EP1107792A1

EP1107792A1 - Pharmaceutical composition containing calcium valproate with delayed active substance release and method for the production of said composition

Info

Publication number: EP1107792A1
Application number: EP99946111A
Authority: EP
Inventors: Dagmar GÖBEL; Michael Pieroth; Bernd Terhaag; Ramona Dieckmann; Evelyn Heuberger-Wieland
Original assignee: Arzneimittelwerk Dresden GmbH
Current assignee: Teva GmbH
Priority date: 1998-09-03
Filing date: 1999-09-03
Publication date: 2001-06-20
Also published as: PL346474A1; NO20011087L; BG105276A; DE19840152A1; EA200100309A1; HUP0201625A2; AU5859799A; WO2000013711A1; SK2592001A3; EA002695B1; CZ2001753A3; US20020052411A1; NO20011087D0

Abstract

The invention relates to novel pharmaceutical compositions containing calcium valproate with delayed active substance release, especially in the form of tablets, to the production and the use of said compositions in the treatment of epilepsy, migraine and manic-depressive diseases. The pharmaceutical composition with delayed active substance release disclosed in the invention is characterized in that it contains the active substance valproic acid in the form of calcium salt, at least one acrylic polymer and at least one sugar ester.

Description

Pharmaceutical compositions containing calcium valproate with a delayed release of active ingredient and process for their production

The present invention relates to new pharmaceutical compositions containing calcium valproate with a delayed release of active substance, in particular in tablet form, to processes for their preparation and their use for the treatment of epilepsy, migraines and manic-depressive disorders.

Calcium valproate (calcium salt of di-n-propylacetic acid) is a well-known antiepileptic which, when used in humans, is to be taken orally in an immediate-release dosage form in a dosage of 900 mg to 2700 mg daily. Caicium valproate can also be used to treat migraines and manic-depressive disorders. The effective component of calcium valproate is free valproic acid.

The known instantly releasing preparations containing calcium valproate have the disadvantage that when high doses are administered, toxic blood level values occur in the flood phase, which e.g. Can cause liver damage.

The active substance should therefore be released in such a way that the plasma levels required for the therapy are achieved without the intermittent occurrence of toxic blood concentrations. Furthermore, the dose unit should contain such an amount of calcium valproate that the therapeutic plasma levels can be reached and maintained by taking it once or twice a day, so that the patient's compliance with therapy (compliance) is better guaranteed. A suitable slow-release formulation can have a calcium valproate content of up to 900 mg or more, preferably from 250 to 600 mg, per dose unit.

The passage time of a substance in the gastrointestinal tract between oral intake and Entry into the large intestine can take up to 14 hours. A passage time of 1 hour to 6 hours is observed for the stomach, while the passage time in the small intestine is between 1.5 and 8 hours, especially with non-disintegrating particles over 3 mm, such as a tablet , but must also be expected with a longer dwell time and a resulting longer passage time of up to a total of 8 hours in the stomach. In practice it has been shown that the complete release of the active ingredient should advantageously take place after 12 to 16 hours Disadvantage that non-absorbed active substance is excreted in the stool

A preparation of valproic acid with delayed release is required to release the active substance with a delay both in the stomach at pH values between 1.0 and 3.0 and in the small intestine at pH 6.8, so that an evenly delayed invasion into Vivo is guaranteed It is important for high-dose valproic acid preparations to avoid high blood levels. This effect can only be achieved by delayed release

A suitable active ingredient release in vitro at buffer pH 6.8 is, for example, the following active ingredient release profile after 1 hour 15-35% release after 4 hours 50-70% release after 8 hours> 70% release after 12 hours of complete release The percentages relate in each case to the actual (declared) content of calcium valproate in the single tablet. The above-mentioned release profile is only an example, without other suitable release profiles being thereby excluded

