BE1023116B1 - PARACETAMOL COMPRISING PREPARATION WITH DELAYED AND CONTINUOUS ISSUE - Google Patents

Abstract

The present invention relates to a composition comprising paracetamol which has a delayed and sustained release of paracetamol. Said preparation is preferably a tablet and the in vivo paracetamol dissolution profile in plasma satisfies a Cmax of 12 to 15 µg / ml and an AUC0-of 80 to 90 µg * hr / ml. Paracetamol is present in the preparation in the form of granules.

Description

PARACETAMOL COMPRISING PREPARATION WITH DELAYED AND CONTINUOUS ISSUE

TECHNICAL DOMAIN

The invention relates to a preparation comprising paracetamol with a delayed and sustained release. More specifically, the preparation is a tablet and paracetamol is present in said tablet in the form of granules. Furthermore, the invention also relates to a method for manufacturing said preparation.

BACKGROUND ART

Paracetamol preparations with sustained release are known, for example, GlaxoSmithKline has "Panadol Osteo" on the market that releases part of the amount of paracetamol immediately after ingestion and gradually releases another part.

A problem with the known sustained-release preparations is that the initial release is still high and this initial release causes a sharp increase in the paracetamol concentration in the plasma. The peak concentration is therefore many times higher than the minimum concentration required to achieve the therapeutic effect. This too high concentration causes unnecessary strain on the liver and kidneys. If the preparation is used orally, the preparation ends up shortly after ingestion in the stomach where there is an acid pH. Paracetamol released here is sensitive to acid hydrolysis, which generates by-products that, in turn, can be harmful to the body.

It is an object of the present invention to find a solution to at least some of the aforementioned problems.

There is a need for an improved paracetamol comprising preparations that are less stressful on the body and in particular on the liver and kidneys. These preparations can then be used in the treatment of already debilitated patients or patients suffering from kidney and liver disorders. SUMMARY OF THE INVENTION --------—

The invention relates to a preparation in the form of a tablet with delayed and sustained release of paracetamol comprising 600 mg to 700 mg of paracetamol per unit dose and a pharmaceutically acceptable carrier, wherein the in vivo paracetamol dissolution profile in plasma of a healthy, fasting, adult man after taking one unit dose, has the following restrictions:

Cmax from 12 to 15 pg / ml; - AUCo-œ from 80 to 90 pg * hour / ml.

Tablets satisfying this in vivo paracetamol dissolution profile in plasma have the advantage that they release paracetamol for a long time where the paracetamol concentration in the plasma is near the minimum concentration to have a therapeutic effect without causing a high paracetamol concentration peak in the plasma.

In a second aspect, the invention provides a method for manufacturing a sustained and sustained release tablet of paracetamol, comprising a) wet granulating a first population of paracetamol comprising granules, b) wet granulating a second population of paracetamol comprising granules, wherein said granules of the second population comprise a release rate controlling polymer; c) mixing first and second population of paracetamol comprising granules with extragranular excipients; d) pressing tablets of the above obtained mixture; wherein the ratio in step c) of granules of the first population to granules of the second population is between 40/60 and 50/50.

This has the advantage that paracetamol is first processed in granules and only then tableted. In this way, the poor flow properties and the problems associated with this in tableting are overcome. Because the granulation of acetaminophen influences the release rate, the inventor has formulated at least two types of granules, each with a different release rate.

The release rate of a granule is mainly determined by the presence of excipients such as a release rate controlling polymer. By mixing at least these two granule populations with extragranular excipients in said ratio, a desired in vitro release rate can be achieved that meets the following restrictions: 10 to 20% released after 15 minutes, - 50 to 75% released after 60 minutes,> 85% issued after 180 minutes, measured according to USP III guidelines.

DESCRIPTION OF THE FIGURES

Figure 1 shows an in vitro paracetamol dissolution profile of a tablet according to an embodiment of the invention in a pH 6.8 phosphate buffer.

DETAILED DESCRIPTION

In a first aspect, the invention provides a composition in the form of a tablet with sustained and sustained release of paracetamol comprising 600 mg to 700 mg of paracetamol per unit dose and a pharmaceutically acceptable carrier, wherein the in vivo paracetamol dissolution profile in plasma of a healthy, sober, mature man after taking one unit dose has the following restrictions:

The term "Cmax" refers to the maximum concentration achieved in the blood plasma after taking a single unit dose.

