BG64835B1 - Process for the production of methoprololene composition - Google Patents

Abstract

The invention relates to a process for the production of a new solid methopropolol composition containing, in wt.%: from 1 to 70 methopropolol as an active ingredient which is not in an amorphous form, from 10 to 95 polyethylene oxide and supplementing conventional additives up to 100. The method includes wet granulation of polyethylene oxide at two-stage wetting and the use of water. By the process the active component of methopropolol is mixed with one or several additives, optionally with aqueous solution, for sufficient time, after which the polyethylene oxide is added and the ingredients are mixed for the required time.

Description

The invention relates to a process for the preparation of a new solid metoprolol composition comprising polyethylene oxide and metoprolol.

Known medicaments should be formulated in a so-called sustained or controlled release form.

BACKGROUND OF THE INVENTION

Polyethylene oxide, referred to below as PO, is also known as a component of oral tablets. This compound is marketed by Union Carbide Corporation under the trade name Polyox. The use of software for the formulation of medicaments has also been the subject of many previous patents.

EP-A-0277092 to Ciba-Geigy relates to a composition comprising a coating of water-permeable material but not the active ingredient. This sheath encloses a central core containing a mixture of a slightly water-soluble substance and a hydrophilic swellable material that is composed of a mixture of PO and vinylpyrrolidone / vinyl acetate polymer. The composition of this patent is an example of known compounds in which a swellable core, when placed in water, is surrounded by a permeable material, thereby releasing the active ingredient slowly or controlled due to the time required to expand the nucleus and to exert of diffusion through the shell after penetration of water.

US-A-4404183 and US-A-4343789 describe two embodiments of a controlled release formulation. In the first embodiment, the composition comprises a PO, an active ingredient in an amorphous form and a major component. In the second embodiment, the active ingredient is nicardipine in amorphous form, with the possibility of omitting the main component.

A disadvantage of the known complex compounds is that they require specific active ingredients or are in a specific form. Moreover, the results achieved are not always very good.

From WO 1996/032097, a pharmaceutical composition is known comprising the PO, the corresponding active ingredient, and optional additives. Among the active ingredients in the cited document, there is no metoprolol compound. From the same document there is also known a method of preparing the described pharmaceutical composition, which comprises a one-step dry-blending of the ingredients and subsequent wet granulation with a granulating liquid-solvent, preferably alcohol.

A disadvantage of the known method is the problems associated with the use of organic solvents, such as flammability and toxicity to the operator and the environment, as well as their higher cost.

The implementation of the method described above with water as a wetting fluid is complicated, since PO is a hygroscopic polymer that immediately forms agglomerations when interacting with water droplets. This results in the formation of lumps with an elastic consistency in the center of the pellet mass, which is difficult to sort by size, even on the oscillating pellet grating.

It is an object of the invention to provide a method for the production of a pharmaceutical composition comprising PO, the active ingredient of metoprolol and optional additives, the method being of low cost and to solve problems related to direct compression (the heterogeneous nature of the mixture), and using organic solvents that are highly flammable and toxic.

SUMMARY OF THE INVENTION

The problem is solved by creating a method for preparing a new solid metoprolol composition, which, expressed in wt. % by weight of the total composition, contains:

(a) from 1 to 70 active ingredient not in amorphous form;

(b) from 10 to 95 polyethylene oxide;

(c) supplementing up to 100 conventional additives, and the active ingredient is the active ingredient of metoprolol. The method involves the following steps:

(i) mixing the active ingredient of meprolol and one or more additives optionally with an aqueous solution for a sufficient time; then (ii) adding the PO and mixing for a sufficient amount of time.

The active ingredient of metoprolol may be metoprolol tartrate. In one embodiment, the composition according to the invention contains by weight. %:

(a) from 5 to 45 active ingredient of metoprolol;

(b) 25 to 70 polyethylene oxide;

(c) supplementing up to 100 conventional additives with the exception of essential components.

The polyethylene oxide may have a molecular weight ranging from 50,000 to 8,000,000, preferably from 100,000 to 3,000,000.

Complementary conventional additives may be microcrystalline cellulose, lactose, ascorbic acid, pigments, plastic agents and / or lubricants.

It is possible to perform step (i) of mixing with the aqueous solution with excess liquid.

It is also possible for the method to include a granulating step which is carried out by passing the dry mixed ingredients through a sieve of a suitable pore size, which is carried out in a granulator-dryer.

