EA002188B1 - Process for preparing a solid composition based on metoprolol - 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

The present invention relates to a method for producing a solid composition based on metoprolol.

Some drugs must be obtained in the so-called sustained release form or the form of a long (prolonged) release.

Polyethylene oxide, hereinafter referred to as PEO, is also known as a drug component in the form of tablets intended for oral administration. This compound is manufactured by the company υηίοη SATYBE Under the tradename Ro1uoh (polyox). The use of PEO to obtain drugs was, in addition, the subject of earlier patents.

EP-A-0 277,092, in the name of Sa'a-Seshcha. relates to a composition containing a shell of a material that is porous to water, but not for the active ingredient, surrounding the central core, consisting of a mixture of a poorly water soluble substance and a hydrophilic swelling material, moreover, this material consists of a mixture of PEO and a polymer based on vinylpyrrolidone / vinyl acetate . The composition, according to the patent, is an example of such compositions, in which the core, swelling when exposed to water, is surrounded by a water-soluble material. Moreover, the release of the active ingredient is slow or prolonged as a result of the time required for the expansion of the core and for diffusion occurring through the shell after water penetration.

In the abstract to the patent υδ-Α-4 404 183 and to the patent υδ-Α-4 343 789, two variants of sustained-release compositions are described. In the first embodiment, the composition contains PEO, the active ingredient in amorphous form and the main component. In the second embodiment, the active ingredient is nicardipine in an amorphous state, and it is possible not to include the main component.

In fact, the compositions according to the prior art are complexes, require specific active ingredients or are provided in a specific form. In addition, the results obtained are not always very good.

The present invention relates to a method for producing a simple composition that is suitable for use with metoprolol and has a remarkable delayed or prolonged effect.

Thus, the present invention relates to a method for producing a solid composition, based on the total weight of composition (a), from 1 to 70% of metoprolol, which is not in amorphous form;

(b) from 10 to 95% polyethylene oxide;

(c) a balance consisting of regular specific additives, excluding the main components.

The expression "solid composition" means that the composition is in the form of tablets or minitablets, which, in turn, can be encapsulated using, for example, ordinary solid gelatin.

Under the active ingredient on the basis of metoprolol refers mainly to salts of metoprolol, such as succinate and tartrate. The preferred active ingredient is metoprolol tartrate.

The expression “not in amorphous form” should be understood in its generally accepted meaning. Different sources give the definition of the term "amorphous" as the value "non-crystalline", not having a lattice structure characterizing a crystalline state. The following references, which define the term “amorphous” (or its opposite term), are not limiting:

On \\ 1yu'5. Soybeizeb Syet1sa1 Oyuioyatu. 12 ^'s Ebyyui. R. 71; Best of £ SietYub aib Ryuzkb. 65 ^4b Ebyuy. E-67; Tye Tyoteu aib RgasCse about £ 1 bib r1a1 Rjagtasu, 1970. pp. 253-255; Wettdyi'b Ryagtaseiysa 8steiseb. 14 ^4th Ebyuy. river 182; Seega1 Syet1b! 1992; pp.314-315; Eisusorrela o £ Ryattaseiysa1 Tesyio1odu. yo1.1. pp. 12-13.

The expression "excluding basic compounds" should be understood as excluding the presence of a compound or a group of compounds that impart basic properties of the composition, in other words, a pH above 1. when the composition is diluted with water at a flow rate of 10 g per liter of water. In particular, this term should be understood as an exception to the presence of one or more primary component (s), such as described in column I. lines 38-62 of the patent υδ-Α-4 404 183. if no acidic compound neutralizes the effect of the above basic compound, or if the primary compound is present in relatively large amounts.

According to one preferred embodiment, the composition contains (a) from 5 to 45% of the active ingredient based on metoprolol;

(b) from 25 to 70% polyethylene oxide;

(c) a balance consisting of conventional additives, excluding the main components.

