HK1155976B - Compositions comprising amlodipine and bisoprolol - Google Patents

Description

Composition containing amlodipine and bisoprolol

Technical Field

The present invention relates to a stable solid pharmaceutical composition containing amlodipine and bisoprolol of the following formulae as active ingredients

More particularly, the present invention relates to compositions packaged in moisture resistant packaging containing amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate (amlodipine besylate) and bisoprolol fumarate of the formula

Further comprising a filler, a disintegrant, a lubricant and an anti-adhesive (anti-adhesive) used in the pharmaceutical industry, and further wherein the amount of the compound of formula 3N- (2- { [4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1, 4-dihydro-2-pyridinyl ] -methoxy } -ethyl) -aspartic acid does not exceed 0.5% during the preparation and storage of the composition

Background

According to the "evidence-based" therapeutic practice, the blood pressure values required to reduce the risk of cardiovascular morbidity and mortality can be achieved by a drug consisting of a single compound or an optimal combination of two compounds.

Combination therapy is more effective, generally reducing the amount of each composition required in a monotherapy regimen, and thus side effects are reduced and patient compliance is improved.

Because of these advantages, the effect of drug combination therapy is increased in the treatment of hypertension and its complications. Combinations of beta blockers, diuretics, ACE inhibitors, ARB-s, individual calcium channel blockers are typically used.

In recent years, these combinations are more and more frequently marketed in the form of so-called "fixed combinations" containing both active ingredients in a single dosage form, for better "patient compliance" and for lower treatment costs.

International guidelines explicitly recommend the use of fixed combinations.

There are currently several fixed combinations containing calcium channel blockers ("calcium antagonists") and beta blockers, such as tablets containing felodipine and metoprolol or nifedipine and atenolol, which are preferred for the treatment of hypertension and angina pectoris.

Fixed combinations of amlodipine and bisoprolol are not yet marketed, but several articles and patent applications relate to combinations thereof. International patent application No. wo2005/099699 discloses a combination of S-amlodipine and a beta blocker, including a combination with bisoprolol.

This application mentions the pharmaceutical solubilization of co-formulations (co-formulations) of several of these ingredients

Liquid, but does not address the major problem of practical use, namely the chemical incompatibility of the two active ingredients.

In the so-called "single composition" containing only one active ingredient, amlodipine is in the form of a besylate salt, and bisoprolol is used as the fumarate salt.

It seems to be practical to formulate amlodipine besylate and bisoprolol fumarate into a single dosage form formulation, since both bisoprolol fumarate and amlodipine besylate are suitable for preparing stable pharmaceutical dosage forms.

According to Indian patent application No.845/MUM/2004, amlodipine besylate and bisoprolol fumarate reacted with each other. To our experiments, the product was the compound of formula (3), N- (2- { [4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1, 4-dihydro-2-pyridinyl ] -methoxy } -ethyl) -aspartic acid. The compound is formed by the chemical reaction of amlodipine base and fumaric acid. The formation of this compound is unexpected because the salt of amlodipine with fumaric acid is claimed to be stable and not converted to the compound of formula (3) in U.S. patent application No. 6518288.

The current requirements of international pharmaceutical authorities are to accept only very low limits (parts per thousand by weight) of degradation products of pharmaceutical compositions.

The absorption properties and pharmacokinetic effects of the above salts are well known. Patients are accustomed to using compositions containing these salts and they are already accustomed to their effects.

There is a need for a stable solid dosage form containing amlodipine or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, and bisoprolol fumarate. The composition should be a tablet or capsule in which contaminants from the incompatibility of the two active ingredients are also maintained at low levels during storage.

According to indian patent application No.845/MUM/2004, a combination of amlodipine besylate and bisoprolol fumarate can be prepared only when the active ingredients are segregated into different granules. The granules are further mixed with excipients and filled into capsules or sachets, or compressed into so-called bilayer tablets. The key to the solution of the indian invention is the separation of the two components from each other. This substantially prevents physical contact between the active ingredients, which aids in the formation of the reaction product of formula (3) during mixing of the particles, especially during compaction with dense contact over a large surface area.

The process of the indian patent application has several disadvantages. Separate granulation and homogenization of the active ingredient increases the number of technical steps required. The preparation of the bi-layer tablets requires complex and special equipment.

There is a need for a stable solid dosage form containing amlodipine or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, and bisoprolol fumarate. The composition should be a tablet or capsule in which contaminants from the incompatibility of the two active ingredients are maintained at low levels even during storage and separate handling of the active ingredients during manufacture or in the composition is not required.

