KR20050010843A - Pharmaceutical composition containing oxcarbazepine and having a controlled active substance release - Google Patents

Abstract

The invention relates to the pharmaceutical compositions, especially for oral administration, containing therapeutically efficient quantity of oxcarbazepin with prolonged release of the active ingredient in vitro.

Description

Pharmaceutical composition containing oxcarbazepine and having a controlled active substance release}

Oxcarbazepine is used to treat epilepsy, to suppress neuralgia or cerebrovascular pain, or to treat alcoholism. Oxcarbazepine is converted to monohydroxydihydrocarbamazepine (MHD), the actual active ingredient in the body.

At present, the compositions used in the oral administration of oxavabazepine are only available in oral dosage forms, not sustained release. After a single administration of such a composition in vivo, the plasma levels of oxcabazepine and MHD increase rapidly. After absorption is complete, the plasma concentration of the active ingredient decreases relatively quickly.

Sudden increase in active ingredients of conventional compositions often leads to serious side effects. Particularly in the case of the administration of oxcabazepine, when the plasma level reaches a peak, it may cause serious damage to the general condition, for example, may cause vomiting and fainting dizziness. To avoid this, the patient must take one or more tablets 2-3 times a day. Only by doing so can a sufficiently uniform pattern of active ingredient levels be achieved in plasma.

However, the correlation between the degree of compliance and the number of daily intakes for drug intake prescribed per day during the treatment period is inversely proportional, i.e. higher daily intake (higher intake) The long term observed drop in response to a given intake regime is low (low “accept”). The cause is, for example, that the patient is not willing to take the drug under unfavorable circumstances other than simply forgetting to take it. Such situations typically include, for example, business meetings or events held in groups or in groups. This is particularly serious for epileptics, because epilepsy still carries a social stigma today.

The present invention relates to pharmaceutical compositions, particularly compositions for oral administration, containing an active content of oxabazepine.

Accordingly, it is an object of the present invention to take advantage of the above-mentioned disadvantages when taken once daily, since the level of metabolite MHD (active ingredient) in plasma can last for a long time and this level can be increased at a suitable rate. It is to prepare a pharmaceutical composition for oral administration without. Minimum-active plasma levels (subtherapeutic plasma levels) must be reached. Especially during the initial absorption phase, so-called plasma peaks should be avoided as much as possible.

In addition, it is an object of the present invention to provide a process for the preparation of such compounds.

These objects are achieved by the pharmaceutical composition according to claim 1 and the method according to claim 6. Surprisingly, following the USP paddle method (at 75 rpm stirring rate, in 1 L of 2% by weight sodium dodecyl sulfate solution as release medium, USP 24, Method 724, Device 2) to release the following amount of oxazabazepine in vitro It has been found that the composition can provide an active ingredient level of metabolite MHD which slowly increases in plasma and lasts for a long time:

15 minutes: 55-85%

30 minutes: 75 to 95%

45 minutes: 85 to 100%

60 minutes: 90-100%.

On the other hand, currently commercially available tablets release the following amount of oxabazepine according to the same release method (see FIG. 3) and have the disadvantages mentioned above:

15 minutes: 88-90% approximately

30 minutes: about 95 to 100%

45 minutes: about 98 to 100%

60 minutes: Approximately 100%.

This result is surprising because the in vitro release pattern of the oxavabazepine of the composition according to the invention is only slightly below the release pattern of commercially available tablets, in which normally no prolonged action is expected. On the other hand, typical sustained release formulations that exhibited low subsequent in vitro release profiles (60 minutes: approximately 40% oxabazepine release) have proven to be ineffective.

The composition according to the invention is preferably prepared in vitro according to the USP paddle method (USP 24, Method 724, Apparatus 2, in 1 L of 2% by weight sodium dodecyl sulfate solution as the release medium, under a stirring speed of 75 rpm). Releases a positive oxavabazepine:

15 minutes: 65-80%

30 minutes: 85 to 95%

45 minutes: 90 to 100%

60 minutes: 95-100%.