According to one alternative embodiment, in the composition, polyethylene oxide has a molecular weight varying from 50,000 to 8,000,000., And preferably from 100,000 to 3,000,000. The required molecular weight for PEO can be obtained by mixing PEO of different molecular weights, which are commercially available.

According to an additional embodiment, in the composition, the balance consisting of conventional additives includes microcrystalline cellulose, lactose, ascorbic acid, pigments, plasticizers, lubricants, and so on. Obviously, other conventional additives known to those skilled in the art can be used.

According to one embodiment of the invention, in the composition, the balance consisting of conventional additives contains magnesium stearate and / or glycerol behenate and / or sodium fumarate, which are used as a lubricant, providing better pressing of the composition when, for example, a tablet form is produced.

According to one or an alternative embodiment, the composition is additionally coated. Surface coating is used to improve the appearance, making the drug more acceptable to the patient, or for the spatial stabilization of the compressed tablet. The coating may be a conventional coating suitable for internal use. Coatings are prepared using any conventional technology, using conventional ingredients. For example, a surface coating can be obtained by using an instant film. It should be noted that the coating according to the present invention is significantly different from the coating used in EP-A-0 277 092, since the invention does not encounter a dichotomy (water-swellable core) / (water-borne casing) and, in addition, the casing according to the invention dissolves and or decomposes, while the shell according to EP-A-0 277 092 does not dissolve.

These solid compositions are suitable for administration of drugs. Thus, the invention also relates to pharmaceutical compositions based on them, as well as to their compositions for use as pharmaceuticals.

The present composition can be obtained by any conventional method known to those skilled in the art, such as, for example, direct compression after simple mixing of dry ingredients, wet or wet granulation, including the use of a granulating fluid and dry granulation, including a compaction phase for the dry mix.

However, it is preferable to use a method comprising the following stages:

(I) mixing in a dry state and for a sufficient time the active ingredient based on metoprolol, polyethylene oxide and, optionally, one or more additives;

(Ii) optionally adding a solvent, if used, followed by stirring for a sufficient period of time;

(Iii) granulation;

(Iv) drying the granules thus obtained for a sufficient period of time;

(V) optionally, adding one or more additives and mixing in a dry state for a sufficient time and passing through an appropriate sieve;

(Vi) optionally adding one or more additives and mixing in a dry state for a sufficient period of time;

(Vii) compressing the mixture obtained in the preceding stages to obtain the desired compressed tablet; and (viii) optionally, coating the said compressed tablet.

The solvent used, when used, is preferably an alcohol. The solvent is removed by drying at one time or another of the process, and it is not substantially found in the final composition.

Granulation can be carried out by passing through an appropriate sieve.

The drying step can be carried out, for example, using a fluidized bed or using a drying cabinet.

The granulation and drying steps mentioned above can be combined by using a fluidized bed granulator (for example, a top spray chamber).

The choice of mixing time, equipment used, screen holes and other working conditions is in the area of ordinary knowledge of specialists in this field.

Not wanting to be bound by any theory, the applicant believes that the PEO in the composition forms a hydrogel upon contact with water. This hydrogel dissolves more or less quickly depending on the molecular weight of the PEO used.

The choice of the molecular weight of PEO, in combination with the appropriate choice of mass concentrations of the active ingredient, PEO and additives, makes it possible to control the release of the active ingredient.

The implementation of the method, as described above, when using water as a wetting fluid is difficult. Indeed, PEO is a water-swellable polymer that instantly forms agglomerates when it comes into contact with water droplets. This leads to the final formation of elastic lumps in the depth of the granulated mass, which are difficult to sort by size, especially on a vibrating granulation lattice.

The present improved method is thus a method of wet granulating PEO using water as a wetting liquid. In this case, it is possible to avoid both the problems associated with direct pressing (the heterogeneous nature of the mixture) and the problems associated with organic solvents (cost, flammability and toxicity for the operator and the environment).