The form of preparation should also be divisible, the parts should have a comparable active ingredient release profile as the undivided preparation European patent application EP-A 0 230 332 describes a delayed release of active substance for the active substance ibuprofen using sucrose monopalmitate, polyvinylpyrrodon (PVP) and stearic acid. A very high proportion of sucrose monopalmitate of 25% by weight is described. based on the active ingredient used, such a high proportion is disadvantageous in the preparation of preparations with a high active ingredient content because of the resulting total weight

European application EP-A 0 385 846 describes the preparation of a sustained release tablet containing sodium valproate and valproic acid as active ingredient using high-viscosity hydroxypropyl methyeliculose as

Retardant described, which was then coated with a film of polyacrylate or methacrylate (Eudragit ®) The film coating has the basic disadvantage that the original effect of the film is impaired or even lost when the tablet is divided

European application EP-A 0 133 110 describes the use of Eudragit® in combination with ethyl cellulose as a retardant for a sustained release tablet containing sodium valproate and valproic acid. Ethyl cellulose is used as a solution in an organic solvent, such as acetone or ethanol However, organic solvents are disadvantageous for large-scale pharmaceutical production because of their flammability and toxicity. The high proportion of Eudragit ® of at least 10% by weight, based on the active substance content, is also unfavorable for highly concentrated sustained-release preparations

Japanese patent application JP-86/248 211 describes the use of sucrose fatty acid esters or other surface-active auxiliaries for the preparation of a pharmaceutical formulation containing cacium valproate, a content of 0.9% by weight of sugar ester, based on calcium valproate, at pH 1 complete dissolution of a 224 mg calcium valproate tablet within 27-46 min. In contrast, the control tablet made without sugar esters only dissolved after 120 min German patent application DD-A 295 543 describes the use of 3 parts of calcium valproate, 1 part of fully saponified polyvinyl alcohol and 2 parts of partly saponified polyvinyl alcohol for the production of sustained-release preparations, the degree of retardation being dependent on the ratio between fully and partly saponified polyvinyl alcohol being a disadvantage of this invention On the one hand, the high proportion of excipients, as this leads to an extremely high gross mass of the oral dosage form in the case of highly concentrated substances

The object of the present invention is to provide a pharmaceutical composition containing calcium valproate with a delayed release of active ingredient, which may contain up to 900 mg or more (for example 1000 mg) calcium valproate, and a process for its preparation. The sustained release preparation according to the invention is intended have the lowest possible total weight (gross weight) and be divisible if possible

The object of the invention is achieved by using the combination of at least one acrylic polymer and a sugar ester as a retardant

Calcium valproate means all calcium salts of valproic acid and their complexes with valproic acid, water or other solvents

The production of calcium valproate is described, for example, in German patents DD 215 530, DD 215 531, DD 215 533 and DD 293 053

Suitable complexes are, for example, the dimer of a molecule of valproic acid and mole of calcium valproate, as described in European patent application EP-A 34 172, polymeric calcium salts of valproic acid, which consist of monomers consist of four valproic acid residues each associated with a calcium ion (see EP-A 141 267), or the complex consisting of one mole of calcium valproate and 3 moles of valproic acid (see EP-A 282 834).

Calcium bis (di-n-propyl acetate), which is composed of one mole of calcium and 2 moles of valproic acid, is preferred. Under normal atmospheric pressure, calcium valproate can be present either as a dihydrate (approximately 9.9% water), 1/3 hydrate (approximately 3.5-3.7% water) or 1/4 hydrate (approximately 2.2% water). Lower crystal water contents can also be achieved under reduced pressure. In addition, water can also be present in an adsorptively bound form to the surface.

The calcium valproate hydrates are preferred, the calcium valproate dihydrate and calcium valproate having a water content of 3.6% by weight being particularly preferred. The dihydrate is preferably used as a starting material in the production. The 1/3 hydrate (approx. 3.6% water content) is preferably present in the end product after the drying step.

