SK96599A3 - Metoprolol composition and process for manufacturing the same - Google Patents

Abstract

1. A method for obtaining of a solid composition comprising, by weight based on the total weight of the composition: (a) from 1 to 70% of an active ingredient based on metoprolol which is not in an amorphous form; (b) from 10 to 95% polyethylene oxide; (c) the balance consisting of conventional additives, comprising the steps consisting of: (i) mixing said active ingredient based on metoprolol and optionally one or several additives with aqueous solution for a sufficient time, and then (ii) adding polyethylene oxide and mixing for a sufficient time; 2. A method according Claim 1, wherein active ingredient based on metoprolol is metoprolol tartrate. 3. A method of Claim 1 or 2, wherein said composition comprises: (a) from 5 to 45% of an active ingredient based on metoprolol which is not in an amorphous form; (b) from 20 to 70% polyethylene oxide; (c) the balance consisting of conventional additives. 4. A method accordind to any of Claims 1 to 3, wherein polyethylene oxide has a molecular weight which varies from 50,000 to 8,000,000 and preferably from 300,000 to 3,000,000. 5. A method according to any of Claims 1 to 4, in which the balance consisting of conventional additives comprises microcrystalline cellulose, lactose, ascorbic acid, pigments, plasticizers, lubricants, etc. 6. A method according to any of Claims 1 to 5, in which (i) stage of mixing with aqueous solution is carried out in precense of liquid surplus. 7. A method according to any of Claims 1 to 6, additionally comprising granulation step. 8. A method according to Claim 7, in which said granulation step is carried out by passage through a suitable sieve. 9. A method according to Claim 7, in which said granulation step is carried out using granulator with air-fluidized bed. 10. A method according to any of Claims 1 to 9, additionally comprising drying step. 11. A method according to any of Claims 7, 9 or 10, wherein granulation and drying steps are combined, using granulator with air-fluidized bed. 12. A method according to any of Claims 1 to 11 additionally comprising pressing step. 13. A method according to Claim 7, in which said pressing step is preceded by the step of introduction of conventional additives and mixing. 14. A method according to any of Claims 1 to 13 comprising the following steps: (i) mixing for a sufficient time an active ingredient based on metoprolol, and optionally, one or several additives with aqueous solvent; then (ii) adding polyethylene oxide and mixing for a sufficient period of time; (iii) granulation the mixture obtained by step (ii); (iv) drying the granules thus formed for a sufficient period of time; (v) optionally adding one or more additives, with mixing in the dry state for a sufficient time; (vi) compressing the mixture obtained from the preceding step to obtain the desired compressed tablet. 15. A method according to Claim 14, in which (i) stage of mixing with aqueous solution is carried out in precense of liquid surplus. 16. A method according to Claims 14 or 15, wherein granulation and drying steps are combined, using granulator with air-fluidized bed. 17. A method according to any of Claims 1 to 13 comprising the following steps: (i) mixing for a sufficient time an active ingredient, and optionally, one or several additives with aqueous solvent; then (ii) granulation the mixture obtained by step (i); (iii) optionally drying the granules thus formed for a sufficient period of time; (iv) adding polyethylene oxide and optionally adding one or more additives, and mixing thereof for a sufficient time; (v) compressing the mixture obtained from the preceding step to obtain the desired compressed tablet. 18. A method according to Claim 17, wherein mixing, granulation and drying steps are combined, using granulator with air-fluidized bed. 19. A method according to any of Claims 1 to 18 wherein said aqueous solvent comprises water and optionally water-soluble additives. 20. A method according to Claim 19, wherein said aqueous solvent comprises water and sticker in the amount of up to 20%.

Description

A preparation based on metoprolol and a process for its preparation

Technical field

The present invention relates to a novel solid metoprolol composition comprising polyethylene oxide and metoprolol and methods for its preparation.

Some medicines need to be prepared in the form of so-called controlled (delayed or continuous) medicines.