Disclosure of Invention

We have surprisingly found that stable pharmaceutical compositions can be prepared if the packaging and conditions are appropriately selected, which, if packaged satisfactorily, can meet a number of safety regulations relating to pharmaceutical formulations, and that the amount of N- (2- { [4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1, 4-dihydro-2-pyridinyl ] -methoxy } -ethyl) -aspartic acid of formula (3) in the composition does not exceed 0.5% either during the preparation or during storage of the pharmaceutical composition over the useful life of the composition (at least two years).

The invention relates to a stable solid pharmaceutical composition, which contains amlodipine or pharmaceutically acceptable salts thereof, preferably amlodipine besylate, and bisoprolol fumarate, further contains pharmaceutically acceptable organic or inorganic fillers, disintegrants, lubricants and anti-adhesives, and is packaged in a moisture-proof package.

Disclosure of Invention

During the course of the experiments we found that the two active ingredients reacted with each other even in simple powder mixtures and that the reaction products were formed in considerable amounts. The incompatibility is even more pronounced if the two components are placed in a dosage form of low porosity, such as a tablet, where their crystals are in large area contact with each other at high pressure.

The interaction is strongly dependent on temperature: the amounts of amlodipine and bisoprolol in the mixture of amlodipine besylate and bisoprolol fumarate after one month storage at different temperatures varied as follows:

TABLE 1

It will be apparent to those skilled in the art of pharmaceutical technology that in the case of forming a composition containing two incompatible ingredients, the ingredients have to be separated by an appropriate method. For this purpose, one active ingredient may be coated with sufficient polymeric excipient. The coated polymer layer may form a suitable separation layer between the crystalline surfaces of the two active ingredients.

Our formulation experiments have failed. The active ingredient is sensitive to heat. On the one hand, the heat sensitivity of the active ingredient causes not only the problem of the aqueous coating method but also the problem of the coating method using an organic solvent because elimination of the solvent necessitates heat stress. On the other hand, during the drying process, there are still traces of moisture in the composition which contribute to the interaction of the active ingredients.

We have surprisingly found that preventing incompatibility between the two active ingredients and self-thermal degradation of the active ingredients is not sufficient to preclude a process using water or organic solvents with concomitant heat stress.

To prevent the adverse effects of heat stress, combination tablets were prepared by a direct compression method. If the tablets are stored in glass containers sealed with polyethylene lids at 30 ℃ and 65% relative humidity, the degradation products remain below the detection limit.

In the case of storing the same tablets for 3 months at 30 ℃ and 65% relative humidity in a PVC/PVdC-type (polyvinyl chloride/polyvinylidene chloride-type) thermoformed blister pack foil (blisterfoil) sealed with aluminium foil (aluminium foil) we have surprisingly found that the minimum humidity penetrates the PVC/PVdC-type blister pack foil-the above-mentioned package is known to be more moisture-proof than PVC-sufficient to form unacceptably high levels of contaminants.

The result is that it is not sufficient to protect the product from moisture during production, but the environment is kept dry during storage.

These experiments show that for the interaction between the components in the solid phase, a very small amount of water adsorbed to the crystal surface is sufficient. In the compositions according to the invention, the reactions which lead to the formation of contaminants do not occur at all or occur only to a very limited extent.

According to the present invention, there is provided a stable, solid-packaged pharmaceutical composition of amlodipine and bisoprolol as active pharmaceutical ingredients, containing less than 0.5%, preferably less than 0.3%, more preferably less than 0.2% of the compound of formula (3), which is packaged in a moisture-proof package, and further containing amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, bisoprolol fumarate, further containing a pharmaceutically acceptable filler, a disintegrant, a lubricant, an antiadherent, optionally a binder (bindingagent).

Amlodipine, according to our knowledge, reacts with fumaric acid. Other salt-forming components (e.g., benzenesulfonic acid anions) do not play any role during the reaction leading to the formation of contaminants. Thus, amlodipine can be used in the form of a base or a salt (e.g., amlodipine besylate) according to the present invention.

The composition according to the invention is of great significance from the point of view of the stability of the pharmaceutical composition.

In order to formulate tablets by dry methods, excipients having suitable compressibility and free-flowing properties in addition to their primary function have to be used.

According to the invention, all compounds in the composition except the active ingredient are excipients.

With regard to excipients, terms such as filler, disintegrant, lubricant, anti-adhesive and binder refer to the class of excipients. They therefore also relate to mixtures of suitable excipients and combinations thereof, and furthermore to the conventional use of the same excipients in the same compositions. This is the case, for example, if, as filler, two different fillers used in the pharmaceutical industry, such as lactose and microcrystalline cellulose, are used in the composition as a composite (composite).