The term "AUC" refers to the area under the curve, or Area Under the Curve. By "the curve" is meant here the dissolution profile, the plasma concentration of paracetamol as a function of the time after taking a unit dose. The term "AUCo-t" refers to the area under the curve since intake (t = 0) up to a specific time point t. The term "AUCo-c °" refers to the area under the curve since intake (t = 0) until when all of the composition's active substance has been incorporated into the plasma.

In a preferred embodiment, the invention provides a composition in the form of a tablet with sustained and sustained release of paracetamol containing 600.00 mg to 700.00 mg, preferably 631.75 mg to 698.25 mg, more preferably 640 00 mg to 680.00 mg, even more preferably 650 to 670 mg and most preferably 665 mg of paracetamol per unit dose and a pharmaceutically acceptable carrier, wherein the in vitro paracetamol dissolution profile determined according to USP guidelines is: and again moving basket, with 250 ml of 0.1 M hydrochloric acid (HCl) at 37 ° C with a cycle speed of 15 strokes / min; has the following restrictions: 10 to 20%, preferably 12 to 18%, more preferably 14 to 15% and most preferably 15%, released after 15 minutes, 50 to 75%, preferably 55 to 70%, more preferably 50 to 55% and most preferably 63% released after 60 minutes,> 85%, preferably> 87%, more preferably> 90%, even more preferably> 92% and most preferably> 95%, released after 180 minutes.

A preparation with such a dissolution profile has the advantage that only a small amount of paracetamol is released in the first 15 minutes. In the first 15 minutes, the tablet is in the stomach where the acidic environment can cause hydrolysis of paracetamol to 4-aminophenol and acetic acid as shown in reaction (I). 4-aminophenol itself is classified as toxic in Europe. Even though the small amounts produced by hydrolysis of paracetamol are poor, less exposure to this toxic component is less stressful for the user or patient. 4-aminophenol is primarily a burden on the kidneys and liver of the user as the study by Kurata et al. Showed: Kurata Y et ai) Carcinogenesis 8 (9): 1281-1285 (1987).

(I)

Because only a small amount of paracetamol dissolves from the tablet in the first 15 minutes, a small amount of paracetamol is therefore exposed to the acidic environment of the stomach. This delayed dissolution profile therefore ensures that less hydrolysis of paracetamol occurs.

The sustained release, in turn, causes a longer release of paracetamol, which means that a user is less likely to have to take the next unit dose. A tablet that has no sustained release often ensures a high maximum plasma concentration that decreases rapidly over time. This maximum plasma concentration is therefore often many times higher than the plasma concentration that is necessary to provide the desired therapeutic effect. A large amount of the paracetamol is used here only to keep the plasma concentration higher than the plasma concentration needed to provide the desired effect. This paracetamol ultimately has no direct therapeutic effect, but must nevertheless be metabolized by the user's body, which in the case of paracetamol is detrimental to the liver and kidneys. For a sustained-release tablet, the maximum plasma concentration is closer to the plasma concentration needed to provide the desired effect, and this concentration is also maintained for a longer period of time. As a result, the therapeutic effect lasts longer and the same amount of acetaminophen can have a longer effect. This allows the level of paracetamol in the tablet to be increased, because it is released over the long term and is therefore less stressful for the liver and kidneys. Currently, sustained-release tablets with 500 mg of paracetamol are available without a prescription, it is also expected that a sustained-release tablet comprising 600 to 700 mg of paracetamol will also be available without a prescription.

The term "USP III" is a technical term and refers to a method for determining a dissolution profile. The method is included in the American pharmacopoeia (United States Pharmacopeia (USP)) and is one of the reference methods that are commonly used to determine dissolution profiles.

In a preferred embodiment, said in vivo release profile also meets the following condition: AUC 0 -t of 75 to 85 pg * h / ml, where t equals 180 minutes.

This restriction means that after 180 minutes more than 80% of the maximum plasma concentration range is already. As a result, the plasma concentration is high enough that it actively has its therapeutic effect and this concentration can be maintained long enough so that a user must use a new unit dose less often to have a long-term therapeutic effect without large fluctuations in the concentration active in the plasma.

