SK164899A3 - Pharmaceutical composition, process for its production, and a composition - Google Patents

Abstract

A pharmaceutical composition comprising Compound (I), characterised in that the composition comprises 2 to 12 mg of Compound (I) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier therefor, the use of such a composition in medicine, processes for the preparation of such a composition and intermediate composition useful in such a process.

Description

A pharmaceutical preparation, a process for its production and an excellent preparation

Technical field

The present invention relates to a formulation, more particularly a pharmaceutical formulation and its use in medicine, to methods of making such a formulation, and to a formulation required in its manufacture.

BACKGROUND OF THE INVENTION

European patent application no. No. 0,306,228 relates to certain thiazolidinedione derivatives which have been found to have a hypoglycemic and hypolipidemic effect. One of the thiazolidinediones disclosed in EP 0306228 is 5- [4- [2-N-methyl-N-2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter "compound (I))". International patent application no. No. WO94 / 0569 discloses certain salts of compound (I), including the maleate in Example 1 of the application.

It has now surprisingly been found that a single and especially daily dose of compound (I) exhibits a particularly good 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.

The inventors have also developed a new and advantageous process for the manufacture of pharmaceutical compositions, in particular in unit dosage form, containing compound (I). The novel process involves the production of a pre-formulation concentrate of compound (I), which is then formulated into the desired unit dosage form in an efficient and economical manner. The novel process is particularly suitable for the manufacture of tablets containing compound (I).

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition, preferably in unit dosage form, comprising Compound (I) which comprises 2 to 12 mg of Compound (I) in a pharmaceutically acceptable form and optionally comprises a pharmaceutically acceptable carrier.

Preferred pharmaceutically acceptable forms of Compound (I) are pharmaceutically acceptable salt forms and pharmaceutically acceptable solvate forms, including pharmaceutically acceptable solvated forms of pharmaceutically acceptable salts.

Preferred formulations comprise 2, 3, 4, 5, 6, 7, 8, 9, 40, 11 or 12 mg of Compound (I) in a pharmaceutically acceptable form.

The individual preparations contain from 2 to 4 mg of Compound (I) in a pharmaceutically acceptable form.

The individual preparations contain from 4 to 8 mg of Compound (I) in a pharmaceutically acceptable form.

The individual preparations contain from 8 to 12 mg of Compound (I) in a pharmaceutically acceptable form.

Each formulation contains 2 mg of Compound (I) in a pharmaceutically acceptable form.

The compositions preferably contain 4 mg of Compound (I) in a pharmaceutically acceptable form.

The compositions preferably contain 8 mg of Compound (I) in a pharmaceutically acceptable form.

Pharmaceutically acceptable salt forms of compound (I) include those described in EP 0306228 and WO94 / 05659. A preferred pharmaceutically acceptable salt is maleic.

Pharmaceutically acceptable solvated forms of compound (I) include those described in EP 0306228 and WO94 / 05659, in particular in the form of hydrates.

Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can be produced using known methods, e.g. those described in EP 0306228 and WO94 / 05659. The inventions of EP 0306228 and WO94 / 05659 are incorporated herein by reference.

Compound (I) may exist in one or more tautomeric forms, all of which are named "Compound (I)" whether they are individual tautomeric forms or mixtures thereof.

Compound (I) contains a chiral carbon atom and thus may exist in up to two stereoisomeric forms, all of which are named "Compound (I)" whether they are individual isomeric forms or mixtures thereof, including racemates.

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

As used herein, the term "pre-diabetes related conditions" includes conditions such as insulin resistance, including hereditary insulin resistance, reduced glucose tolerance, and hyperinsulinemia.

As used herein, the term "diabetes-related conditions" includes hyperglycaemic insulin resistance, including acquired insulin resistance and obesity. Other conditions associated with diabetes mellitus itself include hypertension, cardiovascular disease, in particular atherosclerosis, certain eating disorders, particularly those requiring regulation of appetite and food intake, as well as disorders related to insufficient food intake, e.g. anorexia nervosa and conditions associated with overeating, e.g. obesity and anorectic bulimia.

Other conditions associated with diabetes mellitus itself include polycystic ovarian syndrome and steroid-induced insulin resistance and gestational diabetes.

"Complications related to diabetes mellitus" include kidney diseases, particularly kidney disease associated with type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end-stage renal disease.

As used herein, the term "pharmaceutically acceptable" applies to both human and veterinary medicine: e.g. the term "pharmaceutically acceptable" includes a veterinarily acceptable compound.

As used herein, the term concentrate for Compound (I) in a pharmaceutically acceptable form refers to a proportional amount of Compound (i) in a pharmaceutically acceptable carrier that is greater than the amount in the formulation for administration.