The terms in relation to the above excipients also relate to the case where the composition contains a plurality of excipients of different kinds. These are, for example, the case if fillers are used in addition to disintegrants, for example lactose, as a composite with povidone (povidone) and copovidon (copovidon), or if glidants or anti-binders, for example a composite of microcrystalline cellulose and colloidal silicon dioxide, are generally used together with fillers.

The use of such compositions according to the invention is equivalent to the conventional use of different components, and therefore these technical processes also form part of the invention.

The composition according to the invention may contain as filler a filler or a mixture thereof used in the pharmaceutical industry, preferably microcrystalline cellulose, anhydrous dibasic calcium phosphate, spray dried lactose, or mannitol or a mixture thereof, most preferably low moisture grade (moisturgede) microcrystalline cellulose.

During the compaction experiments we found that the lowest degradation rate was detected with microcrystalline cellulose (preferably microcrystalline cellulose of a low humidity level; see table 2).

TABLE 2

The effect of the filler on the degradation and interaction rate after one month storage at 50 ℃ (blend of amlodipine besylate/bisoprolol fumarate/filler, ratio 0.1: 5) is as follows:

the ratio of filler in the tablet suitable for the direct compression (compressing) process according to the invention is 60% to 90%, preferably 70% to 90%, more preferably 80% to 90%.

The use of fillers is not essential in the case of capsule products. In order to ensure uniform diffusion of the active ingredients in one production batch and thus the amount required for filling both active ingredients in each capsule throughout the entire encapsulation process, it is preferred to use an appropriate amount of a filler with a high specific surface area that can prevent the ingredients from being dispersed during the preparation process.

Such fillers having a high specific surface area are, for example, powdered cellulose or microcrystalline cellulose. Microcrystalline cellulose is preferred even from the following points of view: i.e. due to the mechanical interlocking of the microcrystalline cellulose in combination with its holding together of the fill composition in the capsule by the relatively low thickener pressure and thus preventing dispersion of the composition material during the encapsulation process.

For the reasons stated above, the optimum amount of filler in the encapsulated product is from 10% to 75%, preferably from 45% to 75%, more preferably from 55% to 65%, based on the weight of the filler of the composition.

Fillers of low moisture grade are more preferred according to the invention.

In addition to the main functional features, the excipients used for tabletted (tableted) compositions prepared by the dry process should also have acceptable compressibility and free flowability.

In the case of tabletted and encapsulated compositions, disintegrants have to be used which ensure that the tablets or capsules disintegrate rapidly due to the action of the digestive juices, so that the dissolution and absorption of the active ingredient takes place rapidly and completely.

Any disintegrant commonly used in the pharmaceutical industry may be used as the disintegrant. A large number of alternative disintegrants are available to those skilled in the art which are particularly suitable for direct pressure tabletting processes.

Thus, as a disintegrant, the composition of the present invention may contain any disintegrant or mixtures thereof commonly used in the pharmaceutical industry, preferably crospovidone, sodium starch glycolate, croscarmellose, low substituted hydroxypropylcellulose or mixtures thereof, most preferably sodium starch glycolate. According to the invention, the optimum amount of disintegrant in the composition is 1% to 10%, preferably 4% to 6%, based on the weight of the tablet or capsule fill.

The use of an anti-binder and a flow aid is necessary in both tabletting and encapsulating compositions, wherein the anti-binder prevents the hygroscopic filler and its particles from adhering to each other by strong hygroscopicity.

Thus, as an anti-adhesive, the composition of the invention may contain any type of anti-adhesive or mixtures thereof commonly used in the pharmaceutical industry. Preferably it contains solid (soloids) or colloidal silica or mixtures thereof. Most preferably it contains colloidal silica. The optimum amount of binder in the composition of the invention is 0.3% to 2%, preferably 0.5% to 1%.

In the case of the preparation of tableting and encapsulating compositions, the use of so-called lubricants, which reduce adhesion and friction, is necessary, which facilitates the extrusion of the tablet or capsule filling from the die (tool) and prevents the components from adhering to the molding or filling tool.

As lubricant, the composition according to the invention may contain any type of lubricant used in the pharmaceutical industry or mixtures thereof. Preferably, they include magnesium stearate, sodium stearyl fumarate, glyceryl behenate, or mixtures thereof. Most preferably they comprise magnesium stearate. According to the invention, the optimum amount of lubricant in the composition is 0.5% to 3%, preferably 1% to 2%.

