BG104048A - 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)- ethoxy]benzyl]thiazolidin-2,4-dion containing composition - Google Patents

Abstract

The composition is used in medicine and includes a compound the formula of which is listed in the description. It includes from 2 to 12 mg of the compound in a pharmaceutically acceptable form and, optionally, a pharmaceutically acceptable carrier. The invention also relates to a method for the production of this composition and an intermediate composition used for such a method. 21 claims

Description

Technical field

The invention relates to a composition, in particular to a pharmaceutical composition, and to the use of such a composition in medicine, to a method for preparing such a composition, and to a composition used in this method.

BACKGROUND OF THE INVENTION

European Patent No. 0 306 228 relates to certain thiazolidinedione derivatives which have been reported to have hypoglycemic and hypolipidemic activity. A particular thiazolidinedione compound is described in EP 0 306 228 representing 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter designated as "compound (I)"). In International Patent Application Publication Number WO94 / 05659 describes some salts of compound (I), including its apple salt (maleate) in Example 1 of the description.

It has now surprisingly been found that a single fixed daily dose of compound (I) provides a particularly beneficial effect on glycemic control and is therefore particularly suitable for the treatment of diabetes mellitus, in particular type II diabetes and diabetes mellitus-related conditions.

We have also discovered a novel and advantageous method for the preparation of pharmaceutical compositions, in particular separate dosage compositions containing compound (I). The new method involves the preparation of a pre-concentrate of compound (I), which is then formulated in the desired unit dose in an efficient and economical manner. The new method is particularly suitable for the preparation of tablets of compound (I).

According to a first aspect of the invention there is provided a pharmaceutical composition suitable as a unit dosage form comprising compound (I), characterized in that the composition comprises 2 to 12 mg of compound (I) in a pharmaceutically suitable form and optionally a pharmaceutically suitable carrier.

Suitable pharmaceutically acceptable forms of compound (I) include pharmaceutically acceptable salt forms and pharmaceutically acceptable solvated forms, including pharmaceutically acceptable solvated forms of pharmaceutically acceptable salts. Appropriate

compositions include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I) in a pharmaceutically acceptable form.

Specific compositions include 2 to 4 mg of compound (I) in pharmaceutically acceptable form.

Specific compositions include 4 to 8 mg of compound (I) in pharmaceutically acceptable form.

Specific compositions include 8 to 12 mg of compound (I) in pharmaceutically acceptable form.

One composition comprises 2 mg of compound (1) in a pharmaceutically acceptable form.

Preferred compositions include 8 mg of compound (I) in pharmaceutically acceptable form.

Suitable pharmaceutically acceptable salt forms of compound (I) include those described in EP 0 306 228 and WO94 / 05659. A preferred pharmaceutically acceptable salt is apple.

Suitable pharmaceutically acceptable solvated forms of compound (I) include those disclosed in EP 0 306 228 and WO94 / 05659, specifically the hydrates,

The preparation of compound (I) or a pharmaceutically acceptable salt or solvate thereof can be accomplished by known methods, for example those described in EP 0 306 228 and WO94 / 05659. The descriptions of EP 0 306 228 and WO94 / 05659 are incorporated herein by reference.

Compound (I) may exist in one of several tautomeric forms, all of which are included in the term "compound (I)" as separate tautomeric forms or as mixtures thereof.

Compound (I) contains a chiral carbon atom and can therefore exist in up to two stereoisomeric forms. The term compound (I) encompasses all these isomeric forms either as individual isomers or as mixtures thereof, including racemates.

As used herein, the term "diabetes related conditions" includes those associated with the pre-diabetic stage, conditions associated with diabetes meilitus itself, and complications associated with diabetes meilitus.

As used herein, the term "pre-diabetic stage conditions" include conditions of insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and hyperinsulinemia.

'Diabetic meilitus conditions' include hyperglycemic insulin resistance, including acquired insulin resistance and obesity. Other conditions related to diabetes meilitus itself include hypertension, cardiovascular disease, in particular atherosclerosis, some eating disorders, in particular those requiring appetite regulation and food intake, such as malnutrition disorders such as anorexia nervosa and disorders associated with excessive eating, such as obesity and anorexia bulimia. Other conditions related to diabetes mellitus itself include polycystic ovarian syndrome and steroid-induced insulin resistance and diabetes in pregnancy.

'Diabetes mellitus complications' include kidney disease, in particular type II diabetes related kidney disease, including diabetic neuropathy, glomerulonephritis, glomerular sclerosis, neurotic syndrome, hypotonic neurosclerosis, and end stage renal disease.

As used herein, the term "pharmaceutically acceptable" encompasses agents used for the purposes of human and veterinary medicine, for example, the term "pharmaceutically acceptable" also refers to a veterinarily administered compound.