The acrylic polymers of the Eudragit® type which are suitable according to the invention are described in detail in the publication Handbook of Pharmaceutical Excipients, ed .: Ainley Wade u. Paul J. Weber, in the chapter "Polymethacrylates", 2nd edition, The Pharmaceutical Press, London, 1994, pages 362-365 and in Herbert P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, volume 1, (volume 9 of the series "The pharmaceutical company"), Editio Cantor Aulendorf, 3rd ed., 1989, pages 486-487. The cited references are hereby incorporated by reference into the disclosure content of the present description.

Suitable acrylic polymers are the copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2: 1 (Eudragit® NE), the copolymer of

Ethyl acrylate and methyl methacrylate with a low quaternary content

Ammonium groups in a ratio of 1.0: 2.0: 0.1 (Eudragit® RS) and the copolymer from methacrylic acid and ethyl acrylate in a ratio of 1 1 (Eudragit® L) and in a ratio of 1 2 (Eudragit® S). The copolymer ratios mentioned are particularly advantageous. However, copolymers with other ratios or the polymers polyethyl acrylate, methyl methacrylate and methacrylic acid can also be used become

Eudragit® NE, Eudragit® L and mixtures thereof are preferred

Eudragit® NE and shellac, the latter preferably in an aqueous solution (such as offered by Marchand & Chie GmbH, Mainz, Germany), can also be used

The sugar esters according to the invention are characterized in that they have an HLB value (HLB = hydrophilic-lipophilic balance) of greater than 10, preferably between 14 and 16, particularly preferably of 15, and a solubility in water at 25 ° C. of no more as 1 part ester 100 parts water (weight point) and at 60 to 80 ° C a solubility of at least 1 part ester 10 parts water (weight point) The HLB value is a number system that the hydrophi e-lipophilie balance of surface-active substances For information on determining the HLB value, see, for example, Herbert Stricker (ed.) in "Physikalische Pharmazie", 3 edition, pages 96 and 97, 1987

Suitable sugar esters are, for example, parsley or stearate

A preferred sugar ester is sucrose pa- imitation with a content of approximately 70% monopalmitate. Particularly preferred is sucrose pa- imitation with a content of approx. 70% monopalmitate and approx. 20% di- and approx. 10% tπpalmitate, available for example from Mitsubishi, Japan

With regard to the structure and the known properties of the sugar esters, Editio Cantor is referred to Herbert P Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, Volume 2 (Volume 9 of the series "The pharmaceutical company") Aulendorf, 3 Aufl, 1989, pages 1064-1067. The cited literature reference is hereby incorporated into the disclosure content of the present description by way of reference

The composition according to the invention can preferably also contain an anti-adhesive such as talc

A suitable lubricant can also include a lubricant, such as magnesium stearate, stearic acid or sodium stearyl fumarate, and / or a filler, such as microcrystalline cellulose or lactose monohydrate

The content of calcium valproate in the composition according to the invention can be between 150 to 900 mg or more (for example 1000 mg), preferably between 250 and 600 mg per dosage unit

Surprisingly, it was found that the desired retardation effects are achieved even with very low polyacrylate contents of 2 to 8% by weight, based on the active ingredient used

According to a preferred embodiment, it was found that a content of Eudragit® NE in the range from 1 to 5% by weight, preferably 2 to 3% by weight, particularly preferably about 2% by weight and a content of Eudragit® L of 1 to 3 % By weight, preferably 2 to 3% by weight, particularly preferably about 2.5% by weight, based in each case on the active ingredient used, is advantageous for the desired retardation

The sugar ester content can be in the range from 0.9 to 10% by weight, preferably 4 to 6% by weight, particularly preferably about 5% by weight, based on the active ingredient used

According to a preferred embodiment, a pharmaceutical composition is claimed which is characterized in that it contains 150 to 1000 mg of calcium valproate, 1 to 5% by weight, preferably 2 to 3% by weight of Eudragit® NE, particularly preferably about 2% by weight, 1 to 3% by weight, preferably 2 to 3% by weight, particularly preferably about 2.5% by weight of Eudragit® L and 0.9 to 10% by weight, preferably 4 to Contains 6% by weight, particularly preferably about 5% by weight, of sucrose pa- imity, the weight percentages in each case relating to calcium valproate used

