Title of Invention

A STABLE PHARMACEUTICAL COMPOSITION

Abstract

ABSTRACT IN/PCT/2001/00748/CHE "A stable pharmaceutical composition" This invention relates to a stable pharmaceutical composition comprising 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]ethoxy]-phenyl methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and one or more pharmaceutically acceptable recipients, wherein said recipient or recipients have a low water content.

Full Text

The subject-matter of the present invention is a new pharmaceutical composition containing 5-[[4-{3-Methyl-4-oxc-3/^ihydro-2^uina2olinyi]stocky]phenyl-methyllthia2olidine-2,4-dione as active ingredient and the process for its preparation. 5-{[4-[3-Methyi-4-oxo-3,4-dihydro-2-quina2olinyl]ethoxy]phenyl-rnethynthiazolidine-2,4-dione and pharmaceutical^ acceptable salts thereof has been found useful in the treatment of type 2 diabetes acting as a insulin sensitizer as disclosed in PCT Publication WO 97M1097. The active ingredient is present as the base or as a pharmaceutically acceptable salt, pref¬erably as the potassium salt. Various solutions have been proposed for the preparation of medications based on 5-{[4-f3-Methyl-4-oxo-3,4-dihydro-2-quina2olinyl]methcxy]phenyl-methyl]thiazolidine-2,4-dione. The aim of the present invention is to provide a new composition intended for the prepara¬tion of 5-[[4~[3-Methyl-4-oxo-3.4-dihydro-2-quinazolinyl|methoxylphe 2,4-dione with improved stability, in particular solid dosage forms thereof. It has been found in fact that 5-{[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazclinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione and its pharmaceutically acceptable satts may decom¬pose in the presence of and in contact with water. Further 'rt has been observed that decom¬posing may occur in the presence of oxygen. Thus, from a first aspect, the subject-matter of the present invention is a pharmaceutical composition intended for the preparation of dosage forms and in particutar soiid dosage forms containing an efficacious quantity of 5-[H-[3-Methyl-4-oxo-3,4-dihydro-2-quinazalinyl]methoxy]phenyl-methyl]thiazolfdine-2,4-dicne or of one of its pharmaceutically acceptable salts as active ingredient. The present invention is based on the surprising discovery of the fact that the stability of 5-[[4-[3-rV1ethyi-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione, its pnarmaceutically acceptable sails, can be considerably improved in prepara¬tions containing 5-[[4-{3-Methyf-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-rnethyl]thiazolidine-2,4-dione or of its pnarmaceutically acceptable salts and antioxidant agent if the product is composed of excipients which do not contain water. Pharmaceutical acceptable salts forming part of this invention include salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, am¬monium or substituted ammonium salts, aluminium salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methane-sulplionates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. 5-[[4-[3-Methyi-4-oxo-3,4-dihydrc-2-quinazolinyllmethoxy]phenyl-methyl3thia20lidine-2,4-dione, together with a conventional adjuvant, antioxidant carrier, or diluent, and if desired a pharmaceutical^ acceptable acid addition salt thereof, may be placed into the form of phar¬maceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or oral powders to be diluted immediately before use filled with the same, all for oral use, in the form of suppositories for rectal administration; or as pessaries for vaginal use; or in the form of sterile injectable powders for parenteral, transdermal, nasal, pulmonary and ocular use. Within the framework of the present description and of the claims, by powders is meant any mixture of components, granulated or not, intended to be placed in solution and/or in sus¬pension in water, or again to be ingested directly or by any other appropriate means as for example in a mixture with a food product. In accordance with a particular characteristic of the invention, the manufacture of tablets are carried out as a direct compression. In accordance with another particular characteristic, this composition also contains pharma-ceutically acceptable excipients. In accordance with a particular characteristic of the invention, the antioxidant agent cited above is selected from among a-tocopherol, y-tocopherol, 5-tccopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium safts, ascorbyl paimitate, propyl gallate (PG), octyl gallate, dodecyl gallate, butyiated