The method may include an additional drying step.

The granulation and drying steps may be combined using a granulator-dryer.

The method may include a compression step, which may be preceded by a step in which the additives are added and mixed.

According to another preferred embodiment of the invention, the method comprises the following steps:

(i) mixing for a sufficient amount of time the active ingredient and optionally one of several additives with said aqueous solution, followed by sequentially:

(ii) adding PO and mixing for sufficient time;

(iii) granulating the mixture obtained from the previous step;

(iv) drying the granules thus formed for a sufficient time;

(v) adding one or more optional additives and mixing them for sufficient dry time;

(vi) compressing the tablets into the mixture obtained from the previous step.

It is possible to perform step (i) of mixing with the aqueous solution with excess liquid.

The granulation and drying steps may be combined using a granulator-dryer.

According to another preferred embodiment of the invention, the method comprises the following steps:

(i) mixing for a sufficient amount of time the active ingredient and optionally one of several additives with said aqueous solution, followed by sequentially:

(ii) granulating the mixture obtained from the previous step;

(iii) optionally drying the granules thus formed for a sufficient time;

(iv) adding PO and one or more optional additives and mixing for sufficient time;

(v) compressing the mixture obtained from the prior tablet stage.

Mixing, granulating and drying steps may be combined using a granulator-dryer.

The aqueous solution according to the invention may optionally contain water and water-soluble additives.

Said aqueous solution may contain up to 20% water and binder.

The term "solid composition" means that the composition is in the form of a tablet or mini-tablet, which in turn can be encapsulated using, for example, plain solid gelatin.

The expression "not in amorphous form" should be understood in its traditional meaning. There are many sources that define the term "amorphous" as non-crystalline, without the lattice structure characteristic of the crystal structure. Sources defining the term "amorphous" (or inverse term) are limitless: Hawley's, Condensed Chemical Dictionary, 12 ^th Edition, p. 71; Handbook of Chemistry and Physics, 65 ^th Edition, F-67; The Theory and Practice of Industrial Pharmacy, 1970, pp. 253-255; Remington's Pharmaceutical Sciences, 14 ^th Edition, p. 182;

General Chemistry 1992, pp. 314-315; Encyclopedia of Pharmaceutical Technology, vol. 1, pp. 12-13.

The term "except for the major constituents" shall be understood as excluding the presence of components or a group of constituents that determine the basic nature of the composition, in other words pH above 7 when the composition is diluted with water at a ratio of 10 g to 1 1 water. In particular, this term is understood to exclude the presence of one or more major components, such as those described in column 1, lines 38 to 62 of US-A-4404183, unless there is an acid component neutralizing the effect of said principal component, or if the basic (basic ) component is in relatively large quantity.

An exemplary embodiment of the invention

In one embodiment, the composition according to the invention contains by weight. %:

(a) 5 to 45 active ingredients of metoprolol;

(b) 25 to 70 polyethylene oxide;

(c) supplementing up to 100 conventional additives with the exception of essential components.

The active ingredient of metoprolol relates mainly to salts of metoprolol, such as succinate and tartrate. The preferred active ingredient is metoprolol tartrate.

In this composition according to the invention the polyethylene oxide has a molecular weight ranging from 50,000 to 8,000,000, preferably from 100,000 to 3,000,000. The necessary molecular weight for PO can be obtained by mixing PO with different molecular weight, which are commercially available.

Conventional additives may contain microcrystalline cellulose, lactose, ascorbic acid, pigments, plastic agents, lubricants, etc. Obviously, other conventional additives known to those skilled in the art can be used.

In one embodiment of the invention, conventional additives in the composition include magnesium stearate and / or glycerol bethanate and / or sodium stearyl fumarate used as a lubricant to provide better compression of the composition, for example, when in tablet form.

According to one or the other embodiment, the composition has an additional coating. The surface wrap is used to enhance the appearance, making the drug more acceptable to the patient, or to stabilize the compressed tablet spatially. The sheath may be traditional, suitable for enteral administration. It is obtained by using any traditional technique, using traditional ingredients. The surface coating can be obtained, for example, by using a rapidly soluble layer. It should be noted that the sheath according to this invention differs significantly from the sheath used in US-A-4277092, which does not reflect the separation (water-absorbing core / water-permeable sheath) and also the sheath of the present invention is dissolved and / or disintegrate until the sheath of USA-4277092 dissolves.