The solid dosage form according to the invention is preferably a tablet or a capsule.

Surprisingly, in a preferred case, the tablets are formulated without binders used in the pharmaceutical industry. If it is desired to use due to a change in the properties of the tablet, such as an increase in its hardness, any binder, such as polyvinylpyrrolidone, starch, etc., may be used as the binder.

In case the solid dosage form of the invention is a tablet, according to a preferred embodiment of the invention, the tablet, packaged in a moisture-proof protective package, contains 2-20%, preferably 2-10%, more preferably 1-6% amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, 2-20%, preferably 2-10%, more preferably 1-6% bisoprolol fumarate, further contains 60-90%, preferably 70-90%, more preferably 80-90% filler, 1-10%, preferably 4-6% disintegrant, 0.5-3%, preferably 1-2% lubricant, 0.3-2%, preferably 0.5-1% anti-binder, if necessary, 1-10%, preferably 0.1-5% of a binder.

In case the solid dosage form of the invention is a capsule, according to a preferred embodiment of the invention, the capsule packed in the moisture-proof protective package contains 5% to 80%, preferably 5% to 18%, more preferably 10% to 15%, calculated on the weight of the capsule fill, of amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, 5% to 80%, preferably 5% to 15%, more preferably 1% to 10%, of bisoprolol fumarate, further 1% to 10%, preferably 4% to 6%, of a disintegrant, 0.5% to 3%, preferably 1% to 2%, of a lubricant, 0.3% to 2%, preferably 0.5% to 1%, of an anti-adhesive, if necessary 10% -75%, preferably 45% -75%, more preferably 55% -65% of a filler.

In the packaged dosage form according to the invention, the pharmaceutical composition containing the active ingredient, e.g. a tablet or capsule, is placed in a package that isolates the dosage form from the environment, thus protecting the dosage form from the environment prior to administration.

By way of example, different packaging materials are mentioned with the following abbreviations:

CFF-cold forming foil

OPA/AL/PVC foil (oriented polyamide/aluminum/polyvinyl chloride foil)

PVC/PE/PVdCf Louis (polyvinyl chloride/polyethylene/polyvinylidene chloride foil)

PVC/PCTFE foil (polyvinyl chloride/polychlorotrifluoroethylene foil)

PVdC (polyvinylidene chloride) layer/foil

PVC (polyvinyl chloride) foil

The moisture-proof packaging of the solid dosage forms of the invention is a sealed container or a moisture-proof so-called cold seal blister (CFF) or thermoformed blister.

According to one embodiment of the invention, the moisture-resistant packaging unit may be a container (e.g., a vial, a plastic box, a glass container with a sealed polyethylene or polypropylene lid, a polypropylene canister, etc.) having a closed compartment in which one or more tablets or capsules are placed.

If necessary, the container containing the tablets or capsules may contain, in addition to the capsules and tablets, an adjuvant capable of binding moisture of the atmosphere inside the container, such as zeolite or silica gel. The adjuvants used to bind moisture may be placed directly between the capsules or tablets, but they may be placed in separate containers or bags that are air permeable and placed between the dosage forms. Such containers are also suitable for packaging the solid dosage forms of the present invention, wherein the dosage form and the moisture binding compound are located in two separate parts and ventilation is ensured.

The atmosphere in the package may be air, an inert gas, or, if applicable, a vacuum.

According to one embodiment of the invention, the moisture-proof protective packaging is a so-called cold-seal blister.

Cold seal blisters are a form of packaging in which blisters are cold formed from a composite foil and covered with aluminium foil. Such composite foils may be OPA/AL/PVC (oriented polyamide/aluminium/polyvinyl chloride foils). According to one embodiment of the invention, the dosage forms containing the active ingredient, such as tablets or capsules, are packaged in so-called cold-sealed blisters.

According to another embodiment of the invention, the moisture-proof packaging is a blister, for example made from a thermoformed moisture-proof composite foil, which is covered with an aluminium foil.

According to a further embodiment of the invention, the dosage form containing the active ingredient, such as a tablet or capsule, is packaged in blisters made from a thermoformed moisture-resistant composition, said blisters being covered with aluminium foil. Such a moisture-proof composite foil may be, for example, a PVC/PE/PVdC, a so-called "triple foil" or a PVC/PCTFE foil.