The polyacrylates can be used as an aqueous dispersion, a 30% by weight dispersion in water being preferred

The aqueous solution of the sugar ester can have a content of 10 to 20% by weight of the sugar ester at a water temperature of 60 to 80 ° C. The sugar esters can be used as an aqueous solution, a 10 to 20% by weight solution being preferred

The sucrose pseudo-imitation which is preferably used as the sugar ester consists of 70% of the monoester and dissolves in water at a temperature of 70 ° C in a concentration of 10 to 20% by weight sucrose imitation, whereas it is only poorly soluble in water at 25 ° C

In a preferred embodiment, the pharmaceutical preparation according to the invention containing cicium valproate with delayed release of active ingredient is in the form of a tablet with an active ingredient content of 600 mg. The tablet can have an oblong shape and additionally have a notch for dividing into two or three circumferential notches for dividing into four also have other shapes and recesses to achieve divisibility

The tablet can be provided with a film coating which can contain suitable flavoring or coloring agents

The pharmaceutical preparation according to the invention shows the v / fro release which is suitable from a medical point of view The invention was not obvious to a person skilled in the art. With the mere admixture of, for example, 2 to 4.5% by weight of acrylic polymers without sugar esters, only an incomplete release is obtained after 12-16 hours (see diagram 1). The sugar ester alone does not cause any significant retardation. Surprisingly, when using the combination according to the invention of, for example, 5% by weight of sugar ester, which in turn only causes a maximum delay in the release of calcium valproate of 4 hours, the release profile is controlled in the period of 4-12 to 4-16 hours. where, for example, 50-70% release is achieved after a total of 4 hours and complete release after a maximum of 12-16 hours. The combination of acrylic polymer and sugar ester according to the invention for retarding the release of valproic acid is therefore new and inventive.

The pharmaceutical preparation according to the invention can be administered by oral intake once or several times a day. According to this dosing scheme according to the invention, the treatment of epilepsy, migraines and manic-depressive diseases is possible.

Fig. 1 a shows a tablet in oblong shape with a division notch on one side in supervision. Fig. 1 b shows this tablet in side view.

2a shows a top view of a tablet in oblong form with three circumferential division notches. In this form there are notches on the web. 2b shows this tablet in side view.

According to a further aspect of the invention, there is provided a method for producing a pharmaceutical composition containing retarded active ingredient release containing calcium valproate, comprising the steps of introducing into calcium valproate an aqueous dispersion comprising Eudragit® NE or Eudragit® RS or mixtures thereof, an aqueous dispersion comprising Eudragit® L or Eudragit® S or shellac or mixtures thereof, and an aqueous solution of a sugar ester, if appropriate introducing suitable ones Excipients, such as talc, microcrystalline cellulose and gastro-stearate, and optionally one or more drying steps, whereby a tableting mixture is obtained, which is then compressed into tablets

In a preferred embodiment, the aqueous dispersion comprises Eudragit® L or Eudragit® S or shellac or mixtures thereof, talc

Eudragit® NE, Eudragit® RS, Eudragit® L, Eudragit® S, shellac and the sugar ester each have the meanings described above

In a preferred embodiment, the calcium valproate is introduced in the order 1) Eudragit® NE or Eudragit® RS or mixtures thereof, 2) Eudragit® L or Eudragit® S or shellac or mixtures thereof and 3) sugar esters, each followed by drying steps

The addition can also be done in a different order

Surprisingly, it was found that the use of aqueous sugar ester solutions makes it possible to prepare the pharmaceutical preparations according to the invention. The aqueous sugar ester solution can be added as a heated or hot solution. The aqueous sugar ester solution should preferably be added so that the water can evaporate completely or partially can take place, for example, in a suitable fluidized-bed drying device or in a ventilated stirring device

The pharmaceutical compositions according to the invention can be used for the treatment of epilepsy (in particular for the prophylaxis of grands maux, myoclonic attacks and absences in pπmar generalized epilepsy), manic-depressive diseases and migraines in mammals, especially in humans The term treatment is intended to include all measures in the context of therapy and / or prophylaxis of the disease.