The improved method consists of two-stage wetting, allowing PEO to undergo hydration without the formation of lumps. During the first wetting step, only the active ingredient is wetted with water or, if provided, the active ingredient and one or more excipients, such as, for example, microcrystalline cellulose or lactose. During the second wetting stage, PEO is added to the above wet mixture. These two wetting steps are simply referred to herein as the “wetting step”.

The wetting fluid, if necessary, may include substances in solution in order to modify the properties of the granular product and improve the wetting process. Thus, binders, such as hydroxypropylmethylcellulose or polyvinylpyrrolidone, can be used to improve the properties of the granulated product. When using such substances, their concentration can vary up to about 20%, for example, between 1 and 10%.

It is important to note that in all cases, water is essentially the only solvent for the wetting fluid in the improved process.

The wetting operation can be carried out in any conventional mixer, described in the literature, such as, for example, the apparatus produced by Warpot, Coil, Coillet, Vouatb, B in general, etc. Such mixers can use a mixer, blades, planetary devices or, preferably, but not necessarily, high-speed, with breaking lumps or without this knife. Wetting occurs between 0.5 and 15 minutes, for example, between 2 and 6 minutes.

Preferably, but not necessarily, lightly “over wetting” of the powders is carried out, which facilitates subsequent operations. “Over wetting” should be understood as “adding liquid in excess to the amount needed to agglomerate the powder mixture.”

Excessive water added during a possible light "over wetting" in the first stage improves the agglomeration of PEO with the active ingredient and, if present, with other excipients present.

For example, the water / composition or water / PEO mass ratios may vary from 0.13 to 0.36 and from 0.18 to 0.5, respectively.

After the first stage of wetting, PEO is added to the apparatus and additional mixing is performed, resulting in additional wetting of PEO. During this second mixing, the PEO is combined into a granular product and slightly swells. However, surprisingly, the formation of lumps or clots is absent, in contrast to what is obtained with conventional granulation using one single stage, as described in the literature.

This last operation can be performed in the same mixer that was used for the first stage, or in any other conventional mixer, as described above. The mixing time is from 0.5 to 15 minutes, for example, from 2 to 6 minutes.

The method includes other steps that are common in this area.

One prior step may be provided in which the active ingredient is uniformly mixed with additives, if present.

Stage granulation is carried out exclusively after the introduction and mixing of PEO. This granulation step can be carried out using a sieve having a suitable orifice size.

The drying step, especially using a fluidized bed or a drying cabinet, is also carried out only after the granulation step. It is believed that the drying step is carried out 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 fluid bed granulator (for example, a top spray chamber).

If necessary, can be included the stage at which the additives are added and mixed.

May be provided for the stage at which the granules, especially dry granules, sorted by size. Sorting by size is also carried out on a sieve having opening sizes, for example, from 100 to 1000 microns.

Also provide the final stage of pressing and, optionally, the stage of application of the shell on the tablet. Especially, the stage at which the additive for pressing is introduced may be provided after drying, but before pressing. These final pressing steps are obviously not necessary for the production of capsules containing granules.

It is clear that the above order for the stages, except for the wetting stage, is not strictly defined; It is possible, for example, to introduce additives for pressing immediately at the beginning or immediately after adding PEO. Similarly, the granulation step may be carried out optionally before adding the PEO.

The choice of the duration of mixing, equipment, sieves and other working conditions is left to the discretion of an experienced specialist.

The improved method is thus a method for preparing a solid pharmaceutical composition containing, by weight, relative to the total weight of composition (a) from 1 to 70% of the active ingredient that is not in amorphous form;

(b) from 10 to 95% polyethylene oxide;

(c) a balance consisting of conventional additives; includes the following stages:

(I) mixing the specified active ingredient and, optionally, one or more additives with an aqueous solution for a sufficient period of time; then (ii) adding PEO and mixing for a sufficient period of time.

According to one embodiment, the step (i) of mixing with the aqueous solution is carried out in the presence of excess liquid.