According to a most preferred embodiment of the invention, the dosage form is a tablet packaged in a blister covered with aluminium foil (so-called cold seal blister/CFF /) of a cold formed OPA/AL/PVC composite foil, or a thermoformed moisture barrier composite foil covered with aluminium foil (e.g. a PVC/PE/PVdC triple foil or a PVC/PCTFE foil), or a glass or polypropylene container with a polyethylene or polypropylene closed container lid, wherein the tablet contains 1-6% of besylate, 1-6% of bisoprolol fumarate, 80-90% of microcrystalline cellulose, 4-6% of sodium starch glycolate, 1-2% of magnesium stearate, 0.5-1% of colloidal silicon dioxide, based on the total weight of the tablet.

According to another very preferred embodiment of the invention, there is provided a capsule packaged in a blister covered with aluminum foil for cold forming OPA/AL/PVC composite foil (so-called cold seal blister/CFF /), or in a thermoformed moisture barrier composite foil covered with aluminum foil (e.g. PVC/PE/PVdC triple foil or PVC/PCTFE foil), or in a glass or polypropylene container with a polyethylene or polypropylene closed container lid, wherein the capsule contains 10% to 15% amlodipine besylate, 10% to 15% bisoprolol fumarate, 55% to 65% microcrystalline cellulose, 4% to 6% sodium starch glycolate, 1% to 2% magnesium stearate, 0.5% to 1% colloidal silicon dioxide, based on the total weight of the capsule fill.

The composition according to the invention contains N- (2- { [4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1, 4-dihydro-2-pyridinyl ] -methoxy } -ethyl) -aspartic acid in an amount of less than 0.5%, preferably in an amount of between 0.01% and 0.5%. According to a preferred embodiment of the invention, the aspartic acid derivative compound is present in an amount of less than 0.3%, more preferably in an amount of between 0.01% and 0.3%. According to a more preferred embodiment of the invention, the aspartic acid derivative compound is present in an amount of less than 0.2%, more preferably in an amount comprised between 0.01% and 0.2%. One skilled in the art can use the essential features of the invention to prepare products containing undetectable amounts of the compound of formula (3). The scope of protection of the present invention therefore includes products in which the essential features of the invention are used and which contain undetectable amounts of the compound of formula (3).

In the preparation of the composition according to the present invention, amlodipine base or a pharmaceutically acceptable salt thereof used in the pharmaceutical industry, preferably amlodipine besylate, bisoprolol fumarate, further organic or inorganic fillers, disintegrants, lubricants and optionally binders, are homogenized using known methods, and then anti-binders are added and homogenized.

A.) compressing the resulting homogenate (homogenize) into tablets by known methods, or

B.) filling into hard gelatin capsules by known methods,

the resulting tablets or capsules are then packaged in moisture-resistant packaging by known methods.

If necessary, it may be previously sieved to obtain a component of uniform particle size. The sieving may preferably be performed using a 250 μm sieve. The homogenization may be carried out in any apparatus suitable for homogenization, preferably a drum mixer. For direct compression of tablets by known methods, the tablets may be compressed using any type of apparatus. The capsules may be prepared by known methods using any apparatus suitable for the encapsulation process.

The tablets or capsules are packaged in suitable blisters or containers by known methods.

Tablets are prepared using 2% to 20%, preferably 2% to 10%, more preferably 1% to 6% amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, 2% to 20%, preferably 2% to 10%, more preferably 1% to 6% bisoprolol fumarate, further 60% to 90%, preferably 70% to 90%, more preferably 80% to 90% of a filler, 1% to 10%, preferably 4% to 6% of a disintegrant, 0.5% to 3%, preferably 1% to 2% of a lubricant, 0.3% to 2%, preferably 0.5% to 1% of an anti-adhesive, if necessary, 1% to 10%, preferably 0.1% to 5% of a binder.

The capsules are prepared using 5% to 80%, preferably 5% to 18%, more preferably 10% to 15%, based on the weight of the capsule fill, of amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, 5% to 80%, preferably 5% to 15%, more preferably 10% to 15%, bisoprolol fumarate, further 1% to 10%, preferably 4% to 6%, of a disintegrant, 0.5% to 3%, preferably 1% to 2%, of a lubricant, 0.3% to 2%, preferably 0.5% to 1%, of an anti-adhesive, if necessary 10% to 90%, preferably 45% to 75%, more preferably 55% to 65%, of a filler.