The term mammals here includes in particular people of all ages and developmental levels and of both sexes, as well as pets, such as dogs and cats, and farm animals, such as horses, cows, sheep and goats.

Epilepsy should be understood to mean all types of seizures belonging to this clinical picture. All forms and degrees of severity of migraines and diseases of the manic-depressive type can be treated with the preparations according to the invention.

The pharmaceutical preparations are administered orally. The number and dosage of daily administrations depends on the type and severity of the disease as well as on the age and state of health of the patient. For example, epilepsy can be treated by oral application of the composition according to the invention once or twice daily.

The following examples and comparative examples are intended to explain the invention in greater detail, but without restricting the invention to these examples.

Example 1 :

40.0 g of poly (ethyl acrylate methyl methacrylate) dispersion (30% by weight) (Eudragit® NE 30 D) are introduced into 666.0 g of calcium valproate dihydrate (= 600 g of calcium valproate) and the water in the dispersion is then dried out. Subsequently, 50.0 g of an aqueous methacrylic acid-ethyl acrylate copolymer dispersion 30% (Eudragit® L 30 D-55) and 8 g talcum suspended therein are applied and then the water of the dispersion is dried out. The third step is to apply the 10% strength by weight aqueous solution of the sugar ester with 30 g of the sugar ester component and then the water introduced and the water of hydration of the active ingredient is dried out to 3.6% by weight, based on the active ingredient content

The tableting mixture is produced with 20.0 g of microcrystalline cellulose and 3.0 g of magnesium stearate. The tablet is then compressed to form a divisible tablet

Composition of the tablet obtained

Calcium valproate 600 mg

Poly (ethyl acrylate methyl methacrylate) 12 mg (Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 15 mg

(Eudragit® L)

Talc 8 mg

Parsley sucrose 30 mg microcrystalline cellulose 20 mg

Magnesium stearate 3 mg

Example 2:

In 666.0 g of calcium valproate dihydrate, 50.0 g of poly (ethyl acrylate-methyl methacrylate) -dispersion 30% (Eudragit® NE 30 D) are introduced and then the water of the dispersion is dried out

50.0 g of methacrylic acid / ethyl acrylate copolymer are then

Dispersion 30% (Eudragit® L 30 D-55) and 8 g of talcum suspended therein were applied and then the water of the dispersion was dried out. As a third stage, the 10% by weight aqueous solution of the sugar ester was mixed with 30 g

Applied sugar ester component and then the water introduced and the water of hydration of the active ingredient are dried out to a proportion of 3.6% by weight

Composition of the tablet obtained Calcium valproate 600 mg

Poly (ethyl acrylate methyl methacrylate) 15 mg

Poly (methacrylic acid ethyl acrylate) 15 mg

Talc 8 mg

Parsley sucrose 30 mg microcrystalline cellulose 20 mg

Magnesium stearate 3 mg

Example 3: In 666.0 g of calcium valproate dihydrate, 34.0 g of poly (ethyl acrylate-methyl methacrylate) -dispersion 30% (Eudragit® NE 30 D) are introduced and then the water of the dispersion is dried out

Subsequently, 50.0 g of 30% methacrylic acid / ethyl acrylate copolymer dispersion (Eudragit® L 30 D-55) and 8 g of talcum then suspended are applied and the water in the dispersion is then dried out

