Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-23
2004-03-23
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S465000, C424S489000
Reexamination Certificate
active
06710050
ABSTRACT:
BACKGROUND
The subject-matter of the present invention is a new pharmaceutical composition containing 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione as active ingredient and the process for its preparation.
5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and pharmaceutically acceptable salts thereof have been found useful in the treatment of type 2 diabetes acting as a insulin sensitizer as disclosed in PCT Publication WO 97/41097.
The active ingredient is present as the base or as a pharmaceutically acceptable salt, preferably as the potassium salt.
Various solutions have been proposed for the preparation of medications based on 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione.
BRIEF DESCRIPTION OF THE INVENTION
The aim of the present invention is to provide a new composition intended for the preparation of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-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-quinazolinyl]methoxy]-phenylmethyl]thiazolidine-2,4-dione and its pharmaceutically acceptable salts may decompose in the presence of and in contact with water. Further it has been observed that decomposing 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 particular solid dosage forms containing an efficacious quantity of 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]-methoxy]phenylmethyl]thiazolidine-2,4-dione 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-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione, or of one of its pharmaceutically acceptable salts, can be considerably improved in preparations containing 5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or of its pharmaceutically acceptable salts and antioxidant agent if the product is composed of excipients which do not contain water.
In another embodiment of the present invention, the pharmaceutical composition does not contain an antioxidant agent.
DETAILED DESCRIPTION
Pharmaceutically 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, ammonium 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-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione, together with a conventional adjuvant, antioxidant carrier, or diluent, and if desired a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical 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 suspension 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 is carried out as a direct compression.
In accordance with another particular characteristic, this composition also contains pharmaceutically acceptable excipients.
In accordance with a particular characteristic of the invention, the antioxidant agent cited above is selected from among &agr;-tocopherol, &ggr;-tocopherol, &dgr;-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) and butylated hydroxy toluene (BHT).
In accordance with a currently preferred embodiment, the antioxidant agent will be &agr;-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 have 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-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione, or of one of its pharmaceutically acceptable salts:
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; or
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.
A convenient way of preparing the composition according to the present invention is only to use starting materials (excipients) having a low content of water. Preferably all starting materials used for the preparation of the composition according to the present invention should have a water content below about 1%, preferably below about 0.5%, more preferred below about 0.1%, and even more preferred below about 0.05%, (weight/weight).
Preferably, the composition according to the present invention should have a water content below about 1%, preferably below about 0.5%, more preferred below about 0.1%, (weight/weight).
In accordance with a second aspect, the subject-matter of the present invention is a pharmaceutical 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, colors and lubricants. A person skilled in the art can easily determine the
Hjorth Thyge Borup
Weibel Helle
Cook Rebecca
Green Reza
Novo Nordisk A S
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