Polyethylene oxide, hereinafter referred to as PEO, is also known as a component of medicaments in tablet form intended for oral administration. Carbide Corporation sells it under the commercial name Polyox. In addition, the use of PEO in the preparation of medicaments has already been the subject of many prior patents.

s

BACKGROUND OF THE INVENTION

EP-A-0 277 092 to Ciba-Geigy relates to a composition comprising a casing of a material which is permeable to water but not to an active ingredient that surrounds an inner core consisting of a mixture of a poorly water-soluble substance and a hydrophilic swelling material which consists of a mixture of PEO and polymeric vinylpyrrolidone / vinyl acetate. The composition of the patent is an example of a conventional composition in which the water-swellable core is surrounded by a water-permeable material, wherein the release of the active ingredient (delayed or continuous) is controlled due to the time required to increase the core volume and diffuse through the sheath as water penetrates.

The abstracts of US patents A-4,404,183 and US-4,343,789 disclose two embodiments of a sustained release composition. In a first embodiment, the composition comprises PEO, the active ingredient in amorphous form, and a basic ingredient. In a second embodiment, the active ingredient nicardipine is in amorphous form so that the basic ingredient can be omitted.

However, the compositions of the earlier patents are complex, require specific active ingredients, or are obtained in a specific form. In addition, not always very good results are achieved.

SUMMARY OF THE INVENTION

The present invention provides a simple composition suitable for metoprolol with a pronounced controlled release effect.

Thus, the present invention provides a solid composition comprising the following proportions by weight of the total composition:

(a) 1-70% metoprolol which is not in amorphous form;

(b) 10 to 95% polyethylene oxide;

(C) a residue in conventional ingredients, but without basic ingredients.

The term "solid composition" means that the composition is in the form of tablets or mini-tablets, but can be encapsulated using, for example, conventional hard gelatin.

The metoprolol active ingredient is mainly represented by salts of metoprolol such as succinate and tartrate. The preferred active ingredient is metoprolol tartrate.

The term "not in amorphous form" is to be understood in its conventional sense. Various sources provide definitions of the term "amorphous" in the sense of "non-crystalline", that is, without a crystal lattice characterizing the crystalline state. The definition of amorphous or the opposite is given in the following references, which are far from complete: Hawley's, Condensed Chemical Dictionary, 12th Ed., P. 71; Handbook of Chemistry and Physics, 65th Ed., F-67; Theory and Practice of Industrial Pharmacy, 1970, p. 253-255; Remington's Pharmaceutical Sciences, 14th Ed., P. 182; General Chemistry 1992, p. 314-315; Encyclopedia of Pharmaceutical Technology, Vol. I, p. 12-13.

The term "free of basic compounds" is to be understood as the absence of compounds or groups of compounds that impart a basic character to the composition, in other words, a pH of greater than 7 when the composition is diluted with water at a ratio of 10 g per liter of water. In particular, the term must be understood as the absence of one or more basic compounds as described in column 1, lines 38 to 62 of US-A-4,404,183, when no compound compensates for the effect of said basic compound or when the basic compound is present in a relatively large amount.

According to one preferred embodiment, the composition of the invention comprises:

(a) 5 to 45% of the metoprolol active ingredient;

(b) 25 to 70% polyethylene oxide;

(c) a residue consisting of conventional ingredients but without basic components.

In one alternative embodiment, the polyethylene oxide in the composition of the invention has a relative molecular weight ranging from 50,000 to 8,000,000, and preferably from 100,000 to 3,000,000. The desired relative molecular weight of PEO can be obtained by mixing PEOs of different molecular weights that are market.

In another embodiment, the composition of the invention comprises a residue composed of conventional ingredients comprising microcrystalline cellulose, lactose, ascorbic acid, pigments, plasticizers, lubricants and the like. Of course, other conventional additives known to those skilled in the art may also be used.

In one embodiment of the invention, the remainder of the composition composed of conventional ingredients comprises, for example, magnesium stearate and / or glyceryl behenate and / or sodium stearyl fumarate, used as a lubricant to allow better compression of the composition, for example in tablet preparation.