Microcrystalline cellulose, anhydrous dibasic calcium phosphate, spray-dried lactose or mannitol, preferably microcrystalline cellulose or mixtures thereof, more preferably microcrystalline cellulose with low moisture content, may be used as filler, crospovidone, sodium starch glycolate, croscarmellose, low substituted hydroxypropylcellulose or mixtures thereof, preferably sodium starch glycolate may be used as disintegrant, magnesium stearate, sodium stearyl fumarate, glyceryl behenate or mixtures thereof, preferably magnesium stearate may be used as lubricant for preparing tablets or capsules according to the invention. Solid or colloidal silica or a mixture thereof, preferably colloidal silica, may be used as the anti-adhesive, and if necessary, polyvinylpyrrolidone or starch may be used as the binder.

The tablets or capsules are preferably packed in cold-formed OPA/AL/PVC composite foil blisters (so-called cold-seal blisters/CFF /) of 130 μm thickness covered with aluminium foil of 20 μm thickness, or blisters made of thermoformed moisture-proof composite foil covered with aluminium foil of 20 μm thickness, or containers fitted with a closed polyethylene or polypropylene container lid. Most preferably, the composition is packaged in so-called cold seal blisters (CFFs).

As mentioned above, another embodiment of the moisture resistant packaging is to package the tablet or capsule with a moisture binding drying compound. These packaging forms and adjuvants are described in detail above.

According to the most preferred method for preparing solid pharmaceutical dosage form tablets, 1% to 6% amlodipine besylate, 1% to 6% bisoprolol fumarate, 80% to 90% microcrystalline cellulose, 4% to 6% sodium starch glycolate, 1% to 2% magnesium stearate are homogenized, then 0.5% to 1% colloidal silicon dioxide is added and homogenized, then the homogenate is compressed into tablets by a known method using a direct compression method, the resulting tablets are packed into cold-formed OPA/AL/PVC composite foil blisters (so-called cold-seal blisters/CFF /) covered with aluminum foil, or thermoformed moisture-proof composite foil covered with aluminum foil, such as PVC/PE/PVdC triple foil or PVC/PCTFE foil, or into glass or polypropylene containers with a closed polyethylene or polypropylene lid, the tablets are preferably packed into cold-formed OPA/AL/PVC composite foil blisters covered with aluminium foil (so-called cold seal blisters/CFF /).

According to the most preferred method for preparing solid pharmaceutical dosage form capsules, 10% to 15% amlodipine besylate, 10% to 15% bisoprolol fumarate, 55% to 65% microcrystalline cellulose, 4% to 6% sodium starch glycolate, 1% to 2% magnesium stearate, based on the total weight of the fill, are homogenized, then 0.5% to 1% colloidal silicon dioxide is added and homogenized, then the homogenate is encapsulated in hard gelatin capsules by known methods and packed into cold-formed OPA/AL/PVC composite foil blisters (so-called cold-seal blisters/CFF /) covered with aluminum foil, or thermoformed moisture-proof composite foil covered with aluminum foil, such as PVC/PE/PVdC triple foil or PVC/PCTFE foil, or into glass or polypropylene containers with a sealed polyethylene or polypropylene lid, the tablets are preferably packed into cold-formed OPA/AL/PVC composite foil blisters covered with aluminium foil (so-called cold seal blisters/CFF /).

The advantage of the present invention is that it makes it possible to use a simple, inexpensive direct compression process, even in the case of compositions according to the invention containing incompatible active ingredients. According to the composition of the present invention, the amount of the compound (3) is not more than 0.5% for at least 2 years.

In the case of the use of combination compositions, "patient compliance" is better, and therefore these compositions are better than compositions used as monotherapy.

Detailed Description

The present invention is demonstrated by the following examples, to which the scope of protection is not limited.

Example 1

Composition of 1000 tablets:

the method comprises the following steps:

both active ingredients were sieved with a 250 μm sieve and then homogenized in a drum mixer for 10 minutes with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide. Magnesium stearate was then added to the mixture and the resulting mixture was further homogenized for 2 minutes.

The homogenate was compressed into tablets having a weight of 305mg with a tablet press.

The tablets were packed into cold-formed OPA/AL/PVC composite foil blisters with a thickness of 130 μm and covered with aluminium foil with a thickness of 20 μm.

The results of the contaminant examination of the tablets prepared according to example 1 on the day of production and after storage for 3 months at 40 ℃/75% relative humidity are as follows:

further quality data for the product of example 1 are as follows:

example 2

Composition of 1000 capsules:

the method comprises the following steps:

both active ingredients were sieved with a 250 μm sieve and then homogenized in a drum mixer for 10 minutes with microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide. Magnesium stearate was then added to the powder mixture and the resulting mixture was homogenized for an additional 2 minutes.

The homogenate was filled into capsules with 47mg of fill using a tablet press.

