into the vial and the water removed under vacuum. Parenteral suspensl ms are prepared in substantially the same manner, except that the Compound (I) suspended in the vehicle instead of being dissolved, and sterilization ca mot be accomplished by filtration. The compound can be sterilized by exposui s to ethylene oxide before suspending in the sterile vehicle. Advantageous!;/, a surfactant or wetting agent is included in the composition to facilitate u lifcrm distribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method c f administration.
Composition may, if desired, be in the form of a pack accompj nied by written or printed instructions for use.
The compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts, for cxamp e the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, 11m Pharmaceutical Press) (for example see the 31 sUEdition page 341 and t ages cited therein) and Harry's Cosmeticology (Leonard Hill Books) or the above mentioned publications.
The following example illustrate the invention but do not limit it in any way.
COMPOSITIONS
A Concentrate Preparation
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 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
Ingredient Quantity (%)
Milled Compound (I) as 13.25 (pure
maleate salt 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.
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
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.
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%.






We claim:
1. A pharmaceutical composition in unit dose format for use in the treatment of diabetes mellitus and/or a condition associated with diabetes mellitus comprising a pharmaceutically acceptable carrier or diluent as herein defined and, as active agents, 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt, ester or solvate thereof, and a sulphonylurea selected, from glibenclamide, glipizide, gliclazide and glimepiride, wherein the carrier or diluent is present in an amount of from 1 to 99.9% by weight and the active agents are present in a combined amount of from 0.1 to 99% by weight.
2. A pharmaceutical composition as claimed in claim 1, which
comprises 2 to 4 mg of Compound (I), or a tautomeric form thereof
and/or a pharmaceutically acceptable salt, ester or solvate thereof.
3. A pharmaceutical composition as claimed in claim ■ 1, which comprises 4 to 8 mg of Compound (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt, ester or solvate thereof.
4. A pharmaceutical composition as claimed in claim 1, which comprises 2 mg of Compound (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt, ester or solvate thereof.
0
5. A pharmaceutical composition as claimed in claim 1, which comprises 4 mg of Compound (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt, ester or solvate thereof.
6. A pharmaceutical composition as claimed in claim 1, which
comprises 8 mg of Compound (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt, ester or solvate thereof.
7. A pharmaceutical composition as claimed in any one of the
preceding claims wherein Compound (I) is present in the form of a
pharmaceutically acceptable salt.
8. A pharmaceutical composition according to any one of the
preceding claims wherein Compound (I) is present in the form of a
maleate salt.

Documents:

1693-DEL-1998-Abstract-(14-03-2008).pdf

1693-del-1998-abstract.pdf

1693-DEL-1998-Claims-(14-03-2008).pdf

1693-del-1998-Claims-(23-09-2011).pdf

1693-del-1998-claims.pdf

1693-del-1998-Correspondence-Others (20-11-2009).pdf

1693-DEL-1998-Correspondence-Others-(14-03-2008).pdf

1693-del-1998-correspondence-others.pdf

1693-DEL-1998-Description (Complete)-(14-03-2008).pdf

1693-del-1998-description (complete).pdf

1693-DEL-1998-Form-1-(14-03-2008).pdf

1693-del-1998-form-1.pdf

1693-DEL-1998-Form-13-(14-03-2008).pdf

1693-DEL-1998-Form-13-14-03-2008.pdf

1693-del-1998-form-13.pdf

1693-del-1998-form-18.pdf

1693-DEL-1998-Form-2-(14-03-2008).pdf

1693-del-1998-form-2.pdf

1693-del-1998-Form-3 (20-11-2009).pdf

1693-DEL-1998-Form-3-(14-03-2008).pdf

1693-DEL-1998-Form-6-06-12-2005.pdf

1693-del-1998-form-6.pdf

1693-DEL-1998-GPA-(14-03-2008).pdf

1693-del-1998-gpa.pdf

1693-DEL-1998-Others-(14-03-2008).pdf

1693-DEL-1998-Petition-137-(14-03-2008).pdf

1693-DEL-1998-Petition-138-(14-03-2008).pdf


Patent Number 249114
Indian Patent Application Number 1693/DEL/1998
PG Journal Number 40/2011
Publication Date 07-Oct-2011
Grant Date 30-Sep-2011
Date of Filing 18-Jun-1998
Name of Patentee SMITHKLINE BEECHAM P.L.C
Applicant Address NEW HORIZONS COURT, BRENTFORD, MIDDLESEX TW8 9EP, ENGLAND.
Inventors:
# Inventor's Name Inventor's Address
1 DR.STEPHEN ALISTAIR NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW ESSEX CM19 5AW, ENGLAND.
PCT International Classification Number A61K 31/64
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9712854.0 1997-06-18 U.K.
2 9806710.1 1998-03-27 U.K.