As a third stage, the 10% by weight aqueous solution of the sugar ester is applied with 30 g of the sugar ester component and then the water introduced and the water of hydration of the active ingredient are dried out to a proportion of 3.6% by weight. The tableting mixture is mixed with 20.0 g microcrystalline cellulose and 3.0 g of magnesium stearate are then pressed into a divisible tablet. Composition of the tablet obtained

Calcium valproate 600 mg poly (ethyl acrylate methyl methacrylate) 10 mg

(Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 15 mg

(Eudragit® L)

Parsley sucrose 30 mg talc 8 mg microcrystalline cellulose 20 mg

Magnesium stearate 3 mg Example 4:

80.0 g of poly (ethyl acrylate methyl methacrylate) dispersion 30% (Eudragit® NE 30 D) are introduced into 666.0 g of calcium valproate dihydrate and the water of the dispersion is then dried out.

Subsequently, 40.0 g of methacrylic acid-ethyl acrylate copolymer dispersion 30% (Eudragit® L 30 D-55) and 8 g of talcum suspended therein are applied and then the water of the dispersion is dried out. As a third stage, the 10% by weight aqueous solution of the sugar ester is applied with 30 g of the sugar ester component, and then the water introduced and the water of hydration of the active ingredient are dried out to a proportion of 3.6% by weight.

The tableting mixture is made with 20.0 g of microcrystalline cellulose and 3.0 g of magnesium stearate. It is then compressed into a divisible tablet.

Composition of the tablet obtained:

Calcium valproate 600 mg

Poly (ethyl acrylate methyl methacrylate) 24 mg (Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 12 mg

(Eudragit® L)

Talc 8 mg

Parsley sucrose 30 mg microcrystalline cellulose 20 mg

Magnesium stearate 3 mg

Example 5: (500 mg)

The preparation was carried out analogously to Example 1 using 555 g of calcium valproate dihydrate, 33.3 g of poly (ethyl acrylate-methyl methacrylate) dispersion

30% (Eudragit® NE 30 D), 41.7 g poly (methacrylic acid ethyl acrylate) dispersion 30% (Eudragit® L 30 D-55), 6.67 g talcum, 25 g sucrose pseudo as well as 16.67 g microcrystalline cellulose and 2.5 g magnesium stearate.

Composition of the tablet obtained: calcium valproate 500 mg

Poly (ethyl acrylate methyl methacrylate) 10 mg (Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 12.5 mg (Eudragit® L) sucrose pseudo 25 mg

Talc 6.67 mg microcrystalline cellulose 16.67 mg

Magnesium stearate 2.5 mg

Example 6: (300 mg)

The preparation was carried out analogously to Example 1 using 666 g of calcium valproate dihydrate, 40.0 g of poly (ethyl acrylate methyl methacrylate) dispersion 30% (Eudragit® NE 30 D), 50.0 g of poly (methacrylic acid ethyl acrylate) dispersion 30% (Eudragit® L 30 D-55), 8.0 g talcum, 30.0 g sucrose pseudo as well as 20.0 g microcrystalline cellulose and 3.0 g magnesium stearate.

Composition of the tablet obtained:

Calcium valproate 300 mg

Poly (ethyl acrylate methyl methacrylate) 6 mg (Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 7.5 mg

(Eudragit® L)

Sucrose imitation (sucrose ester 15) 15 mg

Talc 4 mg microcrystalline cellulose 10 mg

Magnesium stearate 1.5 mg Example 7: (250 mg)

The preparation was carried out analogously to Example 1 using 555 g of calcium valproate dihydrate, 33.3 g of poly (ethyl acrylate methyl methacrylate) dispersion 30% (Eudragit® NE 30 D), 41.7 g of poly (methacrylic acid ethyl acrylate) dispersion 30% (Eudragit® L 30 D-55), 6.67 g talcum, 25.0 g sucrose pseudo as well as 16.67 g microcrystalline cellulose and 2.5 g magnesium stearate.