Following oral ingestion of the composition according to the invention containing oxavabazepine 600 mg, the following oxavabazepine plasma concentrations:

1.5 to 2 hours: 0.2 to 0.6 mg / L

5.5 to 6.5 hours: 0.1 to 0.3 mg / L

11-13 hours: 0.1-0.2 mg / L

23-25 hours: 0.0-0.2 mg / L; And

The following MHD plasma concentrations:

1.5 to 2 hours: 1 to 4 mg / L

5.5 to 6.5 hours: 3-5 mg / L

11-13 hours: 3-5 mg / L

23-25 hours: 2.5-4.5 mg / L

Is preferably achieved.

Following oral ingestion of the composition according to the invention containing oxavabazepine 600 mg, the following oxavabazepine plasma concentrations:

1.5 to 2 hours: 0.3 to 0.5 mg / L

5.5 to 6.5 hours: 0.1 to 0.4 mg / L

11-13 hours: 0.1-0.2 mg / L

23 to 25 hours: 0.0 to 0.1 mg / L; And

The following MHD plasma concentrations:

1.5-2 hours: 1-3 mg / L

5.5 to 6.5 hours: 3.5 to 4.5 mg / L

11-13 hours: 3.5-4.5 mg / L

23-25 hours: 2.5-4 mg / L

Is particularly preferably achieved.

The pharmaceutical composition according to the invention preferably has an average of 3 to 5 mg / mL in vivo after oral ingestion of the composition containing 600 mg of oxabazepine, for a period from 4 hours after ingestion to 21 hours after ingestion. MHD plasma levels and maximum MHD plasma levels (C _max ) of 3-5 mg / mL are generated.

The composition according to the invention is based on its total weight,

A. 60-95 weight percent oxabazepine,

B. 3 to 30 weight percent microcrystalline cellulose,

C. 1 to 20% by weight ammonium methacrylate copolymer and / or polymethacrylic acid polymer,

D. 0.05-4 weight percent disintegrant and

E. Dye

It can be prepared by preparing a mixture containing and then compacting it.

The mixture is preferably based on its total weight,

A. 80-90% oxabazepine,

B. 5-15 wt% microcrystalline cellulose,

C. 2 to 10 weight percent ammonium methacrylate copolymer and / or polymethacrylic acid polymer,

D. 0.1 to 2 weight percent disintegrant and

E. Dye

It contains.

Suitable disintegrants are in particular sodium carboxymethyl starch, croscarmellose sodium and polyvinylpolypyrrolidone.

In the case of oxavabazepine preparations, it is common to use dyes, since colored decomposition products can be formed. Iron oxides / iron hydroxides, which are often used as dyes, are not used at all in the compositions according to the invention, since they can promote the formation of degradation products from oxabazepine. In the case of high dose drugs such as oxabazepine Ingestion of iron is not toxicologically acceptable. Organic compounds and lakes from organic compounds can be used as dyes. Riboflavin and yellow-orange S lakes are particularly suitable.

The densified material thus obtained is very good in fluidity and therefore no additional addition of flow-controlling means, for example colloidal silicic acid (eg Aerosil 200 ^® ), is required. Colloidal silicic acid, in particular, can cause the formation of undesirable degradation products from oxabazepine.

The densified material thus obtained can then be sorted and then filled into hard gelatin capsules or filled into small pouches (Sakije). However, based on 100 parts by weight of the densified material to such a material,

F. 0.2 to 5 parts by weight tablet lubricant and

G. 10 to 50 parts by weight microcrystalline cellulose

It is preferred to prepare the tablets from the densified material by initially adding and then subjecting the resulting mixture to further processing to obtain tablets.

In particular magnesium stearate and calcium stearate can be used as tablet lubricants.

The tablet obtained as above is based on 100 parts by weight of the densified material,

F. 0.5 to 10 parts by weight polymethacrylic acid copolymer

G. 0.025 to 2 parts by weight plasticizer

H. 0.025 to 2 parts by weight anti-adhesive and

I. Sufficient Dyes and Pigments

And water can be used to coat the film in a drum coater.