The capsules were packed into cold-formed OPA/AL/PVC composite foil blisters with a thickness of 130 μm and covered with aluminium foil with a thickness of 20 μm.

The results of the contaminant inspection of the capsules prepared and packaged according to example 2 on the day of production and after storage for 3 months at 40 ℃/75% relative humidity are as follows:

reference example:

composition of 1000 tablets:

the method comprises the following steps:

both active ingredients were sieved with a 250 μm sieve and then homogenized with Emcompress, corn starch, povidone, crospovidone and colloidal silica in a drum mixer for 10 minutes. Magnesium stearate was then added to the powder mixture and the resulting mixture was homogenized for an additional 2 minutes.

The homogenate was compressed into tablets having a weight of 280mg with a tablet press.

The tablets were packed in a thickness of 250 μm with a density of 60g/m²PVdC coated thermoformed PVC foil blisters and the blisters were covered with aluminium foil having a thickness of 20 μm.

The results of the contaminant examination of the tablets prepared according to the reference example on the day of production and after storage for 3 months at 40 ℃/75% relative humidity are as follows:

the tablets according to the reference example after 3 months of storage showed a much higher contamination, partly determined by the chemical nature of the excipients used (humidity and chemical incompatibility) and partly due to insufficient moisture resistance of the packaging system.

Claims (26)

1. A stable solid pharmaceutical composition comprising amlodipine base or a pharmaceutically acceptable salt thereof and bisoprolol fumarate and a pharmaceutically acceptable excipient packaged in a moisture-proof package, and further comprising less than 0.5% by weight of the active ingredient of a compound of the formula wherein said amlodipine base or a pharmaceutically acceptable salt thereof and bisoprolol fumarate are not required to be treated separately during the manufacturing process

2. The pharmaceutical composition according to claim 1, characterized in that said composition comprises a pharmaceutically acceptable amlodipine salt, wherein said amlodipine salt is amlodipine besylate.

3. Pharmaceutical composition according to claim 1, characterized in that it contains less than 0.3% of the compound of formula (3).

4. Pharmaceutical composition according to claim 1, characterized in that it contains less than 0.2% of the compound of formula (3).

5. Pharmaceutical composition according to claim 1, characterized in that the composition is packaged in cold-formed blisters of OPA/AL/PVC composite foil covered with aluminium foil.

6. Pharmaceutical composition according to claim 1, characterized in that the composition is packaged in a thermoformed moisture-proof composite foil blister and covered with aluminium foil.

7. Pharmaceutical composition according to claim 1, characterized in that the composition is packaged in a glass or polypropylene container provided with a polyethylene or polypropylene sealed container lid.

8. A solid pharmaceutical composition according to any one of claims 1 to 7, characterized in that the dosage form of the composition is a tablet or a capsule.

9. A solid pharmaceutical composition according to claim 8, characterized in that the dosage form of said composition is a tablet packed in a moisture proof pack, characterized in that it comprises 2% to 20% amlodipine besylate, 2% to 20% bisoprolol fumarate, further comprising 60% to 90% of a filler, 1% to 10% of a disintegrant, 0.5% to 3% of a lubricant, 0.3% to 2% of a binder, based on the weight of the tablet.

10. A solid pharmaceutical composition according to claim 8, characterized in that the dosage form of said composition is a tablet packed in a moisture proof pack, characterized in that it comprises 2% to 10% amlodipine besylate, 2% to 10% bisoprolol fumarate, further comprising 70% to 90% of a filler, 4% to 6% of a disintegrant, 1% to 2% of a lubricant, 0.1% to 5% of a binder, based on the weight of the tablet.

11. A solid pharmaceutical composition according to claim 8, characterized in that the dosage form of said composition is a tablet packed in a moisture proof pack, characterized in that it comprises 1-6% amlodipine besylate, 1-6% bisoprolol fumarate, further comprises 80-90% of a filler, 4-6% of a disintegrant, 1-2% of a lubricant, 0.1-5% of a binder, based on the weight of the tablet.

12. The pharmaceutical composition according to claim 1, which is a tablet packaged in a cold-formed blister of OPA/AL/PVC composite foil covered with aluminum foil, or in a thermoformed moisture-proof composite foil blister and covered with aluminum foil, or in a glass or polypropylene container fitted with a polyethylene or polypropylene sealed container lid, containing 1-6% amlodipine besylate, 1-6% bisoprolol fumarate, 80-90% microcrystalline cellulose, 4-6% sodium starch glycolate, 1-2% magnesium stearate, 0.5-1% colloidal silicon dioxide, based on the weight of the tablet.