Composition of the tablet obtained:

Calcium valproate 250 mg poly (ethyl acrylate methyl methacrylate) 5 mg

(Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 6.25 mg

(Eudragit® L)

Parsley sucrose 12.5 mg talc 3.3 mg microcrystalline cellulose 8.3 mg

Magnesium stearate 1.25 mg

Comparative Examples 1 to 3:

Comparative Example 1: (only sugar esters)

The preparation was carried out analogously to Example 1 using 666 g of calcium valproate dihydrate, 30.0 g of sucrose paraimite and 20.0 g of microcrystalline cellulose and 3.0 g of magnesium stearate.

Composition of the tablet obtained:

Calcium valproate 600 mg

Sucrose imitation 30 mg microcrystalline cellulose 20 mg magnesium stearate 3 mg Comparative Example 2: (only poly (ethyl acrylate methyl methacrylate) The preparation was carried out analogously to Example 1 using 666 g calcium valproate dihydrate, 40.0 g poly (ethyl acrylate methyl methacrylate) dispersion 30% (Eudragit® NE 30 D) and 20, 0 g microcrystalline cellulose and 3.0 g magnesium stearate.

Composition of the tablet obtained:

Calcium valproate 600 mg

Poly (ethyl acrylate methyl methacrylate) 12 mg

(Eudragit® NE) microcrystalline cellulose 20 mg

Magnesium stearate 3 mg

Comparative Example 3: (only poly (ethyl acrylate methyl methacrylate) and poly (methacrylic acid ethyl acrylate))

The preparation was carried out analogously to Example 1 using 666 g of calcium valproate dihydrate, 40.0 g of poly (ethyl acrylate methyl methacrylate) dispersion 30% (Eudragit® NE 30 D), 50.0 g of poly (methacrylic acid ethyl acrylate) dispersion 30% (Eudragit® L 30 D-55), 8.0 g talcum as well as 20.0 g microcrystalline cellulose and 3.0 g magnesium stearate.

Composition of the tablet obtained:

Calcium valproate 600 mg

Poly (ethyl acrylate methyl methacrylate) 12 mg (Eudragit® NE)

Poly (methacrylic acid ethyl acrylate) 15 mg (Eudragit® L)

Talc 8 mg microcrystalline cellulose 20 mg magnesium stearate 3 mg Investigation of drug release behavior:

Diagram 1 shows the retarded active ingredient release of the tablet according to the invention according to Example 1 in comparison to the tablets according to Comparative Examples 1 to 3. It can be seen that only when the composition according to the invention containing calcium valproate, acrylic polymer and sugar ester is used, is complete release possible within 12 hours. In contrast, the use of only sugar ester (comparative example 1) leads to a rapid release within 4 hours, while the use of only poly (ethyl acrylate methyl methacrylate) (comparative example 2) and poly (ethyl acrylate methyl methacrylate) with poly (methacrylic acid ethyl acrylate) ( Comparative example 3) leads to a complete release of active ingredient at pH 6.8 only within 24 hours or later.

The investigations on the active ingredient release behavior were carried out in a borate buffer of pH 6.8 (according to Palitzsch) using a blade stirrer apparatus according to Ph. Eur. General methods 2.9.3. The quantitative determination of valproic acid was carried out by gas chromatography.

Furthermore, it was found that the tablet mixture according to the invention can be easily compressed into tablets according to Example 1. In contrast, the tabletting mixture according to Comparative Examples 2 and 3 tended to stick the compressed tablets to the tabletting tools. The non-sticking of the tablet mixture according to the invention is a considerable advantage, particularly in the case of complicated shapes such as for tablets with three circumferential division notches (see for example tablets according to FIGS. 2a and 2b).