In a preferred embodiment, the in vivo dissolution profile has a tmax of from 15 minutes to 60 minutes, more preferably from 20 to 50 minutes, even more preferably from 25 to 40 minutes and most preferably from 30 to 35 minutes, typically 32 minutes, at a mature sober healthy man.

The term "tw" refers to the time when after taking a unit dose the plasma concentration of the active, here acetaminophen, is highest. In other words, the time at which Cmax occurs.

In a preferred embodiment, paracetamol is present in the composition in an amount of 631.75 to 698.25 mg, more preferably 650.00 to 670.00, even more preferably from 663.00 to 667.00 mg and most preferably 665.00 mg of paracetamol.

As a result, the preparation complies with the tolerance acceptable by the pharmacopoeia and the requirements for correctly displaying the quantity of ingredients on the package of said preparation. Tablets with an amount of paracetamol as mentioned above may be labeled as 665 mg tablets.

In a preferred embodiment, paracetamol is present in the preparation in granules.

Paracetamol per se has very poor flow properties, and therefore the mixing and tableting of paracetamol is problematic. Due to the poor flow properties, direct compression is excluded. Due to the poor flow properties, inhomogeneous mixtures are obtained and tablet molds are not completely filled. The time required to process a powder with poor flow properties is also considerably longer than a powder with good flow properties.

By processing the paracetamol before pelleting into granules which do have good flow properties, the problems with tableting are avoided. The inclusion of paracetamol in granules does have a major impact on the speed of dissolution, which means that additional interventions are required to maintain a desired dissolution profile. It is therefore not enough just to granulate acetaminophen to solve tableting problems. Therefore, the inventor has also had to adapt the other ingredients, optimize the quantities and find a suitable method to arrive at the desired preparation.

In a preferred embodiment, the composition comprises at least two different paracetamol comprising granule populations, said granule populations differing in the ingredients comprising said granules.

As a result, the different granule populations can be formulated in terms of ingredient composition so that they release the paracetamol at different rates and thus have a different dissolution rate. By mixing different amounts of different granule populations, a desired release profile can be achieved.

In a preferred embodiment, at least one granule population comprises a release rate controlling polymer.

This has the advantage that the rate at which granules dissolve from this population can be controlled by the choice of release rate controlling polymer. This can both speed up release and delay. As a result, the delivery rate between different granule populations can drastically differ from each other. This can, for example, ensure that one granule population ensures that the minimum effective concentration to cause a therapeutic effect is rapidly achieved, after which this minimum concentration is maintained by granules with a lower release rate.

In a preferred embodiment, said release rate controlling polymer is ethyl cellulose, cellulose ethers or polyethylene oxide, more preferably hydroxypropyl methyl cellulose (HPMC) also known as hypromellose.

This has the advantage that the release of the active, here acetaminophen, is delayed and is released more gradually. The granules comprising said polymers thus dissolve more slowly and ensure the sustained release of paracetamol.

In a preferred embodiment, at least one granule population comprises a disintegrant.

As a result, these granules swell up rapidly after ingestion due to the presence of the disintegrating agent and eventually fall apart. As a result, the active, here paracetamol is released faster.

In a preferred embodiment, said disintegrating agent is crospovidone, a croscarmellose or a starch glycolate, preferably sodium croscarmellose or sodium starch glycolate, more preferably sodium croscarmellose.

In a preferred embodiment, at least one granule population comprises an release rate controlling polymer and a disintegrating agent.

This ensures that the granule quickly disintegrates after ingestion but still has a gradual paracetamol release. This prevents a high peak shortly after taking a unit dose.

In a preferred embodiment, said composition comprises an intra- and extra-granular matrix, wherein said intragranular matrix has a smaller particle size than said extragranular matrix.

The term "matrix" is a technical term and refers to an inactive ingredient that ensures that a tablet can be obtained that has the necessary mechanical properties.

In a preferred embodiment, the matrix is selected from a starch, cellulose, modified or not, lactose or mannitol, more preferably the matrix is microcrystalline cellulose.