These solid formulations are suitable for administration as medicaments. The invention thus also relates to pharmaceutical compositions derived therefrom, and to other such compositions used as medicaments.

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

Preferably, the method consists of the following steps:

(i) mixing in the dry state and for a sufficient time the active ingredients of metoprolol, polyethylene oxide and one or more optional additives;

(ii) adding an optional solvent, when used, followed by stirring for a sufficient period of time;

(iii) granulation;

(iv) drying the granules thus formed for a sufficient time;

(ν) the addition of one or more additives, optionally mixed in a dry state for sufficient time and passing through a suitable sieve;

(vi) adding one or more optional additives and mixing them in the dry state for a sufficient time;

(vii) compressing the mixture resulting from the above steps to obtain the desired compressed tablet; and (viii) wrapping said compressed tablet optional.

The solvent used, when used, is preferably alcohol. The solvent is removed by drying at some stage of production and is not incorporated into the final compound.

Granulation can be accomplished by passing through a suitable sieve.

The drying step can be accomplished, for example, by using a drying oven or a drying oven.

The aforementioned granulation and drying steps can be combined using a granulator-dryer (eg with a spray chamber).

The choice of mixing time, apparatus used, sieve dimensions and other operating conditions is within the knowledge of one of skill in the art.

Without wishing to be bound by any theory, the Applicant considers that the PO in the formulation forms a hydrogel upon contact with water. This hydrogel dissolves more slowly or faster depending on the molecular weight of the PO used. The choice of molecular weight of the PO in combination with the appropriate choice of the concentration of the active ingredient, the PO and the additives, allows for the control of the release of the active ingredient.

Implementing the method described above with water as a wetting fluid is complicated. Indeed, PO is a hygroscopic polymer that immediately forms agglomerations when interacting with water droplets. This results in the formation of lumps with an elastic consistency in the center of the pellet mass, which is difficult to sort by size, even on the oscillating pellet grating.

The method according to the invention is a method for wet granulation of PO using water as a wetting liquid. Thus, it is possible to avoid both direct compression problems (the heterogeneous nature of the mix) and those related to organic solvents (cost, flammability and toxicity to the operator and the environment).

The method used involves two-stage wetting, allowing the hydration of the PO without forming lumps. During the first wetting step, wetting the active ingredient with water or, if appropriate, the active ingredient and one or more excipients, such as microcrystalline cellulose or lactose, is carried out. During the second wetting step, PO is added to the wet mixture already obtained. These two wetting steps are described herein simply as "wetting stages".

The wetting liquid may, if necessary, include soluble substances to modify the properties of the granular product and to improve wetting. Thus, binders such as hydroxypropylmethyl cellulose or polyvinyl pyrrolidone can be used to improve the properties of the granular product. When such substances are used, their concentration may vary up to about 20%, for example between 1 and 10%.

It is important to note that in all cases, water is in fact the only wetting solution of the method used.

The wetting operation can be performed in any conventional mixer, such as appliances manufactured by Vector, Moritz, Collette, Bouvard, Lodige, etc. Such mixers may use ordinary blade mixers, planetary alignment or, preferably, but not necessarily, high speed, with or without a lump-breaking knife. Wetting takes place over a period of 0.5 to 15 minutes, for example between 2 and 6 minutes.

It is preferable, but not necessary, to slightly divert the dust, which facilitates subsequent actions. Oversampling means the addition of excess fluid to the amount required to agglomerate the powder mixture.

The excess water added during the possible slight overturning in the first step is used in the agglomeration of the PO with the active ingredient, if any, or with other probable excipients.

For example, the weight ratio of water / composition or water / PO may vary from 0.13 to 0.36 and from 0.18 to 0.5, respectively.

After the first wetting step is completed, the PO is mixed further, resulting in additional wetting of the PO. During the second blending, the software integrates into the granular product and swells slightly. It is surprising, however, that no lumps are formed as is the case with traditional granulation using only one step described in the literature.

This latter operation can be performed in the same mixer used in the first step or in any other conventional mixer described above. The mixing time is from 0.5 to 15 minutes, for example between 2 and 6 minutes.

The method also includes other traditional steps in the field.

There may also be a prior step in which the active ingredient is completely mixed with the additives, if any.

The granulation step occurs mainly after the addition and mixing of the PO. This granulation step can also be carried out on a sieve of suitable pore size.