hydroxy anisole (BHA) and buty-latad hydroxy toluene (EHT). In accordance with a currently preferred embodiment, the antioxidant agent will be a-tocopherol. In accordance with another particular characteristic of the invention, the diluent is lactose and/or cellulose microcrystalline, magnesium stearate, talc. However, any other pharmaceutically acceptable diluents could be used if the diluents has a low water content. The quantities of diluents can be easily determined by a person skilled in the art and depend of course on the final pharmaceutical form required. Generally speaking, a composition which complies with the present invention and which are Intended for the preparation of tablets, may contain, expressed in parts by weight per 100 parts of 5-{[4-[3-Methyf-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione, or of one of its pharmaceutical^ acceptable salts: Detween 100 and 400,000 parts by weight of anhydrous lactose; between 1 and 100 parts by weight of an antioxidant; between 50 and 500 parts by weight of pregelatinized starch; between 1000 and 10,000 parts by weight of microcrystalline cellulose; between 10 and 500 parts by weight of crospovidone; between 10 and 500 parts by weight of silicon dioxide; between 10 and 500 parts by weight of hydrogenated vegetable oil; between 10 and 500 parts by weight of magnesium stearate; between 10 and 500 parts by weight of hydroxypropyl methylcedulose; between 10 and 500 parts by weight of hydroxypropyl cellulose; between 1000 and 10,000 parts by weight of Mannitol; between 10 and 500 parts by weight of stearic acid: between 10 and 500 parts by weight of Titanium Dioxide; According to a preferred embodiment of the invention the water content of the excipients is very low. More specifically the water content in the diluents Is very low in order to minimize the water content of the pharmaceutical composition. Lactose is used in its anhydrous form. Furthermore, all excipients may be applied in a dry form. In accordance with a second aspect, the subject-matter of the present invention is a phar¬maceutical preparation, in the form of tablet or powder, characterised in that it contains a composition as defined previously associated if required with at least one customary additive selected from among the sweeteners, flavouring agents, colours and lubricants. The choice of these additives and their quantity can easily be determined by a person skilled in the art. Another manufacturing process for pharmaceutical compositions according to the invention is-mixingcf 5-{[4-{3-Methyl-4-oxo-3,4-dihydrc-2-quinazoliny{lmethoxy3phenyl-methyl]thiazolidine-2,4-dione, one or more antioxidants and other pharmaceutics! excipients followed by melt granulation in a high shear mixer, Hydrogenated, vegetable oil, waxes or other low temperature melting binders can be used. The granules can be filled into capsules, compressed into tablets or used in other pharmaceutical dosage forms. More preferably the manufacturing process applied is direct compression of tablets, wherein 5-[[4-[3.Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy3phenyl-msthyrjthia2olidine-2,4-dione, one or more antioxidants and other excipients suitable for direct compression are mixed followed by tabletting. Yetr another preferred embodiment of the manufacturing process is wet granulation, where granules are obtained by wet massing of 5-{[4-[3-MethyW-oxo-3l4-dihydro-2-quinazolinyl]methoxy3phenyl-methyl]thiazolidine-2,4-dione, together with one or more anti¬oxidants and other excipients. !t is assumed that the contact time with water have to be very short The most preferred process comprises the direct compression whereby 5-{[4-[3-Methyl-4-oxc-3,4-dihydro-2-quinazoiinyl]methoxy]phenyl-methyilthia2oiidine-2,4-dione is kept at condi¬tions of low water vapour pressure. A sweetener may be a natural sugar such as sorbitol or a synthetic product such as saccha¬rine or aspartame. When the antioxidant selected is ascorbylpalmitat, propylgallat, whicn is a powder, it can be advantageous to mix it in an appropriate excipient such as a-tocopherol succinat, lactose or cellulose micrycrystadine. The present invention will further be illustrated with the following non-exhaustive examples. In Example 1 through 4 the tablets were prepared according to the following procedure: The active ingredient is mixed with cellulose microcrystailine in a drum mixer for 10 minutes. Lactose is added and the mixing continued for further two minutes. The lubricants are added and the miking