The tablets thus obtained are also based on 100 parts by weight of the densified material,

F. 0.5 to 10 parts by weight film former

G. 0.0 to 2 parts by weight plasticizer

H. 0.005 to 2 parts by weight anti-adhesive and

I. Sufficient Dyes and Pigments

And water can be used to coat the film in a drum coater.

In particular cellulose derivatives or polyacrylic acid derivatives can be used as film formers.

In particular, triethyl citrate and triacetin can be used as a plasticizer.

In particular talcum, glyceryl monostearate can be used as anti-adhesive.

The densified material is also based on 100 parts by weight of such densified material,

F. 0.5 to 10 parts by weight polymethacrylic acid copolymer

G. 0.025 to 2 parts by weight plasticizer

H. 0.025 to 2 parts by weight anti-adhesive

Can be coated with a film in a high shear mixer or in a fluidized bed with the addition of water.

In each case the abovementioned compounds can be used as plasticizers and anti-adhesives.

The granulated material can be obtained and then sorted and filled into hard gelatin capsules or into small pouches (Sakije). However, based on 100 parts by weight of the granulating material to such a material,

I. 0.2 to 0.5 parts by weight tablet lubricant and

J. 10-50 parts by weight microcrystalline cellulose

It is preferred to prepare tablets from the granulated material by initially adding and then subjecting the resulting mixture to further processing to obtain tablets.

In particular magnesium stearate and calcium stearate can be used as tablet lubricants.

The composition according to the invention is also based on the total weight, in a high shear mixer or in a fluidized bed, with the addition of water,

A. 60-95 wt% oxabazepine

B. 3 to 30 weight percent microcrystalline cellulose

C. 0.05-4 wt% disintegrant

D. 1-20 wt% polymer

E. 0.2 to 5 wt% plasticizer

F. 0-5 wt% anti-adhesive

G. Dyes

It can be prepared by producing a granulated material containing. Such granulated material is preferably based on its total weight,

A. 80-90 wt% oxabazepine

B. 5-15 wt% microcrystalline cellulose

C. 0.1 to 2 wt% disintegrant

D. 2 to 10 weight percent polymer

E. 0.4-2.5 wt% plasticizer

F. 0 to 0.25 weight percent anti-adhesive

G. Dyes

It contains.

In particular, polymethacrylic acid ester and ammonium methacrylate copolymer can be used as the polymer.

The compounds mentioned above in connection with the preparation of tablets are preferably used as plasticizers and anti-adhesives.

In particular the following materials can be used as disintegrants: sodium carboxymethyl starch, croscarmellose sodium and polyvinylpolypyrrolidone.

In particular organic dyes and organic lakes can be used as dyes.

The granulated material obtained as above can then be filled into hard gelatin capsules or into small pouches (Sakije). However, based on 100 parts by weight of the granulating material to such a material,

H. 0.2 to 0.5 parts by weight tablet lubricant and

I. 10-50 parts by weight microcrystalline cellulose

It is preferred to prepare tablets from the granulated material by initially adding and then subjecting the resulting mixture to further processing to obtain tablets.

In particular magnesium stearate and calcium stearate can be used as tablet lubricants.

The pharmaceutical composition according to the invention advantageously produces a drug for preventing or treating primary systemic tonic-clonic seizures and / or lesional seizures with or without secondary generalization. Can be used.

Example 1 Preparation of Densified Materials

30 kg oxavabazepine is mixed with 2 kg ammonium methacrylate copolymer (Eudragit RSPO ^® ), 4 kg microcrystalline cellulose and 0.4 kg sodium carboxymethyl starch for 5 minutes in a high shear mixer. The resulting mixture is densified (compacted) in a compactor (3-W-Polygrane from Gerteis Maschinen + Processengineering AG (Jona, Switzerland)). The ribbon thus produced is broken through forced screening, and the resulting densified material is sorted through a vibrating screen (1 mm screen tray, Engelsmann's vibrating screen, screen channel with 0.25 mm screen tray).

Some of the densified materials so classified are filled into hard gelatin capsules of size 3, 2, 1 and 0 on a capsule-charger. Oxavabazepine doses of 150-300 mg per dose were generated.