13. The pharmaceutical composition according to claim 1, which is a capsule packaged in a cold-formed blister of OPA/AL/PVC composite foil covered with aluminum foil, a thermoformed moisture-proof composite foil blister covered with aluminum foil, or a glass or polypropylene container equipped with a polyethylene or polypropylene sealed container lid, containing 10-15% amlodipine besylate, 10-15% bisoprolol fumarate, further containing 55-65% microcrystalline cellulose, 4-6% sodium starch glycolate, 1-2% magnesium stearate, 0.5-1% colloidal silicon dioxide, based on the weight of the capsule filling.

14. A process for the preparation of a stable solid packaged dosage form containing amlodipine base or a pharmaceutically acceptable salt thereof and bisoprolol fumarate, characterized in that amlodipine base or a pharmaceutically acceptable salt thereof and bisoprolol fumarate, a disintegrant, a lubricant, and if necessary further excipients used in the pharmaceutical industry are homogenized, followed by the addition of an antiadhesive, continued homogenization, followed by homogenization

a.) compressing the homogenate into a tablet by a direct compression method, or

b.) filling the homogenate into hard gelatin capsules by known methods,

the resulting tablets or capsules are then packaged in a moisture-proof protective package by known methods,

wherein the amlodipine base or the pharmaceutically acceptable salt thereof is not required to be treated separately from bisoprolol fumarate in the preparation process.

15. Method according to claim 14, characterized in that 2-20% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 2-20% bisoprolol fumarate, further 60-90% of a filler, 1-10% of a disintegrant, 0.5-3% of a lubricant, 0.3-2% of a binder are used, based on the weight of the tablet.

16. The method according to claim 14, characterized in that 2-20% amlodipine besylate, 2-20% bisoprolol fumarate, further 60-90% of a filler, 1-10% of a disintegrant, 0.5-3% of a lubricant, 0.3-2% of a binder are used, based on the weight of the tablet.

17. Method according to claim 14, characterized in that 2-10% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 2-10% bisoprolol fumarate, further 70-90% of a filler, 4-6% of a disintegrant, 1-2% of a lubricant, 1-10% of a binder are used, based on the weight of the tablet.

18. The method according to claim 14, characterized in that 2-10% amlodipine besylate, 2-10% bisoprolol fumarate, further 70-90% of a filler, 4-6% of a disintegrant, 1-2% of a lubricant, 1-10% of a binder are used, based on the weight of the tablet.

19. Method according to claim 14, characterized in that 1-6% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 1-6% bisoprolol fumarate, further 80-90% of a filler, 4-6% of a disintegrant, 1-2% of a lubricant, 0.5-1% of a binder are used, based on the weight of the tablet.

20. The method according to claim 14, characterized in that 1-6% amlodipine besylate, 1-6% bisoprolol fumarate, further 80-90% of a filler, 4-6% of a disintegrant, 1-2% of a lubricant, 0.5-1% of a binder are used, based on the weight of the tablet.

21. Method according to claim 14, characterized in that 5-80% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 5-80% bisoprolol fumarate, further 1-10% disintegrant, 0.5-3% lubricant, 0.3-2% anti-adhesive, if necessary 10-75% filler, are used, based on the weight of the capsule filling.

22. Method according to claim 14, characterized in that 5-80% amlodipine besylate, 5-80% bisoprolol fumarate, further 1-10% disintegrant, 0.5-3% lubricant, 0.3-2% anti-adhesive, if necessary 10-75% filler, are used, based on the weight of the capsule filling.

23. Method according to claim 14, characterized in that 5-18% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 5-15% bisoprolol fumarate, further 4-6% disintegrant, 1-2% lubricant, 0.5-1% anti-adhesive, if necessary 45-75% filler, are used, based on the weight of the capsule filling.

24. Method according to claim 14, characterized in that 5-18% amlodipine besylate, 5-15% bisoprolol fumarate, further 4-6% disintegrant, 1-2% lubricant, 0.5-1% anti-adhesive, if necessary 45-75% filler, are used, based on the weight of the capsule filling.

25. Method according to claim 14, characterized in that 10-15% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, 10-15% bisoprolol fumarate, further 4-6% disintegrant, 1-2% lubricant, 0.5-1% anti-adhesive, if necessary 55-65% filler, are used, based on the weight of the capsule filling.

26. Method according to claim 14, characterized in that 10-15% amlodipine besylate, 10-15% bisoprolol fumarate, further 4-6% disintegrant, 1-2% lubricant, 0.5-1% anti-adhesive, if necessary 55-65% filler, are used, based on the weight of the capsule filling.