continued for further two minutes. EXAMPLE 1 25 mc 5-IT4-f3-Methvt-4-oxo-3.4-dihvdro-2-ouina7olinvHmethoxv1phenvl-methvnthiazolidine-2.4-dione, potassium salt Tablets 907227 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazo(inyl]methoxy]phenyl-methyl]thiazo!idine-2,4- dione, potassium salt, 003/97 9% Cellulose Microcrystailline 20% Lactose 66% Magnesium Stearate 0,5% Talc 4.5% EXAMPLE 2 50 mo 5-ff4-f3-Methvll-oxo-3,4-dihvdro-2-quina2olinvnmethoxvlDhenvl-methvllthiazolidine-2.4-dione, potassium salt tablets 807237 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazoiinyl]rnethoxy]phenyl-methylthiazoiidine-2,4- dione, potassium salt, 003/97 18% Cellulose Microcrystalline 20% Mannitol 57% Magnesium Stsarats 0.5% Talc 4.5% EXAMPLE-3 50 mq 5-fr443-Me'thvl-4-oxo-3,4-dihvdro-2-quina2olinvniTiethoxv]phenvl-methyl1thiazolid!ne-2.4-dione, potassium salt Tablets 731725 5-[[4-{3-methyl-4-oxo-3I4-dihydro-2-quinazoiinyi]methoxy3phenyi-methyl]thiazoiidine-2,4- dione, potassium salt 18% Lactose 81.5% Magnesium stearate 0.5% EXAMPLE 4 0.25 mq 5-ff4-f3-Methvl-4-oxo-3,4-dihvdro-2-quina20linvllmethoxv]phenyl-methyflthiazolidine-2.4-dione, potassium salt Tablets 728625 5-{[4-[3-methyl-4-oxo-3f4-dihydro-2-quina20linyl]methoxy]phenyl-methyl]thia20l!dine-2,4- dione. potassium salt 0.09% Mannitol 98% Magnesium stearate 2% EXAMPLE 5 5-{t4-[3-Methyl-4-oxo-314-dihydro-2-quinazolinyl]methoxy]pheny!-methyllthiazolidine-214- dione, potassium salt 0.09% Hydrogenated vegetable oil 6.25% Talc 5% a-tocopherol 50% of 5-[[4-[3-methyl-4-axo-3,4-clihydro-2- quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-diane, potassium salt Lactose DCL21/Mannit0( Up to 200 g The granulate is manufactured in a Baker Perkins 1 I high-shear mixer - using a water bath of 70CC. The mixing is carried out at 3000 RPM, chopper 8000 RPM and the granulation is performed at approx. 70°C. The hot granulate is sieved through sieve 1.25 \un, and the cold granulate through sieve 1000 fim. The glidant is added with a card for 2 min. The tablets are manufactured using a Diaf tablet machine with 9 mm punch. In order to protect against light and improve the appearance of the tablets, the tablets are film-coated. The tablets were coated with the following film-coating composition where an amount of coating material of 5 rngfcm2 were chosen as being satisfactory with respect to stability of the tablets: Methylhydroxypropylcellulose, Ph. Eur - 4.34 mg/tablet Titanium Dioxide, Ph. Eur -1.73 - Purified Water, Ph. Eur q.s. - Talc, Ph. Eur. (Added as polishing agent at the end of the film-coating process (0.5 % w/w of tablet core). Absorbed amount is not quantified. EXAMPLE 6 5-[[4-{3-Methyl-4-Qxc-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4- dione, potassium salt 0.09% Povidone 7.5% Hydroxypropylmethyi cellulose 1.5% Croscarmelcse sodium 1.56% Talc 1.1% Magnesium stearate Q.5% Lactose 300 mesh up to 200 g The granulate is manufactured by Baker Perkins 1 L intensive mixer. Dry mixing were carried out at 500 RPM, chopper 1500 RPM and granulation 1000 RPM and 2000 RPM. The wet granulate is sieved through sieve 1.25 μ rn and the dry granulate through sieve 1000 urn. The giidant is admixed with a card for 2 min. The tablets are manufactured by Diaf tablet ma¬chine with 9 mm punch. EXAMPLE 7 Composition: Oral Powder, 1 mg/ml, 100 ml 5^[4-[3-Methyt-4-oxo-3,4-dihydro-2-quina20linyl]rnethoxy]phenyl-rnethyilthia2olidine-2,4- dions potassium salt 0.1096 g Mannitoi 2.5 g Hydroxypropyl-p-cyclodextrin 10 g To be diluted with 92 mL water before use. EXAMPLE 8 Composition; ' Oral Powder, 10 mg/ml, 100 ml 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxylphenyl-methyi]thiazolidine-2,4- dione potassium salt 1.096 g Mannitol 2.5 g Hydroxypropyl-P-cyclodextrin 10 g Sodium Carbonate, anhydrous, Na2CO3 • 15 mg To be diluted with 92 mL water before use. WE CLAIM: 1. A stable pharmaceutical composition comprising 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl|methoxy]-phenylmethyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, microcrystalline cellulose and one or more pharmaceutically acceptable excipients, wherein said excipient or excipients have a low water content. 2. The composition as claimed in claim 1, in the form of a tablet, a powder or a capsule. 3. The pharmaceutical composition comprising 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinylJmethoxyj-phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients with low water content and an antioxidant. 