Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-07
2003-12-16
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S269700
Reexamination Certificate
active
06664278
ABSTRACT:
This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine.
International Patent Application, Publication Number WO94/05659 discloses certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activity including 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (hereinafter also referred to as “Compound (I)”).
Compound (I) is disclosed solely as an anhydrous form. It has now been discovered that Compound (I) exists in a novel hydrated form which is particularly suitable for bulk preparation and handling. This can be prepared by an efficient, economic and reproducible process particularly suited to large scale preparation.
The novel hydrate also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
Accordingly, the present invention provides a hydrate of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Hydrate”) characterised in that the Hydrate:
(i) comprises water in the range of from 0.2 to 1.1% w/w; and
(ii) provides an infra red spectrum containing peaks at 764 and 579 cm
−1
; and/or
(iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in FIG. II.
Suitably, the water content of the Hydrate is in the range of from 0.4 to 0.9% w/w, especially 0.5 to 0.6% w/w, for example 0.54% w/w or 0.6% w/w.
In one favoured aspect, the Hydrate provides an infra red spectrum substantially as set out in accordance with FIG. I.
The Hydrate can exist in certain dehydrated forms which reversibly convert to the Hydrate when contacted with water, either in liquid or vapour form. The present invention encompasses all such reversibly rehydratable forms of the Hydrate.
The present invention encompasses the Hydrate isolated in pure form or when admixed with other materials, for example the known anhydrous form of Compound 1, the above mentioned reversibly rehydratable forms or any other material.
Thus in one aspect there is provided the Hydrate in isolated form.
In a further aspect there is provided the Hydrate in pure form.
In yet a further aspect there is provided the Hydrate in crystalline form.
The invention also provides a process for preparing the Hydrate, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt is crystallised from an aqueous alkanolic solvent, preferably containing from 2.0 to 2.5% by volume of water, most preferably 2.0 to 2.3%, for example 2.1% by volume of water.
Suitable aqueous alkanolic solvents include aqueous ethanol, typically aqueous denatured ethanol, and aqueous isopropanol, or mixtures thereof.
Crystallisation and any recrystallisation is generally carried out at low to ambient temperature, such as in the range of between 0 to 30° C. for example 25° C.: alternatively crystallisation may be initiated at an elevated temperature, such as in the range of between 30° C. and 60° C. for example 35° C., and then completed by allowing the temperature of the solvent to cool to ambient or low temperature, such as in the range of between 0 to 30° C. for example 25° C.
The crystallisation can be initiated by seeding with crystals of the Hydrate but this is not essential.
Compound I is prepared according to known procedures, such as those disclosed in WO94/05659. The disclosures of WO94/05659 are incorporated herein by reference.
When used herein the term ‘prophylaxis of conditions associated with diabetes mellitus’ includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinaemia and gestational diabetes.
Diabetes mellitus preferably means Type II diabetes mellitus.
Conditions associated with diabetes include hyperglycaemia and insulin resistance, especially acquired insulin resistance and obesity. Further conditions associated with diabetes include hypertension, cardiovascular disease, especially atherosclerosis, certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. Additional conditions associated with diabetes include polycystic ovarian syndrome and steroid induced insulin resistance.
The complications of conditions associated with diabetes mellitus encompassed herein includes renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
As used herein ‘aqueous’ with reference to a given solvent or solvent mixture refers to a solvent which contains sufficient water to provide Hydrate i.e having from 0.2 to 1.1% w/w of water.
As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly the Hydrate for use as an active therapeutic substance.
More particularly, the present invention provides the Hydrate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
The Hydrate may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. The formulation of the Hydrate and dosages thereof are generally as disclosed for Compound (1) in International Patent Application, Publication Number WO94/05659.
Accordingly, the present invention also provides a pharmaceutical composition comprising the Hydrate and a pharmaceutically acceptable carrier therefor.
The Hydrate is normally administered in unit dosage form.
The active compound may be administered by any suitable route but usually by the oral or parenteral routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle befor
Blackler Paul David James
Lee David C.
Sasse Michael John
Davis Zinna Northington
Kinzig Charles M.
McCarthy Mary E.
Sieburth Kathryn L.
SmithKline Beecham p.l.c.
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