Claims

claims

1 Pharmaceutical composition with delayed release of active ingredient, characterized in that it contains calcium valproate, at least one acrylic polymer and at least one sugar ester

2 Pharmaceutical composition according to claim 1, characterized in that the acrylic polymer is selected from the group consisting of Eudragit® NE, Eudragit® L, Eudragit® S, Eudragit® RS and mixtures thereof

3 Pharmaceutical composition according to claim 1 or 2, characterized in that part of the acrylic polymer is replaced by shellac

4 Pharmaceutical composition according to one of claims 1 to 3, characterized in that the sugar ester has an HLB value of greater than 10, preferably from 14 to 16, particularly preferably from 15 to 16, and a water solubility at 37 ° C of not more than 1 Part of sugar ester to 100 parts of water, and a water solubility at 60-80 ° C of at least 1 part of sugar ester to 10 parts of water, each based on the weight

5 Pharmaceutical composition according to one of claims 1 to 4, characterized in that it is in the sugar ester to sucrose peak or stearate

6 Pharmaceutical composition according to one of claims 1 to 5, characterized in that the sugar ester is sucrose pseudo-imitation with a proportion of about 70% by weight sucrose monopalmitate, based on the sucrose pseudo-imitation used

7 Pharmaceutical composition according to one of claims 1 to 6, characterized in that it contains 150 to 1000 mg of calcium valproate, 1 to 5% by weight, preferably 2 to 3% by weight of Eudragit® NE, particularly preferably about 2 % By weight, 1 to 3% by weight, preferably 2 to 3% by weight, particularly preferably approximately 2.5% by weight of Eudragit® L and 0.9 to 10% by weight, preferably 4 to 6 % By weight, particularly preferably about 5% by weight, of sucrose paraimitate, the weight percentages in each case relating to calcium valproate used.

8. Pharmaceutical composition according to one of claims 1 to 7, characterized in that it is present as a dividable tablet.

9. Pharmaceutical composition according to claim 8, characterized in that the tablet or a part thereof available after division in vitro at pH 6.8 has a delayed release of active ingredient of at most 70% after 4 hours and complete release after 12-16 hours, in each case based on the active ingredient content.

10. A process for the preparation of a pharmaceutical composition containing calcium valproate with a delayed release of active ingredient according to one of claims 1 to 9, characterized by the steps of introducing it into calcium valproate of an aqueous dispersion comprising Eudragit® NE or Eudragit® RS or mixtures thereof, an aqueous dispersion comprising Eudragit ® L or Eudragit® S or shellac or mixtures thereof, and an aqueous solution of a sugar ester, if appropriate introducing suitable auxiliaries such as talc, microcrystalline cellulose and gastric esium stearate, and if appropriate one or more drying steps, a tablet mixture being obtained, which then becomes tablets is pressed.

11. The method according to claim 10, characterized in that the introduction into calcium valproate in the sequence 1.) Eudragit® NE or Eudragit® RS or mixtures thereof, 2.) Eudragit® L or Eudragit® S or shellac or mixtures thereof and 3. ) Sugar esters, followed by drying steps.

12. The method according to claim 10 or 11, characterized in that the aqueous dispersion comprising Eudragit® L or Eudragit® S or shellac or mixtures thereof, additionally contains talc.

13. The method according to any one of claims 10 to 12, characterized in that the sugar ester used has an HLB value of greater than 10, preferably from 14 to 16, particularly preferably from 15 to 16, and a water solubility at 37 ° C of not more than 1 part sugar ester to 100 parts water and a water solubility at 60-80 ° C of at least 1 part sugar ester to 10 parts water, each based on weight.

14. Pharmaceutical composition with delayed release of active substance, characterized in that it is obtainable by the process according to one of claims 10 to 13.

15. Use of the pharmaceutical compositions according to any one of claims 1 to 9 and 14 for the treatment of epilepsy in humans and other mammals.

16. Use according to claim 15, characterized in that the treatment of epilepsy is carried out by oral administration once or twice a day.

17. Use of the pharmaceutical compositions according to any one of claims 1 to 9 and 14 for the treatment of migraines in humans and other mammals.

18. Use of the pharmaceutical compositions according to one of claims 1 to 9 and 14 for the treatment of manic-depressive diseases in humans and other mammals.