For the avoidance of doubt, when reference is made to Numeric amounts, including mg amounts and amounts in% by weight, of "Compound (I) in a pharmaceutically acceptable form, the numerical amount that is given is the amount of Compound (I) per se: for 2 mg of Compound (I) as a maleate salt, this is the amount of the maleate salt containing 2 mg of Compound (I).

Diabetes mellitus is predominantly Type II diabetes.

In another aspect, the invention provides a process for the manufacture of a pharmaceutical composition comprising 2 to 12 mg of Compound (I), in a pharmaceutically acceptable form, and a pharmaceutically acceptable carrier, the process comprising admixing 2 to 12 mg of Compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier. and optionally, modifying the manufactured composition into a form suitable for administration.

As outlined above, the invention also provides another method of making a pharmaceutical composition comprising Compound (I) in a pharmaceutically acceptable form that is particularly suitable for producing a plurality of single-dose forms of Compound (I). Accordingly, the invention further provides a process for the manufacture of a pharmaceutical composition comprising Compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, the process comprising:

(i) producing a pre-formulation comprising Compound (I) in a pharmaceutically acceptable form and a first pharmaceutically acceptable carrier;

(ii) mixing the pre-formulation with a second pharmaceutically acceptable carrier to obtain the desired formulation containing Compound (I), then optionally adjusting the formulation to a form suitable for administration.

A preferred form of administration of a pharmaceutical composition comprising Compound (I) is a single dose formulation.

Unless otherwise specified, suitable unit doses are up to 12 mg, i.e., up to 12 mg of Compound (I) in a pharmaceutically acceptable form.

Other single dose formulations include those mentioned herein.

A key component of the latter process is the initial formulation.

Accordingly, the present invention also provides a composition for use as a first composition in a process for the manufacture of a single dose of Compound (I) in a pharmaceutically acceptable form.

The invention also provides a composition comprising Compound (I) in a pharmaceutically acceptable form and an optional pharmaceutically acceptable carrier, characterized in that the composition is pharmaceutically acceptable, in the form of a pre-composition.

A preferred pharmaceutically acceptable pre-formulation is a concentrate, preferably a granular concentrate, of Compound (I) in a pharmaceutically acceptable form. The granular concentrate is particularly suitable for dilution to obtain a preparation for administration, preferably in tablet form.

In 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 for dilution to obtain a composition for administration.

Preferably, the initial formulation, pre-formulation or dilutable formulation (hereinafter simply referred to as the initial formulation) contains up to 50% by weight, e.g. from 2 to 50% by weight of compound (I) in a pharmaceutically acceptable form.

Preferably, the initial composition comprises an amount of compound (I) in a pharmaceutically acceptable form in the range of from 5 to 20% by weight, in particular 5.10 or 15% by weight, e.g. 10 wt.

The methods of the invention also provide formulations of Compound (I) in any conventional dosage form, including oral and parenteral dosage forms. These processes are particularly applicable to the manufacture of oral dosage forms, in particular tablet forms of Compound (I) in a pharmaceutically acceptable form.

The first pharmaceutically acceptable carrier may be any conventional pharmaceutically acceptable excipients, including those listed in the Reference Examples below. However, since it is not essential that the first pharmaceutically acceptable carrier be in a administrable form, it is not then necessary for it to contain excipients directly related to administration. For example, it is not necessary that the first pharmaceutically acceptable carrier comprises a humectant.

The second pharmaceutically acceptable carrier is a conventional pharmaceutically acceptable carrier comprising a pharmaceutically acceptable excipient, including disintegrants, diluents, and humectants, including those set forth in the Reference Examples below.

One particular first formulation comprises Compound (I) in a pharmaceutically acceptable form, a disintegrant, a binding agent, and a diluent.

A suitable disintegrant is sodium starch glycolate.

A suitable binding agent is a methylcellulose binding agent, such as e.g. hydroxypropylmethylcellulose 2910.

Preferred diluents include cellulose, e.g. microcrystalline cellulose; and lactose monohydrate.

The preferred humectant is magnesium stearate.

The inventors have found that the most preferred initial formulation comprises Compound (I) in a pharmaceutically acceptable form, sodium starch glycolate, hydroxypropylmethylcellulose 2910, microcrystalline cellulose, and lactose monohydrate, especially when in granular form. This granular form has been shown to be particularly stable.

If the initial formulation contains about 10 wt. of compound (I) in a pharmaceutically acceptable form is readily dilutable to obtain single dose preparations containing between 2 to 12 mg, in particular 2 to 8 mg, 2 to 4 mg, 4 to 8 mg and 8 to 12 mg of the compound (I) in a pharmaceutical in an acceptable form.

The manufacture of the prime preparation is suitably carried out using any conventional methods appropriate to the nature of said prime preparation, e.g. wet granulation methods yield the initial preparation in granular form.