In one alternative embodiment, the composition is additionally coated. Surface coating is used to improve the appearance of the drug, which is then more acceptable to the patient, or to dimensionally stabilize the compressed tablet. The coating may be a conventional coating suitable for intestinal drug use. It is performed using any conventional technique using conventional additives. For example, it can be realized using a rapidly dissolving film. It should be noted that the coating of the present invention is fundamentally different from the coating disclosed in EP-A-0,277,092, since in this invention we do not encounter a two-component (dichotomy) of a water-swellable core and a water-permeable coating, and moreover, the coating according to the invention dissolves and / or disintegrates, whereas the coating in EPA-0,277.092 does not dissolve.

These solid compositions are suitable for drug delivery. Therefore, the invention also relates to pharmaceutical compositions derived therefrom as well as compositions thereof for use in the form of medicaments.

This composition may be prepared by any method known to those skilled in the art, such as by direct compression after simple mixing of the dry ingredients, wet or wet granulation comprising a granulating liquid, and dry granulation comprising a compacting stage of the dry mixture.

Preferably, however, a method comprising the steps of:

(I) dry mixing and for a sufficiently long period of time the active metoprolol component, polyethylene oxide and optionally one or more additives;

(II) optionally adding the solvent followed by stirring for the time required;

(III) granulation;

(IV) drying the granules so formed for a sufficient time;

(V) optionally adding one or more ingredients, dry blending and granulometric treatment with a suitable sieve;

(VI) optionally adding one or more ingredients and dry blending for a sufficient time;

(VII) compressing the mixture obtained by the preceding steps to form the desired tablets; and (VIII) optionally coating said compressed tablets.

The solvent used, if used, is preferably an alcohol. This solvent is removed by drying in one of the steps and is essentially no longer encountered in the final composition.

The granulation can be carried out by sieving through a suitable sieve.

The drying step may be performed using a fluidized bed or in a heated dryer.

The above granulation and drying steps may be combined in a fluidized-bed granulator (for example, a top sprinkling chamber).

The choice of the mixing time, the apparatus used, the mesh size and other operating conditions are within the ability of those of ordinary skill in the art.

Without being bound by theory, the Applicant believes that PEO in this formulation forms a hydrogel upon contact with water. This hydrogel dissolves faster or slower depending on the relative molecular weight of the PEO used. The correct selection of the relative molecular weight of PEO along with the appropriate choice of the concentration of the active ingredient, PEO and other ingredients in weight units allows for controlled release of the active ingredient.

It is not easy to carry out the method described above with water as a humectant. Indeed, PEO is a water-swellable polymer that immediately forms agglomerates when in contact with water droplets. This leads to the final formation of flexible lumps inside the granular material, which is not easy to adjust to an acceptable size, even on a vibrating granulation screen.

Thus, the present improved process is a process for wet granulating PEO and using water as a wetting agent. Thus, both the direct compression problems (heterogeneous nature of the mixture) and the problems associated with the organic nature of solvents (cost, flammability, worker and environmental toxicity) can now be avoided.

The improved method consists in a two-step moistening, which allows the hydration of PEO without the formation of lumps. In the first wetting step, wetting of the active ingredient itself or, if appropriate, the active ingredient and one or more ingredients such as microcrystalline cellulose or lactose is performed. In the second wetting step, PEO is added to the previous wet mixture. These two wetting steps are simply referred to herein as the "wetting step".

The liquid used for wetting may, if desired, contain solutes to modify the properties of the granular product and improve the wetting process. Thus, a binder such as hydroxypropylmethylcellulose or polyvinylpyrrolidone can be used to improve the properties of the granular product. When similar substances are used, their concentration can be up to about 20%, for example varying between 1 to 10%.

It is important to note that in this improved process, water is the only solvent of the wetting liquid in all cases.