As used herein, the term concentrate with respect to compound (I) in pharmaceutically acceptable form means a proportional amount of compound (I) in pharmaceutically acceptable form which is greater than that present in the composition for administration.

For the avoidance of doubt, when scalar quantities, including mg quantities and weight% amounts, of. Compound (I) in a pharmaceutically acceptable form are described herein, then said scalar amount refers to compound (I) per se: For example 2 mg of compound (I) in the form of apple salt is the amount of this salt containing 2 mg of compound (I).

Diabetes mellitus is mainly type II diabetes.

According to another aspect, the invention provides a method of preparing a pharmaceutical composition comprising 2 to 12 mg of compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, which method involves mixing 2 to 12 mg of compound (I) in pharmaceutically acceptable form and a pharmaceutically acceptable carrier and optionally thereafter formulation of the formulation in administration form.

As stated above, the invention also provides a method for preparing pharmaceutical compositions comprising compound (I) in a pharmaceutically acceptable form, which is particularly suitable for the preparation of unit dosage forms of compound (I). Thus, the invention provides a method of preparing pharmaceutical compositions of compound (I) in a pharmaceutically acceptable form and with a pharmaceutically acceptable carrier, which method includes:

(I) preparing a first composition comprising compound (I) in a pharmaceutically acceptable form and a first pharmaceutically acceptable carrier;

(II) mixing the first composition with a second pharmaceutically acceptable carrier to obtain the desired composition of compound (I) and optionally thereafter formulating the resulting composition in a suitable form.

A preferred dosage form of the pharmaceutical composition of compound (I) is the unit dosage form.

Unless otherwise stated, suitable doses include up to 12 mg, such as 1 to 12 mg, of compound (I) in pharmaceutically acceptable form.

Other dosage forms are mentioned herein.

The key ingredient of the two methods mentioned above is the first composition. Accordingly, the invention also provides a composition for use as a first composition in the method of producing single doses of compound (I) in pharmaceutically acceptable form.

· «♦ · · ·

The invention also provides a composition comprising a compound in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier, characterized in that the composition is a pharmaceutically acceptable formulation for pre-administration.

A suitable pharmaceutically acceptable composition for pre-administration is a concentrate, preferably a granular concentrate of compound (I) in a pharmaceutically acceptable form. The granular concentrate is particularly well suited for dilution to give a composition for administration, preferably as a tablet.

According to another aspect, the invention provides a composition comprising compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, wherein the composition is a concentrate of compound (I) in a pharmaceutically acceptable form, adapted to be diluted to obtain composition for application.

Suitably, the first formulation, the pre-formulation composition or the dilution composition (hereinafter referred to as convenience .. first formulation) comprises up to 50% by weight, for example, an amount of the order of 2 to 50% by weight of compound (I) in a pharmaceutical composition. acceptable form.

It is advantageous for the first composition to contain an amount of compound (I) in pharmaceutically acceptable form in the range of 5 to 20% by weight, in particular 5%. 10% or 15% by weight, for example 10% by weight.

The methods of the invention provide pharmaceutical compositions of compound (I) in any form of administration, including oral or parenteral. They are particularly well suited for the preparation of orally administered forms, in particular tablet forms of compound (I) in a pharmaceutically acceptable form.

The first pharmaceutically acceptable carrier may include any conventional pharmaceutically acceptable carrier including the commonly used pharmaceutically acceptable excipients, including those described below. / Since it is not essential that the first carrier is in administration form, it is not necessary contain app-only fillers. For example, the first pharmaceutically acceptable carrier is not required to contain a lubricant.

The second pharmaceutically acceptable carrier includes the usual ones, including the customary pharmaceutically acceptable excipients, including disintegrants, diluents and lubricants, and those mentioned below.

A particular first composition comprises compound (I) in a pharmaceutically acceptable form, disintegrant, binder and diluent.

A suitable disintegrant is sodium starch glycolate.

A suitable binder is methylcellulose. such as hydroxypropyl methylcellulose 2910.

Suitable diluents are cellulose, for example microcrystalline cellulose and lactose monohydrate.

A suitable lubricant is magnesium stearate.

We have found that a particularly suitable first composition comprises compound (I) in a pharmaceutically acceptable form, sodium starch glycollate, hydroxypropyl methylcellulose 2910, microcrystalline cellulose and lactose monohydrate, especially when in granular form. This granular form is particularly stable.

When the first composition contains about 10% by weight of compound (I) in pharmaceutically acceptable form, it is readily diluted to give single dosage compositions comprising compound (I) in the range 2 to 12 mg, in particular 2 to 8 mg, 2 to 4 mg, 4 to 8 mg and 8 to 12 mg in pharmaceutically acceptable form.