The drying step is also carried out using a tumble dryer or oven, especially after the granulation step. The drying step is considered accomplished when the residual water 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 granulator-dryer (eg spray chamber).

If necessary, the steps of adding and mixing additives may be included.

A step may also be included in which the granules, especially the dry ones, are sorted by size. Size sorting is also carried out by means of a sieve with an approximate mesh size between 100 and 1000 pm.

The final compression steps and tablet wrapping steps are also optionally included. The step in which a compression additive is added may occur mainly after drying, but before compression. These final compression steps are obviously not necessary when making the capsules to close the granules.

It is clear that the above stage, except for wetting, is not fixed. For example, compression additives can be added at the beginning or immediately after the addition of the PO. Similarly, the granulating step may be carried out before adding the PO.

Choosing the duration of mixing, the instrument, the sieves and other operating conditions is a matter of skill and judgment of the person skilled in the art.

The method thus used is a process for preparing a solid pharmaceutical composition comprising the following components by weight. %:

(a) from 1 to 70 active ingredient not in amorphous form;

(b) from 10 to 95 polyethylene oxide;

(c) supplementing up to 100 conventional additives and covering the steps of:

(i) mixing said active ingredient and one or more additives optionally with an aqueous solution for a sufficient time; then (s) adding the PO and mixing for a sufficient amount of time.

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

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

According to a third embodiment, the method used also comprises a granulating step which is carried out with a sieve of a suitable pore size or through a granulator-dryer.

According to another embodiment, the method used comprises an additional drying step.

According to another embodiment, the method used further comprises a compression step, which may be preceded by a step of adding and mixing the additives.

A specific exemplary embodiment of the method currently used comprises the steps of:

(i) mixing for sufficient time the active ingredient and optionally one of several additives with said aqueous solution; thereafter (j) adding the PO and mixing for sufficient time;

(iii) granulating the mixture obtained from the previous step;

(iv) drying the granules thus formed for a sufficient time;

(v) adding one or more optional additives and mixing them for sufficient dry time;

(vi) compressing a tablet of the mixture obtained from the previous step.

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

Preferably, steps (iii) and (iv) are carried out together in a granulator-dryer.

Another specific embodiment of the invention corresponds to the method used wherein the granulation (and drying) is preferably carried out simultaneously, for example in a granulator-dryer.

Said specific exemplary embodiment of the method currently used is a method comprising the following steps:

(i) mixing for sufficient time the active ingredient and optionally one of several additives with said aqueous solution; thereafter (ii) granulating the mixture obtained from the previous step;

(iii) optionally drying the granules thus formed for a sufficient time;

(iv) adding PO and one or more optional additives and mixing for sufficient time;

(v) compressing the mixture obtained from the preceding step into a tablet.

Preferably, steps (i) to (iii) are carried out together in a granulator-dryer.

The aqueous solution is preferably comprised of water and a binder up to 20%.

Said embodiment may be carried out not only for metoprolol but also for any other active ingredient.

The following examples are exemplified to illustrate the invention and should not be construed as limiting its scope. Although the amount of water used is given, it should be understood from the examples that water is substantially absent in the final compound. In the examples, the tablet hardness was determined using the Schloiniger 4M hardness tester.

Example 1. An unwrapped tablet is made of the following ingredients (in mg):

Metoprolol salt 200

Polyox WSR N 301 (MW = 4000000) 300

Avicel PH 101 54

Plasdone K29-32 8

Distilled water60

Aerosil 2003

Sodium stearyl fumarate 5

The method of production is as follows. Metoprolol and Avicel were placed in a Stephan UMC mixer and mixed for 5 min. Plasdone K29-32 was dissolved in water and the powder was wetted with this solution. Mixing is continued for 5 min. Polyox was then added and stirring continued for 5 min. Granulation is carried out with an Erweka FGS oscillator granulator with a mesh size of 1.6 mm. The product is dried to a certain constant humidity in a dryer. Size sorting is performed in an oscillating granulator with a grid size of 0.8 mm. Aerosil 200 and sodium stearyl fumarate are then added, with all lumps broken down beforehand. Stirring is continued for another 5 min. The powder was then pressed into a 12 mm diameter Fette P2 rotary press and a 12 mm radius of curved die. The nominal weight of the tablet is 570 mg and its average hardness is 18 kg. The tablets are then coated with the appropriate layer in a conventional manner (e.g., Opadri).