Wetting may be carried out in any of the mixers described in the literature, such as equipment manufactured by Vector, Moritz, Collette, Bouvard, Lodige and the like. Such mixers may use blades, planetary gears for mixing, and preferably, but not necessarily, be high speed and with or without a lump disintegrating blade. Wetting may take 0.5-15 minutes, for example 2-6 minutes.

Preferably, but not necessarily, the powders are wetted with a greater amount of wetting liquid than necessary, which facilitates subsequent operations. 'Excessive wetting' means adding more liquid than necessary to agglomerate the powder mixture.

The excess water added during the event of a slight excess of wetting in the first step improves the agglomeration of PEO with the active ingredient and other optional ingredients.

For example, the water / composition or water / PEO weight ratios may range from 0.13 to 0.36% in the first case and from 0.18 to 0.5% in the second case.

After completion of the first wetting step, PEO is added to the apparatus and additional mixing is performed to provide additional PEO wetting. During this second mixing, the PEO integrates into the granular product and swells slightly. However, it is surprising that beads and lumps are not formed, as opposed to conventional one-step granulation, as described in the literature.

This operation can be carried out in the same mixer as used in the first step or in any conventional mixer of the above. The stirring time is between 0.5 and 15 minutes, for example between 2 and 6 minutes.

The method includes other steps conventional in the art.

An initial step may be included in which the active ingredient is thoroughly mixed with the ingredients, if any.

In particular, after the addition and mixing of the PEO, the granulation step is carried out. This granulation step can be carried out on a sieve of suitable size.

Also, a drying step is carried out in particular using a fluidized bed or dryer, especially after the granulation step. It is believed that this drying step was performed when the residual water content is below 10%, for example below 3%, depending on the type and amount of ingredients.

The above granulation and drying steps can be combined using a fluidized-bed granulator (e.g., top-top chamber).

If necessary, it is possible to include steps in which various ingredients are added and mixed.

It is possible to carry out a granulometric inspection step of granules, in particular of dry granules. This granulometric screening is also carried out on a sieve having a mesh size in the range, for example, between 100 and 1000 µm.

Also the final compression steps and, if desired, the coating of the tablets are carried out. After drying but before pressing, it is mainly possible to carry out the step of adding the pressing additive (lubricant). However, these final compression steps are, of course, not necessary in the preparation of granules protecting the granules.

I i

* I

It is clear that the above workflow sequence is not mandatory except for the humidification step; for example, it is possible to add a lubricant for compression at the beginning or immediately after the addition of PEO. Similarly, the granulation step may be performed, if necessary, prior to the addition of PEO.

The choice of mixing time, the instruments used, the sieves and other operating conditions are within the skill and judgment of the person skilled in the art.

Thus, this improved process is a process for preparing a solid pharmaceutical composition comprising the following percentages by weight of the total weight of the composition:

(a) 1 to 70% of the active ingredient not in amorphous form;

(b) 10 to 95% polyethylene oxide;

(c) a residue consisting of conventional ingredients, with the steps:

(I) mixing said active ingredient and optionally one or more ingredients with the aqueous solution for a sufficiently long time, then (II) adding PEO and further mixing for a sufficiently long time.

In one embodiment, step (I) of mixing with the aqueous solution is performed in the presence of excess liquid.

In another embodiment, said aqueous solution consists of water and optionally water-soluble additives.

In another embodiment, the improved method also comprises a granulation step; this granulation step can be carried out on a sieve with a suitable mesh or by using a fluidized-bed granulator.

In yet another embodiment, the improved method further comprises a drying step.

In yet another embodiment, the improved method further comprises a pressing step; this pressing step may be preceded by the step of adding the ingredients and mixing them into the composition.

A specific embodiment of the claimed improved method is a method comprising the steps of:

(I) mixing the active ingredient and optionally one or more ingredients with said aqueous solution for a sufficiently long time; then (II) adding PEO and stirring for a sufficient time;

I (III) granulating the mixture obtained in step (II);

(IV) drying the granules so formed for a sufficiently long time;

(V) optionally adding one or more ingredients and dry blending for a sufficient time;

(VI) compressing the mixture obtained in the previous step into tablets.