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

According to another embodiment, the improved process further comprises a granulation step; this granulation step can be carried out using a sieve with an appropriately sized hole or using a fluidized bed granulator.

According to another embodiment, the improved method further comprises a drying step.

According to another embodiment, the improved method further includes a pressing step, the said pressing step may be preceded by a step in which additives are added and mixed.

A special variant of the present improved method is a method comprising the following stages:

(I) mixing, for a sufficient period of time, the active ingredient, and, optionally, one or more additives, with the specified aqueous solution;

(Ii) adding PEO and mixing for a sufficient period of time;

(Iii) granulating the mixture obtained in step (ii);

(Iv) drying the granules thus obtained for a sufficient period of time;

(V) optionally adding one or more additives, and mixing in a dry state for a sufficient period of time;

(Vi) pressing the mixture obtained in the previous step into a tablet.

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

Preferably, steps (iii) and (iv) are carried out as a single step in a fluid bed granulator.

Another particular embodiment of the invention relates to an improved process, where the granulation (and drying) steps are carried out before the addition of PEO. Mixing, granulation (and drying) is preferably carried out immediately, for example, in a fluidized bed granulator.

Specified alternative special variant of the present improved method is a method comprising the following stages:

(I) mixing for a sufficient period of time the active ingredient and, optionally, one or more additives, with the specified aqueous solution; then (ii) granulating the mixture obtained in step (i);

(Iii) optionally, drying the granules thus obtained for a sufficient period of time;

(Iv) adding polyethylene oxide and, optionally, one or more additives, and mixing for a sufficient period of time;

(V) pressing the mixture obtained in the previous step into a tablet.

Preferably, the stages (^ - (III) are carried out as a single stage in a fluidized bed granulator.

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

This alternative may be applicable not only to metoprolol, but also to any other active ingredient.

The following examples illustrate the invention and should not be construed as limiting its scope. In the examples, although the amount of water used is indicated, it should be understood that there is essentially no water in the final composition. In the examples, the tablet hardness is measured using an 8C Sheishdet 4M hardness tester.

Example 1

Get the following composition:

Uncoated tablet (mg)

Salt metoprolol200

Poliox \ ¥ 5K N301 (mol. Mass = 4,000,000) 300

Au1se1 PH 10154

Р1азбопе К29-328

Purified Water60

Aerosil 2003

Sodium fumarate5

The method of obtaining the following.

Metoprolol and Au1Ce1 are introduced into the mixer EMER5, and stirring is carried out for 5 minutes. P1a§bop K29-32 is dissolved in water, and the powder is wetted with this solution. Stirring is continued for 5 minutes. Then polyox is added and stirring is continued for an additional 5 minutes. The granulation is carried out on a vibrating granulator Epdeka EC8, equipped with a grid with a hole size of 1.6 mm. The product is dried in a fluidized bed to constant humidity. Sorting by size is carried out on a vibrating granulator with a grid with a hole size of 0.8 mm. Aerosil 200 is added, with all the lumps being broken beforehand, and sodium fumarate. Stirring is continued for 5 minutes. Then the powder is pressed on a rotary press Ebe P2, equipped with punches with a diameter of 12 mm and with a radius of curvature of 12 mm. The nominal mass of the tablet is 570 mg, and its average hardness is 18 kg. Then these tablets are coated with a film using a conventional composition (for example, Orabgu).

Example 2

The following composition is obtained: Uncoated tablet (mg)

Metoprolol Tartrate 200 Polioks coagulant 303 Au1se1 PH302 100 Р1азбопе К29-32 sixteen Aerosil 200 2 Sodium fumarate 9 Purified water 200

The method of obtaining the following.