4. The pharmaceutical composition as claimed in claim 3, in the form of a tablet, a powder or a capsule. 5. The pharmaceutical composition as claimed in claim 3 or 4, containing, expressed in parts by weight per 100 parts of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl |methoxyJ-phenyl-methyl]thiazolidine-2,4-dione or of one of its pharmaceutically acceptable salts and between 1 and 100 parts by weight of an antioxidant and the pharmaceutically acceptable excipients selected among the following: between 100 and 400,000 parts by weight of anhydrous lactose, between 1 and 100 parts by weight of an antioxidant, between 50 and 500 parts by weight of pregelatinized starch, between 1000 and 10,000 parts by weight of microcrystalline cellulose, between 10 and 500 parts by weight of crospovidone, between 10 and 500 parts by weight of silicon dioxide, between 10 and 500 parts by weight of hydrogenated vegetable oil, between 10 and 500 parts by weight of magnesium stearate, between 10 and 500 parts by weight of hydroxypropyl methylcellulose, between 10 and 500 parts by weight of hydroxypropyl cellulose, between 1000 and 10,000 parts by weight of Mannitol, between 10 and 500 parts by weight of stearic acid, between 10 and 500 parts by weight of Titanium Dioxide. 6. The pharmaceutical composition as claimed in claim 1, comprising an antioxidant. 7. The pharmaceutical composition as claimed in claim 3 or 4, wherein the pharmaceutically acceptable excipients are selected from the following: lactose and/or cellulose microcrystalline, magnesium stearate or talc. 8. The pharmaceutical composition as claimed in claim 3 or 4, wherein the pharmaceutically acceptable excipients are in a dry form. 9. The pharmaceutical composition as claimed in claim 3 or 4, wherein the antioxidant is selected from the following: a-tocopherol, y-tocopherol, 5-tocopherol, extracts of natural origin rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbyl palmitate. propyl gallate (PG), octyl gallate, dodecyl gallate, butylated hydroxy anisole (BHA) or butylated hydroxy toluene (BHT). 10. The pharmaceutical composition as claimed in claim 3 or 4, wherein the antioxidant is μ -tocopherol. 11. The pharmaceutical composition as claimed in claims 1 to 4, associated with at least one customary additive selected from among the sweeteners, flavouring agents, colours and lubricants. 12. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methy]]fhiazolidine-2,4-dione, potassium salt 9% Cellulose Microcrystalline 20% Lactose 66% Magnesium Stearate 0.5% Talc 4.5% 13. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 18% Cellulose Microcrystalline 20% Mannitol 57% Magnesium Stearate 0.5% Talc 4.5% 14. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 18% Lactose 81.5% Magnesium stearate 0.5% 15. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 0.09% Mannitol 98% Magnesium stearate 2% 16. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 0.09% Hydrogenated vegetable oil 6.25% Talc 5% a-tocopherol 50% of 5-[[4-[3-methyl-4-oxo-3,4- dihydro-2-quinazolinyl]methoxy]~ phenyl-methyl|thiazolidine-2,4-dione, potassium salt Lactose DCL21 /Mannitol up to 200g. 17. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 0.09% Povidone 7.5% Hydroxypropylmethyl cellulose 1.5% Croscarmelose sodium 1.56% Talc 1.1% Magnesium stearate 0.5% Lactose 300 mesh upto 200 g. 18. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 0.1096g Mannitol 2.5g Hydroxypropyl-(3-cyclodextrin 1 Og and diluted with 92 mL water before use. 19. The pharmaceutical composition as claimed in any one of the preceding claims comprising the following: 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]-phenyl-methyl]thiazolidine-2,4-dione, potassium salt 1.096% Mannitol 2.5g Hydroxypropyl-P-cyclodextrin 1 Og Sodium Carbonate, anhydrous Na2C03 15mg and diluted with 92 mL water before use.

Documents:

in-pct-2001-0748-che abstract-duplicate.pdf

in-pct-2001-0748-che abstract.pdf

in-pct-2001-0748-che assignment.pdf

in-pct-2001-0748-che claims-duplicate.pdf

in-pct-2001-0748-che claims.pdf

in-pct-2001-0748-che correspondence-others.pdf

in-pct-2001-0748-che correspondence-po.pdf

in-pct-2001-0748-che description (complete)-duplicate.pdf

in-pct-2001-0748-che description (complete).pdf

in-pct-2001-0748-che form-1.pdf

in-pct-2001-0748-che form-19.pdf

in-pct-2001-0748-che form-26.pdf

in-pct-2001-0748-che form-3.pdf

in-pct-2001-0748-che form-5.pdf

in-pct-2001-0748-che form-6.pdf

in-pct-2001-0748-che pct search report.pdf

in-pct-2001-0748-che pct.pdf

in-pct-2001-0748-che petition.pdf