Preferably, step (I) of mixing with the aqueous solution is carried out in the presence of excess liquid.

It is preferred to perform steps (III) and (IV) as a single step in a fluidized-bed granulator.

Another specific embodiment of the present invention is an improved method in which the granulation (and drying) steps are performed prior to the addition of PEO. It is preferred that the mixing, granulating (and drying) be carried out at once, for example in a fluidized bed granulator.

Said possible specific implementation of this shortened improved method comprises the steps of:

(I) mixing for a sufficient period of time the active ingredient and optionally one or more ingredients with said aqueous solution; then (II) granulating the mixture obtained in step (I);

(III) optionally drying the granules so formed for a sufficiently long time;

(IV) adding PEO and optionally one or more additives and mixing them for a sufficiently long time;

(V) compressing the mixture obtained in the previous step into tablets.

Preferably, steps (I) to (III) are performed as a single step in a fluidized-bed granulator.

Preferably, the aqueous solution contains water and binder in an amount of up to 20%.

This alternative embodiment can be applied not only to metoprolol, but to any other active ingredient.

The following examples are provided to illustrate the invention and are not intended to limit the scope thereof. While the examples refer to the amount of water used, it is to be understood that water is not substantially present in the final composition. In these examples, the hardness of the tablets is measured with a Schleuniger 4M hardness tester.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The following mixture was prepared with the exact composition:

Uncoated tablet (mg)

Metoprolol salt200

Polyox WSR N 301 (MW = 4,000,000) 300

Avicel PH 10154

Plasdone K29-328

Purified water60

Aerosil 2003

Sodium stearyl fumarate5

Preparation procedure: Metoprolol and Avicel were placed in a Stephan UMC5 mixer and mixed for 5 minutes. Plasdon K29-32 was dissolved in water and the powder was wetted with this solution. Stirring was continued for another 5 minutes. Polyox was then added and stirring was continued for an additional 5 minutes. Granulation was performed on an Erweka FGS vibrating granulator equipped with a 1.6 mm screen. The product was dried to constant humidity in a fluidized bed. Granulometric screening was performed on a vibrating granulator with a sieve of 0.8 mm mesh. After crushing the lumps, Aerosil 200 and sodium stearyl fumarate were added. Stirring was continued for another 5 minutes. The powder was then compressed on a Fette P2 rotor tablet press with 12 mm diameter mandrels and a 12 mm radius of curvature. The nominal weight of the tablets was 570 mg and their average hardness was set to 18 kg. The tablets were then coated with a conventional formulation (e.g., Opadry).

Example 2

The following mixture was prepared with the exact composition:

Uncoated tablet (mg)

Metoprolol tartrate 200 Polyox coagulant 303 Avicel PH 302 100 Plasdone K29-32 16

Aerosil 200

Sodium stearyl fumarate

Purified water

200

Preparation procedure: Metoprolol tartrate, Avicel and Aerosil were placed in a Stephan UMC5 mixer and mixed for 5 minutes. Plasdon K29-32 was dissolved in water. The powder mixture was granulated with this solution in a fluidized-bed granulator (top chamber topped at sprinkling parameters:

air flow (m ³ / h) liquid flow (g / min) inlet temperature nozzle pressure m '/ hg / min ° C

2,0 bar

Polyox and sodium stearyl fumarate were then added and stirring was continued for an additional 5 minutes. Thereafter, the powder was compressed on a rotary tablet press with 12 mm diameter mandrels and a 12 mm radius curvature. These tablets were then film coated using a conventional formulation (e.g., padpadry).