Methods of formulating the compositions of the invention into administrable forms include conventional forms of formulation as set forth in the Reference Examples cited herein, including tableting procedures.

The administrable compositions of the invention are preferably adapted for oral administration. However, they may be adapted for other modes of administration, e.g. for parenteral, sublingual or transdermal administration.

The administrable formulations of the invention may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, soluble powders, or in the form of liquid preparations such as oral or sterile parenteral solutions or suspensions.

In order to achieve a uniform dosage when administered, it is preferred that the composition of the invention is in unit dosage form.

Single-dose forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting humectants, e.g. magnesium stearate; disintegrating agents, e.g. starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable humectants, such as e.g. sodium lauryl sulfate.

Unless otherwise specified, the compositions of the invention are preferably in unit dosage form in amounts for the corresponding daily doses, suitable

The single doses represent 1, 2, 3, 4. 5, 6, 7, 8, 9, 10.11 or 12 mg of Compound (I) in a pharmaceutically acceptable form.

Solid formulations, e.g. oral preparations may be made by conventional methods of mixing, filling or tabletting. If desired, repeated mixing procedures may be used to distribute the active ingredient in those formulations where a large number of fillers are used. Such procedures are, of course, conventional. The tablets may be coated by methods well known in the pharmaceutical art, in particular by solution coating.

Liquid preparations, e.g. oral liquid preparations may be in the form of emulsions, syrups or infusions, or may be in the form of a dry product which may be dissolved in water or other suitable solvent prior to use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, e.g. Iecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may be edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, e.g. methyl or propyl phydroxybenzoate or sorbic acid; and, optionally, conventional flavoring and coloring agents.

Parenteral formulations, including parenteral formulations e.g. in unit dosage form, containing the active ingredient and a sterile vehicle, and depending on the concentration used, may be suspended or dissolved in the vehicle. In the manufacture of solutions for parenteral use, the formulation of the invention may be dissolved in pm injection water and sterilized by filtration prior to filling into suitable vials or ampoules and capped. Advantageously, other agents such as local anesthetics, preservatives and buffering agents may be dissolved in the vehicle. To increase stability, the formulation can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are made in substantially the same manner, except that the active ingredient is suspended in the vehicle, instead of being dissolved and sterilized by filtration. The compound may be sterilized with ethylene oxide prior to suspension in a sterile vehicle.

Preferably, a surfactant or humectant is included in the formulation to facilitate uniform distribution of the compound.

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

If desired, the formulation may be in the form of a package with an accompanying package insert with instructions for administration.

The formulations of the invention may be manufactured and formulated according to conventional procedures as set forth in standard instructions, e.g. in the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hili Books).

The present invention also provides a pharmaceutical composition comprising 2 to 12 mg of Compound (I) and a pharmaceutically acceptable carrier, for use as a therapeutically active agent.

In particular, 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 diseases.

The composition of the invention may be administered 1 to 6 times daily, most preferably 1 or 2 times daily.

Accordingly, the invention provides a method of treating diabetes mellitus, in particular type II diabetes and diseases related to diabetes mellitus in mammals, e.g. in a human, the method comprising administering 2 to 12 mg per day of Compound (I) in a pharmaceutically acceptable form to a mammal indicative of such treatment.

In particular, the method comprises administering 2 to 4 mg, 4 to 8 mg and 8 to 12 mg of Compound (I) in a pharmaceutically acceptable form.

Single doses are 2 mg / day, 4 mg / day, including 2 mg twice daily and 8 mg / day, including 4 mg twice daily.

In particular, the method comprises administering 2 to 4 mg of Compound (I) in a pharmaceutically acceptable form.

In particular, the method comprises administering 4 to 8 mg of Compound (I) in a pharmaceutically acceptable form.

In particular, the method comprises administering 8 to 12 mg of Compound (I) in a pharmaceutically acceptable form.

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

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

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

The 2-4 mg range is 2.1-4, 2.2-4, 2.3-4, 2.4-4, 2.5-4, 2.6-4, 2.7-4.2 , 8 to 4, 2.9 to 4, or 3 to 4 mg.

The range of 4-8 mg is in the range of 4.1-8.4.2-8.4.3-8.4.4-8, 4.5-8, 4.6-8, 4.7-8.4. , 8 to 8, 4.9 to 8, or 7 to 8 mg.

The range of 8 to 12 mg is the range of 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 toxic effects were found with the compounds of the invention in the above mentioned dosage ranges.

The following examples serve to illustrate the invention but are not intended to be limiting in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Production of concentrate

Approximately two-thirds of the amount of lactose monohydrate is passed through a suitable sieve and mixed with the ground maleate salt of compound (I).