The preparation of the first composition is carried out using any suitable method appropriate to the nature of that first composition, · · · · ····· · · ·····

8 · For example, wet granulation methods give the first GbCiab o granular form. 8 · · · · ········ · · · · · · · · · · · · · · · · · ·

Methods for formulating the compositions of the invention in usable forms include the usual formulation methods as described in the texts cited herein, including tableting methods.

Applicable compositions of the invention are preferably adapted for oral administration. However, they can also be adapted for other forms of administration, such as parenteral administration, for use under the tongue and across the skin.

The formulations for administration may be in the form of tablets, capsules, powders, granules, pastilles, suppositories, dissolution powders or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to obtain reproducibility at administration, it is preferred that the composition of the invention be in unit dosage form.

Representative single doses for oral administration may be tablets and capsules and may contain conventional excipients such as binders, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine: tableting lubricants, for example magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Unless otherwise stated, the compositions of the invention are preferably in unit dosage forms containing an amount corresponding to the daily dose as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I) in a pharmaceutically acceptable form.

Solid formulations for oral administration may: by the usual methods of mixing, filling or tabletting. If necessary, re-blending can be used to better distribute the active ingredient in the composition using large amounts of fillers. These operations are common in the area. The tablets may be coated according to methods well known in the pharmaceutical art, in particular aqueous film coating.

Liquid compositions, for example, for oral administration may be in the form of emulsions, syrups or elixirs or may be in the form of dry products which are dissolved in water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oils; emulsifying agents such as lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may contain edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerol, propylene glycol or ethyl alcohol esters; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbitanic acid and, if desired, customary flavoring and coloring agents.

Parenteral compositions, including parenteral compositions such as, for example, unit dosage forms, include the active compound and the sterile vehicle, and depending on the concentration used, they may be either suspended or dissolved in the carrier. For the preparation of solutions for parenteral administration, the composition of the invention may be dissolved in water for injection and sterilized by filtration prior to filling into suitable vials or ampoules and solids. Advantage is given by supplements such as local ^^ βΙββ ··· ΜΜ ········· βΙ ^ • · · ····· · · · · · · · · · · · ····· ·········· Anesthetics, preservatives, and buffers that dissolve in the carrier. To improve stability, the formulation may be frozen after filling in vials and the water removed in vacuo. Parenteral suspensions are prepared in much the same way, except that the active compound is suspended in the carrier instead of dissolved and sterilization cannot be accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Preference is given to the inclusion of a surfactant or wetting agent in the composition to facilitate uniform distribution of the compound.

Unless otherwise stated, the composition of the invention may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of the active substance, depending on the route of administration.

The composition may, if desired, be in the form of a package, accompanied by written or printed instructions for use.

The compositions of the invention can be prepared and formulated by conventional methods, such as those described in standard sources, e.g., British and US pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).

The invention also provides pharmaceutical compositions comprising 2 to 12 mg of compound (I) and a pharmaceutically acceptable carrier for use as a medicamentally active substance.

More specifically, the invention provides a pharmaceutical composition comprising 2 to 12 mg of compound (I) in a pharmaceutically acceptable form for use in the treatment of diabetes mellitus, in particular type II diabetes and diabetes mellitus related conditions.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

I ι · · · · · · · · · · ·

II · · · · · · · · · · · · · · · · · · · ·

The composition of the invention may be administered from 1 to about 10 times daily, but preferably 1 to 2 times daily.

According to another aspect of the invention, there is provided a method of treating diabetes meilitus, in particular type II diabetes and conditions related to diabetes meilitus in mammals such as humans, which method comprises administering to the patient daily from 2 to 12 mg of compound (I) in a pharmaceutically acceptable form.

More specifically, the method involves administering 2 to 4 g, 4 to 8 g, or 8 to 12 mg of compound (I) in pharmaceutically acceptable form.

Specific dosages are 2 mg / day, 4 mg / day, including 2 mg twice daily and 8 mg / day, including 4 mg twice daily.

Specifically, the method involves administering 2 to 4 mg of compound (I) in a pharmaceutically acceptable form.

Specifically, the method involves administering 4 to 8 mg of compound (I) in a pharmaceutically acceptable form.

Preferably, the method involves administering 2 mg of compound (I) in a pharmaceutically acceptable form.

Preferably, the method involves administering 4 mg of compound (I) in a pharmaceutically acceptable form.

Preferably, the method involves administering 8 mg of compound (I) in a pharmaceutically acceptable form.

Limits 2 to 4 include ranges from 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 4 mg.

The limits of 4 to 8 mg include the limits 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 8 mg.

8 to 12 mg ranges include 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 12 mg.

· · · · · ·

No toxicological effects of strangulation or methods of the invention have been established within the limits of the above dosages.

The following examples illustrate the invention without organizing it in any way.

Examples of carrying out the invention

Example 1: Preparation of concentrate

Approximately two-thirds of the lactose monohydrate is sieved through a suitable sieve and mixed with the milled apple salt of compound (I).