The smaller particle size of the matrix in the granules, intragranular, has the advantage that this ensures a better distribution of the active paracetamol in the granules, so that a homogeneous tablet can be obtained. The larger particle size of the matrix that is not in the granules but in the material that holds the granules together in the tablet, extragranularly, has the advantage that it provides better mechanical properties to the tablet, properties such as fragility and hardness .

In a preferred embodiment, the weight ratio of at least two granule populations is between 40/60 and 50/50, preferably 43/57 and most preferably 45/55.

This has the advantage that a sufficient amount of granules are present that ensure the sustained release and a sufficient amount of granules are present that ensure the initial release of paracetamol.

In a second aspect, the invention provides a method for manufacturing a sustained and sustained release tablet of paracetamol, comprising a) wet granulating a first population of paracetamol comprising granules, b) wet granulating a second population of paracetamol comprising granules, wherein said granules of the second population comprise a release rate controlling polymer; c) mixing first and second population of paracetamol comprising granules with extragranular excipients; d) pressing tablets of the above obtained mixture; wherein the ratio in step c) of granules of the first population to granules of the second population is between 40/60 and 50/50, preferably 43/57 and most preferably 45/55.

This has the advantage that paracetamol is first processed in granules and only then tableted. In this way, the poor flow properties and the problems associated with this in tableting are overcome. Because the granulation of acetaminophen influences the release rate, the inventor has formulated at least two types of granules, each with a different release rate. The release rate of a granule is mainly determined by the presence of excipients such as a release rate controlling polymer. By mixing at least these two granule populations with extragranular excipients in said ratio, a desired in vitro release rate can be achieved that meets the following restrictions: 10 to 20% released after 15 minutes, 50 to 75% released after 60 minutes,> 85% released after 180 minutes, measured according to USP III guidelines.

The same tablet also meets the following in vivo paracetamol dissolution profile in plasma:

Cmax from 12 to 15 pg / ml; AUCo-co of 80 to 90 pg * h / ml.

In a preferred embodiment of the method, said paracetamol comprising granules of said second population comprises a disintegrating agent.

This has the advantage that said granules comprise both a release rate controlling polymer and a disintegrant. As a result, the granules disintegrate more quickly after ingestion, but the actual release of paracetamol mP occurs gradually than if there is no release-controlling polymer in the granule. This avoids a peak in plasma concentration of paracetamol shortly after ingestion but still achieves the minimum paracetamol concentration to achieve the therapeutic effect shortly after ingestion.

In a preferred embodiment, both granules and said extragranular excipients comprise a matrix and wherein the particle size of the extragranular matrix is larger than the particle size of the intragranular matrix.

This has the advantage that the larger particle size of the matrix located between the granules provides improved mechanical properties such as hardness and fragility, and that the smaller particle size of the matrix in the granules ensures that paracetamol is homogeneously distributed over the granules and therefore a homogeneous tablet.

In a preferred embodiment, said tablet has a hardness of 105 to 150 N, more preferably 111 to 145 N, and most preferably 132 to 140 N.

In the following, the invention is described a.d.h.v. non-limiting examples illustrating the invention, and which are not intended or may be interpreted to limit the scope of the invention. EXAMPLES Example 1: Composition of the tablet

Table 1: tablet composition according to an embodiment of the invention

Example 2: method of making a tablet - First granulation (amounts of ingredients in a ratio as shown in example 1, dry mix granule 1 and filler granule 1):

Microcrystalline cellulose PH 101 and pregelatinized starch are sieved through a # 40 ASTM sieve and mixed for 10 minutes with paracetamol sieved through a # 8 ASTM sieve.

The mixture obtained above is then subjected to wet granulation with a povidone solution. The wet granules are then dried at 50 to 60 ° C until the LOD ("Loss On Drying" at 105 ° C) was reached from 1.5% to 3.0%.

These dried granules are then sieved through a # 20 ASTM screen. - Second granulation (quantities of ingredients in a ratio as shown in example 1):

Microcrystalline cellulose PH 101, sodium croscarmellose and hypromellose are sieved through a # 40 ASTM sieve and mixed for 10 minutes with paracetamol sieved through a # 8 ASTM sieve. The mixture obtained above is then subjected to wet granulation with a povidone solution. The wet granules are then dried at 50 to 60 ° C until the LOD ("Loss On Drying" at 105 ° C) was reached from 1.5% to 3.0%.