Claims (25)

PATENT CLAIMS 1. A solid composition comprising in weight percent of the total weight of the composition; (a) 1 to 70% of the active ingredient metoprolol, which is not in amorphous form; (b) 10 to 95% polyethylene oxide; (c) a residue in conventional additives excluding the basic components; The composition according to claim 1, wherein the metoprolol active ingredient is metoprolol tartrate. > Composition according to claims 1 and 2, characterized in that it comprises: (a) 5 to 45% of the metoprolol active ingredient; (b) 25 to 70% polyethylene oxide; (c) a residue consisting of conventional ingredients excluding the basic components. Composition according to any one of claims 1 to 3, characterized in that the polyethylene oxide contained has a relative molecular weight in the range of 50,000 to 5,000,000 and preferably of from 100,000 to 3,000,000. Composition according to any one of claims 1 to 4, characterized in that the residue up to 100% consisting of conventional additives comprises microcrystalline cellulose, lactose, ascorbic acid, pigments, plasticizers, lubricants and the like. Composition according to any one of claims 1 to 5, characterized in that it is additionally coated. A method of preparing a composition according to any one of claims 1 to 6, comprising the steps of: (I) dry blending and sufficient time for the active metoprolol component, polyethylene oxide and optionally one or more additives; (II) optionally adding the solvent followed by stirring for the time required; (III) granulation; . (IV) drying the granules so formed for a sufficient time; (V) optionally adding one or more ingredients, dry blending and granulometric treatment with a suitable sieve; (VI) optionally adding one or more ingredients and dry blending for a sufficient time; (VII) compressing the mixture obtained in the preceding steps to form the desired tablets; and (VIII) optionally coating said compressed tablets. Method according to claim 7, characterized in that the granulation is carried out by passing through a suitable sieve. Process according to claim 7 or 8, characterized in that the solvent is an alcohol when the solvent is used. A method of preparing a composition according to any one of claims 1 to 6, comprising the steps of: (I) mixing said active metoprolol component and optionally one or more additives with the aqueous solution for a sufficient time, then (II) adding PEO and then stirring for a sufficiently long time. Method according to claim 10, characterized in that the mixing step (I) with the aqueous solution is carried out in the presence of excess liquid. I Method according to claim 10 or 11, characterized in that it also comprises a granulation step. Method according to claim 12, characterized in that said granulation step is carried out with a suitable mesh size. Method according to claim 12, characterized in that said granulation step is carried out with a fluidized-bed granulator. A method according to any one of claims 10 to 14, characterized in that it further comprises a drying step. Method according to any one of claims 12, 14, or 15, characterized in that the granulation and drying steps are combined using a fluidized-bed granulator. I Method according to any one of claims 10 to 16, characterized in that it further comprises a pressing step. A method according to claim 17, characterized in that said pressing step is preceded by a step in which the ingredients are added and mixed. A method of preparing a composition according to any one of claims 1 to 6, comprising the steps of: I í (I) mixing the metoprolol active ingredient and optionally one or more ingredients with an aqueous solution for a sufficient time; then (II) adding PEO and stirring for a sufficient time; (III) granulating the mixture obtained in step (II); (IV) drying the granules so formed for a sufficiently long time; (V) optionally adding one or more ingredients and dry blending for a sufficient time; (VI) compressing the mixture obtained in the previous step into tablets. Method according to claim 19, characterized in that the mixing step (I) with the aqueous solution is carried out in the presence of excess liquid. Method according to claim 19 or 20, characterized in that the granulation and drying steps are combined using a fluidized-bed granulator. A method of preparing a composition according to any one of claims 1 to 6, comprising the steps of: (I) mixing the active ingredient and optionally one or more ingredients with said aqueous solution for a sufficiently long time; then (II) granulating the mixture obtained in step (I); (III) optionally drying the granules so formed for a sufficiently long time; (IV) adding PEO and optionally one or more additives and mixing them for a sufficiently long time; (V) compressing the mixture obtained in the previous step dp tablets. A method according to claim 22, characterized in that the granulation and drying steps are combined using a fluidized-bed granulator. A method according to any one of claims 10 to 23, characterized in that said aqueous solution consists of water and optionally water-soluble additives. The method of claim 24, wherein said aqueous solution comprises water and binder in an amount of up to 20%.