Sodium starch glycollate, hydroxypropyl methylcellulose, microcrystalline cellulose and other lactose, respectively, were added to the mixture through a suitable sieve. Mixing continues. The resulting mixture was then granulated in moist with purified water. The wet granules are then sieved, dried in a fluid bed dryer, and the dry granules are sieved through an additional sieve and finally homogenized.

Granular concentrate composition in%

Ingredient quantity (%) milled compound (I) as a maleate salt 13.25 (Pure Maleate Salt) sodium starch glycolate 5.00 hydroxypropyl methylcellulose 2910 5.00 microcrystalline cellulose ^ 20.0 lactose monohydrate, usually quality up to 100 Purified water *

* is removed during the process.

Example 2: Formulation of the concentrate into tablets as • · · · · · · ···· ·· · ·····, _l · · · · ········ j ·· ·· ·· · · · · · · · · · · ·

The granules of Example 1 were placed in a drum mixer. Approximately two-thirds of the lactose is sieved and placed in the mixer. The microcrystalline cellulose, sodium starch glycollate, magnesium stearate and other lactose are sieved and added to the drum and the mixture is mixed in total. 300 mg for tablets containing 8 mg.

The tablet cores were then transferred to a tablet coating machine preheated with warm air (approximately 65 ° C) and film coated until the tablet weight increased by 2.0% to 3.5%.

amount (mg per tablet) active tablet content in tablet 1.0 mg 2.0 mg 4.0 mg 8.0 mg Active ingredient: compound (!) maleate concentrate 10.00 8 pm 40.00 80.00 granules other ingredients: .............. sodium starch glycolate ι о.9о ....... _. L _. . . ^ .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 uh50 total weight of the core of 150 0 150.0 ...... 150 0 300.0 the tablet aqueous, film-forming cover 4 5 4.5 4.5 9.0 material total weight of the covered with a movie 154.4 154.5 154.5 309.0 tablet || -. I

• · · · · ·

Claims (21)

Claims A pharmaceutical composition comprising 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter referred to as "compound (I)"), wherein the composition comprises 2 to 12 mg of compound (I) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier. A composition according to claim 1 which comprises 2 to 4 mg of compound (I) in a pharmaceutically acceptable form. A composition according to claim 1 which comprises 4 to 8 mg of compound (I) in a pharmaceutically acceptable form. The composition of claim 1, which comprises 8 to 12 mg of compound (I) in a pharmaceutically acceptable form. The composition of claim 1, which comprises 2 mg of compound (I) in pharmaceutically acceptable form. The composition of claim 1, which comprises 4 mg of compound (I) in pharmaceutically acceptable form. The composition of claim 1, which comprises 8 mg or compound (I) in a pharmaceutically acceptable form. A composition according to claims 1 to 7, which comprises the apple salt of compound (I). A method for preparing a pharmaceutical composition comprising 2 to 12 mg of compound (I) in pharmaceutically acceptable form and a pharmaceutically acceptable carrier, which comprises mixing 2 to 12 mg of compound (I) in pharmaceutically acceptable form and pharmaceutically acceptable carrier. A method for preparing a pharmaceutical composition of compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, which method includes: 99 9999 (I) preparing a first composition comprising compound (I) in pharmaceutically acceptable form and one first pharmaceutically acceptable carrier; (II) mixing the first composition with a second pharmaceutically acceptable carrier to obtain the desired composition of compound (I) and optionally thereafter formulating the resulting composition in formulation. The method of claim 9 or 10, wherein the composition is in unit dosage forms. The method of claim 9 or 10, wherein the composition is in tablet form. A composition for use as a first composition in a method according to claim 10, for preparing single doses of compound (I) in pharmaceutically acceptable form. A composition comprising compound (I) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier, wherein the composition is a pharmaceutically acceptable formulation for pre-administration. The pre-administration composition of claim 13, which is a concentrate of compound (I) in a pharmaceutically acceptable form. A composition comprising compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, wherein the composition is a concentrate of compound (I) in a pharmaceutically acceptable form, adapted for dilution to obtain a composition for administration. A composition according to any one of claims 13 to 16, which contains up to 50% by weight of compound (I) in a pharmaceutically acceptable form. JIMM ·· ···· A composition according to any one of claims 13 to 17, which comprises compound (I) in a pharmaceutically acceptable form in the range of 5 to 20% by weight. A composition according to any one of claims 13 to 18 which contains 5% 10% or 15% by weight of compound (I) in a pharmaceutically acceptable form. A composition according to any one of claims 13 to 19 which comprises compound (I) in a pharmaceutically acceptable form, sodium starch glycolate, hydroxypropyl methylcellulose 2910, microcrystalline cellulose and lactose monohydrate. A composition according to any one of claims 13 to 20 in granular form.