Example 2. Uncoated tablet made from the following ingredients (in mg):

Metoprolol tartrate 200 Polyox coagulant 303 Avicel PH 302 100 Plasdone K29-32 16 Aerosil 200 2 Sodium stearyl fumarate 9 Distilled water 200 The method of production is as follows. Me too-

prool tartrate, Avicel and Aerosil were placed in a Stephan UMC mixer and mixed for 5 min. Placdon K29-32 was dissolved in water. The powder mixture is granulated with the solution in a granulator-dryer (with spray chamber) at the following spray parameters:

Air flow (m ³ / h) 65 m ³ / h

Liquid flow (g / min) 16 g / min

Internal temperature 65 ° C

Spray pressure 2.0 bar

Polyox and sodium stearyl fumarate were then added and stirring continued for another 5 min. The powder is then pressed into a Fette P2 rotary press with a diameter of 12 mm and a radius of curved die 12 mm. The tablets are below 64835 coated with the appropriate layer in a conventional manner (e.g., opadri).

Claims

Claims (20)

1. A method for preparing a solid metoprolol composition which, expressed as a percentage by weight of the total composition, contains: (a) from 1 to 70% of the active ingredient not in amorphous form; (b) from 10 to 95% polyethylene oxide (PO); (c) Complementary to 100% conventional additives, characterized in that the active ingredient is metoprolol and includes the following steps: (i) mixing the active ingredient of metoprolol and one or more additives optionally with an aqueous solution for a sufficient time; then (ii) adding the PO and mixing for a sufficient amount of time. A method according to claim 1, wherein the active ingredient of metoprolol is metoprolol tartrate. A method according to claim 1 or 2, characterized in that said composition comprises: (a) from 5 to 45% of the active ingredient of metoprolol; (b) 25 to 70% polyethylene oxide; (c) Complementary up to 100% conventional additives with the exception of essential components. A method according to claims 1 to 3, characterized in that the polyethylene oxide has a molecular weight ranging from 50,000 to 8,000,000, preferably from 100,000 to 3,000,000. The method according to claims 1 to 4, characterized in that the complementary conventional additives are microcrystalline cellulose, lactose, ascorbic acid, pigments, plastic agents and / or lubricants. Method according to claims 1 to 5, characterized in that step (i) of mixing with the aqueous solution is carried out with excess liquid. A method according to claims 1 to 6, characterized in that it comprises a granulating step. A method according to claim 7, characterized in that the granulating step is carried out by passing the dry mixed ingredients through a sieve of a suitable pore size. A method according to claim 7, characterized in that the granulating step is carried out in a granulator-dryer. A method according to claims 1 to 9, characterized in that it further comprises a drying step. A method according to claim 7,9 or 10, characterized in that the granulation and drying steps are combined using a granulator-dryer. A method according to claims 1 to 11, characterized in that it includes a compression step. 13. A method according to claim 12, characterized in that the compression step is preceded by a step in which the additives are added and mixed. A method according to claims 1 to 13, characterized in that it comprises the following steps: (i) mixing for a sufficient amount of time the active ingredient and optionally one of several additives with said aqueous solution, followed by sequentially: (ii) adding PO and mixing for sufficient time; (iii) granulating the mixture obtained from the previous step; (iv) drying the granules thus formed for a sufficient time; (v) adding one or more optional additives and mixing them for sufficient dry time; (vi) compressing the tablets into the mixture obtained from the previous step. 15. The method of claim 14, wherein step (i) of mixing with the aqueous solution is carried out with excess liquid. The method according to claim 14 or 15, characterized in that the granulation and drying steps are combined using a granulator-dryer. A method according to claims 1 to 13, characterized in that it comprises the following steps: (i) mixing for sufficient time the active ingredient and optionally one of several additives with said aqueous solution, and then performing: (ii) granulating the mixture obtained from the previous step; (iii) optionally drying the granules thus formed for a sufficient time; (iv) adding PO and one or more optional additives and mixing for sufficient time; (v) compressing the mixture obtained from the previous step into tablets. A method according to claim 17, characterized in that the mixing, granulation and drying steps are combined using a granulator-dryer. A method according to claims 1 to 18, 5 wherein said aqueous solution contains water and water-soluble additives optionally. 20. The method of claim 19, wherein said aqueous solution contains water and a binder in an amount up to 20%. Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, 52-B Dr. GM Dimitrov Blvd.