Another portion of the sorted densified material is filled into a small pouch (made by Saki) on a bagging machine. Oxacabazepine doses of 50 to 2400 mg per dose were generated.

Example 2: Preparation of Tablets

Densification material is prepared and classified according to Example 1. This densified material was mixed with 0.5 kg magnesium stearate and 8 kg microcrystalline cellulose and then compressed to obtain tablets, resulting in a dose of 150-600 mg of oxabazepine per tablet.

Example 3: Examination of In Vitro Release Patterns

Tablets prepared according to Example 2, containing 600 mg oxavabazepine, were prepared using USP paddle method (USP 24, Method 724, Apparatus 2, in 1 L of 2 wt% sodium dodecyl sulfate solution as release medium, under stirring speed of 75 rpm). ), And the release pattern was compared to a commercial tablet (Triptal, Novartis). The release pattern of the tablets according to the invention is shown in FIG. 1 and the release pattern of the comparative tablet is shown in FIG. 3. The release of oxavabazepine in vitro appeared to be only slightly slower.

Example 4: Examination of Plasma Levels

Tablets prepared according to Example 2 containing 600 mg oxabazepine were administered to the subject and the plasma level pattern of oxavabazepine and MHD was recorded. These test results (arithmetic mean) are shown in FIG. 2. Here, the black triangles indicate values for oxabazepine, and the black squares indicate values for MHD.

For comparison, a commercial tablet containing 600 mg oxavabazepine (Trileptal from Novartis) was administered and the plasma level patterns of oxavabazepine and MHD were recorded. These test results (arithmetic mean) are shown in FIG. 4. Here, the black triangles indicate values for oxabazepine, and the black squares indicate values for MHD.

The figures show that the MHD plasma levels of the compositions according to the invention slowly increase to a maximum concentration of approximately 3 to 5 mg / L and remain approximately constant over a period from approximately 4 hours after ingestion to 24 hours after ingestion. Present it. On the other hand, the MHD plasma level of the comparative composition rapidly increases to a value of approximately 7 mg / L, and then drops sharply again.

Claims (19)