Starch sodium glycolate, hydroxypropylmethylcellulose, microcrystalline cellulose and the remaining lactose are sieved through a suitable sieve and added to the mixture. Stirring is continued. The resulting mixture is then granulated with wet purified water. The wet granules are sieved, dried in the air, and the dried granules are sieved through another sieve and finally homogenized.

-10% Granular Concentrate Composition

component Quantity (%) The milled compound (I) as a maleate salt 13.25 (pure maleic salt) Sodium starch glycolate 5.00 Hydroxypropylmethylcellulose 2910 5.00 Microcrystalline cellulose 20.0 Lactose monohydrate, conventional grade Ad 100 Purified water *

removed during processing

Example 2

Preparation of concentrate into tablets

The granules of Example 1 are placed in a tumbler mixer. Approximately two-thirds of the amount of lactose is sieved and placed in the drum. The microcrystalline cellulose, sodium starch glycolate, magnesium stearate and the remaining lactose are sieved and placed in a drum and mixed together. The resulting mixture is tabletted by compression on a rotary tablet to a target weight of 150 mg for 1.2 and 4 mg tablets and a target weight of 300 mg for 8 mg tablets.

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

Tablet strength 1.0 mg 2.0 mg 4.0 mg 8.0 mg Active ingredient Maleinan compound (I) granules concentrate 10.00 20.00 40.00 80.00 Other ingredients: Sodium starch glycolate 6.96 6.46 5.46 10.92 Microcrystalline cellulose 27.85 27.85 21.85 43.70 Lactose monohydrate 104.44 96.94 81.94 163.88 Magnesium stearate 0.75 0.75 0.75 1.50 Total tablet core weight 150.0 150.0 150.0 300.0 Coating film solution 4.5 4.5 4.5 9.0 Total weight of the film-coated tablet 154.5 154.5 154.5 309.0

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Claims (19)

PATENT CLAIMS A pharmaceutical composition comprising 5- [4- [2-N-methyl-N-2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione compound (I) comprising 2 up to 12 mg of Compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier. Pharmaceutical preparation according to claim 1, characterized in that it contains 2 to 4 mg of compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to claim 1, characterized in that it contains 4 to 8 mg of compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to claim 1, characterized in that it contains 8 to 12 mg of compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to claim 1, characterized in that it contains 2 mg of compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to claim 1, characterized in that it contains 4 mg of compound (I) in a pharmaceutically acceptable form. A pharmaceutical composition according to claim 1 comprising 8 mg of Compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to any one of claims 1 to 7, characterized in that it contains maleate compound (I). A process for the manufacture of a pharmaceutical composition comprising 2 to 12 mg of Compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, comprising mixing 2 to 12 mg of Compound (I) in a pharmaceutically acceptable form with a pharmaceutically acceptable carrier. -1210. A process for the manufacture of a pharmaceutical composition comprising Compound (I) in a pharmaceutically acceptable form and in a pharmaceutically acceptable carrier, comprising: (i) producing a pre-formulation comprising Compound (I) in a pharmaceutically acceptable form in a first pharmaceutically acceptable carrier; (ii) mixing the pre-formulation with a second pharmaceutically acceptable carrier to obtain the desired pharmaceutical formulation containing Compound (I), then optionally modifying the formulation into a form suitable for administration. Method according to claim 9 or 10, characterized in that the pharmaceutical preparation is produced in a single dosage form. Method according to claim 9 or 10, characterized in that the pharmaceutical preparation is produced in the form of a tablet. The pharmaceutical composition for use as a preliminary composition in the method of claim 10 in the manufacture of a unit dosage form of Compound (I) in a pharmaceutically acceptable form. A pharmaceutical composition comprising Compound (I) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier, which is a pharmaceutically acceptable pre-formulation. The pre-formulation according to claim 13, characterized in that it is a concentrate of compound (I) in a pharmaceutically acceptable form. A pharmaceutical composition comprising Compound (I) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier, characterized in that it is a concentrate of Compound (I) in a pharmaceutically acceptable form, adapted for dilution to provide a composition for administration. -1317. Pharmaceutical preparation according to any one of claims 13 to 16, characterized in that it contains up to 50% by weight of the composition. Compound (I) in a pharmaceutically acceptable form. Pharmaceutical preparation according to any one of claims 13 to 17, characterized in that it comprises compound (I) in a pharmaceutically acceptable form in the range of 5 to 20% by weight. Pharmaceutical preparation according to any one of claims 13 to 18, characterized in that it contains 5%, 10% or 15% by weight of the composition. Compound (I) in a pharmaceutically acceptable form. A pharmaceutical composition according to any one of claims 13 to 19, comprising, compound (I) in a pharmaceutically acceptable form, sodium starch glycolate, hydroxypropyl methylcellulose 2910, microcrystalline cellulose and lactose monohydrate. Pharmaceutical preparation according to any one of claims 13 to 20, characterized in that it is in granular form.