Metoprolol tartrate, Au1c1 and Aerosil are introduced into the 81m IM5 mixer, and stirring is carried out for 5 minutes. P1a§bop K29-32 is dissolved in water. The powder mixture is granulated using a solution in a fluidized bed granulator (top spray chamber) using the following spraying parameters:

Air flow (m ³ / h) 65 m ³ / h

Liquid flow (g / min) 16 g / min

Inlet temperature 65 ° С

Spray pressure 2.0 bar

Polyox and sodium stearyl fumarate are then added and stirring is continued for an additional 5 minutes. After that, the powder is pressed on a rotor press Ebe P2, equipped with punches with a diameter of 12 mm, with a radius of curvature of 12 mm. Then these tablets are coated with a film using a conventional composition (for example, Orabgu).

Claims (20)

CLAIM 1. A method of obtaining a solid composition containing, based on the total weight of the composition: a) from 1 to 70% active ingredient based on metoprolol, which is not in amorphous form; b) from 10 to 95% polyethylene oxide; c) a balance consisting of normal specific additives, comprising the following steps: (ί) mixing the specified active ingredient based on metoprolol and, optionally, one or more targeted additives with an aqueous solution for a sufficient time, then (and) adding polyethylene oxide and mixing for a sufficient time. 2. The method according to claim 1, in which the active ingredient based on metoprolol is metoprolol tartrate. 3. The method according to p. 1 or 2, in which the specified composition contains: a) from 5 to 45% of the active ingredient based on metoprolol, which is not in amorphous form; b) from 20 to 70% polyethylene oxide; c) a balance consisting of regular targeted supplements. 4. Method according to any one of claims. 1-3, in which the polyethylene oxide has a molecular weight in the range of from 50,000 to 8,000,000 and preferably from 300,000 to 3,000,000. 5. A method according to any one of claims. 1-4, in which the balance consisting of the usual target additives, includes microcrystalline cellulose, lactose, ascorbic acid, pigments, plasticizers, lubricants. 6. The method according to any one of claims 1 to 5, in which the stage (ί) of mixing with the aqueous solution is carried out in the presence of excess liquid. 7. A method according to any one of claims. 1-6, further comprising a granulation step. 8. The method according to claim 7, in which the specified stage granulation is carried out using a sieve with the appropriate size of the holes. 9. The method according to claim 7, in which the specified stage granulation is carried out using a fluidized bed granulator. 10. The method according to any one of claims 1 to 9, further comprising a drying step. 11. A method according to any one of claims 7, 9 or 10, in which the granulation and drying steps are combined using a fluid bed granulator. 12. The method according to any one of claims 1 to 11, further comprising a pressing step. 13. The method according to p. 12, in which the specified stage of pressing is preceded by a stage in which the desired additives are introduced and mixed. 14. The method according to any one of claims 1 to 13, comprising the following stages: (ί) mixing the active ingredient based on metoprolol and, optionally, one or more additives with an aqueous solution for a sufficient time; then (ίί) adding polyethylene oxide and mixing for a sufficient period of time; (ίίί) granulating the mixture obtained in step (ίί); (ίν) drying the granules thus obtained for a sufficient period of time; (ν) optionally, adding one or more additives and mixing in a dry state for a sufficient period of time; (νί) pressing the mixture obtained in the previous stage into a tablet. 15. The method according to 14, in which stage (ί) mixing with an aqueous solution is carried out in the presence of excess liquid. 16. The method according to claim 14 or 15, wherein the granulation and drying steps are combined using a fluidized bed granulator. 17. The method according to any one of claims 1 to 13, comprising the following stages: (ί) mixing the active ingredient for a sufficient time and, optionally, one or more additives with an aqueous solution; then (ίί) granulating the mixture obtained in step (1); (ίίί) optionally, drying the granules thus obtained for a sufficient period of time; (ίν) adding polyethylene oxide and, optionally, one or more additives and mixing for a sufficient period of time; (ν) pressing the mixture obtained in the previous step into a tablet. 18. The method according to p. 17, in which the stage of mixing, granulating and drying combine by using a fluidized bed granulator. 19. The method according to any one of claims 1 to 18, wherein said aqueous solution consists of water and, optionally, water-soluble additives. 20. The method according to claim 19, wherein said aqueous solution contains water and a binder in an amount up to 20%.