Ox, which releases the following amount of oxcabazepine in vitro according to the USP paddle method (USP 24, Method 724, Apparatus 2) in 1 L of 2% by weight sodium dodecyl sulfate solution as the release medium under a stirring speed of 75 rpm. Pharmaceutical compositions containing carbazepine: 15 minutes: 55-85% 30 minutes: 75 to 95% 45 minutes: 85 to 100% 60 minutes: 90-100%. The method according to claim 1, wherein the following amount of oxaba is in vitro according to the USP paddle method (USP 24, Method 724, Apparatus 2, in 1 L of 2% by weight sodium dodecyl sulfate solution as release medium, under a stirring speed of 75 rpm). Pharmaceutical compositions containing oxabazepine, which release zepin: 15 minutes: 65-80% 30 minutes: 85 to 95% 45 minutes: 90 to 100% 60 minutes: 95-100%. The following oxabazepine plasma concentrations in vivo following oral ingestion of the pharmaceutical composition according to claim 1 or 2, in the manner of administering 600 mg oxabazepine. 1.5 to 2 hours: 0.2 to 0.6 mg / L 5.5 to 6.5 hours: 0.1 to 0.3 mg / L 11-13 hours: 0.1-0.2 mg / L 23-25 hours: 0.0-0.2 mg / L; And The following monohydroxydihydrocarbamazepine plasma concentrations: 1.5 to 2 hours: 1 to 4 mg / L 5.5 to 6.5 hours: 3-5 mg / L 11-13 hours: 3-5 mg / L 23-25 hours: 2.5-4.5 mg / L Pharmaceutical compositions to produce. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is orally ingested in a manner of administering 600 mg of oxcabazepine in vivo, for a period from 4 hours after ingestion to 21 hours after ingestion. A pharmaceutical composition that produces an average monohydroxydihydrocarbamazepine plasma level of from 5 mg / mL. The maximum monohydroxydihydrocarbamazepine of any one of claims 1 to 4, wherein in vivo, after oral ingestion of the pharmaceutical composition in a manner of administering 600 mg of oxcabazepine. Pharmaceutical compositions that produce plasma levels (C _max ). Based on the total weight of the mixture, a. 60 to 95 weight percent oxabazepine, b. 3-30% by weight microcrystalline cellulose, c. 1-20% ammonium methacrylate copolymer and / or polymethacrylic acid polymer, d. 0.05 to 4 weight percent disintegrant and e. dyes A method for producing a pharmaceutical composition according to any one of claims 1 to 5, comprising preparing a mixture containing the same and then densifying it. The method of claim 6, wherein based on the total weight of the mixture, a. 80-90% oxabazepine, b. 5-15% by weight microcrystalline cellulose, c. 2 to 10 weight percent ammonium methacrylate copolymer and / or polymethacrylic acid polymer, d. 0.1 to 2 weight percent disintegrant and e. dyes Method for preparing a mixture containing and then densifying it. 8. The method of claim 6 or 7, wherein the densifying material is screened and filled into pouches that have not been changed or optionally provided with excipients or into capsules. The method according to claim 6 or 7, wherein after densification, based on 100 parts by weight of the densification material, f. 0.2 to 5 parts by weight magnesium stearate and g. 10-50 parts by weight microcrystalline cellulose And then further processing the mixture thus obtained to obtain tablets. Based on the total weight of the granulating material, A. 60-95 wt% oxabazepine B. 3 to 30 weight percent microcrystalline cellulose C. 0.05-4 wt% disintegrant D. 1-20 wt% polymer E. 0.2 to 5 wt% plasticizer F. 0-5 wt% anti-adhesive G. Dyes A method for producing a pharmaceutical composition according to any one of claims 1 to 5, comprising preparing a granulated material containing the compound in a high shear mixer or in a fluidized bed while adding water. The method of claim 8, wherein the granulation material is based on its total weight, A. 80-90 wt% oxabazepine B. 5-15 wt% microcrystalline cellulose C. 0.1 to 2 wt% disintegrant D. 2 to 10 weight percent polymer E. 0.4-2.5 wt% plasticizer F. 0-2.5 wt% anti-adhesive G. Sufficient Dye Containing. The method according to claim 10 or 11, based on 100 parts by weight of the granulating material, H. 0.2 to 0.5 parts by weight tablet lubricant and I. 10-50 parts by weight microcrystalline cellulose And then further processing the mixture thus obtained to obtain tablets. The method of claim 6 or 7, based on 100 parts by weight of the densified material, F. 0.5 to 10 parts by weight polymethacrylic acid copolymer G. 0.025 to 2 parts by weight plasticizer H. 0.025 to 2 parts by weight anti-adhesive Using the method to coat the densified material with a film in a high shear mixer while adding water. The method of claim 13, based on 100 parts by weight of the film-coated densified material, I. 0.2 to 0.5 parts by weight tablet lubricant and J. 10-50 parts by weight microcrystalline cellulose And then further processing the mixture thus obtained to obtain tablets. The method of claim 9, based on 100 parts by weight of the tablet, H. 0.5 to 10 parts by weight polymethacrylic acid copolymer I. 0.025 to 2 parts by weight plasticizer J. 0.025 to 2 parts by weight anti-adhesive and K. Dyes and / or Pigments And water to coat the tablets with the film in a drum coater. The method of claim 9, based on 100 parts by weight of the tablet, H. 0.5 to 10 parts by weight film former I. 0.0 to 2 parts by weight plasticizer J. 0.005 to 2 parts by weight anti-adhesive and K. Dyes and / or Pigments And water to coat the tablets with the film in a drum coater. A pharmaceutical composition obtainable by the method according to any one of claims 7 to 16. Claims 1 to 5, and for the manufacture of a medicament for preventing or treating primary systemic tonic-clonic seizures and / or lesional seizures, with or without secondary generalization, and Use of a pharmaceutical composition according to claim 17. Use of a pharmaceutical composition according to any one of claims 1 to 5 and 17 for the manufacture of a medicament for preventing or treating neuralgia and cerebrovascular pain or for treating alcoholism.