These dried granules are then sieved through a # 20 ASTM screen.

The two types of granules are mixed in a mixer that generates a low shear force. - Microcrystalline cellulose PH 102 is sieved with a # 40 ASTM sieve and added to the granules and the whole is further mixed for 10 minutes. - This mixture is mixed with magnesium stearate that has previously been sieved with a # 60 ASTM sieve. - This mixture is pressed into tablets. - The tablets obtained are optionally coated with Opadry White II.

Example 3: in vitro dissolution profile

Figure 1 shows an in vitro paracetamol dissolution profile of a tablet according to an embodiment of the invention in a pH 6.8 phosphate buffer. The percentage of acetaminophen release is plotted as a function of time after a tablet has been added to said phosphate buffer.

Example 4: in vivo dissolution profile

A tablet according to an embodiment of the invention has a Cmax of 10.301 pg / ml, an AUCo-t of 81.198 pg / ml and an AUCo-œ of 84.328 pg / ml, measured in a sober adult male.

The same tablet has a Cmax of 13.773 pg / ml, an AUCo-t of 83.699 pg / hour and an AUCo-œ of 86.385 pg / ml, measured in a fed adult male.

Claims (15)

CONCLUSIONS Preparation in the form of a tablet with sustained and sustained release of paracetamol, comprising 631.75 mg to 698.25 mg of paracetamol per unit dose and a pharmaceutically acceptable carrier, characterized in that the in vivo paracetamol dissolution profile in plasma of a healthy, fasted adult man after taking one unit dose, has the following restrictions: Cmax of 12 to 15 pg / ml; - AUCo-œ from 80 to 90 pg * hour / ml. The composition according to claim 1, wherein the in vitro paracetamol dissolution profile, determined according to the USP III guidelines being: reciprocating basket, with 250 ml of 0.1 M hydrochloric acid (HCl) at 37 ° C with a cycle speed of 15 strokes / min; has the following restrictions: 10 to 20% released after 15 minutes, 50 to 75% released after 60 minutes,> 85% released after 180 minutes. The composition of any one of the preceding claims, wherein AUC 0 -t is 75 to 85 pg * h / ml when t is 180 minutes. The composition of any one of the preceding claims, wherein paracetamol is present in granules. The composition of claim 4, wherein the composition comprises at least two different paracetamol comprising granule populations, wherein said granule populations differ in the ingredients comprising said granules. The composition of claim 4 or 5, wherein at least one granule population comprises a release rate controlling polymer. The composition of claim 6, wherein said release rate controlling polymer is ethyl cellulose, cellulose ether or polyethylene oxide, preferably hypromellose. A composition according to at least one of claims 5 to 7, wherein at least 1 S; granule population comprises a disintegrating agent. The composition of claim 8, wherein said disintegrating agent is crospovidone, a croscarmellose or a starch glycolate, preferably sodium croscarmellose or sodium starch glycolate, more preferably sodium croscarmellose. The composition of at least one of claims 5-9, wherein at least one granule population comprises a release rate controlling polymer and a disintegrant. The composition according to at least one of claims 5-10, comprising an intra- and extragranular matrix, wherein said intragranular matrix has a smaller particle size than said extragranular matrix. The composition of at least one of claims 5 to 11, wherein the weight ratio of at least two granule populations is between 40/60 and 50/50, preferably 43/57 and most preferably 45/55. A method of manufacturing a sustained and sustained release tablet of paracetamol according to at least one of claims 1-12, comprising a) wet granulating a first population of paracetamol comprising granules, b) wet granulating a second population of paracetamol comprising granules, wherein said granules of the second population comprise a release rate controlling polymer; c) mixing first and second population of paracetamol comprising granules with extragranular excipients; d) pressing tablets of the above obtained mixture; characterized in that the ratio in step c) of granules of the first population to granules of the second population is between 40/60 and 50/50, preferably 43/57 and most preferably 45/55. The method of claim 13, wherein said paracetamol comprising granules of said second population comprises a disintegrating agent. The method according to claim 13 or 14, wherein both granules and name §§; extragranular excipients comprise a matrix and wherein the particle size of the extragranular matrix is larger than the particle size of the intragranular matrix.